Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]([F:35])([F:34])[C@H:29]([OH:33])[CH2:30][CH2:31]O>ClCCl>[F:27][C:28]([F:35])([F:34])[C@H:29]([OH:33])[CH2:30][CH2:31][I:25]
Reactant: II
Reactant: OCC[C@@H](O)C(F)(F)F
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O[C@H](CCI)C(F)(F)F
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Triphenylphosphine (5.09 g, 19.4 mmol) was dissolved in dichloromethane (66 mL) and treated with imidazole (1.33 g, 19.5 mmol) and iodine (4.92 g, 19.4 mmol), respectively, to give an orange suspension. A solution of (R)-4,4,4-trifluoro-1,3-butanediol (2.34 g, 16.2 mmol) in dichloromethane (18 mL) was added to the suspension and stirred for 30 minutes. The reaction mixture was placed on a silica gel flash column and eluted with 100% dichloromethane to give the product as a pale purple oil (3.30 g, 80%).
Reaction SMILES: [Br:1]CC1C2C(C=CC=1)=CC1C3C=CC=CC=3OC=1C=2.[CH3:20][C:21]1[C:29]2[C:28]3[CH:30]=[C:31]4[C:36](=[CH:37][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH:35]=[CH:34][CH:33]=[CH:32]4>>[Br:1][CH2:20][C:21]1[C:29]2[C:28]3[CH:30]=[C:31]4[C:36](=[CH:37][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH:35]=[CH:34][CH:33]=[CH:32]4
Reactant: Cc1cccc2oc3cc4ccccc4cc3c12
Reactant: BrCc1cccc2cc3c(cc12)oc1ccccc13
Product: BrCc1cccc2oc3cc4ccccc4cc3c12
Yield: 72 %

Procedure:
Using the procedure outlined in 6A, 1-methylbenzo[b]naphtho[2,3-d]furan (Cambridge Chemicals, Inc.) gave 72% yield of crude 1-bromomethylbenzo[b]naphtho[2,3-d]furan which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:21]([CH3:22])=[CH:20][C:5]2[NH:6][C:7]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=4)[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[C:21]([CH3:22])=[CH:20][C:5]2[NH:6][C:7]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=4)[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccc2[nH]nc(-c3nc4cc(C)c(C)cc4[nH]3)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2nc(-c3n[nH]c4ccc(O)cc34)[nH]c2cc1C
Yield: 71.1 %

Procedure:
A solution of 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole [34 mg, Example 235(b)] at 0° C. was treated with a solution of boron tribromide in dichloromethane (0.30 mL, 1M). The mixture was then heated at reflux temperature for 4 hours, then cooled and then treated dropwise with water. The pH was adjusted to between 7 and 8 by the addition of saturated aqueous sodium bicarbonate solution and this mixture was then extracted twice with ethyl acetate. The combined extracts were washed with brine, then dried over magnesium sulfate and then evaporated. The pale yellow solid residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and triethylamine (99:1, v/v) to yield 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-ol (23 mg) as a white solid. LC-MS (METHOD B): RT=2.19 minutes; 279 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[C:17]([Cl:37])=[C:18]([CH:24]2[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]2)[CH:19]=[C:20]([C:22]#[N:23])[CH:21]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:21]=[C:20]([CH:19]=[C:18]([CH:24]2[O:29][CH2:28][CH2:27][NH:26][CH2:25]2)[C:17]=1[Cl:37])[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C2CN(C(=O)OC(C)(C)C)CCO2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(C2CNCCO2)c1
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
TFA (4.5 mL) was added to a solution of tert-butyl 2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)morpholine-4-carboxylate (252 mg, 0.575 mmol) in DCM (4.5 mL) at room temperature. After 0.5 hr, the solvent was removed. The residue in was dissolved in MeOH and this was applied onto an SCX column. After washing with MeOH, the product was eluted with 2N NH3 in MeOH to give 3-amino-4-chloro-5-(morpholin-2-yl)benzonitrile (132 mg) as an oil. This was dissolved in DCM (7 mL) and TEA (0.096 mL, 0.69 mmol) and BOC2O (0.16 mL, 0.69 mmol) were added. After stirring overnight, the solvent was removed and radial silica gel chromatography eluting with hexane containing 0 to 30% EtOAc afforded tert-butyl 2-(3-amino-2-chloro-5-cyanophenyl)morpholine-4-carboxylate (203 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH:6]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5][C:4]([CH3:16])([CH3:15])[O:3]1.C1C(=O)N([Br:25])C(=O)C1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:25][C:12]1[C:11]([NH2:14])=[CH:10][CH:9]=[C:8]([CH:6]2[CH2:7][C:2]([CH3:17])([CH3:1])[O:3][C:4]([CH3:16])([CH3:15])[CH2:5]2)[N:13]=1
Reactant: CC1(C)CC(c2ccc(N)cn2)CC(C)(C)O1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(c2ccc(N)c(Br)n2)CC(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-ylamine (as prepared in the previous step, 13.5 g, 0.057 mol) in DCM (100 mL) was added a solution of freshly recrystallized NBS (10.2 g, 0.0570 mol) in DCM (300 mL) dropwise at 0° C. for 1 h. The reaction mixture was allowed to warm to RT, stirred for 30 min and then treated with satd aq Na2CO3 (300 mL). The organic phase was washed with 10% Na2S2O3 (300 mL) and water (300 mL), dried (Na2SO4) and concentrated to obtain the title compound as red solid (17.1 g, 95%) which was directly used in the next step without further purification. 1H-NMR (CDCl3; 400 MHz): δ 6.95 (d, 1H, J=8.1 Hz), 6.91 (d, 1H, j=8.1 Hz), 4.03 (br s, 2H), 3.08 (m, 1H), 1.73 (m, 2H), 1.44 (m, 2H), 1.28 (s, 6H), 1.26 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C14H21BrN2O, 313.2 and 315.2 (M+H), found 313.2 and 315.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CC#N>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:15][CH2:16][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:18][CH2:19][N:20]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][CH2:22]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)N1CCNCCN(C(=O)OCc2ccccc2)CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCN(C(=O)OCc2ccccc2)CCN(CC(=O)OC(C)(C)C)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 10 h
Yield: 91.9 %

Procedure:
To a solution of compound (18) (6.84 g, 15.53 mmol) in dry MeCN (150 ml) were added N,N′-diisopropylethyl amine (13.52 ml, 10.03 g, 77.63 mmol) and tert-butyl bromoacetate (4.82 ml, 6.36 g, 32.61 mmol). The reaction mixture was slowly heated to 60° C., and stirred for 10 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in a Na2CO3 solution (100 ml). The aqueous layer was extracted with CH2Cl2 (3×100 ml), and the combined extract was washed with brine and dried over MgSO4 to obtain a concentrated white oil. The oil was recrystallized from Et2O to provide compound (19) as a white solid (9.55 g, 92% yield). 1H NMR (500 MHz, CDCl3): δ 7.26-7.19 (m, 10H), 5.04 (s, 4H), 3.34-3.05 (m, 12H), 2.9-2.6 (m, 8H), 1.35 (s, 18H); 13C NMR (125 MHz, CDCl3): δ 170.4, 156.3, 136.7, 128.3, 127.8, 127.7, 80.8, 66.8, 55.8, 54.2, 46.9, 46.5, 28.1; HRMS (FAB) calculated for C36H53N4O8: 669.3863 [(M+H)+], measured value: 669.3860 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1cccc(F)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(F)c1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(3-fluoro-phenyl)-butan-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[C:23]([CH3:33])=[CH:22][C:21]([CH:18]4[CH2:19][CH2:20]4)=[CH:26][N:25]=3)[CH2:28][CH2:29]2)=[O:8])=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(Br)cc1N1CCCS1(=O)=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Yield: 88.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)benzoic acid (6.72 g) described in Preparation Example 178 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (4.56 g) described in Preparation Example 96, the title compound (9.68 g) was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22]CC)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18])[CH3:2].C(O)CO.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(OCC)(=O)C>[CH2:1]([N:3]([CH2:20][CH:21]1[O:22][CH2:27][CH2:26][O:25]1)[C:4]1[C:5]([N+:17]([O-:19])=[O:18])=[CH:6][C:7]([C:13]([F:14])([F:16])[F:15])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOC(CN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])OCC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CCN(CC1OCCO1)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
N-Ethyl-N-(2,2-diethoxyethyl)-2,6-dinitro-4-trifluoromethylaniline (6.10 grams; 0.0154 mole), ethylene glycol (0.96 grams; 0.0154 mole) and toluenesulfonic acid (200 mg) were charged into a glass reaction vessel equipped with stirrer and thermometer. The reaction mixture was heated at 110° C. for a period of 2 hours. After this time the mixture was cooled to room temperature, dissolved in ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The washed product was then dried and stripped of solvent to yield the desired product N-ethyl-N-1,3-dioxolan-2-ylmethyl-2,6-dinitro-4-trifluoromethylaniline as an oil.
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:13][OH:14])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[C:1]([O:9][C:10]1([CH2:13][O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OC1(CO)CC1)c1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a mixture of 1-(hydroxymethyl)cyclopropyl benzoate (500 mg, 2.6 mmol) and TEA (394 mg, 3.9 mmol, Shantou Xilong chemical factory) in 50 mL of dry CH2Cl2, was added MsCl (357 mg, 3.12 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe at rt. After stirring for 2 hrs at rt, the mixture was diluted with icewater and extracted with CH2Cl2 (30 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give the title compound as pale yellow solid (590 mg, 84%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:14][C:13]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=[CH:11][N:10]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: OC(c1ccccc1)(c1ccccc1)c1nccn1Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccccc1)(c1ccccc1)c1nccn1Cc1ccccc1

Procedure:
A slurry of (1-benzyl-1H-imidazol-2-yl)(diphenyl)methanol (1-2, 16.0 g, 47.0 mmol, 1 equiv) in acetic anhydride (120 mL) and pyridine (130 mL) was heated at 60° C. for 18 h. The resulting orange slurry was concentrated to dryness. The residue was suspended in saturated aqueous sodium carbonate solution (300 mL) and the resulting precipitate was filtered and washed with water (2×100 mL) followed by ethyl ether (50 mL). The resulting solid was suspended in ethanol, collected by filtration and air dried to afford (1-benzyl-1H-imidazol-2-yl)(diphenyl)methyl acetate (1-3) as white crystals. 1H NMR (300 MHz, CDCl3) δ 7.43 (m, 3H), 7.30 (m, 10H), 7.12 (d, 1H, J=1.2 Hz), 6.86 (m, 2H), 6.77 (d, 1H, J=1.2 Hz), 4.83 (s, 2H), 1.84 (s, 3H). LRMS m/z (M-OAc) 323.1 found, 323.2 required.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([C:33](O)=[O:34])[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]>>[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([C:33]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[O:34])[CH:22]=1)(=[O:19])=[O:20]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)n1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 2-Piperazin-1-yl-4-trifluoromethyl-pyrimidine [179756-91-3] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 491.1 MH+.
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([NH:13]C(OCC[Si](C)(C)C)=O)[CH2:10][C@@H:9]1[CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(OCC)(=O)C>[C:1]([O:5][C:6]([C@:8]1([NH2:13])[CH2:10][C@@H:9]1[CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H]1C[C@@]1(NC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H]1C[C@@]1(N)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the product of Step 3 (3 g, 9 mmol) was added a 1.0M TBAF solution in THF (9.3 mL, 9.3 mmol) and the mixture heated to reflux for 1.5 hours, cooled to room temperature and then diluted with 500 mL of ethyl acetate. The solution was successively washed with water (2×100 mL), brine (2×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide the title intermediate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CCN2
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a cold solution of methyl indole-5-carboxylate (2 g, 11.4 mmol) in glacial acetic acid at 0° C. (15 ml) sodium cyanoborohydride (1.075 g, 17.1 mmol) was slowly added. The mixture was allowed to warm-up and stirred at room temperature for one more hour, cooled again to 0° C. and quenched with H2O. The pH of the resultant solution was adjusted to the value of 12 by adding aqueous NaOH, extracted with DCM, washed with brine and dried over MgSO4. The dried extract was concentrated in vacuum and purified by flash chromatography (eluent 30% EtOAc in hexane) to give the title compound 20 (1.62 g, 80%) as a beige solid. 1H-NMR (DMSO) δ: 2.94 (t, J=8.6 Hz, 2H); 3.51 (dt, J=1.2, 8.6 Hz, 2H); 3.71 (s, 3H); 6.42 (d, J=8.0 Hz, 2H); 7.54 (m, 2H).
Reaction SMILES: [C:1]1([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]=1.[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26][CH2:25][C:24]=12>>[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]([C:15]([C:14]3[CH:13]=[CH:12][C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:4][CH2:3][CH:2]=4)=[CH:19][CH:18]=3)=[O:16])[CH2:25][C:24]=12
Reactant: O=C(O)c1ccc(C2=CCCc3ccccc32)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: O=C(c1ccc(C2=CCCc3ccccc32)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 51 %

Procedure:
4-(3,4-Dihydro-naphthalen-1-yl)-benzoic acid of Step B (0.280 g, 1.12 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.227 g, 1.23 mmol) were reacted in the manner of Example 15, Step D. Recrystallization from petroleum ether afforded the title compound (0.238 g) as white crystals, m.p. 166° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20]>ClCCl.C([O-])(O)=O.[Na+]>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:20])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCN1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
This compound was synthesised in a method analogous to the method described for intermediates 1 to 3 and prepared according to the method below. To a suspension of 2-piperazinone (2 g, 19.98 mmol, commercially available from e.g. Sigma-Aldrich) in dry dichloromethane (DCM) (28.5 ml) was added triethylamine (6.13 ml, 43.9 mmol), the mixture was cooled to 0° C. and 3,4-dichlorobenzoyl chloride (4.60 g, 21.97 mmol, commercially available from e.g.Sigma-Aldrich, Acros or Alfa Aesar) was added dropwise. The mixture was stirred at 0° C. for 15 minutes then warmed to room temperature overnight. The mixture was diluted with DCM (100 mL) and sat. NaHCO3 (100 ml), the phases separated and the aqueous extracted with DCM (2×100 ml). The combined organics were washed with brine and dried over MgSO4. The crude material (3.37 g) was triturated with iso-hexane and Et2O to the desired product in 3.02 g as an off-white solid.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH:24]1([N:27]2[C:36]3[C:31](=[C:32]([CH3:40])[C:33]([F:39])=[C:34](F)[C:35]=3[F:37])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:26][CH2:25]1>C(#N)C>[CH:24]1([N:27]2[C:36]3[C:31](=[C:32]([CH3:40])[C:33]([F:39])=[C:34]([N:10]4[CH2:11][CH2:12][CH:7]([N:2]5[CH:6]=[CH:5][N:4]=[N:3]5)[CH2:8][CH2:9]4)[C:35]=3[F:37])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:25][CH2:26]1
Reactant: c1cn(C2CCNCC2)nn1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(n3ccnn3)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 47.9 %

Procedure:
4-(1,2,3-triazol-1-yl)piperidine hydrochloride (126 mg, 0.66 mmol) and DBU (130 mg, 0.85 mmol) were added to a suspension of 1-cyclopropyl-5-methyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.34 mmol) in acetonitrile (10 ml). The reaction mixture was refluxed for 24 hrs and then concentrated to dryness. The reaction was diluted with water. The separated solid was filtered and washed with water, acetonitrile and dried to give 70 mg of desired product. m.p. 261°-263° C.; 1H NMR (TFA) δ: 9.36 (s, 1H), 8.55 (s, 1H), 8.62 (s, 1H), 5.25 (m, 1H), 4.60 (m, 1H), 4.12 (m, 2H), 3.80 (m, 2H), 2.94 (s, 3H), 2.60 (m, 4H), 1.30-1.68 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:28](CO)[CH2:27][CH2:26][C@@:9]32[O:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[CH2:10]3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39]([O:42]S(C)(=O)=O)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:28]([O:42][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:26][C@@:9]32[O:13][CH2:12][C@H:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH:23]([CH3:24])[CH3:25])[CH2:10]3)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CC(C)Oc1ccc(C#N)cc1C1CO[C@]2(CC[C@H](CO)[C@H]2c2ccc(F)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(C#N)cc1[C@H]1CO[C@]2(CC[C@H](OS(C)(=O)=O)[C@@H]2c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,6S,7S)-6-(4-fluorophenyl)-3-(5-cyano-2-isopropoxy-phenyl)-1-oxaspiro[4.4]nonane-7-methanol (35 mg, 0.085 mmol) in methylene chloride (1 mL) were added triethylamine (24 μL, 0.172 mmol) and methanesulfonic anhydride (22 mg, 0.126 mmol). The reaction mixture was stirred for 2 hours at room temperature, diluted with methylene chloride, washed with water, 2N hydrochloric acid, saturated sodium hydrogencarbonate solution, saturated brine solution, dried (Na2SO4), and evaporated. The product was used without further purification in Step C.
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH:29]=[CH2:30].O>CN(C)C=O>[Cl:16][C:10]1[C:9]([Cl:17])=[C:8]2[C:13]([CH2:14][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)([CH3:19])[C:7]2=[O:18])=[CH:12][C:11]=1[O:15][CH2:30][CH2:29][CH:28]=[CH2:27]
Reactant: C=CCCBr
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Temperature: 60 °C

Procedure:
2-Cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-5-hydroxy-1H-inden-1-one (12 gm., 0.04 mole) is dissolved in dimethylformamide (30 m.) and treated with potassium carbonate (5.5 gm., 0.04 mole). The mixture is stirred and heated on a steam bath for 30 minutes and 4-bromo-1-butene (5.5 gm., 0.04 mole) is added and the mixture stirred and heated at 60° C. for 24 hours. The reaction mixture is poured into water (300 ml.) and, after standing, the product removed by filtration, dried and recrystallized from petroleum ether. The yield is 11.5 gm., m.p. 63°-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:23]3[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 76.9 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 1,1-dimethylethyl 1-piperazinecarboxylate (0.44 g, 3.4 mmol) and the reaction was carried out by the method of Example 3. Following chromatographic purification, 1.16 g of the title product was obtained as a white solid.
Reaction SMILES: C(#N)CC.[OH:5][CH2:6][CH2:7]C#N.[OH:10][CH2:11][CH:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:13]#[N:14]>>[C:6]([O:10][CH2:11][CH:12]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:13]#[N:14])(=[O:5])[CH3:7]
Reactant: N#CCCO
Reactant: N#CC(CO)c1ccc(Cl)cc1
Solvent: CCC#N
Product: CC(=O)OCC(C#N)c1ccc(Cl)cc1

Procedure:
This ester was prepared using the procedure described in Example 5, except 3-hydroxy-2-4-chlorophenyl)propanenitrile was used in place of 2-2-chloro-5-difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 3-hydroxy-2-(4-chlorophenyl)propanenitrile is described in Example 15. The recovered ester product was a colorless oil (79% yield).