Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](S(C)=O)[N:3]=1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[N:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([O:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Reactant: Cc1ccc(CO)nc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(COc2nc(N)nc(-c3cc(Br)co3)c2C#N)nc1

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 5-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 388 (M{81Br}+H+, 100), 386 (M{79Br}+H+, 95).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].ClS([N:17]=[C:18]=[O:19])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH:11][C:18]([NH2:17])=[O:19])=[O:5])[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1nc(C)sc1N
Solvent: ClCCl
Product: CCOC(=O)c1nc(C)sc1NC(N)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.3 %

Procedure:
To a solution of 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (15.0 g, 0.081 mol) in DCM (550 mL) was added chlorosulfonyl isocyanate (8.92 mL, 0.102 mol) dropwise at −78° C. The thick suspension was allowed to warm to RT and stirred for 45 minutes. The resulting precipitate was collected by filtration and dried in vacuo. The resultant white solid was suspended in an aqueous solution of HCl (6 M, 400 mL) and heated at 90° C. for 1 h. The resulting solution was cooled to 0° C. and pH adjusted to 5 with an aqueous solution of NaOH (6 M). The resultant precipitate was collected by filtration and dried in vacuo at 60° C. for 36 h to give the title compound (16.4 g, 89%).
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].Cl>O>[C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccccc2F)CCC1=O
Agent: Cl
Solvent: O
Product: N#CC1(c2ccccc2F)CCC(=O)CC1
Yield: 40.1 %

Procedure:
Methyl 5-cyano-5-(2-fluorophenyl)-2-oxocyclohexane-1-carboxylate (D2, 30.66 g, 0.11 mol) was stirred at reflux in c. HCl (500 ml) for 17 h, cooled, diluted with water (500 ml), and extracted with ethyl acetate. This organic portion was washed with potassium carbonate solution, dried (Na2SO4) and evaporated to give 4-cyano-4-(2-fluorophenyl)cyclohexanone (9.58 g, 38%) as a yellow foam. The alkaline wash was re-acidified with c. HCl, and the product isolated by extraction with ethyl acetate, drying (Na2SO4) and evaporation. This gave the title compound (16.36 g, 62%) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].C(N(CC)CC)C.[CH2:25]([NH:28][C:29]([CH:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32])=[O:30])[CH2:26][CH3:27]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:36]1[CH2:35][CH2:34][N:33]([CH:31]([C:29]([NH:28][CH2:25][CH2:26][CH3:27])=[O:30])[CH3:32])[CH2:38][CH2:37]1)=[O:9]
Reactant: CCCNC(=O)C(C)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)C(C)N1CCN(C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C

Procedure:
20.00 g of 3,4,5-trimethoxycinnamoyl chloride and 11.77 ml of triethylamine are added with ice cooling to a solution of 12.90 g of 1-[1-(propylaminocarbonyl)ethyl]piperazine in 200 ml of chloroform and stirred at room temperature for one-half an hour.
Reaction SMILES: COC1N=C([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](C)[C:16](=O)C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)C=CC=1.[F:33][C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[C:36]([F:42])[C:35]=1B(O)O>CCCCCC.CCOC(C)=O>[F:33][C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[C:36]([F:42])[C:35]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:16]
Reactant: COc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: COc1ccc(F)c(B(O)O)c1F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNc1cnccc1-c1c(F)ccc(OC)c1F

Procedure:
The title compound was prepared in analogy to compound 284, intermediate, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate) and 2,6-difluoro-3-methoxyphenylboronic acid and using a gradient of n-hexane:EtOAc (70:30 to 60:40) for the chromatographic purification. Brown solid (75%). MS (ESI): m/z=251.2 [M+H]+.
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[C:30]([O:31][C:32](=[O:34])[CH3:33])=[C:29]([O:35][CH3:36])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[Br:37]Br>ClCCCl>[Br:37][C:8]1[O:9][C:10]2[C:30]([O:31][C:32](=[O:34])[CH3:33])=[C:29]([O:35][CH3:36])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1
Reactant: BrBr
Reactant: COc1cc(C(=O)c2c([Si](C)(C)C(C)(C)C)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Solvent: ClCCCl
Product: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (120 mg, 0.44 mmol) in 1,2-dichloroethane (1 mL) at room temperature under nitrogen was added bromine (12 μl, 0.44 mmol) dropwise and the reaction mixture was stirred at this temperature for 10 minutes. After this time the reaction was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate (20 mL), dried over magnesium sulfate and the solvent removed by distillation under vacuum. The crude product was purified by silica gel column chromatography (eluent=Hexane:diethyl ether; 8:2-7:3) to afford the title compound as a colourless crystalline solid (91 mg, 81%); 1H NMR (300 MHz, CDCl3) δ 7.40 (d, 1H, J=8.70 Hz), 7.14 (s, 2H, benzoyl-Hs), 6.98 (d, 1H, J=8.75 Hz), 3.94 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.86 (s, 6H, 2×OMe), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 187.95 (CO), 167.71, 152.75, 149.54, 147.49, 142.59, 131.92, 131.80, 123.91, 121.84, 119.89, 117.72, 109.89, 106.92, 60.69, 56.61, 56.00, 20.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([OH:41])[CH:32]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][C:31]([NH:30][C:24]([CH:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16]3[N:17]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:13]4[N:29]=[CH:28][S:27][C:14]=4[N:15]=3)[CH2:19]2)=[O:25])=[CH:32][C:33]=1[OH:41]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: COC(=O)c1ccc(N)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.5 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (80 mg, 0.19 mmol) and methyl 4-amino-2-hydroxybenzoate (32 mg, 0.19 mmol) in dichloromethane (15 mL) were added the solution of 1-methyl-1H-imidazole (63 mg, 0.76 mmol) and EDCI (147 mg, 0.76 mmol) in dichloromethane (5 mL), the reaction mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, methanol (5 mL) was added, the precipitate was collected by filtration to afford methyl4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)-2-hydroxybenzoate (110 mg, crude) which was used directly in the next step without further purification. LC-MS: tR=565 [M+H]+, 1.64 min.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:15])[CH:10]([NH2:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1COCC1>[CH2:1]([NH:8][C:9](=[O:15])[CH:10]([NH:14][C:22](=[O:24])[CH3:23])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(N)C(=O)NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCC(NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 13 (0.20 g, 0.98 mmol) in dry THF (2.0 mL) is added pyridine (0.086 g, 1.08 mmol), and then acetic anhydride (0.2 g, 1.96 mmol) is added dropwise. The reaction is stirred at room temperature for 18 hours. The solvent is evaporated in vacuo and the residue purified by flash column chromatography to obtain the above compound as the R isomer.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:19]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
A mixture of 2-methylbenzimidazole (1.5 g, 11.35 mmole), Et3N (1.66 mL, 11.92 mmole), DMAP (0.20 g, 1.6 mmole), and (BOC)2O (2.60 g, 11.92 mmole) in anhydrous CH2Cl2 (15 mL) was stirred at RT for 24 hr, then was concentrated. The residue was taken up in H2O, stirred, and filtered to afford the title compound (2.63 g, 100%) as a colorless solid: mp 71-72° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].F[C:17]1[CH:26]=[N:25][C:24]2[C:23]([NH2:27])=[N:22][CH:21]=[N:20][C:19]=2[CH:18]=1>CN(C=O)C>[NH2:27][C:23]1[C:24]2[N:25]=[CH:26][C:17]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:18][C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: Nc1ncnc2cc(F)cnc12
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cnc3c(N)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.181, 32 mg) is dissolved in 1 mL DMF. To this solution is added sodium hydride (60% suspension in mineral oil, 0.229 mmol, 9.18 mg) and the mixture is stirred at rt for 5 min. and then 7-Fluoro-pyrido[3,2-d]pyrimidin-4-ylamine (0.164 mmol, 27 mg) is added. The reaction mixture is stirred at 50° C. for 22 h. The reaction mixture is cooled and quenched by pouring into 20 mL sat. NH4Cl aq. and extracted 3 times with 5 mL CH2Cl2. The combined organics are dried with Na2SO4, concentrated, and purified by silica gel chromatography on Biotage using a gradient of 0-15% MeOH in DCM. 1-(4-Amino-pyrido[3,2-d]pyrimidin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one is isolated (12 mg, LC/MS m/z=322 [M+H]+) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[CH:4]([NH:24][C:25](=[O:46])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35](=[O:45])[CH2:36][O:37]CC2C=CC=CC=2)=[CH:30][CH:29]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:23])[CH2:14][O:15]CC2C=CC=CC=2)=[CH:8][CH:7]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:47])[CH:4]([NH:24][C:25](=[O:46])[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35](=[O:45])[CH2:36][OH:37])=[CH:32][CH:33]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13](=[O:23])[CH2:14][OH:15])=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccc(OC(=O)COCc2ccccc2)cc1)NC(=O)CCc1ccc(OC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OC(=O)CO)cc1)NC(=O)CCc1ccc(OC(=O)CO)cc1
Reaction time: 5 h

Procedure:
3-[4-(2-Benzyloxy-acetoxy)-phenyl]-2-{3-[4-(2-benzyloxy-acetoxy)-phenyl]propionyl amino}-propionic acid methyl ester 25 (10 grams, 15.64 mmol) is dissolved in ethyl acetate (100 mL) in a pressure vessel, palladium on carbon (10%, 5 grams) is added and the mixture is stirred under an atmosphere of hydrogen (4 Kg) for 5 hours. The catalyst is removed by filtration and is distilled of the ethyl acetate. The crude 26 can be purified in appropriate solvent.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[Cl:11])(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: COc1nc(Br)cnc1N
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cc(Cl)ccc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g) and 2,5-dichlorobenzenesulphonyl chloride (0.24 g). Yield 0.14 g.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][O:30][CH2:31][CH2:32][C:33]([NH:35][NH2:36])=[O:34]>>[CH3:29][O:30][CH2:31][CH2:32][C:33]([NH:35][NH:36][C:26]([CH:11]1[CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=2)[CH2:14][N:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH2:10]1)=[O:28])=[O:34]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: COCCC(=O)NN
Product: COCCC(=O)NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
100 mg (0.25 mmol) of the compound from Example 44A and 58 mg (0.50 mmol) of 3-methoxypropanehydrazide were reacted according to the General Method 11A. Yield: 93 mg (75% of theory)
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][C:12]=1[O:19][CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:4]([CH3:9])([CH3:5])[CH:3]=[O:1])=[CH:13][C:12]=1[O:19][CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: COc1cc(CCl)ccc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(CC(C)(C)C=O)ccc1OCc1ccccc1
Temperature: 70 °C

Procedure:
Under argon, a mixture of sodium hydroxide (1.43 g, 35.85 mmol) and tetrabutylammonium iodide (0.30 g, 0.82 mmol) in 8 ml benzene and 2.8 ml H2O was heated at 70° C. to form a homogeneous mixture. A mixture of the product of Step 1 (8.05 g, 30.64 mmol) and isobutraaldehyde (2.95 g, 40.85 mmol) in 20 ml benzene was added to the above solution dropwise. The resulting reaction mixture was heated at 70-75° C. for 6 h. The product was extracted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/9) to yield a colorless oil in 8.32 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[Cl:14][C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][NH:29][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C1CC1
Reactant: NCCOc1ccc(Oc2cccc(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCOc1ccc(Oc2cccc(Cl)n2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
At room temperature, 1.1 g of triethylamine and then 1.0 g of cyclopropanecarboxylic acid chloride are dripped into 2.6 g of 2-[4-(6-chloropyridin-2-yloxy)-phenoxy]-ethylamine in 50 cm3 of dichloromethane. The reaction is slightly exothermic. The mixture is stirred at room temperature for 14 hours.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[N:7][C:6]([CH3:10])=[C:5]2[S:11][CH:12]=[CH:13][C:4]=12)[CH3:2].[H-].[Na+].Cl.[CH3:17][N:18]([CH2:20][CH2:21]Cl)[CH3:19].O>CN(C=O)C>[CH2:1]([C:3]1[C:8]([O:9][CH2:21][CH2:20][N:18]([CH3:19])[CH3:17])=[N:7][C:6]([CH3:10])=[C:5]2[S:11][CH:12]=[CH:13][C:4]=12)[CH3:2]
Reactant: CCc1c(O)nc(C)c2sccc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(OCCN(C)C)nc(C)c2sccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.2 %

Procedure:
4-Ethyl-7-methylthieno[2,3-c]pyridin-5-ol (2.00 g, 10.3 mmol) was added to a suspension of NaH (60% in oil, prewashed with hexanes, 0.46 g, 11.4 mmol) in DMF (30 ml) and stirred at room temperature for two hours. To this was added a mixture of dimethylaminoethylchloride hydrochloride (3.0 g, 20.6 mmol) and NaH (60% in oil, prewashed with hexanes, 546 mg, 22.8 mmol) in DMF (30 ml). The reaction mixture was stirred for two days at room temperature, poured into H2O (300 ml) and extracted with CH2Cl2 (3×200 ml). The combined organic phases were washed with H2O (2×200 ml) and dried over MgSO4. The solvent was removed in vacuo to give an oil (3 g), which was purified by flash chromatography on silica gel 60 (100 g) eluted with 7% MeOH in CH2Cl2 to give an oil (1.5 g, 56% yield). The product was dissolved in CH2Cl2 (100 ml), washed with 1N aqueous NaOH (2×100 ml) and dried over MgSO4. The solvent was removed in vacuo to give the product (0.950 g, 35% yield) as a yellow oil; IR (neat) 1590 and 1440 cm-1 ; mass spectrum m/z 264 (M+); 1H NMR (CDCl3) δ 1.18 (t, J=7 Hz, 3H, CH2CH3), 2.35 (s, 6H, N(CH3)2), 2.63 (s, 3H, 7-CH3), 2.63-3.10 (m, 4H, CH2CH2N, CH2CH3), 4.53 (t, J=6 Hz, 2H, CH2CH2N), 7.27 and 7.53 each (d, J=5 Hz, 1H, thiophene-H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]#[N:12])=[CH:6][CH:5]=1.[Br:22][CH2:23]Br>CN(C=O)C>[Br:22][CH2:23][C:10]([C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1)([C:11]#[N:12])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: BrCBr
Reactant: N#CC(CCOc1ccccc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CBr)(CCOc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a flask was added 6.1 g. (0.127 mole) of a 50% oil dispersion of sodium hydride. After washing the sodium hydride several times with hexane to remove the mineral oil, 50 ml. of dry DMF was added, then a solution of 30 g. (0.11 mole) of 2-(4-chlorophenyl)-4-phenoxybutanenitrile in 25 ml. of dry DMF was added dropwise at 0° C. The reaction was stirred and allowed to warm to room temperature over 1.5 hours, then 21.2 g. (0.127 mole) of dibromomethane was added dropwise at 15° C. Upon completion of the addition, the reaction was stirred and heated to 50° C. and was complete in three hours. The reaction mixture was cooled to room temperature, diluted with 300 ml. of water, and then extracted three times with 100 ml. portions of methylene chloride. The combined extracts were washed with dilute hydrochloric acid and water, then dried using sodium sulfate. Upon removal of the solvent, 31 g. of 1-bromo-2-(4-chlorophenyl)-2-cyano-4-phenoxybutane was obtained (77% yield).
Reaction SMILES: O[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([NH:13][C:8]1[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]2[O:4][C:3]([CH3:21])([CH3:22])[CH:2]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[C:6]=2[CH:7]=1)=[O:20]
Reactant: Cc1cccc(C2(O)c3cc(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccc(C2c3cc(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)c1
Yield: 87 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-3-(3-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 239, the title compound was synthesized in the same manner as in Example 271. Yield: 87%. Melting point: 156-157° C. (ethyl acetate-hexane).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]1[O:8][CH:7]1[CH2:9][OH:10].[OH-].[Na+].[CH2:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([O:21][CH:7]([CH2:9][OH:10])[CH2:6][OH:8])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCO
Reactant: OCC1CO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOC(CO)CO
Temperature: 25 °C
Yield: 15.9 %

Procedure:
0.6 ml of concentrated sulfuric acid was added to 165 g of 1-octanol, the mixture was stirred at room temperature and 23.5 g of glycidol was added dropwise. The reaction mixture was poured on ice water, the mixture was neutralized with 1N aqueous sodium hydroxide solution and extracted with ether, and the ether layer was dried over anhydrous sodium sulfate. The solvent was distilled away, the most part of 1-octanol was removed by vacuum distillation, and the residue was distilled under a vacuum of 1 mmHg to give 10.3 g of the desired product containing a by-product 3-octyloxy-1,2-propanediol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19](=[O:32])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](=[O:29])(=[O:30])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9](=[O:10])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-phenyl-methanone and 131 mg of 3-(4-chlorosulfonyl-phenyl)propionic acid methyl ester. 1H-NMR (400 MHz, CDCl3): δ 2.50 (t, 2H, J=8.0 Hz), 2.83 (t, 2H, J=8.0 Hz), 3.64 (s, 3H), 7.08 (d, 2H, J=8.8 Hz), 7.33 (d, 1H, J=2.8 Hz), 7.36-7.42 (m, 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.58 (m, 3H), 7.75 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). MS: m/z 458.9 (M++1).
Reaction SMILES: [CH3:1][C:2]1(Br)[CH2:4][CH2:3]1.[CH2:6]([NH:13][C:14](=[O:36])[N:15]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][C:24]=2[OH:35])[CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH:4]1([CH2:3][O:35][C:24]2[CH:25]=[C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][C:23]=2[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:15]([CH3:16])[C:14]([NH:13][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:36])[CH:18]=2)[CH2:2][CH2:1]1
Reactant: CC1(Br)CC1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCC2CC2)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 170 μL (1.75 mmol, 1.5 eq) of methylcyclopropyl bromide and 500 mg (1.17 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 3 eq) of potassium carbonate, methyl 3-[2-cyclopropylmethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.