Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[N:11]1([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([O:15][CH3:20])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 1884.4 %

Procedure:
To a solution of N-Cbz-proline (140 g, 562 mmol) in methanol (850 mL) was added p-toluenesulfonic acid monohydrate (5 g, 26 mmol). The solution was heated to reflux and stirring continued for 12 h. The heating mantle was removed, and after cooling to room temperature, the solvent was removed by rotary evaporation. The residue was dissolved in ethyl acetate (500 mL), and washed twice with saturated aqueous NaHCO3 (300 mL), twice with brine (200 mL), dried with MgSO4 filtered and concentrated to give a colorless oil (129 g, 88% yield)
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][O:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:19]>[Cl-].[Zn+2].[Cl-].C(O)C>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:19][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OCCC1(c1ccccc1)c1ccccc1
Reactant: N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: O=C1NCCC1(c1ccccc1)c1ccccc1
Temperature: 225 °C

Procedure:
3,3-Diphenyldihydrofuran-2(3H)-one (3.98 g, 16.70 mmol) and zinc chloride (0.080 g) were placed in an autoclave. Ammonia (8 mL) was added, and the reactor was sealed and heated at 225° C. for 21 hours under an argon atmosphere at an equilibrium pressure of 800 pounds per square inch. The vessel was cooled, the ammonia was vented, and a mixture of solids was obtained. The solid was treated with ethanol (100 mL), filtered and concentrated. Silica gel chromatography eluting with 5% methanol/dichloromethane gave the title compound. MS (DCI+) m/z 238.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:24])[NH:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(OCCCOC1C=CC(CC2C(=O)NNC=2C(C)C)=CC=1)C1C=CC=CC=1.CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:34]3[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]3[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[N:18][NH:19][C:20]=2[CH:21]([CH3:22])[CH3:23])=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCCCOCc2ccccc2)cc1
Product: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (Kunz, H.; Harreus, A. Liebigs Ann. Chem. 1982, 41-48 Velarde, S.; Urbina, J.; Pena, M. R. J. Org. Chem. 1996, 61, 9541-9545) instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[CH:8]([CH:10]([CH3:15])[C:11]([O:13]C)=O)=O.[C:16](O)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[C:16]([NH:1][CH2:2][CH2:3][N:4]1[C:11](=[O:13])[CH:10]([CH3:8])[CH:15]=[N:7][CH2:6][CH2:5]1)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)C(C)C=O
Reactant: CCCCCCCCCCCC(=O)O
Reactant: NCCNCCN
Product: CCCCCCCCCCCC(=O)NCCN1CCN=CC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 103.1 g (1 mole) of diethylenetriamine and 116.1 g (1 mole) of methyl 2-formylpropionate. At 130° to 135° C., 18 g of water and 32 g of methanol were distilled off. Then, after addition of 200.3 g (1 mole) of lauric acid, the amide formation was effected at 200° to 210° C. to distil off 18 g of water, leaving behind 4-lauramidoethyl-6-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl)C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 5 h
Yield: 82.8 %

Procedure:
To a stirred solution of [10-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-a]benzimidazol-7-yl](cyclopropyl)methanol (81.4 mg, 0.186 mmol) in acetonitrile (2.5 mL) was added Dess-Martin reagent (94.7 mg, 0.223 mmol) at room temperature. After 5 h, the reaction mixture was diluted with ethyl acetate, quenched with aqueous sodium hydrogen carbonate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (67.1 mg, 0.154 mmol, 83%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[C:7](=[O:19])[C:8]([CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].C(OCC)(=O)C.O>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[C:7](=[O:19])[C:8]([CH2:12][CH:13]([OH:18])[C:14]([CH3:16])([CH3:17])[CH3:15])=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)c(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)c(CC(O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-{[2-butyl-5-(3,3-dimethyl-2-oxobutyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.33 g) in ethanol (4 mL) was added sodium tetrahydroboron (0.053 g), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.20 g, 62%).
Reaction SMILES: [H-].[Na+].Br[CH:4]([CH3:24])[CH2:5][CH2:6][C:7]([NH:9][N:10]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].C(OCC)(=O)C>O1CCCC1>[C:12]1([C:11](=[N:10][N:9]2[CH:4]([CH3:24])[CH2:5][CH2:6][C:7]2=[O:8])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(Br)CCC(=O)NN=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CCC(=O)N1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
At 0° C., 2.7 g (68.0 mmol) of sodium hydride are added a little at a time to a solution of 33.0 g (68.0 mmol) of 4-bromo-N′-(diphenylmethylene)pentane hydrazide in 200 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 16 h, and ethyl acetate/saturated aqueous NH4Cl solution is then added. The organic phase is separated off and the aqueous phase is extracted with 3×250 ml of ethyl acetate. The combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 17.8 g (89%) of the desired product; log P(HCOOH): 2.73; 1H-NMR (ppm): δ (DMSO-d6)=1.22 (d, 3H), 2.05-2.15 (m, 4H), 3.86 (m, 1H), 7.24-7.26 (m, 2H), 7.40-7.43 (m, 4H), 7.48-7.53 (m, 4H); LC-MS: m/z=279 [M+H]+
Reaction SMILES: Cl[CH2:2][S:3]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].BrC1SC(S(C[N:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[C:30]2=[O:36])(=O)=O)=CC=1.COC1C=CC(B(O)O)=CC=1>>[OH:35][C:31]1[C:30](=[O:36])[N:29]([CH2:2][S:3]([C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)(=[O:5])=[O:4])[CH:34]=[CH:33][CH:32]=1
Reactant: O=c1c(O)cccn1CS(=O)(=O)c1ccc(Br)s1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)CCl)s2)cc1
Agent: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)Cn3cccc(O)c3=O)s2)cc1

Procedure:
The titled compound was synthesized in a similar manner as described in Example 60 by replacing 1-chloromethanesulfonyl-4-methyl-benzene with 2-chloromethanesulfonyl-5-(4-methoxy-phenyl)-thiophene (synthesized from 2-bromo-5-chloromethanesulfonyl-thiophene from Example 63 and 4-methoxy-phenyl boronic acid according the procedure described in example 52 Step A) in Example 60 Step B. MS (EI) 378 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].I[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:13]([O:11][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([F:1])[C:9]([F:10])=[CH:8][CH:7]=1)[CH3:14]
Reactant: O=Cc1c(O)ccc(F)c1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1ccc(F)c(F)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 2,3-difluoro-6-hydroxybenzaldehyde (3.000 g; 21.40 mmol), iodoethane (6.679 g; 42.80 mmol), and K2CO3 (3.551 g; 25.70 mmol) in anh. DMF (60 ml) was heated to 80° C., under nitrogen, for 1.5 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 6-ethoxy-2,3-difluorobenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.72 min.; no ionisation.
Reaction SMILES: [CH3:1]O.C=O.[NH2:5][CH2:6][C:7]([OH:9])=[O:8].C([O:12][P:13]([O-:17])[O:14]CC)C>C(N(CC)CC)C>[P:13]([CH2:1][NH:5][CH2:6][C:7]([OH:9])=[O:8])([OH:17])([OH:14])=[O:12]
Reactant: NCC(=O)O
Reactant: CO
Reactant: CCOP([O-])OCC
Agent: C=O
Solvent: CCN(CC)CC
Product: O=C(O)CNCP(=O)(O)O

Procedure:
By using 500 ml. of anhydrous methanol containing 10% tetrahydrofuran, 47.0 g. of triethylamine, 30.0 g. of paraformaldehyde, 37.5 g. of glycine and 55.0 g. of diethylphosphite one may proceed as disclosed in Example 1. 65-66 g. of N-phosphonomethyl-glycine are isolated in crystalline form, purity, above 95%. The quality of the product is identical with the quality of the product obtained according to Example 1.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]([Br:22])=[CH:14][CH:13]=1>CN(C)C=O.C(OCC)C>[Br:22][C:15]1[C:16]([C:18]([O:20][CH3:21])=[O:19])=[N:17][C:12]([N:11]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(N)ccc1Br
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1nc(N(Cc2ccccc2)Cc2ccccc2)ccc1Br
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a suspension of 60% sodium hydride (880 mg, 22.0 mmol) and benzyl bromide (6.24 mL, 52.5 mmol) in N,N-dimethylformamide (80 mL) was added a solution of methyl 6-amino-3-bromopyridine-2-carboxylate (2.42 g, 10.5 mmol) in N,N-dimethylformamide (25 mL) under ice-cooling and the mixture was stirred for 30 min. The reaction solution was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→20/80) to give the title compound (3.16 g, yield 73%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].C([O:24][C:25](=[O:55])[C@@H:26]([NH:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:47]2[CH2:52][CH2:51][CH:50]([CH:53]=O)[CH2:49][CH2:48]2)(=[O:46])=[O:45])=[CH:40][CH:39]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][NH:1][CH2:53][CH:50]1[CH2:51][CH2:52][N:47]([S:44]([C:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]([NH:34][C@@H:26]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]([OH:55])=[O:24])=[O:36])=[CH:39][CH:40]=2)(=[O:46])=[O:45])[CH2:48][CH2:49]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=CC1CCN(S(=O)(=O)c2ccc(NC(=O)N[C@@H](Cc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(NC(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methane-sulfonamide (0.320 g, 1.3 mmol), (2S)-2-{3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-ureido}-3-phenyl-propionic acid benzyl ester (1.3 mmol) and glacial acetic acid (0.074 g, 1.3 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.086 g, 1.3 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1). to give 0.12 g of the product.
Reaction SMILES: ClC(OCC)=O.CN1CCOCC1.COC(C=C([NH:21][C@H:22]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[C:23]([O-:25])=O)C)=O.[Na+].[CH3:34][C:35]1([CH3:47])[S:39][C@@H:38]2[C@H:40]([NH2:43])[C:41](=[O:42])[N:37]2[C@H:36]1[C:44]([OH:46])=[O:45].Cl>CC(C)CC(=O)C.O>[CH3:34][C:35]1([CH3:47])[S:39][C@@H:38]2[C@H:40]([NH:43][C:23]([C@H:22]([NH2:21])[C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)=[O:25])[C:41](=[O:42])[N:37]2[C@H:36]1[C:44]([OH:46])=[O:45]
Reactant: COC(=O)C=C(C)N[C@@H](C(=O)[O-])c1ccc(O)cc1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
Meanwhile, 4-methylpentan-2-one (70 ml) was stirred and cooled to 0° and ethyl chloroformate (2.0 ml, 0.0208 mole) and a 1% solution of N-methylmorpholine in 4-methylpentan-2-one (3 ml) was added. The solution was cooled to -5° and sodium (R)-N-(1-methoxycarbonyl propen-2-yl)-α-amino-p-hydroxyphenylacetate (5.87 g, 0.02 mole) was added. The suspension was stirred at 0° to -5° for 30 minutes, cooled to -30° and then added to the solution of 6-APA prepared above. The mixture was stirred at -30° for 45 minutes when water (50 ml) was added. The stirred two-phase mixture was acidified to pH 1.1 with concentrated hydrochloric acid and stirred at 0° to 2° for 75 minutes, during which time a white precipitate separated. The mixture was adjusted to pH 5.2 with 10% aqueous potassium hydroxide solution, and the white suspension was stirred and cooled to 0° for 1 hour and filtered. The filter was washed with ice-cold water (20 ml) and ethyl acetate (20 ml), and the solid was air dried at 35° to give amoxycillin trihydrate (6.33 g, 75.5% th.), [α]D25 + 237° (c 0.9; 0.1 N HCl).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:26]([O:28][CH3:29])=[O:27])=[C:14]([C:18]2[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=2)[S:15][C:16]=1Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:26]([O:28][CH3:29])=[O:27])=[C:14]([C:18]2[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=2)[S:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2cnc(OC)cn2)sc(Br)c1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)OCc2ccccc2)csc1-c1cnc(OC)cn1
Reaction time: 4 h

Procedure:
10% Pd/C is added to methyl 4-(benzyloxycarbonylamino)-5-bromo-2-(5-methoxypyrazin-2-yl)thiophene-3-carboxylate (157) in ethanol:ethyl acetate:dichloromethane (2:1:1). The mixture is degassed and placed under H2 (1 atm) and stirred for 4 h. The mixture is filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provides 158.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.C(OCC)(=O)C>[CH:21]1([CH:20]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 88.7 %

Procedure:
A mixture of {4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-dimethyl-amine (80 mg, 0.17 mmol) in ethanol (3 mL), tetrahydrofuran (3 mL) and an aqueous sodium hydroxide solution (10%, 2 mL) was heated at reflux for 36 h. The mixture was diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford {4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-dimethyl-amine (50 mg, 89%) as a white solid: LC/MS m/e calcd for C22H25N3 [M+H]+ 332.46, observed 332.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[C:8]=2[F:14])[N:3]=1
Reactant: F[B-](F)(F)F
Reactant: Oc1ccc2nc(Cl)ccc2c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Oc1ccc2nc(Cl)ccc2c1F
Temperature: 60 °C
Yield: 21 %

Procedure:
To a solution of 2-chloroquinolin-6-ol (Intermediate 2, 1.8 g, 85% pure, 8.5 mmol) in CH3CN (50 mL) was added Selectfluor (4.20 g, 12.0 mmol). The reaction mixture was heated at 60° C. overnight and concentrated. The residue was partitioned between water (50 mL) and EtOAc (100 mL). The aqueous phase was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 2-chloro-5-fluoroquinolin-6-ol using ethyl acetate and hexanes as solvents (0.4 g, 21% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].C(Cl)(Cl)=O.[NH2:15][NH2:16].[C:17](=[O:20])(O)[O-].[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1.ClCCl>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[N:2]([CH3:1])[C:17]([NH:15][NH2:16])=[O:20]
Reactant: CNc1c(Cl)cccc1Cl
Reactant: O=C([O-])O
Reactant: NN
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C(=O)NN)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
2,6-Dichloroaniline (1.62 g, 10 mmol) in THF (5 mL) was cooled to −78° C. and treated with n-buthyllithium (8 mL of a 1.6 M solution in hexanes). After brief warming to −40° C. the solution was cooled again before addition of iodomethane (0.9 mL, ˜15 mmol). The mixture was allowed to warm to room temperature before addition of saturated ammonium chloride solution, extraction with ethyl acetate, drying over anhydrous MgSO4 and solvent evaporation. The resulting residue was purified by column chromatography (dichloromethane) to yield N-methyl-2,6-dichloroaniline (1.70 g, 96%). N-Methyl-2,6-dichloroaniline (0.86 g, 4.89 mmol) dissolved in ethyl acetate (10 mL) was added to an ice-cold solution of phosgene (5.0 mL of a 20% solution in toluene). Cooling was removed and the mixture stirred at room temperature for 10 min and then heated to reflux for 30 min. The solvent was removed and replaced by dichloromethane (20 mL) before drop-wise addition to a cooled (−40° C.) mixture of anhydrous hydrazine (0.64 g, 20 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours before addition of saturated sodium bicarbonate followed by phase separation and solvent removal to yield N-(2,6-dichlorophenyl)-N-methylhydrazinecarboxamide (1.06 g, 93%). The N-methylhydrazinecarboxamide product (500 mg, 2.14 mmol) was stirred with 4-chlorophenyl isocyanate (360 mg, 2.48 mmol) in dichloromethane (10 mL) at room temperature for 3 h. The resulting slurry was cooled (−10° C.), filtered, and washed with cold dichloromethane (10 mL) to give a white powder. A third of the product was treated with POCl3 (3 mL) and heated under reflux for 2½ hours, where after the yellow/brown solution was cooled and added to crushed ice (˜50 g) and neutralized by addition of ammonium hydroxide solution (25% m/V). Filtration and drying gave the crude product as an off-white powder (280 mg) which was purified by silica gel chromatography using 50%-75% EtOAc/hexanes to give 18 (122 mg, 48%).
Reaction SMILES: C(O)(=O)C.C([O-])(=O)C.[Na+].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N+:24]([O-])=O)=[C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=O)[CH:16]=1>C(O)C.O.[Fe].C(O)(=O)C.[Fe]>[Cl:10][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[NH:24][C:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=1
Reactant: O=C1CCCCC1c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Clc1ccc2[nH]c3c(c2c1)CCCC3
Yield: 19.7 %

Procedure:
The reduction can also be carried out using Fe/acetic acid. A mixture of 0.784 g of iron, 1.62 mL of glacial acetic acid, 0.544 g of sodium acetate, and 1 g of 2-(5-chloro-2-nitrophenyl)cyclo-hexanone was refluxed in 80 mL of 4:1 (v/v) ethanol/water for 2 hr. The mixture was cooled, ethanol was evaporated, and the residue was extracted into methylene chloride. Work-up followed by column chromatography on silica yielded 0.160 g (20%) of the named product.