Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[C:5]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:4]=2[C:3]=1[F:23].[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCCCCC>[CH:24]1([S:27]([N:11]2[C:5]3[C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]([F:23])[C:4]=3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:29])=[O:28])[CH2:26][CH2:25]1
Reactant: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c(F)c3ncoc3c2n1S(=O)(=O)C1CC1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
TEA (78 mg, 0.55 mmol) and DMAP (10 mg) were added to a solution of 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-15a: 80 mg, 0.178 mmol) in dry DCM (5 mL) at 0° C. and the resulting mixture was stirred for 15 minutes. This was followed by the addition of cyclopropanesulfonyl chloride (39 mg, 0.27 mmol) and stirring was continued for a further 3 hours at room temperature. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (20-30% ethyl acetate in hexane) afforded 65 mg of the product (65% yield). H1NMR (CDCl3, 300 MHz): δ 8.14 (s, 1H), 7.72-7.65 (m, 2H), 7.28-7.24 (m, 1H), 3.35-3.25 (m, 1H), 1.75-1.60 (m, 2H), 1.35-1.25 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=4[CH3:24])=[N:15][N:14]=[C:13]([C:25]([NH2:27])=[O:26])[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2].[CH:28]([C:30]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:31]=1[C:32]([OH:34])=O)=[O:29].C(O[BH-](OC(=O)C)OC(=O)C)(=[O:43])C.[Na+].C(O)(=O)C>ClCCl.O1CCCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[C:18]([CH3:24])=[C:19]([NH:23][C:32]([C:31]5[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:30]=5[C:28]([OH:29])=[O:43])=[O:34])[CH:20]=[CH:21][CH:22]=4)=[N:15][N:14]=[C:13]([C:25](=[O:26])[NH2:27])[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)nnc(-c3cccc(N)c3C)c12
Reactant: COc1ccc(C=O)c(C(=O)O)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(C(=O)O)c(C(=O)Nc2cccc(-c3nnc(C(N)=O)c4[nH]c5cc(C(C)=O)ccc5c34)c2C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 7-acetyl-1-(3-amino-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide (0.250 g, crude product from the previous step), 2-formyl-5-methoxybenzoic acid (0.251 g, 1.391 mmol), sodium triacetoxyborohydride (0.442 g, 2.087 mmol), and acetic acid (0.100 mL, 1.739 mmol) in dichloromethane (18 mL) and tetrahydrofuran (18 mL) was stirred at room temperature for 3 hr. Additional sodium triacetoxyborohydride (0.442 g, 2.087 mmol) was added and the reaction mixture was stirred at rt. Three hours later, another portion of sodium triacetoxyborohydride (0.442 g, 2.087 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with water (30 mL) and the mixture was extracted with ethyl acetate (4×40 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provided the crude desired product (0.336 g) as a beige solid.
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.C(N(CC)CC)C.C(Cl)(=O)C1C=CC=CC=1>ClCCl>[CH3:29][O:28][C:20]1[CH:19]=[C:18]([NH:17][C:14]2[N:15]=[N:16][C:11]([CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:10])=[CH:12][N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[C:21]=1[O:26][CH3:27]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.28 g, 0.92 mmol), triethylamine (0.28 mL, 2.0 mmol) and benzoyl chloride (0.14 g, 1.0 mmol) in dichloromethane (10 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.30 g) as a white solid. MS m/z 410, (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]1[NH:8][N:9]=[CH:10][C:6]=1[CH2:5]2.[Li]C1C=CC=CC=1.C1CCCCC1.C[CH2:28][O:29]CC.[Li]C(CC)C.C1CCCCC1.CN(C=O)C>C1COCC1>[NH:8]1[C:7]2[C:11]3[C:4]([CH2:5][C:6]=2[CH:10]=[N:9]1)=[CH:3][C:2]([CH:28]=[O:29])=[CH:13][CH:12]=3
Reactant: CCOCC
Reactant: Brc1ccc2c(c1)Cc1cn[nH]c1-2
Agent: [Li]C(C)CC
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)Cc1cn[nH]c1-2
Temperature: -78 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 6-bromo-1,4-dihydro-indeno[1,2-c]pyrazole (0.100 g, 0.425 mmol, see U.S. Pat. No. 6,297,238 for preparation) in THF (3 mL) at −78° C. was added 1.8 M PhLi in cyclohexane/ether (0.71 mL, 1.28 mmol) followed by 1.3 M s-BuLi in cyclohexane (0.98 mL, 1.28 mmol) 30 minutes later. The reaction mixture was stirred at −78° C. for 60 minutes and DMF (0.33 mL, 4.25 mmol) was added. The dry ice bath was removed after 30 minutes. After an additional 30 minutes, the reaction was quenched with water. The reaction mixture was extracted with EtOAc, washed with 50% brine, dried over MgSO4, filtered, and concentrated. The concentrate was purified by flash chromatography eluted with EtOAc/hexane (7:3 to 8:2) to give 0.053 g (68%) of the desired product as brown solid. MS (DCI/NH3) m/z: 185.0 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 3.76 (s, 2H), 7.63 (s, 1H), 7.62-7.97 (m, 2H), 8.04 (s, 1H), 10.00 (s, 1H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([CH3:29])[CH:6]=[C:5]([O:30][CH3:31])[C:4]=1[CH3:32].[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH:44]=O)[CH3:43])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH3:44])[CH:43]=[CH:9][C:8]1[C:3]([Cl:2])=[C:4]([CH3:32])[C:5]([O:30][CH3:31])=[CH:6][C:7]=1[CH3:29])[CH3:34]
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1C
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1Cl

Procedure:
By the procedure of Example 1, 6-chloro-4-methoxy-2,5-dimethyl-benzyl-triphenylphosphonium chloride is reacted with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to obtain 9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester of melting point 106-107° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[C:29]([Cl:44])=[CH:28][N:27]=1>>[Cl:44][C:29]1[C:30]([NH:32][C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(N)c2OC
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)c2OC
Yield: 26.8 %

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2,2,2-trifluoro-acetamide (193 mgs) and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (180 mgs) gave the title compounds as an off-white solid (92 mgs). 1:1 mix of diastereomers. 1H-NMR (CDCl3, 400 MHz): 8.29-8.24 (m, 1H), 8.05-8.02 (m, 1H), 7.59-7.52 (m, 1H), 7.02-7.00 (m, 1H), 4.55-4.53 (m, 2H), 3.94-3.90 (m, 1H), 3.85 (s, 1H), 3.59-3.53 (m, 1H), 3.38-3.32 (m, 1H), 3.16-3.10 (m, 1H), 2.90 (s, 3H), 2.76-2.68 (m, 1H), 2.57-2.52 (m, 1H), 2.20-1.20 (complex series of m, 12H); LC/MS: found (M+H)+=648; MP: 160-2° C.
Reaction SMILES: [N:1]1([C:6]([O:8][C@H:9]2[CH2:14][C@H:13]([C:15]([NH:17][OH:18])=[O:16])[C@@H:12]([C:19]([N:21]3[CH2:26][CH:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[O:20])[N:11]([CH3:33])[CH2:10]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[N:1]1([C:6]([O:8][C@H:9]2[CH2:14][C@H:13]([C:15]([NH:17][OH:18])=[O:16])[C@@H:12]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[O:20])[N:11]([CH3:33])[CH2:10]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CN1C[C@@H](OC(=O)N2CCCC2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CC=C(c2ccccc2)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CN1C[C@@H](OC(=O)N2CCCC2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCC(c2ccccc2)CC1
Yield: 99.1 %

Procedure:
A solution of (3S,5S,6S)-5-[(hydroxyamino)carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidin-3-yl pyrrolidine-1-carboxylate (5.0 mg, 0.000011 mol) TFA salt in 1 mL of MeOH was hydrogenated in the presence of 5% Pd/BaSO4, under a balloon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was concentrated to dry to give the product (5.0 mg, 100%). MS (ESI): (M+H)+=459.15.
Reaction SMILES: [C:1]([C:9]1[C:14]([C:15]([O:17]CC)=O)=[CH:13][N:12]=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[N:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][NH:35][NH2:36]>C(O)CCC>[CH3:34][N:35]1[C:15](=[O:17])[C:14]2[CH:13]=[N:12][C:11]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:25][CH:26]=3)=[N:10][C:9]=2[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:36]1
Reactant: CNN
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1ccccc1
Solvent: CCCCO
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)n(C)nc(-c5ccccc5)c4n3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of Example 3B (50 mg, 0.112 mmol) and methylhydrazine (6.50 μl, 0.123 mmol) in n-butanol (12.5 mL) was heated to 170° C. by microwave irradiation (Biotage Initiator) for 3 hour. The reaction mixture was cooled to room temperature, and the solid was filtered and air-dried to provide the title compound. MS ESI(+) m/z 428.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6): δ ppm 10.34 (s, 1H), 9.29 (s, 1H), 7.94-7.91 (m, 2H), 7.59-7.48 (m, 5H), 6.84 (d, J=8.7 Hz, 2H), 3.75 (s, 3H), 3.13-3.05 (m, 4H), 2.47-2.44 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[C:17]2[C:28]([CH3:29])=[N:27][N:26]([CH3:30])[C:18]2=[N:19][C:20]=1[NH:21][CH2:22][CH:23]1[CH2:25][CH2:24]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.C(N(CC)CC)C.[CH:47]1([C:50](Cl)=[O:51])[CH2:49][CH2:48]1>C1COCC1.C(OCC)(=O)C>[F:38][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[C:17]2[C:28]([CH3:29])=[N:27][N:26]([CH3:30])[C:18]2=[N:19][C:20]=1[N:21]([CH2:22][CH:23]1[CH2:24][CH2:25]1)[C:50]([CH:47]1[CH2:49][CH2:48]1)=[O:51])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nn(C)c2nc(NCC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nn(C)c2nc(N(CC3CC3)C(=O)C3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of (5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclopropylmethyl-amine (0.25 g, 0.45 mmol), triethylamine (0.13 g, 1.3 mmol), and cyclopropanecarbonyl chloride (0.28 g, 2.7 mmol) in THF (5 mL) was prepared in 10 mL reaction vessel and irradiated with 250 Watt microwave power, under 250 psi at 80° C. for 2 h. The vessel was cooled to RT and the reaction mixture was diluted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (3×100 mL), the organic layer was separated out, dried over sodium sulfate, and concentrated. The resulting oil was purified by column chromatography using silica gel (230-400 mesh) and eluting the column with 1% methanol in dichloromethane afforded a colorless solid (0.147 g, yield: 52.5%).
Reaction SMILES: [N+](CC)([O-])=O.C(N)(C)C.C=O.[N+:12]([C:15]([CH3:26])([CH2:21][NH:22][CH:23]([CH3:25])[CH3:24])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])([O-])=O>CC(O)C>[NH2:12][C:15]([CH3:26])([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:21][NH:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)NCC(C)(CNC(C)C)[N+](=O)[O-]
Agent: C=O
Solvent: CC(C)N
Solvent: CC(C)O
Solvent: CC[N+](=O)[O-]
Product: CC(C)NCC(C)(N)CNC(C)C
Reaction time: 4 h

Procedure:
In a manner analogous to that described hereinabove, 1 mol of nitroethane is added slowly to 2 mols of isopropylamine to form the salt intermediate, and thereafter 2 mols of paraformaldehyde are slowly added to the salt with stirring which is continued for 4 hr. The conversion of the nitroethane to 2-nitro-2-methyl-1,3-di(isopropylamino)propane is in excess of 90 mol %. The reaction mixture is then diluted with 250 ml of i-PrOH and hydrogenated in a manner analogous to that described hereinabove, to yield 2-amino-2-methyl-1,3-di(isopropylamino)propane the conversion of which is in excess of 90 mol % based on the nitroethane charged.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]C1C=C2C(C=CN2)=CC=1)([CH3:4])([CH3:3])[CH3:2].C(O[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]([NH2:33])=[O:32])[CH:26]=[C:25]2[N:34]=[C:35]=[O:36])C=C>>[C:1]([O:5][C:6](=[O:17])[CH2:7][C:30]1[CH:29]=[C:28]2[C:24]([C:25]([N:34]=[C:35]=[O:36])=[CH:26][N:27]2[C:31](=[O:32])[NH2:33])=[CH:23][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc2cc[nH]c2c1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: CC(C)(C)OC(=O)Cc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from (1H-indol-6-yl)-acetic acid tert-butyl ester using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.Cl.[NH:18]1CCN=[C:19]1[CH2:23]OC1C=C(NS(C)(=O)=O)C=CC=1.NC1C=C(C=CC=1)OCC#N>>[ClH:1].[Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:5]=[C:6]([CH2:8][C:9]2[NH:18][CH2:19][CH2:23][N:10]=2)[CH:7]=1
Reactant: Cc1c(Cl)cc(CC#N)cc1NS(C)(=O)=O
Reactant: CS(=O)(=O)Nc1cccc(OCC2=NCCN2)c1
Agent: Cl
Agent: N#CCOc1cccc(N)c1
Product: Cc1c(Cl)cc(CC2=NCCN2)cc1NS(C)(=O)=O

Procedure:
N-(3-chloro-5-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-methylphenyl]methane-sulfonamide hydrochloride (mp 256.2-256.7° C.) was prepared from N-(3-chloro-5-cyanomethyl-2-methylphenyl) methanesulfonamide in a manner similar to that described in Example 1 for the preparation of N-[3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)phenyl] methanesulfonamide hydrochloride from (3-aminophenoxy)acetonitrile.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][CH:4]=[O:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O.CC(C)=CCO.[N+]([O-])(O)=O>O>[CH3:6][C:2]([CH3:1])=[CH:3][CH2:4][O:5][CH2:10][CH:9]=[C:8]([CH3:12])[CH3:7]
Reactant: CC(C)=CC=O
Reactant: C=C(C)CC=O
Agent: CC(C)=CCO
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(C)=CCOCC=C(C)C
Reaction time: 16 h

Procedure:
700 g of a mixture containing 90.2% by weight of 3-methyl-but-3-en-1-al and 5.3% by weight of 3-methyl-but-2-en-1-al, 2,780 g of 3-methyl-but-2-en-1-ol and 6 g of 51% strength aqueous nitric acid are boiled under 100 mm Hg in a 4 liter flask surmounted by a packed column (filled with 5 mm Raschig rings). The bottom temperature assumes a value of from 86 to 93° C. The column has a diameter of 45 mm and has 30 theoretical plates. The water formed in the reaction is taken off at the top of the column and the organic materials which separates from the water is returned continuously into the column. With a reflux of 600 g/hour, quantitative conversion of the aldehyde is achieved in 16 hours. After distilling off the excess alcohol, a mixture consisting of 74.5% by weight of 1,1-bis-(3-methyl-but-2-en-1-yloxy)-3-methyl-but- 3-ene and 10.6% by weight of 1,1-bis-(3-methyl-but-2-en-1-yloxy)-3-methyl-but-2-ene, together with the by-products 3-methyl-butadien-1-yl-3-methyl-but-2-en-1-yl-ether (5.9% by weight) and di-(3-methyl-but-2-en-1-yl)-ether is obtained. The selectivity of the acetals obtained is 86.5% based on the sum of the aldehydes employed and 72.5% based on 3-methyl-but-2-en-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=O.C(O)=O.[C:16]([OH:22])(=[O:21])[CH2:17]C(O)=O.C([O-])=O.[NH4+:26].Cl>O>[NH2:26][CH:7]([C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:17][C:16]([OH:22])=[O:21]
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C(O)CC(=O)O
Reactant: [NH4+]
Agent: Cl
Agent: O=C[O-]
Solvent: O=CO
Solvent: O
Product: NC(CC(=O)O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
5-Fluoro-2-nitrobenzaldehyde (16.91 g, 0.10 mol), formic acid (15.2 mL, 0.40 mol) and malonic acid (13.52 g, 0.13 mol) were stirred at 45° C. for half an hour. Then ammonium formate (15.76 g, 0.25 mol) was added thereto. The reaction temperature was raised to 70° C. and stirred for 1 hour. Then it was stirred at 95° C. for another 4 hours, and then concentrated hydrochloric acid (38 mL) was added and stirred maintaining this temperature for another 1 hour. It was cooled. Water (20 mL) was added, extracted with ethyl acetate (2×25 mL), and the aqueous phase was adjusted to pH≈4.2 with 50% potassium hydroxide solution. A solid precipitated, pumping filtered, dried in vacuum to obtain a yellow solid 15.32 g, at a yield of 67.1%.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.Cl[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C@@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:6][N:7]1[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: C[C@@H]1CN(c2ccccn2)CCN1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccccn2)CCN1Cc1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
The product of Example 26A (0.79 g, 4.43 mmol) and N,N-dimethylformamide (15 mL) at 0° C. was treated with a solution of the 2-chloromethyl-1H-benzimidazole (0.70 g, 4.21 mmol) in N,N-dimethylformamide (15 mL). After 10 minutes, the mixture was treated with cesium carbonate (1.37 mmol, 4.21 mmol) and the cooling bath was removed. After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with water (3×) and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (1-3% methanol/dichloromethane gradient) to afford 0.50 g (39% yield) of the title compound as a light yellow solid. mp 151-153° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18 (d, J=6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J=8, 11.2 Hz, 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J=14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J=14 Hz, 1H), 6.60 (dd, J=4.8, 6.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; Anal. calcd for C18H21N5: C, 70.33; H, 6.89; N, 22.78. Found: C, 70.10; H, 7.03; N, 22.63.
Reaction SMILES: N1CC[C@H](N(C2CCCCC2)CC(OC)=O)[CH2:2]1.[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:32](=[O:37])[NH:33][CH:34]([CH3:36])[CH3:35])[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:32](=[O:37])[N:33]([CH3:2])[CH:34]([CH3:35])[CH3:36])[CH2:27][CH2:26]1)([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: CC(C)NC(=O)N(C1CCCCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)CN(C1CCCCC1)[C@H]1CCNC1
Product: CC(C)N(C)C(=O)N(C1CCCCC1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared following the procedure described in Step A of Intermediate 128 using 1-BOC-4-[cyclohexyl(isopropylcarbamoyl)amino]piperidine.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:25]([N:27]1[CH2:38][CH2:37][CH2:36][C@H:28]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)C1C=CC=CC=1.N1CCC[C@H]1C(OC(C)(C)C)=O>[OH-].[OH-].[Pd+2].C(OCC)(=O)C.C(O)C>[CH3:23][C:21]([CH3:24])([O:20][C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:25]([N:27]1[CH2:38][CH2:37][CH2:36][C@H:28]1[C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[O:26])[NH2:11])=[O:19])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
A mixture of the 1,1-dimethylethyl ester product from part (a) (4.13 g., 7.73 mmole) and palladium hydroxide/carbon catalyst (400 mg.) in ethyl acetate (90 ml.) and ethanol (10 ml.) is stirred under a hydrogen atmosphere (balloon). The system is evacuated and refilled with fresh hydrogen every 30 minutes. After stirring for 3 hours, the catalyst is removed by filtration (Teflon millipore) and the filtrate is concentrated at reduced pressure to give 3.15 g. of 1-[N6 -](1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][CH:11]=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[Na+].[Cl-].C(O)(=[O:17])C>>[O:17]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][CH:11]=[O:12])[CH2:7][CH2:8]1
Reactant: CC(=O)O
Reactant: O=CNC1CCCc2sccc21
Agent: [Cl-]
Agent: [Na+]
Product: O=CNC1CCC(=O)c2sccc21
Reaction time: 0.25 h

Procedure:
Ceric ammonium nitrate (726.9 grams) is added portionwise to a stirred solution of 59.6 grams of (-)-N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)formamide in 1712 ml. of 50% aqueous acetic acid. The addition is completed in half an hour and the temperature is kept at 25°-28° C. After 15 minutes of stirring, the mixture is saturated with NaCl and extracted with CH2Cl2 (2×1200 ml., 600 ml.) and the combined extracts are washed with 600 ml. of brine and then with 250 ml. of water. The water is counter-extracted with 250 ml. of CH2Cl2 and the CH2Cl2 solution is added to the main CH2Cl2 solution. The CH2Cl2 solution is evaporated to dryness in vacuo and the residual dark, gummy residue is stirred with 500 ml. of dry diethyl ether for 1.5 hour and the large lumps of solid are pulverized. The title compound is then collected, washed with diethyl ether, and dried. This gives 48.65 g., m.p. 130°-136° C., [α]D24 =144.4° (c, 0.51 in HOAc).