Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[F:11].CC1(C)C(C)(C)OB([C:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([O:28][C:26]([N:23]1[CH2:22][CH:21]=[C:20]([C:2]2[C:3]([F:11])=[CH:4][CH:5]=[C:6]([F:10])[C:7]=2[O:8][CH3:9])[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1c(F)ccc(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(F)ccc(F)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 150 °C

Procedure:
2-Bromo-1,4-difluoro-3-methoxy-benzene (0.7 g, 3.139 mmol) [C.A.S. 1208076-11-2] was added to a stirred solution of 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1(2H)-pyridinecarboxylic acid, 1,1-dimethylethyl ester (1.262 g, 4.08 mmol) [C.A.S. 286961-14-6], Pd(PPh3)4 (0.072 g, 0.062 mmol) and K2CO3 (3.5 ml, aqueous sat. solution) in 1,4-dioxane (7 ml). The reaction mixture was heated at 150° C. under microwave irradiation for 10 min. After cooling, the mixture was diluted with water and extracted with Et2O. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/EtOAc 90/10 to 80/2 as eluent). The desired fractions were collected and concentrated in vacuo to give a residue that was triturated with Et2O to yield intermediate D52 (0.233 g, 22%).
Reaction SMILES: [CH:1]1([C:10]([OH:12])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:13]([N:15]1[CH:19]=[C:18]([CH2:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[CH:17]=[N:16]1)[CH3:14]>>[CH2:13]([N:15]1[CH:19]=[C:18]([CH2:20][N:21]([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([CH3:29])[CH3:30])=[CH:26][CH:27]=2)[C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:12])[CH:17]=[N:16]1)[CH3:14]
Reactant: O=C(O)C1CCc2ccccc21
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCc3ccccc32)c2ccc(C(C)C)cc2)cn1
Yield: 40.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using indan-1-carboxylic acid (0.24 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide (0.23 g) was obtained. melting point: 83-84° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH:16]([O:36][C:37](=[O:47])[CH:38]([O:45][CH3:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][Si](C(C)C)(C(C)C)C(C)C)[C:18]=3[O:34][CH3:35])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[F-].[F-].[F-].[F-].[NH4+].[NH4+].[NH4+].[NH4+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH:16]([O:36][C:37](=[O:47])[C@@H:38]([O:45][CH3:46])[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:18]=3[O:34][CH3:35])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C(OC(=O)C(OC)c1ccccc1)C1CCN(CCc2ccc(F)cc2)CC1
Agent: [F-]
Agent: [NH4+]
Product: COc1c(O)cccc1C(OC(=O)[C@@H](OC)c1ccccc1)C1CCN(CCc2ccc(F)cc2)CC1

Procedure:
Add to methoxy-phenyl-acetic acid {1-[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-yl}-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-methyl ester, Example 1C (207 g, 0.3111 mol) a 0.5M solution of methanolic ammonium tetrafluoride (1.2 L, 0.6 mol) and reflux for 17.5 h. Concentrate and obtain 198 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Se](=O)=[O:16]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH:14]=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2Cl)n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccccc2Cl)n1
Reaction time: 96 h
Yield: 90.6 %

Procedure:
4.2 g of 6-(2-chlorophenyl)-2-methylpyridine was dissolved in 100 ml dioxane, 1.8 g of selenium dioxide (Aldrich, Gold Label) was added and the mixture was refluxed for 16 hours. The solution was decanted, fresh selenium dioxide (1.8 g) was added and refluxing was continued for a further 4 days. The solids were filtered and 250 ml ether was added. The organic solution was washed five times with 50 ml H2O, dried over magnesium sulfate. Evaporation afforded an oil which was filtered through silica gel eluting with 30% ether-hexane to afford 3.2 g of 6-(2-chlorophenyl)-2-pyridinecarboxaldehyde as a pale yellow solid.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[NH:19])=[NH:16])=[CH:10][CH:9]=1.[CH3:31][C:32]([CH3:34])=O>>[ClH:3].[NH2:16][C:15]1[N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)[C:32]([CH3:34])([CH3:31])[N:19]=[C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:17]=1
Reactant: CC(C)=O
Reactant: CCCCCCCCCCNC(=N)NC(=N)Nc1ccc(OC)cc1
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCNC1=NC(C)(C)N(c2ccc(OC)cc2)C(N)=N1

Procedure:
50 ml of methanol, 40 ml of acetone and 0.2 ml of concentrated hydrochloric acid were added to 1.5 g (3.6 mmol) of N1-(4-methoxyphenyl)-N5-decyl-biguanide dihydrochloride, and the mixture was refluxed for 20 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1)). The eluate was dissolved in 80% aqueous acetonitrile, and the solvent was distilled off under reduced pressure, followed by sufficient drying under reduced pressure to obtain 0.92 g of a pale yellow resinous solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:17])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].CN(C)CCN(C)C1N=C(C2SC(NC(=O)C)=NC=2C)C=C(C)N=1>>[C:1]([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([NH:16][C:18](=[O:20])[CH3:19])=[N:13][C:12]=2[CH3:17])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(N)sc1-c1ccnc(C(C)(C)C)n1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)Nc1nc(C)c(-c2cc(C)nc(N(C)CCN(C)C)n2)s1
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C(C)(C)C)n2)s1

Procedure:
This material is prepared by acylating 5-(2-tert-Butyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (Intermediate AG) with acetic anhydride as described for N-(5-{2-[(2-dimethylamino-ethyl)-methyl-amino]-6-methyl-pyrimidin-4-yl}-4-methyl-thiazol-2-yl)-acetamide (Example 39, step 2).
Reaction SMILES: [Br:1]Br.[O:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]1[N:12]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14][CH2:13]1.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[Br:1][C:9]1[CH:10]=[C:11]2[O:3][C:4]([N:12]3[CH:18]4[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[N:5][C:6]2=[N:7][CH:8]=1
Reactant: c1cnc2nc(N3CCN4CCC3CC4)oc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2nc(N3CCN4CCC3CC4)oc2c1

Procedure:
Bromine (0.12 mL, 2.29 mmol) was added to a solution of 4-oxazolo[4,5-b]pyridin-2-yl-1,4-diaza-bicyclo[3.2.2]nonane (560 mg, 2.29 mmol, prepared in Example 27) and sodium acetate (2.26 g, 27.5 mmol) in water (12 mL) and acetic acid (12 mL). The resulting mixture was heated to reflux for 2 h. The mixture was cooled and extracted with ethyl acetate (3×). The combined organic layers were washed with water (2×) and brine (1×) and dried over sodium sulfate, filtered and concentrated. The crude residue was purified by chromatography (Biotage, 25M) using a gradient elution from 4% MeOH/CDCl3 containing 0.1% NH4OH to 8% MeOH/CDCl3 containing 0.1% NH4OH giving 578 mg (78%) of the title compound as an oil: 1H NMR CDCl3, 400 MHz) δ 8.23 (d, 1H, J=1.7 Hz), 7.50 (d, 1H, J=1.7 Hz), 4.51 (br s, 1H), 3.92 (br s, 2H), 3.16-3.04 (m, 4H), 3.02-2.94 (m, 2H), 2.17-2.01 (m, 2H), 1.83-1.74 (m, 2); MS (Cl) m/z 325.0/323.0 (M+1).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl.N([O-])=[O:23].[Na+]>O>[OH:23][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c(O)c1
Reaction time: 0.17 h

Procedure:
To 4.5 g. of ethyl 3-amino-4-cyclohexylphenylglyoxylate suspension in 125 ml. of 80% hydrochloric acid and cooled to 0° C. is added dropwise a solution of 1.2 g. of sodium nitrite in 15 ml. of water. After about 10 min., 200 ml. of 50% hydrochloric acid is added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water and extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is crystallized to obtain 3-hydroxy-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][C:22]([CH:26](O)[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>S(=O)(=O)(O)O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][C:22](/[CH:26]=[CH:27]/[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN(C)CCC(O)c1ccc2c(c1)CCCN2C(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CN(C)C/C=C/c1ccc2c(c1)CCCN2C(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 52.5 °C
Reaction time: 3 h

Procedure:
Concd. sulfuric acid (4 drops) was added to a solution of 3-[1-[(4′-chloro[1,1-biphenyl]-4-yl)carbonyl]-1,2,3,4-tetrahydro-6-quinolinyl]-3-hydroxy-N,N-dimethyl-1-propanamine (0.1 g) obtained in Example 4 in acetic acid (1 mL), and the mixture was stirred at 50 to 55° C. for 3 hours. After the solvent was distilled away under reduced pressure, the residues were made basic with 2 N aqueous sodium hydroxide and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; ethyl acetate) and crystallized from diethyl ether, whereby the title compound (75 mg) was obtained as colorless powder with a mp of 162 to 164° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[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:21][C:22]2[CH:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2].[H-].[Na+].I[CH3:51]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:47])[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:21][C:22]2[CH:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][O:29][CH3:51])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(CO)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(COC)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Reaction time: 15 h
Yield: 79.2 %

Procedure:
To a solution of 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-hydroxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (250 mg, 0.37 mmol) in DMF (5 mL) were added sodium hydride (29.9 mg, 0.75 mmol), and iodomethane (106.2 mg, 0.75 mmol) at room temperature. The resulting suspension was stirred for 15 h and then the excess sodium hydride was quenched by slow addition of water (5 mL). The mixture was diluted with 1.0N hydrochloric acid (25 mL) and the organic compound was extracted into ethyl acetate (2×25 mL). The combined extracts were washed with brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under vacuum afforded the crude residue which was purified by using an ISCO 40 g column to obtain 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(4′-methanesulfonyl-5-methoxymethyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (200 mg, 78%) as a light brown oil: ES(+)-HRMS m/e calcd for C38H50O9S (M+Na)+ 705.3068. found 705.3069.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[S:7][C:6]=2[CH:16]=1.[C:17]1(B(O)O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:9]1[C:5]2[CH:4]=[CH:3][C:2]([C:25]3[C:26]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:22]=[CH:23][CH:24]=3)=[CH:16][C:6]=2[S:7][C:8]=1[C:11]1[NH:12][CH2:13][CH2:14][N:15]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Clc1c(C2=NCCN2)sc2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1c(C2=NCCN2)sc2cc(-c3cccc4ccccc34)ccc12
Temperature: 95 °C

Procedure:
A solution of 60 mg (0.19 mmol) of 2-(6-bromo-3-chlorobenzo[b]thiophen-2-yl)-4,5dihydro-1H-imidazole, 69 mg (0.4 mmol) of naphthalene-1-boronic acid, and 23 mg (0.02 mmol) of Pd(PPh3)4 in a mixture of 2.5 ml dioxane and 0.4 ml 2M aqueous sodium carbonate solution was heated at 95° C. for 24 h. After cooling it was concentrated to dryness under reduced pressure, and the title compound was obtained from the residue by column chromatography on silica gel with dichloromethane/ethanolic ammonia gradient.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH:30]([CH3:32])C)[CH2:24]5)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:36][C:37](=O)C>>[CH:32]1([CH2:30][N:25]2[CH2:24][C:23]3[C:27](=[CH:28][CH:29]=[C:21]([C:18]4[CH:19]=[C:20]5[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=4)[NH:14][CH:13]=[C:12]5[CH:9]4[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]4)[CH:22]=3)[CH2:26]2)[CH2:37][CH2:36]1
Reactant: CC(C)=O
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C(C)C)C5)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(CC4CC4)C5)cc23)CC1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide, substituting cyclopropanecarbaldehyde (14 mg, 0.198 mmol) for 2-propanone to afford 10.8 mg of the title compound.
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:16]([O:18][C:19]([CH:21]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:22]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)([CH3:27])[CH2:23][S+](C)C)=[O:20])[CH3:17]>C(O)C>[CH2:16]([O:18][C:19]([C:21]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:23][C:22]1([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH3:27])=[O:20])[CH3:17]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C[S+](C)C)c1ccc(F)cc1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CC1(C)c1ccc(F)cc1
Reaction time: 1 h
Yield: 75 %

Procedure:
Under ice-cooling and under nitrogen atmosphere, a solution of 21% sodium ethoxide in ethanol (1.6 mL, 4.4 mmol) was added to a solution of the crude product (2.9 mmol) of [3,3-bis-ethoxycarbonyl-2-(4-fluorophenyl)-2-methylpropyl]dimethylsulfonium p-toluenesulfonate in ethanol (10 mL), which was obtained in Preparation Example 1-5, and the mixture was stirred for 1 hour. The obtained solution was concentrated under reduced pressure, and the residue was neutralized by the addition of a 2N aqueous hydrochloric acid solution, and the aqueous layer was extracted with ethyl acetate (10 mL). The organic layer was dried over magnesium sulfate and filtrated, and the solvent was evaporated. Then, the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1 to 5:1) to give the title compound (0.64 g, yield 75%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:12]3[CH:13]=[N:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:16]=3)[N:10]([CH3:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[NH2:35].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([NH:35][C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[C:9]([C:12]4[CH:13]=[N:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:16]=4)[N:10]([CH3:11])[C:4]=3[CH:3]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: Cn1c(-c2cnn(C(=O)OC(C)(C)C)c2)cc2cnc(Br)cc21
Reactant: COc1ccc(N)cc1OC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C)cc1OC
Temperature: 80 °C
Yield: 11 %

Procedure:
Pd2(dba)3 (9.2 mg, 0.01 mmol) was added to a mixture of tert-butyl 4-(6-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-pyrazole-1-carboxylate (28) (38 mg, 0.101 mmol), cesium carbonate (66 mg, 0.201 mmol), 3,4-dimethoxyaniline (18.5 mg, 0.121 mmol) and Xantphos (11.7 mg, 0.020 mmol) in dioxane (1.1 mL). The reaction mixture was heated at 80° C. for 19 hr. The reaction mixture was then filtered and the solution was concentrated under reduced pressure. The residue was purified by prep TLC (DCM/MeOH 95/5) to afford the title compound as a dark red solid (5 mg, 11%). 1H NMR (500 MHz, CDCl3) 1.71 (s, 9H), 3.50 (s, 1H), 3.89 (s, 1H), 3.91 (s, 1H), 6.48 (s, 1H), 6.57 (d, J=0.6 Hz, 1H), 6.64 (m, 1H), 6.89 (m, 2H), 6.92 (m, 1H), 7.91 (d, J=0.6 Hz, 1H), 8.26 (d, J=0.6 Hz, 1H), 8.49 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: COc1ccccc1Cl
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)c1ccccc1OC
Yield: 86.4 %

Procedure:
Method B of the above general procedure was followed using 2-chloroanisole (143 mg, 1.01 mmol) and ethyl cyanoacetate (125 mg, 1.11 mmol). The reaction mixture was purified by column chromatography on silica gel (1:3 dichloromethane/hexanes) to give the desired product (191.4 mg, 87%) as a colorless oil: 1H NMR (CDCl3) δ 7.40-7.35 (m, 2H), 7.03-6.99 (m, 1H), 6.93 (d, 8.0 Hz, 1H), 5.03 (s, 1H), 4.30-4.22 (m, 2H), 3.86 (s, 3H), 1.29 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 165.19, 156.48, 130.73, 129.44, 121.11, 119.11, 115.92, 111.12, 62.97, 55.72, 38.18, 13.97.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH:11]=O)[C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1.[CH3:40][O:41][CH:42]1[CH2:45][NH:44][CH2:43]1.CC(O)=O.C([BH3-])#N.[Na+]>C1COCC1.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][N:44]2[CH2:45][CH:42]([O:41][CH3:40])[CH2:43]2)[C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:33][CH2:34]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCC=O)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COC1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCCN4CC(OC)C4)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
2-((2-chloro-5-cyano-4-(4-oxobutyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (22 mg, 0.041 mmol) was taken up in THF (0.3 mL) and a solution of 3-methoxyazetidine (5.31 mg, 0.061 mmol) in MeOH (0.1 mL) was added, followed by a drop of AcOH and sodium cyanoborohydride (5.11 mg, 0.081 mmol). The reaction was stirred at room temperature for 1 h. The reaction was diluted with EtOAc and washed with water, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-7% MeOH/DCM; 24 g column). 2-((2-chloro-5-cyano-4-(4-(3-methoxyazetidin-1-yl)butyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (12 mg) was obtained as a yellow glass.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].[C:27](Cl)(=[O:29])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([CH:6]1[CH2:7][CH2:8][N:9]([C:27](=[O:29])[CH3:28])[CH2:10][CH2:11]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:13])=[O:14])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC#CCOc1ccc(S(=O)(=O)C(C(=O)OCC)C2CCNCC2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)OCC)C2CCN(C(C)=O)CC2)cc1
Yield: 89 %

Procedure:
Ethyl(1-acetyl-4-piperidinyl){[4-(2-butynyloxy)phenyl]sulfonyl}acetate was prepared according to the general method as outlined in example 116 (step 1), starting from ethyl{[4-(2-butynyloxy)phenyl]sulfonyl}(4-piperidinyl)acetate (1.5 g, 3.61 mmol) and acetyl chloride (0.26 ml, 3.61 mmol); yellow oil (1.35 g). Yield 89%; MS: 422 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16](Cl)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([N:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH3:19])=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: CNC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)N(C)C2CCCCC2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-chlorophenyl)-5-propyl-pyrazole-4-carbonyl chloride (commercially available, 302 mg, 1.07 mmol) in DCM (5 ml) was added 1 drop of DMF followed by N-methylcyclohexylamine (349 μL, 2.68 mmol). The reaction mixture was to stirred at room temperature for two hours then stopped.