Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=O)[CH:17]([CH2:21][C:22]24[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]2)[CH2:29]4)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH2:21][C:22]24[CH2:23][CH:24]5[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]5)[CH2:31]2)[CH2:29]4)=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cccc3c2C(=O)C(CC24CC5CC(CC(C5)C2)C4)C3)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2cccc3c2CC(CC24CC5CC(CC(C5)C2)C4)=C3)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
94.0 g (228 mmole) 7-(4′-tert-Butyl-phenyl)-2-(1-adamantylmethyl)-indan-1-one were dissolved in 291 ml toluene in a 1 l—roundbottom flask equipped with a reflux condenser. 9.5 g (1.1 eq.) sodium borohydride were added. Then 40 ml (4.3 eq.) methanol were added at 50° C. and the mixture was stirred for 6 h at 50° C. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 350 ml of toluene. After addition of 0.7 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate, evaporation of the solvent and crystallization from 900 ml ethanol afforded 76.9 g (85%) of the desired indene as white crystals. 1H-NMR (400 MHz, CDCl3): δ=7.44, 7.32, 7.23, 7.12 (4×m, 7H, aromatic), 6.63 (s, 1H, ═CH), 3.32 (s, 2H, benzylic), 2.29 (d, 2H, aliphatic), 1.69-1.15 (m, 15H, aliphatic), 1.38 (s, 9H, C(CH3)3) ppm.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1)[C:6]([OH:8])=O.N1C=CC=CC=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=1.P(Cl)(Cl)(Cl)=O>C(#N)C.C(OCC)(=O)C.O>[CH3:16][Si:2]([CH3:1])([CH3:17])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1)[C:6]([NH:24][C:25]1[N:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=1)=[O:8]
Reactant: C[Si](C)(C)c1cc(C(=O)O)cc([Si](C)(C)C)c1
Reactant: CCOC(=O)C=Cc1ccc(N)nc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)/C=C/c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)nc1
Yield: 20 %

Procedure:
3,5-Bis(trimethylsilyl)benzoic acid (hereinafter referred to as “BTMB”; 700 mg) was suspended in acetonitrile (5.25 ml) in a nitrogen atmosphere. Pyridine (0.212 ml) and Compound 1a (603 mg) were added to the suspension, and phosphorus oxychloride (0.131 ml) was added dropwise under ice-cooling. The mixture was stirred while refluxing under heating for 3.5 hours. After the reaction mixture was allowed to cool, water and ethyl acetate were added thereto. The organic layer was washed three times with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (5% ethyl acetate/n-hexane) to obtain Compound 1b (232 mg, 20%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].O1CCOCC1.CC(C)([O-])C.[K+].Cl[C:23]1[N:24]=[N+:25]([O-:30])[C:26]([Cl:29])=[CH:27][CH:28]=1>CS(C)=O>[Cl:29][C:26]1[N+:25]([O-:30])=[N:24][C:23]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:28][CH:27]=1
Reactant: [O-][n+]1nc(Cl)ccc1Cl
Reactant: Cc1cccc(C)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cc1cccc(C)c1Oc1ccc(Cl)[n+]([O-])n1
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
268 mg (2.20 mmol) of 2,6-dimethylphenol, 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) were mixed, 270 mg (2.41 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 10 minutes. To the mixture was added 370 mg (2.24 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature for 10 hours and allowed to stand for 2 days. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 350 mg (1.39 mmol, Yield: 63.1%) of 6-chloro-3-(2,6-dimethylphenoxy)pyridazine 1-oxide.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:27]4[C:23]5=[N:24][O:25][N:26]=[C:22]5[CH:21]=[CH:20][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:28])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:27]3[C:23]4=[N:24][O:25][N:26]=[C:22]4[CH:21]=[CH:20][C:19]=3[O:18][CH2:17]2)[C:9]1=[O:28]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc3nonc3c12
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccccc2C12COc1ccc3nonc3c12

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (88%) as a colorless solid: mp>220° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.96-8.89 (m, 1H), 8.47-8.40 (m, 1H), 8.16-7.70 (m, 4H), 5.93 (d, J=9.3 Hz, 1H), 5.82 (d, J=9.3 Hz, 1H); MS (ES+) m/z 280.0 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].O>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In THF (11.2 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.56 g). To the solution were added pyridine (0.17 ml) and ethyl chloroformate (0.18 ml, and the mixture was stirred at room temperature for 3 hours. To the mixture was added 4-dimethylaminopyridine (169 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(ethoxycarbonyl)-2,3-dihydro-1-benzazepine-4-carboxylate (580 mg).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccccc21
Reactant: O=C(Cl)CCCCCBr
Product: CC(=O)N1CCc2cc(C(=O)CCCCCBr)ccc21

Procedure:
Using 1-acetylindoline and 6-bromohexanoyl chloride according to the same method as that of Reference Example 1, the title compound (1.27 g) was obtained as colorless crystals having a melting point of 110 to 111° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[C:22](O)(=O)C.C(N)=N>CCO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:6]([F:12])[C:7]2[N:11]=[CH:22][NH:10][C:8]=2[CH:9]=1)=[O:21]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1Cl
Agent: N=CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
4,5-Diamino-2-(2-chloro-phenylamino)-3-fluoro-benzoic acid methyl ester 6a (0.125 g, 0.404 mmol) is suspended in EtOH (2 mL) and formamidine acetate (63 mg, 0.605 mmol) is added. The reaction mixture is heated to reflux. After 16 hours, the reaction mixture is cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with water, saturated NaHCO3, 10% K2CO3 and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give 0.109 g (85%) pure desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][N:16]1[C:20]([CH2:21][C:22]#[N:23])=[CH:19][CH:18]=[CH:17]1.Cl>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[N:16]([CH3:15])[C:20]([CH2:21][C:22]#[N:23])=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccc(Cl)cc1
Temperature: 21 °C
Reaction time: 1 h

Procedure:
An acylating solution is prepared by the slow addition of 278 g. (1.58 moles) of p-chlorobenzoyl chloride to 210 g. (1.58 moles) of aluminum chloride in 750 ml. of ethylene chloride. The resulting solution is added to a solution of 190 g. (1.58 moles) of N-methylpyrrole-2-acetonitrile in 750 ml. of ethylene chloride. The temperature is maintained at 20-22° C. during the addition; and the solution is further stirred at room temperature for one hour. The solution is then heated rapidly to 74-76° C. at which point there is a vigorous evolution of hydrogen chloride gas. This temperature is maintained about 5 minutes, and the solution is cooled rapidly and poured into ice water. The product is extracted with methylene chloride and washed with water. The organic solution is then shaken with an excess of an aqueous solution of N,N-dimethylaminopropylamine followed by dilute hydrochloric acid to remove any excess p-chlorobenzoyl chloride. After a final wash with brine, the solution is dried over anhydrous magnesium sulfate. Distillation of the solvent leaves a residue which crystallizes. Recrystallization from methyl alcohol yields the product, 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, m.p. 120-124° C. After two additional recrystallizations from methanol, the m.p. is 127-131° C.
Reaction SMILES: Br[C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:10])[C:4]=2[CH:3]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O.CC([O-])=O.CC([O-])=O.[Pd+2].CC1C=CC=CC=1>[Cl:10][C:9]1[C:4]2[CH:3]=[C:2]([CH:12]3[CH2:14][CH2:13]3)[S:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2sc(Br)cc12
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ncnc2sc(C3CC3)cc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with commercially available 6-bromo-4-chlorothieno[2,3-d]pyrimidine (1.5 g, 6.01 mmol, 1.00 equiv), cyclopropylboronic acid (1.2 g, 13.97 mmol, 2.30 equiv), sodium carbonate (2.16 g, 20.38 mmol, 3.40 equiv), PPh3 (552 mg, 2.10 mmol, 0.35 equiv), Pd(OAc)2 (162 mg, 0.72 mmol, 0.12 equiv), water (7.5 mL) and methylbenzene (22.5 mL). The resulting solution was stirred overnight at 110° C. in an oil bath. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3×100 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15-1:5). This resulted in 400 mg (32%) of 4-chloro-6-cyclopropylthieno[2,3-d]pyrimidine as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8]Cl)[CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:17]([CH3:16])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=1
Reactant: CNCc1ccccc1
Reactant: ClCCn1cc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CCn1cc(Br)cn1)Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-bromo-1-(2-chloroethyl)-1H-pyrazole (317 mg, 1.513 mmol, for a preparation see Intermediate 54) was dissolved in N,N-dimethylformamide (DMF) (5 mL) and cesium carbonate (740 mg, 2.270 mmol) added with N-methyl-1-phenylmethanamine (0.973 mL, 7.57 mmol, available from Aldrich). The mixture was heated to 80° C. for 3 hours then allowed to stir at 80° C. overnight. The mixture was cooled to room temperature and loaded on to a 20 g SCX cartridge. The SCX was eluted with MeOH (100 ml) and 2M methanolic ammonia (100 ml). The basic fraction was evaporated to a colourless oil, loaded on to a 25+M Biotage silica column and eluted with a gradient of 0 to 2.5% 2M methanolic ammonia in DCM. The product containing fractions were evaporated to a pale yellow oil (155 mg). LCMS (Method C): Rt=0.67, MH+=294
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:20][C:21]2[C:22]([CH3:37])=[N:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: CCOC(=O)CCc1ccc(O)c2ccccc12
Product: CCOC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc12

Procedure:
In analogy to the procedures described in example 5C] and 5D], 3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester [Helvetica Chimica Acta (2001), 84(8), 2198-2211] was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 4G]) to give 3-{4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-naphthalen-1-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light pink solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)C>[CH3:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cc1cccc(N)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 59.7 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 1 ml of water and 9 ml of ethanol in place of the methanol and 214 mg of 3-methylaniline in place of the 3-(tert-butyl)aniline. 196 mg of N-(3-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:41][C:42]([F:62])([F:61])[C:43]1[CH:44]=[C:45]([S:49]([N:52]2[CH2:57][CH2:56][CH2:55][CH2:54][C@H:53]2[C:58]([OH:60])=O)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1.[NH2:63][C@@H:64]([CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)/[CH:65]=[N:66]/[C:67]1[C:68]([NH:73][CH3:74])=[CH:69][CH:70]=[CH:71][CH:72]=1>C(Cl)Cl>[CH2:75]([C@H:64]([NH:63][C:58]([C@@H:53]1[CH2:54][CH2:55][CH2:56][CH2:57][N:52]1[S:49]([C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([C:42]([F:41])([F:61])[F:62])[CH:44]=1)(=[O:50])=[O:51])=[O:60])/[CH:65]=[N:66]/[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[NH:73][CH3:74])[C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1
Reactant: CNc1ccccc1/N=C/[C@@H](N)Cc1ccccc1
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1ccccc1/N=C/[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.9 %

Procedure:
PyBOP (0.11 g, 0.22 mmoles) and triethylamine (0.076 mL, 0.55 mmoles) were added to a room temperature solution of (S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (0.074 g, 0.22 mmol) in CH2Cl2 (5 mL). After stirring at room temperature for 20 min, a solution of N-[(S)-2-amino-3-phenyl-prop-(E)-ylidene]-N′-methyl-benzene-1,2-diamine (0.052 g, 0.22 mmoles) in CH2Cl2 (5 mL) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give a yellow oil. Purification of the residue by flash chromatography on silica gel, eluting with 10-50% EtOAc/heptane afforded 0.078 g (64%) of the title compound as a colorless powder: ES+ LC/MS m/e 557 (M+H), RT=2.92 min; 1H NMR CDCl3: δ9.99 (bd s, 1), 8.05 (s, 1), 7.94 (d, 1, J=8.0 Hz), 7.83 (d, 1, J=7.9 Hz), 7.62 (t, 1, J=7.9 Hz), 7.23-7.56 (m, 8), 7.00 (d, 1, J=7.5 Hz), 5.45 (m, 1), 4.40 (bd s, 1), 3.72 (dd, 1, J=14.5, 5.1 Hz), 3.54 (d, 1, J=14.1 Hz), 3.44 (dd, 1, J=14.5, 10.8 Hz), 2.13-2.26 (m, 2), 1.37 (m, 1), 1.22 (m, 1), 0.92-1.10 (m, 4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9][CH3:10])[C:3]=1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].ClC1C=C(C=CC=1)C(OO)=O.[O-2:29].[Al+3].[O-2:31].[O-2].[Al+3]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9]([CH3:10])(=[O:31])=[O:29])[C:3]=1[NH:11][C:12](=[O:17])[C:13]([F:15])([F:16])[F:14]
Reactant: CSCc1cccc(Cl)c1NC(=O)C(F)(F)F
Reactant: [O-2]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Al+3]
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cccc(Cl)c1NC(=O)C(F)(F)F

Procedure:
The crude solid N-(2-chloro-6-methylsulfanylmethyl-phenyl)-2,2,2-trifluoro-acetamide from Step 2 was redissolved in methylene chloride (300 ml) and treated at 0° C. with meta-chloroperoxybenzoic acid (39.88 g, 0.177 mole) in portions with stirring. After 90 minutes the entire reaction mixture was poured onto a column of deactivated aluminum oxide (6% water) and the product was washed free of the acid by eluting with 1:1 ethyl acetate:hexane to afford 22.28 g of N-(2-Chloro-6-methanesulfonylmethyl-phenyl)-2,2,2-trifluoro-acetamide, a crystalline product (86%).
Reaction SMILES: C[O:2][C:3](=[O:44])[C@@H:4]([NH:18][C:19](=[O:43])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:36]([O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:27][C:21]2[CH:22]=[CH:23][C:24]([Br:26])=[CH:25][C:20]=2[C:19]([NH:18][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=2)[C:3]([OH:44])=[O:2])=[O:43])=[CH:34][CH:33]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCc1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cc(Br)ccc1OCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
(2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionic acid methyl ester (60 mg, 0.092 mmol) was dissolved in 5 mL of THF-MeOH (4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added. After 30 minutes, 2.2 additional equiv of 2N LiOH was added and the reaction stirred for 30 minutes. The reaction was worked up according to general procedure C to give (2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionic acid (35 mg, 60%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]1.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.[Cl-].[Na+].O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:19][CH:20]1[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:16]
Reactant: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)NC1CC(C)(C)NC(C)(C)C1
Yield: 24 %

Procedure:
A solution of (2Z,4E)-5-(benzofuran-2-yl)-2-methoxy-2,4-pentadienoic acid (122 mg, 0.5 mmol), 4-amino-2,2,6,6-tetramethylpiperidine (78 mg, 0.5 mmol), 1-hydroxy-7-azabenzotriazole hydrate (65 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (95 mg, 0.5 mmol) in DMF (2 ml) was stirred at RT for 6 hours. The solution was poured into brine (20 ml) and repeatedly extracted with EtOAc. The organic phase was washed with 5% aqueous CaCO3, dried (MgSO4) and concentrated to give a solid that was repeatedly washed with isopropyl ether. After drying pure title compound (45 mg, 0.12 mmol, yield 23.5%) was obtained as pale yellow crystals, mp.=250° dec.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:18])[C:9]2[C:17]3[CH:16]=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[CH:16]=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[O:18])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:21])=[O:22]
Reactant: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3ncncc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncncc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To propane-1-sulfonic acid {2-fluoro-3-[hydroxy-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-amide (P-0005, 79 mg, 0.22 mmol) in 1 mL of tetrahydrofuran, Dess-Martin periodane (101 mg, 0.24 mmol) was added. The reaction was stirred at room temperature for one hour. The reaction was poured into sodium thiosulfate and potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography eluting with 5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-0006, 75 mg, 95%). MS(ESI) [M+H+]+=363.1.