Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[N:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:18]2[C:17]([F:16])=[CH:22][C:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:20][CH:19]=2)=[N:33][CH:34]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CCOC(=O)CCSc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCSc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Yield: 80.7 %

Procedure:
A mixture of ethyl 3-(2-bromophenylthio)propanoate (7 g, 24 mmol), 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine (7.6 g, 24 mmol), Pd(dppf)Cl2.CH2Cl2 (378 mg, 0.52 mmol) and Na2CO3 (5 g, 48 mmol) in dioxane/water (20 mL/5 mL) was stirred at 80° Celsius for 5 hours under N2, then poured into water (60 mL) and extracted with EtOAc (50 mL×3). The combined organic extracts were dried over Na2SO4, filtered, concentrated to dryness and purified by FCC to give ethyl 3-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ylthio)propanoate (7.7 g, 80%) as a white solid. MS (ESI): mass calcd. for C21H20FN3O2S, 397.13; m/z found, 397.9 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Br[CH2:30][CH2:31][CH2:32][OH:33]>CS(C)=O>[OH:33][CH2:32][CH2:31][CH2:30][N:12]1[C:8]([CH3:7])=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: OCCCBr
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(-c2ccccc2)c(C(=O)OCC)n(CCCO)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
Potassium tert-butoxide (744 mg, 6.64 mmol) was added to a stirred solution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4 dicarboxylate (1.00 g, 1.99 mmol) in dimethylsulfoxide (15 mL) at 10° C. and stirred at ambient temperature for 1 h. The mixture was cooled to 10° C., 3-bromo-1-propanol (738 mg, 5.31 mmol) added and stirring continued at ambient temperature for 12 h. The mixture was poured onto ice-water and extracted with diethyl ether (5×10 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and subjected to column chromatography over silica gel (100-200 mesh) using 40% of ethyl acetate in petroleum ether as eluent to afford of diethyl 1-(3-hydroxypropyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (600 mg, 50%) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:19][CH3:20])=[C:10]([CH:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)O)[CH:11]=2)=[CH:4][CH:3]=1.CC(C)=[O:25]>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:19][CH3:20])=[C:10]([CH:12]3[C:16](=[O:15])[CH:17]=[CH:18][CH:14]3[OH:25])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C(O)c1ccco1
Reactant: CC(C)=O
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1O
Temperature: 55 °C
Reaction time: 25 h

Procedure:
A solution of (4′-chloro-4-ethylbiphen-3-yl)furan-2-ylmethanol (67.18 g, 214.8 mmol) in acetone (1340 ml) and water (235 ml) is heated to 55° C. and 30 drops of polyphosphoric acid are added. The mixture is stirred at 55° C. for 25 hours, then cooled to room temperature. The reaction mixture is concentrated under reduced pressure to remove most of the acetone then ethyl acetate (600 ml) is added, and the reaction mixture is partitioned. The aqueous phase is extracted into ethyl acetate and the organic solutions are combined, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 5-(4′-chloro-4-ethylbiphen-3-yl)-4-hydroxy-cyclopent-2-enone (59.84 g) as a brown oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9](=[O:11])[CH3:10])=[N:7][CH:6]=[N:5]1.Cl.C([O-])(O)=O.[Na+].[Na+].[Cl-].[CH3:20][O:21][C:22](=O)[O:23]C>>[CH3:3][N:4]1[C:8]([C:9](=[O:11])[CH2:10][C:22]([O:21][CH3:20])=[O:23])=[N:7][CH:6]=[N:5]1
Reactant: CC(=O)c1ncnn1C
Reactant: COC(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Product: COC(=O)CC(=O)c1ncnn1C
Temperature: 90 °C

Procedure:
NaH (7.84 g, 196 mmol of a 60% dispersion in oil) was added portion-wise to a solution of 6.18 g (34.5 mmol) of 1-(1-methyl-1H-1,2,4-triazol-5-yl)ethanone (Ohta, S.; Kawasaki, I.; Fukuno, A.; Yamashita, M.; Tada, T.; Kawabata, T. Chem. Pharm. Bull. (1993), 41(7), 1226-31) in 100 ml dimethylcarbonate. The mixture was heated to 90° C. for 2 hour forming a thick slurry. After cooling to room temperature, the mixture was slowly transferred to 1N HCl over ice. The pH of the mixture was brought to about 7 with NaHCO3 before being saturated with NaCl and extracted 4 times with EtOAc. The EtOAc was dried (MgSO4) and concentrated to give an oil that was chromatographed on silica gel (100% DCM followed by gradient elution to 50% EtOAc in DCM). Product (5.3 g) was obtained as an oil. NMR: 3.78 (s, 3H), 4.11 (s, 2H), 4.22 (s, 3H), 7.94 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9](O)=[O:10])[NH:6][N:5]=1)([O-:3])=[O:2]>C1COCC1>[N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)[nH]n1
Temperature: -5 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a nitrogen inlet was purged with nitrogen and charged with 3-nitropyrazole-5-carboxylic acid (0.56 g, 3.56 mmol) and THF (8 mL). The system was cooled to −5° C. using an ice/acetone bath. Borane-THF complex solution (1.0M, 11 mL, 11.0 mmol) was added at a rate that maintained the internal reaction temperature below 5° C. After the addition was complete the cooling bath was removed and the reaction was stirred at 60° C. for 3 h. After this time the reaction was cooled to −5° C. using an ice/acetone bath, water (2 mL) and 4N hydrochloric acid (2 mL) was added. The reaction mixture was stirred at 70° C. for 1 h in order to destroy the borane-pyrazole complex. It was cooled to room temperature and concentrated under reduced pressure to a volume of approximately 1 mL. Ethyl acetate (20 mL) and water (10 mL) were added and the mixture was stirred for 15 min. The aqueous layer was separated and extracted with ethyl acetate (4×10 mL). The combined organic layer was washed with saturated aqueous sodium bicarbonate (2×10 mL), brine (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to afford 296a (345 mg, 68%) as a light yellow solid. MS-ESI: [M+H]+ 144
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[C:24]([N:27]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:28])(=[O:26])[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[C:24]([N:27]([C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][CH:30]=1)[CH3:28])(=[O:26])[CH3:25]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-acetyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3]>C(O)C>[CH2:1]([OH:10])[CH:2]([OH:3])[CH:4]([OH:5])[CH:6]([OH:7])[CH:8]=[O:9]
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: CCO
Product: O=CC(O)C(O)C(O)CO

Procedure:
The two major chemicals of interest that can be produced from D-xylose by yeasts are ethanol and xylitol. It is known that under normal growth conditions, some pentose-fermenting yeasts (e.g. Pichia stipitis) produce mostly ethanol (Du Preez 1994; Schneider 1989); while others (e.g. Candida guilliermondii, Candida tropicalis) produce mainly xylitol as the end products (Barbosa et al. 1988; Gong et al. 1981). As an intermediate metabolite, xylitol is widely applied in food and pharmaceutical industries because of its equivalent sweetness to sucrose and high negative heat of solution (Borges 1991; Passon 1993), its anti-cariogenic and anti-infection effects (Pizzo et al. 2000; Sakai et al. 1996; Brown et al. 2004), and independent metabolism of insulin, therefore making it useful for diabetic patients (Salminen et al. 1989). Among the xylose-fermenting yeast, the genus Candida is one of the most efficient xylitol producers (Meyrial et al. 1991). Ojama demonstrated that C. guilliermondii VTT-C-71006 is an efficient xylitol producer. A xylitol yield of 0.74g/g xylose was obtained within 50 hours at an initial D-xylose concentration of 100g/1 (Ojama 1994).
Reaction SMILES: F[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([OH:20])=O)=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)=CC=1.C1(CCN2C(=O)N(C3SC(C(O)=O)=C(C)C=3)C=N2)CC1.[NH2:44][CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1>>[CH:22]1([CH2:5][CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([NH:44][CH2:45][C:46]4[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=4)=[O:20])=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)[CH2:23][CH2:2]1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(-n2cnn(CCC3CC3)c2=O)sc1C(=O)O
Product: Cc1cc(-n2cnn(CCC3CC3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 87 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid with 5-(1-(2-cyclopropylethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)-pyridine, the title compound was obtained as a colorless solid in 87% yield: mp 148-150° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.52 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.27 (s, 1H), 6.87 (s, 1H), 6.44 (t, J=5.7 Hz, 1H), 4.60 (d, J=5.7 Hz, 2H), 3.91 (t, J=7.0 Hz, 2H), 2.50 (s, 3H), 1.70-1.61 (m, 2H), 0.75-0.60 (m, 1H), 0.47-0.39 (m, 2H), 0.06-0.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.6, 150.5, 149.2, 149.0, 140.8, 135.6, 134.7, 131.6, 125.0, 123.7, 119.9, 46.0, 41.4, 33.4, 16.0, 8.1, 4.0; MS (ES+) m/z 384.4 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:23][CH:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[Li+].[I-]>N1C=CC=CC=1>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:23][CH:24]([CH3:29])[C:25]([F:28])([F:26])[F:27])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(OC(C)C(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(Oc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-4-phenyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-quinoline-3-carboxylic acid ethyl ester (100 mg, 0.26 mmol) and LiI in pyridine. Off white solid (55 mg, 53%). LC-MS: 396 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[CH:34]=[CH:33][C:31]=1[NH2:32].CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)=[N:4][C:5]([NH:32][C:31]2[CH:33]=[CH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:39][CH2:38]3)=[CH:36][C:30]=2[O:29][CH3:28])=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Cl)ncc3Br)c3ccccc32)cc1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Br)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)n1
Yield: 52.8 %

Procedure:
3-(5-Bromo-2-chloropyrimidin-4-yl)-1-tosyl-1H-indole (INTERMEDIATE 6, 372 mg, 0.83 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27, 343 mg, 0.83 mmol), and DIEA (0.145 mL, 0.83 mmol) in n-butanol (4.0 mL) were heated at 170° C. for 3 h. The reaction mixture was concentrated in vacuo and the crude residue was purified by chromatography on silica gel (10% MeOH/1% NH4OH in DCM) to give the title product (320 mg, 53.9%). m/z 718.
Reaction SMILES: Cl.[F:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[N:8][O:9][C:5]=2[CH:4]=1.[CH2:16](Cl)Cl>CO>[F:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([O:13][CH3:16])=[O:12])=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: ClCCl
Reactant: O=C(O)Cc1noc2cc(F)ccc12
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1noc2cc(F)ccc12
Temperature: 0 °C

Procedure:
Hydrogen chloride gas is bubbled into a cold (ice/water bath) solution of 6-fluoro-1,2-benzisoxazole-3-acetic acid (13.7 g, 0.0702 mol) in methanol over a 15 minute period. The reaction mixture is concentrated in vacuo to obtain a brown-orange solid. Flash column chromatography of the solid using silica gel and methylene chloride gives the title product as a white solid, mp 60°-61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:33][CH2:34][CH3:35])=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:36]1([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[C:24]([O:33][CH2:34][CH3:35])=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1nc(C(F)(F)F)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1nc(C(F)(F)F)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 5) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H35N7O4F3Cl2 [(M+H)+] 720.2074, observed 720.2075.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([I:12])=[C:6]2[C:10]([CH3:11])=[CH:9][NH:8][C:7]=12.[H-].[Na+].O1CCC[CH2:16]1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([I:12])=[C:6]2[C:10]([CH3:11])=[CH:9][N:8]([CH3:16])[C:7]=12
Reactant: Cc1c[nH]c2c(Cl)ncc(I)c12
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(C)c2c(Cl)ncc(I)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-4-iodo-3-methyl-1H-pyrrolo[2,3-c]pyridine (2 g) in dry tetrahydrofuran (100 ml) at 0° C. under argon was added portionwise sodium hydride (60% dispersed in mineral oil 603 mg). After addition the ice-bath was removed and the solution stirred at room temperature for 30 minutes. The solution was re-cooled to 0° C. and a solution of methyl iodide (3.41 ml) in dry tetrahydrofuran (40 ml) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The solution was evaporated and the residue partitioned between ethyl acetate (200 ml) and water (100 ml). Washed with water (2×100 ml, pH7) then dried (MgSO4), filtered and evaporated to an orange/yellow solid. The solid was stirred in hexane for 2 h then filtered off and dried to give the title compound (1.19 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[C:12](OC(=O)CC)(=O)[CH2:13][CH3:14]>C(OCC)C>[CH2:13]([C:14]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1)[CH3:12]
Reactant: CCC(=O)OC(=O)CC
Reactant: Nc1ccncc1S(N)(=O)=O
Solvent: CCOCC
Product: CCC1=NS(=O)(=O)c2cnccc2N1
Temperature: 150 °C

Procedure:
A mixture of 1 g of 4-aminopyridine-3-sulfonamide (Preparation 2) and 10 cm3 of propionic anhydride is heated at 150° C. for 8 hours. After cooling, an equal volume of diethyl ether is added and the precipitate obtained is collected on a filter, washed with diethyl ether and dried. It is recrystallized from hot water.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.B(F)(F)F.[CH3:12][CH2:13][O:14][CH2:15][CH3:16].O1CCOCC1>C(OCC)C>[O:14]1[C:15]2[C:6](=[CH:1][CH:2]=[CH:3][CH:16]=2)[CH2:5][CH2:12][CH2:13]1
Reactant: Oc1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0 h

Procedure:
To a solution of phenol 4 (0.01 mol) and a catalyst, preferably boron trifluoride diethyl etherate (0.016 mol) in an organic solvent, preferably dry dioxane (10 mL), Is added vinyl lactone 2 (0.016 mol) In an organic solvent, preferably dry dioxane (5.0 mL) over 1-60 minutes, preferably 60 minutes, at 0-150° C., preferably 110° C., under an inert gas. The reaction mixture is stirred for 0 to 8 hours, preferably 0 hours, at the selected temperature, cooled to room temperature, and diluted with an organic solvent, preferably diethyl ether (200 mL). The reaction mixture is then washed with water (100 mL, 2×50 mL), dried over sodium sulfate (Na2SO4), and solvent is removed under reduced pressure to afford a brown oily residue. The residue is dissolved in alcohol, preferably methanol (30 mL), and the alcohol is then removed under reduced pressure. The brown oily liquid or semisolid is further purified by chromatography, preferably on silica gel, to afford pure racemic chroman derivative 5.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]([OH:34])=[O:33])[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1.O[CH2:53][C:54]([N:56]([CH3:58])[CH3:57])=[O:55]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:43])([F:45])[F:44])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]([O:34][CH2:53][C:54](=[O:55])[N:56]([CH3:58])[CH3:57])=[O:33])[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1
Reactant: CN(C)C(=O)CO
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc1C(F)(F)F
Product: CN(C)C(=O)COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1

Procedure:
Prepared analogously to Example 9.2 from 70 mg (0.10 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 11 mg (0.11 mmol) 2-hydroxy-N,N-dimethyl-acetamide.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.FC1C=CC=C(OC)C=1OC.[Cl:25]COCCl>C(O)(=O)C>[F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH2:4][Cl:25]
Reactant: ClCOCCl
Reactant: COc1ccc(C=O)c(F)c1OC
Agent: COc1cccc(F)c1OC
Solvent: CC(=O)O
Product: COc1ccc(CCl)c(F)c1OC

Procedure:
The 2-fluoroveratraldehyde used as indicated above is prepared as follows: 3-fluoroveratrole is reacted with monochloromethyl ether in glacial acetic acid to give 2-fluoro-3,4-dimethoxybenzyl chloride which is treated with hexamethylenetetramine in chloroform followed by refluxing in 50% acetic acid to yield the 2-fluoroveratraldehyde.
Reaction SMILES: Cl[C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[OH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(O)C>[CH3:10][N:4]1[C:5]([N:24]2[CH2:25][CH2:26][CH:21]([OH:20])[CH2:22][CH2:23]2)=[C:6]([N+:7]([O-:9])=[O:8])[CH:2]=[N:3]1
Reactant: Oc1ccncc1
Reactant: Cn1cc([N+](=O)[O-])c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(O)CC1
Temperature: 130 °C
Yield: 104.6 %

Procedure:
To a solution of 3-chloro-1-methyl-4-nitro-1H-pyrazole (1.0 g, 6.17 mmol) in ethanol (10 mL) was added DIPEA (2 mL, 11.4 mmol) followed by 4-hydroxypyridine (686 mg, 6.79 mmol). The reaction mixture was heated at 130° C. in the microwave for 60 min before the solvents were removed under reduced pressure. Purification of the residue via silica gel column chromatography (75-100% EtOAc/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-ol as a bright yellow oil (1.46 g). To a solution of this oil (1.40 g, 6.17 mmol) in DCM (40 mL) was added portionwise Dess-Martin periodinane (3.1 g, 7.41 mmol). The reaction mixture was stirred at room temperature for 3 hr, diluted with DCM (100 mL) and washed with saturated aqueous sodium hydrogencarbonate (30 mL), followed by saturated aqueous sodium thiosulphate (30 mL), saturated aqueous sodium hydrogencarbonate (30 mL) and brine (30 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (50-75% EtOAc/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.32 g, 95% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 3.86 (s, 3H), 3.54 (t, J=6.0 Hz, 4H), 2.65 (t, J=6.0 Hz, 4H).
Reaction SMILES: [NH3:1].Cl[C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]>C(O)C>[NH2:1][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: N
Reactant: O=[N+]([O-])c1cc(Cc2ccccn2)ccc1Cl
Solvent: CCO
Product: Nc1ccc(Cc2ccccn2)cc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
Ethanol(1700 ml.) was saturated with ammonia at -20° to a total volume of 3l., then 49.7 g. (0.2 mol) of 2-(4-chloro-3-nitrobenzyl)pyridine was added. The entire mixture was first autoclaved at 100° C. for 24 hours, then 185° C. for 24 hours. The resulting solution was then evaporated in vacuo to a brown solid, which was thereafter dissolved in acetone, dried with magnesium sulfate. filtered and evaporated in vacuo to a light brown solid. The resulting solid was crystallized from water using Norite to give 2-(4-amino-3-nitrobenzyl)-pyridine as yellow-orange prisms, mp. 128- 132° C. (water).