Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[Na+].[Na+].O.[C:15](Cl)([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16]>O1CCOCC1.[Na+].[Cl-]>[O:7]=[C:2]1[NH:1][CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])[CH2:3]1
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
To a solution of piperazin-2-one (2 g, 20 mmol, 1 equiv), Na2CO3 (4.2 g, 40 mmol, 2 equiv) and water (20 mL) in 1,4-dioxane (60 mL) was added Fmoc-Cl (5.7 g, 22 mmol, 1.1 equiv) at 0° C. After the reaction mixture was stirred at room temperature for 4 h, it was diluted with saturated NaCl (200 mL). The solution was extracted with ethyl acetate (3×50 mL) and dried over Na2SO4. The combined organic layers were concentrated to give 6.7 g of the desired product, which was directly used for the next step without further purification. MS (ESI): 323 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O-])=[O:21])=[CH:18][CH:17]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(OCC)(=O)C>O1CCCC1>[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:23][CH:24]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)[O-])cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
A suspension of 1.40 g (36.8 mmol) of lithium aluminum hydride in 150 ml of tetrahydrofuran was stirred at 0° C. A solution of 13.0 g (49.0 imol) of 4-(tert-butoxycarbonylaminomethyl)benzoate in 50 ml of tetrahydrofuran was dropwise added slowly to the suspension. After completion of the dropwise addition, the solution was heated to reflux for 2 hours and then cooled to 0° C. After 20 ml of 50% tetrahydrofuran was dropwise added to the reaction mixture, 100 ml of ethyl acetate was added thereto. Insoluble matters were filtered off and the resulting filtrate was concentrated under reduced pressure. The concentrate was isolated and purified by silica gel column chromatography to obtain 8.80 g (75.7%) of 4-(tert-butoxycarbonylaminomethyl)benzyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH3:34]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:21]([N:23]1[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]1)=[O:22])[CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15](=[O:16])[NH2:34])[CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1CCN(C(=O)C(CCc2cccc(C(=O)O)c2)NC(=O)OC(C)(C)C)CC1
Reactant: N
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1CCN(C(=O)C(CCc2cccc(C(N)=O)c2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 78 %

Procedure:
A mixture of 85 mg (0.21 mmol) of 3-[3-tert-butoxycarbonylamino-4-(4-methyl-piperidin-1-yl)-4-oxo-butyl]-benzoic acid, 81 mg (0.42 mmol) of EDC, 57 mg (0.42 mmol), and 2.6 mg (0.021 mmol) of DMAP is stirred in DMF for 2 h at rt. After cooling to −40° C. ˜0.2 mL of NH3 is condensed into the mixture. The resulting solution is sealed and stirred at rt for 10 h. The mixture is concentrated and purified by preparatory TLC (10% MeOH in CH2Cl2) to provide 66 mg (78%) of [3-(3-carbamoyl-phenyl)-1-(4-methyl-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)N1CCC(CC(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)N1CCC(CC(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a mixture of (1-tert-butyl-piperidin-4-yl)-acetic acid (672 mg, 3.37 mmol), aniline (0.32 ml, 3.5 mmol), and HOBt (568 mg, 4.2 mmol) in DMF (20 ml), EDC (805 mg, 4.2 mmol) was added. It was stirred at r.t. for 2 hours and partitioned between water (200 ml) and ethyl acetate (200 ml). The organic phase was washed with 0.5 N aq. NaOH (2×50 ml) and brine (3×50 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on (SiO2, gradient heptane-ethyl acetate) to give 250 mg of the title compound. 1H NMR (500 MHz, DMSO-d6): 1.07 (s, 9H), 1.32 (br. m, 2H), 1.81 (br. d, 2H), 1.89 (m, 1H), 2.11 (br. t, 2H), 2.25 (d, 2H), 3.03 (br. d, 2H), 7.1 (t, 1H), 7.24 (br., 1H), 7.31 (t, 2H), 7.52 (d, 2H).
Reaction SMILES: C([O:3][C:4]([C:6](=O)[CH:7]([CH3:20])[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[O-])=[O:5])C.[Li+].Cl.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[NH:32][NH2:33].S(=O)(=O)(O)O>C(O)C>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[N:32]1[C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[C:7]([CH3:20])[C:6]([C:4]([OH:3])=[O:5])=[N:33]1
Reactant: CCOC(=O)C(=O)C(C)C([O-])c1ccc(C(F)(F)F)cc1
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CCO
Product: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 10 g of Lithium 3-ethoxycarbonyl-2-methyl-3-oxo-1-(4-trifluoromethyl-phenyl)-propan-1-olate, 6.9 g of (2,4-Dichloro-phenyl)-hydrazine hydrochloride and 74 ml of sulfuric acid (50%) in 184 ml of ethanol was heated to reflux for 7 h. After cooling to room temperature the organic solvents were removed under reduced pressure and the residue was diluted with 100 ml of water and extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was dissolved in 100 ml THF and a solution of 1.4 g of LiOH in 20 ml water was added at room temperature. The reaction mixture was heated to 60° C. for 7 h. Then, after cooling to room temperature the mixture was acidified to pH 1 by addition of half-concentrated hydrochloric acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])(C)(C)C.CCCCC.[B:25](OC)([O:28]C)[O:26]C>O1CCCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:25]([OH:28])[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COB(OC)OC
Reactant: CCCCCCCc1ccccc1Br
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCc1ccccc1B(O)O

Procedure:
Following General Procedure A and using 1-bromo-2-heptyl-benzene (Intermediate 67, 0.4 g, 1.56 mmol), 4 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (1.84 mL, 3.1 mmol) and trimethyl borate (0.45 mL, 3.1 mmol), the title compound was obtained (0.27 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH:15]([CH3:17])[CH2:14][CH:13]([CH3:18])[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:20][O:21][C:22](=[O:45])[C@@H:23]([NH2:44])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][O:21][C:22](=[O:45])[CH:23]([NH:44][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:11]1[CH2:16][CH:15]([CH3:17])[CH2:14][CH:13]([CH3:18])[CH2:12]1)[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:29][CH:30]=1
Reactant: CC1CC(C)CN(c2ccc(Cl)cc2C(=O)O)C1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N1CC(C)CC(C)C1
Yield: 78.1 %

Procedure:
A solution of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.250 g, 0.933 mmol) in DMF (4.0 mL) was reacted with (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.360 g, 0.933 mmol), HBTU (0.355 g, 0.933 mmol), and DIEA (0.500 mL, 2.800 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using DCM (+20% hexane) to give 0.435 g (62%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.200 g, 0.334 mmol) in THF (4.0 mL) was reacted with LiOH (0.050 g, 1.172 mmol) by the general procedure I to give 0.182 g (93%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 584 (M+1)+. 1H NMR (CDCl3) 11.20 [d, 1H], 8.21 [d, 1H], 7.45 [m, 2H], 7.39 [m, 2H], 7.23 [m, 8H], 7.02 [m, 2H], 6.86 [m, 2H], 4.90 [m, 1H], 3.38 [dd, 5.60 Hz, 1H], 3.26 [dd, 1H], 2.80 [m, 2H], 2.16 [t, 1H], 2.04 [t, 1H], 1.70 [m, 2H], 1.43 [m, 1H], 0.76 [m, 6H], 0.58 [m, 1H].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1cc(Nc2cc3ccccc3c(-c3cccc(C#N)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-cyano-phenylboronic acid to give 3-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzonitrile LC-MS m/e 326(MH+).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[N:11]1([C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C1CCNC1
Solvent: CCO
Product: c1ccc2[nH]c(N3CCCC3)nc2c1
Temperature: 165 °C
Yield: 39.7 %

Procedure:
2-Chloro-1H-benzimidazole (10.0 g, 0.066 mol), pyrrolidine (18.5 g, 0.26 mol), and ethanol (100 mL) were combined. The resulting solution was heated at 160-170° C. for 6 hours and then the solvent was evaporated. The resulting residue was mixed with water. The mixture was made strongly acidic with hydrochloric acid and then made basic with ammonium hydroxide. The resulting solid was isolated by filtration, washed with water and then air dried to provide 11.8 g of crude product as a tan powder. This material was recrystallized from ethyl acetate/methanol to provide 4.9 g of 2-pyrrolidino-1H-benzimidazole. Analysis: Calculated for C11H13N3: % C, 70.56; % H, 7.00; % N, 22.44. Found: % C, 70.13; % H, 7.05; % N, 22.70.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:18])[N:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH:19](OC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH:3]=1.B(Cl)(Cl)[Cl:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:18])[N:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH:19]([Cl:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH:3]=1
Reactant: ClB(Cl)Cl
Reactant: CCOC(=O)c1cnn(C)c1-c1ccc(Cl)cc1C(OC)c1ccccc1F
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C)c1-c1ccc(Cl)cc1C(Cl)c1ccccc1F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 20.1 g of 3-[4-chloro-2-(2-fluoro-α-methoxy-benzyl)-phenyl]-4-ethoxycarbonyl-2-methyl-pyrazole in 250 ml methylene chloride is added 54 ml of a 1.4 molar boron trichloride solution in methylene chloride, and the mixture is stirred during 16 hours. Ice/water is then added; the organic layer separated, washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The aqueous layers are reextracted with methylene chloride. After removal of the solvent, the 3-[4-chloro-2-(α-chloro-2-fluoro-benzyl)phenyl]-4-ethoxycarbonyl-2-methyl-pyrazole is obtained as the solid residue, which is directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])=[CH:20][CH:21]=2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CCN(C)C)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(CCN(C)C)cc1
Yield: 31.4 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[2-(dimethylamino)ethyl]phenylamino}-1,5-naphthyridin-3-yl)ethanone (40 mg, 0.11 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) followed by formation of the dihydrochloride salt to afford the desired product (13 mg, 22%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.29 (s, 1H), 8.42 (d, J=9.1 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.41-7.35 (m, 3H), 7.11 (br s, 1H), 3.43-3.36 (m, 2H), 3.23-3.13 (m, 2H), 2.98 (s, 6H), 2.80 (s, 3H); ESI MS m/z 479 [M+H]+; HPLC>99% (AUC), tR=9.67 min.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9]C)=[C:4]([CH3:11])[CH:3]=1.B(Br)(Br)Br.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: COc1cc(C)c(F)cc1C
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(F)c(C)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
9.7 g of 4-fluoro-2,5-dimethylanisol was dissolved in 100 ml of dichloromethane and 76 ml of boron tribromide (1.0M dichloromethane solution) was added to the solution at 0° C. The resulting mixture was brought to room temperature, stirred for one hour, and poured into ice-water. 300 ml of ethyl acetate was added to the resultling mixture. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and brine successively, dried over magnesium sulfate. After the desiccant was filtered off, the resulting mixture was evaporated. The resulting crude product was purified by silica gel column chromatography to give 8.5 g of the title compound as a pale brown oil.
Reaction SMILES: CCO/[CH:4]=[C:5](/[CH:7]=O)\[CH3:6].[NH2:9][C:10]1[N:14]=[C:13]([SH:15])[NH:12][N:11]=1>>[CH3:6][C:5]1[CH:4]=[N:9][C:10]2[N:11]([N:12]=[C:13]([SH:15])[N:14]=2)[CH:7]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: CCO/C=C(\C)C=O
Product: Cc1cnc2nc(S)nn2c1

Procedure:
The title compound was prepared from 3-ethoxymethacrolein and 3-amino-5-mercapto-1,2,4-triazole as previously described by M. Künstlinger and E. Breitmaier in Synthesis, 1983, 44–47.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C>[CH2:1]([OH:13])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCCCCCC#CCCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCO
Yield: 91.5 %

Procedure:
To a solution of 3.20 g (17.5 mmoles) of 3-dodecyn-1-ol in 35 ml. of ethyl acetate was added 0.300 g of Lindlar catalyst (Lindlar, Helvetica Chimica Acta 35, 450 (1952)). The hydrogenation was carried out at atmospheric pressure with stirring. When the theoretical quantity of hydrogen had been taken up, the hydrogenation was stopped and the reaction mixture was filtered through Celite. After removal of the solvent, in vacuo, the residue was evaporatively distilled under reduced pressure to afford 2.95 g (91.6%) of (Z)-3-dodecen-1-ol as an oil.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1.[NH4+].[OH-]>CS(C)=O>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:2]#[N:3])=[N:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccc(C(F)(F)F)cn1
Temperature: 180 °C

Procedure:
Copper (I) cyanide (14.1 g) and 2-bromo-5-trifluoromethylpyridine (3.00 g, 13.3 mmol) in dry DMSO (70 mL) were combined and heated at 180° C. for 2 hours, cooled, and poured into NH4OH (3M). The mixture was then extracted with ethyl acetate (3×500 mL), washed with water (1×200 mL), dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO, 300 MHz) δ 8.22 (m, 1H), 8.42 (m, 1H), 9.01 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1.[O:18]1[CH2:21][CH:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:17][N:14]1[C:15](=[O:16])[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[N:25]2[CH2:26][CH2:27][N:22]([CH:20]3[CH2:21][O:18][CH2:19]3)[CH2:23][CH2:24]2)[N:12]=[N:13]1
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2F)c1=O
Reactant: C1CN(C2COC2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnn(-c2cc([N+](=O)[O-])ccc2N2CCN(C3COC3)CC2)c1=O
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 1-(2-fluoro-5-nitrophenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (1.1 g, 1.0 eq, 4.5 mmol) (see, e.g., WO 2011/068898), 1-(oxetan-3-yl)piperazine (0.64 g, 1.0 eq, 4.5 mmol) was dissolved in annhydrous DMF (100 mL) and stirred at room temperature. K2CO3 (1.9 g, 3.0 eq, 13.5 mmol) was added to the above solution and the heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL) and partitioned with H2O (50 mL). The layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to leave a crude solid. Purification of the crude solid by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 1:9 to 1:1) as eluent gave the product in 50% yield.
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:8])[O:6][CH3:7].[CH2:9]1[C:13]2([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10]1.CC(O)=O>C1COCC1>[O:19]=[C:18]1[CH:17]([C:5]([O:6][CH3:7])=[O:8])[CH2:16][CH2:15][CH2:14][C:13]21[CH2:9][CH2:10][CH2:11][CH2:12]2
Reactant: COC(=O)OC
Reactant: O=C1CCCCC12CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CCCC2(CCCC2)C1=O
Temperature: 80 °C

Procedure:
In a flask containing NaH (4.73 g, 118.20 mmol) in THF (30 mL) was added dimethylcarbonate (8.30 mL, 98.52 mmol). The mixture was heated at 80° C. To the mixture was added a solution of spiro[4.5]decan-10-one, 59, (6.00 g, 39.41 mmol) in THF dropwise (25 mL). The reaction was heated for 6 hrs at 80° C. The mixture was cooled to room temperature and hydrolyzed with AcOH. The solvent was evaporated and the crude residue was diluted with water and extracted with EtOAc. The organic layer was washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[CH:13]([CH3:15])[CH3:14].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: CC(C)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)c1cc(I)ccc1O

Procedure:
2-hydroxy-5-iodobenzoic acid (477 g, 1.8 mol), isobutanol (225 g), conc sulfuric acid (20 ml) in toluene (2 l) was refluxed for 6 h using a water separator. The solution was cooled and washed with water. The solution was treated with decolorizing carbon and the toluene was evaporated. The residue was recrystallized from methanol. Yield 376 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[CH:13]([NH:15][NH2:16])=O>C(O)CCC.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:13]=[N:15][N:16]=[C:7]1[CH2:6][CH2:5]2
Reactant: NNC=O
Reactant: S=C1CCc2cc(Br)ccc2N1
Solvent: O
Solvent: CCCCO
Product: Brc1ccc2c(c1)CCc1nncn1-2
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 6-bromo-3,4-dihydroquinoline-2(1H)-thione (74-4; 0.17 g, 0.0007 mol) in n-butanol (2 mL) was added formic hydrazide (0.105 g, 0.0017 mol) at room temperature. Reaction mass was allowed to stir at 140° C. for 1 h under microwave irradiation conditions. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford title compound. MS (M+3): 252.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[NH:6][CH:7]=1)#[N:2].[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)[CH:19]=2)[CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:10])=[C:20]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)[CH:19]=2)[CH2:16][CH2:17]1
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Reactant: CC1CCN(c2cc(N3CCN(C)CC3)ccc2[N+](=O)[O-])CC1
Product: CC1CCN(c2cc(N3CCN(C)CC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Yield: 55.1 %

Procedure:
The procedure of Example 53 was followed using 4-cyano-1H-pyrrole-2-carboxylic acid (as prepared in Example 2, 56 mg, 0.22 mmol) and 4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenylamine (as prepared in Example 13, step (a), 61 mg 0.21 mmol). Purification of the resulting residue by silica gel preparative TLC eluting with 10% methanol in dichloromethane yielded 47 mg (55%) of the title compound as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 9.60 (br s, 1H), 8.30 (d, 1H, J=8.9), 7.24 (d, 1H, J=3.7 Hz), 7.21 (d, 1H, J=3.7 Hz), 6.79 (d, 1H, J=2.7 Hz), 6.73 (dd, 1H, J=8.9, 2.7 Hz), 3.20 (m, 4H), 3.00-2.97 (m, 2H), 2.76-2.70 (m, 2H), 2.59 (m, 4H), 2.37 (s, 3H), 1.85-1.82 (m, 2H), 1.56-1.46 (m, 2H), 1.07 (d, 3H, J=6.2 Hz). LC-MS (ESI, m/z): Calcd. for C23H31N6O, 407.3 (M+H); found: 407.2.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCN2CCCCC2)cc1

Procedure:
In a manner similar to that described in Example 207, 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and piperidine are converted to the named compound.