Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][O:33][C:34](=[O:38])[CH2:35][CH2:36][NH:37][C:18](=[O:20])[C:17]1[CH:16]=[CH:15][C:14]([CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:24][CH:23]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:22][CH:21]=1
Reactant: COC(=O)CCN
Reactant: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a mixture of 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid (1700 mg, 4.35 mmol) in methylene chloride (43 mL) are added triethyl amine (1.82 mL, 13.4 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (910 mg, 6.52 mmol) and EDCI (2507 mg, 13.04 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving racemic 3-{4-[1-(4-bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (1660 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1NC(C)=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)cc1NC(C)=O
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of methyl 2-acetylamino-4-nitrobenzoate (1.31 g, 5.50 mmol) in MeOH (30 mL) was added 5% Pd on carbon (195 mg), and the stirring under H2 gas (3 atm) was continued for 18 hours at rt. The catalyst was filtered off and the mixture was evaporated. The resulting crude solid was recrystallized with CHCl3—MeOH-hexane to give methyl 2-acetylamino-4-aminobenzoate (1.03 g, 90%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ2.23 (s, 3 H), 3.82 (s, 3 H), 4.20 (s, 2 H), 6.30 (dd, J=2.5 Hz, 8.8 Hz, 1 H), 7.80 (d, J=8.8 Hz, 1 H), 8.06 (s, 1 H), 11.26 (s, 1 H); MS (FAB), m/z 208 (M+).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:27][NH2:28].C(O)C>C(O)(=O)C>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=4)=[N:28][NH:27][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1cccc([N+](=O)[O-])c1)OCO2
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2cc3c(cc2C(c2cccc([N+](=O)[O-])c2)=NN1)OCO3

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(3-nitrobenzoyl)phenylacetate (500 mg, 1.46 mmol), hydrazine hydrate (350 μL, 6.20 mmol), and acetic acid (50 μL) in ethanol (15 mL) as a yellow solid (30 mg, 0.092 mmol, 6%), mp: 251°-253° C. 1H NMR (CDCl3) 8.52 (s, 1H), 8.46 (s, 1H), 8.31 (d, J=8.2, 1H), 7.99 (d, J=8.2, 1H), 7.62 (t, J=8.2, 1H), 6.87 (s, 1H), 6.57 (s, 1H), 6.06 (s, 2H), 3.49 (s, 2H). Anal. Calcd. for C16H11N3O5 : C, 59.08; H, 3.41; N, 12.92. Found: C, 58.95; 11, 3.29; N, 12.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:30])=[O:29]
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2Cl)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.9 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2-chlorobenzene-1-sulfonyl chloride (23 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a brown solid. MS (ESI+) for C18H19ClN2O3S m/z 379 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([C:33](O)=[O:34])[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]>>[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([C:33]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[O:34])[CH:22]=1)(=[O:19])=[O:20]
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 2-Piperazin-1-yl-4-trifluoromethyl-pyrimidine [179756-91-3] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 491.1 MH+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:33])=O.C1(C)C=CC=CC=1>CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:33])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Yield: 89.4 %

Procedure:
A mixture of 4-hydroxy-1-oxo-6-(4-propoxy-phenoxy)-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester (495 mg, 1.20 mmol), POBr3 (379 mg, 1.32 mmol), and toluene was microwaved at 110° C. for 25 min. Subsequently, the mixture was diluted with EtOAc, washed with aqueous NaHCO3 and saturated NaCl solution before it was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title product (509 mg) that was used in the next step without further purification. 1H NMR (200 MHz, CDCl3): δ (ppm)=11.74 (s, 1H), 8.19 (d, 1H, J=9.2 Hz), 7.60-7.46 (m, 2H), 7.07-6.92 (m, 4H), 4.46 (t, 2H, =7.1 Hz), 3.94 (t, 2H, J=6.6 Hz), 1.83 (m, 4H), 1.45 (m, 2H), 1.10-0.94 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[NH:11]1[CH2:14][CH2:13][CH2:12]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[N:11]1([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: C1CNC1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=Cc1c(Cl)ncnc1N1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloropyrimidine-5-carbaldehyde (1.00 g, 5.65 mmol) in chloroform at 0° C. were added azetidine (99%, 0.392 mL, 5.71 mmol) and triethylamine (5 drops). The reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. The reaction mixture was filtered, and the filtrate was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to provide the product. Yield: 880 mg, 4.45 mmol, 79%. LCMS m/z 198.1, 200.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.34-2.43 (m, 2H), 4.12-4.33 (br m, 4H), 8.30 (s, 1H), 10.28 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[NH:10][N:9]=[C:8]([NH2:11])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][CH:13]([CH:16]=O)[CH:14]=O>>[Br:12][C:13]1[CH:14]=[N:11][C:8]2[N:9]([N:10]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=2)[CH:16]=1
Reactant: Nc1n[nH]c(N2CCCC2)n1
Reactant: O=CC(Br)C=O
Product: Brc1cnc2nc(N3CCCC3)nn2c1

Procedure:
The title compound, a light red solid, MS: m/e=268.1/270.1 (M+H+), can be prepared in accordance with the general method of example 42, step 1 from 5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-ylamine (CAS 154956-89-5) and 2-bromomalonaldehyde.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[N:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:8][N:7]([CH2:30][C:27]5[CH:28]=[N:29][C:24]([C:23]([F:33])([F:22])[F:32])=[CH:25][CH:26]=5)[CH2:6][CH:5]4[CH2:1]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Product: FC(F)(F)c1ccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cn1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-(trifluoromethyl)pyridine-3-carbaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[2-[[6-(trifluoromethyl)pyridin-3-yl]methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13]([C:25]([NH:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[O:26])=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>FC(F)(F)C(O)=O.ClCCl>[N:1]1([C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
t-Butyl 2-[({2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-fluorobenzyl)oxy]-5-pyrimidinyl}carbonyl)amino]acetate (210 mg, 0.4 mmol) was dissolved in trifluoroacetic acid-dichloromethane (4:1, 2 mL) and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure and the precipitated crystals were recrystallized from ethyl acetate to give the title compound (140 mg, 70%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][OH:21])[CH:9]=1)([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=[O:21])=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.725 g of [5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol in 10 mL of CH2Cl2 was added 1.14 g of Dess-Martin periodinane. The mixture was stirred at room temperature for 30 min, then filtered and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 40S column, eluting with 1 CV of 1% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 1 to 100% over 10 CV to provide the title compound. Mass spectrum (ESI) 323.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 9.81 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J=1.5 Hz, 8 Hz, 1H), 7.54 (d, J=8 Hz, 1H), 7.33 (dd, J=2 Hz, 8 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 3.74 (s, 3H), 2.95 (septet, J=7 Hz, 1H), 1.29 (d, J=7 Hz, 6H).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[C:29]([O:33][C:34]([NH:36][CH:37]([C:46](O)=[O:47])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:46](=[O:47])[CH:37]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:35])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)O
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Yield: 88.6 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-[N-tert-butoxycarbonyl-β-(4-fluorophenyl)-D,L-alanylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (575 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-tert-butoxycarbonyl-β-(4-fluorophenyl)-D,L-alanine (417 mg) according to a similar manner to that of Example 5, mp. 125°-134° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=1>>[C:19]([C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:4]2[S:3][C:2]([NH:1][C:26]3[CH:27]=[CH:22][N:23]=[C:24]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:25]=3)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=2)=[CH:11][CH:12]=1)([CH3:18])[CH3:17])#[N:20]
Reactant: C[Si](C)(C)CCOc1nccc(Cl)n1
Reactant: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Product: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(OCC[Si](C)(C)C)n3)s2)cc1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-amino-5-[4-(1-cyano-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.350 mmol) and 4-chloro-2-[2-(trimethylsilyl)ethoxy]pyrimidine (81 mg, 0.350 mmol) (see J. Het. Chem., 1994, 989-995) as the starting materials.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH2:8]([SH:13])[CH2:9][CH2:10][CH2:11][CH3:12].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CCCCCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 110 °C
Yield: 79.9 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (277 mg, 6.9 mmol, 60% in mineral oil) were added 1-pentanethiol (2 ml, 16 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 110° C. for 4 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (102 mg, yield 81%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.CS(C)=[O:32].N([O-])=O.[Na+].Cl>O.C(O)(=O)C>[OH:32][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1
Reactant: CS(C)=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4CBr)c3c2)c1=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4CO)c3c2)c1=O
Yield: 38.3 %

Procedure:
To a mixture of 3-[3-[3-(bromomethyl)-2-thienyl]-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil(0.840 g, 1.67 mmol), dimethylsulfoxide and sodium nitrite is added glacial acetic acid. The resultant mixture is stirred overnight at 50° C., cooled and acidified with 10% aqueous hydrochloric acid. The mixture is diluted with water and extracted twice with ethyl acetate. The combined organic layers are washed with saturated sodium carbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with diethyl ether-methylene chloride to afford the title compound as an off-white solid (0.290 g, 38.3%, mp 168-169° C.) which is identified by IR and NMR spectral analysis.
Reaction SMILES: [N:1]1[N:2]=[C:3]([NH:6][CH:7]2[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8]2)[NH:4][CH:5]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([C:37](=O)[CH2:38][CH2:39][CH3:40])[C:32](OCC)=[O:33])=[C:26]([F:42])[CH:25]=1)#[N:17].Cl>C(N(CC)C1C=CC=CC=1)C>[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32](=[O:33])[N:6]([C@H:7]3[CH2:8][C@H:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10]3)[C:3]3[N:2]([N:1]=[CH:5][N:4]=3)[C:37]=2[CH2:38][CH2:39][CH3:40])=[C:26]([F:42])[CH:25]=1)#[N:17]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: CCOC(=O)C1CC(Nc2nnc[nH]2)C1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(=O)OCC)C2)c2ncnn12
Temperature: 180 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 3-(4H-1,2,4-triazol-3-ylamino)cyclobutanecarboxylate (2.5 g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (7.9 g) and N,N-diethylaniline (10 mL) was stirred at 180° C. for 18 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 14%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[CH3:23][CH:24]1[CH2:28][CH2:27][C:26](=O)[CH2:25]1>>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][N:18]([CH:26]4[CH2:27][CH2:28][CH:24]([CH3:23])[CH2:25]4)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reactant: CC1CCC(=O)C1
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC(C)C2)CC3)nc1

Procedure:
Example 253 (E253) was prepared from n-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) and 3-methyl cyclopentanone using the method described for Example 223; MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23](=[O:25])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[CH:10]1.C(O)C>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([CH:23]([OH:25])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:30])([F:31])[F:32])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[CH:10]1
Reactant: COc1cn(-c2ccc(Nc3nc(COCC(F)(F)F)cc(C(C)=O)n3)cc2OC)cn1
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cn(-c2ccc(Nc3nc(COCC(F)(F)F)cc(C(C)O)n3)cc2OC)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-(2-(3-methoxy-4-(4-methoxy-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)ethanone (0.1 g, 0.22 mmol) in ethanol (5 mL) sodium borohydride (0.034 g, 0.89 mmol) was added. The mixture was stirred at rt for 10 min. Acetone (2 mL) was added and mixture was stirred for 20 min. The mixture was filtered, the filtrate was concentrated in vacuum and the residue was purified by preparative HPLC to give the title compound as a dry film, 50 mg (50%).
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3]>[N+](CC)([O-])=O>[O:15]=[C:14]1[C:16]2[S:17][CH:18]=[CH:19][C:20]=2[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: CCOC(=O)C1C(=O)c2sccc2C1c1ccccc1

Procedure:
A solution of ethyl 3-phenyl-2-(thiophene-2-carbonyl)acrylate (3.118 g, 10.9 mmol) and aluminum trichloride (1.725 g, 13 mmol) in nitroethane (50 ml) was heated at 75° C. for 3 hours. The reaction mixture was poured into 1N HCl-ice solution, and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and concentrated to give a brown oil. The crude product was purified via flash chromatography 9 (silica gel cartridge with eluent of 0-15% ethyl acetate/hexane) to give ethyl 6-oxo-4-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate as am amble liquid, 3.12 g, quantitative yield. HPLC: Rt 2.873, 3.188 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][N:4]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]1=[O:17].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)[C:3]1=[O:17]
Reactant: COC(=O)C1CN(c2ncccn2)C(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)N(c2ncccn2)CC1C(=O)O
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A suspension of methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (316 mg, 2 mmol) (prepared as described in step (ii) of Example 8) in THF (10 ml) was stirred at −40° C. Lithium hexamethyldisilazide (2 ml, 1M solution in THF) was added dropwise and the mixture was stirred at −40° C. for 15 minutes and then at −70° C. for 1 hour. A solution of 2-bromopyrimidine (318 mg, 2 mmol) in THF (1 ml) was added dropwise and the reaction was stirred at −70° C. for 1 hour and then warmed to 0° C. over 1 hour and then stirred at room temperature overnight. The reaction mixture was diluted with citric acid solution and dichloromethane. The organic layer was separated, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give crude methyl 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylate (144 mg) which was used in the next step, LC/MS [M+H]+=237. (ii) A stirred solution of methyl 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylate (144 mg, 0.6 mmol) in THF (1.5 ml) at 0° C. was treated with lithium hydroxide (72 mg, 3 mmol) in water (1 ml) and the reaction mixture was stirred at 0-5° C. for 1 hours. The reaction was acidified to pH 2 with 2N hydrochloric acid and the solvent was evaporated. The residue dried to give 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylic acid which was used crude in the next step, LC/MS [M+H]+=223.