Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:2].C([OH:16])C.OO.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:10])=[O:16])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:2]
Reactant: CCO
Reactant: CCc1ccc(C#N)c([N+](=O)[O-])c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A mixture of 2 parts of 4-ethyl-2-nitrobenzenecarbonitrile, 31.6 parts of ethanol, 27.8 parts of hydrogen peroxide (30%) and 1.7 ml of sodium hydroxide 6N was stirred for 1 hour at room temperature. The reaction mixture was diluted with water and the product was extracted with dichloromethane (3×). The combined extracts were washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.3 parts (60.9%) of 4-ethyl-2-nitrobenzamide; mp. 175.0° C. (interm. 4).
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=1[F:38])[NH:21][C:22]1[C:31]2[C:30]([OH:32])=[CH:29][C:28]([O:33][CH3:34])=[CH:27][C:26]=2[N:25]=[CH:24][N:23]=1.[Si:39]([O:46][C@@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:49]([CH2:59]O)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Si:39]([O:46][C@@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:49]([CH2:59][O:32][C:30]2[CH:29]=[C:28]([O:33][CH3:34])[CH:27]=[C:26]3[C:31]=2[C:22]([NH:21][C:20]2[CH:35]=[CH:36][C:37]([F:38])=[C:18]([Cl:17])[CH:19]=2)=[N:23][CH:24]=[N:25]3)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: COc1cc(O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC[C@@H]2C[C@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 44.6 %

Procedure:
Di-tert-butylazodicarboxylate (DTAD, 1.38 g) was added in one portion to a mixture of 4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-ol (1.28 g), tert-butyl (2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)-pyrrolidine-1-carboxylate (1.66 g), and triphenylphosphine (1.58 g) in DCM (100 ml) at room temperature, under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 28 hours and then concentrated in vacuo to leave a brown oil. Purification by column chromatography, using 0-50% ethyl acetate in hexane as eluent, gave tert-butyl (2S,4S)-4-{[tert-butyl(dimethyl)silyl]-oxy}-2-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]-pyrrolidine-1-carboxylate as a white solid (1.13 g, 45%); Mass spectrum MH+ 633.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:18]=[CH:17][C:8]([CH:9]=[N:10][C:11](=[C:14](Cl)Cl)[C:12]#[N:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[O:19]1CCOCC1>>[Cl:1][C:12]1[N:13]=[C:9]([C:8]2[CH:17]=[CH:18][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[NH:10][C:11]=1[CH:14]=[O:19]
Reactant: N#CC(N=Cc1ccc([N+](=O)[O-])cc1)=C(Cl)Cl
Reactant: Cl
Reactant: C1COCCO1
Product: O=Cc1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc1Cl
Temperature: 50 °C
Reaction time: 23 h

Procedure:
HCl gas was bubbled through a solution of 2-(4-nitrobenzylidene)amino-3,3-dichloro-propenonitrile (40.0 g, 0.148 mole) in dioxane (500 ml) at room temperature. The mixture was stirred for 23 hours at 50° C. HCl gas was bubbled through followed by stirring for 24 hours at 50° C. The mixture was stirred for 8 more days at 50° C. with addition of HCl-gas every 24 hours, followed by stirring at 50° C. for 4 more days. More HCl-gas was added and stirred for 3 more days at 500C. The solution was cooled to 0° C. and filtered. The residue was mixed with ethanol (96%, 200 ml) and the title compound, Compound 6, was isolated by filration.
Reaction SMILES: CO.[CH3:3][C:4]1[C:13]([CH2:14][CH:15]=C)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][O:8][C:9]2=[O:17].[O:18]=[O+][O-].CSC>CCOC(C)=O>[CH3:3][C:4]1[C:13]([CH2:14][CH:15]=[O:18])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][O:8][C:9]2=[O:17]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(c1C)CCOC2=O
Solvent: CO
Solvent: CSC
Solvent: CCOC(C)=O
Product: Cc1c(CC=O)ccc2c1CCOC2=O

Procedure:
To a MeOH solution of 5-Methyl-6-(prop-2-en-1-yl)-3,4-dihydro-1H-isochromen-1-one (60 mg, 0.30 mmol) was bubbled ozone until it turned blue. Excess ozone was removed by bubbling nitrogen through. To the reaction was added DMS (0.22 ml, 3.0 mmol), and it was allowed to warm up slowly. The reaction was diluted with EtOAc, washed with water, and purified by MPLC to give the title compound. LC-MS (IE, m/z): 205 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][CH:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:27]([NH:26][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:18])=[O:28])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: CC(N=C=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(NC(=O)N1CCN(c2ccnc3cc(Cl)ccc23)CC1)c1ccccc1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and α-methylbenzyl isocyanate (42 μL, 0.30 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a colorless solid after column chromatography with hexane-EtOAc.
Reaction SMILES: C([N:11]([CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:42]([OH:50])(=[O:49])[CH:43]([CH2:45][C:46]([OH:48])=[O:47])[OH:44].[H][H]>O1CCCC1.[Pd].CCOCC>[CH2:21]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:49][C:42](=[O:50])[CH:43]([CH2:45][C:46]([OH:48])=[O:47])[OH:44])=[O:17])=[CH:19][CH:20]=1)[CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCC=CCCCN(C(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)OC(=O)C(O)CC(=O)O)cc1

Procedure:
A warm solution of N-carbobenzyloxy-4-(4-tetradecenylamino)benzoyl chloride and 1.3 g. triethylamine in 100 ml. ether is treated with 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% palladium-on-carbon at 20 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetic acid to yield the title compound as a tan, crystalline mass.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].[H-].[Na+]>CN(C=O)C.CCOC(C)=O.O>[CH2:17]([O:21][C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1nc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (40 mg, 0.158 mmol) and 1-butanol (0.029 ml, 0.316 mmol) in DMF (2 mL) was added NaH (19 mg, 0.47 mmol) at 0° C. The mixture was stirred for 12 hours at room temperature. The residue was diluted with EtOAc and water. The organic layer was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to give 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (21 mg, 92%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:57]([C:59]1[CH:60]=[C:61]([CH:66]=[C:67]([CH3:70])[C:68]=1[OH:69])[C:62]([NH:64]O)=[NH:63])[CH3:58]>CN(C=O)C.O1CCOCC1>[CH2:57]([C:59]1[CH:60]=[C:61]([C:62]2[N:64]=[C:12]([C:7]3[CH:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:10]=[C:9]([CH3:11])[N:8]=3)[O:14][N:63]=2)[CH:66]=[C:67]([CH3:70])[C:68]=1[OH:69])[CH3:58]
Reactant: Cc1cc(CC(C)C)cc(C(=O)O)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1O
Reaction time: 1 h
Yield: 15.2 %

Procedure:
To a solution of 4-isobutyl-6-methyl-pyridine-2-carboxylic acid (480 mg, 2.09 mmol) and DIPEA (810 mg, 6.27 mmol) in DMF (20 mL), PyBOP (1150 mg, 2.21 mmol) is added at 0° C. The mixture is stirred for 15 min at 0° C. before 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine (429 mg, 2.21 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched by adding water, the mixture is diluted with sat. aq. NaHCO3-solution and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxy-amidine ester intermediate; LC-MS: tR=0.90 min, [M+H]+=370.16. This material is dissolved in dioxane (10 mL) and the mixture is stirred at 80° C. for 15 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give the title compound (112 mg) as a pale purple oil; LC-MS: tR=1.12 min, [M+H]+=352.17.
Reaction SMILES: [CH:1]1([O:11][C:4]2([CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[O:3]1)[CH3:2].[CH:12]([C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:20])=[C:17](O)[CH:16]=1)([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOCC.CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:24](=[O:25])[C:23]2[CH:34]=[CH:35][CH:36]=[CH:37][C:22]=2[NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:39][C:38]=2[O:10][CH:7]2[CH2:8][CH2:9][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:5][CH2:6]2)=[N:28][CH:29]=1
Reactant: CC1OC2(CCC(O)CC2)O1
Reactant: CC(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCC3(CC2)OCCO3)c1
Reaction time: 1 h

Procedure:
4-Hydroxycyclohexanone-1,1-ethylene ketal (0.63 g, 4 mmol), 2-[4-isopropyl-2-hydroxybenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (1.64 g, 4 mmol), triphenyl-phosphine (1.05 g, 4 mmol), and dry DMF (2 mL) were sonicated for 5 min at room temperature. DIAD (0.8 mL, 4 mmol) was added and sonication was continued for 1 h. Ether (40 mL) was added and the solution was chilled overnight in the freezer to crystallize triphenylphosphine oxide. The crystals were filtered, washed with a little ether, and the combined filtrates were evaporated to dryness to give a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:33])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc([C@@H]2[C@H](c3ccc(C#C)cc3)N=C(c3ccc(C(C)(C)C)cc3OCC)N2C(=O)Cl)cc1
Reactant: O=C1CNCCN1
Product: C#Cc1ccc([C@@H]2[C@H](c3ccc(C#C)cc3)N=C(c3ccc(C(C)(C)C)cc3OCC)N2C(=O)N2CCNC(=O)C2)cc1

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12c) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 573.5 [(M+H)+]
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C1OC1C(=O)O
Reactant: CC[K]
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C1OC1C(=O)NCc1ccccc1
Yield: 43.4 %

Procedure:
Following the procedure of Example 1, monoethyl potassium epoxysuccinate (1.0 g) was successively treated with oxalyl chloride (0.75 g) and benzylamine (1.02 g) to give 0.54 g of ethyl N-benzyl-2,3-epoxysuccinamate (Compound No. 13) as colorless needles melting at 90°-91° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].[CH2:10](Br)[CH2:11]Br.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C@@H:21]2[C@@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:10][CH2:11][N:8]4[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[N:6]=[CH:7]4)[C:24]3=[O:32])[CH2:22]2)=[CH:19][CH:20]=1
Reactant: BrCCBr
Reactant: COC(=O)c1c[nH]cn1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: O=C(O)c1cn(CCN2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)cn1

Procedure:
The title compound was prepared in analogy to Example 81 starting from methyl-imidazole-4-carboxylate, ethylene dibromide (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C22H18ClN3O3: 407, observed (M+H)+: 408.8 1H NMR (400 MHz, MeOD-d4) δppm 2.25 (dd, J=8.59, 1.77 Hz, 2 H) 3.31 (br. s., 1 H) 5.28 (d, J=3.03 Hz, 2 H) 6.12 (d, J=7.58 Hz, 1 H) 6.71-6.85 (m, 1 H) 7.03 (d, J=8.08 Hz, 1 H) 7.12-7.19 (m, 1 H) 7.21-7.29 (m, 2H) 7.30-7.39 (m, 2 H) 7.86-7.99 (m, 1 H) 8.40 (d, J=8.59 Hz, 1 H) 8.74 (d, J=5.31 Hz, 1 H) 8.84 (s, 1 H).
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[CH3:8][O:9][C:10]1[CH:29]=[CH:28][C:13]2CO[C:16](=[O:27])[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:12]=2[CH:11]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:40]/[CH:41]=[CH:42]/[C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=1[F:50].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:50][C:44]1[CH:45]=[CH:46][C:47]([F:49])=[CH:48][C:43]=1/[CH:42]=[CH:41]/[CH2:40][N:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][N:17]2[C:12]3[CH:11]=[C:10]([O:9][CH3:8])[CH:29]=[CH:28][C:13]=3[O:4][CH2:3][C:16]2=[O:27])[CH2:26][CH2:25]1
Reactant: COc1ccc2c(c1)N(CCCN1CCNCC1)C(=O)OC2
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(F)c(/C=C/CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc2c(c1)N(CCCN1CCN(C/C=C/c3cc(F)ccc3F)CC1)C(=O)CO2
Temperature: 80 °C

Procedure:
A solution of 6-methoxy-4-(3-piperazin-1-ylpropyl)-2H-1,4-benzoxazin-3(4H)-one trifluoroacetate (Intermediate 118, 985 mg, 1.52 mmol) in dry ethanol (10 mL) was converted to the free base with N,N-diisopropylethylamine for 30 min and then was added 2-[(1E)-4-chloroprop-1-en-1-yl]-1,4-difluorobenzene (Intermediate 124, 315 mg, 1.67 mmol), and potassium carbonate (230 mg, 1.67 mmol). The mixture was heated at 80° C. for 18 hours, cooled to room temperature and then concentrated to dryness under reduced pressure. The residue was partitioned between water (50 mL) and dichloromethane (100 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (95:5) gave the free base of the title compound as a yellow foam. The free base was taken up in dichloromethane (14 mL), followed by the addition of 2M HCl in ether (0.41 mL). The precipitate was collected by filtration and to give the bis hydrochloride salt of the product as a colorless solid, 171 mg (79%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:19]1([N:18]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2cccnc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of [(S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethyl]carbamic acid tertbutyl ester (1.77 g) in DCM (4 mL) was added TFA (20 mL) and the resulting mixture was stirred at RT for 15 min. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM and then the combined organic layers were dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) affording (S)-1-(3-Phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine as colourless gum (540 mg, 20% over three steps). LCMS: RT 1.65 min [M−NH2]+ 222.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([CH2:14][OH:15])[CH2:3]1.[C:16]1([CH3:27])[CH:21]=[CH:20][C:19]([S:22]([O:25]C)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:16]1([CH3:27])[CH:17]=[CH:18][C:19]([S:22]([O-:25])(=[O:23])=[O:24])=[CH:20][CH:21]=1.[CH3:1][N+:2]1([CH3:16])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([CH2:14][OH:15])[CH2:3]1
Reactant: CN1CCC(c2ccccc2)C(CO)C1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C[N+]1(C)CCC(c2ccccc2)C(CO)C1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 94.1 %

Procedure:
The procedures of Reference Example 10 were repeated using 1.0 g of 1-methyl-4-phenyl-3-piperidinemethanol and 910 mg of methyl p-toluenesulfonate to give 900 mg of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[C:36]([C:39]([F:40])([F:41])[F:42])[CH:37]=[CH:38][C:32]=3[F:31])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C(F)(F)F)ccc3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 12.6 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 2-fluoro-5-(trifluoromethyl)aniline (0.071 g, 0.396 mmol), THF (10.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.018 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.14-3.17 (s, 2H), 7.33-7.41 (m, 3H), 7.53-7.62 (m, 3H), 8.92 (d, J=6.6 Hz, 1H), 9.40 (s, 1H), 10.32 (s, 1H), 11.25 (s, 1H); MS [M+H]+: 537.33.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccs3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3cccs3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 46.8 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-(2-thienylmethoxy)benzyl]-3-pyrrolyl]propionate (620 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 7 hours, and 1N hydrochloric acid (3 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(2-thienylmethoxy)benzyl]-3-pyrrolyl]propionic acid (272 mg, yield: 47%). This was recrystallized from ethyl acetate-hexane. Melting point: 127–128° C.
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:33])[C@@H:18]([NH:19][C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])[C@H:15]3[S@@:14](=O)[C:13]2([CH3:36])[CH3:35])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(Cl)(Cl)C([N:43]=[C:44]=[O:45])=O.[O:48]1CCOCC1>>[N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:33])[C@@H:18]([NH:19][C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])[C@H:15]3[S:14][C@:13]2([CH2:36][O:48][C:44](=[O:45])[NH2:43])[CH3:35])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC1(C)[C@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2[S@]1=O
Reactant: C1COCCO1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Product: C[C@@]1(COC(N)=O)S[C@@H]2[C@H](NC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A mixture of (1S,3S,5R,6R) 6-(4-nitrobenzyloxycarbonyl)amino-2,2-dimethylpenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (8.19 g, 15.0 mmol), trichloroacetyl isocyanate (5.0 ml, 7.9 g, 42 mmol) and dioxane (75 ml) was refluxed under nitrogen for 3.5 hours and concentrated in vacuo to a light brown oil. The oil was stirred with warm methanol (150 ml) for 0.5 hour and the solution was decanted from a small amount of dark residue. The methanol solution was adjusted to pH 7.4 with 5% sodium bicarbonate and held at pH 7.4-7.5 with 3% sulfuric acid during a 2.0 hour stirring period. The mixture was then distributed between methylene chloride (250 ml) and water (100 ml). The organic layer was washed with water (100 ml), combined with a CH2Cl2 back-extract (100 ml), dried (4A molecular sieve), polish filtered, and concentrated in vacuo to a light brown oil.