Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:13]([OH:16])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:17][C:18]([N:20]([OH:55])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH2:29][CH2:30][C:31]([N:33]([OH:54])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([CH2:42][CH2:43][C:44]([N:46]([OH:53])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])=[O:45])=[O:41])=[O:32])=[O:28])=[O:19]>>[CH2:1]([S:13]([O-:16])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:17][C:18]([N:20]([OH:55])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH2:29][CH2:30][C:31]([N:33]([OH:54])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([CH2:42][CH2:43][C:44]([N:46]([OH:53])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])=[O:45])=[O:41])=[O:32])=[O:28])=[O:19]
Reactant: CCCCCCCCCCCCS(=O)(=O)O
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Product: CCCCCCCCCCCCS(=O)(=O)[O-]

Procedure:
Following a procedure analogous to that of Example 1, dodecane-1-sulphonic acid and desferrioxamine-B are reacted to give the dodecane-1-sulphonate salt of desferrioxamine-B, Mp 151° C. C37H74O11 N6S Calcd C: 54.79%, H:9.20%, N:10.36%, S:3.95%; Found C: 54.74%, H: 9.15%, N:10.21%, S: 4.07%.
Reaction SMILES: CN(C)[C:3](=[CH:9][CH:10]=[C:11]([S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.C([OH:36])C>>[OH:36][C:3](=[CH:9][CH:10]=[C:11]([S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1cccc(Oc2ccccc2)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SCc1cccc(Oc2ccccc2)c1)C(=O)OCC
Temperature: 20 °C
Reaction time: 0.02 h

Procedure:
The procedure is as in Example 2, starting with diethyl 2-dimethylamino-5-(3-phenoxybenzylthio)-2,4-hexadienedioate (7 g), 12N aqueous hydrochloric acid solution (23 cc) and ethanol (46 cc). The mixture is heated to boiling for 1 minute, and is then cooled to a temperature of approximately 20° C. After purification by chromatography on a silica column with dichloromethane as eluent, diethyl 2-hydroxy-5-(3-phenoxybenzylthio)-2,4-hexadienedioate (4.5 g) is obtained in the form of a yellow oil (Rf=0.2; thin layer chromatography on silica gel; eluent: dichloromethane).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([OH:17])([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])=[CH:6][CH:5]=1.N1C2C(=CC=CC=2)C=CC=1>C(Cl)(Cl)Cl>[Br:1][CH2:15][CH:14]1[CH2:13][CH2:12][C:11]([C:10]([CH3:19])([CH3:18])[CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=2)([CH3:16])[O:17]1
Reactant: BrBr
Reactant: C=CCCC(C)(O)C(C)(C)COc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccc2ncccc2c1
Product: CC(C)(COc1ccc(Cl)cc1)C1(C)CCC(CBr)O1
Yield: 90.4 %

Procedure:
16 g (0.1 mole) of bromine are added dropwise to 28.2 g (0.1 mole) of 7-(4-chlorophenoxy)-5-hydroxy-5,6,6-trimethyl-hept-1-ene in 200 ml of absolute chloroform at room temperature, with stirring, and 13 g (0.1 mole) of quinoline are then added at -10° C., with cooling. The reaction mixture is stirred at room temperature for a further 2 hours and concentrated in vacuo, the residue is taken up in ether, the mixture is filtered, the filtrate is again concentrated in vacuo and the residue is stirred in a waterbath at 95° C. for 1 hour. The resulting mixture is taken up in ether, the mixture is filtered and the filtrate is washed with 15 percent strength hydrochloric acid and then with water, dried over sodium sulphate and freed from the solvent in vacuo. 32.7 g (90% of theory) of 2-bromomethyl-5-[1-(4-chlorophenoxy)-2-methylprop-2-yl]-5-methyl-tetrahydrofuran are obtained as an oil, which can be used in the next stage without further purification. ##STR114##
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.BrC1C=C(S(C)(=O)=[O:33])C=CC=1OCC1CC1.Br[C:42]1[C:51]2[C:46](=[CH:47][CH:48]=C(C(F)(F)F)C=2)[C:45](=[O:56])[N:44]([CH3:57])[CH:43]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:8][C:7]=2[C:42]2[C:51]3[O:33][CH:48]=[CH:47][C:46]=3[C:45](=[O:56])[N:44]([CH3:57])[CH:43]=2)[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Reactant: Cn1cc(Br)c2cc(C(F)(F)F)ccc2c1=O
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c2occc2c1=O

Procedure:
The title compound was prepared in a manner similar to Example 197, by substituting 5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-c]pyridin-4-one for 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene for 4-bromo-2-methyl-6-(trifluoromethyl)isoquinolin-1-one. 1H NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 7.92 (dd, J1=8.6 Hz, J2=1.8 Hz, 1H), 7.50 (m, 2H), 7.07 (m, 2H), 3.95 (d, J=6.7 Hz, 2H), 3.70 (s, 3H), 3.1 (s, 3H), 1.15 (m, 1H), 0.57 (m, 2H), 0.28 (m, 2H). LCMS: 374.1 (M+H)+
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:5][CH:4]=1.[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[C@@H:19]1([NH:29][CH2:15][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=3)[CH:14]=[CH:13][CH:12]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Product: FC(F)(F)c1ccc(-c2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
4′-(Trifluoromethyl)[1,1′-biphenyl]-3-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:38]2[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=2)=[S:45])=[CH:28][C:27]=1[F:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(N=C=S)c1ccc(F)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 86%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([S:30](Cl)(=[O:32])=[O:31])[CH:29]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:30]([C:28]3[CH:29]=[C:24]([F:23])[CH:25]=[CH:26][C:27]=3[O:34][CH3:35])(=[O:31])=[O:32])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: COc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Yield: 79 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (309 mg, 0.934 mmol) and 5-fluoro-2-(methyloxy)benzenesulfonyl chloride (210 mg, 0.934 mmol) the title compound of Step A was obtained as a white solid. (381 mg, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.42 (d, J=5.3 Hz, 1H), 7.39-7.54 (m, 2H), 7.23-7.37 (m, 1H), 7.09-7.23 (m, 4H), 6.87 (d, J=5.3 Hz, 1H), 3.79 (s, 3H), 3.29-3.38 (m, 1H), 1.33 (d, J=6.9 Hz, 6H).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([F:32])=[C:9]([F:31])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])[CH:14]=[C:13]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]2=[O:30].[N+:33]([O-])([O-:35])=[O:34].[K+]>>[Cl:6][C:7]1[C:8]([F:32])=[C:9]([F:31])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[CH:22]=[C:21]([N+:33]([O-:35])=[O:34])[C:20]([F:23])=[CH:19][C:18]=1[F:24])[CH:14]=[C:13]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]2=[O:30]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To 15 ml of sulfuric acid was added 2.5 g of ethyl 8-chloro-6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate. With ice cooling, 950 mg of potassium nitrate was added in portions and the solution was stirred overnight at room temperature. The reaction solution was poured into ice water and stirred overnight at room temperature. The precipitate was collected by filtration and washed with water, ethanol and diethyl ether to give 2.4 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH2:10]([O:12][CH2:13][CH2:14]O)[CH3:11].[H-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[Cl:9][C:5]1[C:4]([CH2:11][CH2:10][O:12][CH2:13][CH3:14])=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: CCOCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOCCc1nc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,3,5-Trichloropyridine (9.12 g, 0.050 mol) and 2-ethoxyethanol (5.40 g, 0.060 mol) were dissolved in 50 mL DMSO, followed by portionwise addition of NaH (2.4 g, 60% dispersion in oil, 0.060 mol). The mixture was heated to 80° C. for 3 hours, stirred at room temperature overnight, then heated to 120° C. for 5 hours. The reaction mixture was then diluted to 900 mL with brine, and extracted three times with 100 mL ether. The ether extracts were combined, washed twice with 100 mL water, diluted with 300 mL hexane, filtered through phase-separating paper, and concentrated in vacuo. The residue was purified via silica gel chromatography (first column with 10-50% EtOAc in hexane; second column with 0-10% EtOAc in hexane). Concentration of pure fractions gave 3,6-dichloro-2-(2-ethoxyethyl)pyridine as the major isomer (5.78 g white solid, M.P. 33-34° C.) and 2,3-dichloro-6-(2-ethoxyethyl)pyridine as the minor isomer (1.43 g white solid, M.P. 47-480° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH:13]([Si:16](OS(C(F)(F)F)(=O)=O)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reaction time: 1 h
Yield: 78.8 %

Procedure:
5-Bromoindole (14.04 g, 72 mmol) in tetrahydrofuran (50 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in oil; 3.04 g, 76 mmol) in tetrahydrofuran (100 ml) and the resultant solution stirred for one hour at room temperature. Triisopropylsilyltrifluoromethane sulphonate (23.3 g, 76 mmol) was added slowly and the solution stirred for a further one hour. The reaction mixture was washed with sodium hydrogen carbonate solution, dried (MgSO4), and concentrated. The crude mixture was purified by flash chromatography, with hexane as eluant, to give 5-bromo-1-triisopropylsilyl-1H-indole (20.0 g, 79%) as a clear oil; δH (CDCl3) 1.10 (18H, d, J 8.4 Hz, 6× CH3), 2.70 (3H, m, 3×CH), 6.55 (1H, d, J 3.9 Hz, ArH), 7.20 (2H, m, ArH), 7.35 (1H, d, J 8.5 Hz, ArH), and 7.75 (1H, d, J 1.4 Hz, ArH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)([Cl:12])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: Cc1csc(C(=O)Cl)c1

Procedure:
220 cc of thionyl chloride were progressively added to 50 gm of 4-methyl-thiophene-2-carboxylic acid [prepared by process in Beil, Vol. 18, p. 294] and the mixture was heated to reflux for 1 hour. Excess thionyl chloride was evaporated off under reduced pressure and the residue was distilled under reduced pressure to obtain 51 gm of 4-methyl-thiophene-2-carboxylic acid chloride boiling at 112°-114° C. at 18 mm Hg. which was used as is for the next step. The light yellow liquid was soluble in ether.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4]Br.[CH3:11][NH2:12]>CO>[CH3:11][NH:12][CH2:4][C:3]1[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][C:2]=1[F:1]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CN
Solvent: CO
Product: CNCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 25 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzylbromide (755 mg, 2.82 mmol) was dissolved in methanol (10 ml). Methylamine (0.99 ml, 14.1 mmol) was added and the mixture was stirred at ambient temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. The solvents were removed by evaporation. The residue was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:25](O)=[O:26].C(N(CC)CC)C.C([O:39]C(Cl)=O)C(C)C.[C:43]1([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(OCC)(=O)C.CN(C)C=O>[OH:39][C:49]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:50][CH2:51][N:52]([C:25]([C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[O:24])=[N:8][CH:7]=2)=[O:26])[CH2:53][CH2:54]1
Reactant: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)c2ncc(C(=O)N3CCC(O)(c4ccccc4)CC3)c3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution of 6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (30.0 mg, 81.65 mmol) in dry, N,N-dimethylformamide (2 mL) was chilled in an ice bath under argon. With stirring, triethylamine (14.4 uL, 102 mmol) and isobutylchloroformate (13.4 uL, 102 mmol) were added. The solution was stirred for 30 min and then 4-hydroxy, 4-phenylpiperidine (28.9 mg 1.633 mM) was added. The solution was allowed to warm to room temperature with stirring for 1 hr. and then diluted with ethyl acetate (30 mL), The ethyl acetate solution was washed sequentially with saturated sodium bicarbonate solution (2×5 mL), water (5 mL), and saturated sodium chloride solution (5 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 50 mg of solid. This crude material was purified by flash chromatography, eluting with 50% ethyl acetate in hexanes (containing 1% acetic acid) and then increasing gradually to 80% ethyl acetate in hexanes After tic analysis, fractions were pooled and evaporated to yield 24 mg (55.8%) of an off-white, powder as an acetate salt: APCI-MS m/e calcd for C31H30N2O6 (M+H) 527.6, found 527; H NMR (300 MHz) compatible.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH:26][S@@](C(C)(C)C)=O)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl.O1CCOCC1>C1COCC1>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH2:26])[C:22]([CH3:24])([CH3:23])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@@H](N[S@](=O)C(C)(C)C)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of (R)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (53 mg, 0.111 mmol) in THF (200 μL) was added MeOH (55.6 μL) and 4 M HCl in dioxane (55.6 μL, 0.222 mmol). The reaction mixture was stirred at room temperature for 1 h. After quenched with saturated Na2CO3 solution and diluted with EtOAc, the reaction mixture was stirred for 15 min and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude (R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropan-1-amine was obtained in 99% yield (41 mg), which was used for the next step without further purification (a major side product, methyl 2-methylpropane-2-sulfinate, was completely removed under high vacuum). 1H NMR (CDCl3, 400 MHz): δ 7.96 (1H, m), 7.35-7.29 (2H, m), 7.28-7.22 (3H, m), 7.08 (1H, m), 7.0 (1H, m), 4.18 (2H, m), 3.8 (1H, s), 1.73 (2H, bs), 1.02 (9H, s). LC/MS (uplc): MH+ 356.2, 1.08 min.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:27][N:28]([CH3:33])[CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:27][N:28]([CH3:33])[CH2:29][C:30]([CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)=[O:31]
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 8 h

Procedure:
To 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 37 mg, 0.1 mmol) and N,N-dimethylglycine hydrochloride (14 mg, 0.1 mmol) in THF (7 mL) was added triethylamine (50 mg, 0.5 mmol), and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU; 43 mg, 0.1 mmol). The resulting mixture was stirred overnight, then partitioned between ethyl acetate and water. The organic phase was washed sequentially with NaHCO3 and brine, then dried and concentrated. The residue was purified by reverse-phase chromatography (acetonitrile/water/trifluoroacetic add) to yield 2-(dimethylamino)-1-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)ethanone.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][NH2:9].[OH-].[Na+]>>[CH3:8][NH:9][C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7]
Reactant: CN
Reactant: C1CCC2OC2C1
Agent: [Na+]
Agent: [OH-]
Product: CN[C@@H]1CCCC[C@H]1O
Reaction time: 1.5 h

Procedure:
Cyclohexene oxide (202 mL, 2 mol) was added dropwise to aqueous methyl amine (466 mL or 40% solution, 6 mol) over 70 minutes. After a further 90 minutes, the temperature of the reaction mixture was 48° C. and was reduced to 30° C. by cooling in a water bath. After a further 2 hours, the mixture had returned to room temperature. It was stirred overnight, and then refluxed for 3 h. The mixture was saturated with sodium hydroxide (cooled during addition), extracted several times with diethyl ether (total 500 mL), the diethyl ether layer dried over sodium sulphate overnight, and the diethyl ether removed on a rotary evaporator. The remaining diethyl ether and cyclohexene oxide were removed by partial vacuum distillation. Distillation under full vacuum yielded a colorless fraction boiling at 95° C., (±)-trans-2-(methylamino)cyclohexanol: 217 g (84%).
Reaction SMILES: C([O:5][C:6](=[O:24])[NH:7][C:8]1([C:12](=[O:23])[NH:13][C:14]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:16][CH2:15]2)[CH2:11][O:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:6]([OH:24])=[O:5].[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1([NH:13][C:12]([C:8]2([NH2:7])[CH2:11][O:10][CH2:9]2)=[O:23])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC2(c3ccccn3)CC2)COC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(C(=O)NC2(c3ccccn3)CC2)COC1
Product: O=CO
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.9 %

Procedure:
To a solution of [3-(1-pyridin-2-yl-cyclopropylcarbamoyl)-oxetan-3-yl]-carbamic acid tert-butyl ester (100 mg, 0.30 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL). The solution was stirred at room temperature for 17 h and then concentrated in vacuo. The residue was purified by reverse phase HPLC to give 3-amino-oxetane-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)-amide formate as a white powder (72 mg, 86%) after lyophilization, m/z 234 (free base) [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12]Cl)=[O:11].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11]
Reactant: C1CNCCN1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1

Procedure:
The crude [(2,6-dimethylphenyl)aminocarbonylmethyl]chloride, prepared in Preparation B (50 g, 0.25 mole) and piperazine (86 g, 1 mole) are dissolved in 500 ml of ethanol. The mixture is refluxed for two hours, and then cooled and evaporated. The product is harvested by adding aqueous ammonia to the residue, and extracting with methylene chloride. Three portions of methylene chloride are used, which are collected, washed with water, and evaporated to a semi-solid. Upon addition of ether, the product crystallizes and is filtered. The resulting crude mixture is boiled with ether and then evaporated to a residue and triturated with hexane to yield pure material, 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine. This material is of sufficient purity for use in Reaction Sequences 2 or 4.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Cl[CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14]>CN(C)C=O>[C:1]([O:4][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=CCCl)CCOC(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCC=C(C)CCOC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 450 g (4.6 mols) of potassium acetate and 637 g (3.6 mols) of 1-chloro-5-isopropoxy-3-methyl-2-pentene in 3000 cc of dimethylformamide is stirred at room temperature for 24 hours and then at 50°C for 4 hours. The reaction mixture is filtered, and solvent is distilled off at 1.4 mm Hg and the residue is fractionally distilled. A cis/trans mixture of 1-acetoxy-5-isopropoxy-3-methyl-2-pentene is obtained. B.P.: 122°-126° /18 mm Hg.