Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([CH2:12][C:13]1[N:17]([CH:18]2[CH2:20][CH2:19]2)[C:16]2[CH:21]=[C:22]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[C:23]([F:25])=[CH:24][C:15]=2[N:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.O.[O:51]1CCC[CH2:52]1>>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[CH:12]=[C:13]2[N:17]([CH:18]3[CH2:19][CH2:20]3)[C:16]3[CH:21]=[C:22]([N:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[C:23]([F:25])=[CH:24][C:15]=3[N:14]2[C:52]1=[O:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(=O)NOCc2ccccc2)n3C2CC2)CC1
Reactant: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)n(OCc4ccccc4)c(=O)cc2n3C2CC2)CC1
Yield: 5 %

Procedure:
tert-Butyl 4-[2-[[(benzyloxy)carbamoyl]methyl]-1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazinecarboxylate (779 mg, 1.18 mmol) is dissolved in tetrahydrofuran (15 ml) and treated with N,N'-carbonyldiimidazole (480 mg, 2.96 mmol) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (225 mg, 1.48 mmol). The suspension obtained is poured into water (200 ml) and then extracted with ethyl acetate. The organic phase is washed in succession with water and 10 percent sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel (eluent: ethyl acetate/n-hexane 8:2). The product is crystallized from ethyl acetate/n-hexane. There are obtained 42 mg (5%) of tert-butyl 4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[CH:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1>>[F:12][C:13]([F:24])([F:23])[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:11][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([C:20]([N:17]3[CH2:16][CH2:15][CH:14]([C:13]([F:23])([F:12])[F:24])[CH2:19][CH2:18]3)=[O:21])[N:7]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Reactant: Oc1n[nH]c2cc(F)ccc12
Product: O=C(Oc1nn(C(=O)N2CCC(C(F)(F)F)CC2)c2cc(F)ccc12)N1CCC(C(F)(F)F)CC1

Procedure:
In analogy to example 1, 200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were reacted with 340 mg (1.578 mmol) of 4-trifluoromethylpiperidine-1-carbonyl chloride.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:42])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:24]=1[CH2:39][CH2:40][CH3:41])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:42])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:39][CH2:40][CH3:41])[CH3:16]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 82.7 %

Procedure:
A mixture of 0.96 g (0.005 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.26 g (0.005 mole) of 4-[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.36 g (0.010 mole) of anhydrous potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 17 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 25% ethyl acetate-hexane to yield 2.36 g (84% yield) of 4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(O)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.5 %

Procedure:
A solution of 4-amino-phenol (1.00 g, 9.2 mmol) and triethylamine (1.42 ml, 10.1 mmol) was cooled to 0° C. and 4-trifluoromethyl-benzoyl chloride (1.36 ml, 9.2 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was poured in water (50 ml). A precipitate was collected by filtration and taken up in ethyl acetate (200 ml). The organic solution was washed with 1N HCl (100 ml), water (100 ml), brine (100 ml), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound as a pale yellow solid (1.98 g, 77% yield).
Reaction SMILES: [CH2:1]([C@@H:3]1[C:6](=[O:7])[O:5][C@H:4]1[CH2:8][C@@H:9]([O:27][C:28](=[O:45])[C@H:29]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:30][C:31](OCC1C=CC=CC=1)=[O:32])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:2]>C1COCC1.[Pd]>[CH2:1]([C@@H:3]1[C:6](=[O:7])[O:5][C@H:4]1[CH2:8][C@@H:9]([O:27][C:28](=[O:45])[C@H:29]([CH2:41][CH:42]([CH3:43])[CH3:44])[NH:30][CH:31]=[O:32])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CC)OC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CC)OC(=O)[C@H](CC(C)C)NC=O

Procedure:
565 mg of N-[(benzyloxy)carbonyl]-L-leucine (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester were dissolved in 12 ml of THF. The mixture was hydrogenated at room temperature in the presence of 40 mg of 10% Pd/C. After the reaction was finished the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in 9 ml of THF and 71 μl of formic acid/acetic acid anhydride were added dropwise. The mixture was diluted with 5 ml of diethyl ether and washed twice with 2% sodium hydrogen carbonate solution and then with water. After drying over sodium sulfate it was filtered and evaporated. By chromatography on silica gel and recrystallization from n-pentane there was obtained N-formyl-(S)-leucine (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2oxetanyl]methyl]octadecyl ester of m.p. 60°-61° C.
Reaction SMILES: [OH2:1].O.P([O-])([O-])(O)=O.[Na+:8].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[O-:17][Si:18]([O-:20])=[O:19].[Na+].[Na+]>>[Si:18]([O-:1])([O-:20])([O-:17])[O-:19].[Na+:8].[Na+:8].[Na+:8].[Na+:8]
Reactant: O
Reactant: O=[Si]([O-])[O-]
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
1104 g of disodium hydrogenphosphate dihydrate, 683 g of anhydrous sodium sulfate and 683 g of anhydrous soda are dissolved in 50 kg of water glass having the composition as in Example 1, and the solution is spray-dried in a laboratory spray dryer (spray tower) from Anhydro to give an amorphous sodium silicate having an active substance content of about 83%. 15 kg of the amorphous sodium silicate are heat-treated at 720° C. for 90 min in a muffle furnace (Nabertherm, model W1000/H). The chilled product (about 10 kg) is pulverized using a jaw crusher and a disk mill.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[C:16]([C:18]([OH:20])=O)[N:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:42][O:43][CH2:44][CH2:45][CH2:46][NH2:47].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:42][O:43][CH2:44][CH2:45][CH2:46][NH:47][C:18]([C:16]1[N:17]=[C:13]([C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][CH:9]=2)[S:14][CH:15]=1)=[O:20]
Reactant: O=C(O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Reactant: COCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCCNC(=O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Reaction time: 18 h

Procedure:
To a solution consisting of 2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylic acid (Example 63, 80 mg, 0.28 mmol) in dichloromethane (10 mL) was added EDAC (75 mg, 0.39 mmol) and HOBt (53 mg, 0.39 mmol) at 0° C. To this mixture was added 3-methoxypropylamine (25 mg, 0.28 mmol) dissolved in dichloromethane (2 mL) and diisopropylethylamine (0.52 mL, 390 mg, 3.0 mmol). The solution was allowed to reach room temperature and stirred for 18 hours. The solvent was evaporated away under reduced pressure and the residue was purified by silica gel flash chromatography (1:1 v/v hexane-ethyl acetate to 100% ethyl acetate gradient) through a 25-g Silicycle® flash silica cartridge. The title compound was obtained as an off-white solid (21 mg, 21% yield); Rf 0.70 with 4:1 v/v ethyl acetate-hexane; melting point 134-136° C.; 1H-NMR (300 MHz; CDCl3) δ 9.31 (s, 2H), 8.52 (dd, 2H), 8.20 (s, 1H), 7.88 (br t, 1H), 7.53 (m, 3H), 3.62 (t, 2H); 3.59 (t, 2H); 3.41 (s, 3H), 1.96 (m, 2H); MS (ESI+) m/z 355 (M+1); H-PGDS FPBA IC50: 3.4 μM.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[N:5]([C:23](=[O:26])[NH:24][N:25]=2)[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].[CH3:27]NN>C(#N)C>[CH3:27][N:24]1[C:23](=[O:26])[N:5]2[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[C:7]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:2]([CH3:1])[N:3]=[C:4]2[NH:25]1
Reactant: CNN
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)n2c(n[nH]c2=O)N1
Solvent: CC#N
Product: CC(C)OC(=O)C1=C(c2cccc([N+](=O)[O-])c2)N2C(=O)N(C)NC2=NC1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
The title B compound of Example 1 (1 g, 2.0 mmol) in acetonitrile (7 ml) was cooled to 0° C. under argon and was treated with methylhydrazine (0.125 mL, 3.2 mmol). The reaction turned yellow instantaneously and a light yellow solid precipitated out. The reaction was allowed to stir at room temperature for 45 minutes and the solid was then filtered off and washed with acetonitrile to provide the title compound (620 mg) as a light yellow solid, m.p. 255°-256° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[OH:25])[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6].Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28].[K+].[Br-]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:22]=[CH:23][C:24]=1[O:25][S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1ccc(O)c(Br)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(Br)c1

Procedure:
The title compound was prepared as a white solid (0.388 g, 40%) from 3-bromo-4-hydroxy-N-(8-phenyloctyl)benzamide and 4-chlorosulfonyl-2-hydroxy-benzoic acid using a procedure similar to step 3 of Example 179. 1H NMR (DMSO-d6) δ8.57 (bt, 1H); 8.50 (d, 1H); 7.99 (dd, 1H); 7.86 (dd, 1H); 7.38-7.32 (m, 3H); 7.26-7.10 (m, 5H); 3.50 (bs, 2H); 3.20 (dd, 2H); 2.53 (t, 2H); 1.50 (m, 4H); 1.28 (m, 8H); IR (KBr) 3480, 3350, 2950, 2850, 1900, 1690, 1630, 1600, 1580, 1540, 1480, 1450, 1360, 1285, 1250, 1205, 1180, 1110, 1080, 1040, 930, 860 cm−1; mass spectrum [(+)APCI], r/z 604 (M+H)+; Anal. Calcd. for C28H30BrNO7S: C, 55.63; H, 5.00; N, 2.32, Found: C, 54.33; H, 5.11; N, 1.95.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([O:10][C:11](=[O:33])[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:32])[C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23](Cl)=[C:22]([O:30][CH3:31])[CH:21]=2)[CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>CN(C)C=O>[C:6]([O:10][C:11](=[O:33])[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:32])[C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:22]([O:30][CH3:31])[CH:21]=2)[CH2:14]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COCCN
Reactant: COc1cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc([N+](=O)[O-])c1Cl
Solvent: CN(C)C=O
Product: COCCNc1c(OC)cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-Methoxyethylamine (0.15 mL, 1.741 mmol) was added to a stirred solution of (R)-tert-butyl(1-(4-chloro-3-methoxy-5-nitrobenzoyl)piperidin-3-yl)carbamate (280 mg, 0.406 mmol) in N,N-dimethylformamide (DMF) (1.5 mL) at rt under nitrogen. The reaction mixture was heated to 80° C. and stirred under nitrogen overnight (16 h). LC/MS showed that the desired product had formed with 55% purity. Water (75 mL) and diethyl ether (75 mL) were added to the reaction mixture and the layers separated. The aqueous layer was further extracted with diethyl ether (2×50 mL). The organic layers were collected, dried (Na2SO4), passed through a hydrophobic frit and concentrated under vacuum to afford 330 mg of crude product as an orange oil. The crude product was dissolved in a minimum volume of DCM and purified by column chromatography (25 g silica). The column was eluted with a gradient of 60-100% ethyl acetate/cyclohexane. TLC was used to determine product fractions and the appropriate fractions were collected and concentrated under vacuum to afford—(R)-tert-butyl(1-(3-methoxy-4-((2-methoxyethyl)amino)-5-nitrobenzoyl)piperidin-3-yl)carbamate (165.7 mg, 0.366 mmol, 90% yield)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:11]>CO.[Pd].C>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N+:3]=1[O-:11]
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cc[n+]1[O-]
Yield: 96.2 %

Procedure:
4 g of 2-methyl-4-nitropyridine-N-oxide were dissolved in 90 ml of methanol and reduced with 1.2 g of 10% Pd/charcoal and H2. The catalyst was filtered off and the filtrate rotated in. The residue was boiled with 200 ml of ethyl acetate, filtered hot and the filtrate was mixed with 100 ml of hexane. The crystals precipitated after cooling the solution was sucked off, washed and dried. 3.1 g of 2-methyl-4- amino pyridine-N-oxide were obtained.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:7]=2[N:8]=1)#[N:2].[N:19]([Sn](C)(C)C)=[N+:20]=[N-:21]>C1(C)C=CC=CC=1>[NH:19]1[C:1]([C:3]2[N:4]=[CH:5][C:6]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:7]=3[N:8]=2)=[N:2][N:21]=[N:20]1
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(C#N)nc2C1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1Cc2cnc(-c3nnn[nH]3)nc2C1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl 2-cyano-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Intermediate 9, Step D) (71 mg, 0.29 mmol) in toluene was added azidotrimethyltin (596 mg, 2.9 mmol). The resulting mixture was heated at 110° C. overnight. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase silica gel chromatography (gradient 5-50% acetonitrile in water containing 0.1% TFA) to yield tert-butyl 2-(1H-tetrazol-5-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. The product was treated as described for Intermediate 9, Step E, to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:34][CH2:35][CH:36]4[CH2:38][CH2:37]4)=[C:17]([NH:20][C:21](=[O:33])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][C@@H:29]([CH3:31])[O:28][C:27](=[O:32])[CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[OH-:40].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:34][CH2:35][CH:36]4[CH2:38][CH2:37]4)=[C:17]([NH:20][C:21](=[O:33])[CH:22]=[CH:23][CH2:24][N:25]([CH2:26][C:27]([OH:28])=[O:32])[CH2:30][C@H:29]([OH:40])[CH3:31])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [OH-]
Reactant: C[C@@H]1CN(CC=CC(=O)Nc2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc2OCC2CC2)CC(=O)O1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C[C@@H](O)CN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)CC(=O)O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
100 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline is mixed with 1.63 ml of water and 0.37 ml of 1N hydrochloric acid. The reaction mixture is stirred for three hours at 60° C. and then left to stand overnight at ambient temperature. For working up, 0.37 ml 1N sodium hydroxide solution is added and the mixture is cooled in an ice bath, whereupon a light-colored precipitate is deposited. This is suction filtered, washed with cold water, and dried. Yield: 60 mg (58% of theory); mass spectrum (ESI−): m/z=556, 558 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([OH:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[CH:22][CH:23]=1>O1CCOCC1>[F:47][C:44]([F:45])([F:46])[C:39]([C:36]1[CH:35]=[CH:34][C:33]([CH2:32][N:29]2[CH2:28][CH2:27][N:26]([C:24]([C:20]3[CH:19]=[C:18]([NH:17][C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:16])[CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:31][CH2:30]2)=[CH:38][CH:37]=1)([OH:48])[C:40]([F:43])([F:42])[F:41]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1cccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1cccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 100 °C
Yield: 36.1 %

Procedure:
A mixture of phenyl pyridin-4-ylcarbamate (1.430 mmol, 306 mg) and (3-aminophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.954 mmol, 440 mg) in dioxane was heated in a Reactivial at 100° C. (heating block temperature) for 2 days. Chromatography on silica (eluting with a gradient of dichloromethane to dichloromethane/methanol) gave the title compound (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[C:4]([N+:20]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(CNc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(CNc2ccc(Cl)cc2N)cc1

Procedure:
The title compound of Example 12, Step A (3.6 mmol, 1.2 g) and SnCl2.2H2O (18 mmol, 4 g) were heated in DMP (10 mL) at 40° C. for 3 hr. The reaction mixture was poured into EtOAc and concentrated NaHCO3 and stirred. The resulting mixture was filtered over celite, and the filter cake was washed with EtOAc. The organic phase was collected, dried with Na2SO4 and reduced in vacuo. Flash chromatography on silica eluting with 20% and 30% EtOAc in hexanes afforded the product as a pale white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.94 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 6.70 (s, 1H), 6.32 (s, 1H), 5.68 (t, J=5.8 Hz, 1H), 5.07 (s, 2H), 4.41 (d, J=5.7 Hz, 2H), 3.85 (s, 3H). LC-MS (ESI, Method C) 3.33 min, 291.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:20][C:19]2[C:14](=[N:15][CH:16]=[CH:17][C:18]=2[NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)[CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cc2nccc(Nc3ccc4[nH]ccc4c3)c2s1
Product: Fc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-fluorobenzeneboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 17. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 10.7 (s, 1H), 8.28 (d, 1H), 7.50 (m, 9H), 7.05 (d, 1H), 6.49 (s, 1H); LC-MS: 360 (MH+); HPLC RT: 5.40 minutes.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[CH2:9]P(=O)(OCC)OCC)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[CH3:28][O:29][C:30]1[C:35]([CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([CH:43]=O)[CH2:39][CH2:38]2)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCCC1>[CH3:28][O:29][C:30]1[C:35]([CH2:36][N:37]2[CH2:42][CH2:41][CH:40](/[CH:43]=[CH:9]/[C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=3[O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:39][CH2:38]2)=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: CCOP(=O)(Cc1ccccc1OC1CCCC1)OCC
Reactant: COc1ncccc1CN1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ncccc1CN1CCC(/C=C/c2ccccc2OC2CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
786 mg of diethyl 2-(cyclopentyloxy)benzylphosphonate was dissolved in 10 ml of tetrahydrofuran. To the mixture was added 281 mg of potassium tert-butoxide, followed by stirring for 15 minutes under ice-cooling. A solution of 500 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-piperidinecarboxaldehyde dissolved in 3 ml of tetrahydrofuran was added dropwise thereinto, followed by stirring at room temperature for 2 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to give 473 mg of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+]>C(O)C.[Cu]>[F:13][C:4]1[CH:3]=[C:2]([NH:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1F
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCNc1ccc(C(=O)OCC)c(F)c1

Procedure:
A mixture of 33 g of ethyl 4-amino-2-fluorobenzoate, 44 ml of 1-bromooctane and 0.50 g of copper powder is heated on a steam bath for 19 hours. The mixture is chilled, diluted with ethanol, filtered and the solid washed with cold ethanol and with water to give tan crystals. The filtrate is neutralized with 10 N potassium hydroxide, chilled and filtered and the solid washed with water and with ethanol to give tan crystals. The two crops of crystals are combined and recrystallized from ethanol to yield ethyl 2-fluoro-4-(octylamino)benzoate as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][C:29]1([CH3:35])[O:33][C:32](=[O:34])[NH:31][CH2:30]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[CH2:30][C:29]([CH3:35])([CH3:28])[O:33][C:32]4=[O:34])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 31.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (679 mg) described in Preparation Example 61 and 5,5-dimethyloxazolidin-2-one (259 mg) described in Preparation Example 43, the title compound (232 mg) was obtained.