Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>O1CCOCC1>[N:19]1[CH:18]=[C:17]([O:16][C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH:22]=[N:21][CH:20]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cncnc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cccc(Oc2cncnc2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
A mixture of (S)-{1-[3-(pyrimidin-5-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.81 g, 2.6 mmol), dioxane (20 mL) and HCl (2.6 mL, 4N) was stirred at 50° C. for 5 h and concentrated in vacuo. CH2Cl2 (50 mL) was added and the reaction mixture was basified with NaOH (5N) followed by extraction with CH2Cl2 (2×50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to give the title compound (0.52 g, 95% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].P(OCC)(OCC)([S-])=[S:15]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])(=[S:15])[NH2:2]
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Reactant: CCOP(=S)([S-])OCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C)c(C(N)=S)c1
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A solution of methyl 3-cyano-4-methylbenzoate (compound 1.7, 880 mg, 5.02 mmol, 1.00 equiv) and O,O′-diethyl dithiophosphate (1.41 g, 8.29 mmol, 1.50 equiv) in THF/H2O (40 mL) was stirred at 80° C. (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After 3 h, the organic solvent was removed under reduced pressure and the residual aqueous phase was extracted with 3×20 mL of ethyl acetate. The combined organic layers were concentrated under reduced pressure to yield 0.85 g (79%) of the title compound as a light yellow solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)CC)C.CN(C)C=O>C(OCC)(=O)C>[C:36]([O:35][C:33](=[O:34])[CH2:32][N:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:15]2[C:16](=[O:19])[C:17]3[S:18][C:10]([C:7]4[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=4)=[CH:11][C:12]=3[N:13]=[CH:14]2)=[CH:23][CH:24]=1)[CH3:30])([CH3:39])([CH3:38])[CH3:37]
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
A mixture of the compound (200 mg) obtained in Example 4, tert-butyl bromoacetate (89 mg), triethylamine (146 mg) and N,N-dimethylformamide (3 ml) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [developing solvent:ethyl acetate-hexane (3:1, volume ratio)], and recrystallized from ethyl acetate-hexane (3:1, volume ratio) to give the title compound (156 mg) as a colorless powder.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([C:11]([O:26][CH2:27][C@@:28]23[CH2:41][O:40][C@@H:30]([C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[OH:39])[O:32]2)[C@@H:29]3[OH:42])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C@@H:31]1[O:32][C@:28]2([CH2:27][O:26][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C@@H:29]([OH:42])[C@H:30]1[O:40][CH2:41]2)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](c4ccccc4O)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1[C@@H]1O[C@@]2(COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)CO[C@@H]1[C@@H]2O
Temperature: 25 °C
Reaction time: 40 h
Yield: 86.1 %

Procedure:
Allyl bromide (0.017 ml, 0.20 mmol) was added to an anhydrous acetone (16 ml) solution of the compound (28) (96 mg, 0.18 mmol), whereafter potassium carbonate (27 mg, 0.20 mmol) was added, and the mixture was stirred for 40 hours at room temperature. After the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate 3 times. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain a colorless oily substance (29) (90 mg, 87%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[CH:38]([NH2:41])([CH3:40])[CH3:39]>>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24][NH:41][CH:38]([CH3:40])[CH3:39])[C:12]2=[O:26])[CH2:27][CH2:28]1)=[O:7]
Reactant: CC(C)N
Reactant: Cc1ccccc1N1CN(CCO)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1CN(CCNC(C)C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=571.1 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and isopropylamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: Cc1cccc(O)c1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1cccc(OCC(=O)c2ccccc2)c1

Procedure:
Equimolar amounts of 3-hydroxytoluene and α-bromoacetophenone are refluxed in benzene in the presence of potassium carbonate to provide α-(3-methylphenoxy)acetophenone.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH2:6]([C:8]([CH2:10][CH3:11])=O)[CH3:7].N1CCCC1>CO.CCOCC.O>[CH2:6]([C:8]([CH2:10][CH3:11])=[C:2]1[CH:1]=[CH:5][CH:4]=[CH:3]1)[CH3:7]
Reactant: C1=CCC=C1
Reactant: CCC(=O)CC
Solvent: CCOCC
Solvent: C1CCNC1
Solvent: CO
Product: CCC(CC)=C1C=CC=C1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
To a solution of 22.00 g (332.8 mmol) of cyclopentadiene in 35 ml of methanol, 36.0 ml (665.1 mmol) of diethyl ketone and 28.0 ml (335.5 mmol) of pyrrolidine were added with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 200 ml of ether, 100 ml of water was added. The organic phase was separated, washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (78-83° C./4 mmHg) to obtain 36.50 g (271.94 mmol) of a yellow liquid (yield: 82%). The analyzed values are given below.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>C(Cl)Cl.CCN(CC)CC>[Cl:26][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cc(F)cc(Cl)c2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCO[C@@H](c1cc(F)cc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-5-fluorophenyl)methyl)piperidine-1-carboxylate (1.1 g, 2.85 mmol) in dry CH2Cl2 (20 mL), Et3N (2 mL) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of ethyl chloroformate (615 mg, 5.7 mmol) in dry CH2Cl2 (2 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at rt. Water (20 mL) was added to quench the reaction. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(2-(ethoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (1.3 mg, 100%). 1H NMR (CD3OD, 400 MHz) δ 7.01 (d, 2H), 6.87 (d, 1H), 4.32 (m, 2H), 4.09 (m, 2H), 3.92 (m, 2H), 3.33 (m, 5H), 1.75 (s, 1H), 1.55 (m, 1H), 1.43 (s, 9H), 1.34 (m, 2H), 1.23 (t, 3H), 1.09 (t, 1H).
Reaction SMILES: [Si]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.C([Li])CCC.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]2=[O:15])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc[nH]c1=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cccc(O)c2=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To stirred solution of 3-[(tert-butyldimethylsilyl)oxy]pyridin-2(1H)-one (1) (4.66 g, 20.7 mmol) in dry THF (150 mL), maintained at −78° C. under a dry nitrogen atmosphere is added n-butyl lithium (1.6 M solution in hexane, 21.0 mmol). After 20 minutes, 4-methylbenzenesulfonyl chloride (3.95 g, 20.7 mmol) is added as a THF solution. The solution is allowed to warm to room temperature over one hour, the water (10 mL) is added and the contents of the reaction vessel is extracted with EtOAc (3×), washed with brine (1×), dried over Na2SO4 and concentrated. The combined organic layers are dried over Na2SO4 and concentrated. The residue is taken up in ethanol (10 mL) and treated with conc. HCl (2 mL). The mixture is allowed to stir for 1 hour and the solvent is removed under reduced pressure to afford the desired compound as a white solid. 1H NMR (300 MHz, DMSO) δ 2.43 (s, 3H), 6.14 (t, J=6.9 Hz, 1H), 6.76 (dd, J=7.65 Hz, 1.5 Hz, 1H), 7.18 (dd, J=6.6 Hz, 1.8 Hz, 1H), 7.32 (d, J=7.3 Hz, 2H), 7.98 (d, J=7.9 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].[CH3:7][O:8][C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([NH:14][NH2:15])=[O:13]>CO.C(O)(=O)C>[CH3:4][C:2]([CH3:1])([CH3:3])[CH:5]=[N:15][NH:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([O:8][CH3:7])[C:10]=1[CH3:19]
Reactant: COc1cccc(C(=O)NN)c1C
Reactant: CC(C)(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(C(=O)NN=CC(C)(C)C)c1C
Yield: 66.6 %

Procedure:
Pivaldehyde (13.45 g, 156 mmoles) was dissolved in 300 mL methanol in a round bottom flask. 3-methoxy-2-methyl-benzoic acid hydrazide (26.6 g, 147.6 mmoles) and 150 drops glacial acetic acid were added, and the mixture was heated at reflux for ca. 8 hours, while monitoring by TLC. Upon completion of the reaction, the solvent was removed in vacuo, and the product was slurried in cold hexanes and filtered on a Buchner funnel to provide 24.4 g (66%) of 3-methoxy-2-methyl-benzoic acid (2,2-dimethyl-propylidene)-hydrazide. Rf=0.19, (2:1 hexanes:ethyl acetate); 1H NMR (400 MHz, DMSO-d6) δ 7.42+7.41 (3s, 1H), 7.1 (t, 1H), 6.9 (d, 1H), 6.82 (d, 1H), 3.78 (s, 3H), 2.2+2.1 (2s, 3H), 1.07+1.0 (3s, 9H), multiple conformations, possibly E/Z mixture.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[N:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[N:12]=[CH:13][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:47]=[N:46]1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cnc32)cc1
Yield: 82.6 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)piperazine-1-carboxylate (Intermediate 66N) (465 mg, 0.7 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (234 mg, 0.77 mmol) using sodium carbonate (223 mg, 21 mmol) and Pd(dppf)Cl2 (26 mg, 0.035 mmol) in toluene/ethanol/water (6/6/2 mL) to afford 410 mg (82.1% yield) of the titled compound after purification by column (Silica gel 60/120) using 30% ethyl acetate in hexane as eluent. MS: m/z=709.3 (M+1).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@@H:7]([CH3:25])[CH2:6]1)=[O:4].[OH-].[Li+].CO.Cl>O1CCCC1.O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH:7]2[CH3:25])=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OC)cc2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)N2c3ccccc3C(C(=O)O)CC2C)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A round bottom flask with magnetic stirrer was charged with cis-1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (3.00 g, 8.8 mmol) in anhydrous tetrahydrofuran (70 mL). To the reaction was added a solution of lithium hydroxide (423 mg, 18 mmol) in water (24 mL), followed by methanol (24 mL). The reaction was stirred at room temperature for 18-20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (3×35 mL) and the combined extractions were washed with brine (1×50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and diethyl ether (50 mL) added to the resulting residue. The precipitated solid was collected via suction filtration to afford 1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid as a mixture of cis and trans-isomers (2.71 g, 95%). 1H-NMR (d6-DMSO) δ: 1.22 (d, 3H), 1.63 (ddd, 1H), 2.94 (ddd, 1H), 3.76 (s, 3H), 3.89 (dd, 1H), 4.83-4.91 (m, 1H), 6.51 (d, 1H), 6.72-6.76 (m, 2H), 6.95 (ddd, 1H), 7.11 (ddd, 1H), 7.26-7.35 (m, 3H). MS m/z=326 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][O-:14])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH:29]12[CH2:35][CH:32]([CH2:33][CH2:34]1)[CH2:31][CH:30]2[CH3:36]>>[NH:8]1[CH:12]=[C:11]([CH2:13][O:14][CH2:36][CH:30]2[CH2:31][CH:32]3[CH2:35][CH:29]2[CH2:34][CH2:33]3)[N:10]=[CH:9]1
Reactant: [O-]Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC1CC2CCC1C2
Agent: [Cl-]
Agent: [Na+]
Product: c1nc(COCC2CC3CCC2C3)c[nH]1

Procedure:
5 mmol of sodium (1-triphenylmethyl-1H-imidazol-4-yl)-methanolate and 5 mmol of (bicyclo[2.2.1]hept-2-yl)-methane chloride are treated as described in Example 5.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH3:17].O>ClCCl>[NH2:17][S:2]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: N
Reactant: COC(=O)c1ccc(OC)cc1S(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)cc1S(N)(=O)=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
A solution of 554 g of the compound of Example 4 in 5 L of dichloromethane was cooled to -40° C. and 79 g of anhydrous ammonia was added at this temperature. The reaction mixture was allowed to warm to -10° C., stirred 1 hour, then poured into 6 L of water. The organic phase was separated and filtered. The filter cake was washed with dichloromethane and dried giving 356 g of crude product. A 180 g portion was recrystallized from methanol to give 130 g of the title compound, m.p. 139°-142° C.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][CH:17]2[CH2:20][N:19](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:18]2)=[CH:14][CH:13]=1>C(Cl)Cl>[Br:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][CH:17]2[CH2:18][N:19]([C:1]([Cl:4])=[O:2])[CH2:20]2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cl
Reactant: Brc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A stirred solution of 18.8 g (0.192 mole) of phosgene in 100 ml of methylene chloride was cooled to 15° C. in a water bath, then treated with 26.5 g (0.192 mole) of potassium carbonate. After stirring for 30 min, 63 g (0.16 mole) of 3-(4-bromophenoxy)-1-diphenylmethylazetidine in 180 ml of methylene chloride was added dropwise and stirring continued for 18 hr. The reaction mixture was diluted with ice water to dissolve the inorganic salts, the aqueous portion was separated and the organic phase washed with 25 ml of ice water. After separation, the methylene chloride solution was dried with magnesium sulfate, then concentrated in vacuo to a viscous yellow oil. Trituration of the residue with 30/60 petroleum ether yielded a crystalline product, 76.9 g, which was recrystallized from isopropyl ether-ligroin (50-50) to yield 34.8 g (74.8%) of white granular crystals, m.p. 77°-78° C.
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][NH:6][C:7]([NH2:9])=N.CN([CH:13]=[C:14]([C:17](=[O:23])[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)C#N)C.[OH-].[Na+]>C(O)C>[NH2:9][C:7]1[C:14]([C:17]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:23])=[CH:13][NH:5][N:6]=1
Reactant: CN(C)C=C(C#N)C(=O)c1cccs1
Reactant: N=C(N)NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: Nc1n[nH]cc1C(=O)c1cccs1
Yield: 17.7 %

Procedure:
To a mixture of aminoguanidine nitrate (17.1, 125 mmol) and α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropanenitrile (3) (20.6 g, 100 mmol) in commercial absolute ethanol (120 mL) is added 10N NaOH (5 g of solid NaOH in 12.5 mL of water). The reaction mixture is refluxed for 6 hrs and the solvents removed at reduced pressure on a rotary evaporator. Water (250 mL) is added and an initial precipitate forms and is filtered (13.3 g, 68.8 mmol, 69%). On further standing the aqueous layer deposits an additional quantity of the titled compound (3.42 g, 17.7 mmol, 18%), yielding product (4) as a tan solid (total 16.72 g, 86.5 mmol, 87%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[C@:18]3([CH2:32][CH3:33])[CH2:26][CH2:25][C@@:24]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:23][C@H:19]3[CH2:20][CH2:21][CH2:22][C:3]=12.[CH3:34]B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH2:32]([C@@:18]12[CH2:26][CH2:25][C@@:24]([C:28]([F:30])([F:31])[F:29])([OH:27])[CH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][C:3]1[C:4]2=[CH:5][C:6]2[CH:7]=[N:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:10]=2[C:2]=1[CH3:34])[CH3:33]
Reactant: CB(O)O
Reactant: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1c2cc2cnn(-c3ccc(F)cc3)c2c1C
Temperature: 80 °C

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-CH2Cl2 adduct (0.012 g, 0.015 mmol) was added to a mixture of (3R,4aR,12bR)-8-bromo-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-3-ol (58, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0393 g, 0.0750 mmol), methylboronic acid (0.0090 g, 0.15 mmol), Na2CO3 (0.020 g, 0.19 mmol), 1,4-dioxane (0.400 mL), and water (0.100 mL) under a nitrogen atmosphere. The reaction vessel was evacuated then back-filled with nitrogen three times. The mixture was warmed to about 80° C. for about 9 h. After cooling to rt, water (2 mL) and EtOAc (5 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Synergy Max-RP column) using a gradient of 10-95% MeCN in aqueous NH4OAc (50 mM). The fractions containing product were combined and concentrated under reduced pressure to remove the organic volatiles. The resulting mixture was frozen then lyophilized to afford (3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-8-methyl-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (59, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0119 g, 34% yield) of a fluffy white solid. LC/MS, method 2, Rt=2.85 mM, MS m/z 461 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.17 (s, 1H), 7.70 (s, 1H), 7.56-7.47 (m, 2H), 7.40-7.31 (m, 2H), 5.84 (bs, 1H), 3.23-3.12 (m, 1H), 2.87-2.73 (m, 1H), 2.42-2.26 (m, 1H), 2.22-1.51 (m, 10H), 2.03 (s, 3H), 1.31-1.11 (m, 2H), 0.46 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C.Cl(O)(=O)(=O)=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: O=C(O)c1ccc(Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 101.2 %

Procedure:
10% Palladium on carbon (0.5 g) was added to a solution of 4-benzoyl-benzoic acid (11.31 g, 50 mmol) in ethanol (250 mL) and 70% perchloric acid (10 mL). The suspension was hydrogenated under 40 psi at room temperature for 8 hours. The catalyst was removed by filtration and the filtrate made neutral with aqueous sodium bicarbonate. Solvents were evaporated, and the residue was partitioned into ethyl acetate and dilute aqueous potassium hydroxide. The aqueous phase was acidified with hydrochloric acid. The precipitated acid was filtered, washed, and dried to give 4-benzyl-benzoic acid (10.74 g,−100%).