Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)Br.C(OC([N:11]([CH2:18][CH:19]([O:29]C1CCCCO1)[CH2:20][P:21](=[O:28])([O:25]CC)[O:22]CC)[O:12]C(OCC)=O)=O)C>C(Cl)Cl>[OH:29][CH:19]([CH2:18][NH:11][OH:12])[CH2:20][P:21](=[O:22])([OH:28])[OH:25]
Reactant: CCOC(=O)ON(CC(CP(=O)(OCC)OCC)OC1CCCCO1)C(=O)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CC(O)CNO
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
Trimethylbromosilane (122 g.) was added dropwise to a solution of diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (79.4 g.) in methylene chloride (160 ml.) under ice-cooling with stirring over a period of 15 minutes. The mixture was further stirred for an hour at 0°-5° C. and for additional 2.5 hours at ambient temperature, and then evaporated under reduced pressure. The oily residue was dissolved in water (500 ml.) stirred at ambient temperature for an hour, and then washed twice with chloroform (200 and 100 ml. portions) to remove off bis(trimethylsilyl)ether. The combined chloroform washings were back extracted once with water (50 ml.). The combined aqueous layers were evaporated under reduced pressure. The dark brown oily residue was dissolved in water (300 ml.) washed twice with chloroform (each 150 ml. portion) and ethyl acetate (100 ml.) successively, treated with activated charcoal (2.5 g.), and evaporated under reduced pressure. The oily residue was dissolved in 1 N hydrochloric acid (750 ml.) treated with activated charcoal (2.5 g.) and then heated to reflux for 13.5 hours. The mixture was evaporated under reduced pressure. The oily residue was dissolved in a mixture of water (50 ml.) and methanol (100 ml.) adjusted to pH about 4 with propylene oxide, and diluted with ethanol (300 ml.). The oily precipitates were collected by decantation, and dissolved in water (60 ml.). This aqueous solution was diluted with methanol (120 ml.) under heating at 60° C., and then allowed to stand overnight at ambient temperature. The precipitates were collected by filtration, washed twice with 80% aqueous methanol (each 20 ml. portion) and methanol (20 ml.), and then dried on phosphorus pentoxide to give 2-hydroxy-3-(N-hydroxyamino)-propylphosphonic acid (10.60 g.). M.p. 153°-155° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=3)[S:10][C:3]=12.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:29].C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[O:29][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=3)[S:10][C:3]=12
Reactant: CC(C)n1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 195 °C
Yield: 88.3 %

Procedure:
To a solution of 123 (1.16 g, 4.18 mmol) in Ph2O (20 ml) was added 2-fluoro-4-nitrophenol (1.31 g, 8.37 mmol) and potassium carbonate (2.31 g, 16.72 mmol). The reaction mixture was heated to 195° C. for 18 hrs then cooled to room temperature. The residue was purified by column chromatography, eluents EtOAc/Hex (9/1 to 5/5), then MeOH/CH2Cl2 (98/2), to afford title compound 124 (1.47 g, 88% yield) as a yellow solid. MS (m/z): 399.0 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=1)[CH2:28][CH:29]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=[O:37].C(OCC)(=O)C>C1COCC1.O>[OH:37][C:30]1([C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:29]1[CH2:28][C:27]1[CH:38]=[CH:39][CH:40]=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: COc1cccc(CC2CCCCCCC2=O)c1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CC2CCCCCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a solution of 4,5-diphenyloxazole (2.1 g) in THF (30 ml) at −78° C. under N2 was added butyllithium (1.6M in hexane, 6.7 ml). After 30 minutes, a solution of 2-(3-methoxybenzyl)cyclooctanone (2.4 g) in THF (10 ml) was added thereto and stirred for 1 hour at the same temperature. The reaction mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-(hydroxy)-1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cyclooctane (3.7 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([NH:14][C:15]([C:17]3[C:18]([CH3:30])=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)=[N:21][CH:22]=3)=[O:16])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[Li+].[OH-]>CO.C1COCC1.O.O>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[N:19]=[C:18]([CH3:30])[C:17]([C:15]([NH:14][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=4[CH:7]=[CH:8]3)=[O:16])=[CH:22][N:21]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cccc2c1ccn2NC(=O)c1cnc(-c2cccc(F)c2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2c(C(=O)O)cccc21
Yield: 99.3 %

Procedure:
A solution of 1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4-carboxylic acid methyl ester (0.48 mmol) and LiOH (1.91 mmol) in Methanol/THF/H2O (1:1:1, 6 mL) is stirred at rt overnight. The reaction mixture is diluted with water and washed with DCM. The aqueous layer is separated and acidified with 10% aqueous HCl to adjust pH to 1. The mixture is extracted with ether twice. The organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4-carboxylic acid (186 mg, 99%) as a solid. MS: 391 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.85 (s, 3H), 7.20 (m, H), 7.24-7.40 (m, 2H), 7.46-7.61 (m, 2H), 7.66 (d, H), 7.92 (d, H), 8.23 (d, H), 8.37 (d, H), 9.16 (s, H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH:6]=[CH:5][CH2:4]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[CH:3]1([CH2:2][O:1][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC1CC=CC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(OCC1CC=CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 91 %

Procedure:
To a stirred, cooled (0° C.) solution of 4-hydroxymethylcyclopentene (J.-P. Depres and A. E. Green, J. Org. Chem. 1984, 49, 928-931, and references therein) (37.0 g, 276 mmol) in pyridine (450 mL) was added benzoylchloride (32.1 mL, 276 mmol) over 30 minutes. The resulting mixture was stirred at room temperature for 1.25 hours. Water (50 mL) was added and the volatiles removed in vacuo. The residual oil was dissolved in chloroform and the solution extracted with water and then dried over sodium sulfate. Evaporation of solvent gave (3-cyclopenten-1-yl)methylbenzoate as a yellow oil (53.94 g, 91%), sufficiently pure for use; 1H-NMR (DMSO-d6) δ: 7.98, 7.67, 7.56 (m, 5, C6H5), 5.72 (s, 2, CH=CH), 4.19 (m, 2, OCH2), 2.71 (m, 1, CH), 2.56-2.77 (m, overlapping solvent, 2CH), 2.21-2.14 (mn, 2, 2CH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(OCC)(=O)C.O>N1C=CC=CC=1>[CH3:17][S:18]([NH:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Oc2ccccc2)c(N)c1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccccc2)c(NS(C)(=O)=O)c1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
10.0 g of 3-amino-4-phenoxyanisole was dissolved in 50 ml of pyridine. Thereto was dropwise added 5.59 g of methanesulfonyl chloride in 10 minutes with ice-cooling. The mixture was stirred for 1 hour at 20°-25° C. The reaction mixture was introduced into a mixture of 200 ml of ethyl acetate and 100 ml of water. The resulting organic layer was separated and washed with three 100-ml portions of 2N hydrochloric acid and then with a saturated aqueous sodium chloride solution. The organic layer was separated, dried with anhydrous magnesium sulfate, and subjected to distillation under reduced pressure to remove the solvent. The resulting crystal was recrystallized from isopropyl alcohol to obtain 12.5 g (yield: 91.9%) of 3-methylsulfonylamino4-phenoxyanisole having a melting point of 109.5°-111° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].O>CN(C=O)C>[C:7]([C:15]1[N:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:17]=[CH:18][CH:19]=1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CBr
Reactant: O=C(c1ccccc1)c1ccc[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1cccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
Potassium tert-butoxide (7.22, 0.064 mol) was dissolved in DMF (40 ml) and 2-benzoylpyrrole (10 g, 0.058 mol) in DMF (10 ml) was added dropwise with stirring at room temperature. This was left for 16 hours then cooled to 0° C. when methyl bromoacetate (5.4 ml, 0.058 mol) in DMF (5 ml) was added dropwise. The reaction mixture was stirred for 16 hours then poured into water (150 ml) and extracted with diethyl ether (2×100 ml). The extracts were washed with brine (2×75 ml) dried and evaporated to give methyl (2-benzoylpyrrol-1-yl)acetate (12.6 g, 89%) as a brown oil which crystallised on standing.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:15][C:16]1([F:30])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][NH:18][CH2:17]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:15][C:16]1([F:30])[CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[CH2:20][CH2:19][NH:18][CH2:17]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCNCC(F)(F)C1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: FC1(F)CNCCN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Temperature: 135 °C
Reaction time: 6 h
Yield: 56.7 %

Procedure:
A mixture of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 g, 4.49 mmol), tert-butyl 6,6-difluoro-1,4-diazepane-1-carboxylate (1.06 g, 4.49 mmol) and DIPEA (1.56 ml, 8.99 mmol) in DMA (15 mL) was stirred at 135° C. for 6 hours. The reaction mixture was concentrated to dryness and DCM (30 mL) was added. The solution was cooled in an ice bath and TFA (15 mL) was added. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness, diluted with water, basified with 6M aqueous sodium hydroxide and extracted with DCM. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in DCM to give 6-(6,6-difluoro-1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.820 g, 56.6%) as a beige solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[N:13]=[C:12]([C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:55]([NH:57][CH2:58][CH2:59][C:60]#[N:61])[CH3:56]>CC(N(C)C)=O>[C:60]([CH2:59][CH2:58][N:57]([CH2:55][CH3:56])[C:19]([C:17]1[S:18][C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:13]=2)=[CH:15][CH:16]=1)=[O:21])#[N:61]
Reactant: CCNCCC#N
Reactant: O=C(O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
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: CC(=O)N(C)C
Product: CCN(CCC#N)C(=O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
Yield: 11 %

Procedure:
Combined 5-[2-(Pyridin-3-ylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid (22 mg, 0.065 mmol), DIEA (27 uL, 0.195 mmol), and HATU (36.8 mg, 0.097 mmol) in DMA (0.5 mL) in a Smith microwave vial. Added 3-ethylamino propionitrile (10.9 uL, 0.097 mmol) and heated in microwave for 900 seconds at 90° C. The crude mixture was purified by prep LCMS to afford title compound (2.7 mg, 10.9%). MS: m/z 379 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ1.203 (br t, 3H), 2.88 (br t, J=6.5 Hz, 2H), 3.65 (Br s, 2H), 3.70 (Br s, 2H), 7.33 (dd, J=5, 8.5 Hz, 1H), 7.469 (dd, J=1.5, 6.5 Hz, 1H), 7.497 (dd, J=1.5, 4 Hz, 1H), 7.985 (dd, J=1.5, 4 Hz, 1H), 8.16 (m, 1H), 8.22 (m, 1H), 8.56 (dd, J=1.5, 5 Hz, 1H), 8.95 (d, J=2.5 Hz, 1H), 9.91, (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][OH:35].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:32][CH2:33][CH2:34][OH:35])=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: NCCO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(C)C1N(CC(=O)NCCO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 36.8 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 2-amino-ethanol (61 mg, 0.86 mmol), N-methylmorpholine (90 mg, 0.86 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 80 mg, 36.8%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([Cl:24])=[C:26]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][N:35]=3)[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.00 g), 4-chloro-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.40 g of desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[CH:10](=[O:12])[CH3:11].CCO[CH2:16][CH3:17]>>[C:10]([N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[N:9]=[CH:16][CH3:17])(=[O:12])[C:11]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: NNc1ccccc1Br
Reactant: CCOCC
Reactant: CC=O
Product: CC=NN(C(=O)c1ccccc1)c1ccccc1Br
Reaction time: 1 h

Procedure:
The acetaldehyde 1-benzoyl-1-(2-bromophenyl) hydrazone was prepared as follows: A solution of 11.2 g. of 2-bromophenyl hydrazine in ether was treated with 7 ml. of acetaldehyde and allowed to stand for 1 hour with occasional swirling. The ether solution was washed with water, a small amount of dilute potassium bicarbonate solution, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was taken up in 25 ml. dry dimethylformamide and the resulting solution was added dropwise, with stirring and water-bath cooling, to a mixture of 1.56 g. of sodium hydride in 25 ml. dry dimethylformamide and stirring was continued for 1 hour. To this solution under nitrogen was added dropwise with stirring a solution of 7 ml. of benzoyl chloride in 10 ml. of dimethylformamide and stirring was continued for 4 hours. The mixture was diluted with ether and treated with water containing sufficient glacial acetic acid to neutralize excess alkali. The ether extract was washed with water, dilute potassium carbonate solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give acetaldehyde 1-benzoyl-1-(2-bromophenyl) hydrazone which was used as such in the above reaction.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]2[CH2:15][O:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:16]=[N+:17]=[N-:18].[Na+].C(OC)=O.CO>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]([OH:14])[CH2:15][N:16]=[N+:17]=[N-:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCCOCC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: COC=O
Product: [N-]=[N+]=NCC(O)COCCCCc1ccccc1
Yield: 99.7 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 3.70 g of 4-phenylbutoxymethyloxirane (prepared as described in Preparation 58), 5.83 g of sodium azide, 37 ml of methyl formate and 135 ml of an 8:1 by volume mixture of methanol and water were used, to give 4.46 g of the title compound as a colorless oil having an Rf value of 0.67 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:4]=1[O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:17]([O-])=O)=O>O1CCOCC1.C(O)C.[Ni]>[CH3:25][O:24][C:20]1[C:4]2[O:5][C:6]3[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=3[NH:17][CH2:1][C:3]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc(Oc2c(C=O)cccc2OC)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)NCc1cccc(OC)c1O2
Yield: 76.4 %

Procedure:
A solution of ethyl 4-(2-formyl-6-methoxyphenoxy)-3-nitrobenzoate (145 g) in dioxane (1.2 l) and ethanol (150 ml) was hydrogenated over Raney nickel catalyst (60 ml) at room temperature under atmospheric pressure. After a pre-calculated amount of hydrogen was absorbed, the catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was treated with ethanol (20 ml) to crystallize and then the separated crystals were collected by filtration. Recrystallization from ethanol gave ethyl 10,11-dihydro-4-methoxydibenz[b,f][1,4]oxazepine-8-caboxylate (96 g) as colorless needles. (Yield: 77%, m.p. 121°-122° C.)
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:19])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl.O.[NH2:28][NH:29][C:30]([NH2:32])=[S:31]>CO>[C:9]1([NH:8][C:7](=[O:19])[O:6][CH2:5][CH2:4][CH2:3][C:2](=[N:28][NH:29][C:30]([NH2:32])=[S:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Nc1cccc2ccccc12)OCCCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCCOC(=O)Nc1cccc2ccccc12)c1ccccc1
Reaction time: 21 h
Yield: 93 %

Procedure:
A suspension of naphthalen-1-carbamic acid 4-oxo-4-phenyl-butyl ester (4.72 g, 14 mmol), prepared in the previous step, in 100 ml of methanol plus 3.8 ml of 1 N HCl and 3.8 ml of water was warmed to dissolve the solid. While still warm thiosemicarbazide (1.29 g, 14 mmol) was added and the reaction stirred for 21 hours. The solid present was collected by filtration and dried under high vacuum to give the title compound (5.29 g, 92%) as a tan solid, mp 189-192° C.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH2:15](OS([O-])(=O)=O)[CH3:16]>O>[CH2:15]([S:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1)[CH3:16]
Reactant: O=C(O)c1cc(S)cc2c1OCCO2
Reactant: CCOS(=O)(=O)[O-]
Solvent: O
Product: CCSc1cc2c(c(C(=O)O)c1)OCCO2
Yield: 80.9 %

Procedure:
166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid, 242 cm3 of water 216 cm3 of soda lye and 181 g of ethylsulfate were introduced into a balloon flask provided with a condenser. The mixture was heated under reflux and then cooled. The solution was poured into 1.3 1 of water, filtered and treated with 110 cm3 of hydrochloric acid. The precipitate was dried off, washed with water and dried. 152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 153°-154° C.; yield: 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:15]=2)[C:10]([Br:24])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(-c3ccc(F)cc3)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1cc(Br)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
To a solution under N2 of 6-(4-fluorophenyl)indole-1-carboxylic acid t-butyl ester (2.00 g, 6.42 mmol), prepared as in step 1, in THF (36 mL) was added N-bromosuccinimide (1.26 g, 7.08 mmol) in a single portion and the clear-orange solution was stirred overnight at ambient temperature. The reaction mixture was diluted with ether (500 mL) and extracted with aqueous NaHSO3 (1-2M, 250 mL) and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give a viscous, clear-yellow oil (2.58 g) , which solidified on standing.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[S:55][C:45]=2[C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[N:47][CH:48]=1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(-c2ccccc2)c2sc(NC(=O)C3CCCCC3)nc12

Procedure:
From cyclohexanecarboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 371 (M+H+, 100).