Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([OH:42])([C:29]2[N:30](COCC[Si](C)(C)C)[CH:31]=[CH:32][N:33]=2)[CH2:27][CH3:28])[CH:5]=[C:6]([CH:25]=1)[O:7][CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:26]([OH:42])([C:29]2[NH:33][CH:32]=[CH:31][N:30]=2)[CH2:27][CH3:28])[CH:5]=[C:6]([CH:25]=1)[O:7][CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1
Reactant: CCC(O)(c1cc(F)cc(OCc2ccc3c(-c4ccoc4)cc(=O)oc3c2)c1)c1nccn1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)(c1cc(F)cc(OCc2ccc3c(-c4ccoc4)cc(=O)oc3c2)c1)c1ncc[nH]1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under N2 the compound from Step 1 (94 mg, 0.159 mmol) was dissolved in THF (2 mL). Tetrabutylammonium fluoride was added (795 μL, 0.795 mmol) and the reaction was stirred at 55° C. for 1 h. Ethyl acetate was added and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to give an oil which was purified by a flash silica column using EtOAc then 5% MeOH in CH2Cl2 as the eluent. The title compound was obtained: 12.8 mg (17%). Mass spec.: 461 (MH+).
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:13]/[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])/[CH:3]=1.[CH3:29][N:30]1[C:34]([SH:35])=[N:33][N:32]=[N:31]1.N1C=CC=CC=1>C1COCC1>[CH3:29][N:30]1[C:34]([S:35][C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)/[C:4](=[N:13]/[S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)(=[O:16])=[O:15])/[CH:3]=2)=[N:33][N:32]=[N:31]1
Reactant: Cn1nnnc1S
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 99 %

Procedure:
81.6 mg 12b was dissolved in 2 ml THF. 1 ml THF solution containing 1 eq. 1-methyl-tetrazole-5-thiol and 1 eq. pyridine was added. The mixture was shaken for 30 min. The organic solvent was removed by V-10 (biotage). The residue was suspended in 10 ml water and sonicated thoroughly. The insoluble was filtered and washed with water. The solid was dried over air affording 96.5 mg (99.0%) title compound 13x.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccncc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccncc1
Yield: 69.4 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and 4-aminopyridine (60 mg, 0.64 mmol) to give 144 mg of the title compound (69%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.10 (bs, 1H), 10.90 (s, 1H), 9.04 (d, 1H, J=2 Hz), 8.50 (d, 2H, J=5.4 Hz), 8.31 (d, 1H, J=9 Hz), 7.78 (dd, 1H, J=5.4, 9 Hz), 7.24 (d, 1H, J=2 Hz), 7.19 (d, 1H, J=2 Hz), 5.17~5.28 (m, 1H), 3.05 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.69 (d, 2H, J=7.2 Hz), 2.13 (dm, 1H, J=13.5 Hz), 1.80~1.96 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCC(CO)CC1
Yield: 20.6 %

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) and piperidin-4-yl-methanol (127 mg, 1.104 mmol) were reacted as described in Example 73. Isolated yield of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea (47 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.40 (m, 1H), 4.20 (m, 2H), 3.98 (s, 3H), 3.25 (m, 2H), 2.87 (d, 2H), 2.45 (m, 2H), 2.10-1.80 (m, 4H), 1.65 (d, 2H), 1.30 (s, 10H), 1.15 (m, 2H); LC-MS (ESI) m/z 621 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].Cl[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:13]=1[C:14]([OH:16])=[O:15].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:24][C:17]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:2]([Cl:1])[CH:3]=2)[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: COc1ccc(N)cc1Cl
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1Cl

Procedure:
A mixture of 30 g of 3-chloro-4-methoxyaniline, 18.9 g of 2,6-dichloro-3-nitrobenzoic acid, and 150 ml N,N-dimethylaniline was heated at 100° under nitrogen for 24 hours. The reaction mixture was dissolved in chloroform and washed with dilute ammonium hydroxide. After the aqueous layer was washed with chloroform, it was acidified and the resulting orange solid was collected to provide 6-chloro-2[(3-chloro-4-methoxyphenyl)amino]-3-nitrobenzoic acid, mp 222°-228° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:28])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH3:27])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[CH2:8][CH2:7]2)[CH3:2].CO>[Pd].C1C=CC=CC=1>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:9]2([CH3:27])[CH2:8][CH2:7][C:6]3[C:11](=[C:12]([CH3:15])[C:13]([CH3:14])=[C:4]([O:3][CH2:1][CH3:2])[C:5]=3[CH3:28])[O:10]2)=[CH:19][CH:20]=1
Reactant: CCOc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: CCOc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2

Procedure:
The procedure described in Preparation 62 was repeated, except that 11 g of 6-ethoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman (prepared as described in Preparation 61), 2.2 g of 10% w/w palladium-on-carbon, 100 ml of methanol and 30 ml of benzene were used as the starting materials to give the title compound, melting at 121°-123° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:6][C:7]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:8]=1[O:9][CH2:10][C@@H:11]1[O:16][C@@H:15]([O:17][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH2:19]Br)[CH2:14][CH2:13][CH2:12]1.[I-].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:8]=1[O:9][CH2:10][C@@H:11]1[O:16][C@@H:15]([O:17][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH2:19][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:14][CH2:13][CH2:12]1
Reactant: Clc1ccc(OC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)c(Cl)c1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OC[C@H]2CCC[C@H](OC(Cn3ccnc3)c3ccc(Cl)cc3Cl)O2)c(Cl)c1
Temperature: 130 °C

Procedure:
A mixture of 163 mg of imidazole, 317 mg of the isomer of lesser polarity of trans-6-(2,4-dichlorophenoxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran and 180 mg of sodium iodide in 5 ml of dimethylformamide was stirred whilst heating at 130° C. for 10 hours, and then treated and purified as in Example 34(b)(i), to give 136 mg of the isomer of lesser polarity of the title compound, as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([C:13]([F:17])([F:16])[CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].S(=O)(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([C:13]([F:17])([F:16])[CH2:14][O:15][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)CO)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)COS(C)(=O)=O)C1
Reaction time: 0.83 h

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (471 mg) and triethylamine (328 μl) in chloroform (4.7 ml) cooled to 0° C. was added methanesulfonyl chloride (118 μl), and the mixture was stirred for 50 minutes. To the mixture was added 5% aqueous potassium bisulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with 1M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (565 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C[O:31]C1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:31])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Yield: 46.1 %

Procedure:
An 8 mL vial was charged with compound 5 (20 mg, 0.0446 mmol), Lawesson's reagent (19.9 mg, 0.0491 mmol). Toluene (3 mL) was added, and the vial was sealed and placed into CEM microwave reactor and irradiated at 130° C. for 1 h. After cooling down, the solvent was removed by evaporation in vacuo and the resulting residue was purified by preparative TLC (hexane: EtOAc=2:1) to give compound 6 (10 mg, 47%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:10]1[C:2]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)=[N:3][C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[C:5]([C:6]([NH2:8])=[O:7])[CH:9]=1
Reactant: OB(O)c1ccncc1
Reactant: CN1CCN(c2ccc(Nc3nc(Cl)c(F)cc3C(N)=O)cc2)CC1
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: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3nc(-c4ccncc4)c(F)cc3C(N)=O)cc2)CC1
Temperature: 90 °C
Yield: 33.3 %

Procedure:
A mixture of 6-chloro-5-fluoro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide (70 mg, 0.192 mmol), pyridin-4-ylboronic acid (23.65 mg, 0.192 mmol), K2CO3 (53.2 mg, 0.385 mmol) and Pd(Ph3P)4 (11.12 mg, 9.62 μmol) in THF (1 mL) was heated at 90° C. overnight in a sealed vial. The reaction mixture was extracted between saturated NaHCO3 and methylene chloride, concentrated and the residue was purified by prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, extracted with methylene chloride, concentrated to give 26 mg of product as orange-red solid. LC-MS: (M+H)+=407.11. 1H NMR (400 MHz, chloroform-d-MIX) δ ppm 8.55-8.60 (2H, m), 7.91 (2H, d, J=5.71 Hz), 7.76 (1H, d, J=11.42 Hz), 7.52 (2H, d, J=9.23 Hz), 6.89 (2H, d, J=8.79 Hz), 3.08-3.16 (4H, m), 2.51-2.60 (4H, m), 2.29 (3H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH3:19])=O)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[CH3:19][C@H:9]1[CH2:10][C@H:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:13][NH:8]1
Reactant: C[C@H]1C[C@H](N2CCCC2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1C[C@H](N2CCCC2)CCN1
Yield: 84 %

Procedure:
Treatment of (trans) 2-methyl-4-pyrrolidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.4 mmol) with 4M hydrochloric acid in dioxane (5 ml) for 1 h and subsequent evaporation of the solvent afforded the title compound (0.06 g, 84%) as a white powder. MS: 169.1 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In analogy to the procedure described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzyl bromide there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzyloxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate; MS: 568 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=2)[C@@H:7]([NH2:18])[CH2:6]1)[CH:2]=[CH2:3].C(OC(=O)[NH:25][C@H:26]([CH:34]1[CH2:36][O:35]1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(C)(C)C>>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=2)[C@@H:7]([NH:18][CH2:36][C@@H:34]([OH:35])[C@@H:26]([NH2:25])[CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C1CO1
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2ccccc2)c2cc(OCCC)ccc21

Procedure:
Step AZ (1): (2R,3S)-1-((1S,3R)-3-(Allyloxy)-6-propoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-phenylbutan-2-ol (590 mg) was prepared from (1S,3R)-3-(allyloxy)-6-propoxy-2,3-dihydro-1H-inden-1-amine (1.2 g, 4.9 mmol, from Step AY (1)) and (S)-(1-oxiranyl-2-phenylethyl)-carbamic acid tert-butyl ester in three steps and 30% overall yield using procedures analogous to the Steps AW (1-3). LC-MS (M+H)+=411.19. 1H NMR (300 MHz, CDCl3) δ 0.9-1.0 (t, 3H) 1.7-1.9 (m, 2H) 2.0-2.2 (m, 1H) 2.4-2.6 (m, 2H) 2.7-3.0 (m, 3H) 3.1-3.2 (m, 1H) 3.8-4.1 (m, 5H) 4.2-4.4 (m, 1H) 4.6-4.8 (m, 1H) 5.1-5.3 (m, 2H) 5.7-5.9 (m, 1H) 6.9-7.0 (m, 1H) 7.0-7.3 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.[F:14][C:15]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:16]=1[CH2:17]Br>>[CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[C@@H:7]([CH2:17][C:16]2[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:15]=2[F:14])[N:8]=1
Reactant: Fc1cc(F)c(CBr)cc1F
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1
Product: COC1=N[C@H](Cc2cc(F)c(F)cc2F)C(OC)=N[C@H]1C(C)C
Yield: 62.7 %

Procedure:
The title compound (3.81 g) was prepared from 3.42 g (18.5 mmol) of (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine and 5 g (22.3 mmol) of 2,4,5-trifluorobenzyl bromide using the procedure described for Intermediate 2, Step A.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:21][C@:8]2([O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:9]2)[CH2:7][N:6]1[C:22](=[O:37])[C@@H:23]([NH:28][C:29]([O:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:4].[Li+].[OH-].CO>C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][C@@:8]3([CH2:21][C@@H:5]([C:3]([OH:4])=[O:2])[N:6]([C:22](=[O:37])[C@@H:23]([NH:28][C:29]([O:31][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:30])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:7]3)[O:12][C:11]2=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)OC1CCCC1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[C@H](NC(=O)OC1CCCC1)C(=O)N1C[C@@]2(C[C@H]1C(=O)O)CN(c1cccc(Cl)c1)C(=O)O2
Reaction time: 8 h
Yield: 46.3 %

Procedure:
(5S,8S)-methyl-3-(3-chlorophenyl)-7-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (C3) (22 mg, 41 μmol, 1 eq.) was diluted with dry THF (0.5 mL) then 1 M LiOH (82 μL, 82 μmol, 2 eq.) and MeOH (20 μL) was added. The reaction was stirred overnight at room temp. and concentrated to give 10 mg (19 μmol) of (5S,8S)-3-(3-chlorophenyl)-7-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (D3). LC MS+: 522.35 at 3.14 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:13]([O-:15])=[O:14])[CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:24]=1
Reactant: O=C(NCCCBr)c1ccccc1[N+](=O)[O-]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1[N+](=O)[O-]
Yield: 87 %

Procedure:
A mixture of 14.4 parts of N-(3-bromopropyl)-2-nitrobenzamide, 12.2 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 16 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 3 hours using a water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 18 parts (87%) of N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]-propyl]-2-nitrobenzamide as an oily residue.
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.[C:24]([N:32]1[C:36]([CH3:38])([CH3:37])[CH2:35][NH:34][C:33]1=[O:39])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([N:32]1[C:36]([CH3:37])([CH3:38])[CH2:35][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:33]1=[O:39])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)CNC(=O)N1C(=O)c1ccccc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)N(C(=O)c5ccccc5)C4=O)cc3)CC2)c(C)c1
Yield: 56.1 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 1-benzoyl-5,5-dimethylimidazolidin-2-one (105 mg) described in Preparation Example 58 and by the reaction and treatment in the same manner as in Example 1, the title compound (115 mg) was obtained.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH:7]1[C:11]#[N:12])=[O:5])C.[OH-].[K+].Cl>O.C(O)C>[C:11]([CH:7]1[C:8]([CH3:10])([CH3:9])[CH:6]1[C:4]([OH:5])=[O:3])#[N:12]
Reactant: CCOC(=O)C1C(C#N)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)C(C#N)C1C(=O)O
Reaction time: 15 h
Yield: 76.2 %

Procedure:
A suspension of 33.4 g (0.2 mol) of 2-cyano-3,3-dimethyl-cyclopropane-carboxylic acid ethyl ester and 16.8 g (0.3 mol) of potassium hydroxide in 200 ml of water and 100 ml of ethanol was stirred at 20°-25° C. for 15 hours. The alcohol was then stripped off and the aqueous solution was acidified with dilute hydrochloric acid and extracted twice with 100 ml of ether (or methylene chloride) each time. The combined organic extracts were dried over Na2SO4 and concentrated and the residue was distilled. 21.2 g (76% of theory) of 2-cyano-3,3-dimethyl-cyclopropane-carboxylic acid were obtained in the form of an oil of boiling point 110°-120° C., which crystallized on cooling (melting point: 101°-106° C.). ##STR45##
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([O:20][C:21]([N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
75 g of 2-methylaminoethanol and 101 g of triethyl amine are mixed with 1000 ml of absolute chloroform. 171 g of chloroformic acid benzyl ester are added dropwise to this solution at about 20° C. The mixture is stirred for 1 hour at room temperature, washed with water, diluted hydrochloric acid and again with water and dried over sodium sulphate. After evaporation of the solvent in vacuo 173 g of oil remain.
Reaction SMILES: Cl[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])=[C:4]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][S:25]2(=[O:31])=[O:30])[CH:3]=1.[CH3:32][C@@H:33]1[CH2:37][O:36][C:35](=[O:38])[NH:34]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:34]4[C@H:33]([CH3:32])[CH2:37][O:36][C:35]4=[O:38])=[CH:3][C:4]=3[N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][S:25]3(=[O:31])=[O:30])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCCS3(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3N3CCCCS3(=O)=O)CC2)c(C)c1
Yield: 31.6 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using [4-chloro-2-(1,1-dioxo-1,2-thiazinan-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (218 mg) described in Preparation Example 128 and (R)-4-methyloxazolidin-2-one (47.6 mg) described in Preparation Example 25, the title compound (78.5 mg) was obtained.