Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[CH:23]=[O:24])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)([OH:38])N.Cl([O-])=O.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]([OH:38])=[O:24])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)c1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)c1
Reaction time: 3 h
Yield: 68.2 %

Procedure:
To a stirred solution of the product from Example 151 (58 mg, 0.11 mmol) in dichloromethane (3 mL) and water (3 mL) at 0° C. was added sulfamic acid (44 mg, 0.44 mmol) and sodium chlorite (30 mg, 0.33 mmol). The reaction was allowed to attain room temperature with stirring over 3 hours, the layers separated and the aqueous layer extracted with further dichloromethane (5 mL). The combined organic layers were dried (MgSO4) and evaporated to leave a residue which was filtered through a plug of silica eluting with ether:dichloromethane:iso-hexane 1:1:3, then purified by column chromatography on silica eluting with ethyl acetate:dichloromethane 1:1 +1% acetic acid to afford the desired compound (40 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[CH2:19]([O+](CC)CC)[CH3:20]>CCOCC>[F:14][B-:15]([F:18])([F:17])[F:16].[CH2:1]([N+:8]1[CH2:12][CH2:11][CH2:10][C:9]=1[O:13][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCOCC
Product: CCOC1=[N+](Cc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-benzylpyrrolidinone (2.18 g, 12.4 mmol) in 25 mL of ether was added at 0° C. triethyloxonium tetrafluoroborate (2.15 g, 11.3 mmol). The reaction was allowed to warm to ambient temperature and stir for 30 minutes, during which a solid product precipitated from the reaction. The ether was decanted off, and the remaining residue washed three times with ether. Residual solvent was removed in vacuo to provide 1-benzyl-5-ethoxy-3,4-dihydro-2H-pyrrolium tetrafluoroborate.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.C1C=CC=CC=1.N1CCCC1>C1(C)C=CC=CC=1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNC1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
Accordingly, the present invention provides the crystalline Form-C obtained in non-polar alicyclic hydrocarbon solvent like cyclopentane, cyclohexane or cycloheptane. According to the process of the present invention, 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-1,3-dihydro-indol-2-one (X) in aromatic hydrocarbon solvents like benzene or toluene are reacted in presence of catalytic amount of pyrrolidine as base at 80-85° C. for 3-9 hours. The resultant Sunitinib base is again triturated with the same solvent at 80-85° C. for 1-2 hours and isolated at a temperature ranging from 20-45° C., preferably at 25-35° and most preferably at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [NH2:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)NN=[C:8]2[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:4].[CH2:21]([N:23](CC)CC)[CH3:22].Cl.[C:29](=N)(OCC)[CH3:30]>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:3]([NH:2][NH:1][CH2:22][CH:21]=[NH:23])=[O:4])[CH:6]=3)[CH2:30][CH:29]=2)=[CH:15][CH:16]=1
Reactant: CCOC(C)=N
Reactant: CCN(CC)CC
Reactant: NNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: CCO
Product: N=CCNNC(=O)c1ccc2c(c1)C(c1ccc(F)cc1)=CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask containing N-amino[3-(4-fluorophenyl)(1H-indazol-5-yl)]carboxamide (196 mg, 0.73 mmol) under a nitrogen atmosphere was added anhydrous ethanol (3 mL) and triethylamine (0.1 mL, 0.73 mmol). In a separate flask ethyl acetimidate hydrochloride (90 mg, 0.73 mmol) was dissolved in anhydrous ethanol (2 mL) and triethylamine (0.1 mL, 0.73 mmol). The flask containing the N-amino[3-(4-fluorophenyl)(1H-indazole-5-yl)]carboxamide solution was placed on ice while the ethyl acetimidate hydrochloride solution was added dropwise to the chilled flask. The flask was kept at 0° C. for 2 hours and then allowed to stir at room temperature for two days. LC-MS indicated the reaction was complete. The solvent was removed and the compound was taken on crude into the next step of the synthesis. ES-MS m/z 312 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][N:31]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH:25][C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][NH:31]3)[CH3:24])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 90 °C
Yield: 76.9 %

Procedure:
A mixture of (S)-1-[1-(cis-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (310 mg, 0.91 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (219 mg, 0.91 mmol) and DIPEA (0.81 mL, 4.57 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded onto an Isolute® SCX-2 cartridge which was washed with DCM, MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound as a glassy white solid (320 mg, 76%). LCMS (Method B): RT 2.76 min [M+H]+ 458. 1H NMR (CDCl3, 400 MHz): δ 8.48 (1H, s), 7.95 (1H, s), 7.71-7.58 (2H, m), 7.42-7.35 (5H, m), 7.07-6.90 (2H, m), 5.95 (1H, s, br), 4.97-4.80 (m, 1H), 4.52 (2H, s), 4.05-3.92 (1H, m), 3.01-2.86 (2H, m), 2.81-2.64 (1H, m), 1.75 (3H, d, J=6.85 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][CH:6]1[CH2:11][C:10]([N:18]([CH3:20])[CH3:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:8][C:7]1=[O:21].[CH:25]1[CH:26]=[CH:27][C:28]2[NH:33][CH:32]=[C:31]([CH2:34][CH2:35]O)[C:29]=2[CH:30]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][CH:6]1[C:7]2([C:32]3[NH:33][C:28]4[C:29]([C:31]=3[CH2:34][CH2:35][O:21]2)=[CH:30][CH:25]=[CH:26][CH:27]=4)[CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([N:18]([CH3:19])[CH3:20])[CH2:11]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)C(Cc2cccc(F)c2)C1
Reactant: OCCc1c[nH]c2ccccc12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC2(OCCc3c2[nH]c2ccccc32)C(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(±)-2-(3-fluorobenzyl)-4-dimethylamino-4-phenylcyclohexanone (325 mg, 1 mmol) together with tryptophol (161 mg, 1 mmol) was dissolved in dichloromethane (30 ml) and mixed with trifluoromethane sulphonic acid trimethylsilyl ester (0.22 ml, 1.14 mmol). The batch was stirred at RT for 2.5 h. A precipitate began to separate out after some time (approx. 1 h). For work up the reaction mixture was mixed with 2N NaOH (20 ml) and stirred for 20 min. During this the precipitate went into solution. The organic phase was separated and the aqueous phase extracted with dichloromethane (4×20 ml). The combined organic phases were dried with MgSO4. The solvent was then concentrated by evaporation in a vacuum. One of the possible diastereoisomers was isolated from the residue obtained (352 mg) by means of chromatographic purification [silica gel 60 G (10 g); ethyl acetate 150 ml].
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][C@@H:5]([C:7](Cl)=[N:8]OS(C)(=O)=O)[C:4]([CH3:16])([CH3:15])[O:3]1.[S-:18][C:19]#[N:20].[Na+].N1C=CC=CC=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][C:35]1[CH:36]=[C:37]([O:42][C:43]2[C:44]([CH3:50])=[N:45][N:46]([CH3:49])[C:47]=2[CH3:48])[C:38]([NH2:41])=[N:39][CH:40]=1>O>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][C:35]1[CH:36]=[C:37]([O:42][C:43]2[C:44]([CH3:50])=[N:45][N:46]([CH3:49])[C:47]=2[CH3:48])[C:38]([NH:41][C:19]2[S:18][N:8]=[C:7]([C@H:5]3[C:4]([CH3:15])([CH3:16])[O:3][C:2]([CH3:1])([CH3:17])[O:6]3)[N:20]=2)=[N:39][CH:40]=1
Reactant: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1N
Reactant: CC1(C)O[C@@H](C(Cl)=NOS(C)(=O)=O)C(C)(C)O1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC(C)(C)OC2(C)C)ns1
Temperature: 40 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A flask was charged with (R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (0.371 g, 1.30 mmol), sodium thiocyanate (0.0929 g, 1.15 mmol), pyridine (0.278 g, 0.764 mmol) was added and the reaction was heated to 40° C. for 30 minutes. 5-(Pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-amine (0.250 g, 0.764 mmol) was added and the reaction was stirred at 70° C. overnight. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (50 to 100% ethyl acetate in hexanes) to afford (S)-N-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine (0.233 g, 56.5% yield) as yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[CH3:25][S:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[C:27]([S:26][CH3:25])[CH:28]=1
Reactant: CSc1cccc(N)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(SC)c3)c2cc1OC
Yield: 38.2 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 167.1 mg (1.2 mmol) of 3-(methylthio)aniline to give 134.1 mg (38.2%) of the product as an off white solid, m.p.>250° C., mass (electrospray, m/e): M+H 351.9.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH2:5]([S:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([C:22]2[NH:23][C:24](=[O:31])[C:25]([CH:28]([CH3:30])[CH3:29])([CH3:27])[N:26]=2)[N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC.O1CCCC1>[CH:1]([NH3+:4])([CH3:3])[CH3:2].[CH2:5]([S:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O-:19])=[O:18])=[C:15]([C:22]2[NH:23][C:24](=[O:31])[C:25]([CH:28]([CH3:29])[CH3:30])([CH3:27])[N:26]=2)[N:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)N
Reactant: CC(C)C1(C)N=C(c2nc(SCc3ccccc3)ccc2C(=O)O)NC1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C1(C)N=C(c2nc(SCc3ccccc3)ccc2C(=O)[O-])NC1=O
Product: CC(C)[NH3+]

Procedure:
0.16 g (2.7 mmol) isopropylamine are added to a solution of 1.0 g (2.7 mmol) 6-benzylthio-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-nicotinic acid in 50 ml ether and 50 ml tetrahydrofuran. The sediment is sucked off and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15]1)[CH3:13]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.1 %

Procedure:
A mixture of 4-nitrobenzylchloride (5 g, 29.14 mmol), N-ethylpiperazine (4.4 ml, 34.97 mmol, 1.2 eq.), potassium carbonate (8 g, 58.28, 2 eq.), and acetone (100 ml) is stirred for 15 h at reflux. The reaction mixture is allowed to cool to RT, filtered and concentrated to afford 7.2 g of the title compound as a brow oil: ESI-MS: 250.1 [MH]+; TLC: Rf=0.31 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]([C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][C:25]([N:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)[CH3:28])=[CH:26][C:19]=3[N:18]=2)C(=O)C(C)(C)C)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][S:37]([CH2:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44])(=[O:39])=[O:38]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][C:25]([N:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([NH:44][C:43]5[CH:45]=[CH:46][CH:47]=[C:41]([CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[CH:42]=5)[N:30]=4)[CH3:28])=[CH:26][C:19]=3[N:18]=2)[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Reactant: CN(c1ccc2c(c1)nc(N(C(=O)C(C)(C)C)c1cc(C(C)(C)C)on1)n2C)c1ccnc(Cl)n1
Product: CN(c1ccc2c(c1)nc(Nc1cc(C(C)(C)C)on1)n2C)c1ccnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
The title compound was prepared following the procedure of Example 134 with N-(5-tert-Butyl-isoxazol-3-yl)-N-{5-[(2-chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H benzoimidazole-2-yl}-2,2-dimethyl-propionamide (23 mg, 0.045 mmol) and 3-[(methylsulfonyl)methyl]aniline (10 mg, 0.139 mmol) to afford a white solid (5 mg, 0.01 mmol). MS (ESI) m/z=561 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:19])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].CO.O>C(O)(C)(C)C>[O:12]([CH2:11][CH2:10][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[CH2:3][OH:2])=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CCOc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(CCOc1ccccc1)N1CCC[C@H]1CO
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A mixture of N-(3-phenoxy)propionyl-proline methyl ester (2.8 g) and sodium borohydride (950 mg) was suspended in tertiary butyl alcohol (40 ml). To the stirred suspension, dry methanol (8 ml) was added dropwise under reflux. Thereafter, the mixture was stirred under reflux for 1 hour. The heated mixture was cooled to room temperature and water (10 ml) was added under cooling with ice. Methanol and tertiary butyl alcohol were distilled off under vacuum and the residue was subjected to extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under vacuum and the resulting crude product was purified by medium-pressure liquid column chromatography on silica gel (solvent: chloroform) to obtain the end compound as an oil (2.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.CCOC(C)=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Fc1ccc(Br)nc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccccc2)nc1
Reaction time: 0.17 h
Yield: 69.1 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (10.0 g, 56.82 mmol, Aldrich) in tetrahydrofuran (100 ml) was added tetrakis(triphenylphosphine)Pd complex and stirred for 10 min. Then, phenylmagnesium bromide (68.2 ml, 1.00 M in THF, 68.19 mmol) was added drop-wise at 0° C. The mixture was stirred overnight. Then the reaction was diluted with EtOAc (600 ml), and filtered. The filtrate was concentrated and purified by flash chromatography by eluting with 2% EtOAc-Hexane to obtain 6.8 g (69%) of 5-fluoro-2-phenylpyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:38]([S:41][CH2:42][CH:43]([CH2:47][C:48]([O:50][CH3:51])=[O:49])[C:44](O)=[O:45])(=[O:40])[CH3:39]>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:44](=[O:45])[CH:43]([CH2:47][C:48]([O:50][CH3:51])=[O:49])[CH2:42][S:41][C:38](=[O:40])[CH3:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: COC(=O)CC(CSC(C)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99.2 %

Procedure:
To a solution of L-proline tert-butyl ester (1.71 g) and 3-hydroxybenzotriazole (1.35 g) in dichloromethane (15 ml), dicyclohexylcarbodiimide (2.06 g) and 3-acetylthio-2-methoxycarbonylmethylpropanoic acid (2.2 g) are added. After eighteen hours stirring at room temperature, the precipitate formed is filtered off, the filtrate is washed neutral, dried, and concentrated to dryness to yield 3.7 g of 1-[3-(acetylthio)-2-methoxycarbonylmethylpropanoyl]-L-proline tert-butyl ester. Rf =0.8 (silica gel-ethyl acetate).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13]([CH2:23][NH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([N:24]([CH2:23][C:13]1[C:12](=[O:33])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:9]([F:34])[CH:10]=2)[N:15]([CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[CH:14]=1)[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCNCc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CCOC(=O)CCCN(Cc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
170 mg of ethyl 4-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}amino)butanoate was dissolved in 2.0 ml of pyridine, and 0.040 ml of acetic anhydride was added, followed by overnight stirring at room temperature. After concentrating the reaction mixture under a reduced pressure, water was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered and concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 165 mg of ethyl 4-(acetyl {[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}amino)butanoate was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O:29]CC)=[O:28])=[CH:5][CH:4]=1.[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccc(OC)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a solution of ethyl (1RS,2RS,3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (0.10 g, 0.2 mmol) in EtOH (5 ml) was added a solution of sodium hydroxide (0.10 g, 2.5 mmol) in H2O (2 ml). The resulting mixture was stirred at room temperature overnight. The mixture was acidified, and the solid which formed was collected by filtration and dried under reduced pressure to afford the title compound as a tan solid (0.04 g, 86%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH2:14]([Li])[CH2:15][CH2:16]C.[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:23]([CH:22]1[CH2:16][CH2:15][CH2:14][CH2:20][CH2:21]1)=[O:19]
Reactant: C1CCOC1
Reactant: COC(CNc1ccccn1)OC
Reactant: [Li]CCCC
Product: COC(CN(C(=O)C1CCCCC1)c1ccccn1)OC
Temperature: 0 °C
Yield: 78 %

Procedure:
To a solution comprising 5.97 g 2-(2,2-dimethoxyethylamino)pyridine (prepared as described by I. Kaye, in J. Am. Chem. Soc., 73, 5467 (195 1)) in 40 mL tetrahydrofurane, stirred under a nitrogen atmosphere at 0° C., was added, in a dropwise manner, 13.1 mL butyl lithium (2.5 M, in hexane). This was followed by removal of the cooling bath, and stirring of the obtained mixture for 1 h, at room temperature. There was then added, in a dropwise manner, 4.46 mL cyclohexanecarbonyl chloride. Then, after 5.5 h stirring at room temperature, 2 mL methanol was added. The solution was then evaporated to dryness under a vacuum, yielding a chestnut-colored oil; this product was then purified by flash chromatography (chloroform—ethyl acetate 7:3). The fractions containing the product were evaporated to dryness affording 8.3 g of Compound 1A (yield 78%); this substance was suitable for use in subsequent reactions with no additional purification processing.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.Cl[CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].Cl>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: OCCOCCCl
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(CCOCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.26 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 34 μl (0.31 mmol) of 2-(2-chloroethoxy)ethanol. The product is in the form of the hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:17])[CH:14]=3)[CH2:9][NH:8]2)=[CH:4][CH:3]=1.C([CH:27]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][NH:28]1)C1C=CC=CC=1>>[C:5]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][NH:28][CH2:27][CH2:36][N:8]2[CH:7]([CH2:6][C:5]3[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:17])[CH:14]=3)[CH2:9]2)=[CH:35][CH:34]=1)([CH3:18])([CH3:6])[CH3:4]
Reactant: c1ccc(CC2Cc3ccccc3CN2)cc1
Reactant: Fc1ccc2c(c1)CC(Cc1ccc(Cl)cc1)NC2
Product: CC(C)(C)c1ccc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(Cl)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 78 using 3-(4-chlorobenzyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline obtained in Example 55-a) instead of 3-benzyl-1,2,3,4-tetrahydroisoquinoline to obtain a title compound as a light yellow oily substance.