Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH:15]=[CH:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CS(O)(=O)=O.C(OC(C)=C)(=O)C>C1(C)C=CC=CC=1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][CH:18]([OH:28])[CH:19]=[CH:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: C=C(C)OC(C)=O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4CC(O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 61.2 %

Procedure:
To a mixture of 19 g (0.05 mol) of cholesta-1,4,6-trien-3-one (I), 4.8 g (0.05 mol) of methanesulfonic acid and 200 g (2 mol) of isopropenyl acetate were added 200 ml of toluene, and the resulting mixture was then heated under reflux for 6 hours. After completion of the reaction, the same treatment as in Example 1 was carried out to yield 11.7 g of cholesta-1,5,7-trien-3-ol (IV). The yield was 61%.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][C:6](N2CCCC2)=[C:5]1[C:14]([C:16]1[C:17]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15])(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)(C)(C)C>[Cl:29][C:25]1[CH:24]=[C:23]([N:22]2[C:17]3[N:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:14](=[O:15])[C:5]3[NH:4][CH:8]=[CH:7][C:6]2=3)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)n1ccc(N2CCCC2)c1C(=O)c1cccnc1Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: O=c1c2cccnc2n(-c2cccc(Cl)c2)c2cc[nH]c12

Procedure:
Reflux a mixture of 1-acetyl-2-[2-[(3-chlorophenyl)amino]-3-pyridinylcarbonyl]-3-(1-pyrrolidinyl)-1H-pyrrole (0.45 g), p-toluenesulfonic acid monohydrate (0.21 g) in a solvent of benzene (20 ml), and tert-butanol for 12 hours. Evaporate solvent and partition the residue between CHCl3 and 1M NaHCO3. Wash the CHCl3 solution with water, dry and filter the solution. Evaporate the solvent, and triturate the residue with CHCl3 to give 4-(3-chlorophenyl)-1,4-dihydro-9H-pyrrolo[3,2-b][1,8]-naphthyridin-9-one, m.p. 300°-301° C.
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.CC1(C)C(C)(C)OB([C:46]2[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]3[C:56](=[O:70])[N:57]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=4)[CH:58]=[CH:59][CH:60]=3)=[O:54])=[CH:48][CH:47]=2)O1.[B].C[O:74][C:75]([C:77]1[CH:78]=[C:79]2[CH:85]=[CH:84][NH:83][C:80]2=[N:81][CH:82]=1)=[O:76]>>[F:69][C:64]1[CH:63]=[C:62]([CH:67]=[CH:66][C:65]=1[F:68])[CH2:61][N:57]1[CH:58]=[CH:59][CH:60]=[C:55]([C:53]([NH:52][CH2:51][C:49]2[S:50][C:46]([C:85]3[C:79]4[C:80](=[N:81][CH:82]=[C:77]([C:75]([OH:76])=[O:74])[CH:78]=4)[NH:83][CH:84]=3)=[CH:47][CH:48]=2)=[O:54])[C:56]1=[O:70]
Reactant: COC(=O)c1cnc2[nH]ccc2c1
Reactant: CC1(C)OB(c2ccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)s2)OC1(C)C
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(O)c1cnc2[nH]cc(-c3ccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)s3)c2c1

Procedure:
Except where indicated, 3-[5-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-thiophen-2-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophen-2-ylmethyl]-amide as activated boron species and 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester as substituted bicyclic heterocycle, to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.338 (m, 1H) 10.072 (t, J=5.8 Hz, 1H) 8.829 (d, J=1.7 Hz, 1H) 8.688 (d, J=1.9 Hz, 1H) 8.403 (dd, J=7.3, 2.2 Hz, 1H) 8.234 (dd, J=6.6, 2.2 Hz, 1H) 7.944 (d, J=2.5 Hz, 1H) 7.480-7.347 (m, 2H) 7.224 (d, J=3.6 Hz, 1H) 7.188-7.134 (m, 1H) 7.040 (d, J=3.5 Hz, 1H) 6.591 (t, J=7.1 Hz, 1H) 5.194 (s, 2H), 4.685 (d, J=5.9 Hz, 2H); MS m/z=521.05 M+H.
Reaction SMILES: C([O:3][C:4](=[O:35])[C@@H:5]([O:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)C.[Li+].[OH-]>>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:33][CH3:34])[C:4]([OH:35])=[O:3])=[CH:12][CH:11]=2)=[CH:20][CH:21]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)OC
Agent: [Li+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propionic acid ethyl ester from Step A under the Standard hydrolysis procedure C. (LiOH). 1H-NMR (200.15 MHz; CDCl3): 7.81 (d, 2H, J=8.9), 7.75 (dd, 2H, J=8.3, 1.4), 7.6–7.4 (m, 3H), 7.15 (d, 2H, J=8.6), 6.81 (d, 2H, J=8.3), 4.2–3.9 (m, 5H), 3.37 (s, 3H), 3:08 (dd, 1H, J=14.2, 4.3), 2.94 (dd, 1H, J=14.2, 7.5), 2.1–1.9 (m, 4H) ppm.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C1C=CC=CC=1>[Cl-].[Zn+2].[Cl-].O>[C:1]1(=[N:7][CH:13]2[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: NC1C=CCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O
Product: C1=CC(N=C2CCCCC2)CCC1
Yield: 69.9 %

Procedure:
A mixture of 2-cyclohexenylamine (9.7 g, 0.1 mole), cyclohexanone (9.8 g, 0.1 mole), zinc chloride (0.16 g) and benzene (50 ml) was heated under reflux, and resulting water removed by azeotropic distillation. The mixture was concentrated and distilled to obtain 12.4 g of N-cyclohexylidene-2-cyclohexenylamine [Compound (344)].
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][CH3:15])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([OH:30])=O)[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([N:14]([C:10]4[CH:11]=[C:12]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]5)[CH3:15])=[O:30])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: CNc1ccc2[nH]c(C(C)(C)C)cc2c1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)C1(c2ccc3c(c2)OCO3)CC1)c1ccc2[nH]c(C(C)(C)C)cc2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-tert-Butyl-N-methyl-1H-indol-5-amine (20.2 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 μL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 80° C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)-N-methylcyclopropanecarboxamide. ESI-MS m/z calc. 390.2. found 391.3 (M+1)+. Retention time of 3.41 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([OH:23])[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.Cl>O>[OH:23][C:13]1([C:10]2[CH:9]=[CH:8][C:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:12][CH:11]=2)[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]1
Reactant: OC1(c2ccc(-c3ncccn3)cc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: O=C1CCC(O)(c2ccc(-c3ncccn3)cc2)CC1

Procedure:
The title compound was prepared by treating the ketal of step B with HCl in water following the procedure described in step B of Example 2. MS (M+H)+ 269.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH2:17][CH3:18])[C:13](SCC)=[N:12]3)[CH2:10][CH:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:28].[I-]>N.CCO>[NH2:28][C:13]1[N:14]([CH2:17][CH3:18])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10]2)[N:12]=1
Reactant: CCSC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CCN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Yield: 23.8 %

Procedure:
A solution of 6-bromo-1′-ethyl-2′-(ethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (195 mg, 0.44 mmol), NH4I (128 mg, 0.88 mmol) in NH3/EtOH (5 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-ethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 24%). 1H-NMR (MeOD): 1.12 (m, 3H), 1.98 (m, 1H), 3.16 (m, 1H), 3.54 (m, 2H), 5.75 (m, 1H), 6.77 (m, 1H), 6.95 (m, 1H), 7.23 (m, 2H), 7.33 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:14])=[O:13])=[CH:3][C:2]=1[NH:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1)#[N:9]
Reactant: N#Cc1ccc(N[C@H](Cc2ccccc2)C(N)=O)cc1Br
Reactant: Cc1cc(N)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccccc3)C(N)=O)ccc2C#N)sn1
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(3-bromo-4-cyanophenylamino)-3-phenylpropanamide (102 mg, 0.296 mmol), 5-amino-3-methylisothiazole hydrochloride (58 mg, 0.385 mmol), BINAP (25 mg, 0.040 mmol), Pd(OAc)2 (20 mg, 0.089 mmol) and K2CO3 (150 mg, 1.08 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 120 C for 18 h. Water and EtOAc were added. After being filtered, the organic phase was separated, washed with 1N HCl, dried over Na2SO4, concentrated in vacuo to give (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-phenylpropanamide as a crude residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=[O:6].C(Cl)Cl.F[B-](F)(F)F.[CH2:20]([O+](CC)CC)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](=[NH:7])[O:6][CH2:20][CH3:21]
Reactant: NC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dichlorobenzamide (139 g.; 0.73 mole) suspended in 600 ml. of methylene chloride is added to 150 g. (0.8 mole) of triethyloxonium fluoroborate in 100 ml. of methylene chloride cooled in an ice-bath to 0° C. over a period of 10-15 min. At the end of the addition, the mixture is allowed to stir at room temperature overnight. The mixture is again cooled in an ice-bath and 141 g. of 50% potassium carbonate in water is added over 30 min. The mixture is stirred for 15 min., the methylene chloride layer separated and the solids washed with methylene chloride. The combined organic layer and washings are dried over sodium sulfate and concentrated in vacuo to a yellow oil which is treated with hexane. A small amount of solids are filtered and the filtrate concentrated to give, after drying in vacuo, 140 g. of the desired imino ether, m.p. 62°-64° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][C:9]=2[O:19][CH3:20])[CH2:4][O:3]1.[H-].[Na+].I[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[N:15]3[CH3:25])=[CH:10][C:9]=2[O:19][CH3:20])[CH2:4][O:3]1
Reactant: COc1cc2c(cc1CC1COC(C)(C)O1)NC(=O)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1CC1COC(C)(C)O1)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
300 mg of 7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one was dissolved in 6 ml of N,N-dimethylformamide. While cooling on ice, 49 mg of 60% sodium hydride was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, 0.29 g of iodomethane was added to the reaction solution while cooling on ice. The obtained mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and then washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate), so as to obtain 310 mg of the subject compound.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([S:11]([CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:22][OH:23].C=O>C(Cl)Cl>[OH:23][CH2:22][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=2[N:9]=[C:8]1[S:11]([CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)=[O:12]
Reactant: COc1ccnc(CS(=O)c2nc3c(F)cccc3[nH]2)c1
Reactant: CO
Agent: C=O
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3c(F)cccc3n2CO)c1
Reaction time: 0.07 h

Procedure:
4-Fluoro-2-[[(4-methoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (1.6 g, 5.2 mmol) was suspended in methylene chloride (50 ml). Methanol was added until a clear solution was obtained. The mixture was concentrated on a rotavapor under reduced pressure. The oily residue, which was not allowed to crystallize, was dissolved in methylene chloride (30 ml). A solution of formaldehyde (5 M, 10 ml, 50 mmol) was added and the mixture was stirred violently for four minutes. After separation the organic solution was dried (Na2SO4) and concentrated until 10 ml of the mixture was left. The flask was chilled for 15 minutes whereupon the formed precipitate was filtered off and washed with cold methylene chloride. In this way the title compound was obtained (1.1 g, 63%). NMR data is given below.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:22][S:23]([NH2:26])(=[O:25])=[O:24].C(O)(=O)C.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:17]=[C:16]([CH2:18][NH:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH:15]=[N:14][CH:13]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cn1c(-c2cncc(CNS(C)(=O)=O)c2)c(C#N)c2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126, 50 mg, 0.169 mmol) and methanesulfonamide (24 mg, 0.254 mmol), acetic acid (20 mg, 0.338 mmol), triethylamine (34 mg, 0.338 mmol) in DCE (10 mL) are stirred for 30 min at ambient temperature before adding NaBH(OAc)3 (100 mg, 0.473 mmol). The reaction mixture is stirred overnight. NaHCO3 (1 mL) is added and the solvents are removed in vacuo. The residue is purified using a Sunfire C18 with a gradient of acetonitrile in 0.1% aqueous TFA and further purified with an Xbridge C18 using a gradient of acetonitrile in 0.1% NH4OH to give N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.97 (s, 3H), 3.78 (s, 3H), 4.36 (s, 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.75 (br. s., 1H), 7.97 (d, J=1.8 Hz, 1H), 8.10 (t, J=2.1 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 375.0681 [(M+H)+ Calcd for C17H16ClN4O2S: 375.0682].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].ClC1C=CC=C(C(OO)=[O:24])C=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH+:8]([O-:24])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCc1ccccn1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[NH+]([O-])Cc1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.7 %

Procedure:
tert-Butyl 2-pyridylmethylcarbamate (11.4 g, 54 mmol) and 3-chloroperbenzoic acid (77%, 5.9 g, 71 mmol) were dissolved in ethyl acetate (150 ml), and the mixture was stirred at room temperature for 15 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:5, v/v) were collected and concentrated to give the titled compound (11.1 g, 90%).
Reaction SMILES: P(=O)(O)(O)O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[OH-].[NH4+:16]>C(O)(=O)C>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:9]2[CH2:10][CH2:11][NH:16][CH2:7][CH:8]=2)=[CH:7]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: [NH4+]
Agent: O=P(O)(O)O
Agent: [OH-]
Solvent: CC(=O)O
Product: C1=C(c2c[nH]c3ccccc23)CCNC1
Temperature: 100 °C

Procedure:
50 ml of N aqueous phosphoric acid and 39.3 g of 4-piperidine-monohydrate hydrochloride were added with stirring under nitrogen to a solution of 10 g of indole in 200 ml of acetic acid heated at 95°-100° C and the mixture was heated for an hour at 100° C and then allowed to cool. The mixture was poured into 350 ml of concentrated ammonium hydroxide containing ice and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and water containing sodium chloride, were dried over magnesium sulfate and evaporated to dryness to obtain 14.7 g of raw product. The latter was crystallized from 75 ml of methanol and the mixture was filtered under reduced pressure. The product was washed with methanol and ether to obtain 1.42 g of 4-([1H]-indol-3-yl)-1,2,3,6-tetrahydro-pyridine melting at 185°-186° C.
Reaction SMILES: [OH:1][C:2]1[CH2:6][NH:5][C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1>CO.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([C:3]2[C:4](=[O:7])[NH:5][CH2:6][C:2]=2[OH:1])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1NCC(O)=C1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C2=C(O)CNC2=O)c1
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
A suspension of 1,5-dihydro-4-hydroxy-3-(3-nitrophenyl )-2H-pyrrol-2-one (0.6 g, 2.7 mmol) in methanol (30 ml) was hydrogenated at 30 psi using a palladium on carbon catalyst (200 mg, 35% (w /w)), for 10 min. The catalyst was filtered off and the solvent evaporated in vacuo. The residue was azeotroped with toluene (2×20 ml) and then triturated with ether (20 ml). 3-(3-Aminophenyl)-1,5-dihydro-4-hydroxy-2H-pyrrol-2-one (0.43 g, 84%) was isolated as a pale yellow solid. mp 262°-265° C. (dec.). 1H NMR (360MHz, D6 -DMSO) δ3.80 (2H, s), 6.37 (1H, d, J=8Hz), 6.93 (1H, dd, J=8 and 8Hz), 7.12 (1H, d, J =7Hz), 7.22 (1H, s), 7.45 (1H, s).
Reaction SMILES: C([O:5][C:6]([C:8]([O:11]/[N:12]=[C:13](/[C:46]1[N:47]=[C:48]([NH:51]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:49][CH:50]=1)\[C:14]([NH:16][CH:17]1[C:44](=[O:45])[N:19]2[C:20]([C:28]([O:30]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:29])=[C:21]([CH:24]=[CH:25][CH2:26]I)[CH2:22][S:23][C@H:18]12)=[O:15])([CH3:10])[CH3:9])=[O:7])(C)(C)C.[N:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>ClCCl.C(OC(C)C)(C)C>[NH2:51][C:48]1[S:49][CH:50]=[C:46](/[C:13](=[N:12]/[O:11][C:8]([C:6]([OH:7])=[O:5])([CH3:10])[CH3:9])/[C:14]([NH:16][CH:17]2[C:44](=[O:45])[N:19]3[C:20]([C:28]([O-:30])=[O:29])=[C:21](/[CH:24]=[CH:25]/[CH2:26][N+:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[N:47]=1
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C/C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1)C(=O)O
Reaction time: 3.5 h
Yield: 7 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-t-butoxycarbonyl-2-propoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-4', 497 mg, 0.5 mmole) and pyridine (0.08 ml, 1 mmole) in dichloromethane (5 ml) was allowed to stand at room temperature for 3.5 hours, and was then diluted with diisopropyl ether. The resulting precipitate was collected by filtration and treated with trifluoroacetic acid (5 ml) and anisole (1 ml) at room temperature for 1 hour, and the resulting mixture was concentrated and triturated with ether to give crude product I-4B which was purified by HP-20 column chromatography, eluted with water (300 ml), 10% methanol (500 ml) and 30% methanol (300 ml). The eluate of 30% methanol was concentrated to a small volume, adjusted to pH 7 with sodium bicarbonate and lyophilized to afford 23 mg (7%) of the title compound I-4B. M.p. >150° C.
Reaction SMILES: C(Cl)CCl.[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[NH:17][CH:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=2[CH:25]=1)([OH:7])=O.[NH2:26][CH2:27][C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2.C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[C:28]1[CH2:27][NH:26][C:5]([C:8]1[CH:9]=[CH:10][C:11]2[NH:17][CH:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=2[CH:25]=1)=[O:7]
Reactant: NCc1cc2ccccc2[nH]1
Reactant: COC(=O)CC1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1Nc2ccc(C(=O)NCc3cc4ccccc4[nH]3)cc2CN(C)C1=O
Yield: 59 %

Procedure:
EDC (1.53 g, 7.99 mmol) was added to a solution of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (2.13 g, 7.26 mmol), 2-aminomethylindole (1.06 g, 7.26 mmol), HOBT.H2O (1.08 g, 7.99 mmol) and diisopropylethylamine (1.53 mL, 8.71 mmol) in anhydrous DMF (10 mL) at RT. After 20 h the reaction was concentrated on the rotavap (high vacuum). The residue was taken up in EtOAc and washed sequentially with H2O and 10% Na2CO3 (2×30 mL). Drying (MgSO4), concentration, and silica gel chromatography (2% MeOH/CH2Cl2) gave the title compound (1.8 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 8.56 (t, 1H), 7.95 (s, 1H), 7.59 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 7.33 (d, 1H), 7.01 (t, 1H), 6.93 (t, 1H), 6.55 (d, 1H), 6.33 (br, 1H), 6.25 (s, 1H), 5.49 (d, 1H), 5.14 (t, 1H), 4.56 (d, 2H), 3.82 (d, 1H), 3.61 (s, 3H), 2.92 (s, 3H), 2.75 (dd, 1H), 2.53 (d, 1H); MS(ES) m/e 421.2 (M+H)+.