Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1)=O.[CH2:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH3:22]>>[C:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:20])[C:9]=1[C:5]1[CH:4]=[C:3]([CH2:1][NH:26][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])[CH:8]=[N:7][CH:6]=1)#[N:19]
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccccc21
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NCc1cncc(-c2c(C#N)c3ccccc3n2C)c1

Procedure:
2-(5-Formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 127) and ethanesulfonamide are processed according to the method described in Example 170 to give ethanesulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.3 Hz, 3H), 3.07 (q, J=7.4 Hz, 2H), 3.79 (s, 3H), 4.34 (d, J=6.1 Hz, 2H), 7.34-7.38 (m, 1H), 7.41-7.46 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.75-7.82 (m, 2H), 8.09 (t, J=2.1 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.1 Hz, 1H). HRMS (ESI) m/z 355.1247 [(M+H)+ Calcd for C18H19N4O2S: 355.1229].
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:38])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33]([O:35]CC)=[O:34])[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:38])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33]([OH:35])=[O:34])[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3cc(F)c4c(c3C)CCCO4)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4 g, 6.07 mmol) in THF (40 mL) was added 1N NaOH (6.07 mL, 6.07 mmol) and the resulting mixture was stirred at rt for 16 h. At this point the LCMS indicated about 70% conversion, so additional 1N NaOH (2.5 mL, 2.5 mmol) was added and the mixture was stirred for another 2 h. At this point LCMS indicated progression of reaction (˜90% conversion) along with small amount of di-acid. Water (20 mL) was then added to the reaction mixture and it was acidified with 1N HCl (10 mL). This aqueous solution was extracted with ether (2×100 mL), washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (2.7 g, 5.41 mmol, 89% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.21 (s, 1H), 6.85 (d, J=10.7 Hz, 1H), 5.00 (s, 1H), 4.36 (t, J=4.4 Hz, 2H), 4.19-4.12 (m, 2H), 2.81 (s, 3H), 2.80-2.74 (m, 2H), 2.20 (dd, J=6.3, 4.1 Hz, 2H), 1.83 (s, 3H), 1.24-1.20 (m, 3H), 1.18 (s, 9H). LCMS (M+H)=500.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].COCCNS(C1C=CC=CC=1C1NC(=O)C2=C(C)N=C(CCC)N2N=1)(=O)=O>ClCCl.CO>[CH3:28][O:29][CH2:30][CH2:31][NH:32][S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]3[N:15]=2)[CH:6]=1)(=[O:12])=[O:11]
Reactant: COCCN
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Agent: CCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3S(=O)(=O)NCCOC)nn12
Solvent: ClCCl
Solvent: CO
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)NCCOC)ccc3OCC)nn12

Procedure:
By the same method, starting with 1.23 g (3 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 680 mg (9 mmol) of 2-methoxyethylamine, 900 mg (67%) of N-(2-methoxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-benzenesulphonamide are obtained. Rf=0.25 (dichloromethane/methanol=95:5)
Reaction SMILES: N[C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].CC(SCC(Cl)=O)C(Cl)=O.CC1C(=O)N(C2C(I)=C(C(Cl)=O)C(I)=C(C=2I)C(Cl)=O)C(=O)CS1>>[I:12][C:5]1[C:6]([C:7]([Cl:9])=[O:8])=[C:10]([I:11])[CH:2]=[C:3]([I:16])[C:4]=1[C:13]([Cl:15])=[O:14]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Agent: CC(SCC(=O)Cl)C(=O)Cl
Agent: CC1SCC(=O)N(c2c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c2I)C1=O
Product: O=C(Cl)c1c(I)cc(I)c(C(=O)Cl)c1I

Procedure:
59.5 g of 5-amino-2,4,6-triiodoisophthalic acid dichloride is condensed with 11 g of 2-methyl-3-thiaglutaric acid dichloride as described in Example 1(A), thus obtaining a mixture of 5,5'-(2-methyl-3-thiaglutaryldiimino)-bis(2,4,6-triiodoisophthalic acid dichloride) and 5-(2-methyl-3,5-dioxoperhydro-1,4-thiazin-4-yl)-2,4,6-triiodoisophthalic acid dichloride; this mixture is separated by chromatography on silica gel. With chloroform as the eluent, the first product separated is 5-(2-methyl-3,5-dioxoperhydro-1,4-thiazin-4-yl)-2,4,6-triiodoisophthalic acid dichloride and then 5,5'-(2-methyl-3-thiaglutaryldiimino)-bis(2,4,6-triiodoisophthalic acid dichloride is obtained as a pure compound. The yield is 15.5 g (24% of theory), m.p. 255° (decomposition). 10 g of this tetrachloride is reacted as described in Example 1(B) with 4 g of N-methylamino-2,3-propanediol. After the mixture has been worked up by precipitation into methylene chloride, removal of the anions and cations by means of weakly alkaline and weakly acidic ion exchangers, and reprecipitation from methanol/isopropanol (1:2), the yield is 6 g (50% of theory) of 5,5'-(2-methyl-3-thiaglutaryldiimino)-bis[2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl-N-methyl)diamide], m.p. 235°-320° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([Cl:12])[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([CH3:29])[N:21]=2)=[CH:16][CH:15]=1.Cl.[CH3:31]N(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:12][C:4]1[CH:3]=[C:2]([NH:1][C:24](=[O:26])[C:23]2[CH:27]=[CH:28][C:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[N:21][C:22]=2[CH2:29][CH3:31])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(Cl)c2cccnc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCc1nc(-c2ccc(F)cc2)ccc1C(=O)Nc1cc(Cl)c2cccnc2c1
Temperature: 25 °C

Procedure:
To a solution of 7-amino-5-chloroquinoline (D83) (50 mg, 0.28 mmol) in DCM (3 ml) was added 6-(4-fluorophenyl)-2-methyl-nicotinic acid (D24) (30 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (59 mg, 0.31 mmol) and 4-dimethylaminopyridine (17 mg, 0.14 mmol) and the reaction stirred at room temperature then at reflux until complete by tlc. The mixture was washed with sat. aq. sodium bicarbonate solution then dried over MgSO4 and concentrated to give the crude product. Purification by SPE column chromatography gave the title compound as an off white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.94 (dd, 1H), 8.54 (d, 1H), 8.29 (s, 1H), 8.05 (m, 3H), 7.92 (d, 1H), 7.78 (br.s, 1H), 7.62 (d, 1H), 7.47 (dd, 1H), 7.18 (t, 2H), 2.84 (s, 3H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([CH:13]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH:14]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])#N.C(O)(=[O:32])C>C1C=CC=CC=1.C(OCC)C>[CH:11]([CH:13]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH:14]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[O:32]
Reactant: CC(=O)O
Reactant: N#CC1CCC2(OCCO2)C1CCCCCCCO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 25 °C

Procedure:
A solution of diisobutylaluminium hydride (53 g.) in dry benzene (145 ml.) was added, with rapid stirring, to a solution of 7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (43.2 g.) in dry diethyl ether (432 ml.) at 10°-15° C. Stirring at ambient temperature was continued for 11/2 hours and the mixture was added to 2 N aqueous acetic acid (1 liter) at a temperature lower than 15° C. The organic phase was separated and the aqueous layer was oxtracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate, dried over sodium sulphate, the solvents removed in vacuo and the residue distilled under reduced pressure to give 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (25.3 g.), b.p. 164°-200° C./0.04-0.05 mm. Hg, νmax. 1710 cm-1, 2700 cm-1 (liquid film).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:18])=[C:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=2)[CH:5]([C:19]([OH:21])=[O:20])[CH2:4][CH2:3]1.O.NN.[OH-].[K+]>C(O)COCCOCCO>[CH:12]1([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][C:8]=2[Cl:18])[CH:5]([C:19]([OH:21])=[O:20])[CH2:4][CH2:3][CH2:2]3)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C1CCC(C(=O)O)c2cc(Cl)c(C3CCCCC3)cc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: O=C(O)C1CCCc2cc(C3CCCCC3)c(Cl)cc21
Temperature: 195 °C
Yield: 78.6 %

Procedure:
A mixture of 6 g of 4-oxo-6-cyclohexyl-7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, 4 g of hydrazine hydrate, 6.4 g of potassium hydroxide and 40 ml of triethyleneglycol is heated for 2 hours at 130°-140°C. Then, while distilling off a mixture of hydrazine and water, the temperature is raised to 195°C and the batch is stirred until nitrogen is no longer being given off, then diluted with 50 ml of water, acidified with concentrated hydrochloric acid and the mixture is extracted with ethyl acetate and the ethyl acetate is evaporated. The resulting crude product is recrystallized from toluene, to yield 4.5 g of 6-cyclohexyl-7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid melting at 119°-120°, of the formula ##SPC10##
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:21][N:22]([CH2:33][CH:34]=O)[C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:34][CH2:33][N:22]([CH3:21])[C:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:32])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN(C)C(=O)OCc1ccccc1

Procedure:
A solution of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (1.78 g, 6.5 mmol) and phenylmethyl methyl(2-oxoethyl)carbamate (2.58 g, 12.4 mmol) under nitrogen in glacial acetic acid (300 mL) was treated with sodium triacetoxyborohydride (2.56 g, 12.1 mmol) at ambient temperature overnight. Concentrated the reaction in vacuo then redissolved in glacial acetic acid (100 mL) and treated with another 1 g of sodium triacetoxyborohydride at ambient temperature for 2 h. The reaction was evaporated in vacuo and the residue was chromatographed on silica gel eluting with 98:2-95:5 CH2Cl2:EtOAc to provide a clear viscous oil. The oil was dissolved in CH2Cl2, washed with saturated K2CO3, water, and brine, dried over Na2SO4, filtered and evaporated in vacuo to afford the product as a yellow viscuos oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27 (t, J=7.09 Hz, 3 H), 2.87 (d, J=5.90 Hz, 3 H), 3.34-3.51 (m, 4 H), 3.89 (d, J=20.22 Hz, 2 H), 4.24 (q, J=7.16 Hz, 2 H), 5.02 (d, J=23.16 Hz, 2 H), 7.09 (t, J=8.84 Hz, 2 H), 7.18-7.39 (m, 7 H), 7.66 (d, J=16.00 Hz, 1 H), 7.77 (s, 1 H); ES+ MS: 466 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:12][CH:13]=1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 0.75 h
Yield: 97.8 %

Procedure:
4-(2-Hydroxyethyl)phenylcarbamic tert-butyl ester (described in Example 38b) (170 g; 0.716 mole) was suspended in dichloromethane (1.7 l) and placed in an ice bath. Pyridine (113 g; 1.43 mole) was added giving a clear yellow solution. p-Toluenesulfonyl chloride (205 g; 1.07 mole) was dissolved in dichloromethane (850 ml) and added slowly with stirring to the reaction mixture during 45 minutes. The reaction mixture was allowed to reach room temperature over night. The solution was then washed with water (4×1 L) and dried with magnesium sulfate. The solvent was evaporated under reduced pressure until the weight was 440 g. The remaining brownish oil was slowly poured into heptane (1.6 L) with vigorous stirring. After approx. 20 seconds the oil started to crystallize. The heavy precipitate was filtered off, washed with heptane (200 ml) and dried in vacuo at 40° C. over night. This procedure gave 274 g (97.8% yield) of crude 2-[4-(tert-butoxycarbonylamino)phenyl]ethyl-4-methylbenzenesulfonate.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH2:11][C:10](=[O:16])[CH2:9][C:8]=2[CH:7]=1)(=[O:5])=[O:4].N(C)[CH3:18]>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH2:11][C:10](=[O:16])[CH2:9][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: CNC
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)CC2
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of 7-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl chloride (see Preparative Example 3, 1.0 g, 4.1 mmol) in CH2Cl2 (10 mL) at 15° C. (using a water bath) was added Me2NH (2M in THF, 8 mL, 16 mmol, 4 eq) dropwise. After stirring at room temperature for 30 minutes, the mixture was diluted with CH2Cl2 (30 mL), washed with H2O (20 mL), dried (Na2SO4), and concentrated. The residue was chromatographed on silica using 20% EtOAc/hexanes to give 0.46 g (45%) of 7-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonic acid dimethylamide as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.61 (d, 1H, J=8.1 Hz), 7.53 (s, 1H), 7.41 (d, 1H, J=8.1 Hz), 3.65 (s, 2H), 3.14 (t, 2H, J=6.6 Hz), 2.71 (s, 6H), 2.58 (t, 2H, J=6.6 Hz).
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[O:3][C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][C:7](=[O:9])[CH:6]=[CH:5]1.[OH:23]O.[OH-:25].[Na+].[Cl-].[NH4+]>CO>[O:23]1[CH:5]2[CH:6]1[C:7](=[O:9])[CH2:8][C:4]2([O:3][Si:2]([CH3:1])([CH3:21])[CH3:22])[CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O:25]1[CH:5]2[CH:6]1[C:7](=[O:9])[CH2:8][C:4]2([OH:3])[CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OO
Reactant: C[Si](C)(C)OC1(CCCCOc2ccccc2)C=CC(=O)C1
Reactant: [OH-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)OC1(CCCCOc2ccccc2)CC(=O)C2OC21
Product: O=C1CC(O)(CCCCOc2ccccc2)C2OC12
Yield: 34 %
Yield: 53 %

Procedure:
To a solution of 2.49 g of 4-trimethylsilyloxy-4-(4-phenoxybutyl)-2-cyclopentenone dissolved in 50 ml of methanol was added 3.9 ml of an aqueous 30% hydrogen peroxide under ice-cooling and stirring. An amount of 1 of 1N aqueous sodium hydroxide was added, and the mixture was stirred for 2 hours. Then saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 892 mg (yield 34%) of 2,3-epoxy-4-trimethylsilyloxy-4-(4-phenoxybutyl)cyclopentanone and 1.38 g (yield 53%) of 2,3-epoxy-4-hydroxy-4-(4-phenoxybutyl)cyclopentanone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:40]([O:39][C:37](=[O:38])[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Reactant: CC(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1

Procedure:
A suspension of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (120 mg, 0.26 mmol), isopropyl 2-chloroacetate (45 mL, 0.36 mmol), K2CO3 (125 μL, 0.24 mmol), in DMF (5 mL) stirred at RT for 2 h. Concentrated in vacuo to afford the crude tert-butyl 5-(2-(3-(2-isopropoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.26 mmol)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[OH:27])[CH2:5]C1C=CC(C2C=CC=CC=2)=CC=1.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Cl)=[CH:40][C:39]=1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:29])[CH:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:39]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:40]=1)[CH3:5]
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Product: COC(=O)C(C)NC(=O)c1cc(Br)ccc1OCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 61.1 %

Procedure:
3-Biphenyl-4-yl-2-S)-[2-(3,4-bis-benzyloxy-benzyloxy)-5-bromo-benzoylamino]-propionic acid methyl ester (340 mg) was prepared from 3-biphenyl-4-yl-2-(S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (400 mg, 0.92 mmol) (See example 136) and 1,2-bis-benzyloxy-4-chloromethyl-benzene (374 mg, 1.1 mmol) as described in general procedure G and purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=2)=[CH:3][CH:4]=1)[OH:13]
Reactant: COc1cccc(B(O)O)c1
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cccc(-c2ccc([C@@H](O)C(F)(F)F)cc2)c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a stirred solution of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (2, 69 g, 0.27 mol, >99% ee), 3-methoxy phenylboronic acid (Matrix, 51 g, 0.34 mol, 97% purity), and bis(triphenylphosphine)palladium(II) dichloride (0.95 g, 0.5% mol) in ethanol (560 ml) was added a solution of potassium carbonate (112 g, 0.81 mol) in water (140 ml) under nitrogen. The resulting mixture was heated at 75° C. for 1 h and deemed complete by GC-MS or TLC. After reaction mixture was cooled to 40° C., it was filtered through a pad of Celite, washed with methanol (3×100 ml). The filtrate was diluted with 100 ml of water and concentrated. The resulting syrup was dissolved in 700 ml of ethyl acetate and washed with 1 N sodium hydroxide (2×100 ml), water (2×100 ml) and brine (1×100 ml). The organic layer was heated with activated carbon (14 g) and Hyflo Super Cel (14 g) at 60° C. for 1 h. This mixture was filtered hot and washed with ethyl acetate (100 ml) and then concentrated to a syrup. This syrup was immediately dissolved in 1% ethyl acetate/heptane (700 ml) and stirred for 4 h. The resulting slurry was filtered and dried to give the titled compound as a white crystalline solid (3, 68 g, 89% yield, >99% ee)
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([C:31]#[N:32])=[C:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([C:14]3[CH:19]=[CH:18]C=CC=3)=[C:8]2[S:7][CH2:6]1)=[O:4].COC([C@H]1N2C(=O)C(Br)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3C=CC=CC=3)=C2SC1)=O.COC(C1N2C(=O)C(Br)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3CC3)=C2SC1)=O>>[CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:33])[C:11]([C:31]#[N:32])=[C:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([CH:14]3[CH2:18][CH2:19]3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Agent: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(Br)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(Br)c(=O)n21
Product: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Yield: 88 %

Procedure:
By following the procedure described for the preparation of 6a from 5a, 5b (100 mg, 0.21 mmol) gave 6b as a white foam (78 mg, 88%). [α]D−44 (c 1.0, CHCl3); IR λ 3004, 2954, 2360, 2213, 1747, 1644, 1481, 1213, 1164, 792; 1H NMR (400 MHz, CDCl3) 8.12 (d, J=8.2 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.62-7.51 (m, 2H), 7.34 (t, 1H), 6,89 (d, J=7.1 Hz, 1H) 5.74 (dd, J=6.7, 2.2 Hz, 1H), 4.83-4.70 (m, 2H), 3.86 (s, 3H), 3.76 (dd, J=9.0, 2.9 Hz, 1H), 3.58 (dd, J=9.8, 2.2 Hz, 1H), 1.27-1.21 (m, 1H), 0.69-0.65 (m, 2H); 0.55-0.53 (m, 2H): 13C NMR (100 MHz, CDCl3) (167.7, 162.9, 158.6, 155.6, 133.8, 132.4, 131.7, 128.9, 127.6, 126.4, 125.9, 125.5, 124.1, 122.8, 115.2, 114.5, 101.7, 63.5, 53.6, 34.8, 31.7, 11.3, 7.7, 7.2; HRMS (FAB+) calcd for C24H21N2O3S 417.1267, obsd 417.1289.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[Cl:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[CH:8]=[CH:9][N+:10]([O-:12])=[O:11]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C@H:8]1[C@H:9]([N+:10]([O-:12])=[O:11])[CH2:4][CH:3]=[CH:2][CH2:1]1
Reactant: O=[N+]([O-])C=Cc1ccccc1Cl
Reactant: C=CC=C
Solvent: Cc1ccccc1
Product: O=[N+]([O-])[C@@H]1CC=CC[C@H]1c1ccccc1Cl
Temperature: 110 °C
Reaction time: 72 h

Procedure:
A 10 mL solution of 1:1 1,3-butadiene and toluene stored at −20° C. and 2-chloro-β-nitrostyrene (2.0 g, 11 mmol) were added to a pressure tube and sealed. The solution was heated to 110° C. and stirred for three days. The reaction mixture was cooled to room temperature, concentrated, and the residue was crystallized from hexanes to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.38 (m, 1H), 7.15-7.29 (m, 3H), 5.71-5.84 (m, 2H), 5.09-5.16 (m, 1H), 4.04-4.13 (m, 1H), 2.76-2.84 (m, 2H), 2.54-2.60 (m, 1H), 2.19-2.28 (m, 1H).