Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[C:17]2[O:18][C:19]3[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][OH:31])=[CH:25][C:20]=3[S:21](=[O:24])(=[O:23])[CH2:22][C:16]=2[CH:15]=[C:14]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[C:17]2[O:18][C:19]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]=[O:31])=[CH:25][C:20]=3[S:21](=[O:23])(=[O:24])[CH2:22][C:16]=2[CH:15]=[C:14]([N:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]2)[CH:13]=1
Reactant: Cc1cc(CO)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
DMSO (2.6 mL, 37.5 mmol) was added at −70° C. to a solution of oxalyl chloride (0.46 mL, 37.5 mmol) in dichloromethane (10 mL). Reaction mixture was stirred for 5 minutes and to this (4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cyclohepten-8-yl)-methanol (0.489 g, 1.19 mmol) [obtained by following the procedure described in Example 34] in dichloromethane (5 mL) was added. Reaction mixture was stirred for 5 minutes and to this triethylamine (8.4 mL, 62.5 mmol) was added. Reaction mixture was warmed to room temperature (22° C.) and stirred for 0.5 h. the reaction mixture was diluted with dichloromethane (200 mL), washed with water (100 mL), brine (50 mL) and dried over sodium sulphate. The crude product obtained was purified by column chromatography (silica gel, ethylacetate-pet ether) to obtain the title compound. Yield: 0.2 g (42%); 1H NMR (DMSO-d6, 300 MHz): δ 2.64 (s, 3H, CH3), 3.20 (s, 4H, 2CH2), 3.20 (s, 4H, 2CH2), 5.15 (s, 2H, CH2), 7.14 (d, 2H, Ar), 8.03 (s, 1H, Ar), 8.24 (s,1H, Ar), 9.97 (s, 1H, CHO); MS: m/e (El) 406 (M+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([C:36](O)=[O:37])[CH:27]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:36]([C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[O:37])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: COc1cc(C(=O)O)nc2ccccc12
Product: COc1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)nc2ccccc12

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 4-methoxy-quinoline-2-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=518.1.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:43]=[CH:42][C:11]([CH2:12][O:13][C:14](=[O:41])[CH:15](O)[N:16]2[CH:19]([S:20][CH2:21][C:22](=O)[CH:23]3[CH2:27][CH2:26][CH2:25][O:24]3)[CH:18]([NH:29]C(=O)CC3C=CC=CC=3)[C:17]2=[O:39])=[CH:10][CH:9]=1)([O-:7])=[O:6].N1C(C)=CC=CC=1C.CP(C)C.O1CCCC1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1C>ClCCl.C(O)(C)C>[N+:5]([C:8]1[CH:43]=[CH:42][C:11]([CH2:12][O:13][C:14]([C:15]2[N:16]3[CH:19]([S:20][CH2:21][C:22]=2[CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[CH:18]([NH2:29])[C:17]3=[O:39])=[O:41])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=C(Cc1ccccc1)NC1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)C1SCC(=O)C1CCCO1
Agent: CP(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C3CCCO3)CSC12
Temperature: -40 °C
Reaction time: 1 h
Yield: 170.3 %

Procedure:
Thionyl chloride (45 ml, 0.615 mol) was added dropwise to a solution of hydroxy-{2-oxo-4-[2-oxo-2-(tetrahydrofuran-2-yl)-ethylsulfanyl]-3-phenylacetylamino-azetidin-1-yl}-acetic acid 4-nitro-benzyl ester (202 g, 0.362 mol) and 2,6-lutidine (58 ml, 0.500 mol) in dichloromethane (4 liters) at −20° C. After stirring for 1 hour, the solution was washed twice with saturated sodium chloride (1 liter) and concentrated. To the concentrated solution was added trimethylphosphine in tetrahydrofuran solution (110 ml, 3M, 330 mmol), the solution stirred for 1 hour, washed with diluted sodium hydrogen carbonate and saturated sodium chloride. After stirring at reflux for 16 hours, the solution was washed with water and saturated sodium chloride. The solution was concentrated and cooled to −40° C. followed by a dropwise addition of phosphorus pentachloride (104 g, 0.5 mol). α-Picoline (92 ml) in dichloromethane (60 ml) solution was added while maintaining the temperature between −40° C. to 30° C. The mixture was stirred for 1 hour followed by the addition of isopropanol (660 ml). The reaction mixture was warmed to 22° C., granulated, filtered and dried to give the title compound (250 g, 45%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH:20]([NH2:24])([CH2:22][CH3:23])[CH3:21]>C(N(CC)CC)C>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([NH:24][CH:20]([CH3:21])[CH2:22][CH3:23])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCC(C)N
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NC(C)CC
Reaction time: 0.17 h

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 Mol.) are dissolved in about 500 ml. methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. of sec. butylamine are added dropwise. After the addition is completed, heating is continued for 10 minutes. The solvent is then removed in vacuo and 500 ml. of ethyl acetate are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting yellow oil, 6-chloro-2-methyl-4-(1-methylpropyl)amino-5-nitropyridine-3-carboxylic acid, ethyl ester is recrystallized with methanol, yield: 107 g. (68%); m.p. 33°-35° (methanol).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[C:22](=[O:23])[N:21]([CH3:24])[C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:5]=1.[Li+].[OH-]>C1COCC1>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][C:6]=1[C:11]1[C:22](=[O:23])[N:21]([CH3:24])[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH:12]=1
Reactant: COC(=O)c1ccc(C)c(-c2cc3cnc(SC)nc3n(C)c2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ncc2cc(-c3cc(C(=O)O)ccc3C)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 100 h
Yield: 85.5 %

Procedure:
4-Methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzoic acid methyl ester (1.0 g, 2.81 mmol) was dissolved in 4 mL THF, and 1.0 M aqueous LiOH (2.8 mL, 2.81 mmol) was added. The reaction mixture was stirred at room temperature for 100 hours, then was partitioned between diethyl ether and water. The aqueous layer was acidified by addition of 5% aqueous HCl, and the resulting precipitate was collected by filtration, washed with water, and dried under vacuum to provide 820 mg of 4-methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzoic acid MS (M+H)=342.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (70 mg, 0.309 mmol) in DCM (3 mL) were added acetyl chloride (32 μL, 0.450 mmol) and triethylamine (54 μL, 0.526 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, and washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-acetyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-acetyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester in DCM (3 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (41 mg, 79%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCC(C(O)=O)CC1.C([O:38][C:39](=[O:50])[C@@H:40]([NH:46]C(O)=O)[CH2:41][CH2:42][C:43](O)=[O:44])(C)(C)C>>[NH2:46][C@@H:40]([CH2:41][CH2:42][C:43](=[O:44])[NH:24][C:21]1[CH:22]=[N:23][C:18]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15]3)=[CH:19][CH:20]=1)[C:39]([OH:50])=[O:38]
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)O
Agent: O=C(O)C1CCNCC1
Product: N[C@@H](CCC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1)C(=O)O

Procedure:
(S)-2-Amino-4-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]butyric acid was prepared as described for piperidine-4-carboxylic acid [6-(2-phenyl-chroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing N-(tert-butoxycarbonyl)isonipecotic acid with (S)-2-carboxyaminopentanedioic acid 1-tert-butyl ester.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.O1CCCC1>O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6])=[CH:20][CH:19]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of t-butyl N-{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (50 g) in tetrahydrofuran (700 mL) was gradually added dropwise at 0° C. to a 2.5M 4-fluorophenylmagnesium bromide/tetrahydrofuran solution (300 mL) which had been prepared previously. The mixture was stirred at room temperature for 14 hours, cooled to 0° C., and extracted twice with ether after addition of saturated aqueous sodium bicarbonate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the organic solvent was evaporated off in vacuo. The resulting residue was purified by column chromatography on silica gel (C-300; hexane:ethyl acetate=4:1) to give the title compound.
Reaction SMILES: C(S([C:8]1[C:13](S(C(C)(C)C)(=O)=O)=[C:12]2[CH2:21][C:9]=1[CH2:10][CH2:11]2)(=O)=O)(C)(C)C.[C:22]1([Li])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>O1CCCC1>[C:22]1([C:13]2[C:8]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:9]3[CH2:21][C:12]=2[CH2:11][CH2:10]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)S(=O)(=O)C1=C2CCC(=C1S(=O)(=O)C(C)(C)C)C2
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(C2=C3CCC(=C2c2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 27 %

Procedure:
First, the intermediate product 2,3-diphenylnorbornadiene was prepared as follows: A solution of 2,3-bis(tert-butylsulfonyl)norbornadiene (prepared according to the procedure of Riera, et al. Tetrahedron Letters 1990, volume 31, page 2173) (5.50 g, 19 mmol) in dry tetrahydrofuran (50 mL) was treated with 95 mmol of phenyl lithium at −78° C. under an argon atmosphere. After allowing the reaction mixture to gradually warm to room temperature overnight, methanol (25 mL) was added, and the solution was partially concentrated at reduced pressure. The resulting mixture was mixed with water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over magnesium sulfate and concentrated to deposit a brown oil. The intermediate product was purified by column chromatography (silica gel, hexane/dichloromethane), followed by recrystallization from methanol to provide 1.25 g (27% yield) of 2,3-diphenylnorbornadiene as a white solid. 1H NMR (CDCl3) δ2.10 (m, 1 H), 2.40 (m, 1 H), 3.92 (m, 2 H), 7.01 (t, 2 H), 7.2-7.3 (m, 10 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:4]([F:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25]
Reactant: Oc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 4-chloro-2-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (130 mg, 0.36 mmol, 1.0 eq) and Cs2CO3 (175 mg, 0.54 mmol, 1.5 eq) in 2-butanone (20 mL) was added ethyl 2-bromoacetate (59.7 mg, 0.36 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 h. Water was then added and the aqueous layer extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (80 mg, 50%).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[C:12]1([NH:18][CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:21][CH2:20][CH2:19][NH:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:3][C:4]=2[CH:10]=1
Reactant: NCCNc1ccccc1
Reactant: Clc1ccc2[nH]c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2nc(NCCNc3ccccc3)[nH]c2c1
Temperature: 110 °C
Yield: 62.6 %

Procedure:
A neat mixture of 2,5-dichloro-1H-benzoimidazole (150 mg, 0602 mmol), N-phenyl ethylenediamine (110 mg, 0.808 mmol, 1 eq) and N,N-diisopropylethyl amine (210 mL, 1.21 mmol, 1.5 eq.) in sealed tube was heated overnight at 110° C. The mixture was directly loaded onto a silica gel column and eluted with 5% methanol in dichloromethane to provide 144 mg of N1-(6-chloro-1H-benzo[d]imidazol-2-yl)-N2-phenylethane-1,2-diamine.
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.Cl.[C:15]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([C:28]([O:30][CH3:31])=[O:29])=[C:23](O)[CH:22]=[CH:21]2)(=[NH:17])[NH2:16].CS([O-])(=O)=O.C1CCC(N=C=NC2CCCCC2)CC1>N1C=CC=CC=1>[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][CH:27]=[C:18]([C:15](=[NH:16])[NH2:17])[CH:19]=3)[C:24]=2[C:28]([O:30][CH3:31])=[O:29])=[O:10])=[CH:7][CH:6]=1
Reactant: NN=CNc1ccc(C(=O)O)cc1
Reactant: COC(=O)c1c(O)ccc2cc(C(=N)N)ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1c(OC(=O)c2ccc(NC=NN)cc2)ccc2cc(C(=N)N)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 Milliliters of anhydrous pyridine was added to 1.9 g of 4-aminoiminomethylaminobenzoic acid.hydro-chloride, 3.0 g of of 6-amidino-1-methoxycarbonyl-2-naphthol.methanesulfonate, and 2.2 g of DCC, followed by stirring for 2 hours under cooling with ice and 24 hours at room temperature. The precipitate was collected by filtration and washed with a small amount of pyridine. To the collected precipitate was added 30 ml of water, followed by stirring for 1 hour. Insoluble matter was filtered off and the filtrate was added dropwise to 100 ml of saturated aqueous sodium bicarbonate solution, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration and washed with a small amount of water and acetone. To the collected precipitate were added 15 ml of methanol and 2.2 ml of methanesulfonic acid. The resulting solution was added dropwise to 300 ml of ether, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration and washed with a small amount of acetone to obtain 2.46 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C@@H:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O=C1C[C@@H](c2ccccc2)c2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1C[C@@H](c2ccccc2)c2ccc(Cl)cc21
Reaction time: 2.75 h
Yield: 90.1 %

Procedure:
(S)-6-chloro-3-phenylindan-1-one (IVa) (isolated as in example 7) (23 g) is added in small portions to a suspension of sodium borohydride (1.6 g) in ethanol (160 ml) at 3-5° C. After the addition has been finalised, the mixture is allowed to reach room temperature. The reaction mixture is stirred for 2.75 hours, where after it is evaporated to dryness. The residue is dissolved in a mixture of water (150 ml) and ethyl acetate (200 ml), the phases are separated, and the water phase is extracted with ethyl acetate (100 ml). The organic phases are combined, washed with water (100 ml), dried with magnesium sulphate, filtered and evaporated to dryness. The residue is recrystallised from heptanes (250 ml), giving 20.9 g (90%) of the title product as a solid. Melting point 108.9° C., NMR conforms to structure, [α]D20 +48.30° (c=1.0, methanol). CHN calculated for C15H13OCl: C, 73.62; H, 5.35; found: C, 73.55; H, 5.29. >99% ee according to the chiral analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C@H:16]([OH:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].O.C(=O)(O)[O-].[Na+].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>O1CCCC1.O.C(OCC)(=O)C>[CH2:29]([O:28][C:26]([N:15]1[C@H:10]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)[CH2:11][O:12][CH2:13][C@@H:14]1[C@H:16]([OH:18])[CH3:17])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@@H](O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanol (2 g) in tetrahydrofuran (20 mL) was added saturated sodium bicarbonate water (20 mL) and benzyl chloroformate (1.31 mL). After stirring the reaction solution at room temperature for 16 hours, benzyl chloroformate (1.33 mL) was further added thereto, and the mixture was then stirred for another 20 hours. The resultant solution was diluted with water and ethyl acetate. The organic layer was partitioned, washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate), to thereby obtain the titled compound (880 mg). The physical properties of this crude product were as follows.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:17][N:8]2[C:7]1=[O:24])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:25]N1C(=O)CCC1=O.C1(O)C=CC=CC=1>C1COCC1>[Br:25][C:12]1[NH:11][C:10]2[C:9]3=[N:15][C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:17][N:8]3[C:7](=[O:24])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c(=O)n2nc(-c3ccccc3)nc2c2[nH]cnc21
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCCCCn1c(=O)n2nc(-c3ccccc3)nc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of 4-pentyl-8-phenyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (25 mg, 0.078 mmol) in THF (5 mL) was added N-Bromosuccinimide (19 mg, 0.11 mmol). After stirring at room temperature for 1 hour, phenol was added to quench the reaction. The reaction mixture was concentrated, and the residue was purified by preparative LCMS (method B) to provide the desired product as white powder. 1HNMR (400 MHz, CD3OD): δ 8.25 (m, 2H), 7.50 (m, 3H), 4.31 (t, J=7.3 Hz, 2H), 1.88 (m, 2H), 1.43 (m, 4H), 0.95 (m, 3H). LCMS calculated for C17H18BrN6O (M+H): 401.1. found: 401.0, 403.0.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([N+:13]([O-])=O)[CH:9]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:7]=2[CH:6]=[N:5]1)[CH3:3]>C(O)C.[Pd]>[NH2:13][C:10]1[CH:9]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:12]=2[CH:11]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c1cnn2C(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N)cc2c1cnn2C(C)C

Procedure:
Methyl 1-(1-methylethyl)-6-nitro-1H-indazole-4-carboxylate (1.39 g, 5.28 mmol) was dissolved in ethanol (70 mL) and hydrogenated using an H-Cube instrument (full H2 mode and 10% Pd/C). The solvent was removed in vacuo and the residue was purified via silica gel chromatography (eluent: 0% to 40% gradient; EtOAc:Hex). The product was obtained as 1.05 g (85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.58 (d, J=6.57 Hz, 6H), 4.00 (s, 5H), 4.70 (dt, J=13.39, 6.69 Hz, 1H), 6.80 (s, 1H), 7.37 (d, J=2.02 Hz, 1H), 8.30 (s, 1H). LCMS (ES) [M+H]+ 234.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][S:10]([C:13]1[N:14]=[C:15]2[S:20][CH:19]=[C:18]([CH3:21])[N:16]2[N:17]=1)(=[O:12])=[O:11].[CH3:22]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH3:22])[S:10]([C:13]1[N:14]=[C:15]2[S:20][CH:19]=[C:18]([CH3:21])[N:16]2[N:17]=1)(=[O:11])=[O:12]
Reactant: Cc1cccc(Cl)c1NS(=O)(=O)c1nc2scc(C)n2n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: Cc1cccc(Cl)c1N(C)S(=O)(=O)c1nc2scc(C)n2n1
Yield: 60.8 %

Procedure:
To a solution of the product of Example 1 (3 g) in dimethylformamide (20 ml) was added potassium t-butoxide (1.1 g) with cooling and stirring. Dimethyl sulphate (0.92 ml) was added dropwise, and the reaction mixture was stirred overnight. Addition to ice/water/ether and filtration, followed by recrystallisation from ethyl acetate gave 1.9 g of the desired product, mp 178°-180° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:11][C:10]=1[N+:25]([O-])=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[NH2:25][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(C#CCOC2CCCCO2)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(CCCOC2CCCCO2)ccc1O
Temperature: 50 °C
Yield: 45.3 %

Procedure:
A mixture of Example 68B (1.19 g, 3.25 mmol), 20% Pd(OH)2/C (100 mg), and ethanol (50 mL) were stirred, and heated at 50° C. for 2 hours under H2 atmosphere (60 psi). The solution was filtered, dried with silica gel powder (8 g), and purified by flash chromatography eluting with 30% ethyl acetate in hexanes (1 L) and then with 1% methanol in ethyl acetate (1 L) to give the title compound (0.37 g, 45%). MS (DCI) m/z 252.05 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 1.46–1.62 (m, 4 H) 1.70 (m, 1 H) 1.76–1.90 (m, 3 H) 2.45–2.58 (m, 2 H) 3.37 (m, 1 H) 3.49 (m, 1 H) 3.71 (m, 1 H) 3.86 (m, 1 H) 4.55 (t, J=3.73 Hz, 1 H) 6.41 (dd, J=7.97, 2.20 Hz, 1 H) 6.59 (m, 1 H) 6.61 (s, 1 H).