Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[C:33]([O:40][CH3:41])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>C(Cl)Cl.CO>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:32][C:33]=1[O:40][CH3:41])(=[O:36])[NH2:44]
Reactant: COc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.1 %

Procedure:
To a stirred solution of 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-methoxybenzoic acid (250 mg, 0.41 mmol) in methylene chloride (8 ml), HATU (154 mg, 0.41 mmol) and DIPEA (0.1 ml, 0.57 mmol) were added. The mixture was stirred for 5 min. at rt and ammonia in methanol (2N, 2 ml) was added and the mixture was stirred overnight. The solvent was reduced to 3 ml and loaded onto a silica gel column, eluted with 3% methanol and methylene chloride to give 230 mg desired product. (ES+) m/z Calcd: [(M+H)+]: 615. found: 615.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[NH2:22]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1cc(C)cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,5-dimethylaniline (36 μl, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (26 mg, 39%). 1H NMR (CDCl3): 9.66-9.64 (m, 1H), 8.73 (s, 1H), 8.72-8.69 (m, 1H), 7.44-7.40 (m, 1H), 7.30 (s, 1H), 7.04 (s, 2H), 6.93 (s, 1H), 6.90 (s, 1H), 2.38 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:11]=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]#[N:24]>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[C:23]([NH2:24])=[N:1][C:2]2[CH:10]=[C:6]3[O:7][CH2:8][O:9][C:5]3=[CH:4][C:3]=2[CH:11]=1
Reactant: COc1ccccc1CCC#N
Reactant: Nc1cc2c(cc1C=O)OCO2
Product: COc1ccccc1Cc1cc2cc3c(cc2nc1N)OCO3

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 6-amino-1,3-benzodioxole 5-carbaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:26]1[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH2:20][CH3:21])[CH2:25]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Solvent: c1ccncc1
Product: CCNCC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3CCS2)C1

Procedure:
A mixture of 3.0 g (10 mmol) of 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid, 1.93 g (15 mmol) of N-ethyl-3-pyrrolidinemethanamine and 50 ml of pyridine is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue triturated with water. The solid which separates is removed by filtration, washed with water and dried in vacuo to give 7-fluoro-8-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-5-oxo-1,2-dihydro-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.[SH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1>>[CH3:1][C:2]([NH:6][CH2:5][CH2:4][S:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:3]
Reactant: Oc1ccc(S)cc1
Reactant: CC1=NCCO1
Product: CC(=O)NCCSc1ccc(O)cc1
Temperature: 130 °C
Yield: 87 %

Procedure:
A mixture of 2-methyl-2-oxazoline (16.9 mL, 0.197 mol) and 4-mercaptophenol (24.85 g, 0.197 mol) was heated under reflux (neat) for 2 h at about 130° C. under Ar (spontaneous heating occurred upon mixing). Upon cooling of the reaction mixture to 0° C., a white solid precipitated, which was collected and recrystallized from dilute EtOH to give a white product (36.2 g, 87%): mp 123°-125° C.; 1H NMR [(CD3)2 =O]δ6.99 (d,d, 4 H) , 3.50-2.60 (m, 5 H), 1.87 (s, 3 H); mass spectrum (EI) , m/e 211 (M+), (CI) m/e 212 (M+1). Anal. (C10H13NO2S) C,H,N.
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.O1CCCC1.N1CCCC1>O1CCOCC1>[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: C1CCOC1
Solvent: C1COCCO1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
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 dipolar aprotic solvents like tetrahydrofuran, 1,4-dioxane is reacted in presence of catalytic amount of pyrrolidine as base at reflux temperature for 6-15 hours. The resultant Sunitinib base is again triturated with the same solvent at reflux temperature 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: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[CH3:34][C:35]1([C:41]([O:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:38]3[CH2:39][CH2:40][C:35]([CH3:34])([C:41]([O:43][CH2:44][CH2:45][N:46]([CH3:47])[CH3:48])=[O:42])[CH2:36][CH2:37]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CN(C)CCOC(=O)C1(C)CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOC(=O)C1(C)CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (3 mL) was added 2-(dimethylamino)ethyl 4-methylpiperidine-4-carboxylate hydrochloride (87 mg, 0.35 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (38.0% MeCN up to 42.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 38.0% in 2 min); Detector, UV 254/220 nm. This resulted in 49.7 mg (41%) of the formic acid salt of 2-(dimethylamino)ethyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate. LCMS (Method 28) [M+H]+=659.2, RT=1.23 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.2, 7.2 Hz), 8.68-8.64 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 4.16 (t, 2H, J=5.6 Hz), 3.97-3.93 (m, 1H), 3.75-3.71 (m, 1H), 3.25-3.20 (m, 1H), 3.00-2.94 (m, 1H), 2.48-2.47 (m, 2H), 2.33 (s, 6H), 2.16-1.95 (m, 2H), 1.49-1.44 (m, 2H), 1.18 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([OH:29])[CH:5]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:29][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH3:32])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Yield: 88 %

Procedure:
A mixture of 11 g (27 mmol) of 3-hydroxy-5-[3-[4-(phenyl-methoxy)phenoxy]propoxy]benzoic acid methyl ester, 9.9 g (29.6 mmol) of 1-bromooctadecane and 7.5 g (55 mmol) of potassium carbonate in 225 ml of DMF was stirred and heated at 80° for 30 hours. The solvent was removed at reduced pressure and the residue was purified by chromatography on 300 g of silica gel using 10% ethyl acetate-hexane to give 15.7 g (88% yield, mp 76°-77°) of 3-(octadecyloxy)-5-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](S(O)(=O)=O)[C:5]2[CH:6]=[CH:7][C:8]([CH3:13])=[N:9][C:10]=2[C:11]=1[OH:12].C([O-])(O)=O.[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(S(=O)(=O)O)cc(Cl)c(O)c2n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2ccc(Cl)c(O)c2n1
Yield: 82.3 %

Procedure:
7-Chloro-8-hydroxy-2-methyl-quinoline-5-sulfonic acid (5.50 g, 20.09 mmol) was dissolved in acetic acid (30 ml) and sulfuric acid (3 ml), and the resulting solution was heated to 130° C. for 72 hours. Upon cooling, the reaction mixture was diluted with water (300 ml) and neutralized by the addition of solid NaHCO3. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 95:5 to 70:30) to afford the title compound (3.20 g, 82%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): δ=10.6-10.1 (br, 1H), 8.30 (d, J=7.7 Hz, 1H), 7.55-7.51 (m, 2H), 7.43 (d, J=8.8 Hz, 1H), 2.77 (s, 3H). MS (ES−): 192.2 (M−H)−.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][N:10]2[C:19]3[C:14](=[C:15]([CH:20]4[O:24][CH2:23][CH2:22][O:21]4)[CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=[O:25])[CH:6]=[CH:5][CH:4]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O.C(O)(=O)C>C(OCC)(=O)C>[O:21]1[CH2:22][CH2:23][O:24][CH:20]1[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH2:13][CH2:12][C:11](=[O:25])[N:10]2[CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:8]=1
Reactant: C1CCNCC1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1Cc1cccc(CCl)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCc2c(C3OCCO3)cccc2N1Cc1cccc(CN2CCCCC2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
1-(6-Chloromethylpyridin-2-ylmethyl)-5-(1,3-dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (1.0 g, 2.8 mmol) was added to piperidine (2 ml), followed by stirring in an argon atmosphere at 100° C. for 2 hours. After cooling to room temperature, water and a small quantity of acetic acid were added to the reaction mixture, and extraction with ethyl acetate was performed twice. The organic layers were combined, washed twice with water and once with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dry product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 0.73 g (yield: 64%) of 5-(1,3-dioxolan-2-yl)-1-(6-piperidinomethylpyridin-2-ylmethyl)-3,4-dihydro-1H-quinolin-2-one as a light yellow amorphous solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.C(=O)=[O:18].CC(C)=O.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:18]
Reactant: O=C=O
Reactant: Clc1ccc(SCCCCCCCBr)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=S(CCCCCCCBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 1-bromo-7-(4-chlorophenylthio)heptane (0.80 g) in dichloromethane (10 ml) was cooled to −78° C. (cardice/acetone) and a slurry of metachloroperbenzoic acid (60%, 0.72 g) in dichloromethane (5 ml) was added over 20min. After 40 min, the reaction was allowed to warm to room temperature and shaken with aqueous sodium sulfite/sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel using dichloromethane to 4% methanol in dichloromethane as eluents to give 1-bromo-7-(4-chlorophenylsulfinyl)heptane (0.43 g). 1H-NMR (CDCl3) δ 1.2-2.0 (10H, m), 2.77 (2H, t), 3.39 (2H, t) and 7.4-7.7 (4H, m).
Reaction SMILES: C(OCl)(C)(C)C.[N+:7]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:17][S:18][CH3:19].C[O-].[Na+]>C(Cl)Cl.C(#N)C.CO>[N+:7]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH2:17][S:18][CH3:19])[CH:11]=1)([O-:9])=[O:8]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CSC
Agent: CC(C)(C)OCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: CSCc1cc([N+](=O)[O-])ccc1N

Procedure:
The starting material is prepared as follows: The solution of 23.4 g of t-butylhypochlorite in 20 ml of methylene chloride is added to that of 30.0 g of 4-nitroaniline and 27.0 g of dimethyl thioether in 650 ml of acetonitrile and 200 ml of methylene chloride while stirring at -40° under nitrogen. After 4 hours the temperature is raised to -20° and maintained there for three hours. After the addition of 30 g of sodium methoxide in 100 ml of methanol the mixture is refluxed for 15 hours, cooled, filtered and evaporated. The residue is dissolved in diethyl ether and filtered through a silica gel column to remove any unreacted 4-nitroaniline as its benzenesulfonate following addition of 17.4 g of benzenesulfonic acid. The filtrate is evaporated and the residue recrystallized from ethanol, to yield the 4 -nitro-2-methylmercaptomethylaniline melting at 72°-77°.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[O:7][C@H:8]([CH:10]=[O:11])[CH2:9][C@@H:4]2[O:3]1.[CH3:13][Mg]Br>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[O:7][C@H:8]([CH:10]([OH:11])[CH3:13])[CH2:9][C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2O[C@H](C=O)C[C@@H]2O1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)[C@@H]1C[C@@H]2OC(C)(C)O[C@@H]2O1
Temperature: -20 °C
Reaction time: 20 h
Yield: 212.5 %

Procedure:
To a solution of (3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (compound 25f, 800 mg, 1 mmol) in THF (20 mL) was added methyl magnesium bromide (2M in THF, 0.7 mL, 1.4 mmol) at −20° C. under argon. After being stirred at −20° C. for 20 hours, the reaction was quenched by saturated NH4Cl solution, extracted with EtOAc (30 mL) three times. The organic layers were combined and concentrated in vacuo to afford 400 mg crude product of 1-[(3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydro furo[2,3-d][1,3]dioxol-5-yl]ethanol (compound 25g), which was used in next step without further purification. MS obsd. (ESI+) [(M+NH4)+]: 206.
Reaction SMILES: CO[C:3]([C:5]1([CH2:11][CH:12]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH:20]1[CH2:24][CH2:23][C@H:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21]1>>[CH3:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH:20]1[CH2:24][CH2:23][C@H:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:12][CH2:11][C:5]4([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)[C:3]3=[O:4])=[CH:27][CH:26]=2)[CH2:21]1
Reactant: COC(=O)C1(CC=O)CCCCC1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(N3CCC4(CCCCC4)C3=O)cc2)C1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 1 by condensing 1-(2-oxo-ethyl)-cyclohexanecarboxylic acid methyl ester (Intermediate 6) with 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14), and subsequently cyclization.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([S:15][C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[C:9]=2[N:8]=[CH:7][C:6]=1[CH3:25])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH2:1]([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([S:15]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)=[O:34])[C:9]=2[N:8]=[CH:7][C:6]=1[CH3:25])[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1c(C)cnc2c1CCCC2Sc1nc2ccccc2[nH]1
Solvent: ClCCl
Product: C=CCOc1c(C)cnc2c1CCCC2S(=O)c1nc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
0.7 Gram of 4-allyloxy-8-(2-benzimidazolyl)thio-3-methyl-5,6,7,8-tetrahydroquinoline was dissolved in 30 ml of methylene chloride, then this solution was cooled to -50° to 31 60° C., next to this solution was added dropwise a solution prepared by dissolving 0.43 g of 80%-meta-chloroperbenzoic acid in 10 ml of methylene chloride, and the reaction mixture was stirred for 20 minutes at the above-mentioned temperature. After the reaction was completed, the reaction mixture was washed with an aqueous solution of sodium carbonate, and dried with anhydrous magnesium sulfate. Methylene chloride was removed by evaporation under reduced pressure, the residue thus obtained was recrystallized from diethyl ether to obtain 0.4 g of 4-allyloxy-8-(2-benzimidazolyl)sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline. White powdery crystals. Melting point: 100°-102° C. (decomposed)
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13](O)=[N:14][CH:15]=[C:16]([Br:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>C(#N)C>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Cl:22])=[N:14][CH:15]=[C:16]([Br:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc(Br)n2nc(SCc3ccccc3)nc12
Solvent: CC#N
Product: Clc1ncc(Br)n2nc(SCc3ccccc3)nc12

Procedure:
A suspension of 1.04 g (3.08 mmol) of crude 2 -benzylthio-5-bromo-8 -hydroxy[1,2,4]triazolo[1,5 -a]pyrazine in 40 mL of dry acetonitrile was prepared in a flask equipped with a condenser and a drying tube and to this was added with stirring 4.0mL (43mmol) of phosphorus oxychloride. The mixture was heated at reflux for 3 hours and the solvent was then removed by evaporation under reduced pressure. The dark residue was dissolved in dichloromethane and the resulting solution was washed with water and dried over sodium sulfate. The residue obtained after removal of the solvent by evaporation under reduced pressure was purified by flash column chromatography on silica gel using dichloromethane as the eluent to obtain 0.26 g (24 percent of theory) of the title compound as an off-white solid melting at 109°-110° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH2:16](O)[CH3:17]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([O:14][CH2:16][CH3:17])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2ccc(O)cc2c1
Agent: Cl
Product: CCOC(=O)c1ccc2ccc(O)cc2c1

Procedure:
A solution of 7-hydroxynaphthalene-2-carboxylic acid (56.09 g) in ethanol (200 ml) was saturated with dry hydrogen chloride and then refluxed for 30 minutes. The mixture was evaporated to about half volume, treated with water, and extracted with ethyl acetate, which was washed with water, and sodium bicarbonate solution, dried and evaporated to give a solid. Crystallisation from ethyl acetate afforded ethyl 7-hydroxynaphthalene-2-carboxylate (37.5 g), m.p. 155°-156°.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)C1NCCc2ccccc21
Yield: 63 %

Procedure:
To a solution of isoquinoline-1-carboxylic acid (12.5, 0.072 mole) in 185 ml of glacial acetic acid was added 2 g of platinum oxide and the suspension was hydrogenated at room temperature under 60 psi hydrogen pressure in a Parr hydrogenation apparatus for 24 h. The reaction mixture was filtered though a filter pad (Celite) to remove the catalyst and the filtrate was evaporated to dryness in vacuo. The solid residue was triturated with water, filtered and dried to yield 8 g (63% yield) of DL-1,2,3,4-tetrahydroisoquinolin-1-carboxylic acid. FD-Mass spectrum 178 (MH+);
Reaction SMILES: [ClH:1].Cl.CN[C@@H]1CCN([CH2:10][CH:11]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)C1.C(O[C:34](=O)[NH:35][C@@H:36]1[CH2:40][CH2:39][N:38](C(=O)C(C2(O)CCCCC2)C2C=CC=C(C(F)(F)F)C=2)[CH2:37]1)(C)(C)C>>[ClH:1].[ClH:1].[CH3:34][NH:35][C@@H:36]1[CH2:40][CH2:39][N:38]([CH:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH3:10])[OH:28])[CH2:37]1
Reactant: CN[C@@H]1CCN(CC(c2cccc(C(F)(F)F)c2)C2(O)CCCCC2)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)C(c2cccc(C(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CN[C@@H]1CCN(C2CCCCC2(O)C(C)c2cccc(C(F)(F)F)c2)C1

Procedure:
In an analogous manner to Example 13, step 2, 1-{2-[(3R)-3-(methylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl((3R)-1-{(1-hydroxycyclohexyl)[3-(trifluoromethyl)phenyl]acetyl}pyrrolidin-3-yl)carbamate MS (ES) m/z 371.1; HRMS: calcd for C20H29F3N2O+H, 371.23102; found (ESI, [M+H]+), 371.2296.