Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:36]=[CH:35][C:7]([CH:8]=[CH:9][C:10]2[C:11]3[C:16]([C:17]([CH:24]=[CH:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=4)=[C:18]4[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]4)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:5]=1)([O-])=O.CN(C)C=O.Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]2[C:11]3[C:16]([C:17]([CH:24]=[CH:25][C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=4)=[C:18]4[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]4)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:35][CH:36]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2c3ccccc3c(C=Cc3ccc([N+](=O)[O-])cc3)c3ccccc23)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C=Cc2c3ccccc3c(C=Cc3ccc(N)cc3)c3ccccc23)cc1
Yield: 95.4 %

Procedure:
After mixing 6.0 g of 9,10-bis(p-nitrostyryl)anthracene, 12.0 g of iron powder and 200 ml of N,N-dimethyl formamide together, by adding dilute hydrochloric acid prepared by employing 5 ml of concentrated hydrochloric acid and 17 ml of water to the resulting mixture and intensely stirring, reaction was effected at a temperature of 90° to 100° C. for an hour. After completing the reaction, the pH value of the reactant mixture was adjusted to be 8 by adding a 5% aqueous solution of sodium carbonate while heating as above, and the undissolved matter was filtered. Then, by diluting the resulting filtrate with 70 ml of water, there were separated yellowish brown-colored crystals. These crystals were collected by filtering, washed in water and dried, whereby there were obtained 5.0 g (yield rate: 96.2%) of 9,10-bis(p-aminostyryl)anthracene. The melting point of this crystal was in the range of from 281.5° to 20° C. (decomposition point).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][S:9]1(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][C@@H:29]1[O:31][CH2:30]1>CC(C)=O.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([CH2:27][CH2:28][C@H:29]2[CH2:30][O:31]2)[S:9]1(=[O:19])=[O:18]
Reactant: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Reactant: BrCC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=S1(=O)N(CC[C@H]2CO2)Cc2ccccc2N1c1ccccc1F
Temperature: 40 °C
Reaction time: 14 h
Yield: 87.7 %

Procedure:
A solution of 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.20 g, 0.72 mmol) in acetone (3 mL) was treated with potassium carbonate (0.11 g, 0.81 mmol), (S)-(−)-4-Bromo-1,2-epoxybutane (0.15 mL, 1.46 mmol) and was heated to 40° C. for two h then at room temperature for 14 h. The reaction mixture was diluted with ethyl ether (40 mL) and washed with 2 N sodium hydroxide (2×20 mL), the organic layer was isolated, dried with MgSO4 and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to provided 1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.22 g, 86%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:14]=3[CH3:22])=[O:12])=[CH:9][N:8]([CH:23]([CH3:25])[CH3:24])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:26]C1C2C(C(C3C=CC=C(N)C=3)=O)=CN(C3CCCC3)C=2N=CN=1>>[NH2:26][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[C:14]=3[CH3:22])=[O:12])=[CH:9][N:8]([CH:23]([CH3:25])[CH3:24])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1c(C(=O)c2cn(C(C)C)c3ncnc(Cl)c23)cccc1[N+](=O)[O-]
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Product: Cc1c(N)cccc1C(=O)c1cn(C(C)C)c2ncnc(N)c12

Procedure:
The title compound was prepared from (4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-methyl-3-nitro-phenyl)-methanone by procedures analogous to those described for the preparation of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)methanone. MS: 310.1 (MH+); HPLC Rf: 1.3 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [CH:1]([S:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=O)[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:17]#[N:18])([CH3:3])[CH3:2].COC1C=CC(/C=[C:34]2/[C:35]([NH:37][C:38]([S:40]/2)=[NH:39])=[O:36])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:39][C:38]1[S:40]/[C:34](=[CH:15]\[C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:17]#[N:18])=[C:5]3[S:4][CH:1]([CH3:3])[CH3:2])/[C:35](=[O:36])[N:37]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CC(C)Sc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Sc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 4-isopropylsulfanyl-6-formyl-quinoline-3-carbonitrile (example 40b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-isopropylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 355 (MH+).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([C:50]#[N:51])=[N:33][C:34]=2[NH:38][CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)(=O)C1C=CC=CC=1>[Pd].N.C(O)C>[NH2:51][CH2:50][C:32]1[N:31]=[C:30]2[C:35]([N:36]=[CH:37][N:29]2[C@@H:11]2[O:12][C@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[C@@H:14]([OH:15])[C@H:10]2[OH:9])=[C:34]([NH:38][CH2:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=[CH:42][CH:41]=2)[N:33]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: [Pd]
Agent: N
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(CN)nc32)[C@H](O)[C@@H]1O
Reaction time: 16 h
Yield: 70.8 %

Procedure:
10% Palladium on carbon was added to a solution of (2R,3R,4S,5S)-4-(benzoyloxy)-2-{2-cyano-6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (487 mg, 0.71 mmol) (Preparation 70) dissolved in a saturated solution of ammonia in ethanol. The reaction mixture was stirred for 16 hours under an atmosphere of hydrogen gas (414 kPa, 60 psi). The reaction mixture was then filtered through Arbocel (Trade Mark) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (80:20:2 by volume). The solvent was removed under reduced pressure to give the title compound (240 mg) as a foam.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:6][C@H:7]([O:9]CC1C=CC=CC=1)[CH3:8])[CH3:5])[CH3:2].Cl>C(O)C.[C].[Pd]>[CH2:1]([O:3][C@H:4]([CH3:5])[CH2:6][C@H:7]([OH:9])[CH3:8])[CH3:2]
Reactant: CCO[C@H](C)C[C@@H](C)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCO[C@H](C)C[C@@H](C)O
Yield: 47.8 %

Procedure:
3.20 g of this (2R, 4R)-2-ethoxy-4-benzyloxypentane was dissolved in 50 ml of ethanol. 0.30 g of 0% palladium-carbon and 5 ml of 1 N hydrochloric acid were added, and hydrogenation was carried out at the room temperature at the atmospheric pressure. The catalyst was removed by filtration. The filtrate was concentrated. The residue was subjected to column chromatography (silica gel, developing solvent=chloroform) to obtain 0.91 g of (2R, 4R)-4-ethoxy-2pentanol.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[CH:31]1[CH2:37][O:36][CH2:35][CH:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33][CH2:32]1)=[O:23])=O)(C)(C)C.Cl>O1CCOCC1.CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[CH:31]1[CH2:32][CH2:33][CH:34]([NH2:38])[CH2:35][O:36][CH2:37]1)=[O:23]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(NC(=O)OC(C)(C)C)COC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CCC(N)COC1
Yield: 32 %

Procedure:
tert-Butyl N-[6-[4-[[5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl]amino]-2-methyl-pyrazol-3-yl]oxepan-3-yl]carbamate was stirred with 4N HCl in dioxane (5 mL) and methanol (2 mL) at room temperature for 3 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 143 (24 mg, 32%). 1H NMR (400 MHz, DMSO) δ 9.73, 9.56 (s, 1H), 7.83, 7.78 (s, 1H), 7.62-7.42 (m, 3H), 7.36-7.18 (m, 2H), 3.96-3.71 (m, 6H), 3.59 (ddd, J=71.3, 12.2, 4.1 Hz, 1H), 3.03-2.91 (m, 1H), 2.94-2.79 (m, 1H), 2.10-1.89 (m, 1H), 1.85-1.68 (m, 1H), 1.68-1.56 (m, 1H), 1.54-1.39 (m, 1H). LCMS (ES+) m/z 449 (M+1).
Reaction SMILES: SCCC(O)=O.[S:7]([CH2:13][CH2:14][C:15]([O-:17])=[O:16])[CH2:8][CH2:9][C:10]([O-:12])=[O:11]>>[S:7]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C([O-])CCSCCC(=O)[O-]
Agent: O=C(O)CCS
Product: O=C(O)CCSCCC(=O)O

Procedure:
U.S. Pat. No. 5,256,818 to Tomioka discloses a method for making β-mercaptopropionic acid (HSCH2XH2COOH) by reacting alkaline thiodipropionate obtained from solid thiodipropionic acid, with alkaline sulfide. Specifically, sodium or potassium hydroxide is used to convert solid thiodipropionic acid to the corresponding thiodipropionate, which in turn is reacted with sodium sulfide at a temperature of 110° to 130° C. for one or several hours, preferably in the presence of residual alkaline hydroxide. The resulting solution is acidified with a strong acid to form the β-mercaptopropionic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]#[N:21])=[C:10]([N+:22]([O-])=O)[CH:9]=2)[CH2:4]1.C(O)(=O)C.O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl.C(OCC)(=O)C.CO>[NH2:22][C:10]1[CH:9]=[C:8]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:1])[CH3:25])[CH2:4]2)[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11]=1[C:20]#[N:21]
Reactant: CN(C)[C@H]1CCN(c2cc([N+](=O)[O-])c(C#N)cc2-c2ccccc2)C1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CN(C)[C@H]1CCN(c2cc(N)c(C#N)cc2-c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
6-[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]-4-nitrobiphenyl-3-carbonitrile (I-242) (7.9 g, 23.5 mmol) was dissolved in concentrated hydrochloric acid (40 ml), and at room temperature, acetic acid (4.0 ml, 70.5 mmol) and methanol (10 ml) were added, followed by cooling at 0° C., and tin(II) chloride dihydrate (15.9 g, 70.5 mmol) was gradually added. After stirred at the same temperature for 20 minutes, this was further stirred at room temperature for 20 minutes. At room temperature, methanol (30 ml) was added to the suspension, followed by stirring at the same temperature for 24 hours. The reaction liquid was fractionated with ethyl acetate and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was subjected to column chromatography with silica gel, and the fraction with chloroform:methanol=95:5 gave the entitled compound (6.475 g, 90%) as a pale brown gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])[CH2:30][CH2:31][C:32]([O-:34])=[O:33]
Reactant: O=C(O)CCC(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of succinic acid (0.59 g) in absolute ethanol (35 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 169.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:9]([O:24][C@@H:25]1[CH2:30][C@H:29]([CH3:31])[CH2:28][CH2:27][C@H:26]1[CH:32]([CH3:34])[CH3:33])(=[O:23])[C:10]([O:12][C@@H]1C[C@H](C)CC[C@H]1C(C)C)=O>C1COCC1>[O:12]=[C:10]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:24][C@@H:25]1[CH2:30][C@H:29]([CH3:31])[CH2:28][CH2:27][C@H:26]1[CH:32]([CH3:33])[CH3:34])=[O:23]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reactant: Brc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A Grignard reagent prepared from bromobenzene (2.36 g, 15.0 mmol) and magnesium (0.39 g, 16.0 mmol) in THF (25 ml) was added dropwise to a stirred solution of bis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl) oxalate (5.00 g, 13.7 mmol) in THF (25 ml) at −78° C. The mixture was slowly warmed to room temperature, quenched with a saturated solution of NH4Cl (50 ml) and ice. The reaction mixture was extracted with ether (2×) and water (2×) and the organic phase dried (Na2SO4). Repetitive column chromatography (SiO2, heptane/ether 9:1) gave 1.28 g (32%) of the pure product as a slightly yellow oil.
Reaction SMILES: CO.[S:3]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4]1)[NH:12][C:11]([C:16]([O:18]CC)=[O:17])=[CH:10]3.[Li+].[OH-]>C1COCC1>[S:3]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4]1)[NH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]3
Reactant: CCOC(=O)c1cc2c3c(ccc2[nH]1)OCCS3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c3c(ccc2[nH]1)OCCS3
Temperature: 70 °C
Yield: 79.9 %

Procedure:
A methanol solution of ethyl 2,3-dihydro-7H-[1,4]oxathiino[3,2-e]indole-8-carboxylate (0.067 g, 0.25 mmol) was treated with 1 N LiOH (4 mL). The reaction mixture turned cloudy and THF was added until the cloudiness disappeared. The reaction was heated to 70° C. until TLC showed consumption of the starting material. The reaction mixture was partitioned between EtOAc and water and the basic layer was separated. The basic layer was acidified with conc. HCl and extracted with EtOAc, the layers were separated and the EtOAc was evaporated to afford the title compound (0.047 g, 80%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 10.85 (br. s., 1H), 7.19 (d, 1H), 7.01 (s, 1H), 6.82 (d, 1H), 4.37-4.46 (m, 2H), 3.20-3.30 (m, 2H). LCMS: m/z=235.9 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=3)=[CH:18][C:13]=2[O:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][N:56]([C:59](=[O:70])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.O>[O:52]=[C:51]([N:53]1[CH2:54][CH2:55][N:56]([C:59](=[O:70])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])[CH2:57][CH2:58]1)[CH2:50][NH:49][C:24]([C:21]1[CH:20]=[C:19]([C:17]2[CH:16]=[CH:15][C:14]3[O:10][CH2:11][O:12][C:13]=3[CH:18]=2)[NH:23][N:22]=1)=[O:26]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccc3c(c2)OCO3)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccc3c(c2)OCO3)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 95.5 %

Procedure:
DIPEA (77 mg, 0.1 mL, 0.59 mmol) was added to a stirred solution of 5-benzo[1,3]dioxol-5-yl-1H-pyrazole-3-carboxylic acid (60 mg, 0.17 mmol))(prepared by the method as described above) in DMF (2 mL). HOBT (24 mg, 0.17 mmol) and EDCI (34.3 mg, 0.17 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (60 mg, 0.17 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 86 mg (95% yield) of 5-benzo[1,3]dioxol-5-yl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.365%. 1H NMR (DMSO-d6): δ 13.6 (s, 1H), 8.0 (s, 1H), 7.7 (m, 2H), 7.6 (m, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.0 (m, 2H), 6.0 (s, 2H), 4.1 (m, 2H), 3.7 (m, 2H), 3.54 (m, 2H), 3.4 (m, 2H), 3.1 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH2:31][CH:20]5[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH:19]5[CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:31][CH:20]5[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:23][CH:19]5[CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(C1=CC3CN(C(=O)OC(C)(C)C)CC3C1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC4CN(C(=O)OC(C)(C)C)CC4C3)cc12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of Example 262C (˜3.93 mmol) in tetrahydrofuran (28 mL) and methanol (20 mL) was added 1M aqueous sodium hydroxide (23.61 mL, 23.61 mmol) and the mixture was stirred at 60° C. for 3 hours. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 6-15% methanol in dichloromethane to give the title compound. LC-MS: 450 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2>C(O)CCC>[CH3:21][N:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]3)[N:7]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: CN(c1ccccc1CCc1ccnc(Cl)n1)S(C)(=O)=O
Solvent: CCCCO
Product: CN(c1ccccc1CCc1ccnc(Nc2ccc3c(c2)CCC(=O)N3)n1)S(C)(=O)=O
Temperature: 120 °C
Yield: 25.7 %

Procedure:
200 mg of N-{2-[2-(2-chloropyrimidin-4-yl)ethyl]phenyl}-N-methylmethanesulfonamide and 70 mg of 6-amino-3,4-dihydroquinolin-2(1H)-one are dissolved in 3 ml of n-butanol and warmed at 120° C. for 12 h in a sealed vessel. After cooling to room temperature, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 50 mg of the title compound as colourless solid;
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH2:7][N:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:5][CH2:4][CH:3]1[NH:18]C(=O)OC(C)(C)C>CO.[Pd]>[F:1][CH:2]1[CH2:8][CH2:7][N:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:5][CH2:4][CH:3]1[NH2:18]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(F)C(NC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(N)C(F)CC1

Procedure:
A solution of tert-butyl 5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (65 mg, 0.182 mmol) in MeOH (20 mL) was passed through the H-Cube® (full H2, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give the free amine, 5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine, as a pale yellow glass (51 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)C.[OH-].[NH4+:27].FC(F)(F)C(O)=O>>[N:11]1([C:9]2[S:10][C:6]([C:4]([NH2:27])=[O:3])=[C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:8]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: CCOC(=O)c1sc(-n2cnc3ccccc32)nc1-c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1sc(-n2cnc3ccccc32)nc1-c1ccccc1
Yield: 13 %

Procedure:
2-Benzoimidazol-1-yl-4-phenyl-thiazole-5-carboxylic acid amide was prepared from 2-Benzoimidazol-1-yl-4-phenyl-thiazole-5-carboxylic acid ethyl ester (75 mg, 0.21 mmol) and ammonium hydroxide as described above in the general amide formation procedure. Preparative HPLC with trifluoroacetic acid, 9.1 mg, 13% yield. MS M/z 321 (M+1).
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([N:12]1[C@H:17]2[CH2:18][CH2:19][C@@H:13]1[CH2:14][CH:15]([C:20](O)=[O:21])[CH2:16]2)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.O>[CH3:27][O:26][N:25]([CH3:24])[C:20]([CH:15]1[CH2:16][CH:17]2[N:12]([C:10]([O:9][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:11])[CH:13]([CH2:19][CH2:18]2)[CH2:14]1)=[O:21]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(C(=O)O)C2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: CON(C)C(=O)C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
EDC (2.99 g, 15.6 mmol) was added portion wise to a stirred solution of (1R,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, (2.0 g, 7.8 mmol), DMAP (10 mg), and N,O-dimethylhydroxylamine hydrochloride (1.52 g, 15.6 mmol) in dichloromethane (20 mL). Triethylamine (4.37 mL, 31.33 mmol) was added dropwise, and the reaction mixture was stirred at room temperature overnight. The resulting solution was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl 3-(methoxy(methyl)carbamoyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 73%) as a colorless oil, which was used without further purification; m/z for C15H26N2O4 expected 298.2. found 321.3 (M+Na)+, 299.3 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[C:29]([OH:37])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>C(O)C>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[C:29]([O-:37])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1
Reactant: O=C(O)c1cccnc1
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCO
Product: O=C([O-])c1cccnc1
Temperature: 0 °C

Procedure:
Amlodipine free base (4.09 g) was added to 40 mL of ethanol. The mixture was heated at reflux and stirred until the solid was completely dissolved. Nicotinic acid (1.23 g) was added to the amlodipine solution and then the mixture was slowly cooled down to 0° C. within one hour. The solids formed were isolated by filtration, washed with ethyl acetate and dried under reduced pressure to yield 4.51 g of amlodipine nicotinate.