Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4=CC=CC=C4C3=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCN(c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of N-[3-(4-phenyl-1-piperazinyl)propyl]phthalimide (18.3 g) in ethanol (300 ml) was added 100% hydrazine hydrate (5.3 g). The resulting mixture was refluxed with stirring for 2 hours. The reaction mixture was evaporated under reduced pressure. After the addition of dil aqueous solution of sodium hydroxide to the residue, the mixture was extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure to give 3-(4-phenyl-1-piperazinyl)propylamine (11.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][CH3:25])[CH:18]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][CH3:25])[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COc1cc(F)ccc1N
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC)c2c1C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (15.0 g), 4-fluoro-2-methoxyaniline (9.5 g), 4M hydrochloric acid in dioxane (4.5 ml) and dioxane (100.0 ml) were stirred at 100° C. overnight. Then the mixture was filtrated and the solid was dried in vacuo.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:12][C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC[N:21]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N>C(Cl)Cl.O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:12][C:13]([C:16]([NH2:21])=[O:18])=[CH:14][N:15]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cnc(C2CCC3(CC2)OCCO3)s1
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1cnc(C2CCC3(CC2)OCCO3)s1

Procedure:
A solution of 2-(1,4-Dioxa-spiro[4.5]dec-8-yl)-thiazole-5-carboxylic acid (as prepared in Example 52, Step C, 700 mg, 2.60 mmol), EDCI (600 mg, 3.12 mmol), HOBT (420 mg, 3.12 mmol) and TEA (490 μL, 3.50 mmol) in DCM (10 mL) were treated with 2N NH3 in dioxane (2 mL) at room temperature overnight. The solvent was removed in vacuo and the residue was purified by a CombiFlash® system using hexanes and ethyl acetate to afford the title compound as a white solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[S:25]([NH:28][C:29]1[C:34](Cl)=[N:33][C:32]([Cl:36])=[CH:31][N:30]=1)(=[O:27])=[O:26]>>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[S:25]([NH:28][C:29]1[C:34]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[N:33][C:32]([Cl:36])=[CH:31][N:30]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: OCc1ccc(COC2CCCCO2)cc1
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1ccc(CO)cc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Examples 106a and 106b using [4-(tetrahydro-2-pyranyloxymethyl)phenyl]methanol (2.0 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (1.0 g). Yield 0.7 g.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([N@@:44]2[CH2:46][CH:45]2[CH2:47][OH:48])=[O:43])=[CH:38][C:37]=1[O:49][CH3:50].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]5[N:15]=[C:16]([CH3:18])[O:17][C:13]=5[CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]([N@@:44]4[CH2:46][CH:45]4[CH2:47][OH:48])=[O:43])=[CH:38][C:37]=3[O:49][CH3:50])[N:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(C(=O)N2CC2CO)ccc1N
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CC2CO)ccc1Nc1nc(OC2CCCC2)c2c(-c3ccc4nc(C)oc4c3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), (R)-(4-amino-3-methoxyphenyl)(2-(hydroxymethyl)aziridin-1-yl)methanone (1.2 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.15 M) was added palladium acetate (0.3 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (2% MeOH in DCM) to afford the desired product (80% yield) as a white powder. MS (ESI) m/z 685.2 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[N:15]([CH2:16][CH:17]=[CH:18][C:19]#[N:20])[CH2:14][CH2:13][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:28]1[CH:32]=[C:31]([C:33]2[C:34]3[CH:41]=[CH:40][N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:35]=3[N:36]=[CH:37][N:38]=2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:1]([O:8][CH2:9][CH:10]1[N:15]([CH2:16][CH:17]([N:28]2[CH:32]=[C:31]([C:33]3[C:34]4[CH:41]=[CH:40][N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:35]=4[N:36]=[CH:37][N:38]=3)[CH:30]=[N:29]2)[CH2:18][C:19]#[N:20])[CH2:14][CH2:13][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CC=CC#N)C(CO[Si](C)(C)C(C)(C)C)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[3-cyanoprop-2-en-1-yl]piperazine-1-carboxylate (0.31 g, 0.78 mmol, as a mixture of E- and Z-isomers from Step 2) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.18 g, 0.56 mmol, prepared as described in WO 2007/070514 Example 65) in DMF (0.50 mL) was added potassium carbonate (0.23 g, 1.7 mmol). The mixture was stirred at ambient temperature overnight. The mixture was filtered, diluted with EtOAc, washed with water three times, and washed once with brine, dried over sodium sulfate, decanted and concentrated in vacuo. Flash chromatography, on a 40 g silica gel cartridge, eluting with a gradient from 0-70% EtOAc in hexanes afforded product as a mixture of diastereomers (330 mg, 83%). 1H NMR (400 MHz, CDCl3): δ 8.84 (s, 2H), 8.33-8.29 (m, 4H), 7.40 (d, 2H), 6.78 (d, 2H), 5.68 (s, 4H), 4.66-4.52 (m, 2H), 3.81-2.29 (m, 30H), 1.43 (s, 9H), 1.43 (s, 9H), 0.92 (dd, 4H), 0.91 (s, 9H), 0.87 (s, 9H), 0.09 (s, 6H), 0.04 (s, 6H), −0.06 (s, 18H); LCMS (M+H)+: 711.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[S:23][C:24]([CH3:30])=[C:25]([C:27]([OH:29])=[O:28])[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:22]1[S:23][C:24]([CH3:30])=[C:25]([C:27]([OH:29])=[O:28])[N:26]=1
Reactant: Cc1sc(Br)nc1C(=O)O
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(-c2nc(C(=O)O)c(C)s2)cccc1[N+](=O)[O-]
Yield: 26 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6a (1.7 g, 6.08 mmol), 2-bromo-5-methyl-thiazole-4-carboxylic acid (900 mg, 4.05 mmol), tetrakis(triphenylphosphine)palladium (233 mg, 0.2 mmol) and sodium carbonate (1.29 g, 12.16 mmol) were dissolved in 30 mL of 1,4-dioxane. The reaction mixture was heated to reflux for 4 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 20 mL of hydrochloric acid (1 N) and 30 mL of ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was recrystallized from a solvent mixture of ethyl acetate and hexane to obtain the title compound 2-(2-methoxy-3-nitro-phenyl)-5-methyl-thiazole-4-carboxylic acid 47a (310 mg, yield 26%) as a yellow solid.
Reaction SMILES: [H-].[Na+].CC[O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([O:34]COC)=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2[CH:30]=O)[CH3:19].O>CN(C)C=O>[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([OH:34])=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2/[CH:30]=[C:8](\[CH3:9])/[C:6]([OH:5])=[O:7])[CH3:19]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
36 g of 60% sodium hydride was suspended in 500 ml of N,N-dimethylformamide and 268 g of triethyl 2-phosphonopropionate was added at ice bath temperature. After stirring at room temperature for 1 hour, a solution of 206 g of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde was added. After stirring at room temperature for 15 minutes, ice cooled water was gradually added at ice bath temperature. The mixture was extracted with ethyl acetate and the combined organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 262.4 g of the titled compound as a yellow oil (containing a small amount of Z isomer).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[C:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:31]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1cncc(-c2ccccc2)c1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)nc1OCC
Temperature: 80 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (700 mg), 3-chloromethyl-5-phenylpyridine (500 mg), potassium carbonate (500 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (720 mg, yield: 67%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]2([F:13])[F:12].[C:14]([N:22]=C=O)(=[O:21])C1C=CC=CC=1.CCO.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:14]([NH2:22])=[O:21])[CH2:7][CH2:6][C:5]2([F:12])[F:13]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: FC1(F)CCNc2ncc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)N1CCC(F)(F)c2cc(Br)cnc21
Temperature: 50 °C
Yield: 87.6 %

Procedure:
A mixture of 6-bromo-4,4-difluoro-1,2,3,4-tetrahydro-[1,8]naphthyridine (86.2 mg, 0.35 mmol) and benzoyl isocyanate (85.9 mg, 0.51 mmol, 90%) in 5 mL CH2Cl2 is heated at 50° C. for 2 hrs. The mixture is concentrated the dryness. The residue is dissolved into 5 mL of EtOH, K2CO3 (81.2 mg, 0.59 mmol) is added and the mixture is heated at 50° C. for 2 h. The mixture is concentrated to dryness. The residue is dissolved into 20 ml of H2O and neutralized by the addition of AcOH. This is extracted with 60 mL EtOAc, washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated. The residue is applied to a silica preparative TLC plate and eluted (75% EtOAc/hexanes) to give 89.6 mg of 6-bromo-4,4-difluoro-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[CH3:16][O:17][C:18]1[N:23]2[N:24]=[C:25]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH:26]=[C:22]2[C:21]([C:34](=[O:37])[CH2:35][CH3:36])=[CH:20][CH:19]=1.Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>O1CCCC1>[CH3:16][O:17][C:18]1[N:23]2[N:24]=[C:25]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])[CH:26]=[C:22]2[C:21]([C:34](=[O:37])[CH:35]([CH3:36])[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCC(=O)c1ccc(OC)n2nc(C(F)(F)C(F)(F)F)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C)CC(=O)OC(C)(C)C)c2cc(C(F)(F)C(F)(F)F)nn12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In an argon atmosphere, a 1 mol/L lithium bis(trimethylsilyl)amide/tetrahydrofuran solution (4.14 mL) was added dropwise to a solution of the compound of Example 356 (1.16 g) in tetrahydrofuran (30 mL) at 0° C. The mixture was stirred at 0° C. for 20 min. Subsequently, t-butyl bromoacetate (0.797 mL) was added at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (200 mL). The extract was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The extract was then concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=2:1 v/v) to afford the title compound as a colorless powder (940 mg).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]1)[CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.[C:16]([OH:21])(=O)[CH:17]([CH3:19])[OH:18]>O>[CH2:1]([CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:16](=[O:21])[CH:17]([OH:18])[CH3:19])[CH2:6][CH2:7]1)[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:21])[CH:17]([OH:18])[CH3:19])[CH2:11][CH2:10]1
Reactant: NC1CCC(CC2CCC(N)CC2)CC1
Reactant: CC(O)C(=O)O
Solvent: O
Product: CC(O)C(=O)NC1CCC(CC2CCC(NC(=O)C(C)O)CC2)CC1
Reaction time: 4 h

Procedure:
Molten 4,4'-methylenebis(cyclohexylamine) (224.0 g, 1.065 moles) was placed in a 1 liter round bottom flask and 85% lactic acid (225.5 g, 2.13 moles) added slowly through an addition funnel with stirring and cooling. The resultant liquid was then heated in an oil bath to 190° C. whereupon distillation of water occurred. Heating was continued at 190° C. for 4 hours after which time distillation of water subsided and the liquid was poured into a Pyrex baking dish. Upon cooling the product solidified into a clear, amber colored glass. The solid was broken up and recrystallized twice from tetrahydrofuran containing 10% methanol to give lustrous, white flakes; m.p. 195°-199° C.; infrared (Nujol), 1640 cm-1, 3300 cm-1 ; proton nuclear magnetic resonance (DMSO-d6 /TMS, 100 MHz), δ0.6-1.5 (complex multiplet with doublet superimposed at δ1.15, 18 protons), δ1.5-1.8 (doublet, 8 protons), δ3.50 (broad singlet, 2 protons), δ3.7-4.1 (multiplet, 2 protons), δ5.35 (doublet, 2 protons), δ7.30 (doublet, 2 protons).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: COCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (78 mg, 62%), MS (ISP) m/z=417.5 [(M+H)+], mp 180° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4]([CH3:11])=[N:3]1.[CH3:12][CH:13]([C:18]1[CH:24]=[C:23]([C:25]([O:34][CH3:35])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=1[NH2:20])[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C>S(Cl)(Cl)=O.O1CCCC1.C(OCC)(=O)C>[CH3:12][CH:13]([C:18]1[CH:24]=[C:23]([C:25]([O:34][CH3:35])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])[CH:22]=[CH:21][C:19]=1[NH:20][C:8]([C:5]1[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7])=[O:10])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: Cc1nn(C)c(C)c1C(=O)O
Reactant: COC(c1ccc(N)c(C(C)CC(C)C)c1)(C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(c1ccc(NC(=O)c2c(C)nn(C)c2C)c(C(C)CC(C)C)c1)(C(F)(F)F)C(F)(F)F
Yield: 40.5 %

Procedure:
1,3,5-Trimethylpyrazole-4-carboxylic acid (154 mg, 1 mmol) was dissolved in thionyl chloride (5 ml), and the solution was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting acid chloride was added to a solution of 2-(1,3-dimethylbutyl)-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-aniline (345 mg, 1 mmol) and triethylamine (150 mg, 1.5 mmol) in tetrahydrofuran (10 ml) under ice-cooling, after which the resulting mixture was heated under reflux for 2 hours. The reaction mixture was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography. (hexane:ethyl acetate 1:2) to obtain 200 mg of the desired compound.
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH3:12])=[CH:10][C:9](=[O:13])[C:4]([C:5]([O:7]C)=[O:6])=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>[OH-].[Na+]>[CH3:1][N:2]1[C:11]([CH3:12])=[CH:10][C:9](=[O:13])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1c(-c2ccccc2)n(C)c(C)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(C(=O)O)c(-c2ccccc2)n1C
Yield: 86.4 %

Procedure:
6.0 g of crude methyl 1,6-dimethyl-2-phenyl-4-oxonicotinate is suspended in 66 g of 5% aqueous sodium hydroxide solution. The reaction mixture is heated on a steambath (85°) for two hours. The resulting homogeneous solution is cooled and acidified with dilute HCl. The resulting solid is collected by filtration yielding 4.9 g of 1,6-dimethyl-2-phenyl-4-oxonicotinic acid. mp (acetonitrile/methylene chloride)=246°-249° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][N:12]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[NH2:1][C:2]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C:15]3([CH2:11][N:12]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:13][CH2:14]3)[CH2:16][CH2:17]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3cc(N)ncc3C#N)CC2)C1

Procedure:
From intermediate 16 and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate, reacted in an analogous manner to the preparation of intermediate 42. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 6.66 (s, 2H), 5.90 (s, 1H), 3.10-3.32 (s, 8H), 1.69-1.79 (m, 2H), 1.52-1.66 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Li+].O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1ccc(F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2c1ccc(F)c(F)c1

Procedure:
The title compound was synthesized from methyl 4-(3,4-difluorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.333 g, 1.20 mmol) and lithium hydroxide (0.508 g, 12.1 mmol in 5 mL water), according to General Procedure 7. A 1:1 mixture of water and methanol (4 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound. 0.265 g. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.17 (ddt, J=12.70, 8.55, 6.38, 6.38 Hz, 1H), 2.67-2.94 (m, 3H), 4.15 (t, J=7.15 Hz, 1H), 6.53 (s, 1H), 6.93-6.98 (m, 1H), 7.01 (ddd, J=11.87, 7.77, 2.12 Hz, 1H), 7.11 (dt, J=10.59, 8.37 Hz, 1H); 19F NMR (376 MHz, METHANOL-d4) δ ppm −145.22-−145.11 (m, 1F) −141.41-−141.30 (m, 1F); LCMS (ESI−) 262.0 (M−H); HPLC (UV=99.7%), (ELSD=100%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([CH2:15][NH2:16])[OH:14].[C:17]([NH:24][C@@H:25]([C:27](O)=[O:28])[CH3:26])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C1COCC1>[C:20]([O:19][C:17](=[O:18])[NH:24][C@@H:25]([C:27](=[O:28])[NH:16][CH2:15][CH2:13][OH:14])[CH3:26])([CH3:21])([CH3:22])[CH3:23]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCO
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
In a round-bottomed flask, Boc-D-alanine (1.0 g, 5.29 mmol was dissolved in THF (40 ml) and 1,1′-carbonyldiimidazole (1.03 g, 6.34 mmol) was added. The reaction mixture was stirred at 60° C. for 45 min then cooled to room temperature and ethanolamine (3.2 ml, 52.9 mmol) was added. The reaction mixture was stirred at room temperature overnight then quenched with 1 M aqueous HCl (15 ml) and extracted with dichloromethane. The organic layer was washed with 1 M aqueous HCl, water and brine. The aqueous layers were back-extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 1.11 g (90%) of [(R)-1-(2-hydroxy-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester as a colorless oil.