Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[CH2:14]([CH2:18][C:19](=O)[CH3:20])[C:15]([CH3:17])=O.O>C1(C)C=CC=CC=1>[CH3:20][C:19]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[C:15]([CH3:17])=[CH:14][CH:18]=1
Reactant: COC(=O)C=Cc1ccc(N)cc1
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=Cc1ccc(-n2c(C)ccc2C)cc1
Reaction time: 16 h

Procedure:
A mixture of 21.4 g of methyl 4-aminocinnamate and 50 g of acetonylacetone in 500 ml of toluene is heated under reflux using a Dean Stark water separator for 16 hours. The solution is washed with ice cold dilute hydrochloric acid, brine, and then dried over magnesium sulfate. The organic phase is filtered through silica gel, evaporated at 60° under reduced pressure and the residue is crystallized from hexane to yield methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-cinnamate, m.p. 73°-75°. A solution of the ester in 150 ml of methanol and 100 ml 1N aqueous sodium hydroxide is stirred at room temperature for 16 hours. Methanol is evaporated at 60° under reduced pressure. The basic solution is washed with ethyl acetate, then made acidic with ice cold 5N aqueous hydroxhloric acid, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, treated with charcoal, and evaporated to dryness at 60° under reduced pressure. The residue is crystallized from ether/hexane (2:1) to yield (E)-4-(2,5-di-methyl-1H-pyrrol-1-yl)-cinnamic acid, m.p. 189°-191°, also named (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-2-propenoic acid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1(C(O)=O)[C:10]([OH:12])=[O:11].Cl.CCOCC>CN1C(=O)CCC1.O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C1(C(=O)O)Cc2ccccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)C1Cc2ccccc2C1
Temperature: 20 °C
Yield: 35.1 %

Procedure:
A solution of indane-2,2-dicarboxylic acid (17 g, Baeyer and Perkin, Ber. 1884, 17, 122) in NMP (200 ml) was heated to 150° C. for 1 hour. After cooling to 20° C. the solution was poured in water (300 ml) and concentrated hydrochloric acid was added to pH=1. Conventional work up with ether gave the title product (4.7 g). Mp 132-33° C. (from ether).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][C:16]1=[O:21])([CH3:14])[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[BrH:26]>C(Cl)(Cl)Cl>[Br:26][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C:16](=[O:21])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([O:24][CH3:25])=[O:23])[CH2:4][C@@H:3]1[OH:1]
Reactant: Br
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2α,3α-Epoxy-17β-methoxycarbonyl-5α-androstan-11-one (500 mg.) in chloroform (32 ml.) was stirred with 48% aqueous hydrogen bromide (10 ml.). After an hour the mixture was washed with an excess of aqueous sodium bicarbonate and with water, was dried (MgSO4) and evaporated to a froth (628 mg.) Crystallisation from ethyl acetate/light petroleum afforded title compound (330 mg.) as colourless needles; m.p. 205°-208°; [α]D + 76°,
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][NH:31][CH3:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:31]([CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])[CH3:32])=[O:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CNCCN(C)C
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCN(C)C(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.3 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (56 mg, 0.15 mmol) in DMF (1 mL) were added N1,N1,N2-trimethylethane-1,2-diamine (17 mg, 0.17 mmol), diisopropylethylamine (DIPEA) (59 pt, 0.34 mmol) and 2-(7 -aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (70 mg, 0.18 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 53 as a solid (11 mg).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]([CH2:31][CH2:32]Cl)C)=[CH:27][C:22]=2[O:21][CH2:20]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>CN(C=O)C>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][NH:29][CH2:31][CH2:32][N:14]3[CH2:15][CH2:16][CH2:17][CH:13]3[C:8]3[CH:9]=[C:10]([CH3:12])[N:11]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:7]=3)=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: Cc1cc(C2CCCN2)nc(-n2ccnc2)n1
Reactant: CN(CCCl)Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2CCCN2CCNCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Temperature: 80 °C
Yield: 60.7 %

Procedure:
A solution of 2-imidazol-1-yl-4-methyl-6-pyrrolidin-2-yl-pyrimidine (2.1 g, 9.2 mmol) in DMF (15 mL) was added all at once to a stirred mixture of benzo[1,3]dioxol-5-ylmethyl-(2-chloro-ethyl)-methyl-amine hydrochloride salt (2.2 g, 8.1 mmol), DMF (10 mL) and diisopropylethylamine (2.5 mL) at ambient temperature under nitrogen. A catalytic amount of potassium iodide (340 mg, 2.0 mmol) is then added. The mixture is heated to 80° C. for 3 h. The solution is then cooled to room temperature, quenched into 200 mL of 1N dibasic potassium phosphate solution (pH 9), and extracted with ethyl acetate. The combined organics are dried over MgSO4, filtered and concentrated to a red residue. Purification via silica gel column chromatography (DCM to 4:1 DCM/MeOH) gave 2.0 g (52%) of benzo[1,3]dioxol-5-ylmethyl-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-amine as a red oil. [M+H]+ 421.30; 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.89 (s, 1H), 7.30 (s, 1H), 7.10 (s, 1H), 6.78 (s, 1H), 6.67 (m, 2 H), 5.88 (s, 2H), 3.52 (t, 1H, J=6.8 Hz), 3.6 (m, 3H), 2.77 (m, 1H), 2.2-2.6 (m, 8H), 1.62-1.95 (m, 3H). 13C-NMR (100 MHz, CDCl3) δ 175.7, 169.6, 154.0, 147.6, 146.5, 136.2, 132.8, 130.1, 121.9, 116.6, 115.0, 109.2, 107.8, 100.8, 69.8, 62.3, 56.0, 54.3, 53.1, 42.5, 33.2, 24.2, 23.4.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C@H:10]([C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[CH3:50][C:51]([CH3:57])([CH3:56])[CH2:52][C:53](Cl)=[O:54]>C(Cl)Cl>[C:22]1([C@H:10]2[C@H:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[CH2:12][N:8]([C:53](=[O:54])[CH2:52][C:51]([CH3:57])([CH3:56])[CH3:50])[CH2:9]2)[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44654.2 %

Procedure:
To a solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 450 μmol) in DCM (5 mL) under a nitrogen atmosphere was added 4M HCl in dioxane (1.7 mL, 6.8 mmol). The mixture was stirred at room temperature for 2 h. The solvent was then removed under vacuum and the residue dissolved in DCM (5 mL). DIPEA (320 μL, 1.8 mmol) and 3,3-dimethylbutanoyl chloride (72 mg, 0.54 μmol) were added and the mixture stirred at roomt for 16 h. The solvent was removed under vacuum and the residue dissolved in DCM, washed with saturated sodium carbonate solution and water and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/hexanes). The resulting solid was recrystallised from methanol to yield 1-[(3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidin-1-yl]-3,3-dimethyl-butan-1-one as a white solid (106 mg, 53%). M.p.=202-204° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.82 (dd, J=7.2 and 1.6 Hz, 1H), 7.56 (dd, J=14.0 and 8.0 Hz, 1H), 7.38 (dd, J=13.6 and 8.0 Hz, 1H), 7.30-7.18 (m, 3H), 7.02 (t, J=8.0 Hz, 1H), 6.93 (m, 1H), 6.86 (m, 1H), 6.77 (m, 1H), 4.21-3.89 (m, 6H), 3.65-3.36 (m, 2H), 2.83 (t, J=5.6 Hz, 2H), 2.21 (s, 2H), 2.04 (m, 2H), 1.04 (s, 9H). LCMS: m/e 440.20 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH2:25]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH3:26]>CN(C=O)C.CS(C)=O.CO>[CH2:25]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:34][CH2:35]1)(=[O:29])=[O:28])[CH3:26]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 110 mg, 0.315 mmol) and 1-(ethylsulfonyl)piperazine (174 mg, 0.957 mmol) in DMF (1.28 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (35-45% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (59.9 mg, 39%). Melting point (176.4-180.4° C.). 1H NMR (DMSO-d6) δ: 10.91 (s, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.36 (s, 1H), 6.20 (s, 1H), 3.69-3.93 (m, 4H), 3.34-3.55 (m, 4H), 3.16 (q, J=7.3 Hz, 2H), 2.39 (s, 3H), 1.45 (s, 6H), 1.26 (t, J=7.3 Hz, 3H); ESI-MS: m/z 487.3 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10](=[O:33])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:29]([F:32])([F:31])[F:30])=[N:18][C:19]([C:20](=[O:28])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:13]2[CH2:12]1)(C)(C)C.[ClH:45]>C(OCC)(=O)C>[ClH:45].[ClH:45].[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]([C:19]1[N:18]=[C:17]([C:29]([F:30])([F:31])[F:32])[N:14]2[CH2:15][CH2:16][N:11]([C:10](=[O:33])[CH2:9][C@H:8]([NH2:7])[CH2:34][C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[CH2:12][C:13]=12)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 89 %

Procedure:
(R)-[3-Oxo-3-[1-(pyridin-2-ylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 21a (0.1 g, 0.16 mmol) was added to a solution of 2.2 N hydrochloric acid in 10 mL of ethyl acetate. The reaction mixture was reacted at room temperature for 4 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (pyridin-2-yl)amide dihydrochloride 21 (80 mg, yield 89%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:12])[CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][C:30](Cl)=[O:31])[CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH2:19]([C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][C:30]([C:16]2[CH:15]=[CH:14][C:13]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:12])[CH2:10][CH3:11])=[CH:7][C:2]=3[F:1])=[CH:18][CH:17]=2)=[O:31])[CH2:27][CH2:28]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC[C@H]1CC[C@H](CC(=O)Cl)CC1
Reactant: CCC(C)Cc1ccc(-c2ccccc2)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H](CC(=O)c2ccc(-c3ccc(CC(C)CC)cc3F)cc2)CC1
Temperature: 23 °C

Procedure:
A mixture of (+)-2-Fluoro-4(2-methylbutyl)biphenyl (10 gram) and trans-4-n-butylcyclohexylacetyl chloride (9.4 gram) in dichloromethane (20 ml) was added over 20 minutes to a cooled (5°-10° C.), stirred suspension of anhydrous aluminium chloride 6.1 gram) in dichloromethane (20 ml). After the addition the reaction mixture was allowed to warm to 23° C. and left stirring for 17 hours. The resulting solution was added to water (200 ml), extracted successively with petroleum spirit (bp. 60°-80°:180 ml +100 ml). The organic extract was then washed with water (200 ml), dried over anhydrous sodium sulphate (5 gram) and evaporated. The yellow crystalline residue (17.9 gram) was recrystallised from ethanol (35 ml) at 25° C. to give the product (14.8 gram; 85% yield). The product had mp=71.4°-72.1° C.; VirtualCH-I, (68.5°-68.8° C.). It was found to be 99.5 % pure by glc.
Reaction SMILES: [C:1]([CH:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[OH:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.C1OCCOCCOCCOCCOCCOC1.[N+:34]([C:37]([CH3:39])=[CH2:38])([O-:36])=[O:35]>C(#N)C.O1CCCC1>[N+:34]([CH:37]([CH3:39])[CH2:38][O:6][CH:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:1]([CH3:4])([CH3:3])[CH3:2])([O-:36])=[O:35]
Reactant: CC(C)(C)C(O)C(C)(C)C
Reactant: C=C(C)[N+](=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(COC(C(C)(C)C)C(C)(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Di-t-butylmethanol is added to a dry flask under argon at 0° C. Dry tetrahydrofuran is added with a syringe. Sec-Butyl lithium (1.5M in Hexanes) is added quickly in one portion and the contents of the flask are stirred for one hour at room temperature. A 10 mM solution of 18-crown-6-ether in acetonitrile is added with a syringe and the flask cooled to 0° C. A tetrahydrofuran solution of 2-nitropropene is added with vigorous stirring over a 10 minute period. After completion of the reaction as judged by thin layer chromatography, it is quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield 2-nitro 1-[di-(t-butyl)methoxy]propane.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.S([O-])([O-])(=O)=O.[Mg+2].[H][H].[C:27]([O:30][CH2:31][CH3:32])(=O)[CH3:28]>[Pt]>[CH2:27]([O:30][CH2:31][C:32]1[N:4]([CH2:3][CH:2]([CH3:18])[CH3:1])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:28]
Reactant: [H][H]
Reactant: CCOC(C)=O
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 130 °C
Reaction time: 2.5 h

Procedure:
4-(2-Methylpropylamino)-3-nitroquinoline (30.5 g; 0.12 mol) was added to a mixture of ethyl acetate (800 mL), 5% platinum on carbon (1.5 g) and magnesium sulfate (10 g). The mixture was hydrogenated on a Parr apparatus at an initial hydrogen pressure of 30 psi. When the hydrogenation was complete, the solids were removed and the ethyl acetate was evaporated. The resulting intermediate diamine was mixed with ethoxyacetic acid (80.5 mL) and heated with stirring at 130° C. for 2-3 hours. The reaction mixture was cooled, poured into 400 mL of water and then made basic with 6N sodium hydroxide. A green solid was collected and dried to provide 8.8 g of the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy. The filtrate was extracted with ether (4×150 mL). The ether extracts were combined then evaporated to provide 11.2 g of a green solid. The solids were combined and used in subsequent reactions.
Reaction SMILES: [CH2:1]([N:18]=[C:19]=[O:20])[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][CH2:16][CH3:17].O.C(Cl)(Cl)Cl.[CH2:26]([OH:30])[CH2:27][CH2:28][OH:29]>C(Cl)Cl>[CH2:1]([NH:18][C:19]([O:29][CH2:28][CH2:27][CH2:26][OH:30])=[O:20])[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][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCN=C=O
Reactant: OCCCO
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCNC(=O)OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
In a mixture of 5.7 g of 1,3-propanediol and 30 ml of methylene chloride is dissolved 5.0 g of n-heptadecyl isocyanate and the mixture is stirred at room temperature overnight. To the reaction mixture are added 20 ml each of water and chloroform, and the organic layer is taken and concentrated to dryness. Then, silica gel column chromatography is carried out [eluent: chloroform-water (97:3)] and the eluate is concentrated to dryness. The procedure provides 3.0 g of the above-indicated compound as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[S:5]C(Cl)=C[CH:8]=1)(=O)[CH3:2].[Cl:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.N1CCOCC1.[S]>CC(=O)CC>[NH2:20][C:19]1[S:5][C:4]([CH3:8])=[C:1]([CH3:2])[C:18]=1[C:16]([C:14]1[S:15][C:11]([Cl:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: N#CCC(=O)c1ccc(Cl)s1
Agent: [S]
Solvent: CCC(C)=O
Solvent: C1COCCN1
Product: Cc1sc(N)c(C(=O)c2ccc(Cl)s2)c1C
Yield: 46 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-chlorothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-chlorothiophene-2-carbonyl)acetonitrile (Steps A and B). 2-Butanone (Aldrich), 2-(5-chlorothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 46%; IR (KBr) cm−1: 3377, 3259, 2918, 1551, 1424, 1326, 1266, 1003, 764; 1H NMR (CDCl3):δ1.90 (s, 3H), 2.17 (s, 3H), 5.77 (bs, 2H), 6.89 (d, 1H, J=4 Hz), 7.16 (d, 1H, J=4 Hz); red solid, mp: 125-127° C. (petroleum ether).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[C:8]([F:22])[CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[C:8]([F:22])[CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3F)nc2c1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3F)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (118 mg) and piperidine (1.5 mL) were heated at 100° C. for 2.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with additional ethyl acetate (10 mL) and the organic portions combined and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (130 mg). 1H-NMR (CD3OD) δ 8.22 (d, J=8.0 Hz, 1H), 7.98 (m, 2H), 7.27 (s, 1H), 6.76 (m, 3H), 4.00 (t, J=6.0 Hz, 2H), 2.48 (m, 6H), 2.38 (s, 3H), 1.96 (m, 2H), 1.61 (m, 4H), 1.47 (m, 2H)
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6](Br)[C:5]([F:10])=[C:4]([C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=2[F:20])[N:3]=1.C(N(CC)CC)C.C(O)C>ClCCl.[Pd]>[F:10][C:5]1[C:4]([C:11]2[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:12]=2[F:20])=[N:3][CH:2]=[C:7]([F:8])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc(Br)c(F)c(Br)c2F)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccc(F)c(-c2ncc(F)cc2F)c1

Procedure:
To 2,4-dibromo-3,5-difluoro-6-(2-fluoro-5-nitrophenyl)pyridine (1.20 g, 2.91 mmol) dissolved in dichloromethane (30 ml) was added triethylamine (3 ml) and ethanol (80 ml), followed by 10% palladium on carbon (0.536 g). The mixture was then shaken under an atmosphere of hydrogen gas at 45 psi until complete reaction was indicated by TLC (0.25 to 3.5 h). The catalyst was then removed by filtration, and the solvent was stripped at reduced pressure to afford 3-(3,5-difluoropyridin-2-yl)-4-fluorophenylamine, which was used subsequently without further purification: MS (ES+) m/z 225 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[C:25]4[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][C:24]=4[NH:23][N:22]=3)=[O:20])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.C(Cl)[Cl:42].Cl>CCOCC>[ClH:42].[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[C:25]4[CH2:26][NH:27][CH2:28][CH2:29][C:24]=4[NH:23][N:22]=3)=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:8]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)c2C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (53, 142 mg, 0.26 mmol) in 1:1 MeOH/CH2Cl2 (2 mL) was added HCl (2N in Et2O, 2 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the resulting solids were collected by filtration to give (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (54) as an off-white solid (127 mg, >99%): 1H NMR (500 MHz, DMSO-d6) δ 9.28 (br s, 2H), 8.02-7.98 (m, 2H), 7.96-7.92 (m, 1H), 5.30-5.09 (m, 1H), 4.78-4.55 (m, 1H), 4.28-4.14 (m, 2H), 3.43-3.28 (m, 2H, overlaps with H2O), 3.26-3.07 (m, 2H), 3.02-2.90 (m, 2H), 2.89-2.75 (m, 1H), 2.00-1.82 (m, 2H), 1.80-1.61 (m, 2H), missing N—H pyrazole; ESI MS m/z 447 [M+H]+.