Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][S:5]([CH2:8][Cl:9])(=[O:7])=[O:6])([CH3:3])[CH3:2].[Cl:10][C:11](Cl)([S:15]Cl)[CH:12]([Cl:14])[Cl:13]>C(N(CC)CC)C>[CH:1]([N:4]([S:15][C:11]([Cl:10])=[C:12]([Cl:14])[Cl:13])[S:5]([CH2:8][Cl:9])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: CC(C)NS(=O)(=O)CCl
Solvent: CCN(CC)CC
Product: CC(C)N(SC(Cl)=C(Cl)Cl)S(=O)(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 32.3 g (0.32 mol) sample of triethylamine was added dropwise to a cooled (0° C.) solution of 50 g (0.29 mol) N-isopropyl chloromethanesulfonamide and 70 g (0.29 mol) 1,1,2,2-tetrachloroethylsulfenyl chloride. After the addition was completed, the reaction was stirred at ambient temperature for 30 minutes and then under reflux for 3 hours. The reaction mixture was then cooled, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the N-isopropyl-N-(trichlorovinylthio)-chloromethanesulfonamide product, which after crystallization from pet. ether melted at 71°-73° C. The product is reported as Compound 1.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>O.C(O)C>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:36]([F:47])([F:46])[F:35])[CH:42]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C(F)(F)F)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
N,N-Dimethylformamide (1 ml), ethanol (0.5 ml), and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-trifluoromethylphenylboronic acid (67 mg) under an argon atmosphere, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (50 mg, yield 95%).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[C:15]1[N:16]=[C:17]([C:28](OCC)=[O:29])[N:18]([CH3:27])[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1>>[CH:1]1([NH:6][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:15]([C:9]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=3[Cl:7])[N:16]=2)=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Reactant: NC1CCCC1
Product: Cn1c(C(=O)NC2CCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 36, Step B (Method B), but using neat cyclopentylamine (1.5 mL), ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate (30 mg, 0.073 mmol) was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42]([OH:44])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:46][NH2:47]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42](=[O:44])[NH:47][CH3:46])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: Cl
Product: CNC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1C(=O)OCc1ccccc1

Procedure:
According to general procedure D, 0.05 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1,2-dicarboxylic acid 1-benzyl ester (from example 3b) and methylamine-hydrochloride are used to afford the title compound as a yellow oil. Rf=0.50 (dichlormethane-methanol 9:1); Rt=4.52.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:2]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl-].[NH4+]>>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([N:7]3[CH2:8][CH2:9][O:10][CH2:11][CH2:12]3)[CH2:2]2)=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CNCC(N2CCOCC2)C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCC(N3CCOCC3)C2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-Piperidin-3-yl-morpholine (1.70 g, 9.98 mmol), 4-Fluoronitrobenzene (1.3 g, 9.1 mmol) and Potassium carbonate (3.14 g, 22.7 mmol) were dissolved in N,N-Dimethylformamide (60 mL, 800 mmol). The reaction mixture was then heated at 100° C. and was allowed to stir overnight. The reaction mixture was poured over saturated ammonium chloride and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was then purified by Isco flash column chromatography (hexanes/ethyl acetate eluent). Combined fractions were reduced and dried under vacuum to afford 4-[1-(4-Nitro-phenyl)-piperidin-3-yl]-morpholine. (M+H)=292.6. 1H NMR (400 MHz, DMSO, d6) δ 8.02 (d, 2H, J=9.45 Hz), 6.99 (d, 2H, J=9.48 Hz), 4.08 (m, 1H), 3.98 (m, 1H), 3.56 (t, 4H, J=4.56 Hz), 2.96 (m, 2H), 2.62 (m, 2H), 2.52 (m, 2H), 2.31 (m, 1H), 1.93 (m, 1H), 1.80 (m, 1H), 1.50 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]#[N:19])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[C:18]#[N:19])[CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N#CCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#CC(=Cc1ccc(Cl)cc1Cl)c1cccnc1
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a stirred solution of 2,4-dichlorobenzaldehyde (5.0 g, 29 mmole) and 3-pyridylacetonitrile (3.05 ml, 29 mmole) in 150 ml absolute ethanol were added 3.95 g K2CO3. After stirring for about 15 minutes, a white solid precipitated out of the reaction mixture. The reaction mixture was stirred overnight and filtered. The filter cake was washed with absolute ethanol and dissolve in CH2Cl2. The CH2Cl2 solution was filtered and concentrated in vacuo. The resulting white solid was recrystallized from 3:2 hexane/ethyl acetate to give 6.0 g (76%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:13]([CH3:15])[CH3:14])(O)[CH2:7][CH2:6][C:5]2([CH3:17])[CH3:16].BrC1C=CC(C(OCC)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:8]([CH:13]([CH3:15])[CH3:14])=[CH:7][CH2:6][C:5]2([CH3:16])[CH3:17])=[CH:10][CH:11]=1
Reactant: CC(C)C1(O)CCC(C)(C)c2cc(Br)ccc21
Agent: CCOC(=O)c1ccc(Br)cc1
Product: CC(C)C1=CCC(C)(C)c2cc(Br)ccc21

Procedure:
Following General Procedure J, 6-bromo-1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-ol (Compound 76, 0.85 g, 2.9 mmol), was reacted with ethyl 4-bromobenzoate to give the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[NH:18][N:17]=2)=[CH:13][C:12]=1[C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[F:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[NH:18][N:17]=2)=[CH:13][C:12]=1[C:29]([N:31]1[CH2:32][CH2:33][CH:34]([O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:35][CH2:36]1)=[O:30]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(OC2CCN(C(=O)c3cc(Cc4n[nH]c(=O)c5ccccc45)ccc3F)CC2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 9 %

Procedure:
A solution of 4-hydroxybenzonitrile (48 mg, 0.40 mmol) and 4-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2a) (150 mg, 0.39 mmol) in dichloromethane (5 mL) was treated with polymer supported triphenylphosphine (ex-Biotage, 742 mg, 1.37 mmol) and di-tert-butyl azodicarboxylate (300 mg, 1.30 mmol). The reaction mixture was agitated at ambient temperature for 4-5 hours. Mixture was then filtered to remove resin, and filter cake washed through with methanol. Filtrate was evaporated to afford a waxy yellow solid, which was purified by repeated preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), firstly using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents, then using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents (Waters Sunfire Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length). Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the desired product (17 mg, 8% yield); 1H NMR (400.132 MHz, DMSO) δ 1.49-1.69 (2H, m), 1.83-1.91 (1H, m), 1.99-2.06 (1H, m), 3.14-3.22 (1H, m), 3.32-3.51 (2H, m), 3.94-4.04 (1H, m), 4.33 (2H, s), 4.78-4.84 (1H, m), 7.15-7.18 (2H, m), 7.23 (1H, t), 7.36-7.44 (2H, m), 7.75-7.78 (2H, m), 7.80-7.90 (2H, m), 7.97 (1H, d), 8.26 (1H, d), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=2.20 (M+H 483.6).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=2)[N:16](COCC[Si](C)(C)C)[CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][CH:2]([CH3:38])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:21]=2)[NH:16][CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:5]
Reactant: CC(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Oc3ccccc3)nc12)C(=O)N1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](NC(=O)c1c[nH]c2ncc(Oc3ccccc3)nc12)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-methyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide from Step 3 in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.7 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was stirred with THF (1 mL), water (0.5 mL), and Et3N (0.5 mL) for 2 h then concentrated. The residue was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by SiO2 column chromatography (5% MeOH/CH2Cl2) to provide 0.049 g (46%, 2 steps) of 2-phenoxy-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-methyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a white foam. MS: 408 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:3]1.[O-]Cl.[Na+].Cl>C(O)(=O)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(O)CCC1CCC(O)CC1
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: O=C(O)CCC1CCC(=O)CC1
Temperature: 5 °C

Procedure:
To the resulting solution of 3-(4-hydroxycyclohexyl)propanoic acid was added RuCl3 (42 g) and acetic acid (5.6 Kg). After cooling to 5° C., aqueous NaOCl (10-13%, 26 Kg) was added slowly with stirring, maintaining the temperature at 5° C. After stirring a further 3 hours at 5° C., 3N HCl (20 L) and IPAc (15 L) were added, the layers were separated and the aqueous layer extracted with IPAc (2×20 L). The combined organics were washed with 2M aqueous NaHSO3 (10 L), dried (MgSO4), treated with charcoal and filtered. The resulting solution was concentrated, and the solvent switched to heptane:IPAc 2:1 (20 L). This solution was seeded and the solvent switched to 9:1 heptane:IPAc, giving the product as a white solid which was collected, washed with heptane and dried under nitrogen.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3([CH2:18][O:17]C[O:15][CH2:14]3)[CH2:12][N:11]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]([CH2:26][C:27]4[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=4)[C:21](=[O:36])[N:20]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]([CH2:26][C:27]4[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=4)[C:21](=[O:36])[N:20]=3)[CH2:12][C:13]2([CH2:18][OH:17])[CH2:14][OH:15])=[CH:6][CH:7]=1
Reactant: Cc1nc(N2CCC(c3ccc(F)cc3)C3(COCOC3)C2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(N2CCC(c3ccc(F)cc3)C(CO)(CO)C2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 32.6 %

Procedure:
To a 1,4-dioxane solution (500 μL) of 4-[11-(4-fluorophenyl)-2,4-dioxa-8-azaspiro[5.5]undecan-8-yl]-6-methyl-1-{[5-(trifluoro methyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (5.00 mg, 9.53 μmol) synthesized in Reference Synthesis Example 363, 12 M hydrochloric acid (500 μL) was added and the resultant mixture was stirred at 110° C. for 2 hours. To the resultant reaction solution, 12 M hydrochloric acid (500 μL) was added and the resultant mixture was stirred at 110° C. for 2.5 hours. After the completion of the reaction, to the reaction solution, saturated sodium carbonate aqueous solution was added and extraction with chloroform from the reaction solution was performed. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0→20/1) to obtain the title compound (1.59 mg, yield: 33%).
Reaction SMILES: [CH3:1][Li].CC1C=CC(S(O[CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])(=O)=O)=CC=1>CCOCC.C(Cl)Cl.[Cu]I>[CH2:14]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To copper(I) iodide (1.25 g, 6.55 mmol) in Et2O (25 mL) was added methyllithium (8.2 mL, 13.1 mmol) at 0° C. A solution of phenylmethyl(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (0.85 g, 2.182 mmol) in CH2Cl2 (4 mL) was added next, and the reaction mixture was stirred for 2 hours at 0° C. The reaction was quenched with saturated aqueous NH4Cl, and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 20% EtOAc/hexanes) afforded the title compound (230 mg, 45%) as a colorless oil. LC-MS (ES) m/z=234 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[N:46]=[CH:45][N:44]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:43]=2)=[CH:32][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:46]=[CH:45][N:44]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:43]=3)=[CH:34][CH:35]=2)[C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Examle 1, Step I) and 4-bromomethyl-2'-(1-triphenylmethyl-1,2,4-triazol-3-yl)-1,1'-biphenyl by the procedure described in Example 2, Step E.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:25])=[C:8](C(OC(C)(C)C)=O)[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH3:26][N:27]=[C:28]=[O:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:25][C:28]([NH:27][CH3:26])=[O:29])=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(F)c2)c(C(=O)OC(C)(C)C)c1N
Reactant: CN=C=O
Product: CCOC(=O)c1cn(-c2cccc(F)c2)cc1NC(=O)NC
Yield: 74 %

Procedure:
Following general method 4, employing 3-amino-1-(3-fluorophenyl)-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester and methyl isocyanate, afforded the title compound as a white solid (194 mg, 74%); LCMS (method B): RT=3.38 min, M+H+=306; 1H NMR (CDCl3, 300 MHz): 8.42 (s, 1H), 7.64 (d, J=2.7 Hz, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.39 (dt, J=8.2, 6.2 Hz, 1H), 7.24-7.20 (m, 1H), 7.15 (dt, J=9.9, 2.3 Hz, 1H), 6.99 (tdd, J=8.3, 2.4, 0.9 Hz, 1H), 4.71-4.65 (m, 1H), 4.31 (q, J=7.1 Hz, 2H), 2.90 (d, J=4.9 Hz, 3H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1OC
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(Cl)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,6-dichloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-chloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:9]=2)[CH:4]=1.C(OC)(OC)OC.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.[BH4-].[Na+].[Cl-].[NH4+]>CO>[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH2:36][NH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:9]=2)[CH:4]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCc1ccc2cc(CN)ccc2c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCc1ccc2cc(CNCc3ncc[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
The compound (67.5 mg) obtained in Example 124-4 was dissolved in anhydrous methanol (2.0 ml) and added with trimethyl orthoformate (0.0354 ml) and 2-imidazole carboxaldehyde (20.8 mg), followed by stirring at room temperature for 2 hours under a nitrogen atmosphere. Subsequently, the solution was added with sodium borohydride (12.3 mg) in an ice bath and then stirred at room temperature for 1 hour. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the solution, and the whole was stirred. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (39.0 mg) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14](=[O:19])C(F)(F)F)=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[OH-:20].[Na+].Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:19])=[O:20])=[CH:7][N:8]2[CH:11]([CH3:12])[CH3:13])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Product: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 110 °C
Yield: 99 %

Procedure:
A mixture of 1-(6-chloro-1-isopropyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (475 mg, 1.64 mmol) in a 20% aqueous sodium hydroxide solution was heated at 110° C. for 18 h. At this time, the reaction was cooled to 25° C. and treated with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (1×50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385 mg, 99%) as a yellow solid: mp 206-208° C.; EI-HRMS m/e calcd for C12H12ClNO2 (M+) 237.0056, found 237.0554.