Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15]CC)=[O:14].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)Cc1ccccc1OCc1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1ccccc1CC(=O)O
Reaction time: 3 h

Procedure:
To a stirred solution Ethyl 2-(2-(2,6-dimethylbenzyloxy)phenyl)acetate (Step B, 4.70 g, 15.7 mmol) in absolute ethanol (75 ml) was added 1N NaOH (35 ml) at room temperature. The reaction mixture was stirred for 3 hours, or until all the starting material is gone, concentrated and diluted with chloroform and acidified by 1M HCl to bring the pH to 3.5-4. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[F:26][C:27]([F:33])([F:32])[O:28][CH2:29][CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH2:29][O:28][C:27]([F:33])([F:32])[F:26])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCCOC(F)(F)F
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCOC(F)(F)F)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(trifluoromethoxy)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3 H) 3.55 (q, J=5.3 Hz, 2 H) 4.16 (t, J=5.3 Hz, 2 H) 7.59 (d, J=7.8 Hz, 1 H) 7.66 (s, 1 H) 7.71 (br. s., 1 H) 8.14 (br. s., 1 H) 8.36 (d, J=7.3 Hz, 1 H) 8.84-8.88 (m, 1 H) 8.93 (t, J=4.4 Hz, 1 H) 13.18 (br. s., 1 H). MS m/z [M+H]+ 432.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: BrCC1CC1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OCC2CC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (3) (400 mg, 1.18 mmol), anhydrous Cs2CO3 (769 mg, 2.36 mmol), and KI (40 mg, 0.24 mmol) in DMF (10 mL) is added bromomethylcyclopropane (229 μL, 2.36 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (30 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10-40% EtOAc in heptane) to give a pure product (10) as white solid (330 mg, 71%).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3CCC([CH2:18][O:19]C)CC3)=CC=2N=1.COCC1CCNCC1.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46](CO)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].[H-].[Na+].CI>C1COCC1>[C:36]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([O:19][CH3:18])[CH2:47][CH2:48]1)=[O:42])([CH3:37])([CH3:38])[CH3:39]
Reactant: COCC1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: COCC1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C

Procedure:
Via 2-Chloro-6-(4-methoxymethyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared from 4-methoxymethyl-piperidine. Amine preparation: To a solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (212 mg) stirring in dry THF (10 mL) under a nitrogen atmosphere was added sodium hydride (60% in paraffin oil; 45 mg) followed after 20 min by methyl iodide and the reaction mixture was warmed to 70° C. After 4 h the mixture was cooled and quenched with water (10 mL) extracted into ethyl acetate, and dried (MgSO4). The residue was purified using flash chromatography to yield 4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (158 mg) as a colourless oil. Treatment with TFA yielded the desired amine which was isolated as the TFA salt.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH:5]=[CH2:6])[CH3:2].[C:10]1([CH:17]=CC=[C:13](O)[CH:12]=1)[OH:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.S(=O)(=O)(O)O>[CH2:1]([O:3][CH:4]1[CH2:5][CH2:6][C:9]2[CH:13]=[CH:12][C:10]([OH:11])=[CH:17][C:8]=2[O:7]1)[CH3:2]
Reactant: C=CC(OCC)OCC
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC1CCc2ccc(O)cc2O1
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A solution of 1.6 g of acrolein diethylacetal in 4 ml of ethanol was added dropwise under cooling to a solution composed of 1.1 g of resorcinol, 0.05 g of conc. sulfuric acid and 6 ml of ethanol. While maintaining the temperature at less than 10° C., the mixture was stirred for 2 hours. The reaction mixture was neutralized with an aqueous solution of sodium carbonate and extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography to give 1.2 g (yield 63%) of the desired product as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([CH:38]=2)[C:36]#[N:37])O1>[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:31]3[CH:32]=[N:33][CH:34]=[C:35]([C:36]#[N:37])[CH:38]=3)[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(Br)c2)COC1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(-c3cncc(C#N)c3)c2)COC1

Procedure:
In a manner analogous to that described for the preparation of Example 1, the palladium-catalyzed coupling of (RS)-[5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (intermediate XIII-1) with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile using [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) as the catalyst yielded the title compounds as a white semisolid. MS (ISP): m/z=393.2 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:21][CH:22]1[CH2:27][N:26]([CH2:19][CH2:18][CH2:17][C:9]2[CH:10]=[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:25][CH2:24][N:23]1[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2C)c1

Procedure:
55 mg (79%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 2-methyl-1-m-tolylpiperazine (27 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:7])[CH:3]1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].C([O-])(=O)C.[Na+].Br[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24].C(Cl)(Cl)Cl>C1C=CC=CC=1>[CH:11]([O:10][C:8]([C:3]1[CH:2]([CH3:1])[CH2:6][N:5]2[C:21](=[CH:22][C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:24])[CH2:20][S:7][C:4]=12)=[O:9])([CH3:13])[CH3:12]
Reactant: O=C(CBr)CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OC(=O)C1C(=S)NCC1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)OC(=O)C1=C2SCC(=CC(=O)Oc3ccc([N+](=O)[O-])cc3)N2CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
8.9 g of isopropyl 4-methyl-2-thioxopyrrolidine-3-carboxylate was dissolved in 200 ml of benzene and 5.1 g of anhydrous sodium acetate and 16.7 g of 4-nitrophenyl 4-bromoacetoacetate were added thereto. The obtained mixture was stirred at room temperature for 8 hours. Then 500 ml of chloroform was added and the mixture was washed with water and a saturated aqueous solution of sodium chloride. After drying and distilling off the solvent, the obtained residue was purified by silica gel column chromatography. A fraction eluted with dichloromethane was crystallized from a mixture of ether and n-hexane. Thus 11.9 g of the title compound was obtained.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[Na]>O>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Brc1ccc2c(c1)C=NCC2
Agent: Cl
Agent: [Na]
Solvent: O
Product: Brc1ccc2c(c1)CNCC2
Temperature: 50 °C
Yield: 91.7 %

Procedure:
219 g (0.89 mol) of 7-bromo-3,4-dihydro-isoquinoline hydrochloride and 1.5 liters of water were combined and heated to 50° C. 33.7 g (0.89 mol) of sodium borohydrde was added in portions over 0.5 hours at which time the temperature rose to 62° C. The reaction was then cooled to ambient temperature and extracted three times with 1 liter of dichloromethane. The combined organic layers were washed with 1 liter of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to yield 173 g of an oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([O:31]C)=[O:30])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH:26]([CH3:27])[CH3:28])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([OH:31])=[O:30])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OCCOC(C)C)cc3)ccc2N(S(C)(=O)=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)OCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 98.2 %

Procedure:
In a mixture of THF and ethanol (1:1, v/v, 30.0 ml) was dissolved methyl 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (354 mg). To the solution was added 1N sodium hydroxide solution (7.7 ml), and the mixture was stirred at room temperature for 15.5 hours. The mixture was a little concentrated, and to the residue was added 1N hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (337 mg, 98%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[N:12]([CH2:30][CH2:29][C:26]4[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(F)cc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(F)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2-(4-fluorophenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH:20]=[CH:21][CH:22]=2)=[CH2:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH:15]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:9]=2[OH:8])[CH3:16])[CH:18]=1
Reactant: C=C(c1cccc(-c2ccccc2OC)c1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cccc(C(C)c2cccc(-c3ccccc3)c2O)c1
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A solution of impure 23 (0.5 g, 1.06 mmol) in methanol (20 mL) and ethyl acetate (40 mL) was treated with 20% palladium on activated carbon (50% wet, 0.05 g) and was hydrogenated at 40 psi in a Parr shaker for 3 hr. The catalyst was filtered out and washed with ethyl acetate. The filtrate was stripped and the crude product was purified by chromatography on silica (45 g) with 2% ethyl acetate in hexane (3 L) to afford pure D1 (0.33 g, 82%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O.O.[Sn](Cl)Cl>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)cn2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Yield: 57.9 %

Procedure:
Prepared as described in the Nitro Reduction section using 6-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (0.423 g, 1.67 mmol) and tin (II) chloride dihydrate (1.89 g, 8.36 mmol) in EtOH (45 ml) to give the title compound (0.216 g, 58%) as a pale orange solid, after work-up and flash chromatography (EtOAc).
Reaction SMILES: [C:1]([C:3]([C:13]#[N:14])=[CH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)#[N:2].C(O)C.[C-:18]#[N:19].[K+].Cl>O>[C:18]([CH:4]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)[CH:3]([C:1]#[N:2])[C:13]#[N:14])#[N:19]
Reactant: C=Cc1ccc(C=C(C#N)C#N)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C=Cc1ccc(C(C#N)C(C#N)C#N)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2.00 g 4-(2,2′-dicyanoethenyl)styrene (11 mmol) and 30 mL ethanol was added a solution of 1.45 g potassium cyanide (22 mmol) in 3 mL water. The mixture was stirred at room temperature for 17 hours. 1.8 mL concentrated HCl (22 mmol) was then added and the mixture was concentrated under vacuum. Ten milliliters (10 mL) water was added to the residue, and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated under vacuum, and the product was purified by column chromatography on silica gel using 20% ethyl acetate in hexane. The product recovered from the separation was mixed with 1.5 mL methylene chloride and 10 mL hexane, then filtered. A white solid was obtained (1.009 g, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[CH3:30][N:31]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)[CH3:32]>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:40][C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:31]([CH3:32])[CH3:30])=[CH:39][CH:38]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN(C)Cc1ccc(N)cc1
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CN(C)C)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (87 mg, 0.21 mmol) and 4-dimethylaminomethyl-phenylamine (32 mg, 0.21 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 66 mg of 2-(4-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.38 (s, 1H), 8.54 (s, 1H), 7.09-7.43 (m, 7H), 4.35-4.42 (m, 2H), 3.57 (s, 2H), 2.90-3.08 (m, 4H), 2.35 (s, 6H), 2.16-2.26 (m, 2H), 1.39 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])=[N:6][C:5]([Cl:19])=[C:4](Cl)[N:3]=1.[CH2:21]([SH:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>CN(C)C=O.ClCCl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])=[N:6][C:5]([Cl:19])=[C:4]([S:29][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1
Reactant: CCCCCCCCS
Reactant: CCCCCCCCOC(=O)c1nc(Cl)c(Cl)nc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOC(=O)c1nc(Cl)c(SCCCCCCCC)nc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 1 ml of dimethylformamide there was mixed n-octyl (2-amino-5,6-dichloropyrazinyl)formate (100 mg; 0.312 mol), prepared in Step B above, and n-octyl thiol (150 mg; 0.936 mol), after which there was added triethylamine (70 mg; 0.624 mol), and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was taken up in dichloromethane and passed through a silica gel column to give the title compound. Elemental Analysis:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:19].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C)C=O>[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:19][C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][C:4]=2[Cl:3])=[CH:23][CH:22]=1
Reactant: Oc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1Cl
Reactant: Cc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccc(Oc3ccc(Cl)c(Cl)c3)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of 0.07 g of sodium hydride (60% oil dispersion) in 10 ml of N,N-dimethylformamide, there was added dropwise a solution of 0.45 g of 2-chloro-4-(3,4-dichlorophenoxy)phenol in 3 ml of N,N-dimethylformamide with stirring and ice-cooling. After 30 minutes, a solution of 0.22 g of p-methylbenzylchloride in 5 ml of N,N-dimethylformamide was added thereto at room temperature, followed by stirring at the same temperature for 10 hours. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.50 g of 4-methyl-1-[2-chloro-4-(3,4-dichlorophenoxy)phenoxy]methylbenzene. Yield, 81%. nD27 :1.6029
Reaction SMILES: F[B-](F)(F)F.C(C1C=CC=C(C(C)C)C=1[N+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[C:46]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:47]=1[CH:48]=[CH:49][N:50]2[S:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(=[O:57])=[O:56].[C:64]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])(=[O:66])[CH3:65]>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].C1(C)C=CC=CC=1>[C:58]1([S:55]([N:50]2[C:51]3[C:47](=[C:46]([CH2:65][C:64]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH:54]=[CH:53][CH:52]=3)[CH:48]=[CH:49]2)(=[O:57])=[O:56])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Reactant: CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1N1C=[N+](c2c(C(C)C)cccc2C(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium tetrafluoroborate (94 mg, 0.196 mmol), tris(dibenzylideneacetone)dipalladium (180 mg, 0.196 mmol), and lithium bis(trimethylsilyl)amide (1.37 M in t-BuOMe, 11.0 mL, 15.1 mmol) were added 4-bromo-1-(phenylsulfonyl)-1H-indole from Step A (2.20 g, 6.54 mmol), tert-butyl acetate (988 mg, 8.51 mmol), and toluene (15 mL). The resulting mixture was stirred at ambient temperature for 18 h then partitioned between Et2O (100 mL) and saturated aqueous NH4Cl (30 mL). The organic layer was washed with brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 85:15, to give the title compound. MS: m/z=316 (M−C4H7).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J13) (230 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown solid (258 mg).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[OH:22]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Brc1cccc2c1OCC2
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1cccc2c1OCC2
Yield: 72.2 %

Procedure:
With 3.00 g of 7-bromo-2,3-dihydro-1-benzofuran and 1.10 g of 5-chloroisatin as starting material, 1.32 g of the title compound (white solid) was obtained by a similar method to Step 21-1.