Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:42])[CH:34]=[C:35]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:42][C:33]2[CH:34]=[C:35]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH:36]=[C:31]([Br:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CCS(=O)(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Yield: 94.9 %

Procedure:
A similar procedure as described in Example 40, step 6 was used, starting from 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.13 g, 2.39 mmol), 3-bromo-5-ethanesulfonyl-phenol (576 mg, 2.17 mmol), and potassium carbonate (600 mg, 4.34 mmol) to afford 4-[3-[6-(3-bromo-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.35 g, 95%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C31H43BrO8S (M+Na)+ 677.1754, found 677.1756.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].F[C:8]1[N:13]=[CH:12][C:11]([C:14]2([OH:41])[CH2:19][CH2:18][CH:17]([N:20]3[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)=[O:26])[CH2:21]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>CN(C=O)C>[OH:41][C:14]1([C:11]2[CH:12]=[N:13][C:8]([O:6][CH:4]([CH3:5])[CH3:3])=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH:17]([N:20]2[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)=[O:26])[CH2:21]2)[CH2:18][CH2:19]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Temperature: 80 °C

Procedure:
NaH (95%, 51 mg, 2 mmol) was added into IPA (4 mL) at 0° C. slowly until bubble disappeared. To this solution was added N-({1-[4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (6a, 200 mg, 0.40 mmol) in DMF (1 mL). After addition, the reaction was heated for another 2 hours at 80° C. The reaction solution was quenched with MeOH and partitioned between DCM and water. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6](C(OC(C)(C)C)=O)[CH2:7][CH3:8])[CH3:2].[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)CN(CC)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 30.8 g (113 mmole) of N-[(1,1-dimethylethoxy)carbonyl]-N-ethylglycine ethyl ester in 50 mL dichloromethane at 3° C. is treated with 200 mL of 1:1 (volume/volume) trifluoroacetic acid in dichloromethane. The reaction mixture is stirred for 2 hours while warming to ambient temperature. The reaction mixture is concentrated in vacuo and the residual highly mobile oil is subjected to high vacuum to give the desired compound (55.2 g), which is used without further purification.
Reaction SMILES: F[B-](F)(F)F.[C:6](=[NH:11])([O:8][CH2:9][CH3:10])[NH2:7].[CH2:12]([CH:19]([C:25](=O)[CH3:26])[C:20](OCC)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+]>CO>[CH2:12]([C:19]1[C:20](=[O:21])[NH:11][C:6]([O:8][CH2:9][CH3:10])=[N:7][C:25]=1[CH3:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=N)N
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: C[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Product: CCOc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Reaction time: 12 h
Yield: 24.3 %

Procedure:
To a solution of ethyl imidocarbamate tetrafluoroborate (2.4 g) and ethyl 2-benzyl-3-oxobutanoate (1 g) in methanol (20 mL) was added sodium methoxide (28% methanol solution, 5.25 mL), and the mixture was stirred for 12 hr. The reaction mixture was concentrated, and the residue was dissolved in water. The solution was weakly acidified with acetic acid, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (0.27 g, 24%) as a colorless solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:34]([NH:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH3:35]>O1CCCC1>[CH2:34]([N:36]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:8]=[N:9][N:10]=1)[CH3:35]
Reactant: CCNC1CCCCC1
Reactant: O=C(O)CCCCc1nnnn1C1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(C(=O)CCCCc1nnnn1C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
5-(1-Cyclohexyl-1,2,3,4-tetrazol-5-yl)valeric acid (2.4 g) is dissolved in tetrahydrofuran (50 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring N-ethyl-cyclohexylamine (1.5 g) at room temperature, and the mixture is further stirred for 2 hours. After distilling off tetrahydrofuran, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is washed with an aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off, and the resulting residue is subjected to column chromatography (Kieselgel 60, made by Merck & Co., eluting solvent, chloroform) to isolate N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide (2.6 g), white crystalline powder (ether), m.p. 92°-95° C.
Reaction SMILES: [C:1]([C:9]1[C:10]([CH3:28])=[N:11][C:12]([CH2:26][CH3:27])=[CH:13][C:14]=1[NH:15]S(C1C=CC(C)=CC=1)(=O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[NH2:15][C:14]1[CH:13]=[C:12]([CH2:26][CH3:27])[N:11]=[C:10]([CH3:28])[C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(NS(=O)(=O)c2ccc(C)cc2)c(C(=O)c2ccccc2)c(C)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCc1cc(N)c(C(=O)c2ccccc2)c(C)n1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A solution of compound D (0.64 g) in concentrated sulphuric acid (3 ml) was heated at 50° C. for 1 hour. The solution was cooled to ambient temperature and added cautiously to crushed ice. The mixture was basified to pH 9 with solid sodium carbonate and the precipitate was collected by filtration to give 4-amino-3-benzoyl-6-ethyl-2-methylpyridine (B) (0.35 g) as a solid, m.p. 149°-151° C.; NMR (d6 -DMSO): 1.19(t, 3H), 1.97(s, 3H), 2.53(q, 2H), 5.78(s, 2H), 6.40(s, 1H), 7.49-7.73(m, 5H); mass spectrum (chemical ionisation, ammonia): 241(M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]([C:10]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:11]([F:15])[C:12]=1[CH2:13][OH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>ClCCl>[Si:35]([O:14][CH2:13][C:12]1[C:11]([F:15])=[C:10]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:2]=1[F:1])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c1OC1CCCCO1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(CO[Si](C)(C)C(C)(C)C)c(F)c1OC1CCCCO1
Yield: 96.7 %

Procedure:
213 mg (0.50 mmol) of the above ethyl 3,5-difluoro-4-hydroxymethyl-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate was dissolved in 5 mL of dichloromethane, 68 mg (1.0 mmol) of imidazole and 302 mg (2.00 mmol) of tert-butyldimethylsilyl chloride were added and the mixture was heated at reflux for 30 minutes. The reaction solution was cooled on ice, water was added and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 256 mg of ethyl 4-tert-butyldimethylsilyloxymethyl-3,5-difluoro-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate (yield: 98%).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[F:25][C:26]([F:31])([F:30])[CH2:27][CH:28]=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: O=CCC(F)(F)F
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2CCC(F)(F)F)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively alkylated with 3,3,3-trifluoropropionaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3,3,3-trifluoro-propyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 450.2 [M+H]+.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:23]=[C:22]3[C:18]=2[C:19](=[O:43])[N:20]2[CH2:42][CH2:41][CH2:40][C@H:21]23)=[CH:13][CH:12]=1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH2:29]([O:28][C:26]([C:25]1[C:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]([OH:10])=[O:8])=[CH:16][CH:15]=2)=[C:18]2[C:22](=[CH:23][C:24]=1[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)[C@@H:21]1[CH2:40][CH2:41][CH2:42][N:20]1[C:19]2=[O:43])=[O:27])[CH3:30]
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)cc2c(c1-c1ccc(C(=O)OCc3ccccc3)cc1)C(=O)N1CCC[C@@H]21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)cc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of Example 48 (300 mg, 0.51 mmol) in ethyl acetate (25 ml) was added 10% Pd/C (10% w/w, 30 mg) and was stirred under H2 (1 atms.) for 18 hr. The Pd/C filtered through celite (1 g) and the filtrate concentrated to provide title compound as a white solid (243 mg, 0.50 mmol). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.4 Hz, 2H), 7.49–7.42 (m, 2H), 7.13 (s, 1H), 7.09–7.06 (m, 2H), 6.96–6.92 (m, 2H), 4.62–4.58 (m, 1H), 3.94 (q, 2H), 3.68–3.61 (m, 1H), 3.33–3.29 (m, 1H), 3.02–2.87 (m, 4H), 2.32–2.03 (m, 3H), 1.24–1.19 (m, 1H), 0.86 (t, 3H) ppm. ESI-MS m/z 488 (M+H)+. HPLC (93%).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][NH:8][S:9]([C:12]2[S:16][C:15]([C:17]3[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=3[CH3:26])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][NH:8][S:9]([C:12]1[S:16][C:15]([C:17]2[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=2[CH3:26])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCC3COC(C)(C)O3)s2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCC(O)CO)s2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-[5-(5-{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]aminosulfonyl}-2-thienyl)-4-methyl-1,3-thiazol-2-yl]acetamide (14) (48 mg; 0.11 mmol; 1 eq), is dissolved in DCM (5 ml). Trifluoroacetic acid (0.2 ml) is added and reaction mixture stirred at room temperature for 30 minutes. The solvents are evaporated and the crude product purified directly by preparative HPLC, affording Compound (17) as a white-off solid (7 mg; 16%). M− (ESI): 390.2; M+ (ESI): 392.2. HPLC (method A), Rt: 2.13 min (purity: 83.5%).
Reaction SMILES: [C:1]([O-:7])([O-])([O:3][CH2:4][CH3:5])[CH3:2].[CH:8]#[C:9][CH:10](O)[CH2:11][CH3:12].C(O)(=O)CCC>C(O)C>[C:1]([O:3][CH2:4][CH3:5])(=[O:7])[CH2:2][CH:8]=[C:9]=[CH:10][CH2:11][CH3:12]
Reactant: C#CC(O)CC
Reactant: CCOC(C)([O-])[O-]
Solvent: CCCC(=O)O
Solvent: CCO
Product: CCC=C=CCC(=O)OCC
Yield: 97 %

Procedure:
A 200 ml- capacity three-necked flask was charged with 78 g of ethyl ortho-acetate, 20 g of 1-pentyn-3-ol and 2.0 g of butyric acid and was heated at 117° to 122°C. and ethanol formed as a by-product was distilled off. Even after completion of the distillation of the ethanol, the mixture was agitated at the above temperature for several hours. After complete extinction of the starting alcohol was confirmed by the gas chromatography, the reaction mixture was subjected to distillation under reduced pressure, and a fraction boiling at 87° to 89.5°C. under 16 mm Hg was collected. The intended ethyl 3,4-heptadienoate was obtained in a yield of 97%.
Reaction SMILES: C1(C[O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[N:11][CH:10]=2)C=CC=CC=1.[ClH:21].[H][H]>CO.[Pd]>[ClH:21].[ClH:21].[NH2:20][CH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:8])=[CH:10][N:11]=1
Reactant: N#Cc1ncc(OCc2ccccc2)c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ncc(O)c2ccccc12

Procedure:
A mixture of the product from step 2 (2 g) and 10% Pd on carbon (800 mg) in 50 ml of methanol containing 4 ml of conc. HCl is hydrogenated with a balloon of hydrogen for about half an hour. The mixture is filtered through CELITE and concentrated under vacuum to a solid. Recrystallization from EtOAc and methanol yields the title compound (1.3 g) as a white solid, m.p. 214-216° C (dec).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][OH:67])[CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH:59]5[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][OH:67])[CH2:61][CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1CCN(CCO)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(4-aminopiperidin-1-yl)ethanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (m, 1 H) 1.39 (m, 3 H) 1.54-1.90 (m, 10 H) 2.02 (t, J=10.99 Hz, 2 H) 2.38 (t, J=6.32 Hz, 2 H) 2.89 (d, J=10.86 Hz, 2 H) 3.31 (s, 3 H) 3.49 (br. s., 2 H) 3.74 (m, 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.39 Hz, 2 H) 4.45 (m, 2 H) 7.47 (d, J=8.0 Hz, 1 H) 7.51 (s, 1 H) 7.90 (s, 1 H) 8.14 (d, J=8.0 Hz, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.0 Hz, 1 H). [M+H] calculated for C29H39F2N7O4, 588; found 588.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH2:31][CH2:32][CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CC(CC)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH:25]([CH2:31][CH2:32][CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reactant: CCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCC(Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1)C(=O)OCC

Procedure:
A solution of 6 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole, 10.2 g of potassium carbonate, 5.12 g of ethyl 2-bromovalerate and 100 ml of methylethyl ketone is stirred under reflux for 3 hr. The reaction mixture is poured into 1 liter of ice/dil hydrochloric acid and the precipitate is collected and dried. Recrystallization from ether gives ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}pentanoate, mp 88° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1.[N:33]([CH:36]([CH3:38])[CH3:37])=[C:34]=[O:35]>>[NH2:32][C:11]1[N:12]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([CH:26]4[CH2:27][CH2:28][N:29]([C:34]([NH:33][CH:36]([CH3:38])[CH3:37])=[O:35])[CH2:30][CH2:31]4)=[CH:20][CH:21]=3)[CH2:16]2)[CH:14]=[C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]2)[N:10]=1
Reactant: CC(C)N=C=O
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC(C)NC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 138 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine HCl salt and 2— isocyanatopropane. LCMS (M+H)+: m/z=507.3.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[CH:7]([CH3:9])[CH3:8].CN(C)[CH:23]=[O:24]>>[CH2:6]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[CH:23]=[O:24])=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[CH:7]([CH3:9])[CH3:8]
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]c(CC(C)C)cc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(CC(C)C)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Dimethylformamide (1 mL) was cooled to 0° C. Phosphorus oxychloride (0.5 mL) was added and the reaction mixture was stirred for 10 minutes. A solution of 2-isobutyl-5-methoxyindole (375 mg, 1.8 mmol) in dimethylformamide (2 mL) was added to the reaction mixture dropwise over 10 minutes. The solution was stirred for an additional 40 minutes. The reaction mixture was added to ice cold 1 N NaOH (35 mL) and stirred for 10 minutes. The precipitate was collected, washed with cold water (30 mL) and dried overnight in a vacuum desiccator set at 40° C. equipped to an oil driven vacuum pump yielding a tan solid (393 mg, 94%): TLC Rf 0.45 in 1:1 ethyl acetate/hexanes. Melting point=146-147° C. 1H NMR (600 MHz, CDCl3) δ 10.13 (s, 1H), 8.74 (s, 1H), 7.81 (d, 1H, J=2.5 Hz), 7.24-7.23 (d, 1H, J=8.7 Hz), 6.89-6.87 (dd, 1H, J1=8.7 Hz, J2=2.5 Hz), 3.87 (s, 3H), 2.93-2.92 (d, 2H, J=7.3 Hz), 2.11-2.05 (m, 1H), 1.02-1.01 (d, 6H, J=6.7 Hz); 13C NMR (150 MHz, CDCl3) δ 184.62, 156.48, 150.72, 129.69, 126.68, 115.22, 113.59, 111.55, 102.99, 55.80, 35.46, 30.08, 22.51. Elemental analysis calculated for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.62; H, 7.52; N, 5.98.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:3]=12.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:3]=12
Reactant: COC(=O)c1cc2c(Cl)cncc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(Cl)cncc2s1

Procedure:
Methyl 4-chlorothieno[2,3-c]pyridine-2-carboxylate (19.76 g) was dissolved in 100 mL THF and treated with 100 mL 2M LiOH at room temperature for 3 hours. The reaction mixture was acidified with concentrated HCl to pH=4. A white solid (17.93 g, y=97%) was obtained after filtration, washing with MeOH and air drying. LCMS (API-ES) m/z (%): 214.1 (100%, M++H); 1H NMR (300 MHz, CD3OD) δ ppm 8.35 (s, 1H) 8.71 (s, 1H) 9.54 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)=[O:3].[ClH:27]>O1CCOCC1>[ClH:27].[NH:16]1[CH2:17][CH2:18][CH2:19][C@@H:14]([NH:13][C:5]2[C:4]([C:2]([NH2:1])=[O:3])=[CH:9][N:8]=[C:7]3[NH:10][CH:11]=[CH:12][C:6]=23)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2c(C(N)=O)cnc3[nH]ccc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cnc2[nH]ccc2c1N[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl(3R)-3-{[5-(aminocarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}-1-piperidinecarboxylate (125 mg) in dioxane (1.25 mL) was added 4M HCl in dioxane (1 ml) and the solution was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated to give 4-[(3R)-3-piperidinylamino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride (112 mg) as a white powder.
Reaction SMILES: [K].P(=O)(O)(O)[OH:3].[CH3:7][C:8]1[O:12][C:11]([CH:13]([CH:15]([CH3:18])[CH:16]=[CH2:17])O)=[CH:10][CH:9]=1.[Cl-].[Na+]>O>[CH3:18][CH:15]([C:13]1[C:11](=[O:12])[CH2:10][CH:9]([OH:3])[C:8]=1[CH3:7])[CH:16]=[CH2:17]
Reactant: O=P(O)(O)O
Reactant: C=CC(C)C(O)c1ccc(C)o1
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: O
Product: C=CC(C)C1=C(C)C(O)CC1=O
Reaction time: 0.92 h

Procedure:
A buffer solution was prepared by dissolving potassium secondary phosphate (4 g) in water (800 ml) and adjusting the pH value to 7.5 (25° C.) with phosphoric acid. In a reaction vessel, 5-methyl-2-furyl-(α-methylallyl)-carbinol (20 g) and the entire amount of the buffer solution as prepared above were charged, and the temperature was elevated up to 180° C. in 55 minutes while stirring. The mixture was stirred at the same temperature for 5 hours, the inner pressure at this time being 9 kg/cm2. After ice-cooling, sodium chloride (100 g) was added thereto, and the mixture was extracted with methyl isobutyl ketone (200 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove methyl isobutyl ketone, and the resultant residue was subjected to distillation (112°-117° C./0.3 mmHg) to obtain 2-(α-methylallyl)-3-methyl-4-hydroxy-2-cyclopentenone (15.3 g). Yield, 76.5%. NMR spectrum (CDCl3 internal standard; TMS, δppm, 60 MHz): 5.99 (complex m, 1H, ##STR8## 5.08 (m, 1H, ##STR9## 4.84 (m, 1H, ##STR10## 4.63 (broad d, 1H, 4-H); 3.33 (m, 2H, 4-OH and ##STR11## 2.73 (dd, 1H, 5-H); 2.21 (dd, 1H, 5-H); 2.08 (s, 3H, 3-CH3); 1.21 (d, 3H, ##STR12##