Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]3[CH:22]=[CH:23][N:24]=[C:12]23)=[C:4]([F:25])[CH:3]=1.C(OCC)(=O)C.C(O)(=O)C>[Fe].O>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:25])=[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]3[CH:22]=[CH:23][N:24]=[C:12]23)[CH:6]=1
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Cl

Procedure:
A mixture of 8-(4-chloro-2-fluoro-5-nitrophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (0.6 g), ethyl acetate (5 ml), acetic acid (2 ml) and water (10 ml) was added with iron powder (0.5 g) and heated to reflux for 3 hours. The mixture was filtered through Celite and the thus obtained solid was washed with hot ethyl acetate. The organic layer was separated from the filtrate and the washing, and dried on anhydrous magnesium sulfate after washing with water. The solvent was distilled off under reduced pressure to give the compound of interest (0.52 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:15]([N:17](CC)CC)[CH3:16].C(N)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:17][CH2:15][CH3:16])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCN(CC)CC
Agent: CCN
Solvent: C1CCOC1
Product: CCNc1nc(SC)ncc1C(=O)OCC
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a room temperature solution of 4-chloro-2-methylthio-5-pyrimidinecarboxylate ethyl ester (10.00 g, 43.10 mmol) in 150 mL of tetrahydrofuran was added triethylamine (18.5 mL, 133 mmol) followed by 9 mL of a 70% aqueous solution of ethylamine. The solution was stirred for 30 minutes, then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to provide 9.32 g (90%) of 4-ethylamino-2-methylthio-5-pyrimidinecarboxylate ethyl ester as an oil.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>CN(C)C=O>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:25]
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1ccccc1Cl
Solvent: CN(C)C=O
Product: O=C(NCC(c1ccccc1)c1ccccc1)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2-diphenylethylamine (2.0 g, 10.1 mmol) in 15 ml of N,N-dimethylformamide (DMF) was cooled to 0° C. and treated with 2-chlorophenyl isocyanate (1.46 g, 12.2 mmol) under nitrogen (N2). The reaction solution was stirred at room temperature for 15 minutes and partitioned between ethyl acetate (EtOAc) and water (H2O). The organic layer was washed with sodium bicarbonate (NaHCO3) and brine, dried over sodium sulfate (Na2SO4), filtered and concentrated in vacuo to provide a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[O:13])[N:3]=1.[CH3:23][C:24]1[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=1.[I-].[K+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:29][C:26]3[CH:25]=[C:24]([CH3:23])[NH:28][N:27]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cc(C(=O)c2nc(Cl)c3ccccc3n2)ccc1F
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2nc(Nc3cc(C)[nH]n3)c3ccccc3n2)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A mixture of (4-chloroquinazolin-2-yl)(4-fluoro-3-methoxyphenyl)methanone (337 mg, 1.06 mmol), 5-methyl-1H-pyrazol-3-amine (206 mg, 2.12 mmol), potassium iodide (528 mg, 3.18 mmol) and DIEA (0.37 mL, 2.13 mmol) in DMF (10 mL) was stirred at rt for 20 h. To the mixture was added water (80 mL) and the resulting solid was collected by filtration and washed with water and then diethyl ether. The solid was dried to afford (4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone as a yellow solid (300 mg, 75%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H), 3.90 (s, 3H), 6.55 (s, 1H), 7.38 (dd, J=11.1, 8.4 Hz, 1H), 7.59 (m, 1H), 7.68 (dd, J=7.8, 7.8 Hz, 1H), 7.77-7.94 (m, 3H), 8.75 (d, J=7.8 Hz, 1H), 10.69 (br s, 1H), 12.23 (br s, 1H); LC-MS (ESI) m/z 378 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH2:15][C:16]([OH:18])=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl>CN(C=O)C.O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH2:15][C:16]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:18])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1CC(=O)O
Reactant: C1COCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(C)(C)C)nn1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
To a solution of 2-(3-tert-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid from Example B17 (0.77 g, 3.02 mmol) in DMF (5 mL) were added EDC (0.75 g, 3.93 mmol), HOBt (0.55 g, 3.62 mmol) and morpholine (0.39 g, 4.53 mmol). After stirring the mixture for 4 h at RT, water (50 mL) and 3M HCl (5 mL) were added and the product was extracted with EtOAc (3×30 mL). The combined organic layers were washed with aq. LiCl, dried (Na2SO4), concentrated and purified by chromatography (EtOAc/CH2Cl2) to afford ethyl 3-tert-butyl-1-(2-morpholino-2-oxoethyl)-1H-pyrazole-5-carboxylate (0.67 g, 69% yield) as a solid. 1H NMR (400 MHz, Acetone-d6): δ 6.74 (s, 1H), 5.40 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.73 (brs, 2H), 3.65-3.62 (m, 4H), 3.51 (brs, 2H), 1.32 (t, J=7.2 Hz, 3H), 1.29 (s, 9H); MS (ESI) m/z: 324.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:11])=[C:3]([C:7]([F:10])([F:9])[F:8])[C:4](F)=[O:5].[CH3:12][OH:13].[F-].[Na+].[OH2:16]>CCOCC>[F:1][C:2]([F:11])([O:13][CH3:12])[CH:3]([C:7]([F:10])([F:9])[F:8])[C:4]([OH:16])=[O:5]
Reactant: O
Reactant: O=C(F)C(=C(F)F)C(F)(F)F
Reactant: CO
Agent: [F-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(F)(F)C(C(=O)O)C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of 50 g (0.28 mol) of perfluoromethacryloyl fluoride in 100 ml of ether was stirred at 0°C while 9.0 g (0.28 mol) of methanol was added at a rate sufficient to keep the reaction mixture near 20°C. When the addition was complete, 100 g of anhydrous NaF was added, and the mixture was stirred while 5.4 g (0.30 mol) of water was added. The temperature was not allowed to go above 35°C. After having stood overnight, the reaction mixture was filtered and distilled. It was necessary to keep the pot temperature below 70°C to avoid excessive etching. 3,3-Difluoro-3-methoxy-2-trifluoromethylpropionic acid was obtained as 22.1 g (38%) of distillate, bp 45°C (0.5 mm); ir (neat): 3.25 (broad, OH), 5.72 (C=O), 7.5-9 μ (CF, COC); nmr (CCl4): 1H at 11.8 (singlet, 1, OH), 3.83 (sextet (quartet, JHF = 7.5 Hz, into triplets, JHF = 7.5 Hz), 1, CH), and 3.67 ppm (singlet, 3, OCH3); 19F at -65.1 ppm (triplet, JFF = 10.5 Hz, into doublets, JHF = 7.5 Hz, 3, CF3) and 14 lines from overlapping center lines of an AB pattern at -4233 Hz and -4247 Hz (both quartets, JFF = 10.5 Hz, into doublets, JHF = 7.5 Hz, 2, CF2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH3:18][N:19](C)C=O>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:18]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1)#[N:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of tert-butyl [(1S)-1-(4-bromophenyl)ethyl]carbamate (step 1 of Example 5, 1.50 g, 5.00 mmol), tetrakis(triphenylphosphine)palladium (0) (0.58 g, 0.50 mmol), zinc cyanide (0.59 g, 5.00 mmol) and N,N-dimethylforamide (30 mL) was stirred at 80° C. for 16 h under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with ether (200 mL) and washed with water (100 mL×3). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (4:1) to afford 1.11 g (90%) of the title compounds as colorless syrup: 1H-NMR (CDCl3) δ 7.64–7.61 (2H, m), 7.41 (2H, d, J=8.3 Hz), 4.83 (2H, br.s), 1.44–1.42 (12H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])[C:8]1[CH:9]=[CH:10][C:11]2[NH:12][C:13](=[O:18])[NH:14][CH2:15][C:16]=2[N:17]=1)([CH3:4])([CH3:3])[CH3:2].I[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13](=[O:18])[N:14]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:15][C:16]=2[N:17]=1)([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:13](=[O:18])[NH:14][CH2:15][C:16]=2[N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3)c(OC)c1
Reactant: Ic1ccccc1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(c2ccccc2)C(=O)N3c2ccccc2)c(OC)c1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3c2ccccc2)c(OC)c1

Procedure:
(2,4-Dimethoxy-benzyl)-(2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (Example 20, product from Step 4) (1.09 g, 2.6 mmol, 1.0 equiv) was treated by following methods similar to those described in Example 21, Step 1 except that iodobenzene was used instead of 1-chloro-4-iodo-benzene to afford 420 mg of (2,4-dimethoxy-benzyl)-(2-oxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (MS: [M+H]+=567) and 358 mg of (2,4-dimethoxy-benzyl)-(2-oxo-1-phenyl-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester. MS: [M+H]+=491.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].[O:21]=[C:22]1[N:26]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25](=[O:33])[CH:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)[S:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:26]1[C:25](=[O:33])[CH:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:42][CH2:43][CH:44]([NH:5][CH2:6][C@H:7]([OH:8])[C:9]4[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=4)[CH2:45][CH2:46]3)=[CH:37][CH:36]=2)[S:23][C:22]1=[O:21])[CH3:32]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)C1=O
Reaction time: 0.33 h
Yield: 73.5 %

Procedure:
Acetic acid (0.05 mL, 0.92 mmol) was added to a mixture of N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (which was obtained in Example 10) (113 mg, 0.46 mmol), ethyl 2-[2,4-dioxo-5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidin-3-yl}acetate (which was obtained in Example 50) (180 mg, 0.46 mmol), and DMF (3 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (117 mg, 0.55 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 5/1) to produce an off-white solid (210 mg, 74% yield); mp 153-155° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18 (t, J=7.1 Hz, 3H), 1.30-1.60 (m, 2H), 1.80-1.83 (m, 2H), 2.50-2.65 (m, 4H), 2.80-2.85 (m, 4H), 3.40 (m, 2H), 3.60 (m, 1H), 4.13 (q, J=7.1 Hz, 2H), 4.47 (m, 1H), 5.04 (m, 1H), 6.80-6.90 (m, 3H), 6.97 (m, 1H), 7.1 (m, 2H), 7.19 (m, 1H); MS (ES) m/z: 621 (MH+); Anal. Calcd. for: C28H36N4O8S2×1CH3CO2H: C, 52.93; H, 5.92; N, 8.23. Found: C, 52.69; H, 5.63; N, 8.23.
Reaction SMILES: [I-].C([N+]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)C1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22].C(=O)([O-])[O-].[K+].[K+].O>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:22]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(N)cc1OC
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2CCC(=O)CC2)cc1OC
Temperature: 100 °C
Yield: 61.8 %

Procedure:
A slurry of 1-benzyl-1-methyl-4-oxo-piperidinium iodide (9270 mg), 3,4-dimethoxy aniline (3900 mg) and anhydrous potassium carbonate (437 mg) in ethanol (90 ml)/water (45 ml) were heated to reflux for 6 hours. Additional potassium carbonate (200 mg) was added and the reaction was heated to 100° C. over night. Water (50 ml) was added to the reaction mixture, which was extracted three times with DCM. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to leave the crude product as a dark oil. The residue was purified by column chromatography (ethyl acetate/hexanes=1:1) to yield the product as a yellow solid (3700 mg). MS (ESI): 236.1 (MH+).
Reaction SMILES: O.[OH-].[Na+].C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=2)[C:13]=1[CH3:14])=[O:8])C.Cl>C(O)C>[Cl:21][C:20]1[C:15]([N:12]2[C:13]([CH3:14])=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]2)=[N:16][CH:17]=[C:18]([CH3:22])[CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2ncc(C)cc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cnc(-n2ncc(C(=O)O)c2C)c(Cl)c1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 70.6 %

Procedure:
Water (9 ml) and 4N aqueous solution of sodium hydroxide (9 ml) were added to a solution of 1-(3-chloro-5-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.03 g) in ethanol (18 ml) at room temperature, and the mixture was stirred at 80° C. for 3.5 hours. After completion of the reaction, the reaction solution was cooled to 0° C. and 1N hydrochloric acid aqueous solution (38 ml) was added. The precipitated solid was collected by filtration to give the titled compound (654 mg) as a light brown solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1>O.C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]3)=[CH:12][CH:13]=2)=[CH:33][N:34]=1
Reactant: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1ncc(-c2ccc(C3(C(=O)O)CC3)cc2)cn1
Temperature: 120 °C
Yield: 60.3 %

Procedure:
A solution of sodium carbonate (0.56 g, 0.0052 mol) in water (5.0 mL) was added to a mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (0.78 g, 0.0026 mol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.87 g, 0.0039 mol), and tetrakis(triphenylphosphine)palladium (0.2 g, 0.0001 mol) in toluene (10 mL) and ethanol (5 mL). The resulting mixture was heated at 120° C. for 15 min, quenched with water (5 mL), and washed with ether (3×10 mL). The precipitate in the aqueous layer was filtered, washed with water, and dried to afford the desired product (0.40 g, 60%). LCMS: (M+H)=256.1.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:20]([N:27]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33]2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:20]([N:27]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([C:2]3[C:3]([CH3:19])=[C:4]([CH2:12][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:32]=[CH:33]2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn2c1CN1CCOCC1
Temperature: 100 °C
Yield: 7.2 %

Procedure:
To a stirred solution of 5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.46 mmol) and tetrakis(triphenylphosphine)palladium(0) (159 mg, 0.14 mmol), in degassed DMF (3.0 mL) was added 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (184 mg, 0.55 mmol), K2CO3 (153 mg, 1.10 mmol), and H2O (0.5 mL). The mixture was degassed and heated (100° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous Na2CO3 solution (25 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 15 mg (7%) of the desired product. 1H-NMR (DMSO-d6) 8.56 (s, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.54 (s, 1H), 7.32-7.38 (m, 5H), 7.02 (d, 1H), 5.65 (s, 2H), 3.81 (s, 2H), 2.53-2.50 (m, 4H), 2.43-2.40 (m, 4H), 2.10 (s, 3H); LC-MS [M+H]+=454, RT=2.30 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]([O:27][CH3:28])=[O:26])=[C:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[H][H]>O1CCOCC1.[Pd]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: [H][H]
Reactant: CCOC(=O)C1=C(COCC#CC(=O)OC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCCCC(=O)OC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 39.7 %

Procedure:
A solution of methyl 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}but-2-ynoate (1.00 g) in dioxane (30 ml) was stirred under one atmosphere (1.0333 kg.cm.-2) of hydrogen at room temperature in the presence of 5% palladium on barium sulphate. When the uptake of hydrogen had ceased the mixture was filtered and evaporated. The residue was purified by chromatography on silica (6 g) using toluene plus 0→50% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated and the residue crystallised from diisopropyl ether to give the title compound (0.40 g), m.p. 78°-80°.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:18])[NH:5][C:4]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:2].O.[O:27]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C1COCC1.CC(O)=O>[CH2:1]([C:3]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH:18]=[O:27])[NH:5][C:4]=1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH3:2]
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C)c1C(=O)OCc1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-benzyl 2-tert-butyl 3-ethyl-5-methyl-1H-pyrrole-2,4-dicarboxylate (2.75 mmol) in THF (32 mL), AcOH (40 mL), and H2O (32 mL) was added CAN in one portion. The reaction was stirred at room temperature for 4 hours, then poured into water (500 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were washed with saturated aqueous sodium bicarbonate (1×200 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography gave a white solid. HRMS (ES) exact mass calcd for C20H23NO5 (M+H+): 358.1649. Found (M+Na+): 380.1478
Reaction SMILES: CS[C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1.[S:17](=[O:21])(=O)(O)[OH:18].OO.S([O-])([O-])=O.[Na+].[Na+].[C:30](O)(=O)C>>[CH3:30][S:17]([C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1)(=[O:21])=[O:18]
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Reactant: CC(=O)O
Reactant: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CS(=O)(=O)c1nnc2n1C=Cc1ccccc1C2
Reaction time: 20 h

Procedure:
To a solution of 0.23 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine in 2 ml of acetic acid was added 0.2 ml of concentrated sulfuric acid and 0.5 ml of 30% hydrogen peroxide was added dropwise under stirring. After 20 hours, a solution of sodium sulfite was added and the solvent was evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over Na2SO4. The solvent was then evaporated off and the residue was treated with ethanol. By the above procedure was obtained 3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazapine as crystals. m.p. 110°-111° C. Based on its infrared absorption spectrum and other data, this compound was identified with the compound obtained in Example 23.