Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]1=[S:24].[I:25]I>C1COCC1.[Cl-].[NH4+]>[I:25][C:22]1[N:17]([CH2:16][CH2:15][O:14][CH3:13])[C:18](=[S:24])[NH:19][C:20](=[O:23])[CH:21]=1
Reactant: COCCn1ccc(=O)[nH]c1=S
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCCn1c(I)cc(=O)[nH]c1=S
Temperature: -20 °C
Reaction time: 20 h
Yield: 108 %

Procedure:
To a stirring solution of diisopropylamine (8.3 mL, 59.10 mmol) in THF (50 mL) was added n-butyl lithium (2N in hexanes, 30.0 mL, 60.0 mmol) dropwise at −78° C. under argon. The reaction mixture was slowly warmed to −20° C. and then cooled to −78° C. A solution of 1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (5.0 g, 26.85 mmol) in THF (50 mL) was added dropwise at −78° C. The reaction mixture was slowly warmed to −10° C. over 1 hour and then cooled to −78° C. A solution of iodine (15.0 g, 59.07 mmol) in THF (50 mL) was added at −78° C. and the reaction mixture was stirred at room temperature for 20 hours. Reaction was diluted with saturated aqueous ammonium chloride (200 mL) and the organic solvents were removed under reduced pressure. The aqueous residue was acidified to pH 4 with 1N aqueous HCl and extracted with CH2Cl2 (3×300 mL, 1×200 mL). The combined organic layers were washed with 10% aqueous sodium thiosulfate solution (400 mL), brine (300 mL), dried over MgSO4 and concentrated in vacuo. The resulting residue was stirred in CH2Cl2 at room temperature and solids were collected by filtration to give the title compound (9.05 g, 54%) as a pale brown solid. The filtrate was concentrated and purified by flash chromatography (0-25% CH2Cl2/EtOAc) to afford a second batch of the title compound (3.10 g, 18%) as a cream colored solid (72% combined yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].B(F)(F)F.CCOCC.[CH:21]([C:23]1(O)[CH2:26][CH2:25][CH2:24]1)=[CH2:22]>O1CCOCC1>[C:23]1(=[CH:21][CH2:22][C:8]2[C:6]([C:5]([CH3:9])=[C:4]([CH3:10])[C:3](=[O:11])[C:2]=2[CH3:1])=[O:7])[CH2:26][CH2:25][CH2:24]1
Reactant: C=CC1(O)CCC1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC1=C(C)C(=O)C(CC=C2CCC2)=C(C)C1=O
Yield: 46.3 %

Procedure:
To a solution of trimethyl hydroquinone (3 g) in 100 mL dioxane at room temperature, was added BF3.Et2O (4.26 g). While stirring, a solution of 1-vinylcyclobutanol (1.96 g) in 20 mL dioxane was added dropwise to the mixture. The reaction was stirred for 1 h and quenched by pouring onto ice (50 g). The aqueous layer was saturated with NaCl and extracted with 3:1 hexane/EtOAc. The combined organic phase was washed with brine and NaHCO3 solution, concentrated and diluted with EtOH (30 mL). 10% FeCl3 aqueous solution (40 mL) was added to the solution and the mixture was stirred for 2 h at room temperature. The mixture was diluted with hexane/EtOAc (4:1, 80 mL) and the aqueous layer was saturated with NaCl. After layer separation, the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was chromatographed to afford 2-(2-cyclobutylideneethyl)-3,5,6-trimethylbenzo-1,4-quinone (2.1 g). MS m/z=231 (M−OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:10]1[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:12][N:11]=1
Reactant: Fc1ccc(-c2[nH]ncc2-c2ccncc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2[nH]nc(Br)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
5-(4-Fluorophenyl)-4-(pyridin-4-yl)pyrazole (6.0 g (25 mmol), prepared as described in WO 00/31063) was dissolved in dimethylformamide (60 ml). To the solution was added N-bromosuccinimide (8.93 g, 50 mmol), and the resulting mixture was stirred at room temperature for 3 days. At the end of this time, water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with diethyl ether, to give the title compound (5.73 g) as a white powder (yield 72%).
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH:12]=[CH2:13])[C@@H:5]1[CH2:9][O:8][CH2:7][C@H:6]1O)[CH:2]=[CH2:3].C([N:16](CC)CC)C.CS(Cl)(=O)=O.[OH-].[NH4+]>C(OC)(C)(C)C>[CH2:1]([N:4]([CH2:11][CH:12]=[CH2:13])[C@H:5]1[C@H:6]([NH2:16])[CH2:7][O:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)[C@@H]1COC[C@H]1O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: C=CCN(CC=C)[C@@H]1COC[C@H]1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-(diprop-2-en-1-ylamino)tetrahydrofuran-3-ol (50.0 g, 0.273 mol) in methyl tert-butyl ether was added triethylamine (44.0 g, 0.437 mol) at 5° C. Methanesulfonyl chloride (25.4 mL, 0.327 mol) was added using an addition funnel over a period of 15 min at 5° C. After 30 minutes, triethylamine (55.0 g, 0.546 mol) was added and the reaction was allowed to warm to ambient temperature. Ammonium hydroxide (29% aqueous solution, 700 mL) was then added. After 16 hours, the organic layer was separated, and the aqueous layer was washed with methyl tert-butyl ether (3×250 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford adduct trans-N,N-di(prop-2-en-1-yl)tetrahydrofuran-3,4-diamine. The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:27].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:3]=1[CH:4]=[O:27]
Reactant: N#Cc1c(F)cccc1OCC(F)(F)F
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1c(F)cccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a suspension of 2-fluoro-6-(2,2,2-trifluoroethoxy)benzonitrile (2.3 g, 11 mmol, J. Hetelocyclic Chem. 1988, 25, 1173-1177) in toluene (40 mL) was added diisobutylaluminium hydride (1.0 M in toluene, 11 mL, 11 mmol) at −78° C. The mixture was warmed to room temperature and stirred for 16 h. Methanol (3.0 mL) was added to the mixture and the mixture was stirred for 10 min, then 2N hydrochloric acid (6.0 mL) was added to the mixture. After being stirred at room temperature for 1 h, the mixture was extracted with ethyl acetate (50 mL×2) and washed with aq. sodium hydrogencarbonate. The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a solid. The residual solid was purified by silica gel column chromatography (hexane/ethyl acetate 4:1) to afford 2.2 g (94%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:9][NH:10][C:11](N)=[O:12].C(OCCO)C.S(=O)(=O)(O)O>O>[N:9]1[NH:10][C:11](=[O:12])[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: NNC(N)=O
Reactant: Clc1ccccn1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCCO
Product: O=c1[nH]nc2ccccn12
Reaction time: 0.5 h

Procedure:
A mixture of 50 g. (0.44 mole) of 2-chloropyridine and 98.22 g. (0.88 mole) of semicarbazide hydrocloride in 150 ml. of 2-ethoxyethanol was heated to reflux and then treated with a solution of 1 ml. of concentrated sulfuric acid (36 N) in 5 ml. of 2-ethoxyethanol. The resulting solution was refluxed for 18 hr., cooled to about 60°, and treated with 150 ml. of water. The mixture was stirred, cooled to 0°, and kept 0.5 hr. and the solid was collected on a filter. The solid was washed well with water and dried under reduced pressure, to give 35.0 g. (59%) of product, m.p. 230°-231°, which was sufficiently pure to be used for the next step.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH3:18][S:19]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:26][C:25]3[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:29][CH:28]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C=Nc2[nH]nc(Nc3cccc(Cl)c3)c2C(N)=O)cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 4-methylsulphonyl benzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][N:11]1C(=O)C2=CC=CC=C2C1=O.[BrH:22]>>[BrH:22].[BrH:22].[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11]
Reactant: Cc1ncoc1CSCCN1C(=O)c2ccccc2C1=O
Agent: Br
Product: Cc1ncoc1CSCCN

Procedure:
Phthalimidoethanethiol (2 g) was added portionwise with stirring to a solution of sodium ethoxide (prepared from 0.23 g of sodium) in ethanol (20 ml) at 0° under a nitrogen atmosphere. After stirring at 0° for a further 21/2 hours, the resulting yellow solution was cooled with an ice-salt bath and a solution of 4-methyl-5-chloromethyloxazole (0.86 g) in ethanol (5 ml) was added dropwise over 10 minutes. After addition the mixture was stirred at room temperature overnight, then acidified with ethanolic hydrogen chloride and evaporated to dryness. Addition of water precipitated unreacted phthalimidoethanethiol (0.6 g) which was removed by filtration. The filtrate was concentrated and basified with aqueous sodium bicarbonate solution to furnish a white precipitate which, on recrystallisation from aqueous ethanol, gave 4-methyl-5-[(2-phthalimidoethyl)thiomethyl]oxazole (0.75 g). A stirred mixture of this phthalimide derivative (0.62 g) in aqueous hydrobromic acid (40 ml. 18%) was heated under reflux overnight. After cooling to 0°, the resulting clear solution was filtered and the filtrate evaporated to dryness. Recrystallisation of the residue from ethanol gave 4-methyl-5-[(2-aminoethyl)thiomethyl]oxazole dihydrobromide (0.52 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Product: O=C(Cc1cccc(Oc2ccccc2)c1)Nc1ccc2c(cnn2CCN2CCCC2)c1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine and (3-phenoxy-phenyl)-acetic acid were processed as described in Example 17 to provide the title compound. MS (DCI/NH3) MS m/z 441 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.83 (m, 2 H), 1.99 (m, 2 H), 3.04 (m, 2 H), 3.52 (m, 2 H), 3.65 (s, 2 H), 3.71 (q, J=5.61 Hz, 2 H), 4.74 (t, J=6.24 Hz, 2 H), 6.89 (m, 1 H), 7.02 (m, 3 H), 7.14 (m, 2 H), 7.37 (m, 3 H), 7.51 (m, 1 H), 7.68 (m, 1 H), 8.12 (m, 2 H), 9.68 (br s, N H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]CC3C=CC=CC=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].C(O)(=O)C.[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Cn1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cn1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
(5-Benzyloxy-indol-1-yl)-acetic acid ethyl ester (3.49 g, 11.31 mmol) is dissolved in EtOH (50 mL) and glacial acetic acid is added (2.0 mL). Palladium on carbon (20% by wt., 0.700 g) is then added to the homogenous solution, and a hydrogen filled balloon is connected to the round bottom flask. A vacuum is created within the flask until the ethanol began to bubble, and the hydrogen allowed to enter the flask; this procedure is repeated three times, then the reaction is left to stir at room temperature overnight. Upon completion, the reaction is diluted with DCM (200 mL), and water (100 mL) is added. The mixture is filtered through a celite plug and the two phases are separated. The organic layer is washed with brine (2×75 mL), then dried over anhydrous magnesium sulfate, and concentrated to yield the title compound (2.42 g) in 98% yield. The residual acetic acid is removed by flash column chromatography. 1H NMR (DMSO-d6, 400 MHz): δ 1.18 (t, J=7.34 Hz, 3H), 4.12 (q, J=6.85 Hz, 2H), 4.99 (s, 2H), 5.73 (s, 1H), 6.23 (d, J=2.94 Hz, 1H), 6.60 (dd, J1=1.96 Hz, J2=8.80 Hz, 1H), 6.84 (d, J=2.45 Hz, 1H), 7.12 (d, J=8.80 Hz, 1H), 7.19 (d, J=2.94 Hz, 2H); MS (ES, m/z):C12H13NO3: 220.21(M++1), 218.7(M+−1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1)(=[O:19])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:26][CH:23]3[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]3)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCC(C=O)CC1
Reactant: CCCNC1CCc2ccc(Br)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
To a solution of (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (536 mg, 2 mmol) and 1-methanesulfonyl-piperidine-4-carboxaldehyde (458 mg, 2.47 mmol) in dichloroethane (10 mL) was added sodium triacetoxyborohydride (551 mg, 2.6 mmol) in a single portion. The reaction was stirred at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (75 mL) and 5% aq. KOH (75 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amine (857 mg) 111 [M+H]+=444.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]([CH3:15])[CH2:10][CH2:11][C:12](Br)(Br)[C:5]2=[N:4][CH:3]=1.CS(C)=O.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]([CH3:15])[CH2:10][CH2:11][C:12](=[N:27][NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]2=[N:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: CC1CCC(Br)(Br)c2ncc(Br)c(=O)n21
Solvent: CS(C)=O
Solvent: O
Product: CC1CCC(=NNc2ccccc2)c2ncc(Br)c(=O)n21
Reaction time: 72 h
Yield: 34.7 %

Procedure:
4.0 g. (0.01 moles) of 3,9,9-tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one are dissolved in 10 ml. of dimethyl sulfoxide. To the solution 2.8 ml. (0.03 moles) of phenylhydrazine are added. The reaction mixture is allowed to stand for three days whereupon 20 ml. of water are added. The solvent is decanted from the precipitated substance and the product is recrystallized from methanol. 1.3 g. (34.7%) of 3-bromo-9-(phenylhydrazono)-6-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one are obtained, melting at 190° to 192° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCc1cccnc1)c1ccc(Br)cc1
Yield: 94.1 %

Procedure:
According to the procedure described for example 26a the use of 4-bromo-benzenesulfonyl chloride (1.278 g, 5.0 mmol) in 10 mL dichloromethane and C-Pyridin-3-yl-methylamine (541 mg, 5.0 mmol) and triethylamine (708 μL, 5.0 mmol) in 5 mL dichloromethane gives 4-bromo-N-pyridin-3-ylmethyl-benzenesulfonamide (1.54 g) as a pale yellow oil which slowly crystallizes upon storage at ambient temperature. Further purification is not necessary. MS (m/e): 328 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:16](O)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[NH3:32].Cl>C1COCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:16](=[O:17])[NH2:32])([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C[C@@](NC(=O)OC(C)(C)C)(C(=O)O)C(=O)OCC
Reactant: N
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@](NC(=O)OC(C)(C)C)(C(N)=O)C(=O)OCC
Yield: 73 %

Procedure:
A solution of (R)-1-ethyl hydrogen 3-t-butyloxycarbonylamino-3-ethoxycarbonylsuccinate (1.0 g) obtained in Example 14 in THF (20 mL) was added with triethylamine (0.62 mL) and isobutyl chloroformate (0.55 mL, 0.57 g) in this order at −15° C. with stirring, and the mixture was stirred for 30 minutes. A solution of 25% aqueous ammonia (0.30 mL) was dropped into the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 30 minutes, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and then the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then crystallized from ethyl acetate/n-hexane to obtain the title compound (0.67 g, yield: 73%) as colorless crystals. Optical rotation [α]D22 was +2.74° (c 0.50, ethanol).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][NH:17][CH2:18]2.C(N(CC)CC)C.[S:30](Cl)([Cl:33])(=[O:32])=[O:31]>C(Cl)Cl>[Br:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][N:17]([S:30]([Cl:33])(=[O:32])=[O:31])[CH2:18]2
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(F)(F)c1ccc(-c2cccc3c2CCNC3)c(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cl)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
A 15-mL round-bottom flask was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 287.2 mg, 0.731 mmol) and triethylamine (224 μl, 1.609 mmol) in DCM (3.8 mL) to give a brown solution. The flask was cooled in an ice-bath for 10 min, then sulfuryl chloride (125 μl, 1.536 mmol) was added dropwise. Stirring was continued for 2 hours at which time the mixture was quenched with water, then extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on a 40 g silica gel column with 0 to 40% EtOAc/Heptane to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (253.01 mg, 0.556 mmol) as a clear, very viscous oil that was immediately used in the next step. A vial was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (40.045 mg, 0.088 mmol), pyrimidin-4-amine (41.9 mg, 0.440 mmol), chloroform (587 μl), and pyridine (71.2 μl, 0.881 mmol) and was placed into a 50° C. bath. The mixture was heated overnight before being allowed to cool to rt. The mixture was concentrated under a vacuum, and the residue was chromatographed on a 12 g silica gel column with 0 to 6% MeOH/DCM to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (29.77 mg, 0.058 mmol) as a yellow solid. [M+H]+=513.0. 1H NMR (400 MHz, DMSO-d6) δ ppm=9.55 (br. s., 1H), 9.07 (br. s., 1H), 8.57 (br. s., 1H), 8.13 (d, J=1.3 Hz, 1H), 7.99 (br. s., 1H), 7.83 (dd, J=1.1, 8.0 Hz, 1H), 7.55-7.44 (m, 1H), 7.35-7.21 (m, 2H), 7.02 (dd, J=2.0, 6.8 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.32-4.17 (m, 2H), 3.24-3.07 (m, 2H), 2.45 (br. s., 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O[C@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a mixture of (S)-tetrahydrofuran-3-ol (1 g, 11.4 mmol) and triethylamine (TEA) (2.3 g, 22.8 mmole) in dichloromethane (DCM) (20 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (2.2 g, 11.4 mmole). The resulting mixture was stirred at room temperature for 8 h. The mixture was washed with water, dried over MgSO4, filtered, and concentrated. The crude product was purified by ISCO (silica gel, 15% ethyl acetate in hexane) to give the title compound (2.5 g). MS (ESI) m/z: Found: 243.3 (M++1). Calc. 242.3 (M+).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[O:15][C:10]3=[C:9](O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=[C:11]2[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[O:15][C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccccc2)nc2c1oc1ccccc12
Product: Clc1cc(-c2ccccc2)nc2c1oc1ccccc12
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
1D (53.6 mmol) was added to POCl3 (90 mL), heated to dissolve and stirred at 110° C. for 2.5 hours. TLC showed the reaction completed. POCl3 was evaporated under reduced pressure. The residue was cooled and poured into ice-water under stirring. The solids were collected by filtration and dried to give the desired product M1 (11.5 g).
Reaction SMILES: Cl[N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH2:16]([CH2:18][NH2:19])[OH:17]>O1CCOCC1>[OH:17][CH2:16][CH2:18][NH:19][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(Cl)S1
Reactant: NCCO
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCCO)S1

Procedure:
A mixture consisting of 4.9 gm., 0.02 mole, of 2-(2-chloro-5-thiadiazolyl)-1-methyl-5-nitroimidazole, 3.0 gm., 0.05 mole, of ethanolamine, and 50 ml. of p-dioxane is stirred at room temperature for twenty-four hours. The precipitate is collected, washed with aqueous sodium bicarbonate solution, dried and recrystallized from methanol to give the pure compound melting at 208°-209° C. Working up the mother liquors gives additional material, the total yield being 3.4 gm.