Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:7]3[C:6]=2[CH:19]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[OH-].[Na+]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[C:14]([CH2:17][N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[N:15][N:16]=[C:7]3[C:6]=2[CH:19]=1
Reactant: CN1C(=O)Cn2c(CCl)nnc2-c2cc(Cl)ccc21
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CN1CCN(Cc2nnc3n2CC(=O)N(C)c2ccc(Cl)cc2-3)CC1
Yield: 65.9 %

Procedure:
10-Chloro-3-(chloromethyl)-7-methyl-5H-s-triazolo[4,3-d][1,4]benzodiazepin-6(7H)-one (5 g, prepared as described in Example 9) is suspended in 50 ml of 1,2-dimethoxyethane. N-methylpiperazine (5.4 g) is added to the suspension and the mixture is heated under reflux for 5 hours. The solvent is stripped off, 3N aqueous sodium hydroxide is added to the residue and the mixture is extracted with several portions of chloroform. The combined chloroform extracts are dried over sodium sulfate and the solvent is removed under vacuum to leave a residue which is recrystallized from absolute ethanol to yield 4 g of the title compound, melting point 228.5°-230.5° C.
Reaction SMILES: BrC1C=CC=C2C=1C=C(C(O)=O)N2.[N:14]1([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]([C:32]3[NH:33][C:34]4[C:39]([CH:40]=3)=[C:38]([Br:41])[CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]C1>>[N:14]1([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]([C:32]3[NH:33][C:34]4[C:39]([CH:40]=3)=[C:38]([Br:41])[CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:25][CH2:24]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Agent: O=C(O)c1cc2c(Br)cccc2[nH]1
Product: O=C(NC1CCN(CCN2CCCCC2)CC1)c1cc2c(Br)cccc2[nH]1

Procedure:
This compound is synthesized from 4-bromo-1H-indole-2-carboxylic acid and amine 4 analogously to the method described above for the synthesis of 194 (see example 156).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: Nc1ccccc1
Reactant: Cc1ncc([N+](=O)[O-])cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc([N+](=O)[O-])cc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-5-nitronicotinic acid (364 mg, 2 mmol), aniline (186 mg, 2 mmol) and DIEA (774 mg, 6 mmol) in DMF (6 mL) is added HATU (798 mg, 2.1 mmol). The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed by rotary evaporation and the crude product is purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to afford-methyl-5-nitro-N-phenylnicotinamide as a light green solid. MS m/z 258.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH2:1]([O:8][CH:9]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:10][O:11][S:32]([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COS(=O)(=O)c1ccc(C)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
In 5 ml of pyridine were dissolved 1 g (2.3 mmole) of 2-O-benzyl-3-O-octadecylglycerol and 1.144 g (6.0 mmole) of tosyl chloride, and the solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and 20 ml of 10% aqueous hydrogen-carbonate solution and 20 ml of ether were added to the residue, followed by shaking thoroughly. The ether layer was separated, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by 15 g of silica gel, with n-hexane-ethyl acetate (9:1) used as an eluent, to give 1.2 g (yield of 88.6%) of a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1C=[CH:15][CH:14]=[CH:13][N:12]=1)[N:6]=[CH:5]2.[NH:17](C1N=CC=CN=1)N>>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[CH:13][CH:14]=[CH:15][N:17]=1)[N:6]=[CH:5]2
Reactant: Ic1ccc2c(cnn2-c2ccccn2)c1
Reactant: NNc1ncccn1
Product: Ic1ccc2c(cnn2-c2ncccn2)c1

Procedure:
Prepared as described for 118b using 2-hydrazinopyrimidine. Yield 296 mg (24%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:20]=[CH:19][S:18][C:4]=2[N:5]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:6](=[O:13])[C:7]=1[C:8]([O:10]CC)=O.[N:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:20]=[CH:19][S:18][C:4]=2[N:5]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:6](=[O:13])[C:7]=1[C:8]([NH:30][CH2:29][CH2:28][CH2:27][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:10]
Reactant: NCCCN1CCCCC1
Reactant: CCOC(=O)c1c(O)c2ccsc2n(CC(C)C)c1=O
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(=O)c(C(=O)NCCCN2CCCCC2)c(O)c2ccsc21
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A mixture of ethyl 6,7-dihydro-4-hydroxy-7-isobutyl-6-oxothieno[2,3-b]pyridine-5-carboxylate (0.1 g, 0.34 mmol), 3-(piperidin-1-yl)propan-1-amine (96 mg, 0.68 mmol) and toluene (15 mL) was heated at 100° C. for 2 h and cooled to room temperature. Solvent was removed under reduced pressure; the residue was purified on a silica gel flash chromatography column eluted with 3% methanol-dichloromethane to afford the title compound as a colorless oil (0.11 g, 83% yield). 1H NMR (400 MHz, CDCl3): δ 10.20 (br s, 1H), 7.38 (d, 1H), 6.95 (d, 1H), 3.92 (d, 2H), 3.49-3.44 (m, 2H), 2.90-2.78 (m, 6H), 2.40 (m, 1H), 2.20-1.38 (m, 8H), 1.00 (d, 6H); MS: m/e 392 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
Combine 3-(4-Iodophenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (50 mg, 0.12 mmol), morpholine (20 μl, 0.23 mmol), Pd2(dba)3 (3.5 mg, 0.006 mmol), cessium carbonate (53 mg, 0.16 mmol) and (+)-BINAP (5.4 mg, 0.009 mmol) in anhydrous toluene (1 ml) and stir at 100° C. for 12 hours. Cool the reaction mixture to room temperature, filtered through celite and washed with ethyl acetate. Evaporate the solvent and purify the residue by column chromatography (silica gel) eluting with ethyl acetate:hexane 1:3 to provide the title compound (22 mg, 49%): 1H NMR (CDCl3, 200 MHz): δ 7.37 (d, 2H, J=8.9); 6.99 (d, 2H, J=8.9); 4.22 (q, 2H, J=7.2); 3.89 (m, 4H); 3.28 (m, 4H); 2.71 (s, 3H); 1.24 (t, 3H, J=7.2).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.[Cl:16][C:17]1[C:24]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=[C:21]([Cl:31])[C:18]=1[CH:19]=[O:20].[OH-].[K+].O>CO>[Cl:16][C:17]1[C:24]([O:25][CH2:26][C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=[C:21]([Cl:31])[C:18]=1[CH:19]([C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)[NH:13][CH:14]=1)[OH:20]
Reactant: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Reactant: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(-c2cnc3[nH]cc(C(O)c4c(Cl)ccc(OCC(F)(F)F)c4Cl)c3c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (109, 100.0 mg, 0.51 mmol, prepared as described in Example 35) in methanol (30 mL) were added 2,6-dichloro-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde (115, 154 mg, 0.56 mmol) and potassium hydroxide (596.0 mg, 10.62 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 25% methanol in dichloromethane to give the desired compound (116, 0.18 g, 75.7%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH:7]=[O:8].[H-].[Na+].[CH2:11](I)[CH3:12]>C1COCC1.CN(C=O)C>[CH2:11]([N:6]1[C:2]([CH3:1])=[C:3]([CH:7]=[O:8])[N:4]=[CH:5]1)[CH3:12]
Reactant: Cc1[nH]cnc1C=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1cnc(C=O)c1C
Reaction time: 0.08 h
Yield: 33.2 %

Procedure:
5-Methyl-1H-imidazole-4-carbaldehyde (940 mg, 8.5 mmol) was dissolved in THF (40 mL) with DMF (5 mL). NaH (380 mg of a 60% dispersion in mineral oil) was added carefully and the reaction mixture was allowed to stir for 5 min. under nitrogen. Ethyl iodide (1.65 g, 9.7 mmol) was added and it was allowed to stir for 1 h. The solvent was removed in vacuo, and the crude was purified on silica eluted with 100% ethyl acetate—1% MeOH/ethyl acetate to yield the title product (390 mg) as the main isomer. MS (ESI-POS): [M+H]+=139.
Reaction SMILES: C([C:3]1[C:4](=[O:20])[NH:5][C:6]([CH3:19])=[C:7]2[C:12]=1[CH2:11][CH2:10][CH:9]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:8]2)#N>S(=O)(=O)(O)O>[CH3:19][C:6]1[NH:5][C:4](=[O:20])[CH:3]=[C:12]2[C:7]=1[CH2:8][CH:9]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:10][CH2:11]2
Reactant: Cc1[nH]c(=O)c(C#N)c2c1CC(c1ccncc1)CC2
Agent: O=S(=O)(O)O
Product: Cc1[nH]c(=O)cc2c1CC(c1ccncc1)CC2
Temperature: 0 °C
Yield: 83.9 %

Procedure:
4-Cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline (0.5 g) was dissolved in 85% sulfuric acid, and the solution was heated under reflux at 180°-200° C. for 5 hours. After cooling the reaction mixture was poured into ice water. Deposited crystals were filtered out and then purified to obtain 0.38 g of 2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline.
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C@H:7]([CH3:18])[CH2:6][N:5]1[C@H:19]([C:27]1[CH:39]=[CH:38][C:30]([C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1.[CH3:40]I>CCCCC.O1CCCC1>[CH3:3][C@H:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C@H:7]([CH3:18])[CH2:6][N:5]1[C@H:19]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])=[CH:38][CH:39]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:40])[CH:21]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH, 10 mmol)) was washed with pentane (2×7 mL), and tetrahydrofuran (10 mL) was added. The product from Example 11, 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (1.007 g, 2.0 mmol) was dissolved in the stirred suspension, and when effervescence had subsided, methyl iodide (249 μL, 568 mg, 4 mmol) was added. The reaction mixture was sealed under nitrogen and stirred for 6 h at ambient temperature. The reaction mixture was evaporated to dryness, and the residue was partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated, the aqueous portion extracted with ethyl acetate (2×10 mL) and the combined organic extracts were dried over anhydrous sodium sulfate. The organic solution was evaporated to a pale yellow gum, which on trituration and sonication with pentane yielded 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide as a flocculent white solid (0.798 g, 77% after drying at room temperature and 5 mm Hg). Calc. for C32H40FN3O20.25H2O: C, 73.60; H, 7.82; N, 8.05; F, 3.64. Found C, 73.58; H, 7.70; N, 8.04; F, 3.84%. 1H NMR (CDCl3, 300 MHz); δ 1.09 (d, J=6.2 Hz, 6H, superimposed on br m, 3H); 1.21 (br m, 3H); 1.99 (m, 2H); 2.57 (br m, 2H); 2.66 (m, 3H); 3.15 (d, J=13.3 Hz, 1H); 3.27 (br m, 2H); 3.54 (br m, 2H); 3.78 (s, 3H); 3.84 (d, J=13 Hz, 1H); 5.10 (s, 1H); 6.76 (s, 1H); 6.70 (d, J=8.1 Hz, 2H); 6.96 (t, J=8.2 Hz, 2H); 7.26 (m, 5H); 7.46 (d, J=7.8 Hz, 2H).
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:39]2[CH2:40][CH2:41][CH:36]([C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=4)[NH:32][CH:31]=3)[CH2:37][CH2:38]2)=[O:25])[CH2:15][CH2:14]1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)N2CCC(c3c[nH]c4ccc(Cl)cc34)CC2)CC1

Procedure:
The non-polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (338 mg, 1.0 mmole) was added to a solution of 5-chloro-3-piperidine-4-yl-1H-indole (218 mg, 1.0 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The non-polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml). It was obtained in a yield of 120 mg (25%) as a colourless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]#[N:29])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(C#N)ccc32)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4nnn[nH]4)ccc32)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-(3-cyanophenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 4a (0.29 g; 0.68 mmol) in DMF (7 mL) were added sodium azide (0.13 g, 2.0 mmol) and ammonium chloride (0.11 g; 2.06 mmol), and the mixture was heated at 120° C. for 16 h. The mixture was allowed to cool to rt, and filtered. The filtrate was acidified with 1N hydrochloric acid (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated, yielding 4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 5a. MS m/z (M+Na) 456.9. The crude material was used as such for the next reaction.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.Cl.[NH2:17][OH:18]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]1
Reactant: NO
Reactant: COCCCCCCN1CCC(=O)CC1
Agent: Cl
Product: COCCCCCCN1CCC(=NO)CC1

Procedure:
1-(6-Methoxyhexyl)-4-piperidone oxime is prepared from 1-(6-methoxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: OC[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](O)=[CH:10][CH:9]=[CH:8]2.COCCl.C(=O)([O-])[O-].[K+].[K+]>>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: OCc1cccc2cccc(O)c12
Agent: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc2ccccc2c1

Procedure:
8-hydroxymethyl-1-naphthol (XXXXXVI) is reacted with chloromethyl methyl ether in a customary manner, for example, by using potassium carbonate as an acid remover to obtain a naphthalene derivative (XXXXXVII).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH2:8][C:9]([OH:11])=O.O.ON1C2C=CC=CC=2N=N1.[CH3:23][C:24]1([C:30]2[CH:31]=[C:32]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=[CH:34][CH:35]=2)[CH:29]2[CH:25]1[CH2:26][NH:27][CH2:28]2.C(=O)([O-])O.[Na+]>>[CH3:23][C:24]1([C:30]2[CH:31]=[C:32]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=[CH:34][CH:35]=2)[CH:29]2[CH:25]1[CH2:26][N:27]([C:9](=[O:11])[CH2:8][CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH2:28]2
Reactant: Cc1ccsc1CCC(=O)O
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Product: Cc1ccsc1CCC(=O)N1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 126.6 %

Procedure:
To a solution of 3-(3-methyl-2-thienyl)propanoic acid (J. W. McFarland et al., J. Med. Chem., 1970, 13, 113, 200 mg, 1.17 mmol) in N,N-dimethylforiamride (25 ml) was added 1-hydroxybenzotriazole monohydrate (200 mg, 1.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodlimide hydrochloride (340 mg, 1.77 mmol). After stirring at room temperature for 10 min, the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 400 mg, 1.32 mmol) and sodium hydrogen carbonate (200 mg, 2.38 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml), dried (MgSO4), and concentrated in vacuo to afford 620 mg of a brown oil. This was purified by chromatography using a Biotage Flash 12™ cartridge packed with silica gel (8 g) eluting with hexane:ethyl acetate (100:0 to 0:100 over 30 min) and then with ethyl acetate:methanol (100:0 to 0:100 over 5 min) to afford the title compound as a colourless oil (244 mg, 50%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]2=[CH:12][CH:13]=[C:14]3[C:18]([NH:17][C:16](=O)[C:15]3=O)=[C:10]2[CH2:9]1.O>C(OCC)C.O1CCCC1>[CH3:7][N:8]1[CH2:22][CH:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11]2=[CH:12][CH:13]=[C:14]3[C:18]([NH:17][CH:16]=[CH:15]3)=[C:10]2[CH2:9]1
Reactant: CN1Cc2c(ccc3c2NC(=O)C3=O)C(c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CN1Cc2c(ccc3cc[nH]c23)C(c2ccccc2)C1

Procedure:
20 g (0.524 mol) of LiAlH4 are suspended in 400 ml of absolute diethyl ether at room temperature, with stirring, while flushing with nitrogen and in the absence of moisture. 550 ml of absolute tetrahydrofuran are then added, followed by 34 g (0.116 mol) of 8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole-2,3-dione in portions. The reaction mixture is subsequently stirred at room temperature for 31/2 hours. To dissociate the reaction complex, a solution of 42 ml of H2O in 160 ml of tetrahydrofuran is added dropwise, with cooling. The inorganic solid is filtered off and the filtrate is freed from the solvent on a rotary evaporator. The residue is chromatographed on silica gel 60 with an eluent mixture of: ethyl acetate and 8.3% of MeOH. The pure substance is dried in a desiccator over P2O5 at 60° C. under a water pump vacuum.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]1([CH3:37])[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[N:20][C:21]([NH:24][C:25]3[O:26][C@:27]4([CH2:35][N:36]=3)[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]4)=[N:22][CH:23]=2)[CH:13]=1>C1COCC1>[C:12]1([CH3:37])[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[N:20][C:21]([NH:24][C:25]3[O:26][C@:27]4([CH2:35][N:36]=3)[CH:32]3[CH2:31][CH2:30][N+:29]([O-:9])([CH2:34][CH2:33]3)[CH2:28]4)=[N:22][CH:23]=2)[CH:13]=1
Reactant: Cc1cccc(-c2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: Cc1cccc(-c2cnc(NC3=NC[C@@]4(C[N+]5([O-])CCC4CC5)O3)nc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
mCPBA (0.074 g, 0.332 mmol) was added to a suspension of (R)—N-(5-m-tolylpyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.116 g, 0.332 mmol) in THF (10 ml). The mixture was stirred at room temperature for 18 h, concentrated and purified by silica gel chromatography (5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford (S)-2-(5-m-tolylpyrimidin-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide as an off-white solid (0.067 g, 0.176 mmol, 53%). 1H NMR (400 MHz, MeOD) δ ppm 8.79 (2H, s), 7.27-7.49 (3H, m), 7.20 (1H, d, J=7.55 Hz), 4.03 (1H, d, J=10.32 Hz), 3.88 (1H, d, J=10.58 Hz), 3.59-3.77 (2H, m), 3.38-3.52 (3H, m), 3.21-3.28 (1H, m), 2.40-2.52 (1H, m), 2.28-2.35 (1H, m), 1.96-2.21 (3H, m). LC/MS RT=1.71; [M+H]+=366.34.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C@:4]2([CH2:10][CH2:9][C@H:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][CH:12]=3)[CH2:7]2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[O:6][CH2:5][C@:4]2([CH2:10][CH2:9][C@H:8]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[CH2:7]2)[NH:3]1
Reactant: CC(C)(C)OC(=O)Cc1ccc([C@H]2CC[C@]3(COC(=O)N3)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1ccc([C@H]2CC[C@]3(COC(=O)N3)C2)cc1
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 2-(4-((5R,7S)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)phenyl)acetate (I-5A, 1 g, 3.02 mmol) in DCM (20 mL) was added TFA (10 mL). After 2 h, the solution was concentrated in vacuo and used as such for the subsequent step without further purification. HPLC retention time=0.65 min (Condition G); LC/MS M+1=276.