Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C1C=CC2C3(C4C(OC=2C=1)=CC(C)=C(NC1C=CC=CC=1)C=4)OC(=[O:20])C1C3=CC=CC=1)CC.P([O-])([O-])([O-])=O.[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:69])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:68])[CH2:64][CH2:65][C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48].C(Cl)Cl>C(O)C>[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:69])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:68])[CH2:64][CH2:65][C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][C:47]([OH:20])([CH3:48])[CH3:49]
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(C)c(Nc3ccccc3)cc1C21OC(=O)c2ccccc21
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]12
Reaction time: 48 h

Procedure:
Nocardia autotrophica N-102 in the same BG medium (100 ml/500 ml-Erlenmeyer flask) as used in Example 1 was cultured at 28° C. under the aerobic conditions for 48 hours. To the culture solution were added 10 ml of a 5% PMCD (made by Mercian Co.) solution (0.01 M phosphate buffer, pH 7.0) and a solution of 2% vitamin D3 in 1 ml of ethanol (in the amount of 7 mol of PMCD relative to 1 mol of vitamin D3), and cultivation was continued for a further 96 hours. After completion of the cultivation, 200 ml of methylene chloride was added to the flask, and the mixture was extracted. The methylene chloride layer was concentrated to dryness under reduced pressure, and immediately after the residue was dissolved in 3 ml of 2-propanol:n-hexane (1:9) and allowed to stand at -20° C. for 2 hours. The resulting insolubles were removed by centrifugation. The supernatant was concentrated under reduced pressure and applied to HPLC on Zorbax SIL column (4.6 mm×25 cm) with n-hexane-2-propanol (86:14) as a mobile phase at a flow rate of 1.5 ml/min. The peak fraction at 3.8 minutes was collected, and concentrated to dryness at 40° C. or below under reduced pressure with a nitrogen gas replacement to give 25-hydroxyvitamin D3, which was strictly identical to the authentic sample of the commercially available 25-hydroxyvitamin D3 (made by Duphar Co., Holland) in terms of the retention time of HPLC, the UV absorption spectrum and mass spectrum cleavage pattern.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:13]([O:15]CC)=O)[C:8]([O:10]CC)=O.[NH2:22][C:23]([NH2:25])=[O:24]>C(O)C>[CH3:2][O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]1[C:8](=[O:10])[NH:25][C:23](=[O:24])[NH:22][C:13]1=[O:15]
Reactant: NC(N)=O
Reactant: CCOC(=O)C(Oc1ccccc1OC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: COc1ccccc1OC1C(=O)NC(=O)NC1=O
Reaction time: 4 h
Yield: 64.5 %

Procedure:
Sodium (3.2 g; 160 mmol) was dissolved in ethanol (200 ml). Diethyl (2-methoxyphenoxy)malonate (2) (11.2 g; 160 mmol) and urea (2.6 g; 44 mmol) were added to the mixture while being cooled on ice. The mixture was stirred for 4 hours under reflux. After being cooled, ethanol was evaporated, and the residue was dissolved in a small amount of water and made acidic with hydrochloric acid. The mixture was allowed to stand overnight at room temperature. The crystals that precipitated were collected by filtration and dried, to thereby obtain 7.1 g of 5-(2-methoxyphenoxy)-pyrimidine-2,4,6-trione (3). Phosphorus oxychloride (70 ml) and y-collidine (14 ml) were added to this compound and the mixture was stirred for 10 hours under reflux with heat. After phosphorus oxychloride was evaporated, the residue was added to ice-water and the mixture was extracted with ethyl acetate. The reaction mixture was washed with water and dried over anhydrous sodium sulfate, evaporated, and purified by silica gel column chromatography (ethyl acetate: hexane=1:2), to thereby obtain 4.8 g (yield: 39%) of 5-(2-methoxyphenoxy)-2,4,6-trichloropyrimidine (4) as a colorless solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][O:14][NH:13][C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([NH:20][CH2:21][CH2:22][S:23][CH:24]([CH2:40][C:41]([O-:43])=[O:42])[C:25](=O)[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27])(=[O:19])[CH3:18].C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][O:14][N:13]([C:25]3([C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=4)=[O:27])[CH:24]([S:23][CH2:22][CH2:21][NH:20][C:17](=[O:19])[CH3:18])[CH2:40][C:41](=[O:42])[O:43]3)[C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@H]1CONC1=O
Reactant: CC(=O)NCCSC(CC(=O)[O-])C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CC(=O)NCCSC1CC(=O)OC1(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1OC[C@H](NC(=O)Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 57.3 %

Procedure:
In 5 ml of dichloromethane were suspended 48 mg of (4S)-4-phenylacetamido-3-isoxazolidinone and 95 mg of the Compound (70) obtained in Example 70. To the suspension was added 71 mg of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. The mixture was stirred for 5.5 hours at room temperature. The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with ethyl acetate to give 75 mg of the subject Compound (71) as a colorless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:29][CH2:30][CH2:31][CH2:32][OH:33])[C:12]=2[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: NCCCO
Product: COc1ccccc1N1CCc2c(NCCCO)nc3c(OCC(F)(F)F)cccc3c21

Procedure:
1-(2-Methoxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydro-pyrrolo[3,2-c]quinoline(500 mg, 1.2 mmol) was dissolved in 3-amino-1-propanol(5.0 ml), and reacted at the same condition of Step 3 in the Example 38 to obtain 425 mg of desired compound as solid in 77% of yield.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[C:15]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:16]=[C:17]([CH3:24])[C:18]=1[S:19][CH2:20][N+:21]([O-:23])=[O:22].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[C:15]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:28])[CH:16]=[C:17]([CH3:24])[C:18]=1[S:19]([CH2:20][N+:21]([O-:23])=[O:22])=[O:9]
Reactant: Cc1cc(NS(=O)(=O)c2ccccc2)cc(C)c1SC[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cc(C)c1S(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.7 %

Procedure:
1.3 g (5.46 mmol) of 70-75% m-chloroperbenzoic acid are added rapidly to a solution of 2.2 g (6.24 mmol) of N-[3,5-dimethyl-4-[(nitromethyl)thio]phenyl]benzenesulphonamide in 79 ml of anhydrous chloroform. The reaction medium is stirred for 24 h at room temperature and then poured into a solution of 0.33 g (3.93 mmol) of sodium bicarbonate. The mixture is extracted with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by successive chromatographies on a column of silica (eluent for the first chromatography: methylene chloride; eluent for the second chromatography; 2/1 hexane/ethyl acetate) and crystallization from hexane, to give 0.98 g (42%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphinyl]phenyl]benzenesulphonamide.
Reaction SMILES: [Si]([O:8][N:9]([CH3:18])[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])=[O:11])(C(C)(C)C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:30][C:31](=O)[C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:35]([O:42]COC)=[C:34]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1.Cl>C1COCC1.CC(C)=O.C(OCC)(=O)C>[OH:8][N:9]([CH3:18])[C:10]([N:12]1[CH2:16][CH2:15][CH:14]([C:31](=[O:30])[C:32]2[CH:37]=[C:36]([C:38]([CH3:39])([CH3:40])[CH3:41])[C:35]([OH:42])=[C:34]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=2)[C:13]1=[O:17])=[O:11]
Reactant: CN(O[Si](C)(C)C(C)(C)C)C(=O)N1CCCC1=O
Reactant: COCOc1c(C(C)(C)C)cc(C(=O)OC)cc1C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CN(O)C(=O)N1CCC(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 1 h
Yield: 10 %

Procedure:
To a chilled solution (-78° C.) of 2 g (7.34 mmol) of the thus obtained 1-(N-tert-butyldimethylsilyloxy-N-methylcarbamoyl)pyrrolidin-2-one in THF (5 ml) was added 8.1 ml (8.1 mmol) of a THF solution of 1.0M lithium bis(trimethylsilyl)amide under a nitrogen atmosphere, and the mixture was stirred for 1 hour. To the reaction mixture was dropwise added 5 ml of a THF solution of 1.55 g (5 mmol) of methyl-3,5-di-tert-butyl-4-methoxymethyloxybenzoate while being stirred at room temperature for 20 hours. The reaction mixture was poured into ethyl acetate, washed with 0.1N hydrochloric acid and saturated brine, dried over magnesium sulfate and evaporated to give a residue, which was dissolved in 12 ml of acetone and added with 0.6 ml of conc. hydrochloric acid. The reaction mixture was stirred at room temperature for 20 hours, and poured into ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate and evaporated to give a residue, which was chromatographed on silica gel (toluene/ethyl acetate=10/1) to give 200 mg of the objective compound (Ia-20) as white amorphous in 10% yield.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:11](O)([CH3:13])[CH3:12])[C:6]([CH3:10])=[N:7][C:8]=1[CH3:9].C(Cl)[Cl:16]>>[Cl:16][CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([C:11]([CH3:13])=[CH2:12])[CH:4]=1
Reactant: Cc1nc(C)c(C(C)(C)O)cc1CO
Reactant: ClCCl
Product: C=C(C)c1cc(CCl)c(C)nc1C
Reaction time: 11 h

Procedure:
To a stirring solution of 2-(5-(hydroxymethyl)-2,6-dimethylpyridin-3-yl)propan-2-ol in 10 mL of CH2Cl2 was added 1.5 mL of SO2Cl2. After 11 h at r.t., the solution was concentrated and CH2Cl2 and 10 mL of sat. NaHCO3 solution were added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (20% Et2O/hexanes) provided 96.5 mg of the desired 3-(chloromethyl)-2,6-dimethyl-5-(prop-1-en-2-yl)pyridine as a mixture.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@H:13]([OH:24])[C@@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.[OH-].[Na+]>ClCCl>[CH2:23]=[CH:22][CH:21]1[CH:16]2[CH2:15][CH:14]([C@H:13]([OH:24])[C:9]3[CH:10]=[CH:11][N:12]=[C:6]4[C:7]=3[CH:8]=[C:3]([OH:2])[CH:4]=[CH:5]4)[N:19]([CH2:18][CH2:17]2)[CH2:20]1
Reactant: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CC1CN2CCC1CC2[C@H](O)c1ccnc2ccc(O)cc12
Temperature: -78 °C
Yield: 64.9 %

Procedure:
A 11 three-necked, round-bottom flask equipped with a condenser under argon atmosphere was charged with 5.0 g (15.4 mmol) of quinidine (97%, Aldrich) and 500 ml of dichloromethane. The solution in the flask was cooled to -78° C. To this cooled solution was slowly added 61 ml (61 mmol) of 1.0M borontribromide in dichloromethane over a period of 45 minutes. The reaction mixture was allowed to warm up to room temperature for a period of 2.5 h and was heated to reflux for 1 h. The reaction flask was cooled to -20° C. and 115 ml of 10% aqueous sodium hydroxide was slowly added. During the addition the temperature of the reaction mixture was maintained at 0° C. and was stirred vigorously. The mixture was transferred into a 21 separatory funnel. The remaining residue in the flask was transferred into the separatory funnel with the aid of a mixture of 5 ml of 10% sodium hydroxide and 20 ml of dichloromethane. The mixture in the separatory funnel, which contained some gummy yellow semi-solid, was shaken vigorously for 10 minutes and the aqueous layer was allowed to separate slowly from the organic phase. The organic layer was discarded and the aqueous phase was washed with 100 ml of dichloromethane and was cooled to 0° C. To the aqueous phase was added 12.5 ml of concentrated hydrochloric acid (HCl). This pH of this solution was adjusted to pH 10 with concentrated ammonium hydroxide. The resulting mixture was extracted with 12×250 ml of chloroform, dried with anhydrous sodium sulphate, concentrated and yielded 3.1 g of 6-hydroxycinchonine (1). The mother aqueous layer was extracted with 2×200 ml of n-butanol and yielded an additional 1.0 g to provide a total yield of 4.1 g of 6-hydroxycinchonine (1) (13.2 mmol, 86%). MS, IR and NMR data confirmed the identity of the compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:8]2[C:9]([Cl:11])=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][N:7]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1

Procedure:
Heat a solution of 5,6-dichloro-nicotinic acid ethyl ester (TCI America) (4.43 g, 0.02 mol), piperazine-1-carboxylic acid tert-butyl ester (4.13 g, 0.022 mol) and DIEA (5.2 mL, 0.03 mol) in DMA at 110° C. for 5 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the title compound as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:26]([CH3:28])[CH3:27].O>CN(C=O)C>[CH3:27][CH:26]([N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18])[CH3:28]
Reactant: CC(C)I
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(-c2cccc(Cl)c2)c2ncccc2c1=O
Temperature: 21 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (128 mg, 0.5 mmoles) and potassium carbonate (83 mg, 0.6 mmoles) in 10 ml DMF was added dropwise 2-iodopropane (0.075 ml, 0.75 mmoles) under an atmosphere of nitrogen and stirred overnight at 21° C. The reaction mixture was poured into 50 ml water and after stirring for one hour the white precipitate was collected and dried. Crystallization from methanol gave 60 mg (40% yield) of the desired 6-(2-propyl)-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 163.5°-164.5° C.; TLC 1:4 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ1.454 (d, 6H, J=6.8), 5.3 (m, 1H, J=6.8), 7.36-7.60 (m, 6H), 8.77 (dd, 1H, J=8.3, 1.7), 8.93 (dd, 1H, J=4.4, 1.7); 13C NMR (75 MHz, CDCl3) δ154.20, 151.13, 137.54, 136.85, 134.18, 129.99,129.55, 128.28, 127.69, 121.95, 119.70, 46.57, 21.87; IR (KBr) vmax 1647, 1614, 1591, 1566, 1552, 1487, 1468, 1441, 1419, 1400, 1388, 1273, 1242, 1182, 1170, 796, 783, 711, 700, 605 cm-1 ; mass spectrum (EI), m/e 298. Anal. (C17H15ClN2O) Calcd.: C, 68.34; H, 5.06; N, 9.38. Found: C, 68.25; H, 5.11; N, 9.38.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.Cl.Cl.[CH:15]([CH:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:8]([O:7][C:1]([N:32]1[CH2:31][CH2:30][NH:29][CH:28]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:33]1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: c1ccc(C(c2ccccc2)C2CNCCN2)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCNC(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
Di-tert-butyl carbonate (996 mg) was added to a mixture of 2-benzhydrylpiperazine dihydrochloride (1.65 g) and N,N-diisopropylethylamine (3.5 ml) in N,N-dimethylformamide (17 ml) under ice-cooling. After being stirred at same temperature for 2 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude oil. The oil was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (50:1) to give 1-tert-butoxycarbonyl-3-benzhydrylpiperazine (1.26 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[C:17]2[C:9]=1[C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=1[NH:16]2.C(Cl)CCl.C1C=CC2N(O)N=[N:34]C=2C=1.[OH-].[NH4+]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:20]=[CH:19][C:18]([C:21]([NH2:34])=[O:22])=[C:17]2[C:9]=1[C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=1[NH:16]2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(-c2ccccc2F)c2c3c([nH]c12)CCCC3
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)c1ccc(-c2ccccc2F)c2c3c([nH]c12)CCCC3
Temperature: 50 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
Step 5 A solution of 5-(2-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (0.097 g, 0.314 mmol), EDC (0.072 g, 0.376 mmol) and HOBT (0.058 g, 0.376 mmol) in THF (2.5 mL) and DCM (0.6 mL) was treated with 28% aqueous ammonium hydroxide (0.073 mL, 1.88 mmol). The mixture was stirred overnight. More EDC (0.072 g, 0.376 mmol), HOBT (0.058 g, 0.376 mmol) and 28% aqueous ammonium hydroxide (0.073 mL, 1.88 mmol) were added, and the mixture was heated at 50° C. in a sealed tube for 2 days. The mixture was cooled to rt, dissolved in EtOAc, washed with NaHCO3 (aq) and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 98:2 DCM-methanol) to give 5-(2-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (0.030 g, 30%) as an off-white solid. Mass spectrum m/z 309.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=3[O:14][CH:13]=[CH:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([NH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH:13]=[CH:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:23])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1C=COc2ccc(C(=O)O)cc21
Product: COc1ccc(Cl)cc1S(=O)(=O)N1C=COc2ccc(C(=O)Nc3ccccc3)cc21

Procedure:
Reaction of 4-(5-chloro-2-methoxy-benzenesulfonyl)-4H-benzo[1,4]oxazine-6-carboxylic acid with aniline in accordance with the general method of example 30, step 4 produced the title compound. Orange solid, MS (ISP)=455.2 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([C:6]1[NH:18][C:17]2[CH2:16][C@@H:15]3[C@:10]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=4)([CH2:11][CH2:12][N:13]([CH3:19])[CH2:14]3)[CH2:9][C:8]=2[C:7]=1[CH3:28])=[O:5])[CH3:2].B(Br)(Br)Br>>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[NH:18][C:17]2[CH2:16][C@@H:15]3[C@:10]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)([CH2:11][CH2:12][N:13]([CH3:19])[CH2:14]3)[CH2:9][C:8]=2[C:7]=1[CH3:28])=[O:5])[CH3:30]
Reactant: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@]1(c3cccc(OC)c3)CCN(C)C[C@@H]1C2
Agent: BrB(Br)Br
Product: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@]1(c3cccc(O)c3)CCN(C)C[C@@H]1C2
Yield: 49.9 %

Procedure:
0.29 g (0.71 mmol) of (±)-trans-2-diethylaminocarbonyl-3,7-dimethyl-4a-(3-methoxyphenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[3,2-g]isoquinoline were treated with 0.4 ml (4.26 mmol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (CH2Cl2 /MeOH/conc. NH4OH 80:12:0.8). The crude product was triturated with a mixture of acetone/MeOH=3:2, yielding 0.14 g of the title compound. M.p.=235°-238 l ° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[CH:17]=[CH:16][N:15]3[CH:18]=[CH:19][N:20]=[C:14]3[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:23]=[O:24]>>[C:6]1([C:12]2[CH:17]=[CH:16][N:15]3[C:18]([CH:23]=[O:24])=[CH:19][N:20]=[C:14]3[CH:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2ccn3ccnc3c2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnc2cc(-c3ccccc3)ccn12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
An oven dried flask under N2 was charged with 2 ml of N,N-dimethylformamide and phosphorous oxychloride (0.048 ml, 0.52 mmol) was added dropwise. 7-Phenylimidazo[1,2-a]pyridine (1-4, 0.100 g, 0.515 mmol) was added and the reaction was heated to 90° C. After 4 h additional POCl3 (0.048 ml, 0.52 mmol) was added and the reaction was heated overnight. Another sample of POCl3 (0.048 ml, 0.52 mmol) was added and heating was continued. After 4 h more, the reaction was cooled to ambient temperature. The reaction was quenched with saturated aqueous NaHCO3 and extracted 3× with DCM. The extracts were dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1O)=[CH:30][C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2>C(#N)C>[Br:1][C:32]1[C:31]2[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[CH:30]=2)[N:25]=[CH:24][C:23]=1[Cl:22]
Reactant: [Br-]
Reactant: COc1cc2ncc(Cl)c(O)c2cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc2ncc(Cl)c(Br)c2cc1OC
Temperature: 20 °C
Yield: 83.3 %

Procedure:
19 g of triphenylphosphine dibromide were added to a solution of 5.39 g of 3-chloro-4-hydroxy-6,7-dimethoxyquinoline in 270 cm3 of acetonitrile, with stirring and at a temperature in the region of 20° C. The reaction mixture was heated at about 80° C. for 8.25 hours. After cooling to a temperature in the region of 20° C., the insoluble material was filtered off. 5.67 g of 4-bromo-3-chloro-6,7-dimethoxyquinoline were obtained in the form of a gray solid.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C(Cl)Cl>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:33]([C:32]2[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=2)=[O:34])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.125 g, 0.43 mmol) and diisopropylethylamine (0.171 g, 1.32 mmol) in methylene chloride (5.0 mL) at 0° C. was added 4-fluorobenzoyl chloride (0.080 g, 0.51 mmol) and the reaction mixture was warmed to room temperature. After 2 h the reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (silica gel, 100:0 to 95:5 dichloromethane/methanol) to provided (4-(2-tert-butylphenyl)piperazin-1-yl)(4-fluorophenyl)methanone (0.044 g, 30%) as a white solid, mp 137-139° C.