Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:41]([O:42][CH3:43])=[CH:40][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:41]([O:42][CH3:43])=[CH:40][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[O:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCN(C)CC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CC(=O)N1CCN(C)CC1)CC2
Yield: 32 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-(4-methyl-piperazin-1-yl)-ethanone. Product was isolated as a white foam (38 mg, 32%). mp: 190° C. (glass 140), MS (ESI+): 595.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.65 (s, 1H), 6.57 (d, J=8 Hz, 1H), 5.60 (br s, 1H), 5.32 (s, 1H), 4.46 (t, J=9 Hz, 1H), 3.88 (s, 3H), 3.72 (m, 2H), 3.67 (m, 2H), 3.30 (s, 2H), 3.09 (s, 1H), 2.89 (s, 5H), 2.68 (s, 4H), 2.53 (d, J=8 Hz, 1H), 2.46 (m, 2 h), 2.41 (m, 2H), 2.34 (s, 3H), 2.28 (d, J=8 Hz, 1H), 1.67 (d, J=9 Hz, 1H), 1.27 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([O:28]C2CCCCO2)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=3.O[CH2:36][CH2:37][C:38]([O:40]CC1C=CC=CC=1)=[O:39].CN(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CC(OC)(C)C>[OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([O:18][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:17])[CH:10]=[CH:9][CH:8]=3
Reactant: CCCCCC(CCC1C(O)CC2Cc3c(cccc3OCC(=O)O)CC21)OC1CCCCO1
Reactant: O=C(CCO)OCc1ccccc1
Agent: CN(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCCCCC(O)CCC1C(O)CC2Cc3c(cccc3OCC(=O)OCCC(=O)O)CC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Compound B (120 mg, 0.25 mmol), benzyl 3-hydroxypropionate (54 mg, 0.30 mmol) and trimethylamine (140 μL, 1.0 mmol) in DCM (4 mL) was added BOP—Cl (95 mg, 0.38 mmol). The reaction mixture was stirred at RT for 16 hr under nitrogen, diluted with MTBE, washed with brine, dried over sodium sulfate, and concentrated to an oil that was purified by silica gel chromatography. A solution of the THP-protected diester in ethanol (4 mL) was treated with PPTS (50 mg), stirred at 50° C. for 4 hr, and concentrated to an oil that was purified by silica gel chromatography. A solution of the THP-deprotected diester in dioxane (5 mL) was treated with wet 5% Pd/C (20 mg) and stirred for 24 hr under a balloon of hydrogen. The reaction mixture was filtered and concentrated to give crude Compound II-4. MS: m/z 485 [M+Na]+
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7](=[O:42])[CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:39][CH3:40])([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]([OH:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:38])[CH:25]=3)[CH2:22][CH3:23])=[CH:17][C:16]=2[CH3:41])=[CH:13][CH:14]=1)C.Cl>CO>[CH2:22]([C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[CH:10][C:9]([CH2:8][C:7]([OH:42])=[O:6])=[CH:14][CH:13]=2)=[C:16]([CH3:41])[CH:17]=1)([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]([OH:37])[C:33]([CH3:35])([CH3:36])[CH3:34])=[C:26]([CH3:38])[CH:25]=1)[CH2:39][CH3:40])[CH3:23]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cn2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A mixed solution of a 6 N sodium hydroxide aqueous solution (0.003 mL) with water (0.01 mL) was added to a solution of [6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example 23-(3); 1.7 mg, 0.0032 mmol) in methanol (0.07 mL) at room temperature, and the mixture was stirred at room temperature for four hours. The mixture was acidified with a hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (1.6 mg, 100%).
Reaction SMILES: C[N:2]1[CH2:15][CH2:14][C@@:13]23[C:16]4[C:22]5[CH2:23][C@@H:3]1[C@@H:4]2[CH2:5][CH2:6][C:7]1([C@@H:12]3[O:18][C:17]=4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=5)[O:11][CH2:10][CH2:9][O:8]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC1(C)CC(=O)CC(=O)C1.CO.Cl>CN(C)C=O>[O:8]1[CH2:9][CH2:10][O:11][C:7]21[CH2:6][CH2:5][C@@H:4]1[C@@:13]34[C:16]5[C:22](=[CH:21][CH:20]=[C:19]([C:24]#[N:25])[C:17]=5[O:18][C@@H:12]23)[CH2:23][C@H:3]1[NH:2][CH2:15][CH2:14]4
Reactant: CN1CC[C@]23c4c5ccc(C#N)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1ccc2c3c1O[C@H]1C4(CC[C@H]5[C@@H](C2)NCC[C@@]351)OCCO4
Temperature: 55 °C
Yield: 81 %

Procedure:
To a suspension of (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (5.0 g, 17.8 mmol) in dimethylformamide (50 mL) was added diisopropyl azodicarboxylate (5.4 mL, 27.5 mmol). The reaction was heated to 55° C. for 3 hours until the starting material was consumed. To the reaction was added dimedone (5.8 g, 41.4 mmol) and methanol (1.75 mL, 54.8 mmol) and the reaction heated to 60° C. for 3 hours. The reaction was allowed to cool to room temperature and poured into 0.5 M HCl(aq) (50 mL). The aqueous phase was washed with diethyl ether: ethyl acetate (3:1). The organic phase was back extracted with 0.5 M HCl(aq) and acidic phases combined before basifying with 2M NaOH until pH9. The aqueous phase was extracted with ethyl acetate (×3). The combined organic phases were washed with water/brine (×3) before drying over MgSO4 and concentrating under reduced pressure. The residue was purified by silica chromatography (5% methanol in dichloromethane to 5% NH3/methanol in dichloromethane) to give to (4R,4aR,7aR,12bS)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile as a pale yellow solid (3.90 g, 95% pure LCMS, 81% yield); [M+H]+ 325.1.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1.[O-]CC.[Na+].[CH:55]([C:57]1[N:58]([CH3:62])[CH:59]=[CH:60][N:61]=1)=O.O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9](/[CH:16]=[CH:55]/[C:57]1[N:58]([CH3:62])[CH:59]=[CH:60][N:61]=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Cn1ccnc1C=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(/C=C/c2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
[6,7-Dimethoxy-4-(3,4-dimethoxyphenyl)-3-ethoxycarbonylquinolin-2-yl]methyltriphenylphosphonium chloride (17.4 g) was added at room temperature to a solution of sodium ethoxide in ethanol (prepared from Na (0.62 g) and ethanol (150 ml)). Then a solution of 2-formyl-1-methylimidazole (3.7 g) in ethanol (20 ml) was added dropwise. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/methanol (100/1, v/v) gave ethyl (E)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[2-(1-methylimidazol-2-yl)vinyl]quinoline-3-carboxylate (8.3 g, 67%) which was then recrystallized from ethyl acetate.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C@@H:13]([OH:23])[CH2:14][CH2:15]2)=[CH:10][CH2:9]3)[CH2:6][CH:5]=1.[NH2:25][C:26]([NH2:28])=[S:27]>C(O)C>[NH2:28][C:26]1[S:27][CH:2]=[C:3]([C:4]2[C@:21]3([CH2:20][CH2:19][C@H:18]4[C@@H:8]([CH2:9][CH:10]=[C:11]5[C@:16]4([CH3:17])[CH2:15][CH2:14][C@H:13]([OH:23])[CH2:12]5)[C@@H:7]3[CH2:6][CH:5]=2)[CH3:22])[N:25]=1
Reactant: NC(N)=S
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(C(=O)CBr)=CC[C@@H]12
Solvent: CCO
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3csc(N)n3)=CC[C@@H]12
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Dissolve 16-dehydropregnenolone (5.00 g, 15.90 mmol) and 5,5-dibromobarbituric acid (4.55 g, 15.90 mmol) in tetrahydrofuran (60 mL). Add concentrated aqueous hydrogen bromide (100 μL of a 48% solution) to the stirring solution and heat the reaction at reflux for 1 hour. Cool slightly and then concentrate under vacuum to produce a brown oily foam. Dissolve the residue in methylene chloride (350 mL), rinse with 50% saturated sodium bicarbonate (2×200 mL), brine (125 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide 21-bromo-3β-hydroxypregna-5,16-dien-20-one (6.53 g) as an orange-brown solid, slightly contaminated with starting material. Scheme II, step B; Suspend 21-bromo-3β-hydroxypregna-5,16-dien-20-one (16 mmol) in ethanol (260 mL) and add thiourea (1.33 g, 17.5 mmol). Heat the reaction at reflux for 1 hour and distill off approximately half of the solvent. Allow the reaction to cool to room temperature. Collect the solid by filtration and dry under high vacuum to provide the title compound (3.62 g) as a bright yellow solid. Concentrate the filtrate to approximately 20 mL to provide a second crop, dry under high vacuum and combine with the first crop to provide a total of 4.25 g. Recrystallize this from ethanol to provide the title compound (2.77 g) as a white crystalline solid , mp 258-260° C. (dec); 1H NMR (DMSO-d6) δ 8.85 (broad singlet, 2H), 6.81 (s, 1H), 6.28 (dd, 1H, J=1.9, 3.3 Hz), 5.29 (broad doublet, 1H, J=4.7 hz), 3.43 (q, 2H, J=7.0 Hz), 3.32-3.18 (m, 1H), 1.05 (t, 3H, J=7.0 Hz), 0.99 (s, 3H), 0.94 (s, 3H); 13C NMR (DMSO-d6) δ 169.4, 142.5, 141.6, 135.6, 131.0, 120.1, 102.0, 69.9, 56.4, 55.9, 49.7, 46.1, 42.2, 36.8, 36.2, 34.4, 31.3, 31.2, 30.8, 29.7, 20.4, 19.0, 18.5, 15.8; MS (CI,CH4) m/z (rel. intensity) 371 (MH+, 76), 370 (33), 369 (34), 353 (100), 83 (26), 81 (27).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8](O)[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=1)[CH3:2].[Cl-].[Cl:15]C=[N+](C)C>C(Cl)(Cl)Cl>[CH2:1]([S:3][C:4]1[N:9]=[C:8]([Cl:15])[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=1)[CH3:2]
Reactant: C[N+](C)=CCl
Reactant: CCCc1cc(O)nc(SCC)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCCc1cc(Cl)nc(SCC)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.6 %

Procedure:
To the solution of 2-ethylthio-4-hydroxy-6-propylpyrimidine (406 mg) in CHCl3 (6 mL) was added (chloromethylene)-dimethylammonium chloride (Villsmier reagent) (786 mg). The reaction was stirred at room temperature under nitrogen for 40 min. Filtration through silica gel followed by removal of solvent provided 380 mg of the title compound as yellowish oil. 1H NMR (500 MHz, CDCl3): δ 6.81 (s, 1H); 3.17 (q, J=7.3 Hz, 2H); 2.65 (t, J=7.5 Hz, 2H); 1.76 (m, J=7.6 Hz, 2H); 1.41 (t, J=7.3 Hz, 3H); 0.99 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[CH3:29]O>>[CH3:29][O:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1ccc(Cl)cc1NC(=O)Nc1cccc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccc(NC(=O)Nc2cc(Cl)ccc2OC)c1

Procedure:
N-(3-carboxyphenyl)-N'-(2-methoxy-5-chlorophenyl) urea (3.00 g, 9.4 mmol) was suspended in methanol (100 ml). Concentrated sulfuric acid (1.0 ml) was added and the reaction was heated at reflux for 6 hours. The reaction mixture was poured into cold (0° C.) water (600 ml). Filtration of the suspension afforded the crude product. The crude product was purified by column chromatography on silica using dichloromethane/ethyl acetate 19:1 as eluent. 2.35 g of the title compound was isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH2:26]([O:28]C(C1C=CNC=1C)=O)C.COC1C=CC(CBr)=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:28][CH3:26])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: COc1ccc(CBr)cc1
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1

Procedure:
Prepared similarly according to a reaction sequence in Example 117 steps (a), (b), (c) and (d) for the synthesis of 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester, 4-methoxybenzyl bromide. The title compound, ESI MS (m/z): 483 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][CH:34]([N:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][C:38]2=[O:47])[CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[CH2:40][CH2:39][C:38]4=[O:47])[CH2:33][CH2:32]3)=[O:23])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(OCC(F)(F)F)c2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetic acid from Step 8 of Example 1 and 1-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one prepared by the method of Ogawa, et al., J. Med. Chem. (1993), vol. 36, pp. 2011-2017) in DMF was added HOBT, EDC, and DIEA. The solution was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (75 mL). The organic phase was separated and washed with H2O (25 mL), saturated aqueous NaHCO3 (75 mL), and brine (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using EtOAc as eluant. The product-containing fractions were evaporated under reduced pressure to give 1-(1-(4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-3,4-dihydro-quinolin-2(1H)-one as an amorphous solid (HPLC retention time=10.8 min (method A); TLC Rf=0.7 (EtOAc)).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[NH:25][C:26]([NH:33][CH2:34][C:35]([CH3:43])([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH3:36])=[C:27]([F:32])[C:28](=[N:30][NH2:31])[N:29]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:24]1[N:29]=[C:28]([NH:30][NH:31][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[C:27]([F:32])=[C:26]([NH:33][CH2:34][C:35]([CH3:43])([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH3:36])[N:25]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(CNc1[nH]c(Cl)nc(=NN)c1F)N1CCOCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(CNc1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F)N1CCOCC1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.238 g, 0.78 mmol), 2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4(1H)-pyrimidinone hydrazone (0.249 g), NMM (0.26 mL, 2.35 mmol), HOAt (0.106 g, 0.78 mmol), EDC (0.150 g, 0.78 mmol) and DMF (4 mL) were combined, and the solution was stirred overnight. Purification by RP-HPLC provided [(2R)-3-[2-(2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide as a brown oil (0.169 g). LCMS: (M+H)+=606.3.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][N:8]([CH3:16])[C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[O:10])[N:3]=1.N1C=CC=CC=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[C:27]1([O:26][C:24](=[O:25])[NH:1][C:2]2[S:6][N:5]=[C:4]([CH2:7][N:8]([CH3:16])[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][O:12]3)=[O:10])[N:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(Cc1nsc(N)n1)C(=O)[C@H]1CCCO1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(Cc1nsc(NC(=O)Oc2ccccc2)n1)C(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step 2, (R)-tetrahydro-furan-2-carboxylic acid (5-amino-[1,2,4]thiadiazol-3-ylmethyl)-methyl-amide (3.0 g, 12.4 mmol), and pyridine (1.08 g, 13.6 mmol) in DCM (120 mL) was added phenyl chloroformate (1.95 g, 12.4 mmol) by syringe at 0 C under N2. The reaction mixture was stirred at room temperature overnight, concentrated and purified by silica gel column chromatography (PE:EA=1:1) to afford Intermediate 39: (3-{[methyl-((R)-tetrahydro-furan-2-carbonyl)-amino]-methyl}-[1,2,4]thiadiazol-5-yl)-carbamic acid phenyl ester (3.0 g, yield: 67%) as a pale solid. LC-MS (m/z): 363.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.N1C=CC=CC=1.[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:14](=[O:15])[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:8][CH:9]=1)[CH3:17])[CH3:25]
Reactant: CCO
Reactant: CC(C(=O)Cl)c1ccc(C2=CCCCC2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)c1ccc(C2=CCCCC2)cc1
Reaction time: 3 h

Procedure:
7 g of α-[para-(1-cyclohexenyl)-phenyl]-propionic acid chloride are added dropwise to a solution, cooled to 10°C, of 10 ml of pyridine in 25 ml of ethanol. The mixture is allowed to stand at room temperature for 3 hours, then evaporated under reduced pressure, and the residue is dissolved in ether and the ethereal solution washed with water, 2N-hydrochloric acid, saturated sodium bicarbonate solution and again with water. The ethereal extracts are dried over sodium sulfate and evaporated, then distilled in a high vacuum to yield α-[para-(1-cyclohexenyl)-phenyl]-propionic acid ethyl ester of the formula ##SPC10##
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[F:9][C:10]([F:34])([F:33])[CH2:11][N:12]1[C:16]([C:17]2[CH:18]=[C:19]3[N:25]([N:26]=2)[C:24]2[CH:27]=[C:28]([CH:31]=O)[CH:29]=[CH:30][C:23]=2[O:22][CH2:21][CH2:20]3)=[N:15][CH:14]=[N:13]1>C(OCC)C>[F:33][C:10]([F:9])([F:34])[CH2:11][N:12]1[C:16]([C:17]2[CH:18]=[C:19]3[N:25]([C:24]4[CH:27]=[C:28]([CH2:31][NH:2][C:3]5[CH:8]=[N:7][CH:6]=[CH:5][N:4]=5)[CH:29]=[CH:30][C:23]=4[O:22][CH2:21][CH2:20]3)[N:26]=2)=[N:15][CH:14]=[N:13]1
Reactant: Nc1cnccn1
Reactant: O=Cc1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Agent: Cl
Solvent: CCOCC
Product: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(CNc3cnccn3)ccc1OCC2

Procedure:
Following the procedure for 128 without the use of HCl in diethyl ether, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehyde was reacted with 2-amino pyrazine to give 131 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 3H); 7.87 (d, J=2.6 Hz, 1H); 7.84 (d, J=2.2 Hz, 1H); 7.31 (dd, J=8.3, 2.2 Hz, 1H); 7.20 (d, J=8.3 Hz, 1H); 6.92 (s, 1H); 5.49 (q, J=8.2 Hz, 2H); 5.42 (br s, 1H); 4.66 (d, J=5.4 Hz, 2H); 4.55 (t, J=6.0 Hz, 2H); 3.16 (t, J=6.0 Hz, 2H). LCMS: RT=9.93 min, M+H+=443
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:21][CH2:20][N:12]3[N:13]=[C:14]4[C:19]([CH:18]=[CH:17][CH:16]=[CH:15]4)=[C:11]3[C:10]2=[O:22])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35]Br)=[CH:32][CH:31]=1>C(O)C>[ClH:1].[F:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][N:9]3[CH2:21][CH2:20][N:12]4[N:13]=[C:14]5[C:19]([CH:18]=[CH:17][CH:16]=[CH:15]5)=[C:11]4[C:10]3=[O:22])[CH2:4][CH2:3]2)=[CH:32][CH:31]=1
Reactant: O=C1c2c3ccccc3nn2CCN1CC1CCNCC1
Reactant: Fc1ccc(CCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2c3ccccc3nn2CCN1CC1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
A solution containing 2-(piperidin-4-yl-methyl)-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one hydrochloride (528 mg; 1.64 mmol), potassium carbonate (610 mg; 4.4 mmol), 4-fluorophenethyl bromide (450 mg; 2.2 mmol) in ethanol (10 ml) was kept stirred under reflux for 24 h. The reaction was then stopped by cooling the mixture at room temperature and concentrating the solvent under reduced pressure. The residue was taken up with DCM (30 ml) and washed respectively with a saturated solution of NaHCO3 (2×20 ml), water (2×15 ml) and a saturated solution of NaCl (10 ml). The organic phase was then dried with Na2SO4 and the solvent was removed by evaporation at reduced pressure. The solid raw product was then purified by flash chromatography on silica gel, using as eluent a mixture of chloroform:methanol in a ratio of 9:1. The product thus purified was dissolved in a mixture of diethyl ether:ethanol in a ratio of 10:1 (10 ml) and treated at room temperature with 3M hydrochloric ethanol (0.33 ml). The solid thus formed was filtered and crystallized by a mixture isopropanol:diisopropyl ether in a ratio of 3:7. Thus, 250 mg of 2-({1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}methyl)-3,4-dihydropyrazino[1,2-b]-indazol-1(2H)-one hydrochloride were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][NH:27][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NCC(F)(F)F)s1
Yield: 68 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (56 mg, 68%) which was obtained as a white solid. MS: m/e=415.2 [M+H]+.