Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([NH:15][CH2:16][C:17](O)=[O:18])=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]2[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:45][C@H:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([NH:15][CH2:16][C:17]([NH:53][C@H:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH3:45])=[O:18])=[CH:9][C:10]([C:11]([F:12])([F:13])[F:14])=[C:5]2[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(NCC(=O)O)nc21
Reactant: C[C@H](N)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C[C@H](NC(=O)CNc1cc(C(F)(F)F)c2c(-c3ccccc3)nn(C)c2n1)c1ccccc1
Reaction time: 16 h
Yield: 41.8 %

Procedure:
A solution of 2-(1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-ylamino) acetic acid (0.035 g, 0.095 mmol), DIC (0.018 g, 0.143 mmol) and HOBt (0.020 g, 0.143 mmol) in THF (5 ml) was stirred at rt for 10 min. (S)-(−)-α-methyl benzyl amine (0.013 g, 0.104 mmol) was added to the reaction mixture dropwise at rt and stirring was continued for 16 h. The reaction mixture was poured into ice cold water and the precipitated product was collected by filtration and dried under vacuum. The crude product was purified by preparative HPLC using acetonitrile/water as mobile phase to yield the title compound as a white solid (0.018 g, 42%). [1H-NMR (CDCl3, 300 MHz) δ 7.52-7.38 (m, 4H), 7.32-7.21 (m, 6H), 6.66 (s, 1H), 6.39 (d, 1H), 5.51 (t, 1H), 5.30-5.15 (m, 1H), 4.20 (dd, 2H), 3.95 (s, 3H), 1.52 (d, 3H); HPLC RtA=5.294 (98%) min; LCMS RtA=1.682 min; [M+H]+=454.1]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20][CH2:21][C:22]([NH:24][CH:25]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:26]([O:28]C)=[O:27])=[O:23])[N:11]([CH3:19])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:20][CH2:21][C:22]([NH:24][CH:25]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:26]([OH:28])=[O:27])=[O:23])[N:11]([CH3:19])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(NC(=O)CSc1nc(-c2ccc(F)cc2)c(-c2ccncc2)n1C)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)CCC(NC(=O)CSc1nc(-c2ccc(F)cc2)c(-c2ccncc2)n1C)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
100 ml of HCl 10% are added to dimethyl 2-{2-[4-(4-fluorophenyl)-1-methyl-5-pyridin-4-yl-1H-imidazol-2-ylsulfanyl]acetylamino}pentanedioate (0.8 mmol/0.400 g) and the mixture is stirred at room temperature for 6 h. The mixture is then slowly neutralized using 2N NaOH, resulting in the precipitation of 1-hydrogen 5-methyl 2-{2-[4-(4-fluorophenyl)-1-methyl-5-pyridin-4-yl-1H-imidazol-2-ylsulfanyl]acetylamino}pentanedioate as a yellowish crystalline powder. The precipitate is filtered off with suction and washed with a little ice-cold water and dried over P2O5.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]([CH2:9][S:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:8]=1.[Cl:15][C:16]1[CH:32]=[CH:31][C:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:24][C:18]=2[C:17]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:11]([S:10][CH2:9][C:6]1[N:5]=[CH:4][C:3]([CH2:2][NH:1][C:17]2[C:18]3[CH2:24][CH2:23][N:22]([C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])[CH2:21][CH2:20][C:19]=3[CH:31]=[CH:32][C:16]=2[Cl:15])=[CH:8][CH:7]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)SCc1ccc(CN)cn1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)SCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cn1
Temperature: 90 °C
Yield: 70.9 %

Procedure:
Use a method similar to the General Procedure 1-3. Add 3-aminomethyl-6-(tert-butylthio)methyl-pyridine (2.99 g, 14.2 mmol), 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (5.05 g, 11.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (275 mg, 0.3 mmol), palladium(II) acetate (133 mg, 0.6 mmol), BINAP (560 mg, 0.9 mmol) and cesium carbonate (5.82 g, 17.9 mmol) to toluene (100 mL) under a nitrogen atmosphere. Heat the mixture at 90° C. for 12 h. Cool the mixture to room temperature. Purify by chromatography on silica gel eluting with hexane/EtOAc (100:0 to 85:15 gradient) to obtain 6-[(6-tert-butylthiomethyl-pyridin-3-ylmethyl)-amino]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.1 g, 71%). MS (APCI+) m/z: 486 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]([CH3:39])[CH2:26][CH2:27][O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[N:23][N:24]=2)[CH:21]=1.[NH4+].[Cl-]>CN(C=O)C.O>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([N:25]([CH3:39])[CH2:26][CH2:27][O:28][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:36]([CH3:37])[CH3:38])=[N:23][N:24]=3)[CH:21]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OCCN(C)c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCN(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Reaction time: 0.25 h
Yield: 28.7 %

Procedure:
Intermediate A (93 mg, 0.568 mmol) was added dropwise to a suspension of NaH (60% dispersion in oil, 68 mg, 1.71 mmol) in DMF (3 mL) at RT under N2. The mixture was stirred for 15 min then Intermediate 25b (160 mg, 0.437 mmol) was added and the mixture stirred at 60° C. under N2 for 3 h. Sat. aq. NH4Cl solution (0.2 mL) was added to the cooled mixture which was then diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organics were washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated, the residue applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo left a brown foam. FCC, using 0-6% [2M NH3 in MeOH] in DCM, gave the title compound (64 mg, 29%). LCMS (Method 1): Rt 2.71 min, m/z 510 [MH+].
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([OH:60])=[O:59])[CH:53]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].[CH2:67](Cl)Cl.C[Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([O:60][CH3:67])=[O:59])[CH:53]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4cccc(C(=O)O)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4cccc(C(=O)OC)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (7 mg) in methylene chloride:methanol (2:1, 0.75 mL) at 0° C. was added a methylene chloride solution of trimethylsilyldiazomethane (10% by weight) until a yellow colored persisted. The mixture was then warmed to room temperature, concentrated in vacuo, and purified by flash chromatography on silica gel (acetone:hexane (1:2)) to give the title compound (5.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[NH:21][C:20](=[O:22])[N:19]([CH:23]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)=[O:25])[C:18]=2[CH:51]=1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:21]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:20](=[O:22])[N:19]([CH:23]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)=[O:25])[C:18]=2[CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)C(c3ccccc3)n3c(=O)[nH]c4ccc(Cl)cc43)CC2)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
167 mg (0.81 mmol) of 4-methoxybenzenesulfonyl chloride were added to a solution of 460 mg (0.73 mmol) of tert-butyl 4-{4-[2-(6-chloro-2-oxo-2,3-dihydrobenzimidazol-1-yl)-2-phenylacetyl]-piperazin-1-yl}piperidin-1-carboxylate (XIIIa), 0.21 ml (1.47 mmol) of triethylamine and a catalytic amount of DMAP in tetrahydrofuran (8 ml) while stirring at room temperature, and the mixture was then stirred at room temperature for 16 h. The reaction solution was mixed with water and extracted with ethyl acetate (3×60 ml). The combined organic phases were washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase gradient 5-10% methanol in dichloromethane). Yield: 517 g (97%) of colorless oil
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccc(O)cc2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a −80° C. solution of 2-(4-methoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (550 mg, 2 mmol) in dichloromethane (20 mL) is added BBr3 (5 mL, 1M solution in dichloromethane). The reaction is stirred at ambient temperature overnight. The reaction is quenched by addition of methanol and is concentrated in vacuo. The residue is partitioned between EtOAc and 1N HCl. The organic layer is concentrated and the residue is purified by chromatography (0 to 30% EtOAc in hexanes) to give the title compound as a tan solid, (500 mg, 95%). LC-ES/MS m/e 264 (M+1), 1H NMR (DMSO-d6) δ 10.22 (s, 1H), 7.82 (d, 2H), 6.86 (d, 2H), 4.27 (q, 2H), 2.64 (s, 3H), 1.29 (t, 3H).
Reaction SMILES: CI.[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11]([NH2:13])=S)[CH:7]=[CH:6][CH:5]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].ClCCl.CCCCC>CO.C(O)C>[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][CH3:14])=[NH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1CN
Reactant: NC(=S)Nc1cccc(Br)n1
Solvent: CI
Solvent: CO
Solvent: CCCCC
Product: COc1ccccc1CNC(=N)Nc1cccc(Br)n1
Yield: 75.1 %

Procedure:
0.87 mL (1384 mmol) methyl iodide diluted in 2 mL methanol was added dropwise to 2.00 g (8.65 mmol) N-(6-bromopyridin-2-yl)thiourea suspended in 30 mL methanol, and the mixture was heated for 1.45 hr under reflux. The reaction mixture was in solution. The methylated intermediate product, consisting of methyl N-(6-bromopyridin-2-yl)imidothiocarbamate hydroiodide (ESI-MS [M+H+]=247.85 calculated for C7H8BrN3S=246), was freed of solvent under vacuum. The intermediate product was then suspended in 25 mL ethanol, and after addition of 2.37 mL (18.168 mmol) 2-methoxybenzylamine was heated for 3 hr under reflux, whereupon the solid completely dissolved. For workup the solvent was removed under vacuum, and the crude mixture was taken up in dichloromethane. Extraction was performed with water (2×100 mL) and with 2 N sodium hydroxide solution (1×100 mL) to liberate the iodide salt. Subsequent washing of the organic phase with water (1×100 mL), drying over magnesium sulfate, and evaporation of the solvent under vacuum resulted in a light brown-yellow oil, from which a colorless crystallizate was isolated from dichloromethane/pentane in a refrigerator at 5° C. Further fractionated crystallization in acetonitrile/water resulted in a total of 2.18 g (6.50 mmol, 75%) N-(6-bromopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[C:22]([F:29])[CH:21]=1.O>O1CCCC1>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Br:19])=[CH:21][C:22]=1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: OCCNCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1F)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a solution of N-benzylethanolamine (6.37 g, 42.1 mmol), triethylamine (8.81 ml, 63.2 mmol) in tetrahydrofuran (200 ml) was added under ice-cooling 4-bromo-2-fluorobenzoylchloride (10.0 g, 42.1 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (1.45 g, 98.0%) as an oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].[CH3:7][CH:8]([CH3:16])[CH2:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13].C(N(CC)CC)C>CCO>[CH2:9]([C:10]1[CH:11]=[C:12]([CH3:13])[C:3]([C:1]#[N:2])=[C:4]([SH:5])[N:6]=1)[CH:8]([CH3:16])[CH3:7]
Reactant: CC(=O)CC(=O)CC(C)C
Reactant: N#CCC(N)=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(CC(C)C)nc(S)c1C#N
Temperature: 50 °C
Yield: 61.7 %

Procedure:
To a stirred solution of cyanothioacetamide (2.20 g, 22 mmol) and 6-methyl-2,4-heptanedione (3.12 g, 22 mmol) in anhydrous EtOH (40 mL) was added triethylamine (0.4 mL) and the reaction was heated at 50° C. for 1 h before it was allowed to cool to room temperature. Filtration and washing of the precipitates with EtOH gave 6-isobutyl-2-mercapto-4-methylnicotinonitrile as a yellow solid (2.8 g, 61%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:26](=[O:37])[NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)=[C:12]([CH:23]([CH3:25])[CH3:24])[N:13]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:9][CH:8]=1)(=O)=O.[CH3:40][C:41]1[C:45](B(O)O)=[C:44]([CH3:49])[O:43][N:42]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>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>[F:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[F:35])[CH2:28][NH:27][C:26]([C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:45]3[C:41]([CH3:40])=[N:42][O:43][C:44]=3[CH3:49])=[CH:8][CH:9]=2)[N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:12]=1[CH:23]([CH3:25])[CH3:24])=[O:37]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2n1Cc1ccccn1
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: Cc1noc(C)c1-c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
Following General Procedure BB, 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (Compound 202, 57 mg, 0. 10 mmol), was reacted with 3,5-dimethylisoxazol-4-ylboronic acid (21 mg, 0.15 mmol), LiCl (13 mg, 0.30 mmol), Na2CO3 (aqueous) (2M, 0.2 ml), Pd(PPh3)4 (6 mg, 0.006 mmol) to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])=[O:17])[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].C(N[C:37]1[CH:42]=CC=[CH:39][CH:38]=1)C>>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:20])=[O:21])=[O:17])[C:9]([N:11]([CH2:12][CH3:13])[C:14]2[CH:39]=[CH:38][CH:37]=[CH:42][CH:15]=2)=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCN(CC)C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CCNc1ccccc1
Product: CCN(C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Yield: 103.9 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (300 mg) obtained in Example 111 (4) and N-ethylaniline (107 mg). This was purified by silica gel column chromatography to give the title compound (344 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[BH4-].[Na+]>CO>[O:13]1[CH2:14][CH2:15][N:10]([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12]1
Reactant: O=Cc1cccc(O)c1
Reactant: C1COCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc(CN2CCOCC2)c1
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution of 0.2 mol of 3-hydroxybenzaldehyde in 100 ml of methanol, is added, at about 20° C., a solution of 0.4 mol of morpholine in 40 ml of methanol. To the mixture thus obtained is added portionwise, under stirring at the temperature of 20°-25° C. within about 90 minutes, 0.2 mol of sodium borohydride, then the reaction mixture is stirred 3 hours at room temperature and the solvent is evaporated under reduced pressure to dryness. The residue is taken up with ice and acidified with hydrochloric acid, the acid solution is washed twice with 40 ml of ethyl acetate and concentrated ammonium hydroxide is added thereto up to clearly basic reaction. The mixture is extracted 4 times with 80 ml of ethyl acetate and the solvent is evaporated off. The product thus obtained melts at 113°-116° C. Yield: 67%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)=[CH:12][C:11]([C:25]([O:27]CC)=[O:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:23])([F:24])[F:22])[CH:15]=3)=[CH:12][C:11]([C:25]([OH:27])=[O:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 28A in analogy to the synthesis of the compound of Example 71A. 3.14 g (96% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=[C:4]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[CH3:24][C:25]12[C:32]([CH3:34])([CH3:33])[CH:29]([CH2:30][CH2:31]1)[CH2:28][NH:27][CH2:26]2.C(N(CC)C(C)C)(C)C.C1(C)C(C)=CC=CC=1>C(OCC)(=O)C.O.ClCCl>[CH3:24][C:25]12[C:32]([CH3:34])([CH3:33])[CH:29]([CH2:30][CH2:31]1)[CH2:28][NH:27][CH:26]2[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=[C:4]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1
Reactant: CC(C)(C)C(C)(C)Nc1nc(Cl)nc(NC(C)(C)C(C)(C)C)n1
Reactant: CC12CCC(CNC1)C2(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)C(C)(C)Nc1nc(NC(C)(C)C(C)(C)C)nc(C2NCC3CCC2(C)C3(C)C)n1

Procedure:
Seven grams (0.02 mole) of 2-chloro-4,6-bis[(1,1,2,2-tetramethylpropyl)amino]-s-triazine, 31 g. (0.2 mole) of 1,8,8-trimethyl-3-azabicyclo[3.2.1]octane, 7.1 ml. (0.04 mole) of N,N-diisopropylethylamine and xylene are refluxed under an argon atmosphere for 22 hours. After cooling, the reaction is diluted with ethyl acetate and water. The mixture is then washed with water, the organic phase dried over magnesium sulfate, filtered through diatomaceous earth and evaporated in vacuo. Addition of toluene and re-evaporation in vacuo several times gives a solid. This solid is then dissolved in dichloromethane, filtered through Magnesol® and the Magnesol® washed with dichloromethane. Evaporation of the solvent and purification by column chromatography gives 2-(1,8,8-trimethyl-3-azabicyclo[3.2.1]octyl)-4,6-bis(1,1,2,2-tetramethylpropylamino)-s-triazine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:31]1([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCCCN1CCCC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NCCCCN4CCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 2 mL of dioxane and 40.2 mg of 4-pyrrolidin-1-ylbutan-1-amine. After chromatography on a column of silica, eluting with a mixture of dichloromethane/methanol/28% aqueous ammonia (95/4/1 by volume), 60.2 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]-methyl}pyridin-2-yl)-3-(4-pyrrolidin-1-ylbutyl)urea are obtained in the form of a white powder, the characteristics of which are as follows: