Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH:13]=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[F:15][C:16]1[CH:21]=[C:20]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]3[CH2:31][CH2:30][CH2:29][C@@H:28]3[CH3:32])[CH2:23]2)[CH:19]=[CH:18][C:17]=1[NH2:33].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH2:13][NH:33][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[CH2:23]3)=[CH:21][C:16]=2[F:15])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(CCC=O)CCOCC1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc(N)c(F)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)C1(CCCNc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)cc2F)CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(3-Oxo-propyl)tetrahydro-pyran-4-carboxylic acid methyl ester (135 mg, 0.515 mmol, 1 eq) was dissolved in 2.4 mL of 1,2-dichloroethane. To this was added 2-Fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine (103 mg, 0.515 mmol, 1 eq) in 6.2 mL of 1,2-dichloroethane. To the combined mixture was added glacial acetic acid (96 mg, 1.6 mmol, 3.1 eq) followed by NaBH(OAc)3 (330 mg, 1.55 mmol, 3 eq). The reaction mixture was stirred at rt for 15 h. The reaction mixture was quenched with water, transferred to a separatory funnel and extracted with CH-2Cl2 (2×100 mL). The combined organics were dried over Na2SO4, concentrated under vacuum and purified by column chromatography on silica gel (40 g column, 6% MeOH in CH2Cl2; 35 mL/min). This gave 130 mg (61%) of the title compound as a beige semi-solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH:31]=O.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH:31]=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: O=CCCc1ccccc1F
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCc2ccccc2F)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 609 mg (4.0 mmol) of 3-(2-fluorophenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 4.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.11 g (81.5%, yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1Cl
Yield: 36.4 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and 2-chlorobenzoyl chloride (Aldrich, 0.26 g, 1.4 mmol) in 15 mL THF were processed as in Example 132 to afford the title compound (0.13 g, 0.40 mmol, 37% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.28 (s, 3H), 2.32 (s, 3H), 3.31 (s, 3H), 3.76 (t, J=5.3 Hz, 2H), 4.42 (t, J=5.1 Hz, 2H), 7.30-7.46 (m, 3H), 7.77-7.83 (m, 1H); MS (DCI/NH3) m/z 325 (M+H)+; Anal. calculated for C15H17ClN2O2S: C, 55.46; H, 5.28; N, 8.62. Found: C, 55.59; H, 4.81; N, 8.47.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH:24](/B(O)O)=[CH:25]/[CH3:26]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][C:11]1[S:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=1[C:6]1[N:5]([CH3:17])[N:4]=[CH:3][C:2]=1/[CH:24]=[CH:25]\[CH3:26]
Reactant: C/C=C\B(O)O
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C/C=C\c1cnn(C)c1-c1cc(C(=O)OC)sc1C
Yield: 87.1 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (320 mg, 1.015 mmol)[prepared in Example 99], potassium carbonate (702 mg, 5.08 mmol), bis(tri-t-butylphosphine)palladium(0) (25.9 mg, 0.05 mmol) and (1Z)-1-propen-1-ylboronic acid (87 mg, 1.01 mmol) in 1,4-dioxane (5.3 ml) and water (1.3 ml) was stirred at 80° C. in a sealed tube for 12 h. The reaction contents were partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-methyl-4-{1-methyl-4-[(1Z)-1-propen-1-yl]-1H-pyrazol-5-yl}-2-thiophenecarboxylate (243 mg, 0.88 mmol, 87% yield) as a yellow oil: LCMS (ES) m/z=277 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH:28]3[CH2:33][CH2:32][N:31]([CH:34]([CH3:38])[CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]3)[CH2:18][C:19]3[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=3[F:27])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH3:40][C:41]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:42]=1[C:43](O)=[O:44]>>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([F:27])=[C:19]([CH:24]=1)[CH2:18][N:17]([CH:28]1[CH2:33][CH2:32][N:31]([CH:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:43](=[O:44])[C:42]2[C:46]([CH3:50])=[CH:47][CH:48]=[CH:49][C:41]=2[CH3:40])[CH2:30][CH2:29]1)[C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:39])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)#[N:26]
Reactant: COC(=O)c1ccc(Oc2ccc(N(Cc3cc(C#N)ccc3F)C3CCN(C(C)CCN)CC3)cc2)cc1
Reactant: Cc1cccc(C)c1C(=O)O
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
Using general procedure E with 4-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-cyano-2-fluoro-benzyl)-amino]-phenoxy}-benzoic acid methyl ester (see EXAMPLE 228) (90 mg, 0.17 mmol) and 2,6-dimethylbenzoic acid (29 mg, 0.19 mmol) followed by general procedure K with the resulting ester afforded COMPOUND 229 as a white solid (58 mg, 53% over 2 steps). 1H NMR (CDCl3) δ 1.06-1.16 (m, 3H), 1.53-1.69 (m, 1H), 1.78-2.04 (m, 3H), 2.28 (s, 6H), 2.32-2.45 (m, 1H), 2.63-2.75 (m, 1H), 2.92-3.18 (m, 3H), 3.29-3.45 (m, 2H), 3.57-3.82 (m, 3H), 4.11 (s, 2H), 6.58-6.65 (m, 2H), 6.82-7.03 (m, 7H), 7.12-7.21 (m, 1H), 7.50-7.85 (m, 2H), 7.79-8.01 (m, 3H). 13C NMR (CDCl3) δ 11.81, 18.19, 26.45, 27.05, 30.35, 36.88, 42.30, 43.32, 49.61, 55.06, 57.96, 107.47, 114.99, 115.37, 115.81, 117.29, 120.17, 125.91, 126.28, 127.40, 128.17 (d, J=15 Hz), 130.59, 131.94, 132.92, 136.93, 143.59, 147.04, 160.57, 161.58 (d, J=256 Hz), 169.66, 170.16. ES-MS m/z 649 (M+H). Anal. Calcd. for C39H41N4O4F.0.9CH2Cl2: C, 66.08; H, 5.95; N, 7.73; F, 2.62. Found: C, 66.11; H, 6.08; N, 7.64; F, 2.48.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](OC(=O)C)(=[O:11])C>C(O)=O>[CH:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: O=CO
Product: O=CN1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5.0 g (0.0434 mol) of L-proline in 92 ml of 97% formic acid maintained at 5°-10° was slowly added 30 ml of acetic anhydride. The solution was stirred for 2 hr. at room temperature followed by the addition of 35 ml of ice-cold water. Evaporation of the mixture afforded (S)-(-)-N-formylproline ([α]D2: =-105°, c=2.885, methanol), a clear, viscous, pale-yellow oil utilized directly in the next step. The (S)-(-)-N-formylproline was reduced by adding a solution of it in 20 ml of tetrahydrofuran to a slurry of 8.23 g (0.217 mol) of lithium aluminum hydride in 125 ml of tetrahydrofuran under a nitrogen atmosphere. The addition was regulated such that a gentle reflux was maintained. Following addition, the mixture was refluxed for 48 hr. After cooling, the mixture was carefully treated with 8.3 ml of water, followed by 8.3 ml of 15% aq. sodium hydroxide, and finally 25 ml of water. The grey-white mixture was filtered, and the filtrate dried with magnesium sulfate and evaporated to an oil. Bulb to bulb distillation [oven temp 40°-55° (0.15 torr)] afforded 2.823 g of V (57% yield based on L-proline). The optical rotation was identical with that obtained by the synthesis via L-prolinol.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[N:25]([C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:24][CH2:23]2
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 102-104° C.; 1H NMR (300 MHz, CDCl3): δ 7.00 (s, 1 H), 6.92 (d, J=2.5 Hz, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 4.99-4.90 (m, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.67 (dd, J=10.6, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.35 (s, 3 H), 3.10 (t, J=7.9 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (CI) calcd for C18H22N3O3BrCl (M+H)+: 442.0533; found m/z 442.0532.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(#N)C>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C)C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21

Procedure:
A mixture of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.64 g), acetonitrile (20 ml), potassium carbonate (0.6 g) and ethyl bromoacetate (0.44 ml) is refluxed for 3 hours. The reaction solution is concentrated and water is added to the resulting residue, and the mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1), and recrystallized from ethyl acetate/petroleum ether to give 5-(N-methyl-N-ethoxycarbonylmethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.82 g) as colorless prisms, m.p. 167°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:37])=[C:17]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20]2)[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:37])=[C:17]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20]2)[CH:18]=1)=[O:6]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cc(F)cc(F)c2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Yield: 97.1 %

Procedure:
3,5-Difluorobenzoyl chloride (0.91 g) was added to a stirred mixture of 3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one (1.5 g), triethylamine (1.04 g) and methylene chloride (50 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution and the organic phase was evaporated. There was thus obtained the title compound (2.04 g); NMR Spectrum: (DMSOd6) 2.05 (s, 3H), 2.22 (s, 3H), 2.45-2.5 (m, 4H), 3.24-3.3 (m, 4H), 7.41-7.56 (m, 3H), 7.61-7.68 (m, 4H), 7.75-7.79 (m, 2H), 8.06 (s, 1H), 10.5 (s, 1H); Mass Spectrum: M+H+ 490.
Reaction SMILES: [N+](C1C=CC([C:10]2[CH:22]=[C:21]([C:23]([O-:25])=O)[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:26])[CH:18]=4)[N:13]([CH3:27])[C:12]=3[C:11]=2[O:28][CH3:29])=CC=1)([O-])=O.[Cl:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([Cl:38])[C:36]=1[NH2:37].[H-].[Na+]>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([Cl:38])[C:36]=1[NH:37][C:23]([C:21]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:26])[CH:18]=3)[N:13]([CH3:27])[C:12]=2[C:11]([O:28][CH3:29])=[CH:10][CH:22]=1)=[O:25]
Reactant: COc1c(-c2ccc([N+](=O)[O-])cc2)cc(C(=O)[O-])c2c3cc(Cl)ccc3n(C)c12
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(Cl)ccc3n(C)c12
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 4-nitrophenyl-6-chloro-1-methoxy-9-methyl-9H-4-carbazole carboxylate (160 mg, 0.4255 mmoles), and 3,5-dichloro-4-amino pyridine (69.36 mg, 0.4255 mmoles) in dry DMF (7 mL) at 25° C., sodium hydride 55% (34 mg, 0.8510 mmoles) was added and stirred under nitrogen atmosphere for 1 hr. The reaction mixture was quenched in ice cold water (25 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with bicarbonate (2×25 mL), followed by 1N HCl (2×25 mL) and with brine (25 mL), dried over sodium sulphate and concentrated to give the 90 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].[F:15][C:16]([F:24])([F:23])[C:17]([C:19]([F:22])([F:21])[F:20])=[O:18].Cl>C1(C)C=CC=CC=1>[F:15][C:16]([F:24])([F:23])[C:17]([C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([OH:10])=[C:3]([O:2][CH3:1])[CH:8]=1)([OH:18])[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: COc1cccc(C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1O

Procedure:
To 2-methoxy-6-methylphenol (27.6 g=0.20 mol) in 300 ml toluene, add aluminum chloride (4.0 g=30 mmol). Bubble in hexafluoroacetone (47 g=0.28 mol) over 7 hours. Heat the reaction mixture in a steel bomb 16 hours at 120° C. Cool, and pour the contents onto 1.0 N HCl. Extract with ether. Wash the ether layer with 1.0 N NaOH. Acidify the basic aqueous layer with concentrated HCl, extract with ether, dry, concentrate and distill to obtain a fraction boiling at 71°-74° C./0.1 mm. Crystallize from cold hexane to obtain, as a solid, m.p. 44°-45° C., 4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-6-methylphenol.
Reaction SMILES: Cl.Cl.[OH:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH:17]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[F:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH2:19][CH2:18]1>CS(C)=O>[CH:17]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27]([N:7]4[CH2:8][CH2:9][N:4]([OH:3])[CH2:5][CH2:6]4)[C:28]=3[F:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH2:18][CH2:19]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: ON1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCN(O)CC3)c(F)cc2c1=O
Temperature: 130 °C
Yield: 71.3 %

Procedure:
1-Hydroxypiperazine dihydrochloride (4.64 g), triethylamine (8.9 g) and dimethylsulfoxide (25 ml) are added to 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (5.0 g), which is prepared according to the procidures described in Japanese Patent First Publication No. 212474/1984, and the mixture is stirred with heating at 130° C. for 45 minutes. After cooling of the mixture to room temperature, the resulting crystals are filtered. To the crystals is added water (20 ml) and the mixture is stirred at 50° C. for 1 hour. The insoluble substance is filtered and recrystallized from a mixture of dimethylformamide and water to afford 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (4.6 g) as pale yellow prisms, m.p. 223°-227° C. (decomposed with foaming).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)NC1Cc2ccccc2C1
Product: CC(=O)NC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 0 °C

Procedure:
18.5 g. of the acetamide (0.105 mole) was added in portions to nitric acid (185 ml.; d=1.51), stirred and maintained below 0° C. The reaction was allowed to warm to 0° C., poured onto crushed ice and extracted with chloroform which was washed with 5% aqueous sodium bicarbonate and evaporated to give crude N-acetyl-5-nitro-2-indanamine which was purified by crystallization from isopropanol, m.p. 143°-144° C.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)C>[OH-].[Na+]>[NH:15]([C:8]1[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[CH:6][C:7]=1[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cc(NCc2ccccc2)c(Nc2ccccc2)c(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Nc1ccccc1

Procedure:
A solution of ethyl-4-anilino-3-benzylamino-5-sulphamyl-benzoate (1 g) in 1N sodium hydroxide (15 ml) was heated on a steam bath for 1 hour. After cooling, the 4-anilino-3-benzylamino-5-sulphamyl-benzoic acid was precipitated by addition of acetic acid, collected and recrystallized from 6% ethanol in water. The melting point was 248°-249°C.
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][NH:2]1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:2]2[CH2:3][CH:4]3[CH2:8][CH2:7][CH2:6][CH:5]3[CH:1]2[CH2:9][OH:10])=[O:34])=[CH:25][CH:26]=1
Reactant: OCC1NCC2CCCC21
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CC3CCCC3C2CO)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the carbamate above in CH2Cl2 was added TFA (1:1 v/v). The reaction was stirred at rt for 30 min before being concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHCO3, brine, dried (MgSO4), and concentrated to afford (octahydrocyclopenta[c]pyrrol-1-yl)methanol as a pale yellow oil. To a solution of (octahydrocyclopenta[c]pyrrol-1-yl)methanol (1 eq) in DMF was added DIPEA (2 eq) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (1.5 eq) and HATU (2 eq). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a clear oil. MS (ESI) 361.1 (M+H)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:13]2[CH:22]=[CH:21][N:20](S(C3C=CC(C)=CC=3)(=O)=O)[C:14]=2[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[OH:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[O:41][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:13]2[CH:22]=[CH:21][NH:20][C:14]=2[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(S(C)(=O)=O)ccc4F)cn(C)c(=O)c32)cc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Yield: 80 %

Procedure:
A mixture of Example 138a (0.05 g, 0.105 mmol), 2,4-difluorophenol (0.016 g, 0.126 mmol), and cesium carbonate (0.069 g, 0.211 mmol) in DMSO (1 mL) was heated at 120° C. for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase Preparative HPLC (10-80% acetonitrile in 0.1% TFA/water) to give the title compound (0.036 g, 0.084 mmol, 79% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 7.99 (d, J=2.44 Hz, 1H), 7.86 (dd, J=8.54, 2.44 Hz, 1H), 7.40-7.56 (m, 3H), 7.31 (t, J=2.9 Hz, 1H), 7.14-7.20 (m, 1H), 6.98 (d, J=8.54 Hz, 1H), 6.28-6.30 (m, 1H), 3.59 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 431.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5](I)=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>[Pd].[Cu]I.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.CN(C=O)C.CCN(CC)CC>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc(I)cn1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(Br)cn1

Procedure:
Reaction of a mixture of 2-bromo-5-iodo-pyrazine and copper (I) iodide under inert conditions in an appropriate solvent and base e.g. DMF/Et3N with ethynyl-trimethyl-silane using a palladium catalyst e.g. Pd(PPh3)4 at room temperature gives 2-Bromo-5-trimethylsilanylethynyl-pyrazine. This material can be used without further purification and reacted to form 6-bromo-2-trimethylsilanyl-pyrazolo[1,5-a]pyrazine using O-(mesitylenesulfonyl)hydroxylamine to form the N-amino adduct. This can then be cyclised by reacting with base e.g. K2CO3 to form pyrazolopyrazine core (Scheme 6).