Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[CH:19]=[C:18](F)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cnc(F)cc23)c1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: C#Cc1cccc(Nc2ncnc3cnc(NCc4ccc(OC)cc4)cc23)c1
Temperature: 70 °C
Reaction time: 158 h
Yield: 80.1 %

Procedure:
A mixture of compound 164 (8.90 g, 33.7 mmol) and 4-methoxybenzylamine (44.2 mL, 337 mmol) in dry DMSO (80 mL) was stirred under nitrogen at 70° C. (bath temperature) for 158 h. The resultant solution was cooled briefly and then stirred with petroleum ether (2×400 mL) at room temperature for 15 min before the petroleum ether layer was decanted. Water (400 mL) was added to the DMSO layer and the mixture was stirred at room temperature for 3 h. The solid thus precipitated was collected by filtration and washed with water (5×100 mL), before being suctioned dry and then washed with petroleum ether (2×100 mL) and suctioned dry again. The resultant brownish orange solid was dissolved in warm acetone (400 mL) and water (500 mL) was added. The mixture was then stirred at room temperature for 1 h and the resultant solid was collected by filtration, washed with acetone/water (1:1, 5×80 mL) and dried in vacuo over silica-gel, to give N4-(3-ethynylphenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (167) (10.3 g, 80%) as a yellow/orange solid, mp 200-203° C.; 1H NMR δ [(CD3)2SO] 9.63 (s, 1H), 8.75 (s, 1H), 8.38 (s, 1H), 8.03 (br s, 1H), 7.94-7.88 (m, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.34 (br d, J=8.6 Hz, 2H), 7.28-7.21 (m, 2H), 7.19 (s, 1H), 6.92-6.85 (m, 2H), 4.50 (d, J=6.3 Hz, 2H), 4.19 (s, 1H), 3.71 (s, 3H). Anal. Calcd for C23H19N5O: C, 72.42; H, 5.02; N, 18.36%. Found C, 72.28; H, 5.05; N, 18.22%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]([OH:18])=[O:17])[CH:6]=[C:7]([Cl:11])[C:8]=1OC.[C:19](O)(=[O:21])C>Cl.[Pd]>[CH3:1][O:2][C:3]1[CH2:8][C:7]([O:21][CH3:19])([Cl:11])[CH:6]=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:4]=1
Reactant: COc1cc(C=CC=CC(=O)O)cc(Cl)c1OC
Reactant: CC(=O)O
Agent: [Pd]
Agent: Cl
Product: COC1=CC(CCCCC(=O)O)=CC(Cl)(OC)C1

Procedure:
A solution containing 6.2 g of the above product obtained in Example 32 was dissolved in a mixture of 30 ml of acetic acid and 3 ml of conc. hydrochloric acid. Palladium on charcoal catalyst (10% Pd) was added and the mixture was hydrogenated at normal pressure and room temperature. After filteration the solvents were evaporated in vacuo. Yield 3.2 g (55%), a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[C:18](=[O:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH:18]([OH:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3,4-Dihydro-9-(2-methylbenzylamino)acridin-1(2H)-one (4.15 g) was suspended in 100 ml of THF and chilled with ice-water. 1M lithium aluminum hydride in THF (8.0 ml) was added dropwise through a syringe and then the reaction mixture was stirred 30 minutes in the cold. It was quenched by the sequential addition of 0.5 ml of water, 0.5 ml of 15% sodium hydroxide and 1.5 ml of water. The inorganic salts were filtered and the organic phase was evaporated to obtain an amorphous solid product. Recrystallization from ethyl acetate gave 3.38 g, mp 167°-169° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C:17]([CH2:18]O)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:22]>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][N:9]2[C:17]([CH2:18][Br:22])=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: Nc1ncnc2c1nc(CO)n2CCC1CCCCC1
Solvent: ClCCl
Product: Nc1ncnc2c1nc(CBr)n2CCC1CCCCC1

Procedure:
A solution of N9-cyclohexylethyl-8-hydroxymethyladenine (1 mmol) in methylene chloride was treated with PBr3 (1 mmol) at 25° C. for 1 h. Extraction and chromatography give N9-cyclohexylethyl-8-bromomethyl-adenine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[Cl:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:25])[N:3]=[CH:4]1
Reactant: NC(=O)c1c(N)ncn1Cc1cccc(Cl)c1
Reactant: O=C(O)c1cccnc1
Product: NC(=O)c1c(NC(=O)c2cccnc2)ncn1Cc1cccc(Cl)c1
Yield: 78 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 1.50 g (5.98 mmol) of 4-amino-1-(3-chlorobenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 51 and nicotinic acid instead of cyclopentylacetic acid to obtain 1.65 g of 1-(3-chlorobenzyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:20])=[O:11])=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:32][CH:33]=[CH2:34]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:34][CH:33]=[CH2:32])[C:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:20])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)c2ccc(C#N)cc2C)cc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)c1ccc(C#N)cc1C)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a solution of A-7 (4-(2-(4-methoxyphenyl)acetyl)-3-methylbenzonitrile) (19 g, 71.6 mmol) in anhydrous tetrahydrofuran (200 mL) was added dropwise lithium hexamethyldisilazide (LiHMDS) (86 mL, 1 mol/L in THF) at −78° C. under nitrogen, and the reaction mixture was stirred at −78° C. for 30 min. A solution of 3-bromo-propene (10.4 g, 86 mmol) in anhydrous tetrahydrofuran (70 mL) was added dropwise into the mixture, and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (200 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate (10 g), evaporated, and purified on silica gel column (petroleum ether/ethyl acetate=25:1) to give A-8 (4-(2-(4-methoxyphenyl)pent-4-enoyl)-3-methylbenzonitrile) (7.7 g, yield 35.2%) as an oil. 1H NMR (CDCl3 400 MHZ): δ 7.36 (m, 3H), 7.01 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 5.72-5.62 (m, 1H), 5.04-4.93 (m, 2H), 4.20-4.17 (m, 1H), 3.69 (s, 3H), 2.92-2.85 (m, 1H), 2.52-2.40 (m, 1H), 2.16 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24]>C(Cl)Cl>[F:21][C:22]([F:26])([F:25])[CH2:23][NH:24][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: NCC(F)(F)F
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
5.0 g (24 mmol) of 4-trifluoromethylbenzoyl chloride and 5.0 ml (36 mmol) of triethylamine were dissolved in 50 ml of CH2Cl2 and 2.4 g (24 mmol) of 2,2,2-trifluoroethylamine were slowly added dropwise at RT. The mixture was stirred at RT for 4 h, then the volatile constituents were removed under reduced pressure. The residue was taken up using 100 ml of MTB and washed initially with 30 ml of a saturated aqueous Na2CO3 solution and then with 30 ml of a saturated aqueous NaHSO4 solution. Drying was effected over MgSO4 and 6.1 g (94%) of a colorless resin were obtained which crystallized when left to stand; mp: 117° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH:12]1[C:22](=O)[NH:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=O)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:40]>>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:13][CH:12]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[N:40]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 1.83 h
Yield: 53.2 %

Procedure:
{1-[2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (192 mg, 0.34 mmol) was dissolved in m-Xylenes (2 mL) and heated at 135° C. Solid ammonium acetate (128 mg, 1.66 mmol) was added and the reaction was stirred at 135° C. After 110 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w MeOH 10%/hexanes) to yield the product {1-[2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98.7 mg, 0.181 mmol): LCMS-ESI+: calc'd for C22H27BrF3N5O3: 546.4 (M+); Found: 546.0/548.2 (M+H+).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[OH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCCCCCCCCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCCCCCOCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
16 q (100 mmol) of nonane-1,9-diol was dissolved in 150 ml of dimethylformamide and instilled in a suspension of 2.88 g (1.20 mmol) of sodium hydride in 100 ml of DMF. It is stirred for 2 hours at 50° C. It is cooled in an ice bath to 0° C. and 17.1 g (100 mmol) of benzyl bromide is instilled within 3 hours. Then, it is stirred for 5 hours at 60° C. The solution is cooled to room temperature, 1 l of water is added and it is extracted 3 times with 150 ml of ether. The combined organic phases are dried on magnesium sulfate and concentrated by evaporation in a vacuum. The remaining oil is chromatographed on silica gel (mobile solvent: hexane/acetone=15:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:17]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:41]([OH:52])(=O)[C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=O)=[CH:44][CH:43]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([CH3:10])[C:11]([NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:17]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:16]=2[N:15]([C:46]([C:45]2[CH:44]=[CH:43][C:42]([C:41]([N:15]3[C:16]4[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[CH:33][C:17]=4[N:18]([CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][C:23]=4[CH3:32])[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([CH3:8])[C:6](=[O:40])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:10])[CH2:14]3)=[O:52])=[CH:50][CH:49]=2)=[O:48])[CH2:14]1)=[O:39])=[O:40])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2cc(C#N)ccc21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(C)ccc5ccccc45)c4ccc(C#N)cc43)cc2)c2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a solution of {(S)-1-[(S)-7-cyano-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 16) (90 mg, 0.166 mmol) in pyridine (1 mL) was added terephthalic acid (13.808 mg, 0.083 mmol). After 10 min the mixture was cooled to 0° C., POCl3 (0.017 mL, 0.183 mmol) was added and the cooling bath was removed. After 1 h, the mixture was concentrated, the residue was dissolved in ethyl acetate and the mixture was washed with water, NaHCO3 solution, and brine, dried over sodium sulfate and concentrated. The residue was purified by preparative reverse phase HPLC to provide tert-butyl N-[(1S)-2-[[(3S)-5-[4-[(3S)-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-7-cyano-1-[(2-methyl-1-naphthyl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepine-5-carbonyl]benzoyl]-7-cyano-1-[(2-methyl-1-naphthyl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate as white solid (5 mg, 5.32%). LC-MS: 1213.6 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:15]([C:22]([OH:24])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:28]2N(O)N=[N:31][C:29]=2[CH:30]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:29]1([NH:31][C:22]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:24])[CH2:30][CH2:28]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 185.7 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(3-methylbutyl)-1H-1,2,3-triazole-4-carboxylic acid (462 mg, 1.40 mmol) obtained in Example 97b), HOBt (95.4 mg, 0.700 mmol, 0.5 eq.) and cyclopropylamine (0.130 ml, 1.82 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 7.5 ml), WSC (328 mg, 1.68 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (40 ml) and washed with 2% aqueous sodium carbonate solution (×2), 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a grayish white powder (481 mg, 1.30 mmol, 93.0%).
Reaction SMILES: N1C=CN=C1.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29].C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:31]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C:13]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[F:6])[CH2:14][CH2:15][C:16](=[O:19])[CH2:17][CH2:18]2)=[CH:25][CH:24]=1)([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(c2ccc(O)cc2)(c2ccccc2F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2(c3ccccc3F)CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Imidazole (128 mg, 1.9 mmol) was added to a solution of 6 (214 mg, 0.75 mmol) and TBDMSCl (136 mg, 0.90 mmol) in DMF (8 mL). The mixture was stirred at room temperature overnight. NaHCO3 (10 mL, saturated aqueous solution) was added and the mixture was extracted with EtOAc (2×40 mL). The combined organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The concentrate was dissolved in EtOAc (50 mL) and the solution was washed with MgSO4 (4% aqueous solution). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. Yield of crude: 394 mg (>100%) as a thick oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3].I[CH2:11][CH2:12][CH2:13]I.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][S:2]([C:5]1([C:6]([O:8][CH3:9])=[O:7])[CH2:13][CH2:12][CH2:11]1)(=[O:4])=[O:3]
Reactant: ICCCI
Reactant: COC(=O)CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C1(S(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of methyl methylsulfonylacetate (1.0 g, 6.6 mmol) in 20 mL of acetonitrile was added 1,3-diiodopropane (2.3 mL, 20 mmol) and cesium carbonate (6.4 g, 20 mmol). After stirring at room temperature for 2 h, the reaction was partitioned between water (50 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness, and the residue was purified by flash chromatography on silica gel eluting with 20 to 50% ethyl acetate in hexane to give methyl 1-methylsulfonylcyclobutanecarboxlate (1.0 g, 79%). δ 3.84 (s, 3H), 3.02 (s, 3H), 2.84-2.65 (m, 4H), 2.25-2.02 (m, 2H).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:9][CH:10]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][C:24]([OH:28])([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: OC1(c2cccc(C(F)(F)F)c2)CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under anhydrous conditions, to a mixture of 11 g. of magnesium in 15 ml. of ethyl ether an iodine crystal is added followed by the addition of a solution of 100 g. of m-bromotrifluoromethylbenzene in 300 ml. of ether over a two hour period. The resulting mixture is stirred for two hours at ambient temperature then cooled to 5° C. A solution of 70 g. of N-benzyl-3-piperidone in 300 ml. of ether is added at this temperature over one hour. After stirring for 15 minutes at 5° C. and one hour at 20°-25° C., the reaction mixture was poured onto 800 ml. of ice-water with stirring. The mixture is filtered, the organic layer extracted with 4×100 ml. of 1 N hydrochloric acid and once with brine. The aqueous phase is made alkaline by addition of triethylamine in the cold and the resulting mixture extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with cyclohexane/chloroform/triethylamine (85:10:5 by volume) to obtain the desired product as an orange colored solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[C:4]([CH3:50])([CH3:49])[CH2:5][CH2:6][C:7]([N:9]([CH2:15][C:16]1[CH:17]=[C:18]([CH:46]=[CH:47][CH:48]=1)[C:19]([NH:21][C:22]1[S:23][C:24]2[CH2:45][CH2:44][CH2:43][CH2:42][C:25]=2[C:26]=1[C:27]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])=[N:34][CH:35]=1)=[O:28])=[O:20])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:8].CN1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[OH:38][CH2:37][C:36]([C:33]1[N:34]=[CH:35][C:30]([NH:29][C:27]([C:26]2[C:25]3[CH2:42][CH2:43][CH2:44][CH2:45][C:24]=3[S:23][C:22]=2[NH:21][C:19]([C:18]2[CH:17]=[C:16]([CH:48]=[CH:47][CH:46]=2)[CH2:15][N:9]([CH:10]([CH2:11][CH3:12])[CH2:13][CH3:14])[C:7](=[O:8])[CH2:6][CH2:5][C:4]([CH3:50])([CH3:49])[C:3]([O:2][CH3:1])=[O:51])=[O:20])=[O:28])=[CH:31][CH:32]=1)([CH3:40])[CH3:41]
Reactant: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(C(C)(C)C(=O)O)nc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(C(C)(C)CO)nc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
To a mixture of 410 mg of 2-{5-[({2-[(3-{[(5-methoxy-4,4-dimethyl-5-oxopentanoyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]pyridin-2-yl}-2-methylpropanoic acid, 75 mg of 4-methylmorpholine and 10 mL of THF was added 0.089 mL of isobutyl chloroformate under ice cooling, followed by stirring for 10 minutes at room temperature. The reaction mixture was filtered, and then the filtrate was cooled with ice. 65 mg of sodium borohydride and 1.0 mL of water were added thereto, followed by stirring for 10 minutes at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2), thereby obtaining 155 mg of methyl 5-[{3-[(3-{[6-(1-hydroxy-2-methylpropan-2-yl)pyridin-3-yl]carbamoyl}-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)carbamoyl]benzyl}(pentan-3-yl)amino]-2,2-dimethyl-5-oxopentanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)(=[O:20])=[O:19])[C:10]=2[C:31]([O:33]C(C)(C)C)=[O:32])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)(=[O:19])=[O:20])[C:10]=2[C:31]([OH:33])=[O:32])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C(=O)OC(C)(C)C)n(S(=O)(=O)c3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2c(C(=O)O)n(S(=O)(=O)c3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Reaction time: 0.08 h
Yield: 42.1 %

Procedure:
tert-Butyl 3(4-methoxyphenyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}indole-2-carboxylate (Example 27, 45 mg, 0.085 mmol) was dissolved in trifluoroacetic acid (0.4 mL). The resulting mixture was allowed to stir for 5 minutes. The reaction mixture was treated with a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3×4 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 3-(4-methoxyphenyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}indole-2-carboxylic acid as an oil (17 mg, 42%): 1H (acetone-d6) δ 3.70 (s, 3 H), 6.85-6.89 (m, 2 H), 7.20-7.34 (m, 2 H), 7.47 (dd, J=0.6, 8.1 Hz, 1 H), 7.60-7.68 (m, 3 H), 7.83 (br d, 1 H), 8.06 (d, J=8.2 Hz, 1 H), 8.63 (m, 2 H); mass spectroscopy HPLC ES MS m/z (rel abundance) 476 ((M+H)+, 48%).