Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][S:24]4(=[O:31])=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 55.1 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (187 mg) described in Preparation Example 165 and [1,2]thiazinane 1,1-dioxide (68 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (118 mg) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:40])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]3([CH2:35][CH3:36])[CH2:34][O:33][CH2:32]3)[NH:17][CH:16]2[C:37](O)=[O:38])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:46][C@@H:45]([CH2:47][CH2:48][NH2:49])[CH2:44][O:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:46][C@H:45]([CH2:44][OH:43])[CH2:47][CH2:48][NH:49][C:37]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:40])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]2([CH2:35][CH3:36])[CH2:32][O:33][CH2:34]2)[NH:17]1)=[O:38]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CCC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC1(CC2NC(C(=O)NCC[C@H](O)CO)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Yield: 60.1 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (1 g, 1.6 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.7 g, 5 mmol), HATU (1.1 g, 3 mmol) and iPr2NEt (1.4 mL, 8 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.56 g, 58%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([OH:12])=[CH:6][CH:5]=[CH:4][C:3]1=2.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([OH:12])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: C=C1CCCc2c(O)cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CCCc2c(O)cccc21
Yield: 36 %

Procedure:
To a suspension of CH3PPh3I (897 mg, 2.22 mmol) in Et2O (10 mL) was added t-BuOK (249 mg, 2.22 mmol). The mixture was stirred for 15 minutes, to which was added dropwise 5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (300 mg, 1.85 mmol). The mixture was stirred at room temperature overnight, diluted with diethylether, and then filtered through a celite pad. The filtrate was concentrated under reduced pressure. The crude residue was purified by short column chromatography and was concentrated under reduced pressure to give 5-methylene-5,6,7,8-tetrahydro-naphthalen-1-ol. A mixture of 5-methylene-5,6,7,8-tetrahydro-naphthalen-1-ol and 10% Pd/C (40 mg) in methanol (10 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 5-methyl-5,6,7,8-tetrahydro-naphthalen-1-ol (110 mg, 36%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[OH:8])=[CH:5][N:4]=[CH:3]1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C(O)c1ccccn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cn1cncc1C(=O)c1ccccn1
Temperature: 25 °C

Procedure:
A heterogenous mixture of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol (1.41 g, 7.45 mmol, Intermediate 33: step a) and manganese dioxide (3.24 g, 37.27 mmol) in 1,4-dioxane (52 mL) was stirred at 100° C. for 2 hours. The reaction mixture was then cooled to room temperature, filtered through Celite®, washed with DCM, and concentrated to provide the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CC(C)([O-])C.[K+].[NH2:18]Cl>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([NH2:18])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2c(ccn2N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A solution of 5-methoxy-1H-indole (16.9 mmol) and potassium tert-butoxide (33.8 mmol) in DMF (76 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (169.2 mL) is added drop-wise for 15 minutes at rt. The reaction mixture is stirred at rt for 2 h, quenched with 5% Na2S2O3 aqueous solution (100 mL), and stirred at rt overnight. The mixture is extracted with ether. The organic layer is separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-20% EtOAc in heptane to afford 5-methoxy-indole-1-ylamine (388 mg, 14%) as a solid. 1H NMR (300 MHz, CDCl3): δ 4.78 (br, 2N—H), 6.35 (d, H), 6.94 (d, H), 7.08 (d, H), 7.17 (d, H), 7.30-7.39 (d, H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:14][NH:15][C@H:16]1[CH2:21][NH:20][C@H:19]([C:22]([O:24][CH2:25][C:26]2C=CC=CC=2)=[O:23])[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O-]CC.[Na+].C(O)(=O)C.O.O.C(O)(=O)C(O)=O>C(O)C.CC(C)=O>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:14][NH:15][C@H:16]1[CH2:21][NH:20][C@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Agent: CC[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A slurry of benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) (100 g, 232 mmol) in ethanol (2000 ml) was cooled to 0° C. A solution of sodium ethoxide in ethanol (216 ml, 580 mmol, 21 wt % solution) was added slowly and the mixture was stirred for 1 h at 0° C. Acetic acid (13.3 ml, 232 mmol) was added and the mixture was concentrated under vacuum below 35° C. to a final volume of 300 ml. Ethyl acetate (700 ml) was added and the mixture was concentrated to 300 ml. This procedure was repeated twice. Water (1800 ml) was added to the mixture followed by aqueous ammonia (variable) until the pH of the aqueous layer was 7.5 to 8. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with water (500 ml) and concentrated to a final volume of 300 ml. The solution was filtered and diluted with ethyl acetate (700 ml) and warmed to 35° C. A solution of oxalic acid dihydrate (30 g, 237 mmol) in acetone (200 ml) was added and the mixture was cooled to room temperature. The solids were isolated by filtration, washed with ethyl acetate and dried under vacuum at 35° C. to obtain ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a white solid (80.7 g, 94%).
Reaction SMILES: [C:1]1([C:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:43]([O:45][C:46]([C:48]1[C:49](Cl)=[N:50][C:51]([CH3:54])=[N:52][CH:53]=1)=[O:47])[CH3:44]>C1COCC1.C(N(CC)CC)C>[CH3:54][C:51]1[N:50]=[C:49]([N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[N:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:9]=[N:10][N:11]=3)=[CH:20][CH:21]=2)[C:48]([C:46]([O:45][CH2:43][CH3:44])=[O:47])=[CH:53][N:52]=1
Reactant: CCOC(=O)c1cnc(C)nc1Cl
Reactant: CCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nc(C)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 1A was dissolved in 15 ml of THF containing 4.6 ml of triethylamine. A solution of 1.94 g (9.7 mmoles) of ethyl-2-methyl-4-chloropyrimidine-5-carboxylate (E. Peters, et al., J. Org. Chem. 25 2137 (1960)) in 2 ml of THF was added and the resulting solution was stirred at room temperature for 2 hours. The solution was then concentrated and the resulting residue was dissolved in toluene. The toluene solution was extracted with potassium bicarbonate, dried over sodium sulfate and concentrated. The crude product was chromatographed on silica gel eluting with 12% ethyl acetate/88%toluene to provide 4.97 g of the desired product, which was crystallized from ether/hexane (1:1). M.p. 130°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.Cl[C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:12]2[CH:22]=[C:16]3[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]3[C:14](=[O:23])[N:13]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(Cl)cc1
Product: CN1CCCn2c1cc(OCCc1ccc(Cl)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from of 2-(4-chlorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][C:18]([OH:20])=O)=[O:8])=[CH:3][CH:2]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][CH:10]([CH2:17][C:18]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:20])[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](CC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: C1COCCN1
Product: CON=C1CC(CC(=O)N2CCOCC2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 98 %

Procedure:
The same method as employed in the preparation of Example 7, but starting from [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid (Intermediate 7) and morpholine, gave the title compound. Yield: 98%. HPLC purity: 100%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>N1C=CC=CC=1>[F:31][C:30]([F:32])([F:33])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:21]=1[O:20][CH3:19])[C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:26]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OC)c(C(F)(F)F)c4)cc3)sc2c1
Yield: 86.1 %

Procedure:
Prepared as described in the Amide Coupling section using 2-(4-aminophenyl)-6-methoxybenzothiazole (0.5 g, 1.95 mmol) and 4-methoxy-3-trifluoromethylbenzoyl chloride (0.47 g, 1.95 mmol) in dry pyridine (15 ml) to give the title compound (0.77 g, 87%) as pale yellow feathery crystals after work-up and recrystallisation from acetic acid.
Reaction SMILES: C[O-].[Na+].[CH:4]1([C:10]2[C:11]3[S:34][C:33]([C:35]([O:37]C)=[O:36])=[CH:32][C:12]=3[N:13]3[C:20]=2[C:19]2[S:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:16]([CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:15](=O)[CH2:14]3)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C1COCC1>[CH:4]1([C:10]2[C:11]3[S:34][C:33]([C:35]([OH:37])=[O:36])=[CH:32][C:12]=3[N:13]3[C:20]=2[C:19]2[S:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:16]([CH2:24][CH2:25][N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[CH2:15][CH2:14]3)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCN(CC)CCN1Cc2ccsc2-c2c(C3CCCCC3)c3sc(C(=O)OC)cc3n2CC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1CCn2c(c(C3CCCCC3)c3sc(C(=O)O)cc32)-c2sccc2C1
Temperature: 50 °C
Reaction time: 96 h
Yield: 24 %

Procedure:
Methyl 6-cyclohexyl-5-(3-formyl-2-thienyl)-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate and N,N-diethylaminoethylamine (10 eq.) were dissolved in THF (0.08 M) and the pH adjusted with AcOH to 6; the solution was left stirring for 4 h, then all volatiles were evaporated i. vac. The residual oil was dissolved in MeOH (0.08M), NaCNBH3 (4 eq.) was added, and the mixture was stirred overnight at RT to give methyl 6-cyclohexyl-5-[3-({[2-(diethylamino)ethyl]amino}methyl)-2-thienyl]-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate. Under the reaction conditions the latter partially closed to afford methyl 12-cyclohexyl-5-[2-(diethylamino)ethyl]-6-oxo-4,5,6,7-tetrahydrothieno[2,3-f]thieno[2′,3′:4,5]pyrrolo[1,2-d][1,4]diazocine-10-carboxylate; to drive this reaction to completion a catalytic amount of NaOMe was added and stirring was continued at 40° C. for 4 days. To a 0.05M solution of the foregoing amide in dry THF a 2M solution of borane-dimethylsulfide complex (13 eq.) in THF was added and the mixture was stirred for 1 h; after evaporation of all volatiles the residue containing (methyl 12-cyclohexyl-5-[2-(diethylamino)ethyl]-4,5,6,7-tetrahydrothieno[2,3-f]thieno[2′,3′:4,5]pyrrolo[1,2-d][1,4]diazocine-10-carboxylate) was suspended in MeOH (0.03M) and water. The pH was adjusted with LiOH to 9. The solution was left stirring at RT. Then an excess of 1N KOH-solution was added and the mixture was warmed to 50° C. and stirred for 2 h; the title compound (24%) was isolated by prep RP-HPLC. 1H-NMR (400 MHz, DMSO-d6, 330 K, δ) 7.67 (d, 1H, J 5.1), 7.18 (d, 1H, J 5.1), 3.15-3.12 (m, 2H), 3.09-3.05 (m, 5H), 2.87-2.81 (m, 2H), 1.79-1.63 (m, 8H), 1.30-1.10 (m, 14H); MS (ES+) m/z 486 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:9](=[O:10])[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C=Nc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)Nc2ccccc2Br)CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 103.9 %

Procedure:
2-Bromophenyl isocyanate (10.2 g, 51.5 mmol) was dissolved in N,N-dimethyl-formamide (40 mL) with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10.36 g, 51.5 mmol). The reaction mixture was stirred at 50° C. for 20 hours before being concentrated under reduced pressure. The crude was taken up in dichloromethane (200 mL) and washed with water (2×150 mL) and brine (1×150 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a light yellow oil (21.36 g). MS m/z: [M+H+] calcd for C17H23BrN2O4 399.08; found 399.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[O:37]C(=O)C3C=C(CC)C=CC=3[N:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([NH:33][C:11]2[CH:12]=[CH:13][C:14]([CH2:16][CH3:17])=[CH:15][C:10]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:18])=[O:37])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCc1ccc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)oc(=O)c2c1
Reactant: CCc1cccc(C(=O)Nc2ccc(Cl)cn2)c1
Product: CCc1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using methods substantially equivalent to those described in Example 51-D, 2-(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino)-N-(5-chloropyridin-2-yl)-5-ethylbenzamide (1.27 g, 47%) was prepared from 2-[(1-tert-butoxycarbonylpiperidin-4-yl)-6-ethyl-4H-3,1-benzoxazin-4-one.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[O:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCO[CH2:37][CH2:36]1>>[CH:31]([N:28]1[CH2:27][CH2:26][N:25]([C:23]([C:19]2[CH:20]=[C:21]3[C:22](=[CH:17][CH:18]=2)[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:6][CH2:36][CH3:37])[CH2:9][CH2:10]2)[CH:15]=[CH:16]3)=[O:24])[CH2:30][CH2:29]1)([CH3:33])[CH3:32]
Reactant: CC(C)N1CCN(C(=O)c2ccc3c(ccn3C3CCN(C(=O)OC(C)(C)C)CC3)c2)CC1
Reactant: C1COCCO1
Agent: Cl
Product: CCCN1CCC(n2ccc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)CC1
Temperature: 60 °C

Procedure:
4-[5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (example 26) was treated with 4N HCl in dioxane and evaporated to dryness. The residue was used in the consecutive step without further purification. The residue was dissolved in THF and treated with KOtBu. Propyliodide was added and heated to 60° C. After evaporation to dryness the residue was dissolved in methanol/DMF and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. The combined product fractions were evaporated to the title compound. MS (m/e): 397.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.O[N:15]1C2C=CC=CC=2N=[N:16]1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:15][NH2:16])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C(=O)NN)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.8 %

Procedure:
To a solution of 2-(4-chlorophenyl)-2-methylpropanoic acid (10.0 g, 50.5 mmol) in dry acetonitrile (100 ml) and dry N,N-dimethylformamide (25 ml) at room temperature was added 1-hydroxybenzotriazole (HOBt, 8.2 g, 61 mmol), followed by ethyl dimethylaminopropylcarbodimide hydrochloride (EDC, 11.65 g, 61 mmol). The mixture was stirred at room temperature for 12 hours, at which time all the starting acid had been consumed as shown by TLC (30% ethyl acetae:hexanes) analysis. The reaction mixture was cooled to 0° C., and slowly added to a solution of hydrazine hydrate at 0° C. (4.8 ml, 100 mmol) in acetonitrile (50 ml). The mixture was stirred at 0° C. for 1 hour, then warmed to room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue diluted with ethyl acetate, which was washed with water (2×), then brine. The organic phase was separated, and solvent removed under reduced pressure to provide 2-(4-chlorophenyl)-2-methylpropanehydrazide (9.64 g, 90%) as a white solid. LCMS (CI) shows M+H 213.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:11]2([C:14](=[O:15])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]1(=[O:15])[C:11]2([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)[CH2:12][NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCC12CCNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-oxo-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (150 mg, 0.624 mmol) in DCM (6 mL) was added TFA (3 mL) and the resulting solution stirred at RT for 1 h. The crude reaction mixture was loaded onto a Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to provide 2,7-diaza-spiro[3.5]nonan-1-one as a colourless oil. To a suspension of 2,7-diaza-spiro[3.5]nonan-1-one (0.624 mmol) in dichloroethane (13 mL) were added 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (130 mg, 0.458 mmol) and sodium triacetoxyborohydride (146 mg, 0.689 mmol) and the resulting suspension stirred at RT for 18 h. The reaction was quenched with water and loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was then purified by column chromatography to give the title compound as a white solid (93 mg, 50%)
Reaction SMILES: Cl.[N:2]1[C:7]2[CH2:8][NH:9][CH2:10][C:6]=2[CH:5]=[N:4][CH:3]=1.C[Al](C)C.C[Al](C)C.C1N2CCN(CC2)C1.[CH3:27][N:28]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:29]1[N:34]=[C:33]([NH2:35])[N:32]=[C:31]([C:36]2[N:40]=[C:39](C(Cl)(Cl)Cl)[O:38][N:37]=2)[N:30]=1>C1COCC1>[CH3:27][N:28]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:29]1[N:34]=[C:33]([NH2:35])[N:32]=[C:31]([C:36]2[N:40]=[C:39]([N:9]3[CH2:10][C:6]4[CH:5]=[N:4][CH:3]=[N:2][C:7]=4[CH2:8]3)[O:38][N:37]=2)[N:30]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Reactant: c1ncc2c(n1)CNC2
Agent: C1CN2CCN1CC2
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3Cc4cncnc4C3)n2)n1
Yield: 8.3 %

Procedure:
To a solution of 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride salt (38 mg, 0.231 mmol) in anhydrous THF (3 mL) was added DABAL-Me3 (bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]-octane) (57 mg, 0.231 mmol) at room temperature. The solution was heated under nitrogen at 40 C for 3 h and N-methyl-N-phenyl-6-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-[1,3,5]triazine-2,4-diamine (Intermediate 60, 60 mg, 0.155 mmol) was added. The resulting reaction mixture was heated at 80 C for 5 h and then quenched with water (2 mL) drop-wise. The solution was extracted into EtOAc (3×25 mL) and the combined organics washed with a 1M aq. solution of HCl (20 mL), brine (20 mL), dried over magnesium sulfate, evaporated to dryness and purified by preparative HPLC-MS (Method B) to afford the title compound as a white solid (5 mg, 8%).
Reaction SMILES: [CH:1]1([C:7]([NH2:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:7](=[S:11])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=S)C1CCCCC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 281.2 %

Procedure:
25.0 g Cyclohexanecarboxamide were dissolved in 200 ml toluene. 8.74 g phosphorus pentasulfide were added, followed by the addition of 33.0 g sodium bicarbonate. The reaction mixture was warmed to 115° C. and stirred overnight. The reaction mixture was filtered over a celite pad, washed with dichloromethane. The filtrate evaporated under reduced pressure. The residue was dissolved in 250 ml dichloromethane and the organic layer was washed three times with 100 ml water and twice with 100 ml brine. The aqueous layer was extracted five times with 100 ml dichloromethane. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The resulting residue was purified by chromatography with the eluent dichloromethane:ethyl acetate=1:1 to obtain 7.92 g Cyclohexanecarbothioic acid amide as a yellow solid.