Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:12])([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:2][CH2:3]Cl.[C:13]([NH:16][C:17]1[C:18]([I:33])=[C:19]([N:28]([C:30](=[O:32])[CH3:31])[CH3:29])[C:20]([I:27])=[C:21]([C:24]([O-:26])=[O:25])[C:22]=1[I:23])(=[O:15])[CH3:14].[K+].[I-].[Na+]>CN(C=O)C>[C:13]([NH:16][C:17]1[C:18]([I:33])=[C:19]([N:28]([C:30](=[O:32])[CH3:31])[CH3:29])[C:20]([I:27])=[C:21]([C:24]([O:26][CH2:3][O:2][C:1]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:12])=[O:25])[C:22]=1[I:23])(=[O:15])[CH3:14]
Reactant: O=C(OCCl)Oc1ccccc1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OCOC(=O)Oc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Chloromethyl phenyl carbonate (0.50 g, 2.7 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (1.62 g, 2.4 mmol) and sodium iodide (0.038 g, 0.25 mmol) in dry DMF (15 ml). After stirring at 50° C. for 5 hours and at room temperature for 18 hours the solvent was removed at reduced pressure. The residue was suspended in chloroform (25 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 0.67 g Purity by HPLC: 99.2% 1H-NMR(DMSO-d6): delta=1.68 (NCH3COCH3); 2.06 (NHCOCH3); 2.97 (NCH3); 6.08 (CH2); 7.28-7.49 (phenyl); 10.14 ppm (NH). FAB/MS: 779 ((M+H)+).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].C1C[O:24][CH2:23][CH2:22]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:23]([NH:2][C:3]([CH3:20])([CH:17]([CH3:18])[CH3:19])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5])(=[O:24])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2-Amino-2,3-dimethyl-N-(p-tolylsulfonyl) butyramide hydrochloride (45 g -0.4 mols) is completely dissolved in 160 mL of pyridine and 500 mL of THF is added. Acetic anhydride (45 mL) is then poured into the solution and the reaction mixture is heated at reflux for one hour. The solvents are removed under reduced pressure, and the oily residue is crystallized from EtOH/water affording 33.09 g of the title product having m.p. 198°-199° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:10]([CH3:11])[CH2:9][N:8]([C:12]2[S:13][C:14]([Br:17])=[CH:15][N:16]=2)[CH2:7][CH:6]1[CH3:18].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)C>O1CCCC1>[Br:17][C:14]1[S:13][C:12]([N:8]2[CH2:7][CH:6]([CH3:18])[N:5]([CH2:4][CH2:3][OH:2])[CH:10]([CH3:11])[CH2:9]2)=[N:16][CH:15]=1
Reactant: COC(=O)CN1C(C)CN(c2ncc(Br)s2)CC1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CN(c2ncc(Br)s2)CC(C)N1CCO
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 71.4 %

Procedure:
To a solution of [4-(5-bromothiazole-2-yl)-2,6-dimethyl piperazine-1-yl]acetic acid methyl ester (20.1 g) in tetrahydrofuran (300 mL) was added dropwise diisobutyl aluminium hydride (1M toluene solution, 200 mL) at −78° C. The mixture was stirred at −78° C. for 3.5 hours. To the reaction solution were added aqueous ammonium chloride solution (150 mL) and diethyl ether (45 mL). The insoluble material was filtrated. The filtrate was extracted diethyl ether. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel to give the title compound (13.2 g). Yield: 71%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[C:26]([F:27])=[CH:25][C:21]([C:22](O)=O)=[C:20]([O:28][CH3:29])[CH:19]=1>>[F:17][C:18]1[C:26]([F:27])=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: COc1cc(F)c(F)cc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 49 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 4,5-difluoro-2-methoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 0:80:20, 168 mg, 49%) which was obtained as a white solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10](O)[C:11]1[CH:12]=[C:13]([C:18]2([O:48][C@H:47]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C@@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:20]2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)O)[CH:14]=[CH:15][C:16]=1[F:17].C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]1[CH:12]=[C:13]([C@@H:18]2[O:48][C@H:47]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C@@H:38]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@H:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:20]2[O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: OC(c1cc2ccccc2s1)c1cc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1F
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1cc2ccccc2s1
Temperature: -20 °C
Reaction time: 5 h
Yield: 31.3 %

Procedure:
To an acetonitrile (5.0 ml) solution of 1-C-{3-[1-benzothien-2-yl(hydroxy)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-benzyl-D-glucopyranose (500 mg) were added triethylsilane (175 mg) and boron trifluoride-diethyl ether complex (196 mg) in an argon atmosphere at −20° C., followed by stirring at −20° C. for 5 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol (150 mg, yield: 30.2%)
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17](Cl)[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:27])[CH:19]=2)=[CH:12][CH:11]=1.[C:29]([NH:33][NH2:34])(=O)[CH2:30][CH3:31]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.O>[CH2:30]([C:29]1[N:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[C:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:27])[CH:19]=2)=[N:34][N:33]=1)[CH3:31]
Reactant: CCC(=O)NN
Reactant: COc1ccc(N=C(Cl)c2ccc([N+](=O)[O-])c(C)c2)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1nnc(-c2ccc([N+](=O)[O-])c(C)c2)n1-c1ccc(OC)cc1
Yield: 90.1 %

Procedure:
1.4 ml of triethylamine, then 3 g of the product of Step B were introduced into a solution of 1.76 g of propionic acid hydrazide in 160 ml of toluene, this latter having been brought to reflux and then cooled. After refluxing for 1 hour, the toluene was eliminated under reduced pressure and the residue was taken up in 50 ml of chloroform and 50 ml of water. The aqueous phase was extracted with chloroform and the organic extracts were dried and concentrated to obtain an oil which was purified by chromatography on silica and elution with ethyl acetate and cyclohexane (8-2) to obtain 3 g of 3-ethyl-4-(4-methoxyphenyl)-5-(4-nitro-3-methylphenyl)-4H-1,2,4-triazole in the form of an oil which had an Rf of 0.6 on thin film chromatography (eluent:chloroformethanol 9-1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)[C:11](=[O:20])[CH:10]=1.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:19])[C:16]([NH:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:24][CH:23]=2)=[O:18])[C:11](=[O:20])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2Br)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
153 mg (purity 93%, 0.4 mmol) of 2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 96 mg (44% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Si]([O:30][C@@H:31]1[CH2:36][CH2:35][C@H:34]([N:37]2[C:41]([CH3:42])=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:39]=[N:38]2)[CH2:33][CH2:32]1)(C(C)(C)C)(C)C.C([O-])([O-])=O.[K+].[K+].O.Cl>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.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:40]3[CH:39]=[N:38][N:37]([C@@H:34]4[CH2:35][CH2:36][C@H:31]([OH:30])[CH2:32][CH2:33]4)[C:41]=3[CH3:42])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@@H](O)CC4)c3C)cc12
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (200.0 mg, 0.5213 mmol), 1-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (328.8 mg, 0.7820 mmol), Pd(PPh3)4 (30.12 mg, 0.02606 mmol), K2CO3 (216.1 mg, 1.564 mmol) and 4:1 dioxane:H2O (10 mL, 100 mmol) was heated to 95° C. for 2 h. The solution was cooled to rt, and 12 M of HCl in H2O (0.4344 mL, 5.213 mmol) was added. The material was concentrated in vacuo, and extracted with DCM and sat. NaHCO3. The organic layer was dry-loaded onto silica gel and purified via column chromatography, eluting with 2-4% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.69-1.80 (m, 4H), 1.82 (d, J=7.3 Hz, 3H), 1.94-2.05 (m, 2H), 2.25 (s, 3H), 2.32-2.46 (m, 2H), 3.67 (br. s., 3H), 4.02-4.08 (m, 1H), 4.17-4.27 (m, 1H), 5.08-5.17 (m, 1H), 6.91 (dd, J=9.1, 4.3 Hz, 1H), 7.10 (t, J=8.8 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.38-7.45 (m, 1H), 7.47 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). MS (ES+): m/z=483.16/485.18 (100/50) [MH+]. HPLC: tR=1.46 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[F:18][C@@H:19]1[CH2:23][CH2:22][N:21]([CH:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:30][CH:27]1[CH2:26][CH2:25][CH:24]([N:21]2[CH2:22][CH2:23][C@@H:19]([F:18])[CH2:20]2)[CH2:29][CH2:28]1
Reactant: NC1CCC(N2CC[C@@H](F)C2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1NC1CCC(N2CC[C@@H](F)C2)CC1)C1CC1
Yield: 74.9 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (278 mg, 0.89 mmol) was reacted with (R)-4-(3-fluoropyrrolidin-1-yl)cyclohexanamine (200 mg, 1.1 mmol) to afford the desired product (307 mg, 75%) as a yellow solid: ESI MS m/z 460 [C23H27BrFN3O+H]+.
Reaction SMILES: C(OC(=O)C(CS(N1CCN(C2C=CC(Br)=CC=2)CC1)(=O)=O)C(C)C)(C)(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:40][CH:41]=2)=[CH:32][CH:31]=1.[CH2:49]([C@@H:56]1[CH2:60][O:59][C:58](=[O:61])[N:57]1[C:62](=[O:72])[C@H:63]([CH2:67][S:68](Cl)(=[O:70])=[O:69])[CH:64]([CH3:66])[CH3:65])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:49]([C@@H:56]1[CH2:60][O:59][C:58](=[O:61])[N:57]1[C:62](=[O:72])[C@H:63]([CH2:67][S:68]([N:46]1[CH2:47][CH2:48][CH:43]([O:42][C:39]2[CH:38]=[CH:37][C:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)=[CH:41][N:40]=2)[CH2:44][CH2:45]1)(=[O:70])=[O:69])[CH:64]([CH3:66])[CH3:65])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: Fc1ccc(-c2ccc(OC3CCNCC3)nc2)cc1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 75.3 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)-piperazine-1-sulfonylmethyl]-3-methyl-butyric acid tert-butyl ester, from 5-(4-fluorophenyl)-2-(piperidin-4-yloxy)pyridine (0.52 g) and 4-(R)-Benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.57 g) to yield the title compound as an off-white solid (0.70 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O.C([O-])(=O)C.[Na+].[BH4-].[Na+]>CO>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[OH:8]
Reactant: Cc1ccc(N)cc1O
Reactant: O=Cc1ccc[nH]1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(NCc2ccc[nH]2)cc1O
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
To a stirred solution of 5-amino-2-methylphenol (9.84 g, 80 mmole) in methanol (100 mL) at 4° C. was added pyrrole-2-carboxaldehyde (11.41 g, 120 mmole) and sodium acetate (13.13 g, 160 mmole). The reaction mixture was stirred for 15 minutes and sodium borohydride (3.78 g, 100 mmole) was added portionwise over 1 hour at 4° C. After the addition was complete, the reaction was allowed to stir for an additional 3 hours. The reaction mixture was poured onto crushed ice slurry (200 g) and the resulting precipitate was collected and washed with cold water three times and air-dried to afford 2-methyl-5-[(1H-pyrrol-2-yl-methyl)amino]phenol (6.62 g, 41% yield): mp 115.4-116.8° C.; 1HNMR (400 MHz, DMSO-d6) δ 1.94 (s, 3H), 4.03 (d, 2H, J=5.6 Hz), 5.37 (t, 1H, J=5.6 Hz), 5.90 (m, 2H), 6.01 (dd, 1H, J=2.2, 8.0 Hz), 6.12 (d, 1H, J=2.1 Hz), 6.61 (m, 1H), 6.70 (d, 1H, J=8.1 Hz), 8.77 (s, 1H), 10.64 (s, 1H); MS m/z 202 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=3)(O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Crude rac-6-chloro-3-(3,4-dimethyl-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one (0.25 g, 0.87 mmol) (from Example 52a supra) was suspended in a mixture of triethylsilane (0.41 mL, 2.61 mmol) (Aldrich) and trifluoroacetic acid (1.48 g, 13.1 mmol) and heated in an 80° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate and treated with solid sodium carbonate (1 g). After stirring for 30 minutes, mixture was extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3,4-dimethyl-phenyl)-1,3-dihydro-indol-2-one as a brown solid. (Yield 0.18 g, 78%)
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:35][C:36]1[CH:37]=[C:38]([OH:50])[CH:39]=[C:40]([C:42]2([O:48][CH3:49])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:41]=1>O>[F:35][C:36]1[CH:37]=[C:38]([CH:39]=[C:40]([C:42]2([O:48][CH3:49])[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)[CH:41]=1)[O:50][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: NS(=O)(=O)c1ccc(-c2oc(CCl)nc2-c2ccccc2)cc1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(OCc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
A mixture of 4-[2-chloromethyl-4-phenyloxazol-5-yl]benzenesulfonamide (Step 3) (0.5 g, 1.4 mmol), potassium carbonate (0.4 g, 2.8 mmol), dimethylformamide (20 mL), and 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol [prepared as described in J. Med Chem., 35, 2600–2609 (1992)] (0.3 g, 1.4 mmol) was stirred at room temperature, for 16 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (4×30 mL) The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The resulting crude product was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexanes to give 0.3 g (40%) of 4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-pyran-4-yl)phenoxy]methyl]-4-phenyl-oxazol-5-yl]benzenesulfonamide as a sticky white solid: m.p. 70–80° C. 1H NMR (CDCl3/300 MHz) δ 7.92 (d, 2H, J=8.9 Hz), 7.77 (d, 2H, J=8.9 Hz), 7.62 (m, 2H), 7.43 (m, 3H), 6.94 (s, 1H), 6.78 (m, 2H) 5.24 (s, 2H), 4.82 (bs, 2H), 3.82 (m, 4H), 3.00 (s, 3H), 1.95 (m, 4H). Anal. calcd for C28H27FN2O6S: C, 62.44; H, 5.05; N, 5.20. Found: C, 62.50; H, 5.11; N, 5.24.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[C:6](\[NH:14][C:15](=[O:17])[CH3:16])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]>CO>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@@H:6]([NH:14][C:15](=[O:17])[CH3:16])[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCC[C@@H](C)[C@@H](C)/C(=C/C(=O)OCC)NC(C)=O
Solvent: CO
Product: CCC[C@@H](C)[C@@H](C)[C@@H](CC(=O)OCC)NC(C)=O
Yield: 99.8 %

Procedure:
A reactor was charged with 166 g of (4R,5R)-3-acetylamino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl ester (substrate), 2650 mL of MeOH, and 36 g of Pd/SrCO3 (lot#D25N17) catalyst. The substrate was reacted with H2 at a pressure of 50 psig to 51 psig of. During hydrogenation, additional catalyst was added at a reaction time of 67 hours (10 g). After the reaction was completed (90 hours), Pd/SrCO3 was filtered off and the filtrate was concentrated under reduced pressure to give 167 g (>99% yield) of the titled compound as an oil: 1H NMR (400 MHz, CHLOROFORM-D): 0.82 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H), 1.25 (t, J=7.3 Hz, 3H), 1.00-1.58 (m, 6H), 1.96 (s, 3H), 2.52 (q, J=5.2 Hz, 2H), 3.47 (s, 1H), 4.10-4.30 (m, 2H), 4.12 (t, J=7.1 Hz, 1H), 5.9 (d, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1.[CH3:33][N:34]([C@@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1)C(=O)OC(C)(C)C>>[CH3:33][NH:34][C@@H:42]1[CH2:46][CH2:45][N:44]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:43]1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCN(c2cc(N3Cc4cc(-c5cnn(C)c5)ccc4CC3C)nc(N)n2)C1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and tert-butyl methyl[(3R)-pyrrolidin-3-yl]carbamate. LCMS (M+H)+: m/z=419.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([NH2:27])[CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([NH:27][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:26]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
3-Nitrobenzaldehyde (0.302 g, 2.0 mmol) was added to a stirred mixture of 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.476 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture was stirred for 2 hours. The mixture was shaken, the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give an orange oil. Recrystallization from ethyl acetate/hexane gave the product (115 mg), mp 160-162° C.