Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:32])[C:29](O)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:32][C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:30]
Reactant: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)O
Reactant: C1COCCN1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N1CCOCC1
Yield: 33 %

Procedure:
Using the same procedure as in Example 44, (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (390 mg, 0.87 mmol) was reacted with morpholine to give the title compound as a white solid (148 mg, 33%); NMR Spectrum 1.58 (d, 3H), 3.40-3.75 (m, 8H), 5.88 (q, 1H), 6.04 (s, 2H), 7.29 (d, 1H), 7.36 (d, 1H), 7.66 (s, 1H), 7.73-7.78 (m, 3H), 7.88-7.90 (m, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.55 (s, 1H), 11.15 (br s, 1H); Mass spectrum MH+ 516.
Reaction SMILES: [CH3:1][C:2](C)=[O:3].[F:5][C:6]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]([OH:12])[NH:10][C:9](=[O:13])[NH:8][C:7]1=[O:14].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:2]([O:12][CH:11]1[NH:10][C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]1([F:5])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:3])[CH3:1]
Reactant: CC(C)=O
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O

Procedure:
In 10 ml. of acetone was dissolved 8.80 g. (40 m moles) of ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, and under ice-cooling, 5.10 g. (50 m moles) of acetic anhydride and 10 ml. of pyridine were added. The mixture was reacted at room temperature overnight. (A sample of the reaction mixture was taken, the solvent was distilled off under reduced pressure and the NMR spectrum of the residue was measured to ensure that there had been produced ethyl 6-acetoxy-5-fluoro-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH:32]=[N+:33]=[N-:34].C1C=CC=CC=1.[CH3:41][O:42][C:43](=[O:66])[C@H:44]([CH2:62][CH2:63][S:64][CH3:65])[NH:45][C:46](=[O:61])[C:47]1[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][C:48]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>O1CCCC1>[CH3:41][O:42][C:43](=[O:66])[C@H:44]([CH2:62][CH2:63][S:64][CH3:65])[NH:45][C:46](=[O:61])[C:47]1[CH:52]=[CH:51][C:50]([CH2:53][N:32]=[N+:33]=[N-:34])=[CH:49][C:48]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1
Temperature: 25 °C

Procedure:
To triphenylphosphine (1.0 equivalent) in tetrahydrofuran (THF) at −78° C. is added diethyl azodicarboxylate (1.0 equivalent) in THF. To this mixture is added a solution of hydrazoic acid in benzene (2.0 equivalents) and then the resultant compound from Example 16D (1.0 equivalent). After one hour the mixture was warmed to room temperature, stirred until the reaction is judged complete by TLC analysis, evaporated and chromatographed on silica gel to afford the title product.
Reaction SMILES: [NH:1]([C:8]([CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][O:19][CH3:20])[CH2:13][CH2:12]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+].O>O1CCCC1.C(OCC)(=O)C>[NH:1]([CH2:8][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][O:19][CH3:20])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOC1CCN(CC(=O)Nc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCOC1CCN(CCNc2ccccc2)CC1
Yield: 98.6 %

Procedure:
A solution of 3.64 g of 1-(anilinocarbonylmethyl)-4-methoxymethoxypiperidine in 10 ml of tetrahydrofuran was added to a suspension of 630 mg of lithium aluminum hydride in 50 ml of tetrahydrofuran. The mixture was refluxed for 3 hours. To the reaction mixture were added 1.5 ml of an aqueous solution containing 10% of potassium hydroxide and 1.5 ml of water. The mixture was diluted with ethyl acetate, and the dilution was filtered. The solvent in the filtrate was removed by distillation to obtain 3.41 g of 1-(2-anilinoethyl)-4-methoxymethoxypiperidine.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[OH:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=1[O:43][CH3:44].N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:40][C:39]1[CH:41]=[CH:42][C:36]([OH:35])=[C:37]([O:43][CH3:44])[CH:38]=1)=[O:28])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: COc1cc(N)ccc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-hydroxy-3-methoxyaniline (135 mg, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective product as a solid material.
Reaction SMILES: [SH:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[NH:4][N:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(O)C.[OH-].[Na+]>O>[CH2:29]([S:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[NH:4][N:3]=1)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CC(C)(C)c1ccc(-c2nc(S)n[nH]2)cc1
Reactant: CCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCSc1n[nH]c(-c2ccc(C(C)(C)C)cc2)n1
Temperature: 20 °C
Yield: 59 %

Procedure:
A mixture of 11.7 parts of 3-mercapto-5-(4-tert.-butylphenyl)-1,2,4-triazole, 12.5 parts of 1-bromododecane and 100 parts by volume of ethyl alcohol was heated at reflux temperature for four hours. After cooling to 20° C., a four percent weight/volume aqueous sodium hydroxide solution was added followed by 100 parts by volume of water. The precipitated product was filtered and dried yielding 59 percent of 3-(n-dodecylthio)-5-(4-tert.butylphenyl)-1,2,4-triazole which had a melting point of 87°-92° and the following elemental analysis:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)=O.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C.[Pd]>[N:24]1([CH2:1][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[O:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCCCOc1cccc(CN2CCCCC2)c1
Yield: 77.3 %

Procedure:
2-[3-[3-Formylphenoxy]propyl]-1H-isoindole-1,3-dione (50 g) and piperidine (20.7 g) in ethyl acetate (750 ml) were hydrogenated over 10% palladium/carbon catalyst. The catalyst was removed by filtration and the solvent evaporated and hydrazine hydrate (40 ml) was added to an ethanolic solution of the residue at 25°. After 67 hr the reaction mixture was diluted with ether, filtered and the filtrate was distilled to give the title compound as a colourless oil (31.05 g) b.p. 154°-8°/0.15 mm. TLC silica, methanol/0.88 ammonia 80:1, Rf 0.2.
Reaction SMILES: O[C@H:2]([CH2:35][CH3:36])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:35]([C@@H:2]1[O:6][C:5]([C:7]2[NH:8][C:9]([C:12]3[CH:17]=[C:16]([O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=3)=[CH:10][CH:11]=2)=[N:4][CH2:3]1)[CH3:36]
Reactant: CC[C@@H](O)CNC(=O)c1ccc(-c2cc(O[C@@H](C)COC)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2)[nH]1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H]1CN=C(c2ccc(-c3cc(O[C@@H](C)COC)cc(O[Si](C(C)C)(C(C)C)C(C)C)c3)[nH]2)O1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
N-[(2R)-2-Hydroxybutyl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (1.01 g, 1.95 mmol) synthesized in Example (106d) was dissolved in tetrahydrofuran (40 mL), and anhydrous methanesulfonic acid (600 mg, 3.44 mmol) and triethylamine (1.60 mL, 11.48 mmol) were added, followed by stirring at 50° C. for 8 hours under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-70%) to afford the desired compound (980 mg, yield 100%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].NCCCN1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.[F:50][C:51]([F:63])([F:62])[O:52][C:53]1[CH:61]=[CH:60][CH:59]=[CH:58][C:54]=1[C:55](Cl)=[O:56].ClC1C=CSC=1C(Cl)=O>>[O:24]=[C:5]1[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]1[CH2:3][CH2:2][NH:1][C:55](=[O:56])[C:54]1[CH:58]=[CH:59][CH:60]=[CH:61][C:53]=1[O:52][C:51]([F:50])([F:62])[F:63]
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: O=C(Cl)c1sccc1Cl
Product: O=C(NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)c1ccccc1OC(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 17, and making non-critical variations using 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 1′-(3-aminopropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(trifluoromethoxy)benzoyl chloride to replace 3-chlorothiophene-2-carbonyl chloride, the title compound was obtained (91%) as a colorless solid: mp 183-184° C.; 1H NMR (300 MHz, CDCl3) δ 7.86-7.83 (m, 1H), 7.50-7.45 (m, 1H), 7.37-7.27 (m, 3H), 7.16-7.11 (m, 2H), 7.07-7.02 (m, 1H), 6.84 (t, 1H), 6.47 (s, 1H), 6.10 (s, 1H), 5.82 (dd, 2H), 4.87 (d, 1H), 4.64 (d, 1H), 4.10-3.94 (m, 2H), 3.90-3.68 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.2, 165.0, 155.9, 148.8, 145.9, 142.3, 141.9, 132.4, 132.1, 131.3, 129.2, 127.6, 127.3, 124.0, 123.6, 121.2, 121.1, 119.2, 108.7, 103.0, 101.4, 93.6, 80.4, 58.2, 39.5, 38.2; MS (ES+) m/z 513.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([OH:23])[CH:19]=[N:20][C:21]=3[F:22])[N:10]=2)=[CH:5][CH:4]=1.Cl[C:36]([F:41])([F:40])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:40][CH:36]([F:41])[O:23][C:18]1[CH:17]=[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=3)[CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:10]=2)[C:21]([F:22])=[N:20][CH:19]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(O)cnc3F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(OC(F)F)cnc3F)n2)cc1
Temperature: 100 °C
Yield: 54.3 %

Procedure:
A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-ol (0.050 g, 0.108 mmol) in DMF (3 mL) was treated with sodium 2-chloro-2,2-difluoroacetate (Aldrich) (0.033 g, 0.217 mmol) and cesium carbonate (Aldrich) (0.053 g, 0.163 mmol). The reaction mixture was heated at 100° C. under N2 for 2 h. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with sat. NaHCO3, water, brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (12 g, 10% to 20% EtOAc in hexanes) to give the product as a white solid (0.030 g). m/z (ESI, +ve ion) 512.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J=7.45 Hz, 1H); 8.18 (br. s., 1H); 7.23 (d, J=7.89 Hz, 4H); 6.87 (t, J=7.60Hz, 4H); 6.23-6.83 (m, 1H); 4.82 (d, J=8.04 Hz, 4H); 3.81 (d, J=4.82 Hz, 6H); 2.55 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[N:33]1(OC(N(C)C)=[N+](C)C)[C:37]2C=CC=CC=2N=N1.CN>C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:20][CH2:21][CH:22]([C:25]([NH:33][CH3:37])=[O:26])[CH2:23][CH2:24]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)O)CC4)nc23)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: CNC(=O)C1CCN(c2ncc3ncnc(Nc4cccc(C)c4)c3n2)CC1

Procedure:
Prepared from compound 46 of Example 1 by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and methylamine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:33]=[N:32][C:18]3[N:19]([CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][C:23]([C:25]([O:27]C)=[O:26])=[CH:24][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:33]=[N:32][C:18]3[N:19]([CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][C:23]([C:25]([OH:27])=[O:26])=[CH:24][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)OC)CCCN3CCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)O)CCCN3CCC)cc1
Temperature: 90 °C
Yield: 89.7 %

Procedure:
To a solution of methyl 3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate (850 mg) in THF (30 ml) and methanol (30 ml) was added a 1 N aqueous sodium hydroxide solution (7.5 ml), and the mixture was heated at 90° C. for 3 hours. After cooling to 0° C., water was added thereto, and the mixture was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was washed with hexane to give 3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylic acid (739 mg) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.C(OCC)(=O)C>O1CCCC1.O>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(Cl)cc(Cl)cc1Br
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1c(Cl)cc(Cl)cc1Br

Procedure:
2.5 g of the acid 35.5 were dissolved in 25 ml of dry tetrahydrofuran and admixed dropwise at 0° C. with 9.26 ml of a 1 molar solution of lithium aluminum hydride in tetrahydrofuran with stirring. The reaction mixture was stirred at 0° C. for another 30 min and at room temperature for 2 h. For workup, the mixture was adjusted to pH 2 with 2.5 N sulfuric acid with cooling and admixed with ethyl acetate and water. The organic phase was removed, dried over magnesium sulfate and concentrated under reduced pressure. (2-Bromo-4,6-dichlorophenyl)methanol 35.4 was obtained and was used in the next stage without further purification.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([N:27]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[C:28](=[O:31])[CH2:29][CH3:30])[CH2:19][C@@H:18]2[CH3:39])=[O:16])=[CH:11][CH:10]=1)C.C(=O)([O-])[O-].[K+].[K+]>O.CO>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([N:27]([C:28](=[O:31])[CH2:29][CH3:30])[C@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:40])=[O:3])=[CH:14][CH:13]=3)=[O:16])[C@@H:18]([CH3:39])[CH2:19]2)=[CH:37][CH:36]=1
Reactant: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCC(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Yield: 31 %

Procedure:
(±)-Cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline1-carbonyl}-phenoxy)-butyric acid was prepared from (±)-cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester. Potassium carbonate (300 mg) was dissolved in water (5 mL) and (±)-cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester (171 mg, 0.303 mmol) was dissolved in methanol (5 mL) was added. The reaction was allowed to stir over night at room temperature. The methanol was removed in vacuo and hydrochloric acid (1 N) was added until acidic. Dichloromethane was added, extracted 2×; the combined organics were dried over magnesium sulfate, filtered and concentrated to afford the carboxylic acid (50 mg, 31%).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.[Pt]=O>[CH2:1]([NH:5][C:6]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1cccnc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCCCNC(=O)C1CCCNC1
Yield: 52.5 %

Procedure:
N-n-Butylnicotinamide (7.0 g) in acetic acid (100 ml) was hydrogenated over platinum oxide at 50° and 50 p.s.i. The catalyst was removed by filtration, the filtrate evaporated and the residue treated with toluene and evaporated in vacuo. The residue in chloroform (50 ml) was washed with sodium bicarbonate solution (3×50 ml) the organic layer separated, dried (Na2SO4) and the solvent evaporated in vacuo to give as an oil 3-(N-n-butylcarbamoyl)piperidine (3.8 g).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[CH2:7]([NH2:10])[CH:8]=[CH2:9].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:7]([NH:10][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[CH:8]=[CH2:9]
Reactant: CCC(=O)CC
Reactant: C=CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=CCNC(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-pentanone (1 g, 11.61 mmol) in anhydrous 1,2-dichloroethane (45 ml) is added allylamine (0.872 ml, 11.61 mmol) followed by NaBH(OAc)3 (3.44 g, 16.254 mmol) at ambient temperature and under nitrogen. The reaction is stirred at room temperature overnight. The reaction mixture is quenched with 1N NaOH and extracted with dichloromethane. The extract is dried over Na2SO4 and concentrated in vacuo to allyl-(1-ethyl-propyl)-amine
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[C:10]3[S:18][CH:19]=[CH:20][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([C:29](Cl)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.[OH-].[Na+].Cl>O1CCCC1CO>[NH:17]1[C:11]2[C:10]3[S:18][CH:19]=[CH:20][C:9]=3[N:8]([C:6]([C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:29]([C:24]4[C:23]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:30])=[CH:3][CH:4]=3)=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=[N:16]1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: O=C(Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)cc1)c1ccccc1-c1ccccc1
Yield: 57.5 %

Procedure:
As described for Example 2, 6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine (297 mg) is reacted with 0.542 g of [1,1'-biphenyl]-2-carbonyl chloride to give 0.70 g of bis acylated product. A mixture of this product in 13 ml of tetrahydrofuran-methanol (9: 4) and 2.3 ml of 1N NaOH is stirred for 18 hours at room temperature. To the mixture is added 2.3 ml of 1N HCl and the solvent removed. The mixture is triturated with 50 ml of CH2Cl2, filtered and the solid washed with CH2Cl2 and water to give 0.27 g of off-white crystals, m.p. 280°-284° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([C:29]#[CH:30])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)[OH:8])(=O)C.O>CO>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[C:17]([C:29]#[CH:30])=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([CH:7]([OH:8])[CH2:6][CH2:5][OH:4])=[CH:13][CH:12]=4)[N:19]=3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: C#Cc1cnc(-c2ccc(C(O)CCOC(C)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Solvent: O
Solvent: CO
Product: C#Cc1cnc(-c2ccc(C(O)CCO)s2)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of 3-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophen-2-yl)-3-hydroxypropyl acetate C-243 (390 mg, 0.92 mmol, 1.0 equiv.) in MeOH (10 mL) was stirred at 23° C., 1 NNaOH was added until the PH of the solution reached 11˜12. After 1 hour, H2O (20 mL) and 1 NHCl were added until the PH of the solution reached 3-4. The reaction mixture was extracted with THF and washed with water, brine, dried and evaporated. The crude product was crystallized with THF/isopropyl to afford 1-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophen-2-yl)propane-1,3-diol (Compound 242) (250 mg, 71.3%). LC-MS (m/z)=382.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75 (m, 2H), 0.98-1.00 (m, 2H), 1.84-1.88 (m, 2H), 1.93-1.98 (m, 1H), 3.47-3.59 (m, 2H), 4.53 (t, J=4.8 Hz, 1H), 4.84 (s, 1H), 4.92-4.96 (m, 1H), 5.72 (d, J=4.8 Hz, 1H), 6.54 (s, 1H), 7.02 (d, J=3.6 Hz, 1H), 7.72 (d, J=3.2 Hz, 1H), 8.45 (s, 1H), 8.55 (s, 1H), 12.27 (s, 1H).