Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]([CH3:9])([OH:8])[C:6]#[CH:7])[CH3:2].[H-].[Na+].I[CH3:13]>CN(C)C=O>[CH2:1]([S:3][CH2:4][C:5]([O:8][CH3:13])([CH3:9])[C:6]#[CH:7])[CH3:2]
Reactant: CI
Reactant: C#CC(C)(O)CSCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(CSCC)OC
Reaction time: 8 h

Procedure:
1-Ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.29 g, 2.0 mmol) was added to a mixture of sodium hydride (60% dispersion in mineral oil, 88 mg, 2.2 mmol) in dimethylformamide (5 mL) under argon. Iodomethane (0.12 mL, 2.0 mmol) was then added to the reaction mixture via syringe and the mixture allowed to stir overnight. The mixture was poured onto water and extracted twice with diethyl ether. The diethyl ether extracts were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to yield a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[Cl:16][N:17]1[N:22]=[C:21](Cl)[CH:20]=[C:19]([NH:24][C:25]2[CH:26]=[C:27]([S:52]([OH:55])(=[O:54])=[O:53])[C:28]([CH:31]=[CH:32][C:33]3[C:34]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:35][C:36]([NH:39][C:40]4[NH:45][N:44]([Cl:46])[N:43]=[C:42](Cl)[CH:41]=4)=[CH:37][CH:38]=3)=[CH:29][CH:30]=2)[NH:18]1>>[Cl:16][N:17]1[N:22]=[C:21]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=2)[CH:20]=[C:19]([NH:24][C:25]2[CH:26]=[C:27]([S:52]([OH:55])(=[O:54])=[O:53])[C:28]([CH:31]=[CH:32][C:33]3[C:34]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:35][C:36]([NH:39][C:40]4[NH:45][N:44]([Cl:46])[N:43]=[C:42]([NH:1][C:2]5[C:11]6[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=6)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=5)[CH:41]=4)=[CH:37][CH:38]=3)=[CH:29][CH:30]=2)[NH:18]1
Reactant: O=S(=O)(O)c1cc(NC2=CC(Cl)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Cl)=NN(Cl)N2)cc1S(=O)(=O)O
Reactant: Nc1ccc(S(=O)(=O)O)c2ccccc12
Product: O=S(=O)(O)c1cc(NC2=CC(Nc3ccc(S(=O)(=O)O)c4ccccc34)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Nc3ccc(S(=O)(=O)O)c4ccccc34)=NN(Cl)N2)cc1S(=O)(=O)O
Temperature: 20 °C
Reaction time: 24 h

Procedure:
An aqueous solution of 1-aminonaphthalene-4-sulfonic acid (0.012 mol) was added to the freshly produced solution according to Example 4 of 4,4′-bis-(2,4-dichlorotriazin-6-ylamino)-stilbene-2,2′-disulfonic acid (0.006 mol). The mixture was stirred at pH 5.5 and 20° C. for 24 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(O[CH2:17][C:18]1[CH:23]([C:24]([OH:26])=[O:25])[N:22]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:21]2[S:20][CH:19]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]([C:24]([OH:26])=[O:25])[N:22]3[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@H:21]3[S:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: COc1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)c2ccccc12
Reaction time: 0.25 h

Procedure:
A solution of 0.8 g of freshly distilled 1-methoxynaphthalene in 2.2 ml of trifluoroacetic acid is mixed with 0.4 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the resulting solution is left to stand for 15 minutes at room temperature. It is then diluted with an equal amount of toluene and evaporated to dryness under reduced pressure. The residue is taken up in 50 ml of acetic acid ethyl ester and 30 ml of a 10% strength aqueous dipotassium hydrogen phosphate solution. The whole is thoroughly shaken, the organic layer is separated off and the aqueous phase is extracted with two 50 ml portions of acetic acid ethyl ester. The aqueous phase is covered with 50 ml of acetic acid ethyl ester and the pH value is adjusted to 2 by adding 2% strength aqueous phosphoric acid. After vigorous shaking, the organic solution is separated off, and the aqueous phase is twice extracted with 50 ml portions of acetic acid ethyl ester. The combined organic extracts are washed three times with 50 ml portions of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. 3-(4-Methoxy-1-naphthylmethyl)-7-(N-phenylacetylamino)-ceph-2-em-4ξ-carboxylic acid is obtained as an oily residue, which on trituration with acetic acid ethyl ester crystallises and after recrystallisation from methanol melts at 196°C; thin layer chromatogram (silica gel): Rf = 0.71 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.76 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.52 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (in methanol): λmax = 225 mμ (ε = 17,600) and 298 mμ (ε = 8300) and shoulder at 308 mμ (ε = 6400) and 322 mμ (ε = 3950); infrared absorption spectrum (in mineral oil): characteristic bands at 3.02μ, 5.69μ, 5.77μ, 6.06μ and 6.59μ.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCC(=O)CC2
Reactant: CN1CCNCC1
Product: COc1c([N+](=O)[O-])ccc2c1CCC(N1CCN(C)CC1)CC2

Procedure:
1-(1-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-4-methyl-piperazine was prepared from 1-methoxy-2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 1-methylpiperazine in a similar manner to Example 907e. Product was isolated as a brown film.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[NH:28][C:27]([NH2:30])=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:15]1[CH:16]=[CH:17][N:13]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[N:28]=[C:27]([NH:30][C:10]([C:8]3[CH:9]=[C:4]4[CH:3]=[CH:2][S:1][C:5]4=[CH:6][N:7]=3)=[O:12])[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: O=C(O)c1cc2ccsc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccsc2cn1
Yield: 2.6 %

Procedure:
2.6 mg (3%) of thieno[2,3-c]pyridine-5-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was prepared according to general procedure A using 54 mg (0.3 mmol) thieno[2,3-c]pyridine-5-carboxylic acid, 61 mg (0.25 mmol) intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 114 mg (0.3 mmol) of HBTU, 0.106 mL (0.6 mmol) of DIEA in 1 mL of DMF stirring at 85° C. for 1 h. LCMS: 404 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][C@H:17]([C:24]([OH:26])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](O)[CH3:28].Cl>C(O)C>[CH2:27]([O:25][C:24](=[O:26])[C@H:17]([CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)[NH:16][C:14](=[O:15])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:28]
Reactant: CCO
Reactant: O=C(CCNC(=O)OCc1ccccc1)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CCNC(=O)OCc1ccccc1

Procedure:
A 1 L round-bottom flask, under nitrogen atmosphere, is loaded with 40 g of 3-(benzyloxycarbonylamino) propionyl-L-histidine, 200 g of absolute ethanol and 80 g of an 8M HCl ethanol solution.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[C:6]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])[C@@H:7]([CH3:9])[OH:8]>P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:8][C@H:7]([CH3:9])[C:6]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])[CH3:5])[CH3:2]
Reactant: C=COCC
Reactant: CC(C)COC(=O)[C@@H](C)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@H](C)C(=O)OCC(C)C
Temperature: 25 °C
Yield: 82.1 %

Procedure:
17.2 g of dehydrated ethyl vinyl ether was dropwise added to a mixture of 32.7 g of isobutyl (R)-(+)-lactate and 0.3 g of phosphorus oxychloride which was being stirred at room temperature, so that the internal temperature of the reaction system could be kept at 40° C. or less. Then, the resulting mixture was stirred at room temperature overnight. After the reaction, thereto was added 200 ml of ethyl acetate, followed by washing with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 40.1 g (yield: 91.8%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([CH3:15])=[C:7]([CH3:14])[C:8]=1[C:9](OCC)=O)[CH2:2][CH3:3].[CH3:16]C1OC(C)OC(C)O1>>[CH2:1]([C:4]1[NH:5][C:6]([CH3:15])=[C:7]([CH3:14])[C:8]=1[CH2:9][CH3:16])[CH2:2][CH3:3]
Reactant: CCCc1[nH]c(C)c(C)c1C(=O)OCC
Reactant: CC1OC(C)OC(C)O1
Product: CCCc1[nH]c(C)c(C)c1CC

Procedure:
2-n-propyl-3-carbethoxy-4,5-dimethyl-pyrrole was reductively alkylated with paraldehyde to yield 2-n-propyl-3-ethyl-4,5-dimethyl-pyrrole. ##STR87##
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:44]1[C:45]([OH:53])=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=1)[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:44]1[C:45]([OH:53])=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=1)([CH2:5][OH:16])[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2c(Cl)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2c(Cl)cccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [4-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (99%) as a gummy solid: MS (ES+) m/z 418.7 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[OH-].[Na+]>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:5]2[CH:6]=[CH:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:4]=2[C:3]([OH:24])=[O:2])=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(S(N)(=O)=O)ccc1OCc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(S(N)(=O)=O)cc2C(=O)O)cc1
Temperature: 60 °C

Procedure:
To 2.5 mmol 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid methyl ester in 6 ml THF was added 5 mmol 2 M aq NaOH, and the mixture was heated at 60° C. for 30 min. The mixture was then cooled to RT and extracted twice with ethyl acetate. The aqueous phase was acidified to pH 1 with 5 M aq HCl and extracted with ethyl acetate. The combined organic phases were washed with saturated aq NaCl and dried with Na2SO4. Evaporation in vacuo afforded the title compound. MS (m/e): 336.1 ([M−H]−, 100%)
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH3:7][N:8]1[C:12]([NH:13][C:14](=O)[CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19][CH2:18]2)=[CH:11][C:10]([CH3:32])=[N:9]1>O1CCCC1>[CH3:7][N:8]1[C:12]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19][CH2:18]2)=[CH:11][C:10]([CH3:32])=[N:9]1
Reactant: COc1ccccc1N1CCN(CCC(=O)Nc2cc(C)nn2C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CCCNc2cc(C)nn2C)CC1

Procedure:
0.5 g (13 mmol) of lithium aluminium tetrahydride are suspended in 100 ml of tetrahydrofuran and a solution of 3.9 g (11 mmol) of 1,3-dimethyl-5-{3-[4-(2-methoxyphenyl) -1-piperazinyl]-propionamido}-1H-pyrazole in 50 ml of tetrahydrofuran is added dropwise in the course of 30 minutes. The mixture is kept at ambient temperature during the addition and is then refluxed for 3 hours. The excess lithium aluminium hydride is destroyed, the insoluble inorganic fraction is filtered off, the tetrahydrofuran is removed, the product is dissolved in chloroform, washed with water, dried over anhydrous sodium sulphate and evaporated to dryness and 3 g (81%) of 1,3-dimethyl-5-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-1H-pyrazol are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18](=O)[CH3:19])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[CH:18]([NH2:27])[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(C(C)N)n(-c2cccc(F)c2)c2ccccc12
Temperature: 65 °C
Yield: 96.6 %

Procedure:
A mixture of 1-[1-(3-fluorophenyl)-3-methyl-1H-indol-2-yl]ethanone (0.165 g, 0.617 mmol) and ammonium acetate (0.476 g, 6.17 mmol) in methanol (2.0 mL) and acetonitrile (2.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.12 g, 1.9 mmol) was added to the resultant mixture. The reaction was heated at 65° C. over the weekend. The reaction was cooled to room temperature and quenched with saturated NaHCO3 solution and then extracted with dichloromethane, dried over MgSO4 and concentrated to give the crude amine (0.16 g), which was used directly in next step. LCMS calculated for C17H18FN2(M+H)+: m/z=269.1. Found: 252.1.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=2)[CH:8]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[C:26]([O:25][C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][O:13][C:9]2[CH:8]=[C:7]([CH2:6][CH:5]([O:30][CH2:31][CH3:32])[C:4]([OH:33])=[O:3])[CH:12]=[CH:11][CH:10]=2)=[CH:21][CH:20]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C(Cc1cccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1cccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 70.9 %

Procedure:
3-{3-[2-(4-tert-Butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester (described in Example 48) (0.8 g; 1.74 mmole) was dissolved in tetrahydrofuran (15 ml). Lithium hydroxide hydrate (0.073 g; 1.74 mmole) dissolved in water (5 ml) was added slowly. The reaction mixture was stirred at room temperature for 4.5 hours. More lithium hydroxide hydrate (0.036 g; 0.87 mmole) was added and the stirring continued for 2 more hours. Tetrahydrofuran was carefully evaporated and a large amount of water was added. pH was adjusted to about 12 with sodium hydroxide (2M) and the solution was extracted with ethyl acetate. The water phase was cooled to <10° C., acidified with potassium hydrogensulfate (1 M) and extracted with ethyl acetate. The organic phase was washed with water and dried with sodium sulfate. Evaporation gave 0.53 g (70.9% yield) of 3-{3-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH3:16])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([Br:10])[C:7]=1[CH2:8][OH:9].[H-].[Na+].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>O1CCCC1>[Si:19]([O:9][CH2:8][C:7]1[C:6]([Br:10])=[C:5]([C:11]([F:14])([F:13])[F:12])[N:4]=[C:3]([O:15][CH3:16])[C:2]=1[Br:1])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COc1nc(C(F)(F)F)c(Br)c(CO)c1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C(F)(F)F)c(Br)c(CO[Si](C)(C)C(C)(C)C)c1Br
Reaction time: 0.5 h

Procedure:
To a solution of the compound from Step D above (880 mg, 2.41 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (60 weight % dispersion in oil; 107 mg, 2.65 mmol). After 30 min at room temperature, a solution of tert-butyl(dimethyl)silyl chloride (434 mg, 2.89 mmol) was added and the reaction was then stirred for an additional 1 h. The solvent was evaporated and residue was purified by flash chromatography (silica gel; 20% ethyl acetate/hexanes as eluant) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 5.03 (s, 2H), 4.05 (s, 3H), 0.95 (s, 9H), 0.19 (s, 6H). LC/MS: 480 (M+H+2).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][CH3:13])[C:8](=[O:14])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[CH:30]=[C:25]3[CH:24]=[CH:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:12]([N:9]1[CH2:10][C:11]2[C:2]([O:37][C:34]3[CH:33]=[CH:32][C:31]([C:29]4[CH:30]=[C:25]5[CH:24]=[CH:23][N:22]([C:19]6[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=6)[C:26]5=[N:27][CH:28]=4)=[CH:36][CH:35]=3)=[CH:3][CH:4]=[N:5][C:6]=2[NH:7][C:8]1=[O:14])[CH3:13]
Reactant: Oc1ccc(-c2cnc3c(ccn3-c3ccc(F)cc3)c2)cc1
Reactant: CCN1Cc2c(Cl)ccnc2NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN1Cc2c(Oc3ccc(-c4cnc5c(ccn5-c5ccc(F)cc5)c4)cc3)ccnc2NC1=O
Reaction time: 2 h

Procedure:
Into a 10-mL microwave vial equipped with a stir-bar was added 5-chloro-3-ethyl-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (30.00 mg; 0.14 mmol), 4-[1-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenol (64.70 mg; 0.21 mmol) and cesium carbonate (138.55 mg; 0.43 mmol). The mixture was suspended in DMF (2.00 ml). The vial was then loaded onto the microwave reactor and run at 160° C. for 2 h. The reaction mixture was filtered through a bed of silica under reduced pressure. The crude material was purified via Biotage eluting with a gradient of 50 to 100% EtOAc in Hexanes to provide 275 as an off-white solid. LC-MS (M+H=480, obsd.=480). 1H-NMR: (DMSO-D6) δ 9.66 (s, 1H); 8.64 (d, 1H); 8.37 (d, 1H); 7.97 (m, 4H); 7.84 (d, 2H); 7.41 (t, 2H); 7.30 (d, 2H), 6.78 (d, 1H); 6.27 (d, 1H); 4.54 (s, 2H); 3.40 (q, 2H); 1.11 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([NH:24][CH3:25])[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH:29]([OH:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]([NH:24][CH2:25][CH2:30][CH2:29][OH:31])[CH3:23])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)[CH3:9])=[O:7])=[CH:26][CH:27]=1
Reactant: CNC(C)c1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1
Reactant: CC(O)Br
Product: CC(NCCCO)c1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-methyl-4-[4-(1-methylaminoethyl)phenyl]cyclohexylamine and bromoethanol. Melting point: 118°-120° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1[C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: COc1nc(N2CCC(O)C2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCC(O)C4)nc3OC)cc12
Temperature: 80 °C
Yield: 35.3 %

Procedure:
A vial was charged with 1-(5-bromo-6-methoxypyridin-2-yl)pyrrolidin-3-ol (100.0 mg, 0.37 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (176.4 mg, 0.55 mmol), Pd(dppf)C12 (26.8 mg, 0.04 mmol), potassium carbonate (152 mg, 1.10 mmol, 2M/L aqueous) and toluene/ethanol (1.5 mL/0.5 mL). The mixture was purged with nitrogen for 5 minutes and then sealed. The reaction was heated to 80° C. overnight. The mixture was cooled to room temperature and filtered. The filtrate was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×3). The organic layer was dried (sodium sulfate) and concentrated. The resulting residue was purified through prep. TLC (petroleum ether: ethyl acetate, 2:1) to give the title compound (52.5 mg, 35.7%) as an off-white solid. 1H NMR (400 MHz, CDCl3) ppm: 8.62 (br. s), 8.05 (s, 1H), 7.89 (d, 1H), 7.50 (s, 1H), 7.35 (d, 1H), 6.00 (d, 1H), 4.61 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.73-3.57 (m, 4H), 2.24-2.05 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[OH-].[K+].[OH-].[Na+]>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CCOC(=O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(ccn4C)c3)c(Cl)c2)CC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1ccc2cc(Sc3ccc(/C=C/C(=O)N4CCC(C(=O)O)CC4)cc3Cl)ccc21

Procedure:
The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester from Example 137 with ethyl ester from Example 285, and KOH with NaOH, giving a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.60-1.90 (m, 2H), 1.90-2.10 (m, 2H), 2.57-2.72 (m, 1H), 2.80-3.40 (m, 2H), 3.85 (s, 3H), 3.91-4.20 (m, 1H), 4.30-4.68 (m, 1H), 6.53 (d, J=3.0 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.80 (d, J=15.3 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.15 (d, J=3.0 Hz, 1H), 7.37 (dd, J=1.5, 9.0 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.51 (s, 1H), 7.51 (d, J=15.3 Hz, 1H), 7.89 (br s, 1H). MS (ESI+) (M+H)+ at m/z 455, 457. Anal. Calcd for C24H23ClN2O3S.0.42 H2O: C, 62.32; H, 5.20; N, 6.06. Found: C, 62.35; H, 5.30; N, 5.87.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:27])[C:13]([NH:16]C(OCC2C=CC=CC=2)=O)([CH3:15])[CH3:14])=[N:8][C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])[CH3:2].Br.[OH-].[K+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:27])[C:13]([NH2:16])([CH3:15])[CH3:14])=[N:8][C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(NC(=O)C(C)(C)NC(=O)OCc2ccccc2)nc1-c1ccccc1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(NC(=O)C(C)(C)N)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-Benzyloxycarbonylamino-2-methyl-propionylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (1.57 g, 3.36 mmol) and 33% HBr (in acetic acid, 8 mL) in acetic acid (7 mL) was stirred at RT for 2 h, basified carefully to pH 7˜8 by addition of aqueous KOH, and the product was extracted with ethyl acetate, dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 334.1 (MH+).