Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.[SH:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C[O-].[Na+].O>CN(C)C=O>[C:8]([C:7]1[C:2]([S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:3][CH:4]=[CH:5][N:6]=1)#[N:9]
Reactant: COC(=O)CCS
Reactant: N#Cc1nccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCSc1nccnc1C#N
Temperature: 25 °C
Yield: 43.7 %

Procedure:
To a solution of 2-chloro-3-cyanopyrazine (9.9 g, 73.8 mmol) and methyl 3-mercaptopropionate (9.36 mL, 84.5 mmol) in anhydrous dimethylformamide (40 mL) cooled to 4° C. was added solid sodium methoxide (4.7 g, 87.0 mmol). The reaction mixture was allowed to warm to room temperature overnight. The mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed once saturated aqueous sodium bicarbonate solution, five times with brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 7:3 hexanes:ethyl acetate gave methyl 3-(3-cyanopyrazin-2-ylthio)propanoate (7.2 g) as a pale yellow liquid. 1H NMR (300 MHz, CDCl3): 8.51 (d, 1H), 8.32 (d, 1H), 3.72 (s, 3H), 3.50 (t, 2H), 2.79 ppm (t, 2H). MW=223 confirmed by LC-MS, tr=11.11 min (Method Y) MH+=221-225.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+].I[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(=[O:45])=[O:44])C(OC(C)(C)C)=O)[CH:33]=2)[N:28](C(OC(C)(C)C)=O)[N:27]=1>CN(C)C=O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:35][S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(=[O:44])=[O:45])[CH:33]=2)[NH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Temperature: 122 °C
Yield: 66.3 %

Procedure:
N-[3-(1H-Indol-2-yl)-1H-indazol-5-yl]benzenesulfonamide can be obtained in the following way: 158.1 mg of N-tert-butoxycarbonylindole-2-boronic acid and 360 μl of a saturated sodium hydrogencarbonate solution and then 48.2 mg of tetrakis(triphenyl-phosphine)palladium[0] are added to a solution of 101.9 mg of tert-butyl 3-iodo-5-(N-tert-butoxycarbonylbenzenesulfonylamino)indazole-1-carboxylate in 4.5 ml of dimethylformamide. The suspension is heated in the region of 122° C. for 16 hours. After cooling to a temperature in the region of 20° C., the catalyst is filtered through a bed of Celite® 535, and the filtrate is concentrated to dryness under reduced pressure. The reaction crude is purified by preparative HPLS chromatography coupled to a mass detector (LC/MS, conditions A). The fractions containing the expected product are pooled and concentrated. 43.8 mg of N-[3-(1H-indol-2-yl)-1H-indazol-5-yl]benzenesulfonamide are obtained in the form of the trifluoroacetate salt (LC/MS analysis: Tr=3.49 minutes; [M+H]+=389.13).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:9]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1.O1CCOCC1.[ClH:33]>>[ClH:33].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: COCCCCOC(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COCCCCOC(c1ccccc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 3-((4-methoxybutoxy)(phenyl)methyl)pyrrolidine-1-carboxylate (47 mg, 0.13 mmol) was dissolved in 4 M HCl in dioxane (4 mL, 16 mmol). The solution was stirred at rt for 2 h and concentrated to afford 3-((4-methoxybutoxy)(phenyl)methyl)pyrrolidine hydrochloride (41.3 mg, quant) as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[ClH:10].Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36](O)=[O:37])=[CH:31][CH:30]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[ClH:28].[ClH:10].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][N:40]2[CH2:41][CH2:42][CH2:43][CH2:44]2)[C:36]([N:25]2[CH2:26][CH2:27][N:22]([C:20]3[C:21]4[C@H:13]([CH3:12])[CH2:14][CH2:15][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:23][CH2:24]2)=[O:37])=[CH:31][CH:30]=1
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Reactant: O=C(O)C(CN1CCCC1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C(CN4CCCC4)c4ccc(Cl)cc4)CC3)c21
Reaction time: 120 h
Yield: 27.8 %

Procedure:
DIPEA (44.4 mg, 0.343 mmol) was added to a suspension of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (20 mg, 0.69 mmol), 2-(4-chlorophenyl)-3-(pyrrolidin-1-yl)propanoic acid (59.8 mg, 0.082 mmol), and O—(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31.3 mg, 0.082 mmol) in CH2Cl2 (5.0 mL) at room temperature. The resulting mixture was stirred for 5 days, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous. NH4Cl. The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g), and eluted by a mixture of MeOH and CH2Cl2 (3:97 to 5:95) to give 2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one dihydrochloride (6 mg, 17%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1.C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(O)c3ccccc3-c3ccccc32)cc1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: COc1ccc(C2(O[C@H](C)[C@H](N)C(=O)O)c3ccccc3-c3ccccc32)cc1

Procedure:
from 9-(4-methoxyphenyl)-9H-fluoren-9-ol (Example 3n) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH2:21][CH:22]([CH3:24])[N:23]=4)[C:8]=3[CH:25]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CS(C)=O>[CH:1]1([C:4]2[C:5]([N:26]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[C:22]([CH3:24])[N:23]=4)[C:8]=3[CH:25]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C4=NC(C)CN4)c3cc2C2CC2)S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4nc(C)c[nH]4)c3cc2C2CC2)S(C)(=O)=O)cc1
Yield: 80 %

Procedure:
The title compound was prepared according to the procedure described in Example 1N using the imidazoline prepared in Example 2A (0.816 g, 1.49 mmol), anhydrous dimethyl sulfoxide (7.5 mL), powdered potassium carbonate (0.412 g, 2.98 mmol) and iodobenzene diacetate (0.528 g, 1.639 mmol) giving the title compound as a tan solid (0.65 g, 71%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.19-0.41 (m, 1H) 0.64-1.02 (m, 2H) 2.18-2.32 (m, 2H) 2.37 (s, 3H) 3.23 (s, 3H) 3.68 (s, 3H) 4.67-4.79 (m, 1H) 4.81-4.97 (m, 1H) 6.80 (d, J=8.82 Hz, 2H) 6.98 (s, 1H) 7.07-7.25 (m, 2H) 7.33-7.49 (m, 2H) 7.54-7.74 (m, 3H) 7.92 (s, 1H) 14.47 (s, 1H); MS (ESI+) m/z 546.1 (M+H)+, (ESI−) 544.1 (M−H)−.
Reaction SMILES: C1(S([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=O)C=CC=CC=1.C1([Mg]Br)C=CC=CC=1.[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([CH:42]=[O:43])[CH:36]=[CH:35]2.[NH4+].[Cl-]>C1COCC1>[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([CH:42]([C:9]1[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=1)[OH:43])[CH:36]=[CH:35]2
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Reactant: COc1cc2nccc(S(=O)c3ccccc3)c2cc1OC
Agent: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc2nccc(C(O)c3ccc4cc(Br)ccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-benzenesulfinyl-6,7-dimethoxy-quinoline (step b, 1 g, 3.2 mmol) in THF (15 mL) at −10° C., was added phenylmagnesium bromide (1M in THF, 3.5 mL, 3.5 mmol). The reaction was warmed to RT and stirred for 20 min. 6-Bromo-naphthalene-2-carbaldehyde (Step d, 0.75 g, 3.2 mmol) was added in THF. The resulting mixture was stirred at RT for 2 h, then poured into saturated NH4Cl solution and extracted with ethyl acetate 3×. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (15-35% acetone/CH2Cl2) to give the titled compound. MS (ESI, pos. ion) m/z: 424.1 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:15][C:16](=[O:38])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]4[CH2:37][O:36][CH2:35]4)[CH:29]=3)[CH:18]=2)[CH2:10][CH2:9][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6]1)=[O:4].CO.[OH-].[Na+].OS([O-])(=O)=O.[Na+]>O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:5]2([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6]2)=[O:38])=[CH:18][C:19]=1[O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]2[CH2:37][O:36][CH2:35]2)[CH:29]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C4COC4)c3)c2)CCC(C(F)(F)F)CC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)NC2(C(=O)O)CCC(C(F)(F)F)CC2)cc1OCCc1cccc(C2COC2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
77 mg of 1-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester were dissolved using 3.5 ml of methanol and 173 μl of a 1M aqueous solution of NaOH added. The mixture was stirred at 60° C. for 8 h. The mixture was then poured into 10 ml of water and acidified to pH=5 using 5% aqueous NaHSO4-solution. The mixture was then extracted three times using 15 ml of EA each. The organic layer was then dried using MgSO4 and evaporated.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1.[C-:22]#[N:23].[K+]>C(O)C.O>[C:22]([CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1)#[N:23]
Reactant: COc1ccc(-c2nc3c(CBr)cc(OC)cc3s2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc3c(CC#N)cc(OC)cc3s2)cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of 4-bromomethyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (0.47 g, 1.29 mmol) in ethanol (6 mL) was added a solution of potassium cyanide (0.1 g, 1.54 mmol) in water (0.5 mL). The mixture was refluxed for 1.5 h, then cooled to room temperature. Ethanol was evaporated and the mixture was extracted with ethylacetate. After chromatographic purification gave 4-cyanomethyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole as a yellow solid (0.29 g, 73% yield). Mass spec: MH+=311.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[H-].[Na+].CS(O[CH:17]1[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][CH2:18]1)(=O)=O>CN(C=O)C>[Si:24]([O:23][CH:20]1[CH2:19][CH2:18][CH:17]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)[CH2:22][CH2:21]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(n2ccc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of 3-trifluoromethyl-1H-pyrazole (1.0 g, 7.35 mmol) in DMF (10 mL) cooled in an ice bath was added NaH (0.3 g, 60% in mineral oil). The mixture was stirred for 10 minutes before the mesylate (1.13 g, 3.68 mmol) of step B in DMF (5 mL) was added. Stirring was continued at room temperature for 1 hour and then at 100° C. overnight. After being cooled to room temperature, the solution was poured into ice water and extracted with EtOAc three times. The combined extract was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 5:1 EtOAc/hexanes provided the title compound (0.56 g, 44%) as an oil. MS calculated (M+H)+ 349, found 349.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[H-].[Na+].[OH2:18]>C(OCC)(=O)C>[Cl:11][C:4]1[C:3]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:2]([OH:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O
Reactant: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Temperature: 45 °C
Reaction time: 72 h
Yield: 76.8 %

Procedure:
A mixture of 2,6-dichloro-3-nitrobenzenesulfonamide (2.61 g, 9.64 mmol), 60% sodium hydride (1.15 g, 28.9 mmol) and water (174 μL, 9.64 mmol) was heated to 45° C. while kept at argon atmosphere for 3 days. The reaction was monitored by 1H NMR. 0.1 equivalent water was added to the mixture when the reaction was not completed. The solvent was evaporated when the reaction almost completed indicated by 1H NMR. The residue was diluted with ethyl acetate and washed with 1N aq. HCl. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (50/48/2, v/v/v), gave the desired product (1.87 g, 77%). EI-MS (m/z)250.84, 252.89 (M−).
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C@@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH2:1]([N:8]1[CH2:25][C@@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27][C@H:20]([C:21]([O:23][CH3:24])=[O:22])[C@H:9]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CN(Cc1ccccc1)[C@@H](CC(=O)OC)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(C)O[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of 1-benzyl 4-methyl(2S)-2-[benzyl((2R)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate (34.30 g, 0.05464 mol) in a mixture of tetrahydrofuran (90.0 mL, 1.11 mol) and toluene (470.0 mL, 4.412 mol) at −78 Celsius was added 1.00 M of Lithium hexamethyldisilazide in tetrahydrofuran (65.6 mL). The resulting mixture was stirred at −78 Celsius overnight, and then allowed to warm up to at 0 Celsius gradually and stirred at 0 Celsius for 30 min. After quenched with aq ammonium chloride, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried (sodium sulfate), and concentrated to dry. The residue was purified on silica gel column, eluting with 0 to 20% EtOAc in hexane, to yield the cyclized product (19.47 g, 78.2%). MS (ESI): (M+H)+=456.0.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20](OCC)=[O:21])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.S(=O)(=O)(O)O>O>[CH3:4][C:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(OCCO)cc2)cc1

Procedure:
2.2 g. of the compound of Example 31 are reduced with 0.65 g. lithium aluminum hydride in 50 ml. boiling diethyl ether. The reaction mixture is mixed with water, sufficient 10% sulphuric acid is added thereto just to dissolve the precipitate, extracted with diethyl ether, evaporated to dryness and the remaining oil purified by column chromatography (silica gel; dichloromethane/methanol 99:1 v/v). The appropriate fractions are evaporated to dryness in a vacuum, the residue is first recrystallised from ethyl acetate/ligroin (1:1 v/v) and then from toluene to give 0.6 g. (31% of theory) of the title compound; m.p. 136°-142° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]#[CH:13]>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH2:13][C:12]#[CH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#CCBr
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOc1cccnc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-bromo-3-hydroxypyridine (10 g) in dry THF (100 ml) was treated with 1 equivalent of sodium hydride (80% in oil) (1.72 g) and stirred at room temperature under nitrogen for 0.75 hours. Propargyl bromide (80% in toluene) (19.2 ml) was added and the mixture was heated under reflux for 88 hours. After cooling, the solvent was evaporated under reduced pressure and the residue partitioned between 5% aqueous NaOH and EtOAc. The organic layer was removed, dried (Na2SO4) and concentrated in vacuo to give a pale yellow gum. This was purified by column chromatography on silica using dichloromethane as eluant to give 2-bromo-3-propargyloxypyridine as an off white solid 6 g.
Reaction SMILES: [CH3:1][C:2]1[O:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.S(OC)(O[CH3:13])(=O)=O>>[CH3:13][S:7][CH2:6][C:5]1[O:8][C:2]([CH3:1])=[CH:3][CH:4]=1.[CH3:1][C:2]1[O:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Agent: Cc1ccc(CS)o1
Product: CSCc1ccc(C)o1

Procedure:
5-Methylfurfuryl methyl sulfide was prepared by reacting 5-methylfurfuryl-mercaptan with dimethyl sulfate in alkaline solution according to known methods. 5-Methylfurfuryl-mercaptan was obtained from the corresponding alcohol by the method described in Org.Syn. 35, 67 (1955). The product is a colorless liquid boiling at 71°-72°C./11 mm. Hg.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)=[O:21])=[C:15]([F:33])[CH:14]=3)[C:9]([CH2:11]O)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C(Cl)Cl.ClC(Cl)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][N:24]=4)=[O:21])=[C:15]([F:33])[CH:14]=3)[C:9]([CH3:11])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2cc(CO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Cc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A suspension of Intermediate AJ (N-{4-[4-amino-6-(hydroxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea) (200 mg, 0.433 mmol) in CH2Cl2 (5 mL) was treated with thionyl chloride (129 mg, 1.08 mmol) and allowed to stir for 30 min at rt. The reaction mixture was diluted with dichloroethane (25 mL) and the volatiles removed under vacuum. The residue was suspended in dichloroethane (25 mL) and concentrated a second time. The residue was then placed under high vacuum for 1 h. All material was then suspended in THF (10 mL) and cooled to −78° C. L-Selectride (438 mg, 2.29 mmol) was added and the reaction moved to a rt water bath. After 1 h the reaction was quenched with MeOH (1 mL) and diluted with 1N NaOH (4 mL). 2 mL 30% H2O2 (2 mL) was added dropwise, and the reaction allowed to stir for 0.5 h. The mixture was diluted with EtOAc (50 mL) and washed well with sodium thiosulfate solution and brine. The organic layer was dried with sodium sulfate and the volatiles removed under vacuum to provide an amorphous solid. Trituration with CH2Cl2 provided the desired compound as a white solid (111 mg, 59%). 1H-NMR (DMSO-d6) δ 10.10-10.30 (m, 2H), 8.54 (d, 1H, J=5 Hz), 8.28 (t, 1H, J=8 Hz), 8.02 (s, 1H), 7.81 (s, 1H), 7.60 (s, 1H), 7.36-7.40 (m, 1H), 7.28-7.32 (m, 1H), 7.14-7.18 (m, 1H), 2.10 (s, 3H); MS [M+H]+=446.0; LCMS RT=2.97 min.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:10](=[S:13])[NH:11][CH3:12])#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=[O:40].[Na+].[K+]>ClCCl>[CH:1]([CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:10](=[S:13])[NH:11][CH3:12])=[O:40]
Reactant: CNC(=S)C1(c2cccnc2)CCCCC1=CC#N
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNC(=S)C1(c2cccnc2)CCCCC1=CC=O
Temperature: 25 °C

Procedure:
A solution of (±)-2 -cyanomethylene-N-methyl-1-(pyrid-3 -yl}cyclohexane carbothioamide (1.3 g, 4.8 mmol) in dichloromethane (30 ml) was cooled to -20° C. and treated with a 1 M solution of diisobutylaluminium hydride in toluene (10.6 ml, 10.6 mmol). The mixture was allowed to warm to room temperature over 2 hours. Dichloromethane (50 ml) was added to the reaction mixture followed by an aqueous solution of Rochelle salt (sodium potassium tartrate) (50 ml). The layers were separated and the organic layer was washed with an aqueous solution of Rochelle salt (50 ml). The organic extract was dried over magnesium sulphate and concentrated in vacuo to give a crude gum which was purified by flash chromatography over silica gel, eluting with a 4:1 (v/v) mixture of ethyl acetate/hexane to give (±)-2 -formylmethylene-N-methyl-1-(pyrid-3 -yl)cyclohexane carbothioamide as a white foam (230 mg, 0.84 mmol);
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][N:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[O:23]>Cl.O1CCOCC1>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][N:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: NN1CC(=O)NC1=O
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The resulting Boc-Phe-Aminohydantoin (0.25 mmol) was dissolved in 5 ml 4M HCl/Dioxan. The solution was stirred for 2 hours at room temperature. Afterwards the solvent was removed and the residue was washed with diethyl ether. Solid product was dried in vaccuo.