Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([F:38])[C:31]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:45]([C:43]3[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:31]4[C:32]([F:38])=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:30]=4[F:29])[N:44]=3)=[O:46])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1F
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxy carbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (13.6 mg, 0.035 mmol), 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (9.0 mg, 0.032 mmol), HATU (30.2 mg, 0.080 mmol) in DMF (0.07 mL) and DIPEA (0.017 mL, 0.095 mmol) was stirred at room temperature for 16 h. The mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (5.0 mg, 24%). LCMS calc. for C33H37F3N5O6 (M+H)+: m/z=656.3. Found: 656.3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:13][CH2:14][CH3:15])[C:6]([CH3:12])=[N:7]2.[NH2:16][C:17]1[N:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][CH:18]=1>Cl>[ClH:1].[CH2:14]([O:13][C:5]1[C:6]([CH3:12])=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([O:23][CH2:24][CH3:25])[N:22]=1)[CH:11]=[CH:10][N:9]=2)[CH3:15]
Reactant: CCOc1cccc(N)n1
Reactant: CCOc1cc2c(Cl)ccnc2nc1C
Agent: Cl
Product: CCOc1cccc(Nc2ccnc3nc(C)c(OCC)cc23)n1

Procedure:
A mixture of 5-chloro-3-ethoxy-2-methyl-1,8 naphthyridine (0.98 g), 6-amino-2-ethoxypyridine (0.6 g), IMS (25 ml) and concentrated hydrochloric acid (2 drops) was boiled under reflux for 18 hours. The mixture was cooled and filtered to give 3-ethoxy-5-(6-ethoxy-2-pyridylamino)-2-methyl-1,8-naphthyridine hydrochloride, m.p. >250° C. Active (1/1) at 30 mg/kg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:9]([O:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:20])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: CCOC(=O)CCCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCC(=O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 65.1 %

Procedure:
To a mixture of fluorobenzene (37.3 g) and adipic acid monoethyl ester chloride (18.0 g) was added gradually aluminum chloride (26.6 g) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (500 ml) and extracted with diethyl ether (200 ml×2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (200 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(4-fluorophenyl)-6-oxohexanoate as an oil (14.1 g, 57%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:34])[N:14]([CH3:33])[N:15]=[C:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[C:17]=1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[CH2:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[H-].[Na+]>CN(C=O)C.O>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12]1[C:13](=[O:34])[N:14]([CH3:33])[N:15]=[C:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[C:17]=1[O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:11]
Reactant: OCc1ccccc1
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(COCOC)nn(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(COCOC)nn(C)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (2.38 g, 4.91 mmol) and benzylalcohol (797 mg, 7.37 mmol) in dry DMF (10 ml) was added 60% sodium hydride (294 mg, 7.35 mmol) at 5° C. The reaction solution was stirred at 0° C. for 1 hour. The reaction solution was diluted with water, and extracted with tert-butyl methyl ether 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 2.12 g of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-benzyloxy-2-methyl-3(2H)-pyridazinone (yield: 99%) as oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[N+:15]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[NH2:28])=[N:25][CH:24]=[CH:23][CH:22]=2)([O-])=O>>[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([NH2:14])=[C:4]([NH2:1])[CH:5]=1.[N:20]1[C:21]2[C:26](=[N:25][CH:24]=[CH:23][CH:22]=2)[C:27]([NH2:28])=[C:18]([NH2:15])[CH:19]=1
Reactant: Nc1c([N+](=O)[O-])cnc2cccnc12
Reactant: Nc1c([N+](=O)[O-])cnc2ccccc12
Product: Nc1cnc2ccccc2c1N
Product: Nc1cnc2cccnc2c1N

Procedure:
In step (2) of Reaction Scheme I, a 3-nitroquinolin-4-amine or 3-nitro[1,5]naphthyridin-4-amine of Formula XVII is reduced to provide a quinoline-3,4-diamine or [1,5]naphthyridine-3,4-diamine of Formula XVIII. The reaction can be carried out by hydrogenation using a heterogeneous hydrogenation catalyst such as platinum on carbon. The hydrogenation is conveniently carried out in a Parr apparatus in a suitable solvent such as toluene, methanol, isopropanol, ethyl acetate, or acetonitrile. The reaction can be carried out at ambient temperature.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=12.[N+:12]([CH2:15][CH3:16])([O-:14])=[O:13].C(N)C>C(O)C.C(N)CCC>[N+:12]([C:15]([CH3:16])=[CH:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=1)([O-:14])=[O:13]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc2nccn2c1
Agent: CCN
Solvent: CCO
Solvent: CCCCN
Product: CC(=Cc1ccc2nccn2c1)[N+](=O)[O-]
Yield: 11.9 %

Procedure:
In 40 ml of ethanol, 6.9 g of 6-imidazo[1,2-a]pyridinecarbaldehyde was stirred under reflux for 14 hours, together with 10.6 g of nitroethane and 30 drops of n-butyl amine. Then, a small quantity of ethyl amine was added thereto and the mixture was stirred under reflux for further 18 hours. After insoluble matters were removed by filtration upon heating, 50 ml of ethanol and 150 ml of ether were further added to remove insoluble matters by filtration. The solvent was removed by distillation under reduced pressure and the residue was recrystallized twice from ethanol to obtain 1.14 g of 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine.
Reaction SMILES: N1C=CC=CC=1C1N[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2N=1.C([O-])([O-])=[O:17].[Cs+].[Cs+].CN(C=O)C.I/[CH:28]=[CH:29]/[O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:32]=1>[Cu]I.CCCCCC.C(OCC)(=O)C>[O:17](/[CH:28]=[CH:29]/[O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: I/C=C/Oc1ccc(-c2ccccc2)cc1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)nc1
Agent: [Cu]I
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C(=C/Oc1ccc(-c2ccccc2)cc1)\Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
General procedure for coupling reactions using 2-pyridin-2-yl-1H-benzoimidazole (L2): (E)-4-((2-(Phenoxy) vinyl)oxy)-1,1′-biphenyl (5): An oven dried, three-necked, round-bottomed flask (50 mL) equipped with a nitrogen inlet, reflux condenser, rubber septum was repeatedly evacuated and back-filled with dry and pure nitrogen, and was then charged with CuI (0.074 g, 0.39 mmol, 0.5 eq), L2 (0.076 g, 0.39 mmol, 0.5 eq) and Cs2CO3 (0.63 g, 2.0 mmol, 2.5 eq), followed by addition of DMF (2 mL). The solution was stirred for 10 min at rt until reaction turn light green color. The appropriate substrate phenol (0.073 g, 0.78 mmol, 1 eq) was added to the reaction mixture and then stirred for addition 5 min at rt. Compound 4 (0.25 g, 0.78 mmol, 1 eq) was dissolved in minimum amount of solvent and then added into the reaction mixture. The reaction mixture was then heated from rt to between 50-75° C. for 12-36 h depending on the substrate. The reaction mixture was cooled and then through pad of silica gel using ethyl acetate and hexane mixture (20:80, 100 mL) and then washed three times with the same solvent mixture (100 mL). Filtrate was washed with water (100 mL×3) followed with brine (200 mL), dried using anhydrous sodium sulfate and concentrated in vacuo to yield brown oil. The crude oil was then purified by silica gel column chromatography using 100% hexane to afford 5 as white crystals. (0.18 g, 70%): mp 60-63° C. 1H NMR (300 MHz, CDCl3): 7.59-7.54 (m, 4H, HAr), 7.47-7.40 (m, 2H, HAr), 7.37-7.31 (m, 1H, HAr), 7.16-7.03 (m, 7H), 6.92 (s, 2H, HC═CH); 13C NMR (75 MHz, CDCl3): 157.6, 157.2, 140.4, 135.8, 134.9, 134.6, 129.7, 128.8, 128.4, 127.0, 126.9, 122.7, 116.0, 115.8; IR (cm−1): 3061, 2962, 2870, 1606, 1510, 1485, 1419, 1365, 1230, 1183, 1174, 1124, 1105, 1006, 896, 836, 728; HRMS (ESI), Calculated for C20H16O2 [M−H]− 287.1072. Found 287.1053; HPLC analysis: 91% purity.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH3:1][C:2]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15]
Reactant: BrCc1ccccc1
Reactant: CC1CCCN(Cc2ccccc2)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)CCCN(Cc2ccccc2)C1=O
Yield: 166.6 %

Procedure:
The reaction of 3-methyl-1-phenylmethyl-2-piperidinone (3.65 g, 18 mmol) with benzyl bromide (4.84 g, 28.3 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (2.73 g, 27 mmol) with butyllithium in hexanes (2.5 M, 10.3 mL, 25.7 mmol)) in THF (45 mL) and HMPA (2.7 mL, 15.5 mmol) as described above in the preparation of Example 10, gave 8.80 g of pale yellow colored oil. Column chromatography over silica gel (hexanes-EtOAc, 9:1) afforded the product lactam (3.72 g, 71%) as a colorless viscous residue. Analytical sample was prepared by bulb-to-bulb distillation (pot temp. 150-155° C. (1.3 mmHg)).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=O)[CH2:26][CH2:25]4)=[O:23])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].Cl.CN.F[P-](F)(F)(F)(F)F.[N:46]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:50]2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][C:33](=[O:35])[NH:46][CH3:50])[CH2:26][CH2:25]4)=[O:23])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(CCCC(=O)O)CC4)c3)ccc21
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CCCC1CCN(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NC)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
4-(1-((4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonyl)piperidin-4-yl)butyric acid (170 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (7.0 ml); methylamine hydrochloride (48 mg, 0.71 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (314 mg, 0.71 mmol) and triethylamine (0.35 ml) were added thereto; and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH silica gel, hexane-ethyl acetate-methanol system). After a small amount of acetone and ethyl acetate were added to the obtained amorphous solid; this solution was diluted with diethyl ether; and the solid portion was filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (30 mg, 0.061 mmol, 17%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[C:16]([F:18])([F:17])[F:15])=[CH:5][N:6]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cnc(Cl)s1)C(F)(F)F

Procedure:
According to Reference Example 8-2, by use of 2-chlorothiazole-5-carbaldehyde (300 mg, 2.03 mmol) dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (56 mg, 0.41 mmol) and (trifluoromethyl)trimethylsilane (0.360 mL, 2.44 mmol), the mixture was stirred and reacted at room temperature for 1.3 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[NH:8][CH2:7]2)[O:5][CH2:4]1.Br[CH2:20][CH2:21][CH2:22][Cl:23].O>COCCOC.CCOCC>[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[N:8]([CH2:20][CH2:21][CH2:22][Cl:23])[CH2:7]2)[O:5][CH2:4]1
Reactant: O=S1(=O)NCC2(OCCO2)c2ccccc21
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: O=S1(=O)c2ccccc2C2(CN1CCCCl)OCCO2
Temperature: 100 °C
Yield: 55.9 %

Procedure:
In 1,2-dimethoxyethane (450 mL) was suspended 60% sodium hydride (2.0 g, 502 mmol.), and then 2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethylene ketal (12.06 g, 50 mmol.) was added to the suspension. The suspension was heated to 100° C. for 1 hour under stirring. The reaction liquid was cooled to 50° C., and to this was added a solution of 1-bromo-3-chloropropane (23.62 g, 150 mmol.) in 1,2-dimethoxyethane (50 mL). The mixture was heated to 100° C. for 21 hours under refluxing. The reaction liquid was filtered to remove insolubles and the solvent was evaporated to give a residue. The residue was treated with water and ether, and the organic layer was taken out. The organic solution was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to leave the desired compound (8.89 g, yield 56%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[CH3:20][O:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.[I-].[Na+]>CN(C)C=O>[CH3:20][O:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8](=[O:9])[C:7]1[CH:18]=[CH:19][C:4]([Cl:3])=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
As described in example 1(a), 2.4 g (0.1 mol) of sodium hydride, 25.2 g (0.1 mol) of 4-chloro-N-(4-chlorophenyl)-benzamid, 200 ml dimethylformamide, 23.7 g (0.1 mol) of 8-bromocaprylic acid methyl ester and 3 g (0.02 mol) of sodium iodide are reacted. Reaction time: 5.5 hours; reaction temperature: 110° C. The crude product is used in the next step without any further purification.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C:14]1[C:22]2[O:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:33]([NH2:35])[CH3:34])[CH:29]=[C:30]([F:32])[CH:31]=1>>[F:25][C:26]1[CH:27]=[C:28]([CH:33]([NH:35][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:13][C:14]4[C:22]5[O:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=5[CH:17]=[CH:16][CH:15]=4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH3:34])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: CC(N)c1cc(F)cc(F)c1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: CC1(C)Cc2cccc(N)c2O1
Product: CC(Nc1cccc2nc(Nc3cccc4c3OC(C)(C)C4)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=446.1 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) and rac-1-(3,5-difluorophenyl)ethylamine.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.C(Cl)Cl.[C:24]([O:27]CC)(=[O:26])[CH3:25].[CH2:30]1[CH2:34]O[CH2:32][CH2:31]1>>[CH2:34]=[CH:30][C@@H:31]([CH3:32])[C@@H:3]1[C@:2]2([CH3:1])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:20])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:14]([CH2:13][C:12](=[O:20])[C:11]4[CH:10]=[C:9]([CH2:25][C:24]([O-:27])=[O:26])[CH:8]=[CH:7][C:6]=43)[C@@H:15]1[CH2:17][CH:18]=[CH:19]2
Reactant: C1CCOC1
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@@]12C=CC[C@H]1[C@@H]1CC(=O)c3cc(CC(=O)[O-])ccc3[C@H]1CC2
Yield: 48 %
Yield: 48 %

Procedure:
These syntheses are depicted in FIG. 178. Androsta-4,16-dien-3-one (4) was reduced at -55° with 5 lithium tris (1, 2-dimethylpropyl) hydridoborate in THF (c) as described for the preparation of 2 (FIG. 1). Chromatography on silica gel with CH2Cl2 /ethyl acetate 9:1 gave pure axial alcohol 5 (48% yield) and pure equatorial alcohol 6 (48% yield). Analytical samples were further purified by recrystallization (from PE at -30° for 5, from cyclohexane at RT. for 6).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: CCO
Product: COC(=O)c1cc(Cl)ccc1N=Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A mixture of 2-amino-5-chloro-benzoic acid methyl ester (11.7 g, 63 mmol) and 3-bromo-benzaldehyde (11.7 g, 63 mmol) in ethanol (200 mL). The reaction mixture was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 2-{[1-(3-bromo-phenyl)-methylidene]-amino}-5-chloro-benzoic acid methyl ester (5.3 g, 24%) as a white solid: LC/MS m/e calcd for C15H11BrClNO2 M+: 353.6, observed: 353.6.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:16]1[CH:17]=[N:18][CH:19]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccccc1Br
Product: O=C(O)c1ccncc1NCc1ccccc1Br
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from 2-bromobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. [M+H] calc'd for C13H11BrN2O2, 307, 309. Found 307, 309.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[CH3:31][O:30][C:28](=[O:29])[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)=[O:32]
Reactant: COC(=O)C(=O)Cl
Reactant: COC(=O)C1(C)CCN(c2ccc(N)cn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1ccc(N2CCC(C)(C(=O)OC)CC2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of methyl 1-(5-aminopyridin-2-yl)-4-methylpiperidine-4-carboxylate (2.96 g, 11.89 mmol) in DCM (100 mL) was added triethylamine (2.2 mL, 15.84 mmol) followed by methyl chlorooxoacetate (1.6 mL, 17.15 mmol) and the reaction mixture was allowed to stir at ambient temperature for 1.5 hrs. The reaction mixture was washed with brine (2×100 mL), the aqueous layer was re extracted with DCM (50 mL) and the organic washings were combined, dried and concentrated to leave the title compound as a brown gum (3.98 g, 11.89 mmol, 100%). 1H NMR (CDCl3) δ 1.72-1.82 (m, 2H), 1.96-2.02 (m, 2H), 2.52-2.59 (m, 1H), 2.95-3.03 (m, 2H), 3.70 (s, 3H), 3.97 (s, 3H), 4.16-4.22 (m, 2H), 6.67 (d, 1H), 7.93 (d, 1H), 8.28 (s, 1H), 8.66 (s, 1H); MS m/e MH+ 336.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[C:13](Cl)(Cl)=[S:14].C(N(CC)CC)C>ClCCl.[OH-].[Na+].CO>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[O:5][C:13]([SH:14])=[N:2][CH:3]=2)=[CH:7][CH:8]=1
Reactant: S=C(Cl)Cl
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Sc1ncc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Yield: 14.5 %

Procedure:
To a solution of 2-amino-4′-chloroacetophenone hydrochloride (1.48 g) in 30 ml of dichloromethane were added 1.65 g of thiophosgene and 3.63 g of triethylamine at 0° C. and the mixture was stirred over night at room temperature. To the reaction mixture were added IN sodium hydroxide solution and methanol. The resulting mixture was stirred at room temperature and partitioned between ethyl acetate and water. The aqueous layer was neutralized by adding dil. hydrochloric acid and the resulting crystal was collected and dried to give 220 mg of 5-(4-chlorophenyl)-2-mercaptooxazole.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:14]=[C:15]([C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([C:21]2([CH3:8])[CH2:22][O:23]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CO2)cc1F
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3-fluoro-4-methoxyphenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS, the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.