Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=1>C1COCC1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][C:13]2[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Nc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OCC(COc2nccc(N)n2)O1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of solketal 58 (34.4 g, 260 mmol) in THF (150 mL) was added NaH (10.4 g, 260 mmol) at room temperature and the mixture stirred for 1 h. 2-chloro-4-aminopyrimidine 97 (15.0 g, 115 mmol) was then added, and the mixture was stirred at 70° C. for 48 h. The reaction mixture was concentrated and the crude residue was purified by flash chromatography (dichloromethane:methanol=15:1-10:1) to give 98 (18.2 g, 70% yield) as an oil. The acetonide protecting group could be removed after coupling with the appropriate aniline by treatment with EtOH/3 N HCl (4:1) at reflux for 12 h.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][O:13][CH3:14])=[C:6]([CH:10]=1)[CH2:7][C:8]#[N:9].Br[C:16]1[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[CH:18][N:17]=1.C1(C)C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][O:13][CH3:14])=[C:6]([CH:10]=1)[CH:7]([C:16]1[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[CH:18][N:17]=1)[C:8]#[N:9]
Reactant: COCOc1cccnc1Br
Reactant: COCOc1ccc(Br)cc1CC#N
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(Br)cc1C(C#N)c1ncccc1OCOC
Yield: 80 %

Procedure:
To a mixture of 5-bromo-2-methoxymethoxybenzyl cyanide (2.10 g), 2-bromo-3-methoxymethoxypyridine (1.79 g), sodium p-toluenesulfinate (0.44 g) and THF (30 ml) was added, at room temperature, 60% sodium hydride (0.69 g), followed by heating for 2 hours under reflux under argon atmosphere. The reaction mixture was poured into a saturated aqueous saline solution, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(5-bromo-α-cyano-2-methoxymethoxybenzyl)-3-methoxymethoxypyridine (2.58 g), whose physical properties and spectrum data are shown in Table 9 and Table 12.
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>C1C=CC=CC=1>[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([N:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8])=[O:12]
Reactant: CN1CCCCC1=N
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: c1ccccc1
Product: CN1CCCCC1=NC(=O)N(C)c1ccccc1
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (14.8 g.; 0.1 mole) is converted to free base by adding 10 ml. of 50% NaOH and extracting into benzene. After drying over K2CO3, the benzene layer is stirred at room temperature and 8.84 g. (0.05 mole) of N-methyl-phenylcarbamoyl chloride (prepared according to the method of J. A. Aeschlimann, U.S. Pat. No. 2,449,440), dissolved in anhydrous benzene, is added dropwise to this solution. The mixture is stirred at room temperature overnight (about 17 hours) and then filtered. The filtrate is taken to dryness in vacuo and the residue is dissolved in and recrystallized from hexane to give the product, 1-methyl-3-(1-methyl-2-piperidylidene)-1-phenylurea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([C:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=3)=[N:9]2)=[CH:5][CH:4]=1.CC1C=CC(S(NN)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[N:9]=[C:10]([CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: COc1ccc(Cn2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 96 h
Yield: 33.8 %

Procedure:
A 100 mL round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.248 g, 0.455 mmol), 4-methylbenzenesulfonohydrazide (0.0846 g, 0.455 mmol) and toluene (10 mL). The reaction mixture was stirred at 100° C. for 4 days. The reaction was cooled to ambient temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford the product (84.3 mg, 33.9%). LRMS (APCI pos): >96% purity, 254 nm, m/e 548 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH2:18][N:17]([C:22]3[S:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:16][CH:15]2[CH2:14]1)=[O:12]
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Reactant: Clc1nc2ccccc2s1
Product: COc1ccc(C(=O)N2CC3CN(c4nc5ccccc5s4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-benzothiazole. MS (ESI) mass calcd. for C22H23N3O3S, 409.51; m/z found, 410.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[C:12]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[N:13][NH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:6]([O:5][C:3]([CH2:2][N:14]1[CH:15]=[C:11]([Cl:10])[C:12]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)=[N:13]1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: Clc1cc(Cl)cc(-c2n[nH]cc2Cl)c1
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
A solution of 5.00 g (0.033 mol) of t-butyl chloroacetate in 30 ml of DMF is run, dropwise and at room temperature, into a mixture of 7.62 g (0.030 mol) of 4-chloro-3-(3,5-dichlorophenyl)pyrazole and 5.60 g (0.040 mol) of K2CO3. The reaction mixture is stirred for 12 h at room temperature, diluted with 200 ml of H2O and extracted with ether. After drying the organic phase and concentration under vacuum, the residue is triturated with 20 ml of heptane, filtered and dried. We obtain 10.20 g of 1-t-butoxycarbonylmethyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 86° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1cc(N)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Yield: 63 %

Procedure:
A solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (1.41 g, 7.1 mmol) and 4-fluoro-3-methoxyaniline (1 g, 7.1 mmol) was stirred at room temperature for 1 h. Sodium tri(acetoxy)borohydride (1.95 g, 9.2 mmol) was then added and stirring continued over-weekend. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution, dried and then concentrated in vacuo. Column chromatography eluting with 0-50% Et2O/petroleum ether gave the title compound as a white solid (1.45 g). δH (CDCl3, 400 MHz) 6.89 (1H, dd), 6.22 (1H, dd), 6.09 (1H, m), 4.03 (2H, br s), 3.84 (3H, s), 3.36 (1H, br s), 2.92 (2H, m), 2.03 (2H, m), 1.46 (9H, s), 1.32 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].F[B-](F)(F)F.C([O+](CC)CC)C.[N+](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N-].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH3:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][CH:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:7](=[O:13])[C:8]=2[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCCc2c(C)cc(C)cc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one (1 g, 5.74 mmol) in anhydrous CH2Cl2 (20 mL) under nitrogen atmosphere was cooled to 0° C. To this solution was added triethyloxonium tetrafluoroborate (1M in CH2Cl2, 23 mL, 23 mmol), followed with ethyl diazoacetate (1.2 mL, 11.5 mmol). The mixture was stirred at ambient temperature for 16 hrs. The reaction was worked up with saturated sodium bicarbonate, diluted with water and CH2Cl2, and the layers were separated. The organic layer was dried with MgSO4, concentrated and the residue was purified by chromatography on silica gel eluting with 10% EtOAc/Hexanes to provide the title compound. 1H NMR (CD3OD) δ 1.29 (t, 3H), 1.97-2.12 (m, 4H), 2.28-2.30 (m, 3H), 2.30-2.31 (m, 3H), 2.59 (t, 2H), 4.28 (q, 2H), 6.86-6.90 (m, 1H), 6.95-6.99 (m, 1H), 13.17-13.22 (m, 1H). MS (M+H)+ m/z 261.
Reaction SMILES: ClC1C=NC=C(Cl)C=1C(NCC1C=CC([CH2:14][N:15]([CH2:26][CH2:27][C:28]2[N:32](C)[C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[N:29]=2)[CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=CC=1)=O.[C:43]([NH2:51])(=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1>>[NH:29]1[C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[N:32]=[C:28]1[CH2:27][CH2:26][N:15]([CH2:14][C:18]1[CH:19]=[C:20]([CH:25]=[CH:16][CH:17]=1)[CH2:21][NH:51][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1)[CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1
Reactant: Cn1c(CCN(Cc2ccc(CNC(=O)c3c(Cl)cncc3Cl)cc2)C2CCCc3cccnc32)nc2ccccc21
Reactant: NC(=O)c1ccncc1
Product: O=C(NCc1cccc(CN(CCc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1)c1ccncc1

Procedure:
3,5-Dichloro-N-(4-{[[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-isonicotinamide 8-yl)-amino]-methyl}-benzyl)-isonicotinamide
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[C:26]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>C1COCC1>[C:26]([N:29]1[CH2:34][CH2:33][C:32]([OH:35])([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
Di-isopropyl amine (11.9 ml, 85 mmol) was dissolved in THF (200 ml) and cooled to 0° C. and n-butyllithium (2M, 42 ml, 85 mmol) was added over one minute. This solution was stirred at 0° C. for 15 minutes and tributyltin hydride (22.8 ml, 85 mmol) was added over one minute to give a yellow solution. After 45 minutes at 0° C. the solution was cooled to -70° C. and 1-acetyl-4-piperidone (10.2 g, 71 mmol) in THF (60 ml) was added to the solution dropwise. Upon completion of this addition, the reaction mixture had become difficult to stir and an additional 100 ml of THF was added, and stirring continued at -70° for 2.5 hours. At -70° C. the reaction was quenched by addition of sodium dihydrogen phosphate buffer, pH 6.5. The reaction was allowed to warm to 0° C. This slurry was diluted with diethylether (600 ml) and water. The organic layer was separated, washed with NaCl solution, dried over MgSO4, and evaporated to give the crude product. This was purified by flash column chromatography on silica gel using methylene chloride and 9/1 methylene chloride-ethanol. Evaporation of the appropriate fractions gave 16.4 g of the title compound, 20, which was used without further characterization.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[F:58][C:59]1[CH:60]=[C:61]([S:65](Cl)(=[O:67])=[O:66])[CH:62]=[CH:63][CH:64]=1>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:65]([C:61]3[CH:62]=[CH:63][CH:64]=[C:59]([F:58])[CH:60]=3)(=[O:67])=[O:66])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (65 mg, 0.189 mmol) and 3-fluorobenzenesulfonyl chloride (0.030 mL, 0.227 mmol), the title compound was obtained as an off white solid (64 mg, 67% yield). MS (ESI): 502.2 [M+H]+.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1C=CC2N(O)N=NC=2C=1.[CH3:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[C:37]([CH3:39])[CH:38]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[C:7]([O:6][C:5](=[O:11])[CH2:4][CH2:3][C@H:2]([NH:1][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([N:43]1[CH2:44][CH2:45][N:40]([C:35]2[CH:36]=[C:37]([CH3:39])[CH:38]=[C:33]([CH3:32])[CH:34]=2)[CH2:41][CH2:42]1)=[O:14])([CH3:8])([CH3:9])[CH3:10]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(N2CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
75 mg of Boc-Glu(OtBu)—OH and 44 mg HOBT was dissolved in 1 ml of DMF. 52 mg of 1-(3,5-Dimethyl-phenyl)-piperazine and 97 mg of DIPEA in 1 ml of DMF was added, followed by 43 mg of EDC in 0.5 ml of DMF. The mixture was stirred for 16 h at RT (closed tube). The mixture was filtered, and the filter was washed with 20 ml ethyl acetate in two portions. The collected filtrate was washed with 20 ml of a 5% Na2CO3 solution and 20 ml of brine, dried with sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(OCC)C.C(Cl)Cl>[CH3:25][C:22]([C:13]1[CH:12]=[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[O:2])[CH:16]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:14]=1[OH:21])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccccc1Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)c1cc(Nc2ccccc2C=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
2-[(3,5-Bis[1,1 -dimethylethyl]-4-hydroxyphenyl)amino]-benzoic acid methyl ester (1.1 g, 3.1 mmols) is dissolved in 100 mL of diethyl, ether and added to a suspension of lithium aluminum hydride (0.46 g, 12.4 mmols) in 20 mL of diethyl ether at room temperature under an argon atmosphere. After 30 minutes the reaction is quenched with 0.46 mL of water, followed by 0.46 mL of 15% (w/v) aqueous sodium hydroxide and then 1.38 mL of water. The solids are removed by filtration of the reaction mixture into a flask containing sodium dithionite (15 g) and 300 mL of 50% aqueous tetrahydrofuran. The filtrate is concentrated in vacuo and the organics are extracted into two 100 mL portions of methylene chloride. The methylene chloride extracts are washed with 100 mL of brine, dried over magnesium sulfate, and filtered. The filtrate is added to a suspension of pyridinium chlorochromate (2.0 g, 9.3 mmols) and alumina (7.0 g) in 100 mL of methylene chloride. The reaction is stirred at room temperature for 12 hours, then filtered through a silica gel pad which is washed with 100 mL of diethyl ether. The filtrate is concentrated in vacuo and the residue is taken up in 100 mL of tetrahydrofuran. Sodium dithionite (15 g) is dissolved in 100 mL of water and added to the tetrahydrofuran solution. After 15 minutes the mixture is concentrated in vacuo and then extracted with three 50 mL portions of diethyl ether. The ether extract is washed with 50 mL of brine and dried over magnesium sulfate. Evaporation gives 1.0 g (100%) of 2-[(3,5-bis[1,1-dimethylethyl]-4-hydroxyphenyl)amino]benzaldehyde, mp 105°-107° C. An analytical sample is obtained by recrystallization from water/methanol.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([N:14]2[C:18]3=[N:19][C:20]([C:23](=O)[CH3:24])=[CH:21][N:22]=[C:17]3[N:16]=[N:15]2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[C:11]([CH:12]([N:14]2[C:18]3=[N:19][C:20](/[C:23](=[N:28]/[OH:29])/[CH3:24])=[CH:21][N:22]=[C:17]3[N:16]=[N:15]2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NO
Reactant: CC(=O)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Agent: Cl
Product: C/C(=N\O)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Yield: 65 %

Procedure:
The title compound (26.4 mg, 63%) was synthesized from 1-(1-(1-(5,7-difluoroquinolin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (73.7) (40.0 mg, 0.11 mmol) and hydroxylamine hydrochloride (15.7 mg, 0.23 mmol) using the same procedure as described in the synthesis of example 73. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.28 (bs, 1H), 9.23 (s, 1H), 9.01 (d, 1H), 8.52 (d, 1H), 7.73 (d, 1H), 7.63 (dd, 1H), 6.80 (q, 1H), 2.36 (d, 3H), 2.05 (s, 3H). LCMS (method A): [MH]+=370, tR=5.53 min.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:11]4[O:12][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:9][N:10]=4)=[CH:20][CH:21]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(Cc2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using (5-benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2/[C:19](/[C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:20]\[CH:21]2[CH2:29][CH2:28][C:23]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[O:24]1[C:23]2([CH2:28][CH2:29][CH:21](/[CH:20]=[C:19](\[C:11]3[NH:10][C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)/[C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH2:22]2)[O:27][CH2:26][CH2:25]1
Reactant: CS(=O)(=O)c1ccc(/C(=C/C2CCC3(C2)OCCO3)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C/C2CCC3(C2)OCCO3)c2cc3cccnc3[nH]2)cc1
Yield: 94.6 %

Procedure:
A mixture of (Z)-1-benzenesulfonyl-2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (800 mg, 1.42 mmol) in ethanol (24 mL), tetrahydrofuran (16 mL) and an aqueous sodium hydroxide solution (10%, 4 mL) was heated at 45° C. for 3 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (Z)-2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (570 mg, 95%): LC/MS m/e calcd for C23H24FN2O4S [M+H]+ 425.52, observed 425.0.
Reaction SMILES: Br[CH:2]([CH3:5])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:30])([C@H:27]([SH:29])[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>CN(C)C=O.C1C=CC=CC=1>[C:3]([CH:2]([S:29][C@H:27]([CH3:28])[C@:20]([C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[F:12])([OH:30])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[CH3:5])#[N:4]
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(Br)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C#N)S[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
134 mg (1.00 mmole) of 2-bromopropionitrile and 69 mg (0.50 mmole) of potassium carbonate were added to a solution of 143 mg (0.50 mmole) of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol in 3 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 1 hour under an atmosphere of nitrogen. The reaction mixture was then dissolved in benzene, and the resulting solution was washed, in turn, with water and with a saturated aqueous solution of sodium chloride. The solvent was then removed by distillation under reduced pressure, after which the resulting oily residue was purified by preparative thin layer chromatography on silica gel, using a 3:2 by volume mixture of ethyl acetate and hexane as the developing solvent, to afford 57 mg of stereoisomer A of the title compound (having the lower polarity) as an oil and 72 mg of stereoisomer B of the title compound (having the higher polarity) as crystals; these crystals were recrystallized from a mixture of benzene and hexane to give a pure specimen melting at 66°-68° C.