Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[C:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10][C:9]=2[N:25]=1)(=O)=O.[C:37]1(S)[CH:42]=[CH:41]C=[CH:39][CH:38]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[C:1]1([S:2][C:5]2[N:6]=[C:7]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[C:8]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10][C:9]=3[N:25]=2)[CH:41]=[CH:42][CH:37]=[CH:38][CH:39]=1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Reactant: Sc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Nc2nc(Sc3ccccc3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 100 °C

Procedure:
To a microwave reaction vial were added [2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine (53 mg, 0.1 mmol), thiophenol (16 mg, 0.15 mmol), p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol), and DMF (0.4 mL). The vial was capped, and the mixture was heated via microwave irradiation at 100° C. for 10 min, filtered through a 0.45 μm filter, and the filtrate was purified by reversed phase HPLC (Phenomenex Gemini 30 mm×100 mm column, gradient of acetonitrile in 20 mM aqueous NH4OH). The title compound was obtained as a white solid (27 mg, 48%). MS (ESI): mass calcd. for C27H21F6N5S, 561.14; m/z found, 562 [M+H]+. 1H NMR (CDCl3): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.68-7.62 (m, 2H), 7.56-7.50 (m, 1H), 7.50-7.42 (m, 2H), 7.23 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 6.96 (dd, J=7.4, 4.6 Hz, 1H), 6.58 (bs, 1H), 3.66-3.55 (m, 4H), 3.23-3.17 (m, 2H), 2.96-2.90 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:28][CH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]1>CC(N(C)C)=O>[NH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:29]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:3]=2)[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCCCC(N)C1
Reactant: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Oc1ccccc1-c1nc(NC2CCCCNC2)c2ccccc2n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 5.8 %

Procedure:
2-(4-Chloroquinazolin-2-yl)phenol (0.093 g, 0.362 mmol) was dissolved in DMA (3.6 mL) and then treated with diisopropylethylamine (0.189 mL, 1.087 mmol) followed by tert-butyl 3-aminoazepane-1-carboxylate (0.078 g, 0.362 mmol) and the solution was heated at 60° C. After 18 hours, the reaction mixture was concentrated in vacuo to remove the excess amine and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The solvent was removed in vacuo and the residue was dissolved in methanol (0.22 mL) and treated with 4 M HCl in dioxane (0.22 mL). After 18 hours, the reaction mixture was concentrated in vacuo and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography, eluting with a gradient of 3% to 30% methanol in dichloromethane, gave the title compound as a yellow solid (0.007 g, 6%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Cl)C1C=CC=CC=1>>[CH2:19]([N:16]1[CH2:17][CH:13]([C:9]2([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11][CH2:10]2)[CH2:14][C:15]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(C2CNC(=O)C2)CCC1
Reactant: BrCc1ccccc1
Solvent: ClCc1ccccc1
Product: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CCC1

Procedure:
Next, 4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone is allowed to react with benzyl bromide or benzyl chloride using a base to yield 1-benzyl-4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone.
Reaction SMILES: O.[OH-].[Li+].O.C(O)C.C([O:10][C:11](=[O:52])[C:12]([CH:15]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]=2)=[CH:36][CH:35]=1)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:18][CH:17]=1)=[N:13][OH:14])C>C1COCC1.C(O)C.O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]([C:12](=[N:13][OH:14])[C:11]([OH:52])=[O:10])[C:34]2[CH:35]=[CH:36][C:37]([O:40][CH2:41][C:42]3[CH:51]=[CH:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:43]=3)=[CH:38][CH:39]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(=NO)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=NO)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1 h
Yield: 85.3 %

Procedure:
Lithium hydroxide monohydrate (1.4 g, 33.4 mmol) in 1:1 water-ethanol (20 mL) was added a solution of bis(4-(2-quinolylmethoxy)phenyl)-methyloximinoacetic acid ethyl ester (8.5 g, 14.2 mmol), prepared as in Example 3, in THF (80 mL) and ethanol (10 mL). The turbid reaction was stirred for 1 hour, and then was diluted with water (80 mL). The aqueous layer was washed with 1:1 ether-hexane (50 mL) and then filtered to remove fine solids. The filtrate was acidified to pH 4 with 1N HCl, and the precipitated solid collected by filtration and dried in vacuo to give bis(4-(2-quinolylmethoxy)phenyl)methyloximinoacetic acid (6.9 g, 85%): mp 183°-185° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:21]1[CH:22]=[CH:23][S:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccsc1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccc2c(cc(-c3ccsc3)n2Cc2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 3-thienylboronic acid (0.044 g, 0.34 mmol, Aldrich) and Na2CO3 (0.16 g, 1.6 mmol) in 1,2-dimethoxyethane (3 mL) and water (0.6 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.031 mmol) was added and the reaction was stirred at reflux for 15 minutes. Upon cooling to room temperature, the reaction was diluted with water. The product was extracted with EtOAc, and the combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a light yellow solid (47 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.37 (m, 2H), 7.36-7.27 (m, 4H), 7.20 (dd, J=5.0, 1.3 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 7.02-6.96 (m, 2H), 6.80 (d, J=0.8 Hz, 1H), 5.43 (s, 2H). LCMS (M+H)+: 324.9.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[C:11]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CO)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
L-Serine (20.00 g, 190.3 mmol) was dissolved in water, and aqueous sodium hydroxide was added to adjust the pH of the solution to about 8.5 while maintaining the temperature at about 25° C. Benzyl chloroformate (36.0 g, 211.0 mmol) was added while the pH was maintained between 8.3 and 8.5 by the addition of aqueous sodium hydroxide and the temperature was maintained at about 30° C. The mixture was stirred for about 2 hours. The reaction mixture was extracted with methylene chloride. The phases were separated, and the pH of the aqueous phase was adjusted to about 7 with concentrated hydrochloric acid. The aqueous phase was heated to about 40° C. under low vacuum to remove any residual methylene chloride. Water was added and the aqueous solution was heated to about 60° C. The pH was adjusted to about 2 with concentrated hydrochloric acid while maintaining the temperature at about 60° C. The solution was cooled to about 50° C. while stirring and seed crystals were added. With stirring, cooling was continued to about 0° C. to complete the crystallization. The product was collected and the cake was washed with cold (about 5° C.) water. The product was dried under vacuum at about 40° C. to afford carbobenzyloxy-L-serine.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:9][C:7](=[O:8])[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]2)[C:4](=[O:5])[CH2:3]1.P(OCC)(OCC)[O:28]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C=NC(N2CCN(CCCCN3C(=O)CC4(CCCC4)CC3=O)CC2)=NC=1>C1COCC1>[CH3:1][C:2]1([CH3:26])[CH:3]([OH:28])[C:4](=[O:5])[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[C:7](=[O:8])[CH2:9]1
Reactant: CC1(C)CC(=O)N(CCCCN2CCN(c3ncccn3)CC2)C(=O)C1
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(CCCCN2CCN(c3ncccn3)CC2)C(=O)C1O
Temperature: 25 °C
Yield: 89.3 %

Procedure:
Gepirone (4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6-piperidinedione) (10.0 g, 27.8 mmol) was charged to a 500 mL flask equipped with a mechanical stirrer and a React-IR probe under inert gas. Tetrahydrofuran (250 mL, 25 mL/g) was charged and the mixture agitated at ambient temperature until homogeneous. Triethyl phosphite (28.9 g, 174 mmol, 29.8 mL, 6.25 eq) was added and the mixture was cooled to −65 to −80° C. The mixture was agitated at this temperature for at least 10 minutes to allow the React-IR signal to stabilize. 1.0 M Sodium bis(trimethylsilyl)amide in THF (27.8 mL, 27.8 mmol, 1.00 eq) was charged to the mixture at such a rate so as to maintain the temperature less than −60° C. Small amounts of sodium bis(trimethylsilyl)amide were charged to the mixture until the IR signal for buspirone reached a minimum indicating complete deprotonation of gepirone. Additional gepirone in THF (25 mL/g) was then charged to the reaction mixture in small increments until the IR signal indicated a 3.24% excess of gepirone. Air was sparged into the reaction mixture, controlling the initial rate of sparging so as to maintain the temperature of the reaction mixture less than −60° C. The sparging was continued until the reaction was complete as indicated by HPLC. Methyl tert-butyl ether (40.0 mL) was added followed by 1M hydrochloric acid (45.0 mL) and the solution was warmed to ambient temperature. The pH (9.48 at 20.6° C.) was adjusted to between 6.5 and 6.9 using hydrochloric acid and Na3PO4 (pH=6.95 at 22.7° C.). The phases were separated and the organic phase was washed twice with 25 wt % brine (40.0 mL). The solvent of the rich organic layer was then replaced by isopropyl alcohol and the solution was cooled to ambient temperature to crystallize the reaction product. The crystalline slurry was then filtered and the wet cake was washed twice with isopropyl alcohol (15.0 mL) and dried to provide 3-hydroxygepirone (9.32 g, 89%), mp 128° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[ClH:4].[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:24]([N:26]1[CH2:34][CH2:33][CH2:32][C@H:27]1[C:28](OC)=[O:29])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[ClH:4].[CH2:1]([NH:3][C:28](=[O:29])[C@@H:27]1[CH2:32][CH2:33][CH2:34][N:26]1[C:24](=[O:25])[C@H:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:22])[NH2:23])[NH:15][C:13]([O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14])[CH3:2]
Reactant: CCN
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1

Procedure:
To a cold solution of 9.7 g. ethylamine in 50 ml. of methanol is added 2 g. of Nα -benzyloxycarbonyl-L-arginyl-L-proline, methyl ester, hydrochloride. The reaction is let stand in a sealed pressure bottle at room temperature and then warmed occasionally to 40°-45° C. during eight days. It is then evaporated to small volume under reduced pressure. The residual solution is dropped into stirred ethyl ether to precipitate a somewhat sticky white solid which is dried under reduced pressure; [α]D25 -53° (c 1.02, methanol); ultraviolet in methanol λmax 257 E11 4.2.
Reaction SMILES: [BrH:1].[CH2:2]([O:9][C@H:10]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:14]([CH3:33])[O:13][CH:11]1O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+](C1C=CC(C([O-])=O)=CC=1)([O-])=O>C(Cl)Cl>[BrH:1].[CH2:2]([O:9][C@H:10]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:14]([CH3:33])[O:13][C@H:11]1[Br:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H]1OC(O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: Br
Agent: O=C([O-])c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: C[C@@H]1O[C@@H](Br)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.58 h

Procedure:
A saturated solution of HBr in CH2Cl2 (20.0 mL) was prepared by passing anhydrous HBr in CH2Cl2 at 0° C. for 30 min. This solution was added to a cold solution of the α-isomer of the 2,3,4-tri-O-benzylfucopyranose-p-nitrobenzoate (compound 8) (6.5 g, 11 mmol) in CH2Cl2 (150 mL) at 0-5° C., and the mixture was stirred at 5° C. for 30-40 min. The precipitated p-nitrobenzoic acid was filtered off, and the filtrate was successively washed with cold sat. NaHCO3 and water until neutral. The extract was dried (MgSO4) and the solvent removed at RT in vacuo to afford exclusively the α-fucopyranosyl bromide as a highly viscous liquid (5.3 g, yield 95%).
Reaction SMILES: [C:1](=[S:3])=S.[N:4]1([CH2:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C>CC(C)=O.[Hg](Cl)Cl>[N:4]1([CH2:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[O:14][CH2:15][CH2:16][CH2:17][N:18]=[C:1]=[S:3])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: S=C=S
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl[Hg]Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: S=C=NCCCOc1cccc(CN2CCCCC2)c1
Temperature: -14 °C

Procedure:
A solution of carbon disulphide (3.3 ml) in acetone (8 ml) was added dropwise to a solution of 3-[3-(1-piperidinylmethyl)phenoxy]propanamine (12.4 g) in acetone (30 ml) over a 15 minute period, between -5° and -10° C. The solution was cooled to -14° C. and mercury (II) chloride (13.6 g) in acetone (30 ml) was added, during 45 minutes. Triethylamine (16 ml) was added at 0° C. during 15 minutes, and the mixture was heated at reflux for 45 minutes. The resulting suspension was purified by filtration and the filtrate evaporated in vacuo. The residue was purified by column chromatography using methanol as eluant to give the title compound (6 g) as an amber oil. TLC silica/cmethanol Rf 0.4.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[NH:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11].[N:14]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:21][CH2:20][CH2:19][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:8])[NH:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1[nH]c(C(=O)Cl)cc1Cl
Reactant: NCCN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1[nH]c(C(=O)NCCN2CCCC2)cc1Cl
Yield: 69 %

Procedure:
A solution of methyl 3-chloro-5-(chlorocarbonyl)-1H-pyrrole-2-carboxylate (0.100 g, 0.387 mmol) in 4 mL of DCM was treated with [2-(1-pyrrolidinyl)ethyl]amine (0.110 g, 0.967 mmol). After 1 hour saturated NaHCO3 was added and the mixture shaken. The DCM layer was separated, dried over MgSO4 and evaporated onto silica gel. Purification was accomplished on silica with 0 to 10% MeOH in EtOAc to afford the title compound (0.080 g, 69%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (t, 1H), 6.80 (d, 1H), 3.78 (s, 3H), 3.32 (q, 2H), 2.52 (t, 2H), 2.45 (br. s., 4H), 1.65 (br. s., 4H). LCMS: m/z 298.2 (M−1).
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[C:15]([OH:16])=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=1)=O>CO>[OH:16][C:15]1[C:6]([C:4]([NH2:1])=[O:3])=[CH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: COC(=O)c1cc2c(cc1O)CCCC2
Reactant: N
Solvent: CO
Product: NC(=O)c1cc2c(cc1O)CCCC2
Temperature: 100 °C

Procedure:
To 300 ml of methanol saturated with ammonia gas at 0° C. was added 122 g of 3-hydroxy-5,6,7,8-tetrahydro-2-naphthoic acid methyl ester, and the mixture was maintained in an autoclave at 100° C. for 5 hours. After cooling, the precipitating solid was filtered off, washed with a small amount of methanol, and dried, giving 96 g of a pale yellow crystal having the following physical properties.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.C(=O)([O-])N.[Cl:26][C:27]1[CH:28]=[C:29]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:30]([N:32]=[C:33]=[O:34])=[O:31]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:30]([NH:32][C:33](=[O:34])[O:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=1)=[O:31]
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)c1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CCn1c(COC(=O)NC(=O)c2cc(Cl)cc(Cl)c2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 78 %

Procedure:
The compound 19 (300 mg, 0.869 mmol) was converted to the carbamate with 3,5-dichlorobenzoyl isocyanate (1.5 eq.) in the same manner as the example 66 to give the compound 87 (380 mg, 78%) as crystals. Mp.124-125° C. Rf 0.23 (1:2 EtOAc-hexane)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Br>[CH:1]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Agent: Br
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Yield: 68.8 %

Procedure:
16.1 g (0.05 mol) of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benz[e]indole were boiled at 120° for 3 hours with 270 ml of 48 percent aqueous hydrobromic acid. After distilling off the hydrobromic acid in a vacuum the residue was dissolved in methylene chloride/water. After extraction with methylene chloride at pH 8 the solvent was distilled off in a vacuum. After chromatography over silica gel (methylene chloridemethanol 10:1) there were obtained 10.3 g (67%) of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol as a beige oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([N:20]1[CH2:23][CH:22]([O:24]S(C)(=O)=O)[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:29]1([C:35]2[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH:7]([N:20]1[CH2:23][CH:22]([O:24][C:38]2[CH:39]=[CH:40][C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:36][CH:37]=2)[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(OC3CN(C(c4ccccc4)c4ccccc4)C3)cc2)cc1
Yield: 21.3 %

Procedure:
Potassium carbonate (2.39 g, 17.4 mmol) was added to a stirred mixture of 1-benzhydryl-3-methanesulphonyloxyazetidine (J.Org.Chem., 1972, 37, 3953; 5 g, 15.8 mmol), 4-phenylphenol (2.95 g, 17.4 mmol) and anhydrous dimethylformamide (65 ml), then the resulting mixture heated under reflux for 4 hours, allowed to cool and partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure, then the residue purified by flash chromatography, using hexane:ethyl acetate (95:5) as eluant, to give the title compound (1.32 g) as a colourless, amorphous solid. δ(CDCl3): 3.17 (dd,2H), 3.75 (dd,2H), 4.43 (s,2H), 4.83 (m,1H), 6.81 (d,1H), 7.16-7.55 (m,17H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:34]([NH:35]C(=O)OCC3C=CC=CC=3)=[CH:33][C:32]3[C:27](=[CH:28][C:29]([C:46]4[CH2:47][CH2:48][O:49][CH2:50][CH:51]=4)=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:35][C:34]1[C:25]([C:23]([NH:22][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:11]2[CH2:12][C@H:13]([CH3:15])[CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]2)=[O:24])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[CH:28]=2
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(C4CCOCC4)ccc3cc2N)C1
Yield: 89.2 %

Procedure:
A mixture of benzyl [2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate (0.017 g, 0.024 mmol) in 1.5 mL of MeOH was hydrogenated in the presence of 10% Pd on carbon (10 mg) under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl {(3S,5R)-1-[3-({[3-amino-7-(tetrahydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate (0.012 g, 87%). LCMS calc. for C31H41N6O4 [M+H]+: m/z=561.3. found: 561.4. To the intermediate made above was added 1 mL of 4 M HCl in dioxane and 1 mL of MeOH. The mixture was stirred at room temperature for 1 h, then evaporated under vacuum. The residue was dissolved in 4.5 mL of MeOH and treated with 0.3 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H33N6O2 [M+H]+: m/z=461.3. found: 461.3.