Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:29]=[CH:28][C:11]2[O:12][C:13]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:14]=3[CH:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:16][C:10]=2[CH:9]=1.[CH2:30](Br)[C:31]#[CH:32]>C(O)C>[Cl:7][C:8]1[CH:29]=[CH:28][C:11]2[O:12][C:13]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:14]=3[CH:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:32][C:31]#[CH:30])[CH2:19][CH2:18]3)[CH2:16][C:10]=2[CH:9]=1
Reactant: C#CCBr
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1cc(Cl)ccc1O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN1CCN(C2Cc3cc(Cl)ccc3Oc3ccc(Cl)cc32)CC1

Procedure:
2.87 G. of sodium carbonate are added to a solution of 7.6 g. of 1-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine in 76 ml. of ethanol. Then, a solution of 1.9 ml. of propargyl bromide in 15 ml. of ethanol is added dropwise with stirring. The mixture is stirred for 20 hours at room temperature and the solvent is then evaporated under reduced pressure. The residue is partitioned between water and chloroform. The phases are separated. The aqueous solution is extracted again with chloroform. The chloroform solutions are washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is crystallized using diisopropyl ether, and there is obtained 1-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-(2-propynyl)-piperazine having a melting point of 105°-107° C. The dihydrochloride, prepared in ethanol, melts at 213°-215° C. (with decomposition).
Reaction SMILES: Br[CH2:2][C:3](=[O:27])[C@:4]1([OH:26])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][C@@H:5]1[CH3:25].[C:28]([O-:31])(=[O:30])[CH3:29].[K+]>>[C:28]([O:31][CH2:2][C:3](=[O:27])[C@:4]1([OH:26])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][C@@H:5]1[CH3:25])(=[O:30])[CH3:29]
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@@]1(O)C(=O)CBr
Reactant: CC(=O)[O-]
Agent: [K+]
Product: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Temperature: 25 °C
Yield: 92 %

Procedure:
The suspension of 21-bromo-17α-hydroxy-16β-methyl-4-pregnene-3,11,20-trione is heated under agitation with 61.74 g of potassium acetate and for 90 minutes to 50° C. Then the methanol is extensively removed by distillation, the reaction mixture is allowed to cool down to room temperature, the reaction product is suctioned off, washed with water, and dried under vacuum at 50° C., thus obtaining 42.9 g of 21-acetoxy-17α-hydroxy-16β-methyl-4-pregnene-3,11,20-trione, mp 214°-219° C. Yield=92% of theory. Product purity 93.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[N:9][C:10]3[CH:11]=[C:12]([CH3:19])[CH:13]=[C:14]([OH:18])[C:15]=3[C:16]=2[CH3:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>CN(C)C=O>[CH3:29][O:30][C:31](=[O:34])[CH2:32][O:18][C:14]1[CH:13]=[C:12]([CH3:19])[CH:11]=[C:10]2[C:15]=1[C:16]([CH3:17])=[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=1)[C:8]([CH3:20])=[N:9]2
Reactant: COC(=O)CBr
Reactant: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(C)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C)cc2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 3-(4-chlorobenzyl)-2,4,7-trimethylquinolin-5-ol (0.24 g), N,N-dimethylformamide (2.0 mL), potassium carbonate (0.12 g) and bromoacetic acid methyl ester (0.12 mL) was stirred at room temperature for 17 hours. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was triturated with diethyl ether and further purification by column chromatography on silica gel, eluting with a mixture of methyl tert-butyl ether and dichloromethane (1:4 to 3:7 by volume) gave title compound, 0.078 g.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].O>N1C=CC=CC=1>[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([O:1][CH2:2][C@@H:3]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:30]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: COc1cc2ncnc(N[C@H](CO)c3ccccc3)c2cc1OC
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ncnc(N[C@H](COC(=O)c3cccc(Br)c3)c3ccccc3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a solution of (S)-4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline (49 mg, 0.15 mmol) in pyridine (2 ml) was added dropwise at 0-5° C. 3-bromobenzoylchloride (33 mg, 0.15 mmol). After 6 h stirring at room temperature the reaction mixture was poured into iced water and extracted with dichloromethane. The organic layer was dried and evaporated to dryness. The residue was purified by flash chromatography on silica gel using as eluant dichloromethane/methanol 95:5 to give pure title compound as a white solid in 71% yield (54 mg).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:24]=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)c1

Procedure:
The title compound, light grey solid (78 mg, 96%), MS (ISP) m/z=327.5 [(M+H)+], mp 225.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][S:2]([CH2:4][CH:5]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC(Cl)(Cl)Cl>[CH3:1][S:2][CH2:4][CH:5]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CS(=O)CC(NC(=O)OC(C)(C)C)c1ccccc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSCC(NC(=O)OC(C)(C)C)c1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
Of the compound from Example 108A, 400 mg (1.14 mmol), and 567 mg (2.16 mmol) of triphenylphosphine, were dissolved in 14 ml of tetrachloromethane. The reaction mixture was stirred overnight at reflux temperature and then freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC [Method 20]. The product fraction was freed from the solvent on a rotary evaporator. Drying in an HV gave 340 mg (85% of theory) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.C(N(CC)CC)C.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>C(Cl)Cl>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:31]
Reactant: COC(=O)c1ccc2occ(CCN)c2c1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2occ(CCNC(=O)c3ccco3)c2c1
Reaction time: 0.33 h

Procedure:
1 mmol of the compound obtained in Step A is introduced into 30 ml of anhydrous CH2Cl2. The temperature is lowered with the aid of an ice bath, and 1.5 mmol of triethylamine and then 1.5 mmol of 2-furoic acid chloride are added dropwise in succession. The mixture is stirred for 20 minutes, and the organic phase is then washed with water, dried over MgSO4 and evaporated. The residue is purified by chromatography on a silica gel column and the title product is recrystallised.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=O)=[CH:11]2)[O:6][CH2:5][CH2:4][O:3]1.[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH:26]=[CH:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH2:9][CH2:8][CH2:7][C:2]2([CH3:1])[O:3][CH2:4][CH2:5][O:6]2)[CH:11]=1)[CH3:25]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(CCCn2cc(C=O)c3ccccc32)OCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cn(CCCC2(C)OCCO2)c2ccccc12

Procedure:
A mixture of 27.3 g of 1-[3-(2-methyl-2-dioxolanyl)propyl]-3-indolecarboxaldehyde (0.1 mole) and 40 g. (0.11 mole) of carbethoxymethylene triphenylphosphorane in 400 ml. of toluene is heated at reflux overnight. The resulting cold solution is filtered through a Silica gel column to remove the inorganic material to give 1-[3-(2-methyl-2-dioxolanyl)propyl]-3-indoleacrylic acid ethyl ester, m.p. 61°-62° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[N:8]=[CH:7]2)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[N:8]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2CCN2CCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-Nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (3.00 g, 11.5 mmol), iron powder (6.50 g, 116 mmol), and ammonium chloride (310 mg, 5.85 mmol) in a 4:1 mixture of ethanol/H2O was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62 (m, 4H), 2.44 (m, 4H), 2.81 (t, 2H, J=6.78), 4.36 (t, 2H, J=6.78), 4.77 (s, 2H), 6.72 (m, 1H), 6.79 (m, 1H), 7.35 (m, 1H), 7.68 (s, 1H); MS (DCI/NH3) m/z 231 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3Cl)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9].[CH:38]1[C:50]2[CH:49]([CH2:51][NH2:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1>C(#N)C>[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3[NH:52][CH2:51][CH:49]2[C:50]3[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=3[C:43]3[C:48]2=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCC1c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC4c5ccccc5-c5ccccc54)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
Triethylamine (0.38 ml, 2.7 mmol) was added to a stirred solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (1.0 g, 2.3 mmol) (Preparation 45) and 9H-fluoren-9-ylmethanamine (0.49 g, 2.5 mmol) (J. Org. Chem., 1971, 36(23), 3539) in acetonitrile (30 ml) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was partially redissoved in ethyl acetate (30 ml). The ethyl acetate was washed with water (1 ml) and a saturated aqueous sodium chloride solution (10 ml). The organic phase was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate (96:4 by volume) increasing in polarity to dichloromethane: ethyl acetate (94:6 by volume). The solvent was removed under reduced pressure to give the title compound (1.23 g) as a foam.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([NH:14]C(=O)OC(C)(C)C)[CH2:10][N+:11]([O-:13])=[O:12]>O1CCOCC1.ClCCl>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([NH2:14])[CH2:10][N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1ccccc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(C[N+](=O)[O-])c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 ml of a 4 N solution of hydrogen chloride in dioxane were added to a solution of 1.037 g (3.45 mmol) of tert-butyl [1-(2-chlorophenyl)-2-nitroethyl]carbamate [see, for example, Tetrahedron Lett. 2009, 50 (9), 1016] in 10 ml of dichloromethane, and the mixture was stirred at RT for 2 h. The volatile components were then removed on a rotary evaporator. 5 ml of dichloromethane were added to the residue, and the mixture was once more freed from the solvent on a rotary evaporator and then dried under high vacuum. This gave 898 mg of the title compound (quant., still contains about 8% dioxane according to 1H NMR).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][CH2:20][F:21]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:19][CH2:20][F:21])([C:10]#[N:11])[C:12]#[N:13])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: FCCBr
Reactant: N#CC(C#N)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc([N+](=O)[O-])cc1
Yield: 20.5 %

Procedure:
Using 0.40 g of (4-nitrobenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.10 g of 2-(4-nitrobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (47)).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[C:7]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:7]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=[C:1]=[O:2])=[CH:17][CH:16]=2)=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Reaction time: 0.33 h

Procedure:
Dry toluene (225 ml) was cooled to a temperature of from about 0° to 5° C. and a stream of phosgene gas passed therethrough until 17.4 grams has been absorbed. A solution of 4-((3,6-dichloro-2-pyridinyl)methoxy)benzenamine (15.8 grams; 0.058 mole) in 125 ml. of toluene was added portionwise thereto over a period of about 8 minutes while maintaining the reaction temperature at about 2° to 5° C. The cloudy reaction mixture was then stirred for about 20 minutes with the temperature thereof slowly increasing as excess phosgene was purged from the reaction mixture with nitrogen. At a temperature of about 85° C., the reaction mixture became clear. The toluene solvent was then removed from the reaction mixture under reduced pressure and the residue obtained extracted with hexane. The yellow crystalline product recovered from the hexane extract upon cooling was identified as the desired 3,6-dichloro-2-((4-isocyanatophenoxy)methyl)pyridine compound and was found to have a melting point of 61.5°-62.5° C.
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH2:6][N:7]=[CH:8][C:9]2([CH3:23])[CH:20]([CH3:21])[CH:18]3[CH2:19][C:13]4=[C:14]([N:17]3C)[CH2:15][CH2:16][C:10]2=[C:11]4[CH:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH2:6][N:7]=[CH:8][C:9]2([CH3:23])[CH:20]([CH3:21])[CH:18]3[CH2:19][C:13]4=[C:14]([N:17]3[C:2]#[N:1])[CH2:15][CH2:16][C:10]2=[C:11]4[CH:12]=1
Reactant: N#CBr
Reactant: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2C#N
Temperature: 25 °C
Yield: 162.5 %

Procedure:
To a stirred solution of 1.68 g of cyanogen bromide and 35 ml of chloroform was added, at room temperature with stirring under nitrogen, a solution of 3.8 g of 10-chloro-1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 100 ml of chloroform. The mixture was heated at reflux for 2 hr, under nitrogen, and cooled to room temperature. Dilute aqueous sodium bicarbonate solution was added and the layers separated. The organic layer was extracted with dilute aqueous sodium bicarbonate solution. The combined aqueous layers were extracted with ether and the combined organic layers were washed with brine, dried over anhydrous potassium carbonate and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 2% triethylamine/ethyl acetate) to afford 6.41 g (78%) of 10-chloro-3-cyano-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo-[3,2-h][3]benzazocine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Reactant: Cc1ccc(N)cc1Cl
Product: COCC1COc2cc3ncnc(Nc4ccc(C)c(Cl)c4)c3cc2O1
Yield: 48.4 %

Procedure:
The titled compound (54 mg, 49%) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (80 mg, 0.3 mmol) and 3-chloro-4-methylaniline (84 mg, 0.6 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[C:7]([CH3:18])([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.[OH:39]OS([O-])=O.[K+]>O1CCCC1.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:34])[F:35])=[O:39])[C:7]([CH3:18])([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccncc2)COc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ccncc2)COc2cc(O)ccc2C1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Reaction time: 5 h
Yield: 81 %

Procedure:
To a solution of (3RS,4RS)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]-3-(4-pyridyl)chroman (6.1 mg, 0.011 mmol) in tetrahydrofuran (0.5 ml) was added under ice-cooling a solution of Oxone® (monopersulfate compound; DuPont product) (3.4 mg, 0.0055 mmol) in water (0.5 ml), which was then stirred for 5 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) to give (3RS,4RS)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-3-(4-pyridyl)chroman (5.1 mg, yield 81%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of 3-nitroaniline (13.8 g, 99.9 mmol) in pyridine (200 mL) were added 3-(trifluoromethyl)benzoyl chloride (21.4 g, 103 mmol) and N,N-dimethylpyridine-4-amine (69.1 mg, 566 μmol), and the mixture was stirred at room temperature for 1.5 hr. Methanol (50 mL) was added to the reaction solution to stop the reaction, and the solvent was evaporated under reduced pressure. The residue was suspended in ethyl acetate (300 mL), washed with water (200 mL×2), 0.1N hydrochloric acid (200 mL×2), saturated aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (31.0 g, 100%) as a colorless solid.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][C:3]2[CH:10]=[CH:11][C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[C:2]1=2.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[O:1]1[CH:6]([C:7]([O:9][CH2:23][CH3:24])=[O:8])[CH2:5][CH2:4][C:3]2[CH:10]=[CH:11][C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[C:2]1=2
Reactant: O=C(O)C1CCc2ccc3c(c2O1)CCCC3
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2ccc3c(c2O1)CCCC3
Yield: 100 %

Procedure:
A mixture of 20 parts of 3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-carboxylic acid, 200 parts of ethanol and 4.6 parts of sulfuric acid was stirred and refluxed for 2 hours. The reaction mixture was evaporated. Water and a sodium hydroxide solution were added to the residue. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated, yielding 21 parts (100%) of ethyl 3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-carboxylate as a residue (intermediate 30).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (160 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (151 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (94 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][C:13]([OH:15])=O)=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:11]3[C:6]=2[CH:7]=[CH:8][N:9]=[CH:10]3)[S:20][CH:21]=1
Reactant: O=C(O)Cc1ccc(F)c2cnccc12
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cc1ccc(F)c2cnccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(8-fluoroisoquinolin-5-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine using protocol B. Retention time (min)=1.987, method [7], MS(ESI) 432.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 9.74 (s, 1H), 8.66 (d, J=6.6 Hz, 1H), 8.30 (d, J=6.1 Hz, 1H), 8.20 (b s, 1H), 8.1 (dd, J=8.24, 5.5 Hz, 1H), 7.67 (dd, J=9.9, 7.7 Hz, 1H), 7.1 (s, 1H), 4.46 (s, 2H).