Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([F:4])[F:3].C(N(CC)CC)C.[NH2:20][C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1>CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:28]#[C:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([NH2:20])[CH:22]=2)=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Reactant: C#Cc1cccc(N)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2ccc(SC(F)(F)F)cc2)c1
Temperature: 75 °C
Yield: 61.9 %

Procedure:
A multinecked flask as described in Example 1 was charged with 5.4 g (0.021 mol) of p-bromophenyl trifluoromethyl sulfide, 75 ml of dried, degassed triethylamine, 2.46 g (0.021 mol) of 3-aminophenylacetylene, 0.048 g (0.068 mmol) of bis(triphenylphosphine) palladium II chloride, 0.0148 g (0.564 mmol) of triphenylphosphine, and 0.03 g (0.157 mmol) of cuprous iodide. The reaction mixture was heated at 75° C. for 20 hours after which gas chromatography showed the reaction to be complete. The mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble triethylamine hydrobromide salt by-product followed by concentration of the filtrate gave the crude product in near quantitative yield as an off-white solid. Short path distillation of the crude product under reduced pressure gave 3.9 g (0.013 mol, 62% yield) of the purified product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[CH:6]=[CH:7][N:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2nccc(O)c2n1
Product: Cc1ccc2nccc(Cl)c2n1
Temperature: 25 °C
Yield: 67 %

Procedure:
The suspension of 6-methyl-[1,5]naphthyridin-4-ol (1.60 g, 9.99 mmol) in POCl3 (25 mL) was heated under refluxing for 2 hrs. After cooling to room temperature, the reaction mixture was quenched with ice water and basified with NH4OH followed by extraction with AcOEt. The organic layer was washed with brine and dried over NaSO4, and concentrated to give 8-chloro-2-methyl-[1,5]naphthyridine as a brown solid (1.2 g, 67%). HR-MS-EI (+) m/e calcd for C9H7N2Cl (M+) 178.0298. found 178.0297.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12]C(=O)C)[C@H:10]([O:16]C(=O)C)[C@@H:9]([O:20]C(=O)C)[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([C:34](=[O:53])[C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=O)C.C1COCC1.[BH4-].[Na+].Cl>O.ClCCl.C(O)C>[CH2:46]([O:45][CH2:44][CH2:43][CH2:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH:34]([OH:53])[C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[N:24]([C@H:8]3[C@H:9]([OH:20])[C@@H:10]([OH:16])[C@H:11]([OH:12])[C@@H:6]([CH2:5][OH:4])[O:7]3)[CH:25]=2)=[CH:40][CH:39]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(OCCCOCc4ccccc4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc2c1c(C(O)c1ccc(OCCCOCc3ccccc3)cc1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
To a 0.5 L stirred round bottom flask, purged with nitrogen, charge [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[4-(3-benzyloxypropoxy)benzoyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (12.33 mmol), THF (50 mL), and ethanol (100 mL). Add sodium tetrahydroborate (37.0 mmol) and stir at room temperature for 6 hours. Acidify by dropwise addition of 5N HCl then dilute with water (200 mL) and dichloromethane (200 mL). Separate the organics and wash with brine (200 mL). Dry over sodium sulphate, filter, and concentrate to give the title compound as a mixture of diastereomers in sufficient purity to be used without further purification in the next step (7.2 g crude) mass spectrum (m/z): 546.4 (M+1-18).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][NH:6]1)=[N+]=[N-].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:34]([O:33][C:31]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:5]1[CH2:4][NH2:1])=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccccc1

Procedure:
(2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine and benzyl chloroformate/N-ethyldiisopropylamine in CH2Cl2 (see cabamate synthesis, Method A)—followed by Staudinger reduction gave (2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid benzyl ester as white foam, MS: 509 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[NH:12][C:11]([C:13](N[C@H](C(NC(C=O)CC(O)=O)=O)C)=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].[Br-].C[OH:31]>>[CH2:1]([C:8]1[NH:12][C:11]([C:13]([OH:14])=[O:31])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)c1ccc(Cc2ccccc2)[nH]1)C(=O)NC(C=O)CC(=O)O
Reactant: CO
Agent: [Br-]
Agent: [K+]
Product: O=C(O)c1ccc(Cc2ccccc2)[nH]1

Procedure:
3-[N-(5-Benzylpyrrole-2-carbonyl)-L-alaninyl]amino-4-oxobutanoic acid (36b), was prepared (41%) from 35b by the method described for compound 36a, to afford an off white solid: mp. 109-112° C.; [α]D25 +6.3° (c 0.3, methanol); IR (KBr) 3368, 1724, 1630, 1530, 1453, 1414, 1233, 1049; 1H NMR(d4 methanol) δ 7.25-7.11 (5H, m), 6.76 (1H, d, J=3.5), 5.84 (1H, d, J=3.5), 4.51 (1H, m), 4.43 (1H, q, J=7.1), 4.23 (1H, m), 2.5 (2H, m),1.35 (3H, d, J=7.0). Anal. Calcd for C19H21N3O5. 1.75H2O: C, 56.64; H, 6.13; N, 10.43. Found: C, 56.34; H, 5.72; N, 10.00.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22](O)=[O:23])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:30][N:31]([CH:33]=O)[CH3:32]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([NH:19][C:13]4[CH:14]=[CH:25][C:10]([CH2:33][N:31]([CH3:30])[CH:32]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:11][CH:12]=4)=[O:23])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In DMF (5 ml) was dissolved 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2 g). To the solution was added, under ice-cooling, thionyl chloride (0.11 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (15 ml). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.15 g) and triethylamine (0.41 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-(4-ethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:10][C:11]1[C:15]([C:16](OC)=[O:17])=[C:14]([CH:20]([CH3:22])[CH3:21])[O:13][N:12]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1.C(OCC)(=O)C.CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:20]([CH3:22])[CH3:21])[O:13][N:12]=1
Reactant: COC(=O)c1c(CSc2c(Cl)cccc2Cl)noc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1onc(CSc2c(Cl)cccc2Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of methyl 3-{[(2,6-dichlorophenyl)thio]methyl}-5-(1-methylethyl)-4-isoxazolecarboxylate (50 mg, 0.14 mmol) in tetrahydrofuran (0.5 mL) at 0° C. was slowly added a 1.5 M solution of diisobutylaluminum hydride in toluene (0.46 mL, 0.69 mmol). The solution was allowed to warm slowly to ambient temperature and stir overnight. The next day the solution was cooled to 0° C. and methanol (approximately 0.25 mL) was added followed by aqueous Rochelle's salt (approximately 3 mL). The mixture was diluted with ethyl acetate and allowed to warm to ambient temperature while stirring. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated to afford [3-{[(2,6-dichlorophenyl)thio]methyl}-5-(1-methylethyl)-4-isoxazolyl]methanol (43 mg, 93%). 1H-NMR (400 MHz, CDCl3) δ 7.35-7.16 (m, 3H), 4.60 (s, 2H), 4.10 (s, 2H), 3.17 (septet, J=8 Hz, 1H), 1.28 (d, J=6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]4[O:18][CH2:19][O:20][C:14]=4[CH:13]=3)[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CC(C)=O>[F:1][C:2]1[N:7]=[C:6]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]4[O:18][CH2:19][O:20][C:14]=4[CH:13]=3)[C:9](=[O:11])[N:10]([CH2:25][CH:24]=[CH2:23])[C:5]2=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: O=c1[nH]c2ccc(F)nc2n1-c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Treat a suspension of 1.4 g. (0.005 mole) of the imidazopyridine product of Step D in 80 ml. of acetone with 560 mg. (0.01 mole) of powdered potassium hydroxide. Stir at room temperature for 20 minutes and add 1.21 g. (0.01 mole) of allyl bromide. Continue stirring overnight. Concentrate the reaction mixture to one-half volume and dilute with 75 ml. of water. Separate the solid product by filtration and crystalize from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27]Br>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27][O:16][N:15]=[CH:14][C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:11][C:5]1[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1
Reactant: Clc1cccc(C=CCBr)c1
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)nc(Oc2ccccc2C=NOCC=Cc2cccc(Cl)c2)n1
Yield: 61.5 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 4.6 g of 3-chlorocinnamyl bromide were dissolved in 30 ml of dry acetone containing 2.7 g of anhydrous potassium carbonate. The solution was heated for 5 hours under stirring and reflux. After the reaction mixture was allowed to cool down, the acetone was distilled out under reduced pressure and the resulting residue was dissolved in 200 ml of ethyl acetate. The ethyl acetate solution was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate: 4:1) to obtain 5.2 g of O-(3-chlorocinnamyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as a semi-solid substance.
Reaction SMILES: N1C2C(=C(C3N=[C:12]([N:22]4[CH2:27][CH2:26]OCC4)[C:13]4SC(COC)=[CH:16][C:14]=4N=3)C=CC=2)C=N1.[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[C:32]2[S:37][C:36]([CH2:38][OH:39])=[CH:35][C:33]=2[N:34]=1.N1C=CC=CC=1CCl>CN(C=O)C.[H-].[Na+]>[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:32]2[S:37][C:36]([CH2:38][O:39][CH2:26][C:27]3[CH:16]=[CH:14][CH:13]=[CH:12][N:22]=3)=[CH:35][C:33]=2[N:34]=1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(COCc3ccccn3)cc2n1

Procedure:
Following the procedures for compound 314, (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMF and sodium hydride was alkylated with 2-picolyl chloride to give 4-(2-chloro-6-((pyridin-2-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine. Suzuki coupling of 4-(2-chloro-6-((pyridin-2-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine and 7 was carried out via General Procedure A. Purification using column chromatography gave 317. NMR: CDCl3: 3.80-3.90 (4 H, m, CH2), 4.01-4.08 (4 H, m, CH2), 4.72 (2 H, s, CH2), 4.88 (2 H, s, CH2), 7.10-7.14 (1 H, m, Ar), 7.38 (1 H, s, Ar), 7.40-7.48 (2 H, m, Ar), 7.51 (1 H, d, J 8.23, Ar), 7.65 (1 H, t, J 8.22, Ar), 8.18 (1 H, d, J 7.20, Ar), 8.52 (1 H, d, J 4.60, Ar), 8.96 (1 H, s, Ar) and 10.06 (1 H, s, NH). MS: (ESI+): MH+ 459.17
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[O:14]=[C:15]([NH:30][CH2:31][C:32](=O)[NH:33][C@@H:34]1[CH2:38]CNC1)[CH2:16][NH:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:33]2[CH2:34][CH2:38][C@@H:31]([NH:30][C:15](=[O:14])[CH2:16][NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:32]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(O)(c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a mixture of 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanone (0.075 g, 0.38 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide (0.10 g, 0.317 mmol) in 2% AcOH/CH2O2 (10 mL) was added NaB(OAc)3H (0.134 g, 0.634 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed [EtOAc to MeOH/EtOAc (1:9) then to 5% MeOH/EtOAc/Et3N (1:9:0.5)] to give 0.141 g of the title compound in 90% yield. MS (EI) calcd: (M+H)+=497.2; found: 497.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:7][CH:6]=[CH:5]2.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.[OH-].[K+]>CN(C=O)C.N1C=CC=CC=1.C(Cl)Cl.O.[Cu]>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][O:34][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([NH:12][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][CH:6]=[CH:5]4)=[CH:23][CH:24]=[N:25]2)=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: O=C(Nc1cccc2cc(O)ccc12)c1ccccc1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCN(C)C
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc2c(Oc3ccc4c(NC(=O)c5ccccc5)cccc4c3)ccnc2cc1OCCN(C)C
Temperature: 120 °C

Procedure:
To a microwaveable vial containing 0.300 g (1.1 mmol) of N-(6-hydroxy-naphthalen-1-yl)-benzamide in 1.5 mL DMF and 1.5 mL pyridine, was added 0.771 g (2.8 mmol) of [2-(4-chloro-6-methoxy-quinolin-7-yloxy)-ethyl]-dimethylamine. Then added (5 mmol %) copper grind into the mixture, along with 0.158 g (2.5 mmol) KOH pellets. The vial was heated in a microwave for 18 min at 120° C. (60 Watts constant power, CEM powermax). The mixture was diluted with CH2Cl2 and water, then transferred to seperatory funnel. The organics were extracted 3× with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in-vacuo. The crude was purified by reverse-phase HPLC. A tan oil was collected, which was titled product. MS (ESI pos. ion) m/z: 508 (M+H). Calc'd for C31H29N3O4-507.22.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]2=[O:24])[CH:9]=[CH:8][N:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccccc3Cl)cc1C(C)=O)C2=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3Cl)C=C1C(C)=O)C2=O

Procedure:
The title compound 157 is prepared according to the procedure reported in Example 39.1 with compound 126 (60 mg, 0.12 mmol) and BNAH (25 mg, 1 equiv) as reactants. Yellow solid. (Yield 25 mg, 49%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[CH:17]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:23]/[C:21]2[S:22][C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:25]=[CH:24][C:19]=3[N:20]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(OCCCCl)cc1
Reactant: COc1ccc2nc(C)sc2c1
Product: COc1ccc2nc(/C=C/c3ccc(OCCCCl)cc3)sc2c1
Yield: 27.8 %

Procedure:
The procedure of Example 28 was followed starting with 4-chloropropoxybenzaldehyde (5.0 g, 25 mmol) and using 6-methoxy-2-methylbenzothiazole (4.2 ml, 25 mmol) in place of 2-methylbenzothiazole to give (E)-2-[2-(4-chloropropoxyphenyl)ethenyl]-6-methoxybenzothiazole (2.5 g, 28% yield) as an amber oil. 1H NMR (CDCl3): δ 7.44-6.82 (m, 9H9, 4.21 (t, J=5.3 Hz, 2H), 3.93 (s, 3H), 3.41 (t, J=5.3 Hz, 2H), 2.51 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:26][NH2:27]>N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][CH:23]=[CH:22][CH:21]=3)[NH:27][N:26]=2)[CH:7]=[C:8]([C:17]([CH3:19])([CH3:20])[CH3:18])[C:9]=1[OH:16])([CH3:13])([CH3:14])[CH3:15]
Reactant: NN
Reactant: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Yield: 96.7 %

Procedure:
A solution of 69.1 g of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol and 45 g of hydrazine hydrate in 380 ml of pyridine is refluxed for 5 hours. After the pyridine is distilled off under reduced pressure, to the obtained residue is added water. The crude crystals precipitated are recrystallized from ethanol to give 62.5 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 216°-217° C.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]3[N:19]([CH3:20])[C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[N:16]=3)[CH2:10][C@@H:9]2[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)C=CC=CC=1>CO.[Pd]>[CH3:20][N:19]1[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]=[C:15]1[NH:14][C@H:11]1[CH2:12][CH2:13][NH:8][C@@H:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10]1
Reactant: Cn1c(N[C@H]2CCN(Cc3ccccc3)[C@@H](Cc3ccccc3)C2)nc2ccccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(N[C@H]2CCN[C@@H](Cc3ccccc3)C2)nc2ccccc21
Yield: 16.4 %

Procedure:
A mixture of (±)-cis-N-[1,2-bis(phenylmethyl)-4-piperidinyl]-1-methyl-1H-benzimidazol-2-amine (4.7 g) in methanol (200 ml) was hydrogenated with palladium on activated carbon (10%; 2 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated. The residue was suspended in DIPE, filtered and dried, yielding 0.6 g (17%) of (±)-cis-1-methyl-N-[2-(phenylmethyl)-4-piperidinyl]-1H-benzimidazol-2-amine (interm. 31; mp. 86.3° C.).
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][CH2:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[C@@H:11]([C:30]([OH:32])=[O:31])[CH2:10]1)(=O)C1C=CC=CC=1.[ClH:33]>>[ClH:33].[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:12]1[CH2:13][CH2:14][NH:9][CH2:10][C@@H:11]1[C:30]([OH:32])=[O:31]
Reactant: COc1ccc2nccc(CCC[C@@H]3CCN(C(=O)c4ccccc4)C[C@@H]3C(=O)O)c2c1
Agent: Cl
Product: COc1ccc2nccc(CCC[C@@H]3CCNC[C@@H]3C(=O)O)c2c1

Procedure:
8.8 g of (3R,4R)-1-benzoyl-4-[3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylic acid were heated, with stirring, in 200 cm3 of 5N aqueous hydrochloric acid at a temperature in the region of 100° C. for 48 hours. The reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. The residue was taken up in 100 cm3 of acetone. The mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 60° C. This operation was repeated an additional two times. The residue was finally triturated in 100 cm3 of acetone until it crystallized. After filtering off the crystals and drying in a desiccator under reduced pressure (10 kPa), 7.2 g of (3R,4R)-4-[3-(6-methoxyquinolin4-yl)propyl]piperidine-3-carboxylic acid hydrochloride were obtained in the form of a beige solid melting at approximately 270° C. (melting with softening).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])CCC.CCCCCC.[Br-].[Mg+2].[Br-].Br[C:24]1[CH:28]=[CH:27][S:26][CH:25]=1.Cl>O1CCCC1.C(OCC)C>[S:26]1[CH:27]=[CH:28][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[CH:25]1
Reactant: Cc1ccccc1Br
Reactant: Brc1ccsc1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1-c1ccsc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromotoluene (11.7 mmol) in tetrahydrofuran (25 mL) at -78° C. under nitrogen was added n-butyllithium in hexane (11.7 mmol) and the resulting yellow suspension stirred for 45 minutes at -78° C. To this suspension at -78° C. was added magnesium bromide etherate (11.5 mmol) and after stirring for 15 minutes at -70° C., the reaction mixture was allowed to warm to ambient temperature over 45 minutes. The resultant solution was added at ambient temperature to a suspension of 3-bromothiophene (11.0 mmol) and bis(1,2-diphenylphosphino)ethane nickel (II) chloride (0.05 mmol) in diethyl ether (25 mL) that has been stirred for 15 minutes. The reaction mixture was heated at reflux for 16 hours and then cooled in an ice bath. To the cooled reaction mixture was added dilute hydrochloric acid (20 mL) and then diethyl ether (50 mL). The organic phase was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue fractionated to give Compound 2a as a clear oil (b.p. 110°-114° C./7 mm).