Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(OC)(=O)C=C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([O:16][C:14]([N:13]1[CH2:12][C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]1[CH2:4][C:3]([O:2][CH3:1])=[O:21])=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: COC(=O)C=Cc1ccccc1CNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C=CC(=O)OC
Product: COC(=O)CC1c2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 71 %

Procedure:
3-[2-(tert-Butoxycarbonylamino-methyl)-phenyl]-acrylic acid methyl ester: To a solution of 161.0 g (561.8 mmol) of material from Part A, 58.0 g (674.2 mmol) of methyl acrylate and 170.5 g (1685.4 mmol) of triethylamine in 800 mL of N,N-dimethylformamide was added 7.9 g (11.2 mmol) of dichlorobis(triphenylphosphine)palladium(II) and the mixture was heated at 80° C. for 32 hr. The mixture was cooled, diluted with 1000 mL of ethyl acetate and washed with 10% aqueous sodium bisulfate. The aqueous portion was extracted three times with ethyl acetate and the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and filtered through 7 in. of silica gel in a 2 L sintered glass funnel eluting with 25% ethyl acetate/hexanes. The eluant was concentrated in vacuo and recrystallized from ethyl acetate/hexanes to afford 116.9 g (71%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:40]=[CH:39][C:25]([C:26]([NH:28][CH:29]2[CH2:36][C@H:35]3[N:37]([CH3:38])[C@H:31]([CH2:32][CH2:33][CH2:34]3)[CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:41][CH3:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO.O>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[NH:6][C:5]3[C:11]2=[N:12][C:2]([NH:21][C:22]2[CH:40]=[CH:39][C:25]([C:26]([NH:28][CH:29]4[CH2:36][C@H:35]5[N:37]([CH3:38])[C@H:31]([CH2:32][CH2:33][CH2:34]5)[CH2:30]4)=[O:27])=[CH:24][C:23]=2[O:41][CH3:42])=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)NC2C[C@H]3CCC[C@@H](C2)N3C)ccc1N
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2C[C@H]3CCC[C@@H](C2)N3C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2
Temperature: 160 °C
Yield: 54.3 %

Procedure:
10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 127; 62 mg, 0.21 mmol) and 4-amino-3-methoxy-N-[(1S,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 161; 63 mg, 0.21 mmol) were taken up in 4-methyl-2-pentanol (2 mL) and p-toluenesulphonic acid monohydrate (81 mg, 0.42 mmol) added. The reaction mixture was heated at 160° C. by microwave irradiation for 60 minutes. The cooled reaction mixture was treated with a mixture of methanol & water (5:2 v/v, 7 mL). The resultant solution was loaded onto an SCX-3 cartridge (5 g) pre-wet with methanol. The cartridge was washed through with Methanol (˜40 mL). Products were then eluted with 2M ammonia in methanol (˜30 mL). The ammoniacal solution was evaporated and the resultant material was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (64 mg, 54%).
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:17]([C:20](=[O:26])[CH:21](O)OCC)=[CH:16][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])C1C=CC=CC=1.[NH2:27][C:28]([CH3:41])([CH3:40])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[CH:32]1.[BH4-].[Na+]>>[OH:8][C:9]1[CH:19]=[CH:18][C:17]([CH:20]([OH:26])[CH2:21][NH:27][C:28]([CH3:41])([CH2:29][CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[CH:32]2)[CH3:40])=[CH:16][C:10]=1[NH:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(N)CCn1cnc2ccccc21
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(CCn1cnc2ccccc21)NCC(O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 53.7 %

Procedure:
A mixture of 14.4 gm of 2'-benzyloxy-5'-(1-oxo-2-hydroxy-2-ethoxy-ethyl)-methanesulfonanilide, 7 gm of 1-(3-amino-3-methylbutyl)-benzimidazole and 150 ml of alcohol was heated for 3 hours at 50° C. and then admixed in portions with 9.2 gm of sodium borohydride. The resulting solution is kept for 12 hours at room temperature, the alcohol is then removed under reduced pressure on a Rotavapor, and the residue is dissolved with 200 ml of water and 500 ml of ethyl acetate. After decomposition of the sodium borohydride by stirring with concentrated hydrochloric acid and ice cooling, the mixture was made alkaline with aqueous ammonia, and the ethyl acetate phase was separated, dried with sodium sulfate and evaporated on a Rotavapor. The residue was dissolved in 200 ml of alcohol, the solution was acidified with 6.3 gm of oxalic acid, and the precipitated 2'-benzyloxy-5'-[1-hydroxy-2-[4-(1-benzimiazolyl)-2-methyl-2-butylamino]-ethyl]methane sulfonanilide dioxalate (m.p. 185°-187° C.) is extracted. The base (m.p. 65°-70° C.) was liberated from this compound with aqueous ammonia. Catalytic hydrogenation of this compound (m.p. 65°-70° C.) in 250 ml of methanol under standard conditions with palladium charcoal as a catalyst yielded 8 gm of 2'-hydrox-5'-[1-hydroxy-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethyl]-methanesulfonanilide (m.p. 170°-173° C.; 81% of theory) whose formates of the formula ##STR34## had a melting point of 161°-164° C.
Reaction SMILES: [Br-].[N+:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH:34]=O.[OH-].[Na+]>C(Cl)Cl>[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1/[CH:34]=[CH:9]/[C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:30][CH:29]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(/C=C/c2c(F)cccc2F)cc1
Temperature: 50 °C
Yield: 68.9 %

Procedure:
To a solution of 956 mg (2 mmol) of (4-nitrobenzyl)triphenylphosphonium bromide and 284 mg (2 mmol) of 2,6-difluorobenzaldehyde in 20 mL of CH2Cl2 was added 5 mL of 0.48 M NaOH solution (2.4 mmol, 1.2 equiv) dropwise over a 10 min period. The red solution was heated at 50° C. for 1 h. The organic layer was separated, washed with a saturated aqueous NaHSO3 solution and water, and dried over anhydrous MgSO4. The residue was recrystallized from ethanol to afford 360 mg (69%) of 8 as light yellow crystals: mp 136-137° C. 1H NMR (DMSO-d6): δ 8.23 (d, 2H, J=8.8 Hz), 7.93 (d, 2H, J=8.8 Hz), 7.50 (d, 1H, J=16.8 Hz), 7.46-7.40 (m, 1H), 7.37 (d, 1H, J=16.8 Hz), 7.23-7.17 (m, 2H). 13C NMR (DMSO-d6): δ 160.79 (dd, J1=249.4 Hz, J2=7.3 Hz, two C), 147.27, 143.81, 133.35 (t, J=7.9 Hz), 130.82 (t, J=10.7 Hz), 128.21 (two C), 124.46 (two C), 119.70 (t, J=1.6 Hz), 113.79 (t, J=15.1 Hz), 112.65 (dd, J1=19.5 Hz, J2=5.9 Hz, two C). MS: m/z (%) 261 (61), 231 (67), 214 (45), 194 (34), 183 (100). Anal. Calcd for C14H9F2NO: C, 64.37; H, 3.47. Found: C, 64.56; H, 3.42.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.ClC1C=C(Cl)C=C([N+]([O-])=O)C=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O.C(O)(C)C>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1

Procedure:
103.5 parts of 2,6-dichloro-4-nitro-aniline and 103.5 parts of 2,4-dichloro-6-nitro-aniline are introduced into 180 parts of isopropanol and 300 parts of water, and 200 parts of concentrated sulfuric acid (98 percent strength by weight) are then added to the mixture. A solution of 125 parts of NaNO2 in 175 parts of water is run in at 50° C., as described in Example 1. The mixture is cooled, 400 parts of water are added and the product is filtered off. 192 parts (a practically quantitative yield) of 3,5-dichloro-nitro-benzene, of melting point 60°-61° C., are obtained.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[S:32]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:32]
Reactant: Fc1ccccc1N=C=S
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccccc4F)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol) and 2-fluorophenyl isothiocyanate (10 μL, 0.0824 mmol) were used. Purification on silica yielded compound 30 in Table 1, below (24 mg, 64%). 1H NMR (300 MHz, CDCl3) δ 9.35 (s, 1H), 8.69 (s, 1H), 7.64 (t, J=7.34 Hz, 1H), 7.21-7.12 (m, 3H), 4.35 (q, J=6.90 Hz, 2H), 4.28-4.02 (m, 8H), 1.50 (t, J=7.09 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22].C1CCN2C(=NCCC2)CC1>C1COCC1.C(OCC)(=O)C>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH:20]([C:21](=[O:22])[CH3:23])[C:19]([O:25][CH2:26][CH3:27])=[O:24])(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC)C(C)=O

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I, 3.00 g), ethyl acetoacetate (II, 1.4 ml), and DBU (0.25 ml) are heated to 50° in THF (20 ml) for 1.5 hours. The reaction is cooled, diluted with ethyl acetate, filtered through magnesium sulfate and concentrated under reduced pressure. The concentrate is chromatographed eluting with ethyl acetate, ethyl acetate/acetone (1/1). The appropriate fractions are pooled and concentrated to give the title compound, MS (m/e) 430 (M+), 388, 339, 301 and 288; IR (neat) 2984, 1740, 1716, 1478, 1444, 1392, 1368 and 1250 cm-1 ; NMR (CDCl3) 4.20, 2.43, 2.29, 1.35 and 1.28 δ.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](Cl)=[O:12].[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([O:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20]1)=[O:12]
Reactant: O=C(Cl)c1c[nH]c2ccc(F)cc12
Reactant: CCCCN1CCC(CO)CC1
Product: CCCCN1CCC(COC(=O)c2c[nH]c3ccc(F)cc23)CC1
Yield: 30 %

Procedure:
5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n butyl-4-piperidyl)methanol (D6) using the method of Example 1a to afford (1-n butyl -4-piperidyl)methyl 5-fluoroindole-3-carboxylate as an orange oil (30%), following flash chromatography on silica gel eluting with 10% ethanol/chloroform.
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH2:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1.[N+:25]([CH:28]([CH3:30])[CH3:29])([O-:27])=[O:26]>CC#N>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH2:24][C:28]([CH3:30])([N+:25]([O-:27])=[O:26])[CH3:29])[C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=1
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Reactant: CC(C)[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(CC(C)(C)[N+](=O)[O-])c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (33.68 mL, 225.2 mmol) was added to a solution of methyl 2-(4-chlorophenyl)acrylate (36.9 g, 187.7 mmol) and 2-nitropropane (20.23 mL, 225.2 mmol) in CH3CN (500 mL) at 0° C. under nitrogen. The mixture was warmed to room temperature and stirred overnight. The solution was concentrated in vacuo and subjected to column chromatography (20% EtOAc/hexanes) to give methyl 2-(4-chlorophenyl)-4-methyl-4-nitropentanoate (52.9 g, 98.66% yield) as a colourless oil. 1H NMR (CDCl3, 400 MHz) δ 7.31-7.29 (m, 2H), 7.21-7.19 (m, 2H), 3.66 (s, 3H), 3.60-3.57 (m, 1H), 2.87-2.81 (dd, 1H), 2.39-2.34 (dd, 1H), 1.56 (s, 3H), 1.55 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][C:15](OCC)=[O:16])([O-:13])=[O:12].N1CCCCC1>CC1C=CC=CC=1C>[I:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:15](=[O:16])[C:14]([N+:11]([O-:13])=[O:12])=[CH:4]2
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: Nc1ccc(I)cc1C=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccc(I)cc2cc1[N+](=O)[O-]

Procedure:
A stirred mixture of 2-amino-5-iodobenzaldehyde (2.0 g), ethyl nitroacetate (4.2 g), and piperidine (0.7 g) was heated under reflux for 1.5 hours in o-xylene (100 cm3). The cooled solution was then concentrated in vacuo and the solid residue was recrystallised from chloroform-isopropanol to afford 6-iodo-3-nitro-2-(1H)-quinolone, m.p. 279°-282°, (1.14 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[CH3:16].[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:17])=[C:8]([CH3:16])[CH:9]=2)=[O:13])[CH2:30][CH2:31]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCCS1(=O)=O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)c(C)c3)CC2)c(C)c1
Yield: 54.1 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-3-methylbenzoic acid (268 mg) described in Preparation Example and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (242 mg) was obtained.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[N:20]([CH3:31])[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[CH:23]=3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[CH:23]=[C:19]([CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[CH:9][N:8]4[CH2:7][C:6]([OH:32])=[O:5])=[CH:12][CH:13]=3)[N:20]([CH3:31])[N:21]=2)=[CH:25][CH:26]=1
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(-c2ccc(Cl)cc2)cc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 f], {6-[5-(4-chloro-phenyl)-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {6-[5-(4-chloro-phenyl)-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as off-white crystals.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]([F:36])([F:35])[F:34])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH2:4][O:3]1.Cl>C1COCC1.CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([C:18]2[C:26]3[N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:35])([F:36])[F:34])[NH:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)OC[C@@H](COc2cccc(NC(=O)c3cccc4[nH]c(-c5ccccc5C(F)(F)F)nc34)c2)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cccc(OC[C@@H](O)CO)c1)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-N-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (134; 51.5 mg, 0.1 mmol) in 3 mL of THF was added 4 N HCl dropwise until observe color change, solution darkens, at which point an additional 1 mL of HCL is added and the solution is allowed to stir at room temperature for 18 h. The reaction mixture was diluted with MeOH and then concentrated under reduced pressure. The resulting yellowish suspension is purified by preparatory HPLC. The desired product (Compound 725) was obtained as a white solid (32.5 mg, 64%). MS (ESI) calcd for C24H20F3N3O4: 471.14; found: 472 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[NH:18][CH:17]=[C:16]([C:21]#[N:22])[C:15]3=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:30])=O>>[CH2:1]([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[N:18]=[CH:17][C:16]([C:21]#[N:22])=[C:15]3[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCc1ccccc1
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of 8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile (11.4 g, 31.9 mmol) and phosphorus oxychloride (147 g, 959 mmol) is heated under reflux for one hour. After cooling to room temperature, the reaction mixture is evaporated under vacuum to remove the volatiles. The residue is carefully slurried in cold saturated aqueous sodium bicarbonate solution (500 mL). The solids are collected by filtration, washed thoroughly with saturated aqueous sodium bicarbonate solution and water and dried to give 11.7 grams of crude 8-(benzyloxy)-4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile as a light orange solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:5][CH2:4][N:3]1[C:21]([C@@H:23]1[CH2:27][C@H:26]([S:28][C:29]2[C@H:30]([CH3:53])[C@@H:31]3[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]3[C:33]=2[C:34]([O:36]CC2C=CC([N+]([O-])=O)=CC=2)=[O:35])[CH2:25][N:24]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:22].[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:21]([C@@H:23]1[CH2:27][C@H:26]([S:28][C:29]2[C@H:30]([CH3:53])[C@@H:31]3[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]3[C:33]=2[C:34]([OH:36])=[O:35])[CH2:25][NH:24]1)=[O:22]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C[C@@H]4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC[C@@H]4C)C3)[C@H](C)[C@H]12

Procedure:
205 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(2S)-2-methyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 3 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 240 μl of 1N aqueous hydrochloric acid were added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 250 mg of 10% w/w palladium-on-charcoal. The reaction mixture was then worked up and purified by the same procedure as described in Example 7(b), to give 30 mg of the title compound as a powder.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[SH:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[C:15]([OH:23])(=[O:22])[C:16]([CH2:18][C:19]([OH:21])=[O:20])=[CH2:17].O>C(OCC)C.C(OCC)(=O)C>[S:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[S:5][CH2:17][CH:16]([C:15]([OH:23])=[O:22])[CH2:18][C:19]([OH:21])=[O:20]
Reactant: Sc1nc2ccccc2s1
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: O=C(O)CC(CSc1nc2ccccc2s1)C(=O)O
Reaction time: 24 h
Yield: 50.5 %

Procedure:
13.3 g of AlCl3 are dissolved in 100 ml of diethyl ether at 0° to 5°. 3.4 g of 2-mercaptobenzothiazole and 2.6 g of itaconic acid are then added. After the mixture has been stirred at 20°-25° for 24 hours, the ether solution is poured off and the residue is stirred with 100 ml of water and 100 ml of ethyl acetate. The organic phase is separated off, dried and evaporated. 3 g of 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylic acid are obtained as the residue.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18]C3CCCCO3)=[CH:13][CH:12]=2)=[C:5]([CH3:25])[N:4]=1>CO>[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)=[C:5]([CH3:25])[N:4]=1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(COC2CCCCO2)cc1
Agent: Cl
Solvent: CO
Product: Cc1nc(N)nc(O)c1Cc1ccc(CO)cc1
Reaction time: 0.5 h

Procedure:
Conc. HCl (4 ml) was added to a mixture of the product from example 34 step (ii) (5.2 g) in MeOH (100 ml) at rt and stirred for 30 min. The solvent was evaporated under reduced pressure and the residue dissolved in water (150 ml). Aq sat, NaHCO3 soln was added until basic then the solid filtered, washed with water, ether and dried to afford the subtitle compound, 3.48 g.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][CH3:18])=[C:12]2[CH2:19][CH2:20]O)=[O:5].[Br:27]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:27][CH2:20][CH2:19][C:12]1[C:11]2[C:16](=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([Cl:1])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:26])[CH:8]=[CH:9][CH:10]=2)[N:15]=[CH:14][C:13]=1[CH2:17][CH3:18]
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCBr
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-(2-hydroxyethyl)quinoline (405 mg) in dichloromethane were added N-bromosuccinimide (241 mg) and triphenylphosphine (355 mg) under water cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (dichloromethane) and crystallized from n-hexane to give 4-(2-bromoethyl)-8-(2,6-dichlorobenzoylamino)-3-ethylquinoline (424 mg).
Reaction SMILES: Cl[CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]([N:5]([CH2:15][C:16]1([OH:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+]>CN(C=O)C.O>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][N:5]2[CH2:15][C:16]3([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[O:29][CH:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:3]2=[O:4])=[CH:12][CH:11]=1
Reactant: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(=O)C(Cl)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OC(c3ccccc3)C2=O)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a suspension of tert-butyl 4-[[(2-chloro-2-phenyl-acetyl)-[(4-methoxyphenyl)methyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate (322 mg, 0.64 mmol) in DMF (3 mL) at 0° C. was added NaH (27 mg, 0.67 mmol). The reaction mixture was allowed to warm to room temperature overnight, then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 0-40% EtOAc/DCM to give tert-butyl 10-[(4-methoxyphenyl)methyl]-9-oxo-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (215 mg, 72%) as a colorless oil. ESI-MS m/z calc. 502.2. Found 503.5 (M+1)+; Retention time: 1.90 minutes (3 min run).