Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[C:37](=O)([O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[O:38]N1C(=O)CCC1=O>O1CCOCC1.C(Cl)Cl>[CH3:50][Si:49]([CH3:52])([CH3:51])[CH2:48][CH2:47][O:46][C:37]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCN(C(=O)OCC[Si](C)(C)C)CC4)sc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of tert-butyl 4-(2-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (450 mg, 1.083 mmol) in dioxane (10 mL) was added Et3N (0.45 mL, 3.25 mmol) followed by 2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)ethyl carbonate (281 mg, 1.083 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2 (30 mL), washed with water (30 mL) and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 35% EtOAc) to afford tert-butyl 4-(2-(1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (555 mg, 0.991 mmol, 92% yield) as a white solid. LCMS (m/z)=560 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14][CH2:13]2)(=O)=O)=CC=1.O.[Br-:22].[Li+].O>CC(C)=O>[Br:22][CH2:11][CH:12]1[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14][CH2:13]1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Agent: [Li+]
Solvent: O
Solvent: CC(C)=O
Product: FC1(F)CCC(CBr)CC1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
In 15 ml of acetone, 1.5 g of 4,4-difluorocyclohexylmethyl p-toluenesulfonate was dissolved. Thereto 1.6 g of lithium bromide monohydrate was added and the mixture was heated under reflux for 8 hours. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.76 g of 4-bromomethyl-1,1-difluorocyclohexane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[CH:4][C:3]=1[C:17]([C:19]1[N:23]([CH3:24])[N:22]=[CH:21][C:20]=1I)=[O:18].NC1C=CC(CC2C=CC(Cl)=CC=2)=CC=1C(C1N(C)N=CC=1I)=O>>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:20]3[CH:21]=[N:22][N:23]([CH3:24])[C:19]=3[C:17](=[O:18])[C:3]=2[CH:4]=1
Reactant: COc1ccccc1Cc1ccc(N)c(C(=O)c2c(I)cnn2C)c1
Agent: Cn1ncc(I)c1C(=O)c1cc(Cc2ccc(Cl)cc2)ccc1N
Product: COc1ccccc1Cc1ccc2[nH]c3cnn(C)c3c(=O)c2c1

Procedure:
The title compound was prepared according to the procedure of step 6 in EXAMPLE 13 using [2-amino-5-(2-methoxybenzyl)phenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanone (EXAMPLE 21, step 4), instead of [2-amino-5-(4-chlorobenzyl)phenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanone.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:33]=[C:7]([CH:8]=[N:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[N:16]=[CH:17][C:18]2[C:19](=[C:21]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=2)[OH:20])[C:6]=1[OH:40])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>ClCCl>[C:29]([C:21]1[C:19]([OH:20])=[C:18]([CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=1)[CH2:17][NH:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][CH2:8][C:7]1[CH:33]=[C:34]([C:36]([CH3:37])([CH3:38])[CH3:39])[CH:35]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:40])([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1cc(C=N[C@@H]2CCCC[C@H]2N=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(CN[C@@H]2CCCC[C@H]2NCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1

Procedure:
(R,R)-1,2-bis(3,5-di-tert-butylsalicylidenamino)cyclohexane (5.0 g, 9.2 mmol, 1 mol equiv) is suspended in a mixture of dichloromethane/96% ethanol (1:3, 200 ml). Then NaBH4 (1.74 g, 45.7 mmol, 5 mol equiv) is added portionwise and the mixture is stirred until it becomes colorless (24 h). Water (50 ml) is added to the reaction mixture and it is extracted with dichloromethane (3×50 ml). The combined organic layers are dried over Na2SO4 and the solvent is evaporated to give the title product as a solid residue (4.95 g, 98% yield): 1H NMR (300 MHz, CDCl3) δ 7.30 (1H, d), 6.96 (1H, d), 4.13 (1H, d), 3.99 (1H, d), 2.56 (1H, m), 2.26 (1H, m), 1.78 (1H, m), 1.47 (9H, s), 1.37 (11H, s); 13C NMR (75 MHz, CDCl3) δ 24.1, 29.6, 30.7, 31.7, 34.1, 34.8, 50.8, 59.8, 122.3, 123.0, 123.1, 135.9, 140.6, 154.3; ESI mass spectrum: 551 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:69][C:70]1[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=1>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:74][C:73]3[CH:75]=[CH:76][C:70]([F:69])=[CH:71][CH:72]=3)=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:37]
Reactant: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2ccc(C(=O)Nc3ccc(F)cc3)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To the compound 4-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (28 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 4-fluoroaniline (7.92 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (15.8 mg, 48%). LC-MS m/z 601 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:23][C:24]1[S:28][C:27]([S:29]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:21])[F:22])=[CH:14][CH:13]=3)[CH2:16][CH2:17]2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)s1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 0.25 h

Procedure:
A 100-mL round-bottomed was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (0.54 g, 1.65 mmol, published PCT patent application no. WO 2006/094842), 10 mL of CH2Cl2, and 5-bromo-2-thiophenesulfonyl chloride (0.43 g, 1.65 mmol, Sigma-Aldrich, St. Louis, Mo.). To this was added triethylamine (0.28 mL, 2.06 mmol). After 15 min at room temperature, the mixture was diluted with 10 mL of CH2Cl2 and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (0-50% EtOAc in hexanes) to give 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.83 g) as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH:25]([O:28][CH3:29])[O:26][CH3:27])[CH:17]=1>C(O)C>[CH3:29][O:28][CH:25]([O:26][CH3:27])[C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23])[O:14][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
K2CO3 (0.076 mol) was added to a mixture of 3-amino-phenol (0.069 mol) in ethanol (200 mL) and the mixture was stirred for 10 min at room temperature, then 4-chloro-2-dimethoxymethyl-1-nitro-benzene (0.046 mol) was added and the reaction mixture was stirred for 16 hours at reflux temperature. The mixture was allowed to reach room temperature and the solvent was evaporated. The residue was washed with water and extracted 2 times with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 100%). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([F:19])([F:18])[F:17])[CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:20]([O-])=O)[CH:3]=1.C1COCC1>[Pt].CO>[Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([F:19])([F:18])[F:17])[CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[NH2:20]
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1N
Temperature: 35 °C
Reaction time: 4 h

Procedure:
A mixture of 4-chloro-N-methyl-2-nitro-5-(3-(trifluoromethyl)piperidin-1-yl)aniline (250 mg, 0.7 mmol), THF (6 mL), MeOH (6 mL) and Pt/C (50 mg) was stirred for 4 h at 35° C. under a hydrogen atmosphere (3.2 bar). The catalyst was removed by filtration and the mixture was concentrated to give the sub-title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][O:20][CH2:21]3)[CH:3]=1>C(N)(C)C>[CH:22]12[N:17]([C:4]3[N:5]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=4)[N:7]=[C:2]([NH:14][CH:11]([CH3:12])[CH3:10])[CH:3]=3)[CH:18]([CH2:24][CH2:23]1)[CH2:19][O:20][CH2:21]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3C4CCC3COC4)n2)cc1
Solvent: CC(C)N
Product: CC(C)Nc1cc(N2C3CCC2COC3)nc(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 140 °C
Yield: 195.2 %

Procedure:
In a 2-5 mL microwave vial was placed 8-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (36, 200 mg, 0.577 mmol) in iPrNH2 (5 mL) to give a yellow suspension. The reaction was heated under microwave irradiation at 140° C. for 3×45 min. The mixture was concentrated. The residue was dissolved in dichloromethane and washed with sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to give the title compound (208 mg, 98%) as a yellow foam. HRMS: For [M+H]+ mass error=0.1 mDa or 0.23 ppm.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH:2]=[CH2:3].I[CH2:22]I.[Cl-].[NH4+]>CCCCCC.C([Zn]CC)C>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][O:4][CH2:1][CH:2]2[CH2:22][CH2:3]2)=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ICI
Reactant: C=CCOCCc1ccc(OCc2ccccc2)cc1
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Product: c1ccc(COc2ccc(CCOCC3CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of compound of formula (7), (12 g, 0.0447 mol) in dry hexane (50 ml), diethyl zinc (1.1 M solution in hexane, 185 ml) was added at 0° C. under nitrogen atmosphere followed by diiodomethane (18 ml, 0.224 mol). The reaction was stirred for 6 h at 0° C. and poured over cold aqueous solution of ammonium chloride. The organic layer was separated and the aqueous layer extracted repeatedly with diethyl ether. The combined organic layer was washed with aq. solution of sodium thiosulphate, dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified over silica gel column using ethyl acetate and light petroleum ether (1:50) as an eluent to afford compound of formula (8), as a colorless liquid 11.365 g (90%).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][NH:5][C:4]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:3]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](Cl)=[CH:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([O:12][C:10]3[CH:9]=[CH:8][C:4]4[NH:5][CH2:6][CH2:7][O:2][C:3]=4[CH:11]=3)=[CH:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccc2c(c1)OCCN2
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(c3)OCCN4)ccnc2cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 17 h
Yield: 40.5 %

Procedure:
A solution of 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 mmol), cesium carbonate (4.35 g, 13.3 mmol), and 7-(benzyloxy)-4-chloro-6-methoxyquinoline (1.000 g, 3.34 mmol) in DMF (10.0 mL) was stirred at 80° C. After 17 h, additional 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 mmol) was added, and the mixture stirred at 80° C. for 20 h. Additional 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.6259 g, 3.336 mmol) and cesium carbonate (4.35 g, 13.3 mmol) were added, and the mixture stirred at 80° C. for 3 days. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange-brown oil. This material was purified twice via column chromatography (RediSep 120 g column, gradient elution with 0-5% methanol-dichloromethane) to afford an orange oil. Trituration with methanol and filtering the resulting suspension afforded 7-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.560 g, 40.5% yield) as a tan solid. MS (MH+) 415.1; Calculated 414 for C25H22N2O4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([S:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1ccc2c(Sc3ccccc3)ccnc2c1
Temperature: 100 °C

Procedure:
A resealable tube under N2 was charged with 4-chloro-7-methoxyquinoline (1.00 g, 5.16 mmol), thiophenol (0.528 ml, 5.16 mmol), cesium carbonate (2.52 g, 7.75 mmol) and DMSO (5 mL). The mixture was heated at 100° C. for 2 hrs. The crude reaction mixture was directly purified by silica gel chromatography using 0-10% CH2Cl2:MeOH to afford 7-methoxy-4-(phenylthio)quinoline as a off-white solid. MH+=268.0.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][C:10]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:14])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(COC)OC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(NCc2ccccc2)CC(=O)N(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: CC1(NCc2ccccc2)CCN(Cc2ccccc2)C1

Procedure:
51 g of 93% pure 1-benzyl-3-benzylamino-3-methylpyrrolidine-2,5-dione (0.154 mol) are reduced in 330 ml of dimethoxyethane using 12.4 g (0.33 mol) of lithium aluminum hydride. The work up is carried out as in A of Example 5.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C(N(CC)CC)C>C(O)C>[C:15]1(=[O:24])[N:14]([CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]12
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00g, 20 mmoles) and N-[2-(bromo)ethyl]phthalimide (5.59 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 3 hours and heated at reflux for 4 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 3.95 g of the desired product (61.1%, yellow crystals).
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:56])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.[CH3:57][O:58][C:59]1[N:64]=[C:63]([CH:65]=O)[CH:62]=[CH:61][CH:60]=1>>[Cl:55][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][C:51]=1[Cl:54])[CH2:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([C@H:38]2[CH2:37][O:36][C:32]3=[CH:33][C:34]4[CH2:35][C@@H:26]([C:24]([NH:23][C@@H:6]([CH2:7][C:8]5[CH:9]=[CH:10][C:11]([O:14][C:15]6[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=6[CH3:22])=[CH:12][CH:13]=5)[C:5]([OH:4])=[O:56])=[O:25])[N:27]([CH2:65][C:63]5[CH:62]=[CH:61][CH:60]=[C:59]([O:58][CH3:57])[N:64]=5)[CH2:28][C:29]=4[CH:30]=[C:31]3[O:39]2)=[CH:45][CH:44]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: COc1cccc(C=O)n1
Agent: Cl
Product: COc1cccc(CN2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)n1

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride (30 mg) was reductively aminated with 6-methoxy-pyridine-2-carbaldehyde according to General Procedure D (with excess of aldehyde). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (20 mg). LCMS (m/z): 876.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[F:18].O>CN(C)C=O>[F:18][C:12]1[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Reactant: Fc1cccc(CBr)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCN1Cc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of pyrrolidin-2-one (9.38 mL, 121 mmol) in N,N-dimethylformamide (DMF) (200 mL) was added in portions sodium hydride (6.04 g, 151 mmol) (60%/mineral oil) in 10 min and the mixture was stirred under nitrogen atmosphere at ambient temperature for 2 h then 1-(bromomethyl)-2,3-difluorobenzene (15.37 mL, 121 mmol) was added dropwise over 15 min and the mixture was stirred at ambient temperature for 2.5 h. Water (600 mL) was added and the mixture was stirred at ambient temperature for 30 min then extracted with EtOAc. The organic phase was washed with water (3×), and brine, dried (Na2SO4), concentrated, dissolved in acetonitrile and washed with hexanes (2×). The acetonitrile phase was concentrated, dried in vacuo to provide 1-(2,3-difluorobenzyl)pyrrolidin-2-one (19.14 g, 86 mmol, 71.2% yield) as a yellowish oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03 (quint, J=7.61 Hz, 2 H), 2.43 (t, J=8.10 Hz, 2 H), 3.34 (t, J=7.02 Hz, 2 H), 4.54 (s, 2 H), 6.99-7.17 (m, 3 H); LCMS (m/z) ES+=212 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([CH:27]2[CH2:29][CH2:28]2)[CH:3]=1.[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20]([N:30]5[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]5)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([CH:27]2[CH2:28][CH2:29]2)[CH:3]=1
Reactant: O=C(O)C1CNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C3CC3)c2)S1
Product: O=C1NC(N2CC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C2CC2)c1

Procedure:
1-(5-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-dihydro-thiazol-2-yl)-azetidine-3-carboxylic acid was prepared from 5-[1-(4-chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid following General Procedure C.
Reaction SMILES: [CH3:1]C1C=CC(OCC2C=CC=CC=2)=CC=1.C1(C=NC2C=CC=CC=2)C=CC=CC=1.[C:30]1([N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][C:47]1[CH:46]=[CH:45][C:44]([N:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:49][CH:48]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(OCc2ccccc2)cc1
Agent: C(=Nc1ccccc1)c1ccccc1
Product: Cc1ccc(N(Cc2ccccc2)c2ccccc2)cc1
Yield: 51 %

Procedure:
Methyl-4-(phenylmethoxy)benzene (1.98 g, 0.01 mol) and N-(phenylmethylene)benzenamine (1.81 g, 0.01 mol) were reacted in Na/DMF (1 g: 50 mL) at 75° C. for 30 min. Aqueous work-up, extraction with petroleum ether, 3×100 mL, and chromatography with petroleum ether/ethyl acetate 95:5 afforded a total of 1 g. of solid which by HPLC chromatography contained N,N-diphenyl-benzenemethanamine and the title compound in the ratio 6:94 (51% yield by HPLC). The purer fractions from chromatography on silica were combined and the solvent removed. The residual oil was dissolved in methanol and some petroleum ether. On cooling this crystallized the title compound. Two recrystallizations from methanol gave the title compound (98.1% pure; 36% yield), mp 85°-6° C. 1H NMR (200 MHz, CDCl3) δ(assignment): 2.29 (s, 3H, methyl), 4.97 (s, 2H, --NCH2Ph), 6.80-6.97 (m, 3H, aromatic) 7.06-7.27 (d, 4H, J=1.37 Hz, --NC6H4CH3), 7.14-7.36 (m, 7H, aromatic). MS [m/e (70 eV, % of base peak)]PhCH2N(Ph)(C6H4)CH3 272 (M+·, 96.5), 196 (M+· --Ph`, 31.7), 182 (M+· --PhCH3 ·, 100), 167 (M+· --PhCH2 ·--CH3·, 81.2), 91 (C7H7+, 98.3). FTIR (CDCL3): 3089, 3064, 3030, 2924, 2864, 1596, 1572, 1512, 1497, 1453 cm-1.