Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]([CH2:15][CH2:16][CH3:17])[N:13]=[CH:12][N:11]=1)(C(C)(C)C)(C)C.CO.[OH-].[Na+]>C(O)C>[CH2:15]([N:14]1[C:10]([CH2:9][OH:8])=[N:11][CH:12]=[N:13]1)[CH2:16][CH3:17]
Reactant: CCCn1ncnc1CO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCn1ncnc1CO
Temperature: 25 °C
Reaction time: 19 h
Yield: 87 %

Procedure:
To a solution of 5-(tert-butyldimethylsilanyloxymethyl)-1-propyl-1H-1,2,4-triazole (from Step a) (4.10 g, 16.1 mmol) in ethanol (18 ml) and methanol (36 ml) was added 4 M aqueous NaOH (6 ml, 24 mmol) and the mixture was stirred at room temperature for 19 h, then at 45° C. for another 5 h. The solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, EtOAc, then 10% MeOH/CH2Cl2) to leave 1.976 g (87%) of the title compound as a pale yellow oil: 1H NMR (250 MHz, CDCl3) δ 0.95 (3H, t, J=7.4 Hz), 1.91 (2H, sextet, J=7.4 Hz), 4.16 (2H, t, J=7.3 Hz), 4.76 (2H, s), 7.81 (1H, s).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]1([C:7]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ncccc1-c1ccccc1
Yield: 79.7 %

Procedure:
To a solution of methyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyridine-2-carboxylate (148.6 g, 521 mmol) in anhydrous toluene (550 ml) were added potassium carbonate (148.6 g), tetrakis(triphenylphosphine)palladium(0) (6 g), and phenyl boronic acid (70 g, 574 mmol). The reaction was equipped with a mechanical stirring apparatus and heated to reflux for 2 h. The reaction suspension was filtered through a bed of celite and washed with EtOAc. The filtrate was concentrated in vacuo and purified via flash chromatography (silica, 20% EtOAc/hexanes isocratic) to provide methyl 3-phenylpyridine-2-carboxylate (88.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:30][O:31][NH2:32]>C1(C)C=CC=CC=1.O>[CH3:30][O:31][NH:32][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)[C:9]([F:11])=[CH:10][C:2]=1[Cl:1]
Reactant: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CONC(=O)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Reaction time: 4 h

Procedure:
A solution of 8.4 g (22 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzoyl chloride in 150 ml of toluene was treated with 34 g (0.24 mol) of potassium carbonate, and 16 g (48 mmol) of a 25% strength aqueous methoxyamine hydrochloride solution was subsequently added dropwise. After the reaction mixture had been stirred for 4 hours, it was diluted with 0.5 l of water. The organic phase was then separated off, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and finally concentrated. Yield: 8.3 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:35]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:35]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN1CCCC(N)C1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1CCCC(NC(=O)Cn2c(-c3ccc(Br)cc3)nc3cccnc32)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), 1,1'-carbonyldiimidazole (3.1 g, 0.019 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and a solution of 3-amino-N-ethylpiperidine (2.6 g, 0.020 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (100 ml) and filtered. The filter cake was washed with water and recrystallized from isopropyl alcohol to give 4.9 g, (62%) of a white solid, mp 190°-192° C.
Reaction SMILES: [S:1]([CH2:6][CH2:7][CH2:8][OH:9])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C1COCC1>[C:15]([Si:12]([CH3:14])([CH3:13])[O:5][CH2:4][CH2:3][CH2:2][S:1][CH2:6][CH2:7][CH2:8][OH:9])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCSCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCSCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 3,3′-thiodipropanol (900 mg, 6 mmol) in THF (3 ml) was added dropwise to a suspension of sodium hydride (240 mg, 6 mmol) in THF (15 ml) under an atmosphere of N2. The reaction mixture was stirred at RT for 30 mins, then a solution of tert-butyldimethylsilylchloride (900 mg, 6 mmol) in THF (2 ml) was added and stirring was continued for 16 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 20% EtOAc in cyclohexane to give the title compound as a colourless oil (793 mg).
Reaction SMILES: [F:1][CH:2]1[CH2:4][CH:3]1[C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[N:6]=1.[Cl-].[NH4+]>CCO.O.[Zn]>[F:1][CH:2]1[CH2:4][CH:3]1[C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH:11]=2)[NH2:17])[N:6]=1
Reactant: Cc1ccc(-c2noc(C3CC3F)n2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2noc(C3CC3F)n2)cc1N
Temperature: 85 °C

Procedure:
To a suspension of 5-(2-fluorocyclopropyl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (129) (162 mg, 0.62 mmol) in EtOH:H2O (4:1) (3.3 mL) was added zinc dust (161 mg, 2.46 mmol) and ammonium chloride (132 mg, 2.46 mmol). The reaction mixture was heated at 85° C. for 24 hours, then filtered hot over celite and rinsed with ethyl acetate. The solvent was concentrated to give 5-(5-(2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (130).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C)C=O>[CH2:13]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Br:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
3-Bromo-4-hydroxy-benzaldehyde (1.9 g, 9.45 mmol) was added slowly, at 0° C., to a suspension of NaH 95% (290 mg, 11.34 nol) in dry N,N-dimethylformamide (45 mL). The mixture was stirred for 0.5 hours. Benzyl chloride (1.3 mL, 11.34 mmol) was added and the reaction stirred at room temperature overnight. 1N HCl (40 mL) was added and the layers separated. The aqueous layer was extracted with diethyl ether (5×50 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under vacuum. The residue was chromatographed (silica gel, hexanes/ethyl acetate 9:1) to produce 4-Benzyloxy-3-bromo-benzaldehyde as a white solid (2.47 g, 90%). 1H-NMR (CDCl3, 200.15 MHz): δ 9.82 (s, 1H), 8.09 (d, 1H, J=1.8), 7.76 (dd, 1H, J=8.4, 1.8), 7.47–7.32 (m, 5H), 7.02 (d, 1H, J=8.4), 5.24 (s, 2H.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.[H-].[Na+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C)C=O>[C:31]([O:30][C:29]([NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:4]4[N:3]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:2](=[O:1])[CH2:7][O:6][C:5]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)=[O:35])([CH3:32])([CH3:34])[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.106 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give a red solution, then cooled to 0° C. under a nitrogen atmosphere. Sodium hydride, 60% in oil (6.4 mg, 0.159 mmol) was added and the mixture stirred at 0° C. for 15 minutes. Ethyl 2-bromoacetate (0.035 mL, 0.318 mmol) was added and the mixture stirred at 0° C. for 30 minutes, allowed to warm to room temperature then stirred for one hour. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (5 mL) and extracted into ethyl acetate (3×3 mL). The organic phase was washed with 50:50 water:brine (2×5 mL) then brine (5 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as an off-white solid (22 mg, 39% yield). 1H-NMR (500 MHz, CDCl3) δ 7.13-7.28 (8H, m), 7.37-7.43 (2H, m), 5.24 (1H, br s), 5.18 (2H, s), 4.89 (2H, s), 4.49 (2H, q), 2.40-2.90 (4H, m), 2.21-2.35 (1H, m), 1.90-2.10 (1H, m), 1.20-1.75 (9H, br m), 1.53 (3H, t). LCMS (Method A) RT=7.20 min, M+H+=558.13.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([S:14][C:15]1([CH2:21][N+:22]([O-])=O)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C.O1CCCC1>[CH2:7]([S:14][C:15]1([CH2:21][NH2:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])CC1(SCc2ccccc2)CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NCC1(SCc2ccccc2)CCOCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a mixture of lithium aluminum hydride (2.23 g) and diethyl ether (120 ml) was added a solution of 4-(benzylthio)-4-(nitromethyl)tetrahydro-2H-pyran (5.35 g) in diethyl ether (30 ml) and tetrahydrofuran (15 ml) at 0° C., and the reaction mixture was stirred at 50° C. for 2 hr. The reaction mixture was ice-cooled, sodium sulfate 10 hydrate (19.33 g) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was dried (MgSO4), and the inorganic salt was removed by filtration. The filtrate was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound (3.20 g, yield 67%) as a yellow oil from a fraction eluted with ethyl acetate-methanol (3:1, volume ratio).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: C1CCNC1
Product: Clc1ccc(-c2nsc3cc(OCCCCN4CCCC4)ccc23)cc1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and Pyrrolidine were converted to yield 3-(4-Chloro-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole, MS: 387 (MH+, 1Cl).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH2:15]([N:33]=[C:34]=[O:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:15]([NH:33][C:34]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: NCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCCCCCCCCCCCN

Procedure:
12 grams 1,12 diaminododecane was reacted with 5 gms octadecyl isocyanate as in Example 2. Yield: 13.8 gms., melting point 105°-159°C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[O:5][C:4]=1[N:19]=[CH:20]OC)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[NH2:27]>CO>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:1]2[C:3]3[C:11]4[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7][C:6]=4[O:5][C:4]=3[N:19]=[CH:20][N:2]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: COC=Nc1oc2c(c1C#N)CCN(C(=O)OC(C)(C)C)C2
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2c(oc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1

Procedure:
tert-Butyl 3-cyano-2-[(1-methoxymethylidene)amino]-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 47A (134 mg, 0.44 mmol) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline from Example 4A (221 mg, 0.88 mmol) were heated in methanol (3.0 mL) in a microwave oven for 1 h at 160° C. The title compound was isolated by preparative HPLC to yield 18 mg (8%).
Reaction SMILES: [H-].[Na+].C(S)C.[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:17]C)[CH:8]=1>CN(C)C=O>[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:17])[CH:8]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: Nc1cc(O)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
A cooled (5° C.) suspension of 60% sodium hydride/oil dispersion (20.0 g, 0.50 mole) in anhydrous dimethylformamide (300 mL) under nitrogen was treated slowly dropwise with ethyl mercaptan (18.7 g, 0.30 mole) so as to maintain a pot temperature below 15° C., then stirred at room temperature for 15 minutes, cooled (5° C.), and treated in portions with 4-amino-5-chloro-2-methoxybenzoic acid (40.33 g, 0.20 mole). The mixture was heated to 105°±5° C. for 4 hours, cooled, and concentrated in vacuo to remove most of the dimethylformamide, then plunged into water (500 mL). The aqueous solution was extracted with methylene chloride (2×150 mL), and ether (150 mL), acidified with concentrated HCl (55 mL), filtered, and the filter cake washed with water and dried in vacuo to afford 35.7 g of crude product. Crystallization from tetrahydrofuran/hexane afforded 31.3 g (83%) of white solid; mp 192° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[C:27]([N:30]1[C:35]2[N:36]=[C:37]([C@H:50]([NH:52][CH2:53][C:54]3[N:55]([CH3:60])[N:56]=[C:57]([CH3:59])[CH:58]=3)[CH3:51])[N:38]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[C:39](=[O:40])[C:34]=2[CH2:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[C:27]([N:30]1[C:35]2[N:36]=[C:37]([C@H:50]([N:52]([CH2:53][C:54]3[N:55]([CH3:60])[N:56]=[C:57]([CH3:59])[CH:58]=3)[C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=3)[CH3:51])[N:38]([C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=3)[C:39](=[O:40])[C:34]=2[CH2:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOc1ccc(-n2c([C@@H](C)NCc3cc(C)nn3C)nc3c(c2=O)CCCN3C(C)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@@H](C)N(Cc3cc(C)nn3C)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3c(c2=O)CCCN3C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
4-fluoro-3-trifluoromethylphenylacetic acid (45 mg, 0.20 mmol) was dissolved in dichloromethane and cooled to 0° C. Oxalyl chloride (18 μL, 0.20 mmol) was added, then after 5 min, dimethylformamide (1.6 μL, 0.02 mmol) was added. The reaction stirred at 0° C. for 30 min and room temperature for 1 h. The solution was added slowly to a mixture of D5 (55 mg, 0.12 mmol) and triethylamine (50 μL, 0.36 mmol) in dichloromethane at −78° C. This stirred for 30 min, then was washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purified by reverse-phase HPLC to yield 49 mg of a colorless solid, 3. MS (MH+): 669.1. 1H NMR (500 MHz; CDCl3; T=298 K): δ 7.47-7.02 (m, 7H), 5.74-5.42 (m, 1H), 5.30-5.04 (m, 1H), 4.63-4.31 (m, 2H), 4.09-3.86 (m, 3H), 3.75-3.59 (m, 3H), 2.81-2.60 (m, 1H), 2.60-2.43 (m, 5H), 2.18 (m, 3H), 1.93 (broad s, 2H), 1.46 (t, 3H, J=6.7 Hz), 1.30 (t, 3H, J=7.7 Hz) ppm.
Reaction SMILES: [Na].[CH2:2]([CH:4]1[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[CH2:8][CH2:7][CH2:6][C:5]1=O)[N:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[N:14]=[CH:13]3)[CH3:3].[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27]>CCO>[CH2:2]([C:4]12[CH2:27][CH2:26][C:28](=[O:29])[CH:30]=[C:5]1[CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[C:16]3[C:12](=[CH:11][C:10]=12)[CH:13]=[N:14][N:15]3[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH3:3]
Reactant: C=CC(C)=O
Reactant: CCC1C(=O)CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Agent: [Na]
Solvent: CCO
Product: CCC12CCC(=O)C=C1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
A three necked round bottom flask with septum, nitrogen line, thermometer and stir bar was charged with EtOH (50 mL) and sodium (0.348 g, 15.1 mmol). The mixture was stirred until the reaction was complete, then 5-ethyl-1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (7, R1=4-Fluorophenyl, R2=Ethyl) (3.25 g, 10.1 mmol) suspended in EtOH (50 mL) was added. The mixture was heated to about 35° C. for about 10 min then methyl vinyl ketone (0.777 g, 11.09 mmol) was added. The mixture was stirred for about 45 min at about 35° C. then heated to about 60° C. for about 1 h. Methyl vinyl ketone (0.27 g, 3.85 mmol) was added and stirring was continued for about 30 min. Methyl vinyl ketone (0.22 g, 3.14 mmol) was added then heating was continued for about 45 min. The mixture was cooled to rt then concentrated under reduced pressure. Water (100 mL) and EtOAc (100 mL) were added then the mixture was acidified to about pH 1 with 6 N aq. HCl. The layers were separated then the aqueous layer was extracted with EtOAc (20 mL). The combined organic solutions were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (120 g) using a gradient of 10-50% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to yield 12b-Ethyl-9-(4-fluorophenyl)-1,2,6,7,9,12b-hexahydro-5H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one (8, R1=4-Fluorophenyl, R2=Ethyl) (3.03 g, 80%); LC/MS, method 3, Rt=2.73 min, MS m/z 375 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 7.89 (s, 1H), 7.85-7.78 (m, 2H), 7.63 (s, 1H), 7.47-7.38 (m, 2H), 5.89 (s, 1H), 3.03-2.95 (m, 1H), 2.88-2.63 (m, 2H), 2.58-2.27 (m, 4H), 2.21-2.00 (m, 2H), 1.93-1.73 (m, 3H), 0.92-0.84 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(O[C:6]([N:8](C)[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:6][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3,5-Dichlorobenzyl 4-((tert-butoxycarbonyl)(methyl)amino)piperidine-1-carboxylate (2.4 g, 5.75 mmol) in DCM (13 ml) was treated with and 4M HCl in dioxane (14.38 ml, 57.5 mmol) to give a colourless solution. The mixture was stirred for 3.5 hours at room temperature and then concentrated under reduced pressure to afford the title compound which was used without further purification;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([NH2:28])=[CH:23][CH:24]=3)[CH2:19]2)[CH2:16][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>CCOC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][CH3:17])[CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([NH:28][C:37](=[O:38])[C:36]4[CH:35]=[CH:34][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:41][CH:40]=4)=[CH:23][CH:24]=3)[CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)cc1
Reactant: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(N)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a solution of 4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.87 mmol) in EtOAc (50 mL) and 20% aq. potassium carbonate (50 mL) was added 4-methanesulfonyl-benzoyl chloride (760 mg, 4.1 mmol) dropwise in EtOAc (75 mL). The reaction was stirred at room temperature overnight and the layers separated. The EtOAc layer was concentrated onto silica gel and placed on top of a flash column. The column was eluted with 35% acetone in hexanes. Product containing fractions were pooled and concentrated to afford 4-({ethyl-[7-(4-methanesulfonyl-benzoylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a light pink solid (1.33 g).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>O1CCCC1.[Ni]>[C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 106.2 %

Procedure:
To a solution of (R)-indan-1-yl-(5-nitro-4H-benzo[d][1,3]oxazin-2-yl)-amine (example 1) (1.90 g, 6.1 mmol) in tetrahydrofuran (250 mL) at 23° C. were added three Pasteur pipettes of Raney-Nickel (ready to use 10% suspension in water) and the mixture was vigourously stirred under an atmospheric pressure of hydrogen for 23 h. The catalyst was filtered off, washed with tetrahydrofuran, the solvent was removed in vacuum to give the title compound as a light yellow foam (1.81 g, 99%), MS (ISP) m/e=280.4 [(M+H)+].