Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][C:32]4[CH:49]=[CH:48][CH:47]=[CH:46][C:33]=4[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][C:32]4[CH:49]=[CH:48][CH:47]=[CH:46][C:33]=4[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:27][CH2:28]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCOCCC(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCOCCC(=O)O)CC3)C2)cs1
Reaction time: 16 h

Procedure:
trifluoroacetic acid (2 mL) was added to a stirred solution of tert-butyl 3-(2-(2-(4-(2-s isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethoxy)phenethoxy)propanoate (0.320 g) (example 178 step c) in DCM (5 mL). After 16 h, the solution was evaporated to a gum. The gum was dissolved in acetonitrile (5 mL) and evaporated in vacuo (repeated 3 times). Yield 0.4 g.
Reaction SMILES: [OH:1][CH:2]1[C:13]2[C:14](=[O:15])[C:9]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])([CH2:10][CH2:11][CH:12]=2)[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]1.FC(F)(F)S(O)(=O)=O.[C:32]([O:35][CH2:36]C)(=[O:34])[CH3:33]>CCOCC>[CH3:36][O:35][C:32]([CH2:33][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:1][CH:2]2[C:13]3[C:14](=[O:15])[C:9]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])([CH2:10][CH2:11][CH:12]=3)[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]2)=[CH:10][CH:11]=1)=[O:34]
Reactant: CC(C)(C)[Si](C)(C)OC12C#CC=CC#CC(O)C(=CCC1)C2=O
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)Cc1ccc(COC2C#CC=CC#CC3(O[Si](C)(C)C(C)(C)C)CCC=C2C3=O)cc1
Yield: 59 %

Procedure:
To a solution of the alcohol 6 (208 mg., 0.63 mmol) and imidate 7 (300 mg, 0.92 mmol) in 5 mL of anhydrous ether was added trifluoromethanesulfonic acid (25 μL, 0.28 mmol). The solution was diluted with ethyl acetate and washed with saturated bicarbonate. The organic fraction was dried over MgSO4, concentrated and the residue chromatographed over silica gel (5:1 hexane/ethyl acetate) to give compound 8a (184 mg, 59%) and 77 mg of recovered alcohol 1 (37%).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:29][CH3:30])=[C:16]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([N:22]2[CH2:23][CH2:24][CH:25]([OH:28])[CH2:26][CH2:27]2)[C:15]([O:29][CH3:30])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1N1CCC(O)CC1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1N1CCC(O)CC1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (5 mg, 0.03 mmol), 1-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]piperidin-4-ol (7 mg, 0.02 mmol), and N,N-diisopropylethylamine (0.0082 mL, 0.047 mmol) in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H26ClN6O2 (M+H)+: m/z=417.2. found: 417.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].CS(C)=O.[Br:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])Br>C1(C)C(C)=CC=CC=1>[Br:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Oc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CS(C)=O
Product: FC(F)(Br)C(F)(F)Oc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
3-bromophenol (0.582 mol), potassium hydroxide (0.582 mol), methyl sulfoxide (3.2 L) and xylene (0.08 L) were put in a 2-bulb flask equipped with a Dean-Stark azeotropic distillation unit, which has been purged with nitrogen. The reactor was heated to 100° C. and reaction was performed for 48 hours to remove water. The reactor was cooled to 30° C. and 1,2-dibromotetrafluoroethane (0.640 mol) was slowly dropped for 4 hours maintaining the reactor temperature below 30° C. The reaction solution was mixed at 22° C. for 12 hours, and then reaction was performed at 35° C. for 10 hours. After the reaction was completed, the reaction solution was extracted with methylene chloride diluted in water. The obtained product was washed with water for three times and dehydrated with magnesium sulfate. Methylene chloride was removed from the filtrate using a vacuum evaporator. From vacuum distillation, 3-(2-bromotetrafluoroethoxy)bromobenzene was obtained as clear liquid (boiling point: 107 to 110° C.). The yield was 72%.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8]O.[ClH:11].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[ClH:14].[Cl:11][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][Cl:14]
Reactant: O=S(Cl)Cl
Reactant: CN(CCCO)CCCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(CCCCl)CCCCl
Reaction time: 15 h

Procedure:
A solution of about 60 grams of N,N-bis(3-hydroxypropyl)methylamine in 110 ml of chloroform is saturated, with cooling and stirring, with anhydrous hydrogen chloride gas. To the resulting two-phase liquid mixture is added, over a period of about 30 minutes at a temperature of 0-5° C., approximately 66 ml of thionyl chloride. The homogeneous solution thus obtained is allowed to stand at room temperature for a period of about 15 hours, the solution is then heated at reflux temperature for an additional two-hour period, and the chloroform is evaporated in vacuo from the light brown-colored reaction solution. The residual material is washed with ethanol, and is then crystallized from a mixture of 200 ml ethanol: 800 ml ether. The white crystalline product thus obtained is recovered by filtration, washed with three portions of ether, then with hexane, and dried in vacuo at 25° C. to give about 80 grams of N,N-bis(3-chloropropyl) methylamine hydrochloride; m.p. 86-88° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCOCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN3CCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (100 mg, 0.26 mmol) in dioxane (5 mL) was added pyrrolidine (0.2 mL, 2.6 mmol). The mixture was stirred at 70° C. for 1 hour and then was concentrated in vacuo to give a residue, which was purified by chromatography (5%-15% methanol in methylene chloride) to give 85 mg (91%) of the desired product as a thick oil: MS(APCI+): m/z 363.2 (MH+).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2].[NH3:21]>>[C:1]([CH2:4][O:5][C:6]1[CH:16]=[C:15]([S:17]([NH2:21])(=[O:19])=[O:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2]
Reactant: N
Reactant: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Product: NC(=O)COc1ccc(S(N)(=O)=O)cc1OCC(N)=O
Reaction time: 16 h

Procedure:
2-Carbamoylmethoxy-4-chlorosulfonylphenoxyacetamide (Intermediate A65, 12.9 g, 0.040 mol) was dissolved in methanolic ammonia and stirred for 16 hr. The solvent was removed at aspirator pressure, and the residue was crystallized in water. The resulting solid was washed with hot water and several additional portions of water. The product, title compound weighed 8.6 g (71%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=2)[C:4]1=O)[CH3:2].Cl.O1CCOCC1>O>[CH2:1]([CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=2)[CH2:11]1)[CH3:2]
Reactant: CCC1Cc2ccc(C(C)C(=O)O)cc2C1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCC1Cc2ccc(C(C)C(=O)O)cc2C1

Procedure:
A mixture of 10.5g. of 2-(2ethyl-1-oxoindan-6-yl)propionic acid, 20g. of zinc amalgam, 30 ml. of conc. hydrochloric acid, 150 ml. of dioxane and 20 ml. of water was heated under reflux for 15 hours. After completion of the reaction, the reaction mixture was extracted with ether and the ether extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract and the residue was subjected to vacuum distillation to give 8.2g. of the desired product as a colorless oily substance of b.p. 165° - 166° C./1.5 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:14]([CH2:15][O:16][CH2:17][C:18](O)=[O:19])=[N:13][N:12]2[C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=[C:11]2[C:10]=1[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1)[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C)C=O>[CH2:24]([C:21]1[N:12]2[N:13]=[C:14]([CH2:15][O:16][CH2:17][C:18]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:19])[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:33])=[C:10]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:11]2=[CH:23][CH:22]=1)[CH3:25]
Reactant: C1COCCN1
Reactant: CCOC(=O)CCCCc1c(COCC(=O)O)nn2c(CC)ccc2c1-c1cncc(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(COCC(=O)N2CCOCC2)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of {[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}acetic acid (55 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (34.9 mg) and 1-hydroxybenotriazole (24.6 mg) in dimethylformamide (2 mL) was added morpholine (12.7 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of ethyl acetate and methanol (50:1-20:1) to give ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oxoethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate as yellow oil (50 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]#[N:7].B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccccc2)c(O)c1
Reaction time: 6 h
Yield: 66.2 %

Procedure:
3-Methoxy-4-phenylbenzonitrile (17.8 g) was dissolved in dichloromethane (200 mL). To the stirred mixture was added dropwise boron tribromide (14 mL) under ice-cooling, and the mixture was stirred at continuous temperature for 6 hours. To the stirred reaction mixture was added dropwise water (200 mL) under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (11.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([SH:15])=[N:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].CC(O[CH2:25][C:26]1[CH2:35][S:34][C@@H:29]2[C@H:30]([NH2:33])[C:31](=[O:32])[N:28]2[C:27]=1[C:36]([OH:38])=[O:37])=O.Cl>CC(C)=O>[NH2:33][CH:30]1[C:31](=[O:32])[N:28]2[C:27]([C:36]([OH:38])=[O:37])=[C:26]([CH2:25][S:15][C:13]3[S:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:11][N:12]=3)[CH2:35][S:34][C@H:29]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCc1nnc(S)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reaction time: 2 h
Yield: 56.2 %

Procedure:
5-Tert-butoxycarbonylaminomethyl-1,3,4-thiadiazole-2-thiol(1.24 g.) was dissolved in acetone (10 ml.). The solution was added to the aqueous solution (40 ml.) containing sodium bicarbonate (0.84 g.). The mixed solution was warmed on water bath heating at 70°-75° C. To the solution was added all at once 7-aminocephalosporanic acid (1.35 g.) at 55° C. The mixture was stirred at 65°-70° C for 2 hrs. and then cooled to 0°-5° C with ice. The reaction mixture was adjusted to pH5.0-5.2 with 10% hydrochloric acid. The precipitating pale yellow substance was separated out by filtration, washed with water and acetone, and then dried to give 7-amino-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.28 g.) m.p. over than 220° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:21][C:22]6[O:26][C:25]([C:27]([O:29]C)=[O:28])=[C:24]([C:31](=[O:34])[NH:32][CH3:33])[C:23]=6[CH:35]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.O[Li].O>O1CCOCC1.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:21][C:22]6[O:26][C:25]([C:27]([OH:29])=[O:28])=[C:24]([C:31](=[O:34])[NH:32][CH3:33])[C:23]=6[CH:35]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(C(=O)OC)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(C(=O)O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a suspension of compound methyl 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylate (540 mg, 0.93 mmol) in 1,4-dioxane/H2O (6 mL/1 mL) was added LiOH.H2O (196 mg, 4.67 mmol). The mixture was stirred at RT overnight. Then it was concentrated in vacuo, diluted with water, acidized with HCl(aq. 2 M) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated give the product of compound 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (500 mg, yield: 95%). It was used for the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 9.21 (br s, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.54˜7.58 (m, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.28˜7.11 (m, 2H), 7.07 (s, 1H), 6.95˜6.88 (m, 1H), 6.25 (s, 2H), 3.28 (s., 3H), 2.95 (s, 3H), 2.83 (d, J=4.4 Hz, 3H). MS (M+H)+: 565.
Reaction SMILES: N1C2C(=CC=CC=2)C(CCS)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36](=O)[C:37]([O:39][CH2:40][CH3:41])=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]1[C:40]([CH3:41])([CH3:2])[O:39][CH2:37][CH2:36][C:30]2=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: SCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21

Procedure:
5-Benzyloxy-3-tryptophol (II; R2, R3, R4 and R5 = H, R6 = 5-benzyloxy and X1 = OH), m.p. 93° - 95° C., is prepared by lithium aluminum hydride reduction of ethyl 5-benzyloxy-3-indoleglyoxalate (British Patent 778,823) according to the procedure of Example 309. Subsequent treatment of 5-benzyloxy-3-tryptophol with the ketone, acetone, according to the procedure of Example 785 affords 6-benzyloxy-1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (VII; R1M CH3), nmr (CDCl3) δ1.53 (6H), 2.73 (t, 2H), 4.03 (t, 2H), 5.10 (2H), 6.67 - 7.83 (9H). The latter compound is then N-alkylated with the organic halide, dimethylaminoethyll chloride, according to the procedure of Example 838 to afford 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, which on treatment with hydrochloric acid gives the corresponding hydrochloric acid addition salt thereof, m.p. 209° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.C([Li])CCC.CN([CH:37]=[O:38])C>C1COCC1>[CH:37]([C:9]1[C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)=[O:38]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccccc2)cc1C=O
Temperature: -72 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
A solution of 1C (2.40 g, 8.88 mmol) in dry THF (35 mL) and TMEDA (3.35 mL, 22.2 mmol) under argon was cooled to −72° C. and treated dropwise with n-butyllithium (2.5 M in hexanes, 8.9 mL, 22.2 mmol) at such a rate so that the temperature did not exceed −65° C. Upon completion of the addition, the reaction was stirred at −72° C. for an additional 15 min and then at −20° C. for 1.5 h. The reaction was cooled again to −72° C., and dry DMF (1.4 mL, 17.8 mmol) was added while the temperature was maintained below −65° C. The mixture was allowed to stir at RT for 30 min. After this time, no starting material was detected by LC-MS. The solution was cooled to 0° C. and quenched by the addition of 1 M aqueous HCl to bring the pH to 6-8. The reaction was stirred at RT for 15 min, extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel (110 g) column chromatography, eluting with a gradient of EtOAc (0-100%) in hexane to give the title compound as a yellow solid (1.1 g, 42%). LC/MS (method A): retention time=3.43 min, (M+H−tBu)+=243.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[N:11]=[C:12]([NH:15][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[S:13][CH:14]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
A mixture of 0.5 g of 4-(3,4-dichloro-phenyl)-thiazol-2-ylamine hydrobromide with 0.50 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.33 g of N-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide was obtained as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]#[N:12])[O:8][C:7]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[CH:25]=1.C[Sn]([N:30]=[N+:31]=[N-:32])(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]3[NH:32][N:31]=[N:30][N:12]=3)[O:8][C:7]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[CH:25]=1
Reactant: N#CC1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: Clc1ccc2c(c1)C(C1CCCCC1)(C1CCCCC1)OC(c1nnn[nH]1)O2

Procedure:
500 mg 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carbonitrile and 572 mg trimethyltin azide were dissolved in 23 ml xylene. The reaction mixture was refluxed for 4 hours. Then the solvent was removed in vacuo and the crude product purified by preparative HPLC (C18 reverse phase column, elution with water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a solid which was washed three times with heptanes to remove traces of tin by-product. Yield: 238 mg.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 6-Hydroxy-2H-isoquinolin-1-one (0.1 g, 0.62 mmol) and potassium carbonate (0.13 g, 0.93 mmol) in DMF (2.5 ml) was heated to 110° C. and a solution of methanesulfonic acid trans-4-tert-butoxycarbonylaminocyclohexyl ester (0.27 g, 0.93 mmol) in DMF (1.5 ml) was added dropwise. Heating was continued at 110° C. for 16 hours and the solvent removed in vacuo. The residue was taken up in chloroform/isopropanol (3:1) and washed with 1M NaOH. The organics were collected through a hydrophobic frit and concentrated to afford crude product. The residue was purified by prep-H PLC to give cis-[4-(1 -oxo-1,2-dihydroisoquinolin-6-yloxy)cyclohexyl]carbamic acid tert-butyl, EI-MS: m/z=359.1 [M+H]+. A mixture of the above cis-[4-(1-Oxo-1,2-dihydroisoquinolin-6-yloxy)cyclohexyl]carbamic acid tert-butyl ester in dichloromethane (0.9 ml) and trifluoroacetic acid (0.1 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo then purified by ion exchange chromatography to give cis-6-(4-aminocyclohexyloxy)-2H-isoquinolin-1-one ( 3.1 mg), El-MS: m/z=259.1 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11](=[O:17])[CH2:12][NH:13][CH:14]([CH3:16])[CH3:15])=[CH:6][C:5]=1[Cl:18].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH:11]([OH:17])[CH2:12][NH:13][CH:14]([CH3:15])[CH3:16])=[CH:6][C:5]=1[Cl:18]
Reactant: CC(C)NCC(=O)c1cc(F)c(N)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)NCC(O)c1cc(F)c(N)c(Cl)c1

Procedure:
m.p. of the hydrochloride: 152°-154° C. (decomp.), was prepared from 4'-amino-3'-chloro-5'-fluoro-2-isopropylamino-acetophenone hydrochloride and sodium borohydride analogous to Example 1.