Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)=[CH:34][C:33]=1[C:48]([F:51])([F:50])[F:49]>CN(C)C1C=CN=CC=1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([O:22][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:24]=2)=[O:40])=[CH:34][C:33]=1[C:48]([F:49])([F:50])[F:51]
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1OCCN1CCOCC1
Reactant: COc1ccc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Agent: CN(C)c1ccncc1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4ccc(OC)c(C(F)(F)F)c4)c3)ncnc2cc1OCCN1CCOCC1
Yield: 27 %

Procedure:
Using the procedure described in Example 230B 3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline (90 mg, 0.23 mmol) was reacted with phenyl 4-methoxy-3-(trifluoromethyl)phenylcarbamate described in Example 138A (99 mg, 0.32 mmol) and 4-(dimethylamino)pyridine (28 mg, 0.23 mmol) to give 1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea (38.72 mg, 27%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.92 (bs, 1H), 8.85 (bs, 1H), 8.56 (s, 1H), 7.60-7.51 (m, 3H), 7.43-7.35 (m, 2H), 7.26-7.19 (m, 2H), 6.92 (d, 1H), 4.33 (bs, 2H), 3.99 (s, 3H), 3.84 (s, 2H), 3.61 (s, 4H), 2.90-2.69 (m, 2H), 2.65-2.55 (m, 2H); LC-MS (ESI) m/z 614 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH2:8][C:9](OC)=[O:10])=[CH:4][CH:3]=1.[NH2:15][OH:16].CO[Na]>CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH2:8][C:9]([NH:15][OH:16])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CSCc1ccc(Cl)cc1
Reactant: NO
Agent: CO[Na]
Solvent: CO
Product: O=C(CSCc1ccc(Cl)cc1)NO

Procedure:
A solution of 0.15 mol of methyl p-chlorobenzylmercapto-acetate in 50 ml of methanol is mixed with a solution of 0.225 mol of hydroxylamine (base) and 0.15 mol of CH3ONa in 150 ml of methanol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[OH-].[Na+].[I:13]I>CO>[I:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:10])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: II
Reactant: Cc1cc(C=O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C=O)cc(I)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
At 5° C., to a stirred solution containing commercial 4-hydroxy-3-methylbenzaldehyde (4.65 g, 34.1 mmol) and sodium hydroxide (2.73 g, 68.25 mmol) in MeOH (171 mL) was added iodine (10.8 g, 42.7 mmol). The reaction was stirred for 16 h, eventually warming to ambient temperature. The reaction was quenched with 1N HCl (200 mL) and extracted with ether. The ethereal extracts were washed with 10% Na2S2O3 (3×), with brine (3×), dried (MgSO4) and concentrated. Purification on Biotage KP-Sil eluting with 70% CH2Cl2/pet. ether to give 7.28 g (81%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ2.30 (s, 3H), 7.65 (d, J=1.02 Hz, 1H), 8.09 (d, J=1.91 Hz, 1H), 9.74 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH2:13])=[S:12])=[CH:6][CH:5]=1.Br[CH2:17][C:18](=O)[C:19]([OH:21])=[O:20]>C(O)C>[F:15][C:2]([F:14])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[S:12][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[N:13]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)Nc1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: O=C(O)c1csc(Nc2ccc(OC(F)(F)F)cc2)n1
Temperature: 60 °C

Procedure:
A mixture of 12.9 g (54.6 mmol) [4-(trifluoromethoxy)phenyl]-thiourea, and 9.3 g (55.7 mmol) bromopyruvic acid in 70 ml ethanol was heated to 60° C. for 1 h. The precipitate was filtered off and washed with small portions of cold ethanol to yield after drying 8.9 g (53%) of the title compound as crystalline solid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccccc1

Procedure:
From benzyl alcohol (50 ml) and 5-amino-4-oxopentanoic acid hydrochloride (10.0 g; 60 mmol). After 23 h at 900, excess benzyl alcohol was distilled off at 900 (bath temperature) and 0.33 mm Hg. The yield was 8.1 g (53%) of tan powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=O)[NH:7]2.Cl.Cl.Cl.[N:18]1([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:18]1([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=4)=[O:14])[CH2:31][CH2:32]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cccc2[nH]c(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
A solution of 4-Methoxy-1H-indole-2-carboxylic acid (930 mg, 4.86 mmol), amine 5 (1.63 g, 4.86 mmol) and DIEA (2.5 ml, 14.58 mmol) in 20 ml of DMF is treated with solid TBTU (1.56 g, 4.86 mmol). The mixture is stirred over night and then evaporated. The crude residue is dissolved in EtOAc and washed twice with sodium bicarbonate (10%). The aqueous layers are re-extracted with DCM, the combined organic layers are washed with brine and dried over sodium sulfate. The crude product is then purified by chromatography on silicagel using DCM (saturated with ammonia) and MeOH (from 0% to 2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:26]=[C:15]3[C:16]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:27]([O-])(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:26]=[C:15]3[C:16]([N:20]4[CH2:25][CH2:24][N:23]([C:27](=[O:29])[CH3:28])[CH2:22][CH2:21]4)=[N:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CC(=O)[O-]
Reactant: COc1cc(Nc2nc3c(N4CCNCC4)nccn3n2)cc(OC)c1
Product: COc1cc(Nc2nc3c(N4CCN(C(C)=O)CC4)nccn3n2)cc(OC)c1

Procedure:
N-(3,5-dimethoxyphenyl)-8-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-2-amine (synthesized as described earlier) is converted into the acetate using standard conditions.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[F:20])[C:6]1=[S:21])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CO>[CH2:1]([N:5]1[CH2:9][CH:8]([OH:10])[N:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[F:20])[C:6]1=[S:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC(=O)N(c2cc(OC)c(Cl)cc2F)C1=S
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCN1CC(O)N(c2cc(OC)c(Cl)cc2F)C1=S
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
33.3 g (0.10 mol) of 1-butyl-3-(4-chloro-2-fluoro-5-methoxyphenyl)-4-oxo-2-thioxoimidazolidine are dissolved in 300 ml of methanol, and 5.7 g (0.15 mol) of sodium borohydride are added at a rate such that the temperature increases to 30° C. When the addition is complete, the mixture is stirred for a further 30 minutes at 30° C. and poured into 800 ml of ice-water. The precipitate is filtered off under suction and dried. 31.8 g (95% of theory) of 1-butyl-3-(4-chloro-2-fluoro-5-methoxyphenyl)-4-hydroxyimidazolidine 2-thione are obtained in the form of colorless crystals having the melting point 137°-138° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>[Ni].N>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Agent: [Ni]
Agent: N
Product: CCOC(=O)N1CCN(C(=O)c2cc(O)cc(Oc3ccc(CN)cc3)c2)CC1
Yield: 79.5 %

Procedure:
Raney nickel (0.1 g, 1.7 mmols) was added to a stirred solution of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]piperazine-1-carboxylic acid ethyl ester (0.5 g, 1.26 mmols) dissolved in methanolic ammonia (50 ml) and the reaction mixture was heated to 50° C. in Paar apparatus under 50 Psi hydrogen gas pressure for 3 h. The reaction mixture was cooled and filtered through celite pad. The filtrate was concentrated to afford 0.4 g of the required product which was used for the next step without further purification. Percentage purity (LCMS): 74.3%, (M+1)=399.1+1.
Reaction SMILES: [O:1]=[C:2]1[NH:17][C:6]2[N:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH:15]=O)[N:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1.Cl.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:8]2[N:9]=[CH:10][C:5]3[CH:4]=[CH:3][C:2](=[O:1])[NH:17][C:6]=3[N:7]=2)[CH2:29][CH2:28]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=CCCCOc1ncc2ccc(=O)[nH]c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: O=c1ccc2cnc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde (235 mg, 1.01 mmol) in dichloroethane (5 mL) was added 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (270 mg, 1.01 mmol) followed by Et3N (0.28 mL, 2.0 mmol, 2 equiv). After 10 min at RT, NaBH(OAc)3 (297 mg, 1.4 mmol) was added as a powder. The reaction was stirred for 2 h at room temperature and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc (with a little MeOH to help dissolve the solids). The organic layer was washed with brine and concentrated. Purification by liquid chromatography (5% MeOH/CH2Cl2 with 1% NH4OH) gave the title compound as a white solid (375 mg, 0.836 mmol, 83%). MS: APCI: M+1: 448.1 (Exact Mass: 447.12).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: CC(C)(C)CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 27.6 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 4,4-dimethylpentylamine (0.317 g, 2.75 mmol) and 3 Å molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.248 g, 28%): TOF MS ES+ 360.2 (M+H)+, HRMS calcd for C20H27N3O2F 360.2087 (M+H)+, found 360.2076, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.3 min, 98.2% purity.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:41]=[CH:40][C:33]4[O:34][C:35]([CH3:39])([CH3:38])[O:36][CH2:37][C:32]=4[CH:31]=3)[OH:29])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:41]=[CH:40][C:33]4[O:34][C:35]([CH3:38])([CH3:39])[O:36][CH2:37][C:32]=4[CH:31]=3)[OH:29])=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCC#Cc3ccc(S(=O)(=O)C4CCCC4)cc3)ccc2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3ccc(S(=O)(=O)C4CCCC4)cc3)ccc2O1
Yield: 50.8 %

Procedure:
A solution of (1R)-2-{[6-({4-[4-(cyclopentylsulfonyl)phenyl]but-3-ynyl}oxy)hexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (127 mg) in EtOAc (10 ml) was hydrogenated over a palladium on carbon catalyst (50% water by weight, 6.35 mg) for 19 h. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residual oil was purified on a silica bond elut SPE cartridge (5 g), gradient 0% to 20% [MeOH-aqueous ammonia(10:1)] in DCM (Gradmaster™). The appropriate fractions were evaporated to give the title compound (65 mg) LCMS RT=2.85 min
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31][CH2:32][CH2:33][CH2:34][CH2:35]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:35][CH2:34][CH2:33][CH2:32][S:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)=[CH:7][CH:6]=1
Reactant: OCCCCSc1ccc2ccccc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCSc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate prepared from 4-(2-naphthylthio)butanol (1.55 g). The mixture was stirred and heated under argon at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 3:1) and crystallized from diethyl etherhexane to provide 0.625 g of 4-[[4-(2-naphthalenylthio)butyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 64°-65° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17](OC)=[O:18])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)CN(Cc1ccccc1)C2
Yield: 99 %

Procedure:
Methyl 2-benzyl-2,3-dihydro-1H-isoindole-5-carboxylate (from above) was dissolved in anhydrous tetrahydrofuran (75 ml) and added dropwise over 15 minutes to a rapidly stirred suspension of lithium aluminium hydride (1.71 g, 45.0 mmol) in anhydrous tetrahydrofuran (75 ml). The mixture was stirred at room temperature for 2 hours whereupon excess lithium aluminium hydride was destroyed by the slow dropwise addition of 1M sodium sulphate solution (12 ml). The solids were removed by filtration, rinsed with ethyl acetate (2×50 ml) and sucked dry. The solvent was removed in vacuo to afford (2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-methanol (7.15 g, 99%) as a tan solid. 1H NMR (DMSO-d6) 7.40-7.30 (4H, m), 7.28 (1H, m), 7.17-7.10 (3H, m), 5.10 (1H, t), 4.47 (2H, d), 3.85 (2H, s), 3.82 (2H, s), 3.80 (2H, s). MS: [M+H]+ 240.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:54]=[CH:53][C:6]2[N:7]=[C:8]([S:10]([C:13]3[CH:35]=[CH:34][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:20])=[C:15]([O:36][CH2:37][C:38]([O:40][CH2:41][CH2:42][S:43]([C:46]4[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=4)(=[O:45])=[O:44])=[O:39])[CH:14]=3)(=[O:12])=[O:11])[NH:9][C:5]=2[C:4]=1[S:55][CH2:56][C:57]1[C:62]([CH3:63])=[C:61]([O:64][CH3:65])[C:60]([CH3:66])=[CH:59][N:58]=1.ClC1C=C(C=CC=1)C(OO)=[O:72].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:54]=[CH:53][C:6]2[N:7]=[C:8]([S:10]([C:13]3[CH:35]=[CH:34][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)(=[O:25])=[O:26])=[O:20])=[C:15]([O:36][CH2:37][C:38]([O:40][CH2:41][CH2:42][S:43]([C:46]4[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=4)(=[O:44])=[O:45])=[O:39])[CH:14]=3)(=[O:12])=[O:11])[NH:9][C:5]=2[C:4]=1[S:55]([CH2:56][C:57]1[C:62]([CH3:63])=[C:61]([O:64][CH3:65])[C:60]([CH3:66])=[CH:59][N:58]=1)=[O:72]
Reactant: COc1ccc2nc(S(=O)(=O)c3ccc(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c3)[nH]c2c1SCc1ncc(C)c(OC)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2nc(S(=O)(=O)c3ccc(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c3)[nH]c2c1S(=O)Cc1ncc(C)c(OC)c1C
Reaction time: 0.67 h

Procedure:
2-(4-Tolylsulfonyl)ethyl 4-[{5-methoxy-([4-methoxy-3,5-dimethyl(2-pyridyl)]methylthio)benzimidazolyl}sulfonyl]-2-(2-[4-tolylsulfonyl]ethoxycarbonylmethoxy)phenoxyacetate (Intermediate A20, 4.8 g, 0.0054 mol) was dissolved in 20 mL of tetrahydrofuran, and the solution was left in a freezer for 40 min. A solution of 3-chloroperoxybenzoic acid (1.3 g, 0.0075 mol) in 6 mL of tetrahydrofuran was cooled for 30 min. The two were combined and left in the freezer for 16 hr. The mixture was then poured into a rapidly stirring mixture of 5% aqueous sodium metabisulfite and ethyl acetate. The layers were separated, and the organic layer was washed with 2 portions of 2.5% aqueous sodium bicarbonate and with saturated aqueous sodium chloride. The solution was filtered through 1PS paper and concentrated at aspirator pressure. The residue was separated on a column of flash silica gel (2:1 ethyl acetate:hexanes→ethyl acetate)to yield 2.0 g (41%) of the title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[N:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=1[C:16]([OH:18])=O.[NH2:24][C:25]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:13][C:14]1[N:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=1[C:16]([NH:24][C:25]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:18]
Reactant: NC1(CO)CCCC1
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NC1(CO)CCCC1)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
Carbonyldiimidazole (254 mg, 1.57 mmol) was added to a suspension of 2-chloro-5-fluoro-nicotinic acid (250 mg, 1.42 mmol) in dichloromethane (10 ml) under nitrogen at room temperature. The resulting solution was stirred for 15 min after which a solution of (1-amino-cyclopentyl)-methanol (197 mg, 1.71 mmol) and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in dichloromethane (5 ml) was added. The reaction was stirred at room temperature for 18 h then diluted with dichloromethane (20 mls) and washed with sat. ammonium chloride solution (20 ml). The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with dichloromethane (5 ml) to give 2-Chloro-5-fluoro-N-(1-hydroxymethyl-cyclopentyl)-nicotinamide (100 mg) as white solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:29]1([C:35]([NH:37][NH2:38])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([NH:38][NH:37][C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:36])=[O:28])[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NNC(=O)c1ccccc1
Product: O=C(NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)c1ccccc1

Procedure:
100 mg (0.25 mmol) of the compound from Example 44A and 65 mg (0.50 mmol) of benzenecarbohydrazide were reacted according to the General Method 11A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:18][O:19][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:10][C:9]3=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:37][C@H:38]2[CH2:42][CH2:41][CH2:40][O:39]2)(=O)=O)=CC=1>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:18][O:19][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:37][C@H:38]1[CH2:42][CH2:41][CH2:40][O:39]1)[C:9]3=[O:17]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(Br)ccc12
Yield: 101.7 %

Procedure:
To a stirred solution of 6-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.3 g, 4.3 mmol) in 2-butanone (40.0 mL) was added cesium carbonate (4.2 g, 12.9 mmol) and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (1.4 g, 5.4 mmol). The reaction was refluxed for 16 h, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with 25% ethyl acetate in hexanes to afford 6-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.75 g, 100%) as a colorless solid: MS (ES+) m/z 400.0 (M+1), 402.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C:26]1([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:29][CH2:28][CH2:27]1)[C:9]1[N:14]=[N:13][C:12]([CH:15]2[N:19]=[C:18]([O:20][CH3:21])[CH:17]([C:22](O)=[O:23])[S:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>C(OCC)(=O)C.CN1C(=O)CCC1>[C:22]([CH:17]1[S:16][CH:15]([C:12]2[N:13]=[N:14][C:9]([N:8]([CH2:25][C:26]3([C:30]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:27][CH2:28][CH2:29]3)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:11]=2)[N:19]=[C:18]1[O:20][CH3:21])(=[O:23])[NH2:38]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC1=NC(c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)SC1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC1=NC(c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)SC1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a 50 dram vial was added 2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5-carboxylic acid (175 mg, 0.34 mmol), HATU (194 mg, 0.51 mmol), HOAt (70 mg, 0.51 mmol), DIPEA (296 μL, 1.7 mmol), NMP (2 mL), and ammonium chloride (180 mg, 3.4 mmol). The reaction was stirred overnight at rt. The reaction was then poured into ethyl acetate (50 mL), washed with aqueous sodium bicarbonate, and brine (50 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EtOAC/hexanes) to afford 120 mg of t-butyl 6-(5-carbamoyl-4-methoxy-2,5-dihydrothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.