Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:14][CH2:13][NH:12][C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Reactant: NCCN1CCCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Yield: 75.9 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3.0 g, 19.6 mmol) reacted with 1-(2-aminoethyl)pyrrolidine (2.73 mL, 21.5 mmol) to give 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (3.71 g, 76%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]([O:15][C:16]([NH:18][CH:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].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.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:11]([O:15][C:16](=[O:17])[NH:18][CH:19]([C:20](=[O:22])[N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:23]([CH3:25])[CH3:24])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNCCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of N-methyl-phenethyl-amine (2.2 mL, 15.3 mmol), 2-tert-butoxycarbonylamino-3-methyl-butyric acid (3.33 g, 15.3 mmol), HBTU (8.7 g, 22.95 mmol), DIPEA (6.1 mL, 33.7 mmol) and DMF (75 mL) was stirred at room temperature for 14 hours. To the resulting mixture was added sodium bicarbonate (400 mL) and the desired product was extracted with ethyl acetate (400 mL×2). The combined organic layers were washed with water, dried over MgSO4 and concentrated under reduced pressure to yield an oil. The oil was purified by column chromatography (50% EtOAc/heptane) to yield a residue.
Reaction SMILES: [NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33](C(F)(F)F)[CH:32]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][N:18]=[C:13]2[CH:12]([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:53](Br)[CH:54]=[CH:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C1COCC1>[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:17][N:18]=[C:13]2[C@:12]([CH3:42])([CH2:53]/[CH:54]=[CH:55]/[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CC1C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@]1(C/C=C/c2ccccc2)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1ccccc1)C(=O)OCc1ccccc1)c2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of 12c (32 mg, 0.063 mmol) in 1 mL THF at −78° C., was added LiHMDS (157 μL, 0.157 mmol). The mixture was stirred at −78° C. for 10 min, then cinnamyl bromide (18.6 mg, 0.095 mmol) in 250 μL THF was added. The reaction was stirred at −78° C. for 1.5 h, then quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with sat NH4Cl and brine, dried (Na2SO4), and concentrated. The crude mixture was purified by flash chromatography (35% EtOAc/hexanes) to afford 26.0 mg (66%) of 116a. 1H NMR (300 MHz, CDCl3) δ9.57 (br s, 1H), 7.74 (br s, 1H), 7.47 (d, J=8.1, 2H), 7.29-7.23 (m, 17H), 7.07 (t, J=7.5, 1H), 6.47 (d, J=15.7, 1H), 6.02-5.97 (m, 1H), 5.20-5.17 (m, 3H), 4.80 (br s, 1H), 2.70-2.41 (m, 4H), 1.48 (s, 3H).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([O:25][Si](C(C)(C)C)(C)C)[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][C:13](=[O:16])[N:12]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([OH:25])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][C:13](=[O:16])[N:12]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1cccc(-c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: N#CCCCCCCN1C(=O)CCC1CCC(O)Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.9 %

Procedure:
Following the procedure described for Example 5, Step B, 7-{2-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (187 mg, 0.351 mmol) was deprotected with TBAF (1M in THF, 0.53 mL, 0.53 mmol). The addition was performed at 0° C. and the reaction mixture was stirred at room temperature for 24 h. Purification by medium pressure chromatography (CH2Cl2 to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 6% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) provided 7-[2-(4-biphenyl-3-yl-3-hydroxy-butyl)-5-oxo-pyrrolidin-1-yl ]-heptanenitrile (85 mg). 1H NMR (CDCl3) δ7.58 (m, 1H), 7.51-7.33 (m, 4H), 7.21-7.12 (m, 4H), 3.85 (m, 1H), 3.60 (m, 2H), 2.90 (m, 1H), 2.83-2.60 (m, 2H), 2.45-2.30 (m, 4H), 2.14 (m, 1H), 1.73-1.25 (m, 14H).
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2]>C(#N)C.O=[Mn]=O>[CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[CH:23]=[O:24])=[CH:19][CH:20]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(/C=C/CO)cc1
Agent: O=[Mn]=O
Solvent: CC#N
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(/C=C/C=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(E)-3-[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-prop-2-en-1-ol (6) (650 mg, 2.02 mmol), was dissolved in 20 ml acetonitrile. MnO2 (1.76 g, 20.2 mmol) was added and the black suspension was stirred at rt for 2.5 h. The reaction mixture was filtrated over celite and washed with acetonitrile. The filtrate was evaporated and purified by flash chromatography (silica gel, EtOAc/cHex (0-40%) to give a beige powder.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5]>CCOC(C)=O.[Pd]>[NH2:22][C:20]1[CH:19]=[CH:18][C:3]([C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])=[C:2]([F:1])[CH:21]=1
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1F)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)NCC(=O)O)c(F)c1
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a solution of benzyl 2-(2-fluoro-4-nitrobenzamido)acetate (100 mg) in EtOAc (10 mL) was added Pd/C (10%, 100 mg) at rt and stirred under the atmosphere of H2 gas for 30 min. The reaction mixture was filtered and washed with EtOAc (2×5 mL). The residue obtained after evaporation of the solvents was recrystallized from EtOAc to give the product as a white color solid (50 mg, 79%), mp 194-196° C. 1H NMR (400 MHz, DMSO-d6): δ 12.53 (1H, br s), 7.74-7.78 1H, m), 7.52 (1H, t, J=8.8 Hz), 6.42 (1H, dd, J=8.4, 1.6 Hz), 6.31 (1H, d, J=14.4 Hz), 5.99 (2H, s), 3.90 (2H, d, J=5.6 Hz); 13C NMR (100 MHz, DMSO-d6): δ 171.3, 163.4 (d, J=3.0 Hz), 161.7 (d, J=244 Hz), 153.8 (d, J=13.0 Hz), 131.9 (d, J=5.0 Hz), 109.6, 107.8 (d, J=12.0 Hz), 99.1 (d, J=26.0 Hz), 41.3; LC-MS (negative ion mode): m/z 211 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:13]([C:31](O)=[O:32])=[C:14]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[CH3:30])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[N:5][N:4]2[C:13]([C:31]([N:44]3[CH2:43][CH2:42][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:46][CH2:45]3)=[O:32])=[C:14]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[CH3:30])[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:3]2[C:2]=1[Cl:1])=[O:9])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1cnn2c(C(=O)O)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1Cl
Yield: 94.8 %

Procedure:
The compound of step 8 (2.335 g, 5.00 mmol), 1-tert-butoxycarbonyl-piperazine (1.024 g, 5.50 mmol), EDIA (2.18 ml, 12.50 mmol) and TBTU (1.766 g, 5.50 mmol) in 50 ml of anhydrous DCM were stirred at room temperature for 1 h. The solution was then washed with 0.5 N hydrochloric acid (75 ml) and the aqueous phase was extracted with DCM (25 ml). The combined organic phases were washed with a saturated solution of sodium hydrogencarbonate (50 ml) and brine (50 ml), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 80:20, then 75:25) to give 3.01 g of the title compound as a yellow solid melting at 88-90° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:24]([CH3:26])[CH3:25])[C:11]([C@@H:13]1[CH2:18][CH2:17][C@@H:16]([CH3:19])[CH2:15][C@@H:14]1[O:20]C(=O)C)=[O:12])=[O:4].[Li+].[OH-]>O1CCOCC1.O>[CH:24]([N:10]([C:11]([C@@H:13]1[CH2:18][CH2:17][C@@H:16]([CH3:19])[CH2:15][C@@H:14]1[OH:20])=[O:12])[C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])([CH3:26])[CH3:25]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@@H]1CC[C@@H](C)C[C@@H]1OC(C)=O)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N(C(=O)[C@@H]1CC[C@@H](C)C[C@@H]1O)c1cc(-c2ccccc2)sc1C(=O)O
Temperature: 50 °C
Yield: 13.2 %

Procedure:
(1R,2S,4R)-3-[Isopropyl-(2-Acetoxy-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (36 mg, 0.17 mmol) was dissolved in a mixture of dioxane:H2O (4:1) (700 μl) and then 470 μl of LiOH 1N was added to it. After 3 h at 50° C. the reaction mixture was cooled to room temperature and the solvents were removed. The residue was then partitioned between 10 ml of H2O acidified to pH 4 and 10 ml of EtOAc. The organic layer was separated and the aqueous phase was washed with ethyl acetate (2×10 ml). The combined ethyl acetate layers were dried (Na2SO4), concentrated and the residue was purified by preparative chromatography to obtain 9 mg (29%) of (1R,2S,4R)-3-[Isopropyl-(2-hydroxy-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid. NMR 1H (CDCl3, 400 MHz): 3:2 mixture of rotamers. 7.76-7.73 ppm (m, 2H, Haro); 7.50-7.38 ppm (m, 3H, Haro); 7.36 ppm (s, 1H, Haro); 4.93-4.87 ppm (m, 1H); 4.25 ppm (s, 0.70H, major rotamer); 3.97 ppm (s, 0.3H, minor rotamer); 2.35-2.28 ppm (m, 1H); 1.99-1.53 ppm (m, 5H); 1.28 ppm (d, 0.6H, minor rotamer); 1.25 ppm (d, 1,4H, major rotamer); 1.06-1.03 ppm (m, 3H), 0.96-0.72 ppm (m, 1H); 0.79 ppm (d, 3H); 0.67-0.56 ppm (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C(N1CCCCC1=O)(OC(C)(C)C)=O.C1(N)CCCCC1.[CH3:50][N:51]([CH3:56])[S:52](Cl)(=[O:54])=[O:53]>>[CH:22]1([N:15]([CH:16]2[CH2:21][CH2:20][N:19]([S:52](=[O:54])(=[O:53])[N:51]([CH3:56])[CH3:50])[CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:28])=[CH:8][N:9]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCNCC2)s1
Agent: CC(C)(C)OC(=O)N1CCCCC1=O
Solvent: NC1CCCCC1
Product: CN(C)S(=O)(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
{2-[3-Cyclohexyl-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was pre-pared in a similar manner to the synthesis of example 12 from N-Boc piperidone, cyclo-hexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl, Boc deprotection, reaction with dimethylsulfamoyl chloride and hydrolysis of the ester moiety as described in general procedure (I) gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (84 mg, 63%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[Na+].[C:12]([O:16][C:17](=[O:36])[N:18]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[C:21]([Cl:27])[N:20]=1)([CH3:15])([CH3:14])[CH3:13].O>CO>[C:12]([O:16][C:17](=[O:36])[N:18]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[C:21]([Cl:27])[N:20]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)c(Cl)n1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C(O)c2c[nH]c3ncccc23)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (1, 465 mg, 3.93 mmol) in methanol (50 mL) were added sodium hydroxide (0.630 g, 0.0157 mol) and (4-chloro-benzyl)-(6-chloro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (541, 1.5 g, 0.0039 mol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (542, 1.0 g, 51%). MS (ESI) [M+H+]+=499.1.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:45][C:46](=[O:50])[CH2:47][CH2:48][NH2:49])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([NH:49][CH2:48][CH2:47][C:46]([OH:50])=[O:45])=[O:35])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)NCCC(=O)O)c2)cc1

Procedure:
The product from Example 116B and β-alanine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.90 (t, 1 H), 7.14-7.36 (m, 8 H), 6.85-7.12 (m, 5 H), 6.67 (ddd, 1 H), 6.48 (m, 2 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 3.90 (t, 2 H), 3.80 (br.s, 1 H), 3.22 (dd, 2 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.35 (t, 2 H), 2.19 (t, 2 H), 1.76-1.98 (m, 2 H); MS (APCI) m/z 646 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:37][CH2:36][C:35](=[O:38])[NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:31]5[CH2:37][CH2:36][C:35](=[O:38])[NH:34][CH2:33][CH2:32]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C1CCNCCN1
Product: O=C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-5-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and [1,4]diazepan-5-one following General Procedure B.
Reaction SMILES: [N+](=[CH2:3])=[N-].[N+:4]([C:7]1[CH:37]=[CH:36][C:10]([CH2:11][O:12][C:13]([C:15]2[N:20]3[C:21](=[O:34])[C@@H:22]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:19]3[S:18][CH2:17][C:16]=2[OH:35])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(Cl)(Cl)Cl>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]([C:15]2[N:20]3[C:21](=[O:34])[C@@H:22]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:19]3[S:18][CH2:17][C:16]=2[O:35][CH3:3])=[O:14])=[CH:36][CH:37]=1)([O-:6])=[O:5]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 ml of an ethereal diazomethane solution (0.5 molar, 1.5 equivalents) are added in the course of about 10 minutes to a solution, cooled to 0° C, of 485 mg of 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 10 ml of dry chloroform. The pale yellow solution is stirred for 1 hour at 0° C, flushed with nitrogen in order to remove excess diazomethane and concentrated in vacuo. The residue is recrystallized from methylene chloride and gives 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester of melting point 140.5°-142° C.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10](=O)([O-])[O-].[K+].[K+].P(OC)(OC)(OC)=O>>[CH3:10][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccccc1O
Agent: [K+]
Solvent: COP(=O)(OC)OC
Product: COc1ccccc1C=O
Temperature: 85 °C
Yield: 188.9 %

Procedure:
To a three-necked 100 ml flask equipped for reflux and fitted with a mechanical stirrer was added 5.0 ml (0.047 mol) of salicylaldehyde, 2.0 g (0.014 mol) of potassium carbonate, and 10.0 ml (0.085 mol) of trimethyl phosphate. The mixture was heated to 85° C. for two hours, then cooled to 50° C. and quenched with 20 ml of water. After two hours the mixture was extracted with 50 ml of methylene chloride, the extracts washed with dilute caustic and then water. The organic extracts were dried over anhydrous potassium carbonate then filtered and concentrated in vacuo to give 3.6 g (53%) of o-methoxybenzaldehyde.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].OO.[Cl:16][CH2:17][C:18](=[C:21]([CH2:24][Cl:25])[CH2:22][Cl:23])[CH2:19][Cl:20]>C(Cl)Cl>[Cl:16][CH2:17][C:18]1([O:4][C:21]1([CH2:24][Cl:25])[CH2:22][Cl:23])[CH2:19][Cl:20]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: ClCC(CCl)=C(CCl)CCl
Agent: OO
Solvent: ClCCl
Product: ClCC1(CCl)OC1(CCl)CCl
Temperature: 32 °C

Procedure:
A reaction flask was charged with 145 ml of methylene chloride, chilled in an ice bath, and placed under a positive nitrogen atmosphere. Trifluoroacetic anhydride 51.9 g (0.247 mole) was added in one portion when the pot temperature was 10° C. Hydrogen peroxide solution (50%) 6.9 g (0.101 mole) was then added in several portions. The exotherm raised the pot temperature to 32° C. The reaction mixture was then chilled to 80° C. A solution of 2,3-bischloromethyl-1,4-dichloro-2-butene 5.6 g (25.6 m moles) in methylene chloride 30 ml was added dropwise over a twenty-minute period. The resulting reaction mixture was warmed to ambient temperature for three hours and refluxed for five hours.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:25]1[CH:26]=[CH:27][C:28]2[S:34](=[O:36])(=[O:35])[CH2:33][CH2:32][C:31]([C:37]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][N:47]([CH3:54])[CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[CH:42][CH:41]=3)=[O:38])=[CH:30][C:29]=2[CH:55]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:54][N:47]([CH2:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([C:31]2[CH2:32][CH2:33][S:34](=[O:36])(=[O:35])[C:28]3[CH:27]=[CH:26][C:25]([C:6]4[O:7][C:8]5[CH:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:9]=5[CH:10]=4)=[CH:55][C:29]=3[CH:30]=2)=[O:38])=[CH:41][CH:42]=1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCOc1ccc2cc(OB([O-])[O-])oc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)oc2c1
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 6-propoxyethoxy-benzofuran-2-yl borate (250 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (262 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 1 day and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give yellow amorphous of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(6-propoxyethoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 142) (200 mg).