Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C(C)=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:13]1([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:12][CH:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To 80 mL of methyl ethyl ketone, 9.05 g (50 mmol) of 4-hydroxybiphenyl, 10.20 g (60 mmol) of 6-bromo-1-hexanol, and 20.7 g (150 mmol) of potassium carbonate were added. This solution was refluxed for 24 hours and then cooled to room temperature. This solution was diluted with 200 mL of methylene chloride and rinsed with water three times. The organic phase was then separated and dried over magnesium sulfate, and the solvent was distilled off. The residue was dissolved in toluene and purified by recrystallization to provide 10.25 g of 6-(4-phenylphenoxy)hexane-1-ol.
Reaction SMILES: C[O:2][C:3]([C:5]1([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:10][CH2:9][N:8]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][N:8]([C:11]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:12])[CH2:9][CH2:10]2)(=[O:20])=[O:19])=[CH:26][CH:25]=1)[C:29]#[C:30][CH3:31]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)N3CCCC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)N3CCCC3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbonyl)-piperidine-4-carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbonyl)-piperidine-4-carboxylic acid methyl ester (250 mg, 0.52 mmol) in 4 ml of tetrahydrofuran:methanol (1:1) and 1N sodium hydroxide (1.03 ml, 1.03 mmol), 150 mg of (62%) of the acid was isolated. HR-MS: m/z Calculated for C24H25N7S 472.1425; Found 472.1426.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(N)(=[S:13])C.Cl>CN(C)C=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([NH2:10])=[S:13])=[CH:3][CH:4]=1
Reactant: CC(N)=S
Reactant: COc1ccc(C#N)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=S)cc1
Yield: 75.4 %

Procedure:
A mixture of 53.26 g of anisonitrile and 60.10 g of thioacetamide in 600 ml of dimethylformamide was saturated with dry hydrogen chloride gas while being cooled in an ice bath. The mixture was then distilled on an oil bath at 100° C. After the liquid had been removed, aqueous sodium bicarbonate was added and the solid was collected and recrystallized from toluene, giving 50.47 g of 4-methoxythiobenzamide as a yellow solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O)[CH3:2].C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:26]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[S:3][CH2:1][CH3:2])=[N+:27]=[N-:28]
Reactant: CCSc1ccccc1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCSc1ccccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(ethylthio)benzyl alcohol (3.98 g, 23.6 mmol) in THF (48 mL) at 0° C. under Ar was added DPPA (6.1 mL, 28.4 mmol) followed by DBU (4.0 mL, 26.0 mmol). The reaction was allowed to warm to room temperature and stirred for 2 days. The solution was concentrated to an oil, which was taken up in EtOAc, and washed successively with 10% aqueous citric acid, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated to an oil which was purified by silica gel chromatography (gradient elution with 100% hexanes to 5% EtOAc-hexanes). Concentration of the product fractions at reduced pressure afforded a pale yellow oil which was dried on a high vacuum line overnight to afford the title compound:
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>CS(C)=O>[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COC[C@@H]1CCCN1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Solvent: CS(C)=O
Product: COC[C@@H]1CCCN1c1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C

Procedure:
To a solution of N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (180 mg, 0.51 mmol) in DMSO (2 mL) was added (s)-(+)-2-(methoxymethyl)-pyrrolidine (0.29 mL, 2.55 mmol). The reaction mixture was heated at 80° C. for 16 h. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organics were dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 40% EtOAc in hexanes, followed by reverse-phase preparative HPLC using a Phenomenex Gemini™ column (10 micron, C18, 110 Å, 150×30 mm), 0.1% TFA in CH3CN/H2O as mobile phase, gradient 10% to 90% over 15 min., then treated with Si-carbonate resin to provide (S)—N-(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as off-white solid. MS (ESI, pos. ion) m/z: 434.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([CH2:15][C:16]([NH:18][CH:19]([OH:23])[CH2:20][CH2:21]O)=[S:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CN([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29]N=1)C.[CH2:33](CC(O)=S)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>ClCCl>[CH2:1]([CH2:15][C:16]([NH:18][C:19]([O:23][C:16](=[S:17])[CH3:15])([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH3:33])[CH2:20][CH2:21][CH2:27][CH2:32][CH2:31][CH2:30][CH2:29][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[S:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCCC(=S)NC(O)CCO
Reactant: CN(C)c1ccccn1
Reactant: CCCCCCCCCCCCCCCC(O)=S
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)(NC(=S)CCCCCCCCCCCCCCC)OC(C)=S
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-tetradecylthioacetamidopropan-1,3-diol (1 g, 2.77 mmol) (example 5a) was dissolved in dichloromethane (180 ml), then dicyclohexycarbodiimide (1.427 g, 6.91 mmol), dimethylaminopyridine (0.845 g, 6.91 mmol) and tetradecylthioacetic acid (1.995 g, 6.91 mmol) (example 1a) were added in that order. The reaction mixture was stirred at room temperature for 48 hours. The dicyclohexylurea precipitate was filtered and washed with dichloromethane and the filtrate was concentrated. The residue obtained was purified by silica gel chromatography (eluent:dichloromethane-cyclohexane 7:3). The desired compound was obtained as a white powder (yield: 66%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.Cl.[C:12]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[NH2:19])([CH3:15])([CH3:14])[CH3:13].CCN(C1C=CC=CC=1)CC>C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:17]=[C:18]([NH:19][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[CH:4][CH:3]=2)[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: Clc1ccnc2ccnn12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CC(C)(C)c1cc(Nc2ccnc3ccnn23)cc(C(C)(C)C)c1O
Temperature: 120 °C
Yield: 40.4 %

Procedure:
A suspension of 7-chloropyrazolo[1,5-a]pyrimidine (1.0 g), 3,5-di-t-butyl-4-hydroxyaniline hydrochloride (1.8 g) and diethylaniline (2.3 ml) in toluene (50 ml) is heated at 120° C. for 30 minutes. After cooling, the solvent is distilled off, and the residue is purified by silica gel column chromatography (solvent; CHCl3) to give 7-(3,5-di-t-butyl-4-hydroxyphenyl)aminopyrazolo[1,5-a]pyrimidine (890 mg) as colorless crystal.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:10][CH:9]=[C:8]([C:23]#[C:24][CH:25]2[CH:30]=[CH:29][C:28](OC)=[CH:27][C:26]2=C=O)[N:7]=1.[OH-:36].[Na+].[CH3:38][OH:39]>>[C:38]([C:28]1[CH:29]=[CH:30][C:25]([C:24]#[C:23][C:8]2[N:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:35])[C:11]([O:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:20])[CH3:21])=[CH:10][CH:9]=2)=[CH:26][CH:27]=1)([OH:39])=[O:36]
Reactant: [OH-]
Reactant: COC(=O)CCc1nc(C#CC2C=CC(OC)=CC2=C=O)ccc1OCCC(C)CCC=C(C)C
Reactant: CO
Agent: [Na+]
Product: CC(C)=CCCC(C)CCOc1ccc(C#Cc2ccc(C(=O)O)cc2)nc1CCC(=O)O

Procedure:
Under the conditions of example 3 C, 500 mg of 3-{6-[2-(4-methoxy-carbonylphenyl)-ethinyl]-3-[(3RS)-3,7-dimethyl-6-octenyloxy]-2-pyridyl}-propionic acid methyl ester in 10 ml of methanol is saponified with 7.2 ml of 2n sodium hydroxide solution and worked up. 437 mg of the title compound of melting point 154°-156° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1c(C)cc(C)[nH]c1=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc(C)n(-c2ccccc2)c1=O
Temperature: 80 °C
Yield: 28.6 %

Procedure:
A suspension of ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (7.5 g, 0.038 mol), phenylboronic acid (14.1 g, 0.115 mol), cupric acetate (1.38 g, 0.008 mol), pyridine (7.5 mL) in 1,4-dioxane (80 mL) is heated at 80° C. for 96 hours. The solid is filtered off and the filtrate is concentrated. The residue is partitioned with EtOAc (50 mL) and 2N HCl (70 mL), and the precipitate is collected by filtration and washed with EtOAc to give the title product (2.95 g). The EtOAc solution is separated, dried and concentrated. The residue is purified by silica gel column chromatography eluting with PE:acetone (2:1) to give another portion of (0.3 g). (3.25 g, 31.2% yield). MS (m/z): 272.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C/c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)C(=O)O
Yield: 68.9 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionate (example 127) (522 mg, 1.0 mmol) and sodium hydroxide (1M, 10.0 ml, 10.0 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionic acid (325 mg, 67%) as a colourless wax, which contained 0.167 molar equivalents of AcOEt.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([OH:20])=[CH:18][C:17]([C:21]([O:23][CH3:24])=[O:22])=[N:16]1.S(OC)(OC)(=O)=O>C(C(C)=O)C(C)C>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([O:20][CH3:1])=[CH:18][C:17]([C:21]([O:23][CH3:24])=[O:22])=[N:16]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(OC)n(-c2ccccc2F)n1
Reaction time: 2.5 h
Yield: 81.7 %

Procedure:
Potassium carbonate (27.8 g, 201 mmol) and water (3.62 g, 201 mmol) were added to a suspension of methyl 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylate (31.6 g, 134 mmol) in methyl isobutyl ketone (323 ml) at room temperature. Then dimethyl sulfate (16.9 g, 134 mmol) was added slowly and the mixture was stirred for 2.5 h. Water was added and the phases were separated. The organic phase was evaporated to give 27.4 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>CN(C)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=3)[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CNc1ccccc1C2=O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1C2=O
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 8-methoxy-11-oxo-6,11- dihydrodibenz[b,e]azepine (150 mg) in N,N-dimethylaniline (1 ml) was added 4-nitrobenzoyl chloride (140 mg) at 110° C. The mixture was stirred for 1 hour at the same temperature and diluted with ethyl acetate. The solution was washed successively with diluted hydrochloric acid and brine. The organic phase was dried over magnesium sulfate, and evaporated in vacuo to give crude 8-methoxy -5-(4-nitrobenzoyl)-11-oxo-6,11-dihydrodibenz[b,e]azepine (240 mg).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:17]2[C:21]([C:22]([F:25])([F:24])[CH3:23])=[N:20][N:19]=[N:18]2)[CH:5]=1.CO.[OH-].[Na+]>C(Cl)Cl>[F:24][C:22]([C:21]1[N:17]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=3)[CH:7]=2)[C:3]([OH:26])=[O:2])[N:18]=[N:19][N:20]=1)([F:25])[CH3:23]
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2nnnc2C(C)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C(C)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 235.1 %

Procedure:
3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (0.605 g, 0.68 mmol) was added to a mixture of methanol (10 mL), methylene chloride (2 mL) and 3N aqueous NaOH (0.5 mL). The reaction mixture was stirred at room temperature for 18 hours, then solvent was removed under reduced pressure. The liquid residue was diluted with water and acidified to pH 5 by addition of 1N aqueous HCl. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give 0.552 g of 3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoic acid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]1[CH:6]=[CH:5]2.[SH:16][C:17]1[CH:18]=[C:19]([C:23]2([C:29]#[N:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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]>[CH3:15][C:13]1[N:14]=[C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([S:16][C:17]4[CH:18]=[C:19]([C:23]5([C:29]#[N:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)[CH:20]=[CH:21][CH:22]=4)[CH:3]=3)[N:8]2[CH:12]=1
Reactant: Cc1cn2c(ccc3cc(I)ccc32)n1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
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
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn2c(ccc3cc(Sc4cccc(C5(C#N)CCOCC5)c4)ccc32)n1
Temperature: 80 °C

Procedure:
1m (30 mg, 0.13 mmol) and 4-(3-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (1n, 35 mg, 0.11 mmol) were dissolved in 1,4-dioxane (4 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.04 mL, 0.22 mmol), Pd2dba3 (catalytic), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (catalytic) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 80° C. overnight, then cooled to room temperature, concentrated, and purified by preparative HPLC to give the desired product, 1o.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH2:9]1COCC1>>[CH3:9][O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](N)CO
Reactant: C1CCOC1
Product: COC[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-2-amino-4-methylpentan-1-ol (0.276 ml, 2.133 mmol) was added to a stirred, ice-bath cooled suspension of KH (267 mg, 2.327 mmol) in THF (10 ml) under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for ˜10 minutes and then treated with Mel (0.121 ml, 1.939 mmol). After stirring for 30 minutes the reaction mixture was quenched by addition of saturated NH4Cl(aq) (˜20 ml) and extracted with EtOAc (25 ml×2). The combined organic phases were dried over MgSO4, filtered under vacuum and the filtrate was evaporated to afford an orange oil. The oil was purified by chromatography on silica eluting with 10% (2M NH3 in MeOH)/DCM to afford the title compound which was used without further purification.
Reaction SMILES: [OH:1][P:2]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=[CH:10][CH:11]=1)([O:4][CH3:5])=[O:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:31]=2N=N1.CCN(C(C)C)C(C)C.CN(C=O)C>CO>[CH3:5][O:4][P:2]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=[CH:10][CH:11]=1)([O:1][CH3:31])=[O:3]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COP(=O)(O)c1cccc(/C=C/C(=O)OC(C)(C)C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COP(=O)(OC)c1cccc(/C=C/C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl (2E)-3-{3-[hydroxy(methoxy)phosphoryl]phenyl}acrylate was dissolved in methanol (8 ml). BOP (0.4958 g, 1.121 mmol) and Hunig's base (0.2 ml, 1.145 mmol) were added. DMF (2 ml) was added. The reaction was allowed to stir overnight at room temperature. The reaction was not complete. The reaction was partially concentrated under reduced pressure. BOP (0.4836 g, 1.093 mmol) and Hunig's base (0.2 ml, 1.145 mmol) were added. The reaction was allowed to stir. After several hours additional BOP (0.495 g, 1.119 mmol) and Hunig's base (0.2 ml, 1.145 mmol) were added. The reaction was allowed to stir overnight at room temperature. The reaction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane. MS: calc'd 313 (MH+), exp 313 (MH+).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:36])[N:24]([CH2:32][CH2:33][C:34]#[N:35])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:20]=[C:19]([Cl:37])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[OH2:39].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:34]([CH2:33][CH2:32][N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:23](=[O:36])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=[C:19]([Cl:37])[CH:20]=1)(=[O:39])[NH2:35]
Reactant: O
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)c2ccccc2F)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-(2-fluoro-phenyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.055 g) and water (0.020 ml) in a mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stirred at room temperature for 2 h and then the solvent removed under reduced pressure. The residue was purified by preparative hplc to give the title compound (0.035 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([NH:9][C:10](=[O:16])OC(C)(C)C)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:17]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18].C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:49][C:50]1[CH:59]=[C:58]2[C:53]([C:54]([N:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)=[CH:55][C:56]([NH2:60])=[N:57]2)=[CH:52][CH:51]=1>>[NH2:60][C:56]1[CH:55]=[C:54]([N:61]2[CH2:62][CH2:63][N:64]([C:10]([NH:9][C@H:8]3[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([C:17]([NH:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[O:18])[C:2]3=[O:1])=[O:16])[CH2:65][CH2:66]2)[C:53]2[C:58](=[CH:59][C:50]([Cl:49])=[CH:51][CH:52]=2)[N:57]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)NCC(F)(F)F)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)NCC(F)(F)F)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, [(3R)-hexahydro-2-oxo-1-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 542 (M++1). 1H NMR (CDCl3,): δ 1.44 (m, 1H), 1.64 (m, 1H), 1.82˜2.02 (m, 4H), 3.14 (m, 4H), 3.31 (dd, 1H), 3.68 (m, 4H), 3.98 (m, 2H), 4.84 (dd, 1H), 4.88–5.00 (m, 3H), 5.80 (d, 1H), 6.03 (s, 1H), 7.16 (dd, 1H), 7.60 (d, 1H), 7.71 (d, 1H), 9.54 (t, 1H).
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][CH:5]([F:21])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][C:8]=1[O:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1>O.CN(C=O)C>[F:4][CH:5]([F:21])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:1]#[N:2])=[CH:9][C:8]=1[O:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: OCc1ccc(OC(F)F)c(OC2CCOC2)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(OC(F)F)c(OC2CCOC2)c1
Temperature: 80 °C
Yield: 80.4 %

Procedure:
A mixture of KCN (0.076 mol) in H2O (4 ml), heated to 80° C., was added dropwise to a mixture of intermediate 3 (0.038 mol) in DMF (82.4 ml), stirred at 60° C. The resulting reaction mixture was stirred for 30 minutes at 60° C. The reaction mixture was cooled, washed with water, extracted with DIPE. The extract was dried, filtered, and the filtrate was evaporated, yielding 8.23 g (80%) of (±)-4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]benzeneacetonitrile (intermediate 4).