Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][S:17](Cl)(=[O:19])=[O:18])=[O:15])[CH3:3].[CH2:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C1COCC1>[CH2:21]([O:27][S:17](=[O:18])(=[O:19])[NH:16][C:14]([NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:2]([CH3:3])[CH3:1])=[O:15])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)NS(=O)(=O)Cl
Reactant: CCCCCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCOS(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
A solution of [[[2,6-bis(1 methylethyl)phenyl]amino]carbonyl]sulfamoyl chloride (5.0 g, 15.7 mmoles) in 80 mL THF was added dropwise to a solution of n-hexanol (1.60 g, 15.7 mmoles) and excess triethylamine (~3 mL) in 150 mL THF at room temperature under an atmosphere of N2. This was stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between IN HCl and EtOAc and the organic layer was dried with MgSO4, filtered, and evaporated to give an oily tan solid. Trituration with acetone/hexanes (9:1) gave 1.56 g of the title compound as a white solid, mp 148-151° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:27](CC)CC)C.C([Cl:37])(=O)OCC.N.CO>C1COCC1>[ClH:37].[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22]([NH2:27])=[O:24])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1csc(Nc2ncccc2OCc2ccccc2)n1
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Cl
Product: NC(=O)Cc1csc(Nc2ncccc2OCc2ccccc2)n1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A 100 mL round-bottomed flask was charged with 2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)acetic acid (prepared according to Example 24; 0.050 g, 0.1465 mmol) and THF (30 mL) and cooled to −5° C. Triethylamine (0.03112 g, 0.3076 mmol) and ethyl carbonochloridate (0.07002 mL, 0.7323 mmol) were added successively, and the reaction mixture was stirred at −5° C. for 30 minutes. 7M NH3 in methanol (2.186 mL, 15.31 mmol) was added and the reaction mixture was stirred at −5° C. for 30 minutes and then at room temperature for 1 hour. The reaction mixture was washed with water, the organic layer was separated, dried and concentrated, and the residue was purified first by silica gel chromatography and then by reverse phase chromatography to give the title compound as the free base. The free base was dissolved in dichloromethane, and then 2M HCl in ether was added. The mixture was concentrated to provide 2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)-1-(4-methylpiperazin-1-yl)ethanone hydrochloride (0.024 g, 33.01% yield). 1H NMR (DMSO-d6) δ 11.04 (bs, 1H), 7.97 (d, 1H), 7.59 (m, 4H), 7.42 (m, 2H), 7.36 (m, 1H), 7.17 (bs, 1H), 7.10 (m, 1H), 6.96 (s, 1H), 5.33 (s, 2H), 3.57 (s, 2H). Mass spectrum (apci) m/z=341.0 (M+H-HCl).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1>CS(C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=2)[N:13]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][N:23]=2)[CH:12]=1)=[O:10]
Reactant: COC(=O)c1c[nH]c2ccc(C)cc12
Reactant: Clc1nccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2nccc3ccccc23)c2ccc(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
1.65 g (11.9 mmol) of potassium carbonate are added at 25° C. under an argon atmosphere to 0.900 g (4.75 mmol) of 3-methoxycarbonyl-5-methyl-1H-indole in 10 cm3 of dimethyl sulphoxide. After stirring at 25° C. for 0.5 hour, 0.677 cm3 (4.75 mmol) of 1-chloroisoquinoline is added. After stirring at 100° C. for 48 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and then washed with 3 times 50 cm3 of water and 25 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.50 g of a residue which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), 1.4 g of 3-methoxycarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole are obtained in the form of a white solid melting at 142° C.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[F:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[CH3:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(C)c(F)c1)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(C)c(F)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 54 %

Procedure:
3-[(3-Fluoro-4-methylbenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 65-A) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as white crystals (54% yield); mp 145° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.26 (3H, broad s, CH3), 3.11 (3H, s, NCH3), 3.73 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.83 (2H, s, NCH2), 6.99 (2H, m, aromatics), 7.16 (1H, m, aromatic). Anal. calcd for C15H17FN2O4: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.16; H, 5.44; N, 8.88.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:30][C:31](=[O:41])[C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[C:4]([CH2:42][OH:43])[CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:12][CH2:13]2)=[CH:6][C:5]([NH:30][C:31](=[O:41])[C:32]2[CH:33]=[CH:34][C:35]([N:38]([CH3:39])[CH3:40])=[CH:36][CH:37]=2)=[C:4]([CH:42]=[O:43])[CH:3]=1
Reactant: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c(CO)cc2Cl)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c(C=O)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 18.5 %

Procedure:
A solution of N-(4-chloro-2-(hydroxymethyl)-5-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)phenyl)-4-(dimethylamino)benzamide (60 mg, 0.099 mmol) in DCM (1.2 mL) was added to PCC (300 mg, 0.278 mmol) in an 8-mL vial. The reaction mixture was stirred at RT for 40 min. PCC on basic alumina was removed by filtration. The crude product was purified by flash chromatography (EtOAc/DCM, 20% gradient to 40%, Rf 0.66) to give 11.0 mg of the title compound. 1H-NMR (CDCl3, 400 MHz): δ 12.00 (1H, s), 9.77 (1H, s), 8.58 (1H, s), 7.97 (2H, d, J=9.0 Hz), 7.61-7.56 (2H, m), 7.52-7.45 (1H, m), 7.15-6.99 (2H, m), 6.77 (2H, d, J=9.0 Hz), 3.83 (3H, s), 3.80 (2H, s), 3.26 (2H, s), 3.17 (2H, s), 3.09 (6H, s), 2.59 (3H, s). HPLC/MS (Method H): (ES+) m/z (M+H)+=602; Rt=2.07 min.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21].[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)=[CH:30][NH:29][N:28]=1>>[F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:28]3[N:29]=[CH:30][C:31]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=4)=[C:27]3[N:26]=2)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(OCC(F)(F)F)c(C(F)(F)F)c1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(OCC(F)(F)F)c(C(F)(F)F)c4)nc23)ccn1
Yield: 67.6 %

Procedure:
Reaction of 1-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (176 mg, 68%). MS (ISP) 521.5 [(M+H)+]; mp 210° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH3:28])=[O:10])([CH3:5])[CH3:4])#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[CH:15]=[CH:14][C:13]([CH3:28])=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cc2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 80 °C
Yield: 93.7 %

Procedure:
A suspension of 3-(1-cyano-1-methylethyl)-N-[2-methyl-5-(4-nitrophenoxy)phenyl]benzamide (3.50 g, 8.0 mmol), calcium chloride (2.36 g, 21.2 mmol) and reduced iron (4.75 g, 85 mmol) in ethanol (180 mL)/water (20 mL) was stirred with heating at 80° C. for 10 hr. The reaction mixture was cooled to room temperature, passed through a pad filled with celite to separate insoluble material, and the insoluble material was washed with ethanol. The filtrate and the washing were combined and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with 5% aqueous ammonium chloride solution (200 mL), water (200 mL), 5% aqueous sodium hydrogencarbonate solution (200 mL) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (2.89 g, 94%) as a colorless amorphous substance.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=[O:11])=[O:5])C.[OH-].[Na+]>CO>[C:4]([CH2:6][O:7][C:8]1[C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([OH:12])=[O:11])([OH:5])=[O:3]
Reactant: CCOC(=O)COc1cccc(C(=O)OC)c1OCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc(C(=O)O)c1OCC(=O)O
Yield: 68.1 %

Procedure:
To a solution of methyl [2,3-bis(ethoxycarbonylmethoxy)]benzoate (58.0 g, 170 mmol) in methanol (100 mL) at 60° C. was added 3N-aqueous sodium hydroxide solution over 30 minutes, and the reaction mixture was refluxed for 2 hours. The solvent was then distilled off under reduced pressure. To that residue was added 4N-hydrochloric acid. The crystal was collected with filtration, and dried to provide 31.3 g of the title compound. Yield 68%.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:12]([O:14]C)=O)=[C:5]([N:9]=[C:10]=[S:11])[S:6][C:7]=1[CH3:8])[CH3:2].[N:16]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][N:18]=[CH:17]1>>[CH2:1]([C:3]1[C:4]2[C:12](=[O:14])[N:24]([CH2:23][CH2:22][CH2:21][N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)[C:10](=[S:11])[NH:9][C:5]=2[S:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCc1c(C)sc(N=C=S)c1C(=O)OC
Reactant: NCCCn1ccnc1
Product: CCc1c(C)sc2[nH]c(=S)n(CCCn3ccnc3)c(=O)c12

Procedure:
The compound was synthesized starting from methyl 4-ethyl-2-isothiocyanato-5-methylthiophene-3-carboxylate (0.010 g. 0.04 mmol) and 3-(1H-imidazol-1-yl)propan-1-amine (0.005 g, 0.04 mmol) as described above.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19]CC)=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].C(O)(=O)C.Cl>O>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([OH:19])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)CCN2C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2c(F)c(F)c(F)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Yield: 80.2 %

Procedure:
30 mg of the compound (198) obtained in Example 69 was added to 0.4 ml of acetic acid and 0.1 ml of 12 N hydrochloric acid, and the solution was heated at 100° C. for 2 hours. After air-cooling, water was added to the reaction solution, and deposited solids were filtered off and washed with water, ethanol and ether in this order to obtain 22 mg of the subject compound (199) in a 81% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:9][CH3:10].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:10][CH:9]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=C(c1ccccc1)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1C(=CCBr)c1ccccc1
Yield: 75.3 %

Procedure:
To a solution of 1-(2-methylphenyl)-1-phenyl-1-propene (9.0 g, 43 mmol) in carbon tetrachloride (40 ml), N-bromosuccinimide (7.7 g, 43 mmol) and benzoylperoxide (0.1 g) were added. The reaction mixture was heated at reflux temperature for 18 h. The cooled reaction mixture was filtered through silica gel and the solvent evaporated in vacuo to give 9.3 g (76%) of 3-bromo-1-(2-methylphenyl)-1-phenyl-1-propene.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:12][CH2:13][OH:14])[CH3:2].N1C2C(=CC=CC=2)C(CCO)=C1.[C:27]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])(=O)[CH:28]([CH3:30])[CH3:29]>>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][C:27]1([CH:28]([CH3:30])[CH3:29])[C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH2:12][CH2:13][O:14]1)=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:1][CH3:2])[CH3:37]
Reactant: CCc1cccc2c(CCO)c[nH]c12
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: OCCc1c[nH]c2ccccc12
Product: CCOC(=O)CC1(C(C)C)OCCc2c1[nH]c1c(CC)cccc21

Procedure:
Following the procedure of example 22.A. except using 2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component and ethyl iso-butyrylacetate as ketone component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 9.12 (br, 1H), 7.36 (d, 1H), 7.07 (m, 2H), 4.13 (m, 3H), 3.81 (m, 1H), 3.04 (q, 2H), 2.87 (m, 3H), 2.66 (m, 1H), 2.56 (m, 1H), 1.37 (t, 3H), 1.25 (t, 3H), 1.05 (d, 3H), 0.69 (d, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(O[C:32]1(O[Si](C)(C)C)[CH2:34][CH2:33]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:32]1([N:21]2[CH2:22][C:19]([CH2:23][C:24]#[N:25])([N:17]3[CH:18]=[C:14]([C:12]4[N:11]5[CH:26]=[CH:27][N:28]=[C:10]5[CH:9]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=5)[N:13]=4)[CH:15]=[N:16]3)[CH2:20]2)[CH2:34][CH2:33]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C5CC5)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
To a fine suspension of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62, 50.2 mg, 0.107 mmol) in 2:1 MeOH/acetic acid (0.60 mL) was added (1-ethoxycyclopropoxy)trimethylsilane (94.2 mg, 0.535 mmol) and the mixture was stirred at ambient temperature for 5 minutes. Sodium cyanoborohydride (42.5 mg, 0.642 mmol) was added in one portion and the mixture was stirred at 50° C. for 3 hours. The mixture was cooled to ambient temperature and concentrated to dryness. The residual white solid was partitioned into DCM and 1M K2CO3 (3 mL each) and the mixture was stirred until both layers were homogeneous. The DCM layer was removed and the aqueous layer was extracted with DCM. The combined DCM extracts were dried over Na2SO4, filtered through a Celite pad and concentrated to give a colorless glass. The glass was purified on a silica gel column eluting with a step gradient of EtOAc, 5% MeOH/EtOAc, and 10% MeOH/EtOAc to furnish the title compound (35 mg, 82% yield) as a white solid. MS (apci) m/z=400.2 (M+H).
Reaction SMILES: [NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][C:15](=O)[CH2:14]2)=[CH:9][CH:8]=1.Cl.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([C@H:31]([NH2:33])[CH3:32])[C:25]=2[O:24][CH2:23]1>>[NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][CH:15]([NH:33][C@@H:31]([C:30]3[C:25]4[O:24][CH2:23][O:22][C:26]=4[CH:27]=[CH:28][CH:29]=3)[CH3:32])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: NC(=O)CCNC(=O)c1ccc([C@H]2CCC(=O)C2)cc1
Reactant: C[C@@H](N)c1cccc2c1OCO2
Agent: Cl
Product: C[C@@H](NC1CC[C@H](c2ccc(C(=O)NCCC(N)=O)cc2)C1)c1cccc2c1OCO2

Procedure:
General procedure B was followed using N-(3-amino-3-oxo-propyl)-4-[(1S)-3-oxocyclopentyl]benzamide as the ketone and (1R)-1-(1,3-benzodioxol-4-yl)ethanamine hydrochloride as the amine. 1H NMR (600 MHz, DMSO) δ 8.39 (t, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.36-7.31 (m, 3H), 6.92 (d, J=7.8 Hz, 1H), 6.84-6.79 (m, 2H), 6.78-6.75 (m, 1H), 5.97 (s, 2H), 3.91 (q, J=6.7 Hz, 1H), 3.46-3.31 (m, 2H), 3.01-2.93 (m, 2H), 2.33 (t, 2H), 2.24-2.17 (m, 1H), 1.96-1.86 (m, 1H), 1.80-1.59 (m, 2H), 1.54-1.46 (m, 1H), 1.42-1.34 (m, 1H), 1.26 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[O:4][C:5]([C:8](OCC)=O)=[N:6][N:7]=1.B.[NH2:15][CH2:16][CH2:17][SH:18]>>[CH3:13][N:2]([CH3:1])[C:3]1[O:4][C:5]([CH2:8][S:18][CH2:17][CH2:16][NH2:15])=[N:6][N:7]=1
Reactant: CCOC(=O)c1nnc(N(C)C)o1
Reactant: NCCS
Agent: B
Product: CN(C)c1nnc(CSCCN)o1

Procedure:
When 2-dimethylamino-5-ethoxycarbonyl-1,3,4-oxadiazole [prepared according to the procedure described in Org. Magn. Resonance, 6, 144 (1974)] is hydrolyzed and reduced with borane as described in Example 58, Step A, and then is reacted with cysteamine according to the procedure described in Example 60, Step A, there is produced 2-[(2-dimethylamino-1,3,4-oxadiazol-5-yl)methylthio]ethylamine.
Reaction SMILES: [CH2:1]([N:17]=[C:18]=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25]>O1CCCC1>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][C:18]([NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19]
Reactant: CCCCCCCCCCCCCCCCN=C=O
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNC(=O)NCCCN(C)C

Procedure:
1.34 ml (5 meq) of hexadecyl isocyanate and 0.7 ml (5 meq) of 3-dimethylaminopropylamine are combined in 5 ml of tetrahydrofuran and reacted over a weekend at room temperature. The reaction mixture is filtered, washed with tetrahydrofuran, dried in vacuo and recrystallized from acetone to yield 1.2 gm of title compound with a m.p. of 78°-79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=1[OH:17])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:17][C:9]3[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1O)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2nc(-c3cccc(Cl)c3)oc12
Temperature: 190 °C
Yield: 102.7 %

Procedure:
A stirred suspension of N-(3-chlorobenzoyl)-2-hydroxy-3-nitroaniline (4.5 g, 0.0117 mol), p-toluenesulfonic acid (0.30 g) and 50 ml of diphenyl ether were heated at 190° C. for 1 hour. The dark reaction mixture was dissolved in 100 ml CH2Cl2 and washed with saturated sodium bicarbonate and then water. The CH2Cl2 was evaporated and hexane was added, causing a brown solid to separate. The dark solid was filtered, dissolved in 75% CH2Cl2 in hexane and washed onto a silica gel column. Elution with this solvent, gave 3.3 g of the title compound. This material could be recrystallized from methanol to give 2-(3-chlorophenyl)-7-nitrobenzoxazole although it was pure enough from the chromatography to use for the next step without any further purification.
Reaction SMILES: [OH:1][C:2]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=1)=[O:3].[H][H]>[Pt]=O.C(O)(=O)C>[CH:8]([CH:7]1[CH2:11][CH2:12][CH:4]([C:2]([OH:3])=[O:1])[CH2:5][CH2:6]1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)C1CCC(C(=O)O)CC1
Yield: 96.3 %

Procedure:
Platinum oxide (500 mg) as a catalyst was suspended in acetic acid (50 ml) and cumic acid (10 g, 61 mmole) was added thereto. The mixture thus obtained was stirred vigorously for 2 hours at room temperature under a pressure of hydrogen 5 kg/cm2. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to a solid state. The resultant substance was distilled under reduced pressure of 1 mmHg (1.3×10-3 kg/cm2), at 113°-116° C. to obtain 4-isopropylcyclohexane carboxylic acid yielding 10 g (96%) ij a ratio of 3 parts of cis-form per 1 part of trans-form by weight.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:23]([OH:31])(=[O:30])[C:24]([CH2:26][C:27](O)=[O:28])=[CH2:25]>C(OCC)(=O)C>[CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:23]([OH:31])=[O:30])[CH2:26][C:27]2=[O:28])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N)c1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)O)CC2=O)c1
Temperature: 25 °C

Procedure:
A mixture of 9.0 g. of N-decyl-3-(3-aminophenyl)propenamide and 3.9 g. of itaconic acid was heated as a melt at 140°-145° C. for 1 hour, and then ca. 70 ml. of ethyl acetate was added to the hot mass. The resulting mixture was stirred, and a solid appeared. The mixture was cooled to room temperature, and the solid was recovered by filtration to give 9.5 g. of the title compound. This product was recrystallized from acetonitrile to give 8.4 g. (69% yield) of product having a melting point of 152.5°-153.5° C.