Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([S:12][CH2:13]C(O)=O)=[S:11])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+]>[OH-].[Na+]>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([S:12][CH3:13])=[S:11])=[CH:8][CH:9]=1
Reactant: Nc1ccc(C(=S)SCC(=O)O)cc1
Agent: CS
Agent: O=C([O-])O
Agent: [Na+]
Product: CSC(=S)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
Methyl mercaptan was passed into a filtered solution of crude carboxymethyl 4-aminobenzenecarbodithioate (7.48 g, 0.033 mol)in 66 ml of 0.5 N of sodium hydroxide solution containing 10% by weight sodium bicarbonate under external ice-cooling for about 10 minutes. A yellow precipitate separated out gradually as the colour of the aqueous solution was discharged. After standing for 1 hour at 0°-5°C, the precipitate was filtered off, washed with 10% by weight sodium bicarbonate solution, then with water and dried in vacuo at a temperature of below 50°C. The yield of the yellow crystalline powder, m.p. 74.5°-75.5° (decomp.) was 5.3 g or 87.7%.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([CH2:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.Cl>C(O)(C)C>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)[C:3]=2[N:10]=1
Reactant: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2s1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC(C)O
Product: FC(F)(F)c1ccc(Nc2ncnc3sc(Cc4c(Cl)cccc4Cl)nc23)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 73.2 %

Procedure:
To a solution of 7-chloro-2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidine (45.0 mg, 0.15 mmol) and 4-trifluoromethyl-phenylamine (23 mg, 0.15 mmol) in isopropanol (IPA) (2 mL) was added 1.25 M HCl in IPA (0.26 mL, 0.32 mmol). The resulting solution was heated in a sealed tube to 90° C. After 12 h, the solution was cooled and purified by preparative reverse-phase HPLC to afford the title compound as a colorless solid (50 mg, 74%). MS (ESI): mass calcd. for C19H11Cl2F3N4S, 454.0; m/z found, 455.0 [M+H]+. 1H NMR ((CD3)2SO): 10.46 (s, 1H), 8.58 (s, 1H), 8.19 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.47 (dd, J=8.5, 7.8 Hz, 1H), 4.82 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[C:7]([CH3:11])[CH:8]=2)[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:14]([NH:13][C:2]1([CH3:1])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[C:7]([CH3:11])[CH:8]=2)[CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc2c(cc1C)CC(C)(NC(=O)c1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)CC(C)(NCc1ccccc1)C2

Procedure:
To a solution of N-(2,5,6-trimethyl-indan-2-yl)-benzamide in THF under nitrogen is added LiAlH4 and the mixture refluxed for 48 hours. Quenched at 0° C. with ice/water and extracted with ether, dried (Na2SO4) and solvent removed in vacuo. Purification by chromatography (silica, ethyl acetate/hexane 1:4) gives a colourless oil.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][CH2:10]/[C:11](/[CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12]\[Cl:13])=CC=1.C(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[OH:8][CH2:9][CH2:10]/[C:11](/[CH2:14][O:15][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:12]\[Cl:13]
Reactant: COc1ccc(COCC/C(=C\Cl)COC(=O)c2ccccc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: O=C(OC/C(=C/Cl)CCO)c1ccccc1
Reaction time: 2 h

Procedure:
Combine (E)-4-(p-methoxybenzyloxy)-2-benzoyloxymethyl-1-chlorobut-1-ene (1.02.6 g, 7.18 mmol) with methylene chloride (16 mL) and water (1 mL) and stir rapidly. Add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.79 gm, 7.90 mmol). After 2 hours, filter the reaction mixture, rinse the filter cake with methylene chloride (200 mL) and concentrate the filtrate in vacuo. Chromatograph on silica gel eluting with 1/2 ethyl acetate/hexane to give the title compound as an oil. Rf =0.25; silica gel, 1/2 ethyl acetate/hexane.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH2:20]([O:22][C:23](=[O:52])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32](OC(=O)C)[C:33]2[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([O:42][CH3:43])=[C:35]([O:44][CH3:45])[C:34]=2[O:46][CH3:47])=[CH:28][CH:27]=1)[CH3:21]>C(Cl)Cl>[CH2:20]([O:22][C:23](=[O:52])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]2[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([O:42][CH3:43])=[C:35]([O:44][CH3:45])[C:34]=2[O:46][CH3:47])=[CH:28][CH:27]=1)[CH3:21]
Reactant: CCOC(=O)C=Cc1ccc(C(OC(C)=O)c2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a solution of triethylsilane (720 mg, 6.21 mmol) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) in methylene chloride (250 ml) was added dropwise a solution of the compound (2.37 g, 5.17 mmol) obtained in Step 3 in methylene chloride (50 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water, dried, and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=4:1) to yield the title compound (1.90 g, 4.74 mmol, yield 92%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:9][N:8]2[C:10]3[CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=[CH:14][C:15]=3[C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:7]2[C:6]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:5]=2[O:4][CH2:3]1.C(OC)(OC)OC.[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[BH3-]C#N.[Na+]>>[CH2:39]([NH:1][C@@H:2]1[CH2:9][N:8]2[C:10]3[CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=[CH:14][C:15]=3[C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:7]2[C:6]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:5]=2[O:4][CH2:3]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N)COc1cc(F)ccc1-3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NCc1ccccc1)COc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (7R)-7-amino-14-cyclohexyl-3-fluoro-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (Example 11, Step 5) was dissolved in HC(OMe)3 (50 eq) and a solution of benzaldehyde (1.1 eq) in HC(OMe)3 (50 eq) was added. The mixture was stirred overnight at RT to allow formation of the imine. All volatiles were evaporated and the residual material was dissolved in MeOH/HOAc (0.05 M). NaCNBH3 (1.1 eq) was added and the mixture was stirred at RT for 1 h. The solution was used directly in the next step. (ES+) m/z 513 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([NH:48][C:49]1[CH:57]=[C:56]2[C:52]([CH:53]=[C:54]([C:58](O)=[O:59])[NH:55]2)=[CH:51][CH:50]=1)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[C:45]([NH:48][C:49]1[CH:57]=[C:56]2[C:52]([CH:53]=[C:54]([C:58]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]4[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=4)[C:28]=3[F:44])=[O:59])[NH:55]2)=[CH:51][CH:50]=1)(=[O:47])[CH3:46]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(=O)Nc1ccc2cc(C(=O)O)[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
HATU (0.086 g, 0.227 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.047 g, 0.151 mmol), 6-(acetylamino)-1H-indole-2-carboxylic acid (0.033 g, 0.151 mmol) and DIPEA (0.040 mL, 0.227 mmol) in DMF (1 mL). The mixture was stirred at RT for 2 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water and dried over sodium sulfate, and the solvent was evaporated. The resulting oil was triturated with methylene chloride:methanol. The resulting solid was collected by filtration and dried under vacuum to give the title compound (0.024 g, 31%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.46 (s, 1H), 9.85 (s, 1H), 9.01 (m, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.40-7.53 (m, 4H), 7.35 (t, 1H), 7.11 (m, 2H), 4.51 (d, 2H), 2.00 (s, 3H). MS: m/z 511 (M+1).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14]4[C:15]5[CH:29]=[CH:28][S:27][C:16]=5[C:17](=[O:26])[NH:18][C:19]=4[C:20]([Br:25])=[CH:21][C:22]=3[O:23]C)=[CH:9][CH:8]=2)[CH2:6][CH2:5]1.BrB(Br)Br>>[ClH:1].[NH2:2][CH2:3][C:4]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:14]4[C:15]5[CH:29]=[CH:28][S:27][C:16]=5[C:17](=[O:26])[NH:18][C:19]=4[C:20]([Br:25])=[CH:21][C:22]=3[OH:23])=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CN)CC2)cc1
Agent: BrB(Br)Br
Agent: Cl
Product: NCC1(c2ccc(-c3c(O)cc(Br)c4[nH]c(=O)c5sccc5c34)cc2)CC1
Yield: 54 %

Procedure:
Following General Procedure F, 9-(4-(1-(aminomethyl)cyclopropyl)phenyl)-6-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one hydrochloride (100 mg, 0.22 mmol was reacted with tribromoborane (1.0 M in methylene chloride, 1.32 mL, 1.32 mmol) to afford the desired product (52 mg, 54%) as a white solid: 1H NMR (500 MHz, MeOD) δ 7.63 (t, J=6.8 Hz, 3H), 7.48 (s, 1H), 7.33 (d, J=8.2 Hz, 2H), 6.14 (d, J=5.4 Hz, 1H), 3.26 (s, 2H), 1.19 (t, J=5.6 Hz, 2H), 1.12 (t, J=5.5 Hz, 2H); ESI MS m/z 442 [C21H17BrN2O2S+H]+; HPLC >99% (AUC), tR=9.25 min.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1([CH3:15])[CH2:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1.[N+:18]([O-])([O-:20])=[O:19].[NH4+].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1([CH3:15])[CH2:9][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)C1(C)CC(=O)c2ccccc2O1
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(OC)C1(C)CC(=O)c2cc([N+](=O)[O-])ccc2O1
Yield: 55 %

Procedure:
In 15 ml of chloroform were dissolved 1.99 (8.1 mmole) of the compound obtained in step 1 and 0.64(8.1 mmole) of ammonium nitrate; and, 4.5 ml (32 mmole) of anhydrous trifluoroacetic acid was added thereto at room temperature. The resultant mixture was stirred at room temperature for 3 hours; and, the reaction was terminated with a saturated NaHCO3 aqueous solution. The resultant solution was extracted with dichloromethane (50 ml×2), washed with 50 ml of water and with 20 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain residue, which was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (4:1) as an eluent to obtain 1.24 g (yield 55%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[C:25]([N:27]=[C:28]=[S:29])=[O:26]>C1COCC1>[C:16]([O:15][C:13]([C:3]1[C:4]2[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][C:5]=2[S:12][C:2]=1[NH:1][C:28]([NH:27][C:25](=[O:26])[C:24]1[CH:30]=[CH:31][CH:32]=[C:22]([O:21][CH3:20])[CH:23]=1)=[S:29])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Reactant: COc1cccc(C(=O)N=C=S)c1
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)OC(C)(C)C)CC(C)(C)OC3)c1
Temperature: 50 °C
Yield: 68 %

Procedure:
tert-Butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.28 g, 1.00 mmol) and 3-methoxybenzoyl isothiocyanate (0.20 g, 1.01 mmol) were dissolved in THF (5 mL) and heated at 50° C. for 22 hours. The solvent was removed and EtOH (10 mL) was added. The product was filtered and rinsed with EtOH (2×10 mL). tert-Butyl-2-(3-(3-methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.32 g, 0.68 mmol, 68% yield) was isolated as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 14.71 (s, 1H), 9.06 (s, 1H), 7.51-7.49 (m, 1H), 7.44-7.40 (m, 2H), 7.19-7.13 (m, 1H), 4.74 (apparent t, J=1.5 Hz, 2H), 3.89 (s, 3H), 2.77 (apparent t, J=1.5 Hz, 2H), 1.64 (s, 9H), 1.31 (s, 6H).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]=[O:12])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[C:14]#[CH:15]>C1COCC1>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:12])[CH2:15][C:14]#[CH:13])([CH3:3])[CH3:2]
Reactant: C#CC[Mg]Br
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C=O
Solvent: C1CCOC1
Product: C#CCC(O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 0 °C
Yield: 37.6 %

Procedure:
To a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbaldehyde (1.0 g, 6.0 mmol) in THF (10 mL) at 0° C. was slowly added propargyl magnesium bromide (1 M, 8.9 mmol). After the reaction was allowed to warm to room temperature overnight 1.5 equivalents of additional propargyl magnesium bromide were added and the reaction was allowed to stir for 6 additional h. The reaction was again cooled to 0° C. and then quenched with 1 N HCl and partitioned between brine and MTBE. The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica chromatography to give the desired alcohol (0.47 g).
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([F:15])=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.ClC1C(S(NC)(=O)=O)=CC=C(Cl)C=1C(O)=O>>[CH3:17][C:16]([NH:20][S:2]([C:5]1[C:6]([F:15])=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1F
Agent: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1cc(C(=O)O)c(F)cc1F

Procedure:
Prepared from a mixture of 5-(chlorosulfonyl)-2,4-difluorobenzoic acid (200 mg, 0.78 mmol, 1 equiv), tert-butyl amine (98 mL, 0.94 mmol, 1.2 equiv) and DIEA (280 μL, 1.56 mmol, 2 equiv) following the general procedure for 2,6-dichloro-3-[(methylamino)sulfonyl]benzoic acid 880-1b. The crude reaction mixture was carried on without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[Cl:12]C1C=CC=C(C(OO)=[O:20])C=1.Cl.C(OCC)C>ClCCl.CO>[ClH:12].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:20])[CH:6]=[CH:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1ccc2cnccc2c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: [O-][n+]1ccc2cc(Br)ccc2c1
Yield: 90.8 %

Procedure:
To a stirred solution of 13.2 g of 6-bromoisoquinoline (Tyson, F. L., J. Am. Chem. Soc. 61, 183 (1939)) in 250 mL of dichloromethane at room temperature was added in portions 16.2 g of m-chloroperbenzoic acid (purity 70%). After stirring the mixture for one hour 200 mL of methanol was added and the bulk was reduced to 150 mL. A hydrogen chloride solution in methanol (100 mL, 0.75 M) was added and after slightly heating a clear solution was obtained. Diethylether (250 mL) was added to this solution and cooled in an ice bath. The hydrochloride salt precipitated and was isolated by filtration to give 15 g of 1a. M.p. 194-196° C.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.I[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[C:45]([O:53][CH:54]([CH3:56])[CH3:55])[CH:44]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:1]1([C:43]2[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[C:45]([O:53][CH:54]([CH3:56])[CH3:55])[CH:44]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(I)cc1OC(C)C
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C2CC2)cc1OC(C)C
Reaction time: 15 h
Yield: 93.7 %

Procedure:
Cyclopropylboronic acid (3.19 g), a 2 M aqueous sodium carbonate solution (37 mL), tris(dibenzylideneacetone)dipalladium(0) (1.59 g), and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.52 g) were added at room temperature to a toluene (100 mL) solution of methyl 4-iodo-2-isopropoxybenzoate (7.92 g), and the mixture was stirred at 100 C for 15 hours in an argon atmosphere. Water was added to the reaction mixture at room temperature. The mixture was filtered through celite, and then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.43 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=1)[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25](O)=[O:26])[S:24][C:17]=12)=[O:11].C1C[N:34]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(N)C.C1COCC1.Cl>CN(C=O)C.O>[CH2:33]([NH:34][C:25]([C:23]1[S:24][C:17]2[C:18](=[N:19][CH:20]=[CH:21][C:16]=2[O:15][C:14]2[CH:28]=[CH:29][CH:30]=[C:12]([C:10]([NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[F:1])=[O:11])[CH:13]=2)[CH:22]=1)=[O:26])[CH3:32]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc4cc(C(=O)O)sc34)c2)c1
Agent: CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc2nccc(Oc3cccc(C(=O)Nc4cc(C)ccc4F)c3)c2s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred, cooled (0° C.) solution of 7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.28 mmol) in anhydrous DMF (10 ml) were added PyBOP (161 mg, 0.31 mmol) and N,N-diisopropylethylamine (72 mg, 0.56 mmol). The mixture was stirred at 0° C. for 5 minutes, followed by addition of 2M ethylamine solution in THF (0.2 ml, 0.4 mmol). Stirring was continued at 0° C. for another 30 minutes. The mixture was poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried to give N-ethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 112 mg, 88%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH2:13][CH2:12][C:7]3(OCC[O:8]3)[CH2:6][C:5]2=1.O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][C:5]2=1
Reactant: Fc1ccc2[nH]c3c(c2c1)CC1(CC3)OCCO1
Solvent: O=CO
Solvent: O
Product: O=C1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-fluoro-1,2,4,9-tetrahydrospiro[carbazole-3,2′-[1,3]dioxolane] (33.7 g, 0.136 mol) in formic acid (123 ml) was stirred at rt for 4 h30. Then water was added carefully at 0° C., the resulting suspension was stirred for 30 min at 0-5° C. The suspension was filtered off and the yellow solid was washed twice with water (2×14 ml), dried in high vacuum overnight to yield the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[N:29]=[C:28]3[CH2:30][O:31]C(C)(C)[O:33][C:27]3=[CH:26][CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:36])[N:10]1[CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[NH:43][S:44]([CH3:47])(=[O:46])=[O:45].Cl.C(=O)([O-])O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([OH:33])=[C:28]([CH2:30][OH:31])[N:29]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:36])[N:10]1[CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[NH:43][S:44]([CH3:47])(=[O:45])=[O:46]
Reactant: CC1(C)OCc2nc(CONC(=O)C3c4ccccc4C(=O)N(C4CCCCC4NS(C)(=O)=O)C3c3ccc(Cl)cc3Cl)ccc2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccc(O)c(CO)n2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
To a solution of 566 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(2,2-dimethyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)methoxy]-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 11.3 ml of THF was added 3.2 ml of 1 M hydrochloric acid, followed by stirring at room temperature for 2 hours. 1.6 ml of 1 M hydrochloric acid was further added, followed by stirring for 2 days. The solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 196 mg of rel-(3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-hydroxy-6-(hydroxymethyl)pyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:19]=[CH:18][C:9]2[CH2:10][CH2:11][CH:12]([C:16]#[N:17])[CH2:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4].C(O)C>O>[OH:15][C@H:14]1[C:8]2[CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:19]=[CH:18][C:9]=2[CH2:10][CH2:11][C@H:12]([C:16]#[N:17])[CH2:13]1
Reactant: N#CC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#C[C@H]1CCc2ccc([N+](=O)[O-])cc2[C@H](O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
10 g of sodium borohydride were added over 5 minutes under nitrogen to a mixture of 20 g of 3-nitro-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile, 200 ml of ethanol and 20 ml of water and the mixture was stirred for one hour at room temperature and then evaporated to dryness under reduced pressure. 400 ml of water were added to the residue and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 18 g of raw product which were chromatographed over silica gel. Elution with a 9-1 ethyl acetate-triethylamine mixture yielded 2 fractions. The first fraction of 6.5 g of trans product occured in the form of a yellow oil with an Rf = 0.65 which was crystallized from ethyl acetate to obtain 4.5 g of trans 5-hydroxy-3-nitro-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile in the form of white crystals melting at 160° C. The second fraction of 7.9 g of cis product occured in the form of a yellow oil with a Rf = 0.55 which crystallized from ethyl acetate to obtain 6.5 g of cis 5-hydroxy-3-nitro-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile in the form of white crystals melting at 142° C.