Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[SH:19]>>[Br:10][C:4]1[S:3][C:2]([S:19][C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc(Br)sc1Br
Product: O=[N+]([O-])c1cc(Br)sc1Sc1ccc(Cl)cc1Cl

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 2,5-dibromo-3-nitro-thiophene (1.4 g, 4.9 mmol) and 2,4-dichlorobenzenethiol (0.877 g, 4.9 mmol). The title compound was obtained as a solid (0.56 g, 30% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.61 (1H, s), 8.11 (1H, m), 8.03 (1H, m), 7.76 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Br[CH2:25][C:26]([NH2:28])=[O:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:25][C:26]([NH2:28])=[O:27])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Reactant: NC(=O)CBr
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCC(N)=O)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 120 from 4-[2-(2,4-dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 100 mg) and 2-bromo-acetamide (45 mg). MS (m/e)=423.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]1[NH:4][C:5](=[O:21])[C:6]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8][C:7]=2[N:20]=1.F[B-](F)(F)F.[CH3:34][O+](C)C>>[F:1][C:2]([F:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]1[N:4]=[C:5]([O:21][CH3:34])[C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[N:20]=1
Reactant: C[O+](C)C
Reactant: CC(C)(C)OC(=O)N1CCc2nc(C(F)(F)c3ccccc3)[nH]c(=O)c2CC1
Agent: F[B-](F)(F)F
Product: COc1nc(C(F)(F)c2ccccc2)nc2c1CCNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-[difluoro(phenyl)methyl]-4-oxo-3,4,5,6,8,9-hexahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate of Preparation 8, Step A (535 mg, 1.37 mmol) was added trimethyloxonium tetrafluoroborate (3 eq, 606 mgs 4.10 mmol) and the reaction mixture was stirred overnight at room temperature, after which time an orange solid had precipitated. The reaction mixture was quenched with saturated NaHCO3 (aq) and stirred rapidly until a complete solution was attained. The organic layer was collected, dried over MgSO4, filtered and dried in vacuo to give a brown oil. This material was chromatographed on silica, eluting with ethyl acetate/10% methanol, then dichloromethane/methanol/ammonia, 95/5/0.5. The relevant fractions were combined and evaporated in vacuo to give a coloured oil (quantitative yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH2:42](N)[CH2:43]CC.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:36]([NH:35][CH2:34][CH2:33][N:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])[CH2:14][CH2:15]2)[CH:29]=[N:30]1)[CH2:37][CH2:42][CH3:43]
Reactant: CCCCN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCO
Product: CCCCNCCn1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cn1
Yield: 26 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting 1-butanamine (31 mg, 0.43 mmol) for the 2-aminoethanol to afford 7 mg of the title compound (26%).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:9]([C:10]([NH:12][C:13]2[CH:14]=[C:15]3[CH:21]=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[O:11])[CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:22]1[CH:23]=[CH:24][C:7]([C:6]([OH:26])=[O:5])=[CH:8][C:9]=1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20][NH:19][C:16]2=[N:17][CH:18]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To 45 mg 4-Chloro-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)-isophthalamic acid tert-butyl ester in 1 ml dichloromethane were added 1 ml trifluoroacetic acid at room temperature. Stirring was continued for 2 hrs and the mixture was evaporated under vacuum to give 28 mg of the title product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]4[N:26]=[C:27]([NH:29][C:30]([CH:32]5[CH2:34][CH2:33]5)=[O:31])[N:28]=[C:24]4[CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:25]4[N:26]=[C:27]([NH:29][C:30]([CH:32]5[CH2:33][CH2:34]5)=[O:31])[N:28]=[C:24]4[CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2cccc(-c3ccc(N4CCNCC4)cc3)n2n1)C1CC1

Procedure:
A solution of 4-{4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (0.042 g, 0.091 mmol) in trifluoroacetic acid (2 mL) was stirred for 2 h. Saturated sodium hydrogen carbonate was then added and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. After filtration and concentration under reduced pressure the crude product was purified by preparatory HPLC. LCMS method: 2, RT: 1.97 min; MI: 363 [M+1]. NMR 1H (DMSO) 0.79-0.82 (m, 4H), 1.05 (s, 1H), 2.01 (brs, 1H), 3.10-3.16 (m, 4H), 3.38-3.43 (m, 4H), 7.10 (d, 2H), 7.24 (dd, 1H), 7.58 (dd, 1H), 7.65 (t, 1H), 7.99 (d, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CCCCCC>[CH:7]1([NH:13][C:14]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C=NC1CCCCC1
Reactant: C1CCNCC1
Solvent: CCCCCC
Product: O=C(NC1CCCCC1)N1CCCCC1
Yield: 98.3 %

Procedure:
A solution of 18.62 g of piperidine (0.219 mol) in 360 ml of hexane is admixed dropwise with 23.8 g of cyclohexyl isocyanate (0.190 mol) and then the cloudy mixture is heated at reflux for 2 hours, after which it is cooled and filtered to give 39.3 g of pure N-cyclohexylpiperidine-1-carboxamide (98.3% yield). A suspension of 15.05 g of this pure product (71.6 mmol) in 65 ml of dry toluene is admixed with 12 g of POCl3 (78 mmol) over 1 hour, and then, after a number of hours at 20° C., 18.1 g of N-butyl-N-ethylamine (0.179 mmol) are added over 2 hours, and then, after a further 2 hours at 20° C., 50 ml of water are added. 49 g of 35% sodium hydroxide solution are then added with cooling, after which the two-phase mixture is extracted with diisopropyl ether. Following drying and evaporation to dryness, the oil obtained, 20 g, is distilled at 185° C. under 1 mbar to give 17 g of the expected guanidine (81% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([Cl:11])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:36][C:35]3[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([NH2:31])=[O:30])[C:27]=3[N:26]=2)=[C:4]([Cl:11])[CH:3]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(Br)cc3Cl)nc12
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To 4-bromo-2-chlorobenzoic acid (2.48 g) in pyridine (12 mL) and DMF (12 mL) was added CDI (1.88 g). The solution was stirred at 45° C. for 2 hours, cooled, treated with 2,3-diaminobenzamide dihydrochloride (2.36 g), stirred at ambient temperature for 18 hours, and concentrated. The concentrate was partitioned between ethyl acetate (70 mL) and water (100 mL) and filtered. The filtrant was washed with water and ethyl acetate and dried. This solid was suspended in acetic acid (40 mL) and the mixture was heated at 125° C. for 4 hours and filtered. The filtrate was cooled to ambient temperature and filtered. The filtrant was washed with methanol and dried to give the first batch of product. The mother liquor was concentrated and the concentrate was treated with dichloromethane and filtered to provide a second batch of solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[CH2:10][C:11]1[NH:12][C:13](=[O:21])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.[OH-].[Na+]>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[CH2:10][C:11]1[NH:12][C:13](=[O:21])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: COc1cccc(Cc2cc3ccccc3c(=O)[nH]2)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=c1[nH]c(Cc2cccc(O)c2)cc2ccccc12
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A solution of boron tribromide in dichloromethane (1M; 8.5 ml, 8.5 mmol) was added dropwise under nitrogen to an ice-cooled, stirred suspension of 3-(3-methoxybenzyl) isoquinolinone (1 g, 3.8 mmol) in dichloromethane (5 ml), the stirred mixture was heated under reflux for 6 hours, then it was cooled to ambient temperature and poured onto 10% aqueous sodium hydroxide solution (30 ml). The basic solution was washed with dichloromethane (3×50 ml), then it was acidified by the addition of concentrated hydrochloric acid. The product was extracted into ethyl acetate (3×50 ml), the combined extracts were dried (MgSO4) and the solvent was removed in vacuo to leave 3-(3-hydroxybenzyl)isoquinolinone (0.4 g, 42%) as a white solid; m.pt. 225-227° C.; δH 3.80 (2H, s), 6.35 (1H, s), 6.60-7.70 (7H, m), 8.10 (1H, d), 9.30 (1H, s), 11.20 (1H, br s); m/z (M+H)+. 252 (100% purity).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:13][C:14]([C:16]([CH3:18])=[CH2:17])=[CH2:15]>C(#N)C>[CH3:13][C:14]1[CH2:15][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[O:11][CH2:17][C:16]=1[CH3:18]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: C=C(C)C(=C)C
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)CC(C)=C(C)CO1
Yield: 325.8 %

Procedure:
Part A. The method of Bonjouklian and Ruden, J. Org. Chem., v. 42, p. 4095 (1977), was used here. Thus, a solution of diethylketomalonate (10.0 mL, 65.6 mmol) and 2,3-dimethyl-1,3-butadiene (16.3 mmol, 144 mmol) in acetonitrile (22 mL) was heated in a sealed tube at 140° C. for 6 hours. The contents of the tube was cooled, extracted with methylene chloride washing, evaporated and separated by flash chromatography (1:9 ethyl acetate-hexane) to afford diethyl 3,6-dihydro-4,5-dimethyl-2H-pyran-2,2-dicarboxylate as an oil (13.6 g, 53.1 mmol, 81%). 1H NMR (CDCl3): δ 4.26 (4H, q, J=7.0 Hz); 4.15 (2H, br s); 2.57 (2H, br s); 1.69 (3H, s); 1.51 (3H, s); 1.28 (6H, t, J=7.0 Hz). Mass spectrum (NH3 -CI/DDIP): m/z 275 (14%); 274 (100%); 257 (23%); 183 (1%).
Reaction SMILES: P(Cl)(OCC)(OCC)=O.C([O:13][C:14]1[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([OH:22])=O)=[CH:16][C:15]=1[O:25][CH3:26])(=O)C.[CH3:27][N:28]([CH3:41])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C1C=CN=CC=1.CO.C(Cl)Cl.C(N(CC)CC)C>[CH3:41][N:28]([CH3:27])[CH2:29][CH2:30][CH2:31][CH2:32][N:33]([C@H:34]1[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]1)[C:20](=[O:22])[CH:19]=[CH:18][C:17]1[CH:23]=[CH:24][C:14]([OH:13])=[C:15]([O:25][CH3:26])[CH:16]=1
Reactant: CN(C)CCCCN[C@H]1CC[C@H](C)CC1
Reactant: COc1cc(C=CC(=O)O)ccc1OC(C)=O
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C=CC(=O)N(CCCCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture solution of 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 2.3 g of 4-acetoxy-3-methoxycinnamic acid, and 100 ml of methylene chloride was stirred for 1 hour at room temperature. Next, 3.5 ml of N-(4-dimethylaminobutyl)-trans-4-methylcyclohexylamine (Example 74) and 0.5 g of 4-dimethylaminopyridine were added to the solution under ice-cooling. The solution was stirred further for 4 hours at room temperature. Then, 100 ml of methanol and 5 g of potassium carbonate were added to the solution, and the solution was stirred for 1.5 hours at room temperature. After stirring, the reaction solution was neutralized with 2N hydrochloric acid under ice-cooling. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed twice with an aqueous sodium hydrogencarbonate solution and twice with aqueous sodium chloride solution, and was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/either, yielding 1.7 g of N-(4-dimethylaminobutyl)-N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (a compound of the present this invention) as a pale yellow oily oil, which had the following physiochemical properties:
Reaction SMILES: [OH:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=O)[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.O>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[S:32])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=S)CC[C@@H]12
Yield: 35.9 %

Procedure:
A solution of 1.09 g (3.63 mmol) of 3-hydroxy-2-methoxy-estra-1,3,5(10)-trien-17-one in 60 ml of toluene (abs.) was mixed with 3.7 g of Lawesson's reagent, and it was refluxed for four hours. After water was added, it was extracted with dichloromethane (3×), and the combined organic phases were washed with water, dried on sodium sulfate, and concentrated by evaporation in a rotary evaporator. Flash chromatography (n-hexane/ethyl acetate) yielded 412 mg (36%) of the desired product as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6]2.CN(C)[CH:16]=[O:17]>CCCCCC>[CH3:12][C:8]1([CH3:13])[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([CH:16]=[O:17])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)CCC2(C)C
Solvent: CCCCCC
Product: COc1cc2c(cc1C=O)C(C)(C)CC2
Temperature: 100 °C
Yield: 39.7 %

Procedure:
To a mixture of 10.60 g (60.0 mmol) of 5-methoxy-1,1-dimethylindane (see U.K. Patent Application No. GB 2,067,195 A for a method of obtaining this compound) and 6.5 g (90.0 mmol) of dimethylformamide was added 11.5 g (75.0 mmol) of phosphorous oxytrichloride. The mixture was heated at 100° C. for 5 h. The reaction mixture was cooled to ambient temperature and poured onto 100 g of ice. The aqueous residue was extracted with ether. The organic phase was washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on silica gel (70 g) using a gradient from hexane to 2:98 (v/v) ether:hexane as eluent, There was obtained 4.86 g (23.8 mmol, 40%) of 1,1-dimethyl-5-methoxyindan-6-carboxaldehyde as a white solid after crystallization from hexane mp 51°-52° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH2:8][CH2:7]1)=O.S(C)C>C1COCC1>[F:1][C:2]([F:19])([F:20])[CH2:3][NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)CC2
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)c1ccc2c(c1)[C@H](NCC(F)(F)F)CC2
Yield: 43 %

Procedure:
To a cooled (0° C.) solution of (R)-methyl 3-(2,2,2-trifluoroacetamido)-2,3-dihydro-1H-indene-5-carboxylate (1.8 g, 6.27 mmol, 1.0 eq.) in THF (30 ml) is added BH3.Me2S (0.9 ml, 9.4 mmol, 1.5 eq.) drop wise and the reaction mixture is heated at reflux for 2 h. The reaction mixture is then quenched with MeOH (0.5 ml) and then partitioned between water (30 ml) and ethyl acetate (100 ml). The organic layer is washed with brine (30 ml), dried over anhydrous Na2SO4 and evaporated to get the crude which is purified by column chromatography (silica gel; 4% ethyl acetate/hexanes) to yield the desired compound as a colourless oil. Yield: 43% (730 mg, 2.67 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([NH:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])(=[O:13])=[O:12])=[C:7]([CH3:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CO.[C:27](N1C=CN=C1)(N1C=CN=C1)=O>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([NH:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([O:20][CH3:27])=[O:19])(=[O:12])=[O:13])=[C:7]([CH3:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2c(Cl)cccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3c(Cl)cccc3c2C)c1
Yield: 74 %

Procedure:
The product was prepared from 3-{[(7-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (9.2 mg, 0.024 mmol) (Example 44) and MeOH (50 μL, 1.23 mmol) according to the General Procedure 8, described in Example 119, using a different amount of 1,1′-carbonyldiimidazole (10.0 mg, 0.0621 mmol). The title compound was obtained in 74% yield (7.0 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.46 (s, 3 H) 3.87 (s, 3 H) 6.79 (s, 1 H) 7.37 (dd, J=8.06, 7.70 Hz, 1 H) 7.41 (dd, J=8.06, 7.69 Hz, 1 H) 7.43 (ddd, J=8.06, 2.32, 1.21 Hz, 1 H) 7.48 (dd, J=7.69, 0.98 Hz, 1 H) 7.65 (dd, J=8.06, 0.98 Hz, 1 H) 7.74 (dd, J=2.32, 1.51 Hz, 1 H) 7.84 (ddd, J=7.70, 1.51, 1.21 Hz, 1 H). MS (ESI+) m/z 396 [M+H]+.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][C:18]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:19][C:4]=2[S:3]1.ClC1C=CC=C(C(OO)=[O:33])C=1.C(O)(=O)C(O)=O.C([O-])(=O)C([O-])=O>O.O1CCOCC1.CC(C)=O>[NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)=[O:33])[C:5]2[CH:16]=[CH:17][C:18]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:19][C:4]=2[S:3]1
Reactant: N=c1sc2cc(OC(F)(F)F)ccc2n1CCSc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])C(=O)[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCS(=O)c1ccncc1
Yield: 59 %

Procedure:
The procedure is as in Example 8, starting with 2-imino-3-[2-(4-pyridylthio)ethyl]-6-trifluoromethoxybenzothiazoline (2 g) and meta-chloroperbenzoic acid (90 pure by weight) (0.68 g) dissolved in water (25 cc) and dioxane (25 cc). The reaction mixture is stirred for 12 hours at 25.C and then concentrated to dryness at 40.C under reduced pressure (20 mm Hg; 2.7 KPa) to remove the dioxane. The aqueous solution is taken to a pH of 12-13 with concentrated ammonia solution (l0N) and then extracted with dichloromethane (2×50 cc). The organic phase is dried over anhydrous magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The oil thereby obtained is purified by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bars), with a mixture of ethyl acetate and methanol (90:10 by volume) as eluent. An oil is thereby isolated, which oil, when treated with oxalic acid (0.25 g) and acetone (5 cc), gives 2-imino-3-[2-(4-pyridylsulphinyl)ethyl]-6trifluoromethoxybenzothiazoline (0.9 g) directly in the form of an oxalate, m.p. 194° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22]O)=[C:14]([Br:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][Br:45])=[C:14]([Br:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CO)nc3N21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CBr)nc3N21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.400 g (4R,9aR)-7-bromo-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 21 step 1) in 5 ml dichloromethane was added at room temperature 0.4 g triphenylphosphine and carbontetrabromide and the mixture was stirred at room temperature for 30 min. The red-orange solution was purified by chromatography on silica gel with heptane:ethyl acetate=1:1. The product fractions were collected and evaporated. The resulting oil (showing crystal seeds) was triturated with hexane. The crystalline solid was collected and dried to constant weight to yield 0.307 g of the title compound (MS: 406.1; 404.2 (M+H+)).
Reaction SMILES: Cl.C(N1CC2CC1CN2C(=O)N(CC)CC)C1C=CC=CC=1.I.I.[CH2:25]([N:32]1[CH2:37][CH:36]2[CH2:38][CH:33]1[CH2:34][NH:35]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[CH2:25]([N:32]1[CH2:37][CH:36]2[CH2:38][CH:33]1[CH2:34][N:35]2[C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Agent: CCN(CC)C(=O)N1CC2CC1CN2Cc1ccccc1
Agent: Cl
Agent: I
Product: CCOC(=O)N1CC2CC1CN2Cc1ccccc1
Yield: 68 %

Procedure:
Using the procedure for preparation of 2-benzyl-5-(N,N-diethylcarbamyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride as related in Example 11, 29.0 g of 2-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydroiodide, prepared according to the procedure given in Example 11, was treated with 1.5 equivalents of ethyl chloroformate to yield crude product. Dry column chromatography, a technique described by B. Loev and M. M. Goodman in Chem. Ind. (London), p 2026, 1967, on 1700 g alumina using chloroform development provided 11.6 g (68%) of pure product, characterized as the maleate salt, melting point 124°-128° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C@@H:4]([N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:3]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(N(CC)CC)C>C(Cl)Cl>[C:36]([NH:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C@@H:4]([N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:3]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
Compound 31 (0.10 g, 0.213 mmol) was suspended in DCM (5 ml), and to this was added acetic anhydride (0.047 g, 0.044 ml, 0.469 mmol) and triethylamine (0.065 ml, 0.469 mmol). The mixture was stirred at room temperature for 3 hours. After this time the solvent was evaporated to give a white solid. The product was purified by column chromatography (MeOH/DCM 2%→6%), and evaporation of the solvent gave the title compound as a white solid (0.103 g, 95%).