Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)=[O:7].[H][H]>CO.C(OCC)(=O)C>[CH3:28][Si:25]([CH3:26])([CH3:27])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:1])([CH3:30])[CH3:29])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=1)=[O:7]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 99.5 %

Procedure:
Compound 17a (150 mg) was dissolved in methanol (35 ml) and ethyl acetate (35 ml). The obtained mixture was stirred for 30 minutes in a hydrogen atmosphere. After the reaction was over, the obtained reaction mixture was filtered through Cerite, and then washed with methanol. The solvent was distilled off from the filtrate, and the obtained residue was dried. Thus, Compound 20a (150 mg, quant.) was obtained as a white solid.
Reaction SMILES: Cl.[C:2]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)C(=O)C)[CH:11]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[C:2]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:19][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:11]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)N(c1ccc(F)cc1)c1cc(C(=O)c2ccccc2)ccc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccc(C(=O)O)c(Nc2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
6.0 mol/L Hydrochloric acid 2.0 mL was added to dioxane 2.0 mL solution of 4-benzoyl-2-(N-(4-fluorophenyl)acetamido)benzoic acid 0.39 g, and it was heated and refluxed for 2 hours and 30 minutes. After the reaction mixture was cooled to room temperature, 6.0 mol/L hydrochloric acid 1.0 mL was added to it, and it was heated and refluxed for 4 hours. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; chloroform:methanol:acetic acid=20:1:1] to give 4-benzoyl-2-(4-fluoroanilino)benzoic acid 0.27 g of yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(O)C=CC=CC=1.O>[C:18]1([N:17]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Solvent: O
Solvent: Oc1ccccc1
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1ccccc1
Temperature: 190 °C
Yield: 82.1 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 7 ml of phenol and aniline (228 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 190° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium surface and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 240 mg of desired compound as solid in 83% of yield.
Reaction SMILES: Cl.N[C@@H](CC(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.C([O-])(=O)C.[BH4-].[Na+].C(O)(=O)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[C:40](/[N:47]2[CH:51]=[N:50][CH:49]=[N:48]2)\[C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[C:40](/[N:47]2[CH:51]=[N:50][CH:49]=[N:48]2)\[CH:41]([OH:46])[C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: CC(=O)[O-]
Agent: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Yield: 73 %

Procedure:
Reaction was carried out in the same manner as in Example 1 except that the hydrochloride of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol was replaced by the acetate thereof, the amount of sodium borohydride used was 0.075 g (1.98 mmoles), and that the reaction was carried out for 91 hours with addition of 0.0162 g (0.27 mole) of acetic acid to (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one, to obtain (+)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol. The conversion was 100%, and the composition of the product was: E-form alcohol, 90.3%; Z-form alcohol, 6.3%; and saturated alcohol, 3.4%. The enantiomer ratio of the E-form alcohol was: (+)-isomer, 86.5% and (-)-isomer, 13.5%. The optical yield was 73%.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:20][C:3]1[CH:4]=[C:5]2[C:14]3[N:9]([CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]2=[O:19])[CH:10]([CH3:15])[CH2:11][CH2:12][C:13]=3[C:2]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1CCc2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCCCC3)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Yield: 24.4 %

Procedure:
In a 200 ml autoclave were placed 4.6 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 5 g of piperidine and 50 ml of hexamethylphosphoric triamide and the mixture was reacted at 160° C. on an oil bath for 5 hours. After completion of reaction hexamethylphosphoric triamide and piperidine were distilled off under reduced pressure and to the residue was added ethyl acetate and crystallized. Recrystallization from dimethylformamide-water gave 1.3 g of 9-chloro-8-(1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 246° to 248° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:31]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:39](=[O:40])[CH2:38][CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)CCc3ccccc3)ccc2O1

Procedure:
The titled compound was prepared following the procedure using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-phenylpropanoyl chloride as an oil (77%). HPLC, Rt: 5.9 min (Purity: 97.3%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13])#[N:9].Cl[C:25]1[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:8]([C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:25]2[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=2)[CH2:18][CH2:19]1)=[O:13])#[N:9]
Reactant: COc1ccnc(Cl)n1
Reactant: N#Cc1ccccc1C(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccnc(N2CCN(C(=O)c3ccccc3C#N)CC2)n1
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of 1.0 g (3.04 mmol) of 1-(2-cyanobenzoyl)piperazine trifluoroacetate, 0.5 g (3.35 mmol) of 2-chloro-4-methoxypyrimidine and 1.0 g (6.68 mmol) of potassium carbonate in 20 mL of DMF is heated to 100° C. for 1 hour. The solvent is eliminated at reduced pressure and water is added. The resulting solid is filtered, washed with water and purified by chromatography over silica gel, using as eluent ethyl acetate, yielding 0.51 g (1.58 mmol) of 2-[4-(2-cyanobenzoyl)-1-piperazinyl]-4-methoxypyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([P:8]([C:16]2[N:21]=[C:20]([Br:22])[CH:19]=[CH:18][CH:17]=2)[C:9]2[N:14]=[C:13]([Br:15])[CH:12]=[CH:11][CH:10]=2)[N:3]=1.[OH:23]O.O>C(Cl)(Cl)Cl>[Br:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([P:8](=[O:23])([C:9]2[N:14]=[C:13]([Br:15])[CH:12]=[CH:11][CH:10]=2)[C:4]2[N:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[N:21]=1
Reactant: Brc1cccc(P(c2cccc(Br)n2)c2cccc(Br)n2)n1
Reactant: OO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=P(c1cccc(Br)n1)(c1cccc(Br)n1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension, heated to boiling, of 50.2 g (100.0 mmol) of tris(2-bromo-6-pyridyl)phosphine in 500 ml of chloroform was admixed with intensive stirring dropwise with a mixture of 11 ml of 35% by weight H2O2 and 50 ml of water, which afforded a clear solution. After stirring under reflux for 5 h, the solution was allowed to cool to room temperature. The solution was washed with 500 ml of water, and the organic phase was removed and concentrated to 50 ml under reduced pressure. After standing for 2 h, the precipitated crystals were filtered off, washed three times with 100 ml of n-hexane and then dried at 70° C. under reduced pressure. The yield at a purity of 99.0% was 47.1 g (90.9%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C(O)CCC>[C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([O:15][CH2:6][CH2:1][CH2:2][CH3:3])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Solvent: O=S(Cl)Cl
Solvent: CCCCO
Product: CCCCOC(=O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Yield: 66.9 %

Procedure:
2 g of 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetic acid, 3 g of thionyl chloride and 30 ml of n-butanol are treated in the same manner as described in Example 13. 0.8 g of n-butyl 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetate is thereby obtained. Yield: 33.5%
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]2[CH2:15][CH:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:13]=43)[CH2:8][C:7]=2[CH:24]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[C:32](Cl)=O>N1C=CC=CC=1>[CH3:23][O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:12]2[CH2:11][CH2:10][N:9]3[CH:14]([CH2:15][C:6]4[CH:5]=[C:4]([O:25][CH3:26])[C:3]([O:2][CH2:32][C:31]5[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:29]([O:28][CH3:27])[CH:30]=5)=[CH:24][C:7]=4[CH2:8]3)[C:13]=2[CH:16]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1cc2c(cc1O)CN1CCc3cc(OC)c(OC)cc3C1C2
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C1Cc3cc(OC)c(OCc4cc(OC)c(OC)c(OC)c4)cc3CN1CC2
Yield: 45.8 %

Procedure:
1.9 g of 10-hydroxy-2,3,11-trimethoxy-5,6,13,13a-tetrahydro-8H-dibenzo[a, g]quinolizine hydrochloride was treated in the same manner as described in Example 6, using 2.0 g of 3,4,5-trimethoxybenzoyl chloride and 200 ml of anhydrous pyridine and there was obtained 1.2 g (44.4% yield) of 5,6,13,13a-tetrahydro-2,3,11-trimethoxy-10-(3', 4', 5'-trimethoxybenzoxy)-8H-dibenzo-[a, g]quinolizine as a pale yellow powder. The methiodide derived from this compound was found to be in agreement with the methiodide of the compound obtained in Example 3 as determined from the melting point and IR spectrum.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(C(C)C)CC)(C)C.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(Cl)(Cl)Cl>O>[Br:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:30])=[C:3]([C:4](=[O:5])[N:6]([CH3:7])[CH3:8])[CH:9]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1cc(Br)ccc1NC(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
2-Amino-5-bromo-N,N-dimethyl-benzamide (2.00 g, 8.22 mmol), diisopropylethylamine (6.5 ml, 37.32 mmol), 4-morpholinecarbonyl chloride (4.3 ml, 37.46 mmol), and chloroform (20 ml) were combined and stirred for 18 hours at 50° C. Water was added to the mixture, and the organic layer was extracted. The organic layer was dried over sodium sulfate, concentrated in vacuo, and the crude material was purified by flash chromatography (50% to 100% ethyl acetate in hexanes) to give 1.13 g (39%) of morpholine-4-carboxylic acid (4-bromo-2-dimethylcarbamoyl-phenyl)-amide. 1H-NMR (250 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.56-7.45 (m, 2H), 7.42 (t, J=9.3 Hz, 4H), 3.35-3.28 (m, 4H), 2.96-2.86 (m, 6H); MS: m/z 356.0+358.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:18]([N:20]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:21]1[CH2:26][C@@H:25]([C:27]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1)=[O:19].C(OCC)(=O)C.[ClH:51]>C(OCC)(=O)C>[ClH:51].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[N:9][C:8]=1[C:18]([N:20]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:21]1[CH2:26][C@@H:25]([C:27]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])[CH2:24][NH:23][CH2:22]1)=[O:19]
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCCC3)C2)nnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate (245 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the object product (205 mg).
Reaction SMILES: OC1C=CC=CC=1/C=[N:5]\[C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10]([CH:27]=[CH2:28])=[C:11]2[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16].O.CS(O[C:39](=[O:57])/[C:40](/[C:51]1[N:52]=[C:53]([NH2:56])[S:54][CH:55]=1)=[N:41]\[O:42][CH2:43][C:44]([O:46]C(C)(C)C)=[O:45])(=O)=O.ClCCl>C(OC)(C)(C)C>[NH2:56][C:53]1[S:54][CH:55]=[C:51](/[C:40](=[N:41]/[O:42][CH2:43][C:44]([OH:46])=[O:45])/[C:39]([NH:5][C@@H:6]2[C:13](=[O:14])[N:12]3[C@@H:7]2[S:8][CH2:9][C:10]([CH:27]=[CH2:28])=[C:11]3[C:15]([OH:17])=[O:16])=[O:57])[N:52]=1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)OS(C)(=O)=O)c1csc(N)n1
Reactant: C=CC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](/N=C\c3ccccc3O)[C@H]2SC1
Solvent: O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reactor is charged with (6R,7R)-4-methoxybenzyl 7-((Z)-(2-hydroxybenzylidene)amino)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (1 eq), water (6-9 weight % relative to the Schiff base), (Z)-2-(2-aminothiazol-4-yl)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)acetic methanesulfonic anhydride (2.5 eq) and dichloromethane (1.75 mL per gram of Schiff base). The mixture is stirred for three hours at room temperature, then added to methyl tertiary butyl ether over the course of 2-3 hours, resulting in the formation of a solid. The solid is filtered and the filter cake was washed with additional methyl tertiary butyl ether. The filtered solid is deprotected using conventional methods and dried under vacuum to yield the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[O:29]([C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[N:44][C:36]=3[O:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1cccnc1Oc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cccnc3Oc3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-phenoxynicotinoyl chloride. ESMS m/e: 577.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH:25]=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].Cl.[F:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][N:39]4[CH2:40][CH2:41][C@@H:37]([F:36])[CH2:38]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CC=O)ccn34)c12
Reactant: F[C@@H]1CCNC1
Agent: Cl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CCN5CC[C@@H](F)C5)ccn34)c12

Procedure:
Prepared according to procedure for Example 128 from N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (Example 127, Steps A-B) and (R)-3-fluoropyrrolidin hydrochloride. MS (ES+APCI) m/z=526 (M+H) detected.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][CH:31]=[N:32]2)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:37])=[O:5])(=[O:14])=[O:13])=[C:16]([O:24][CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[N:32]3)[CH:17]=1)(=[O:23])[NH2:22]
Reactant: CC(C)(C)OC(=O)C[C@@H](C=O)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2cccc3ncccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
To a solution of (S)-3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (0.08 g, 0.15 mmol) in dichloromethane (10 mL) and water (0.1 ml) was added trifluoroacetic acid (1 mL). The reaction was stirred for 1 h at room temperature. The reaction was then concentrated under reduced pressure to yield a clear oil. The residue was purified by reverse phase high-pressure liquid chromatograph using a gradient of 0% to 30% acetonitrile containing 0.1% TFA and water containing 0.1% TFA over 140 minutes to yield 3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid as a white solid (0.01 g, 14%). MS(APCI) m/z 472.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][OH:32])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:33])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2)C=CC=1C(C1C=C(C2N=NN(CCOC3CCCCO3)C=2)C=CC=1C)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][OH:32])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:33])=[O:18]
Reactant: Cc1ccc(-c2cn(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Product: Cc1ccc(-c2cn(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 102, using compound 121 (1.63 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 50:50 to 100:0 as the eluent to afford the title compound as yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.Cl.[CH3:18]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][CH3:12])[N:10]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: CNc1cc(C(=O)O)cc(Cl)n1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CNc1cc(C(=O)OC)cc(Cl)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 2-chloro-6-(methylamino)isonicotinic acid (18.1 g, 97 mmol) in 600 mL MeOH was added thionyl chloride (7.783 mL, 107 mmol) very slowly (emits HCl gas violently). Reaction refluxed to 65° C. for 2 h. After 2 h, reaction was concentrated in vacuo. The residue was dissolved in EtOAc (400 mL) and neutralized with saturated NaHCO3 solution (300 mL). The aqueous solution was extracted with EtOAc (150 mL×3). The combined organics were washed with brine (150 mL), dried over Mg2SO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (5% EtOAc/hexanes, then 20% EtOAc/hexanes) yielded 11.3 g (58%) of methyl 2-chloro-6-(methylamino)isonicotinate as a yellow brown solid. 1H NMR (CDCl3, 400 mHz) 7.08 (d, J=0.91 Hz, 1H); 6.84 (d, J=0.73 Hz, 1H); 5.09 (s, NH); 3.92 (s, 3H); 2.96 (d, J=5.31 Hz, 3H); LC/MS [M+H]+=201.0.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(#N)C>[N:1]1([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=C(CCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCCn1cncn1)OCc1ccccc1
Yield: 81.1 %

Procedure:
4.7 g of 1,2,4-triazole and 9.5 g of potassium carbonate were added to a solution of 15 g of benzyl 4-bromobutyrate in 150 ml of acetonitrile. The mixture was refluxed by heating, for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added 30 ml of methylene chloride. The insolubles were collected by filtration and washed. The filtrate and the washings were combined and purified by silica gel column chromatography (eluant: methylene chloride/methanol=50/1) to obtain 11.6 g of benzyl 4-(1,2,4-triazol-1-yl)butyrate as a colorless oily substance.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][C@H:5]1[CH3:18])(=O)C.[ClH:19].O1CCOCC1>CO>[ClH:19].[CH3:18][C@@H:5]1[CH2:6][C:7]2[C:12](=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([O:16][CH3:17])[CH:8]=2)[NH:4]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)[C@H](C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])N[C@H](C)C2
Temperature: 25 °C
Yield: 97 %

Procedure:
A slurry of (2R)-1-acetyl-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (5.78 g, 23.10 mmol) in MeOH (50 mL) and a 4N HCl solution in dioxane (57.7 mL, 231 mmol) was heated at 70° C. for 8 h. The resulting mixture was allowed to cool to rt and concentrated to afford (2R)-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrogen chloride as a brown sticky solid (5.47 g, 97%). 1FI NMR (400 MHz, DMSO-d6) δ ppm 1.38 (d, J=6.59 Hz, 3H), 2.82 (dd, J=16.85, 7.69 Hz, 1H), 3.32 (dd, J=16.85, 8.06 Hz, 1H), 3.90 (s, 3H), 4.09-4.26 (m, 1H), 7.39 (s, 1H), 7.60 (s, 1H); ESIMS (M+H)+=209.00.