Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2]CCCN.BrC[CH2:9][CH2:10][C:11]1[C:16]2[C:17]([O:23][CH3:24])=[C:18]([C:20]([NH2:22])=[O:21])[S:19][C:15]=2[CH:14]=[CH:13][CH:12]=1>>[Br:2][CH2:9][CH2:10][C:11]1[C:16]2[C:17]([O:23][CH3:24])=[C:18]([C:20]([NH2:22])=[O:21])[S:19][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: NCCCBr
Reactant: COc1c(C(N)=O)sc2cccc(CCCBr)c12
Agent: Br
Product: COc1c(C(N)=O)sc2cccc(CCBr)c12

Procedure:
Similarly prepared using 3-bromopropylamine hydrobromide was 3-bromopropyl-3-methoxy benzothiophene-2-carboxamide.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:15]=[CH:14][C:11]=1[CH:12]=O.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[Cl:9][C:10]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:15]=[CH:14][C:11]=1[CH2:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=Cc1ccc(OC2CCCCO2)cc1Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 4-iodoaniline (4.618 g, 21.1 mmol) and 2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (5.33 g, 22.1 mmol) in 100 mL methylene chloride was added magnesium sulfate (25.38 g, 211 mmol). The reaction mixture was stirred at room temperature overnight. The magnesium sulfate was filtered off and additional magnesium sulfate (26 g) was added to the filtrate. The reaction mixture was stirred at room temperature for 3 days. The magnesium sulfate was filtered off and additional magnesium sulfate (40 g) was added to the filtrate. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was dissolved in 50 mL of toluene and was heated to reflux for 3 hr., then was stirred at room temperature overnight. The toluene was removed in vacuo and the residue was crystallized from methanol/ethanol/methylene chloride. The crystalline product (9.07 g) was dissolved in 150 mL methylene chloride and 30 mL methanol and was treated with sodium borohydride (3.90 g, 103 mmol) which was added in portions. The reaction was stirred at room temperature overnight at which time saturated aqueous sodium bicarbonate was added. The mixture was extracted with methylene chloride and the organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (1:1 methylene chloride:hexanes) afforded 5.97 g (64%) of the title compound of Step A.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[S:21]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22]1.C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:26]([C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)=[O:27])[N:8]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)c1ccsc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (75 mg, 0.229 mmol), thiophene-3-carbonyl chloride (44.9 mg, 0.306 mmol) and triethylamine (42.5 μl, 0.306 mmol) were combined in CH2Cl2 (4 ml) and stirred 10 min. at 25° C. The reaction was concentrated and chromatographed on silica gel (2% MeOH in CH2Cl2) to give the title compound as a white solid from Et2O: (m.p. 238°-239°).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:22]([O-:25])(=[S:24])[CH3:23].[K+]>CN(C)C=O>[C:22]([S:24][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:25])[CH3:23]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCCC3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCCC3)cs2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (335 mg, 1.01 mmol) (obtained as described in Reference Example 26(3)) in dimethylformamide (15 ml) was added potassium thioacetate (1.10 g, 8.80 mmol) at room temperature, and the reaction mixture was stirred in an oil bath (80° C.) for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-acetylthio-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (235 mg, yield 75%) as a pale brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH:27]([C:28]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccccc1
Product: CC(C)OC(Cc1cccc(CCOC(=O)Nc2ccccc2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[CH:10]1([C:13]#[N:14])[CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: N#CC1CC1
Reactant: Fc1cc(Cl)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC1(c2ncc(Cl)cc2F)CC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of argon, 5-chloro-2,3-difluoropyridine (6 g, 4.17 ml, 40.1 mmol, Eq: 1.00) was combined with toluene (60.0 ml). Then cyclopropanecarbonitrile (2.69 g, 3.02 ml, 40.1 mmol, Eq: 1.00) was added to the solution. At −5° C., potassium bis(trimethylsilyl)amide (80.3 ml, 40.1 mmol, Eq: 1.00) was added dropwise over 30 min. The dark brown reaction was stirred for 1 hour at −5° C., and then for 2 h at room temperature. The reaction mixture was poured into satd. NH4Cl solution (50 ml) and extracted with 2×100 ml ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, from 100% to 50% heptane in ethyl acetate). The title compound was obtained as a orange oil (1.55 g, 13.8%, MS (m/e)=197.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.S(=O)(=O)(O)O.O.[C:17](=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:17])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nccnc1N
Reaction time: 48 h
Yield: 63 %

Procedure:
3-Aminopyrazine-2-carboxylic acid (55.5 g, 0.4 mol) is suspended in 400 mL of methanol, cooled in an ice bath and concentrated sulfuric acid (80 mL) is gradually added with stirring and stirring then continued for 48 hours at room temperature. The resulting dark brown solution is poured into 700 mL of water containing sodium bicarbonate (160 g). The brown crystalline solid which precipitates is collected and dried. The crude product is purified by recrystallization from water to yield the product as yellow needles in 63% yield, melting point 169°-170° C.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].CN1CCCC1=O.[Cl:16][C:17](Cl)=[CH:18][C:19]([CH3:24])([CH3:23])[CH:20]([CH3:22])[CH3:21]>C(Cl)Cl>[Cl:16][CH:17]=[C:18]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:19]([CH3:24])([CH3:23])[CH:20]([CH3:22])[CH3:21]
Reactant: [O-]c1ccccc1
Reactant: CC(C)C(C)(C)C=C(Cl)Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)C(C)(C)C(=CCl)Oc1ccccc1
Temperature: 200 °C
Yield: 70.6 %

Procedure:
487 g of sodium phenolate are introduced into 1.6 liters of N-methylpyrrolidone at about 100° C., and dissolved by heating the mixture to 200° C. 360 g (2 mols) of 1,1-dichloro-3,3,4-trimethyl-pent-1-ene are added dropwise in the course of 3 hours at a rate such that the temperature of the reaction mixture does not fall below 195° C. Thereafter, the mixture is heated at 200°-210° C. for 8 hours. Working-up is carried out by diluting the solution with methylene chloride and extracting it by shaking withh dilute sodium hydroxide solution. After drying and stripping off the solvent, 406 g of crude product remain, this product being distilled at 105°-120° C./0.1 mbar. 337 g (71% of theory) of 1-chloro-2-phenoxy-3,3,4-trimethyl-pent-1-ene are obtained. ##STR18##
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:7]1[N:8]=[C:9]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH2:28][CH3:29])=[C:25]([Cl:27])[N:26]=3)=[O:21])[CH2:16]2)[S:10][C:11]=1[C:12]([OH:14])=[O:13])[CH2:4][CH2:5]C.O>CO.C1COCC1>[Cl:27][C:25]1[N:26]=[C:22]([C:20]([NH:19][CH:17]2[CH2:16][N:15]([C:9]3[S:10][C:11]([C:12]([OH:14])=[O:13])=[C:7]([CH2:3][CH2:4][CH3:5])[N:8]=3)[CH2:18]2)=[O:21])[NH:23][C:24]=1[CH2:28][CH3:29]
Reactant: CCCCc1nc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)sc1C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1nc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)sc1C(=O)O
Reaction time: 18 h
Yield: 36.2 %

Procedure:
A 2 N aqueous lithium hydroxide solution (1.53 mL, 3.07 mmol) was added to a mixed solution of ethyl 4-n-butyl-2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl)]amino}azetidin-1-yl-1,3-thiazole-5-carboxylate obtained in Example (220d) (214 mg, 0.50 mmol) in methanol/THF (3 mL/0.5 mL) at room temperature, followed by stirring for 18 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (2.5 mL) was added to the aqueous layer. The precipitated solid was collected by filtration to obtain 72 mg of the title compound as a white solid (57%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[C:20]([F:26])[CH:19]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][C:20]=2[F:26])[N:3]=1
Reactant: NCc1ccc(Cl)cc1F
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Fc1cc(Cl)ccc1CNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(4-chloro-2-fluorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-chloro-2-fluorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:10](=O)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: O=c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (6.96 g, 25.3 mmol) and phosphoryl chloride (80 mL) according to the general procedure I. Obtained as an off-white solid (7.35 g, 99%). MS (EI) 292.0 [(M)+]; mp 108° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C:4]([CH3:8])=[N:3]1.[F-].[K+].Cl[CH2:12][N:13]1[C:17](=[O:18])[C:16]2[C:19]([CH:25]([CH3:27])[CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[S:14]1(=[O:29])=[O:28]>CN(C=O)C>[CH:25]([C:19]1[C:16]2[C:17](=[O:18])[N:13]([CH2:12][O:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:8])[CH:5]=3)[S:14](=[O:29])(=[O:28])[C:15]=2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=1)([CH3:27])[CH3:26]
Reactant: CC1=NN(C)C(=O)C1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C)nn1C)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.7 %

Procedure:
To a solution of 2,4-dihydro-2,5-dimethyl-3H-pyrazol-3-one (475 mg; 4.24 mmol) in DMF (25 ml) was added 280 mg (4.83 mmol) of KF followed by 2-chloromethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1 g, 3.3 mmol), and the resulting mixture was stirred at room temperature for 24 hours and then was poured into ice/water. The above mixture was extracted with ethyl acetate and the organic layer was washed with water, dried, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.46 g (37%) of 4-isopropyl-6-methoxy-2-(1,3-dimethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =R2 =CH3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 146°-147° C.
Reaction SMILES: O.[C:2]([O:6][C:7](=[O:14])[N:8]([N:12]=O)[CH:9]1[CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].[Cl-].[NH4+]>CO.[Zn]>[C:2]([O:6][C:7]([N:8]([CH:9]1[CH2:10][CH2:11]1)[NH2:12])=[O:14])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(N=O)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(N)C1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
Water (24 mL) was added over 1 min to a mixture of N-nitroso-N-cyclopropyl-carbamic acid tert-butyl ester (2.01 g, 10.8 mmol), zinc powder (7.2 g, 110 mmol) and ammonium chloride (8.8 g, 165 mmol) in methanol (48 mL). An exotherm and gas evolution were noted. The mixture was stirred at room temperature for 2.25 h and at 50° C. for 2 h. The mixture was allowed to cool. It was filtered through Celite, and the Celite was washed well with methanol. The colvents were evaporated and dichloromethane (250 mL) was added. Salts were filtered off and the solution was dried (magnesium sulfate), filtered, and evaporated. The residue was passed through a cotton plug with a small amount of dichloromethane, the solvent was evaporated to give a clear oil. This was purified by chromatography using an ISCO 120 g column, eluting with 10-60% ethyl acetate/hexanes to give N-cyclopropyl-hydrazinecarboxylic acid tert-butyl ester (207 mg, 11%) as a pale yellow oil, along with a 36% yield of over-reduced cyclopropyl-carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:8]2.C[O-].[Na+].CO.[C:33](OCC)(=[O:35])C>CO.CCCCCC>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([O:35][CH3:33])[CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:8]2
Reactant: CCOC(C)=O
Reactant: O=C1c2c(cc(Br)cc2C(F)(F)F)CN1Cc1ccc(OC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1cc2c(c(C(F)(F)F)c1)C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 7-trifluoromethyl-5-bromo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.060 g, 0.15 mmol), and 30% sodium methoxide-methanol (0.21 mL) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-trifluoromethyl-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.043 g, 70%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.88 (s, 3H), 4.25 (s, 2H), 4.76 (s, 2H), 7.02 (s, 1H), 7.17 (d, 2H), 7.28 (s, 1H), 7.37 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[NH:10][C:9]2=O)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[NH:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1NS(=O)(=O)CCC1c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S1(=O)CCC(c2ccc(Br)cc2)CN1
Temperature: 0 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
4-(4-Bromophenyl)-1,1,3-trioxotetrahydro-1,2-thiazine: To a 0° C. solution of 9.0 mL (9.0 mmol) of a 1.0 M tetrahydrofuran solution of potassium tert-butoxide in 15 mL of tetrahydrofuran was added a solution of 1.7 g (4.5 mmol) of material from Step D in 14 mL of tetrahydrofuran dropwise over 30 minutes. After stirring at 0° C. for two hours, the cooling bath was removed and stirring continued for 30 minutes. The mixture was diluted with 25 mL of water and extracted two times with 10 mL each of ethyl ether. The aqueous portion was acidified to pH 2 with 10% aqueous sodium bisulfate and extracted four times with 20 mL each of ethyl acetate. The combined ethyl acetate layers were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (75 g silica gel, 0.25% acetic acid/40% acetone/hexanes) of the residue affords 0.2 g (17%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])=[C:4]([Cl:31])[CH:3]=1.Cl.N1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])=[C:4]([Cl:31])[CH:3]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc(Br)cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccc(Br)cc4Cl)oc23)[C@@H]1CO

Procedure:
Compound of example 99 (0.3 g, 0.59 mmol) was demethylated using pyridine hydrochloride (3 g, 26.0 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[C:23]([F:24])=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([F:25])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[C:23]([F:24])=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:25])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Yield: 49.5 %

Procedure:
To a solution of tert-butyl 4-((5,6-dichloropyridin-3-yl)methoxy)-2,5-difluorobenzoate (Preparation 13, 490 mg, 1.27 mmol) in DCM (5 mL) was added TFA (5 mL). After 30 minutes the reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse phase chromatography eluting with H2O/MeCN/HCOOH (95/5/0.1 to 5/95/0.1, Biotage™ 40 g C18-silica gel) to yield the title compound (210 mg, 50%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[S:26]1[CH2:29][C:28]([CH2:32][NH2:33])([CH2:30][NH2:31])[CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[NH2:31][CH2:30][C:28]1([CH2:32][NH:33][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:29][S:26][CH2:27]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1(CN)CSC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)CSC3)c2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
A flask containing 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (250 mg, 0.67 mmol), thietane-3,3-diyldimethanamine (266 mg, 2.01 mmol), tris(dibenzylideneacetone)dipalladium(0) (61.8 mg, 0.067 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (42 mg, 0.067 mmol), sodium tert-butoxide (160 mg, 1.66 mmol) and toluene (15 mL) was evacuated and then filled with nitrogen (balloon). After being stirred at 110° C. overnight, the resulting mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×4). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography and preparative HPLC to afford 63 mg of the product as a white solid (yield was 20%). MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, CD3OD) δ ppm 7.96-7.94 (m, 1 H), 7.68-7.66 (d, J=7.2 Hz, 1 H), 7.47-7.43 (m, 2 H), 7.31-7.27 (m, 1 H), 7.22-7.21 (d, J=1.6 Hz, 1 H), 7.19 (s, 1 H), 5.88 (s, 1 H), 5.07 (s, 2 H), 4.50 (s, 2 H), 3.55-3.49 (m, 4 H), 3.11 (s, 2 H), 3.06-3.03 (d, J=9.6 Hz, 2 H), 2.94-2.91 (d, J=9.6 Hz, 2 H), 2.31 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14]Br)=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])=[O:4].[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K].O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][N:30]1[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]1=[O:31])=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])=[O:4]
Reactant: COC(=O)c1cc2cc(CBr)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(CN3C(=O)c4ccccc4C3=O)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
1-BOC-5-bromomethyl-7-nitro-indole-2-carboxylic acid methyl ester (4.9 g, 11.4 mmol) prepared in Step B of Preparation 37 was dissolved in N,N-dimethylformamide (50 mL). Potassium phthalimide (2.7 g, 14.8 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. Water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography to give the title compound (3.6 g, Yield 66%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: OCCO
Reactant: O=Cc1occc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Brc1ccoc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
3-Bromo-2-furaldehyde (14.22 g, 81.3 mmol) is combined with ethylene glycol (6.55 mL, 117.4 mmol) and para-toluene sulfonic acid monohydrate (772 mg, 4.06 mmol) in benzene (200 mL) and heated to reflux with a Dean-Stark trap for 5 h. Additional ethylene glycol (1.64 mL, 29.41 mmol) and benzene (150 mL) are added and the solution is heated for an additional 2 h. The mixture is cooled to rt, treated with saturated NaHCO3 and stirred for 0.5 h. The layers are separated and the organics are dried over Na2SO4 and concentrated to a brown oil (18.8 g). The crude material is chromatographed over 700 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 16.45 g (92%) of 2-(3-bromo-2-furyl)-1,3-dioxolane as a yellow-orange oil. MS (EI) m/z: 218 (M+).