Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][C@H:24]4[CH2:29][CH2:28][C@@H:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:26][CH2:25]4)[CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+].O1CCCC1.O>>[C:30]1([C@@H:27]2[CH2:26][CH2:25][C@H:24]([O:23][C:18]3[CH:19]=[C:20]4[C:15](=[CH:16][CH:17]=3)[CH:14]=[C:13]([CH2:12][N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[CH:22]=[CH:21]4)[CH2:29][CH2:28]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)CC1

Procedure:
A solution of 1-[6-(cis-4-phenyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (0.9 g, 2 mmol) and lithium hydroxide (457 mg, 19.1 mmol) in tetrahydrofuran (7.74 mL, 95.4 mmol) and water (1.72 mL, 95.4 mmol) was stirred at room temperature overnight. LCMS showed a single desired product peak Rt=1.60 min, m/z=444.35, [M+1], 100%. The solvent was concentrated and neutralized with conc. HCl and concentrated and purified on HPLC to give product (245 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=[O:15])[CH3:14].[Br:16]Br>Br>[BrH:16].[BrH:16].[Br:16][CH2:14][C:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1])=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1nc(-c2cccnc2)[nH]c1C
Agent: Br
Product: Cc1[nH]c(-c2cccnc2)nc1C(=O)CBr
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 10 g of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone in 60 ml of 48% hydrobromic acid at 80° C. was added, dropwise during 5-10 minutes, 2.8 ml of bromine. After addition was complete, the mixture was stirred at 80° C. for 10 minutes, then allowed to cool to room temperature. The resulting solid was collected, washed with three 25 ml portions of acetone and dried, giving 13.4 g of 2-bromo-1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone, dihydrobromide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Product: O=C(Nc1nc(-c2ccc(C(F)(F)F)cc2)cs1)c1cc(Cl)ccc1O
Yield: 16 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-[4-(trifluoromethyl)phenyl]thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:16][C:17](=[O:26])[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])(=[O:3])[CH3:2].[BH4-].[Na+].O>O1CCCC1>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[C:17]([NH:16][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[C:13]2[O:14][CH3:15])=[O:26]
Reactant: COc1c(C(C)=O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(C)O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 3-acetyl-8-(2,6-dichlorobenzoylamino)-4-methoxyquinoline (115 mg) in tetrahydrofuran was added sodium borohydride (16.8 mg) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 8-(2,6-dichlorobenzoylamino)-3-(1-hydroxyethyl)-4-methoxyquinoline (85.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([CH3:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>C(O)C.CCCCCC>[F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([CH3:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(F)c(F)c1C
Temperature: 5 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 8.3 g (26 mmol) of ethyl 2-(2,4,5-trifluoro-6-methylbenzoyl)-3-ethoxyacrylate in 30 ml of absolute ethanol at 5° C. was added 1.64 g (29 mmol) of cyclopropylamine. The reaction mixture was stirred at 5° C. for 90 minutes and at room temperature for two hours. The solution was concentrated to give a brown oil which was dissolved in hexane and reconcentrated to give a tan solid. Recrystallization from hexane gave 7.2 g of colorless crystals, mp 69°-72° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[C:13]2=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]2[CH:11]=[CH:10][CH:9]=1>C1COCC1.CO.[C].[Pd].[C].[Rh]>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[CH:8]1[C:13]2=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]2[CH2:11][CH2:10][CH2:9]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3F)C2=N1
Agent: [Pd]
Agent: [Rh]
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(-c4ccccc4)cc3F)C2=N1
Temperature: 50 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a solution of 9-(3-fluorobiphenyl-4-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (200 mg) in THF/methanol (30 mL/30 mL) was added 10% palladium carbon (50 mg). The reaction mixture was stirred under a hydrogen atmosphere at 50° C. for 1 day. 5% Rhodium carbon (100 mg) was added, and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr, and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by recrystallization (methanol-THF/diisopropyl ether) to give the title compound (154.4 mg).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]2[C:3](=[O:20])[N:4]([CH3:19])[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8]2)=[O:24])=[CH:35][CH:34]=1
Reactant: COc1ccc(CNC(=O)C(C)C(=O)O)cc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: COc1ccc(CNC(=O)C(C)C(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1

Procedure:
The title compound, MS: m/e=485.4 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(4-methoxy-benzyl)-malonamic acid.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]2[CH2:18][O:19][C@@H:5]1[O:6]2)=[N+]=[N-].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:11]([O:10][C@@H:8]1[C@H:7]2[CH2:18][O:19][C@H:5]([O:6]2)[C@H:4]([N:1]2[C:23](=[O:24])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:25])[CH2:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reactant: O=C1OC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reaction time: 360 h
Yield: 14.3 %

Procedure:
1,6-Anhydro-2-azido-4-O-benzyl-2,3-dideoxy-β-D-ribo-hexoyranose (see Example 13) (1.0 g), phthalic anhydride (0.74 g), triphenylphosphine (1.21 g) and tetrabutylammonium cyanide (0.1 g) were heated under reflux in a nitrogen atmosphere in benzene (50 ml) for 40 h. Methanol (10 ml) was then added and the solution was allowed to stand at room temperature for 15 days. The solution was then evaporated and the residue was chromatographed on silica gel to yield the title compound as a crystaline solid (0.2 g, 14%) from amongst a variety of products (t.l.c.evidence). Recrystallised from ethanol it had m.p. 135°-136° C., [α]D -28.4°; 13C-nmr data: 100.4 (C-1), 51.1 (C-2), 25.0 (C-3), 76.5 and 75.7 (C-4 and C-5), 67.4 (C-6), 70.4 (PhCH2O), 167.7 (C=0), 156.0 and 131.8 (q-aromatic), 134.0, 128.3, 127.6, 127.5 and 123.3 (aromatic).
Reaction SMILES: C1([O:6][C:7](=[O:43])[C@@H:8]([NH:16][C:17](=[O:42])[CH2:18][CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:40])[NH:38][OH:39])=[CH:23]3)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)CCCC1.[OH-].[Na+]>C1COCC1.CO>[OH:39][NH:38][C:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([CH2:19][CH2:18][C:17]([NH:16][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([OH:43])=[O:6])=[O:42])=[CH:28][CH:27]=2)=[O:41])=[O:40]
Reactant: O=C(CCCCCCNC(=O)c1cc2cc(CCC(=O)N[C@@H](Cc3ccccc3)C(=O)OC3CCCC3)ccc2[nH]1)NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCCCCCNC(=O)c1cc2cc(CCC(=O)N[C@@H](Cc3ccccc3)C(=O)O)ccc2[nH]1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
Compound (100) (80 mg, 0.14 mmol) was dissolved in THF/MeOH (1 ml/0.5 ml) and 1.4 M NaOH (0.5 ml) added. The reaction was stirred at room temperature for 2 h. THF was removed by blowing a stream of N2 gas at the surface of the solution and the residual material purified by preparative HPLC to give compound (101) (34.9 mg), LCMS purity 95%, m/z 523 [M++H]+, 1H NMR (400 MHz, MeOD), δ: 1.35-1.50 (4H, m, alkyl), 1.60-1.75 (4H, m, alkyl), 2.15 (2H, br t, CH2), 2.55 (2H, br t, CH2), 2.95 (3H, m, CH+CH2), 3.10 (1H, dd, CH), 4.65, (1H, m, NHCHCO), 7.00-7.15 (7H, m, Ar), 7.35-7.41 (2H, m, Ar)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:29][C@H:30]1[CH2:32][O:31]1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH2:29][C@@H:30]([OH:31])[CH3:32])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: C[C@H]1CO1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Solvent: CCO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C[C@H](C)O)C1
Temperature: 120 °C
Yield: 26.5 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (2.5 g, 6.3 mmol) in ethanol (130 mL) was treated with (S)-(−)-methyloxirane (1.1 mL, 16 mmol) and heated in the microwave at 120° C. for 25 min. The reaction mixture was concentrated to give a residue that was purified by flash column chromatography using methanol in dichloromethane (0%-10%; methanol contained 0.5% triethylamine) and by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.76 g, 26%). The product was isolated as a single diastereomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.46 (s, 1H), 7.34 (br s, 2H), 6.23 (q, J=7.0 Hz, 1H), 4.35 (br s, 1H), 4.14-3.99 (m, 1H), 3.98-3.87 (m, 2H), 3.64 (s, 3H), 3.60-3.52 (m, 1H), 3.13-2.99 (m, 2H), 2.55 (s, 3H), 2.28 (d, J=5.9 Hz, 2H), 1.75-1.69 (m, 3H), 1.00 (d, J=6.2 Hz, 3H). LCMS for C22H27ClN7O2 (M+H)+: m/z=456.2; Found: 456.2.
Reaction SMILES: F[C:2]1C=CC(COC2C=C(C)N(C3C=C(C=CC=3C)C(O)=O)C(=O)C=2)=C(CNC(OC)=O)C=1.Br[C:35]1[C:36](=[O:68])[N:37]([C:58]2[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=2[CH3:67])[C:61]([OH:63])=[O:62])[C:38]([CH3:57])=[CH:39][C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[CH2:50][NH:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>>[CH2:55]([O:54][C:52]([NH:51][CH2:50][C:44]1[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=1[CH2:42][O:41][C:40]1[CH:39]=[C:38]([CH3:57])[N:37]([C:58]2[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=2[CH3:67])[C:61]([O:63][CH3:2])=[O:62])[C:36](=[O:68])[CH:35]=1)=[O:53])[CH3:56]
Reactant: CCOC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1Br
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1
Product: CCOC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)OC)ccc2C)c(=O)c1

Procedure:
Prepared using a procedure similar to that used in the preparation of 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid. 1H NMR (CD3OD/400 MHz) δ 8.03 (m, 1H), 7.74 (s, 1H), 7.48 (m, 2H), 7.11 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 4.08 (q, 2H, J=7.2 Hz), 2.11 (s, 3H), 1.90 (s, 3H), 1.23 (t, 3H, J=7.2 Hz). ES HRMS m/z 469.1738 (M+H calculated for C25H26FN2O6 requires 469.1769). Step 3: Preparation of 3-[3-bromo-4-[(2-{[(ethoxycarbonyl)amino]methyl}-4-fluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Cl:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]1([OH:61])[CH2:60][CH2:59][NH:58][CH2:57]1>CN(C=O)C>[Cl:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]1([OH:61])[CH2:60][CH2:59][N:58]([C:14]([C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:10][O:11][CH:12]=2)=[O:16])[CH2:57]1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Reactant: OC1(c2ccccc2Cl)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccccc3Cl)C2)cc1
Yield: 75.2 %

Procedure:
A solution of 3-(4-methoxyphenyl)isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(2-chlorophenyl)pyrrolidin-3-ol hydrochloride (7 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z: calcd for C21H19ClN2O4: 398.1033, found 398.1036.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][NH:12][C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=[O:21])[N:7]([CH3:22])[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3].Br[CH2:25][C:26]#[C:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:25][C:26]#[C:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:9]2[C:8](=[O:21])[N:7]([CH3:22])[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)[nH]nc21
Reactant: BrCC#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(CC#Cc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7-isobutyl-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (48.6 mg, 0.155 mmol), (3-bromoprop-1-ynyl)benzene (60.5 mg, 0.31 mmol) and potassium carbonate (42.8 mg, 0.31 mmol) in DMF (1.5 mL) is stirred at room temperature overnight. The mixture is filtered through a 0.45 μm microfilter and the filtrate is purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 428.2 [M+H]+.
Reaction SMILES: CS([O:5][CH:6]([CH2:16][N:17]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:24]2[C:19]([N:20]([CH3:36])[C:21](=[O:35])[N:22]([CH3:34])[C:23]2=[O:33])=[CH:18]1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.[C:37]([O-])(=[S:39])[CH3:38].[K+]>CN(C=O)C.O>[C:37](=[S:39])([O:5][CH:6]([CH2:16][N:17]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:24]2[C:19]([N:20]([CH3:36])[C:21](=[O:35])[N:22]([CH3:34])[C:23]2=[O:33])=[CH:18]1)[CH2:7][O:8][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])[CH3:38]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)cc2n(C)c1=O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=S)OC(CO[Si](C)(C)C(C)(C)C)Cn1cc2c(c1-c1cccc(F)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C

Procedure:
A solution of 1-((tert-butyldimethylsilyl)oxy)-3-(5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)propan-2-yl methanesulfonate (705 mg, 1.241 mmol) and potassium thioacetate (709 mg, 6.20 mmol) in DMF (4964 μL) was heated at 70° C. for 4 hours. Further portions of potassium thioacetate (709 mg, 6.20 mmol) were added as necessary to allow the reaction to run to completion. The reaction mixture was cooled to room temperature, diluted with water (15 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-50% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:22]=[C:23]([C:26](O)=[O:27])[NH:24][N:25]=1>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:26]([C:23]3[NH:24][N:25]=[C:21]([CH3:20])[CH:22]=3)=[O:27])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C(=O)O)[nH]n1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(C3CCCCC3)c2)[nH]n1
Yield: 53.1 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and 5-methyl-2H-pyrazole-3-carboxylic acid (40.6 mg, 0.33 mmol) as starting materials. The title compound (67 mg, 48.2%) was isolated as off white solid; MS (ESI): 383 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-4-fluorophenylacetic acid (2.078 g, 8.92 mmol) and thionyl chloride (1.3 mL, 17.84 mmol) were combined in MeOH (20 mL) and stirred at room temperature for 10 minutes. The mixture was concentrated, and the residue was worked up with CH2Cl2 and 1N aqueous NaOH. The organic layer was dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[Cl:9][C:10]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Cl:22])[C:11]=1[CH:12]=O>CO>[NH2:1][C:2]([C:7]#[N:8])=[C:3]([N:6]=[CH:12][C:11]1[C:14]([Cl:22])=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:10]=1[Cl:9])[C:4]#[N:5]
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#C/C(N)=C(/N)C#N
Solvent: CO
Product: N#CC(N)=C(C#N)N=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 77.3 %

Procedure:
Diaminomaleonitrile (4.4 g, 0.04 mol) was dissolved in methanol (100 ml) and 2,6-dichloro-4-trifluoromethylbenzaldehyde (9.6 g, 0.04 mol) was added with stirring at ambient temperature. The reaction mixture was stirred for 30 minutes and heated at reflux for 1 hour. After cooling to 10° C. a solid which had separated was filtered off co give 1-amino-2-(2,6-dichloro-4-trifluoromethylbenzylideneamino)-1,2-dicyanoethylene (10.3 g) as a yellow crystalline solid, m.p. 218°-219° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[Si]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Temperature: 60 °C
Yield: 84.6 %

Procedure:
0.5 g (1.85 mmol) of 1-ethyl-6-fluoro-7-chloro-4-oxo1,4-dihydro-quinoline-3-carboxylic acid (II, R1 : ethyl; X: chloro) and 1.1 g (5.5 mmol) of 1-(t-butyldimethylsilyl) piperazine (R2 : hydrogen, R3 and R4 : methyl; R5 : t-butyl) are added to 5 ml of pyridine and then heated at 60° C. A solution of 1.73 g (5.5 mmol) of tetrabutylammonium fluoride trihydrate in 5 ml of pyridine is added dropwise to the reaction mixture. After completion of addition, the reaction mixture is heated at 80° C. for 2 hours and then distilled under reduced pressure (10 mmHg, 60° C.). The residue is added with water and then stirred to afford a crystal. After filtering and drying, 0.50 g of a solid product is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9](Cl)=[O:10])([O-:3])=[O:2].[N+:15]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16].N1C=CC=CC=1>CC(C)=O>[N+:15]([C:18]1[CH:19]=[C:20]([O:24][C:9](=[O:10])[CH:8]=[CH:7][C:6]2[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(C=Cc1cccc([N+](=O)[O-])c1)Oc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 90.2 %

Procedure:
64.5 g (0.3 mole) of 3-nitrocinnamoyl chloride and 300 g of acetone were placed in a reaction vessel and stirred at 50° C. under a nitrogen current. 41.73 g (0.3 mole) of 3-nitrophenol, 60 g of pyridine, and 300 g of acetone were added dropwise to the above reaction vessel using a dropping funnel. After the completion of the addition, the reaction mixtures were stirred under a nitrogen current for 2 hours. After the reaction, the solid obtained by concentrating the solution was washed by water and dried. 85 g of light yellow colored needle-like crystals ((3-nitrophenyl)-3-cinnamate) was yielded.