Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:26]=[CH:25][C:10]([CH2:11][O:12][C:13]3[CH:24]=[CH:23][C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:15]=4[CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Cl.[C:31](=O)([O:34]C)[O:32][CH3:33]>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]3[CH:24]=[CH:23][C:16]4[CH2:17][CH2:18][CH2:19][CH:20]([C:31]([O:32][CH3:33])=[O:34])[C:21](=[O:22])[C:15]=4[CH:14]=3)=[CH:25][CH:26]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)OC
Reactant: O=C1CCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1CCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2C1=O
Temperature: 110 °C
Yield: 73 %

Procedure:
To 3-(4-phenylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.90 g, 8.47 mmol) dissolved in dimethyl carbonate (80 ml) was added sodium methoxide (2.29 g, 42.4 mmol), and the resulting mixture was stirred at reflux with heating (110° C.) for 6 hours. The reaction mixture was mixed with 1 N hydrochloric acid (60 ml) under ice cooling and was concentrated under reduced pressure to remove the organic solvent, and then the aqueous layer was extracted with a mixed solvent of ethyl acetate and THF ((30 ml/15 ml)×3). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 50 g, ethyl acetate/hexane=1/30). The objective fractions were concentrated under reduced pressure, diisopropyl ether was added to the residue and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain methyl 3-(4-phenylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.47 g, 6.17 mmol, 73%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27](O)=O)=[CH:19][CH:18]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:27]([C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]=[CH:18][CH:19]=2)=[N:16][N:15]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccnc3ccccc23)o1
Yield: 23 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using quinoline-4-carboxylic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=50:30:20 to 20:60:20, 75 mg, 23%) which was obtained as a white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C1(CN)CCCCC1.[O:15]=[C:16]1[C:24]2([CH2:28][O:27][C:26]3[CH:29]=[C:30]4[C:34](=[CH:35][C:25]2=3)[CH2:33][CH2:32][O:31]4)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:15]=[C:16]1[C:24]2([CH2:28][O:27][C:26]3[CH:29]=[C:30]4[C:34](=[CH:35][C:25]2=3)[CH2:33][CH2:32][O:31]4)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:41]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:42])=[CH:44][CH:45]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: Nc1nccs1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1nccs1)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-aminothiazole to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-1,3-thiazol-2-ylbenzamide was obtained (46%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, CDCl3) δ12.63 (s, 1H), 8.11-8.05 (m, 2H), 7.57-7.47 (m, 3H), 7.31-7.18 (m, 3H), 7.08-6.98 (m, 2H), 6.49 (s, 1H), 6.44 (s, 1H), 5.12-4.96 (m, 2H), 4.82 (ABq, 2H), 4.58-4.43 (m, 2H), 3.08-2.89 (m, 2H); MS (ES+) m/z 496.1 (M+1).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[CH:16]=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.S1[C@@H]2CC(=O)N2C([C:37]([OH:39])=[O:38])=CC1.[ClH:40]>CO.O1CCCC1.C(OC(C)C)(C)C>[ClH:40].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:37]([OH:39])=[O:38])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Reactant: COCC1=CN2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 111.3 %

Procedure:
To a suspension of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-3-cephem-4-carboxylic acid (syn isomer) (0.52 g) in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml) was added conc. hydrochloric acid (0.18 g), and the mixture was stirred at 30° C. for 4 hours. After the reaction mixture was cooled and diluted with diisopropyl ether, the precipitated crystals were collected by filtration, washed with diisopropyl ether and then dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (0.45 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1COc2ccccc2N1C1CCNCC1

Procedure:
4-(1-tert-butyloxycarbonyl-4-piperidinyl)-(2H)-1,4-benzoxazin-3(4H)-one from Step 4 was N-deprotedcted with HCl in EtOAc using the procedure given in Step 4 of Example 1. The hydrochloride salt of 4-(4-piperidinyl)-(2H)-1,4-benzoxazin-3(4H)-one was obtained as a solid (95% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CO[C:11](OC)([N:13]([CH3:15])[CH3:14])[CH3:12]>C1(C)C=CC=CC=1>[CH3:14][N:13]([CH3:15])[C:11](=[N:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1)[CH3:12]
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(Cl)nn1)N(C)C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
3-Amino-6-chloropyridazine (1.29 g, 10 mmol) was suspended in dry toluene (20 ml) and dimethylacetamide dimethyl acetal (1.46 ml, 10 mmol) was added. The mixture was stirred and heated at reflux for 3 hours and then left to stand at ambient temperature for 18 hours. Insolubles were removed from the reaction mixture by filtration and the filter washed with ethyl acetate. The filtrate was then evaporated and the residue triturated with isohexane, the solid product collected by filtration and washed with isohexane to give the title compound (1.7 g, 85%) as a yellow solid. NMR: (CDCl3) 2.13 (s, 3H), 3.1 (s, 6H), 6.92 (d, 1H), 7.25 (d, 1H); m/z: 199 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18]([OH:20])=O)=[N:10]2)=[N:7][CH:8]=1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24]>>[OH:24][CH2:23][C:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=2)[N:10]=1)=[O:20])([CH3:26])[CH3:25]
Reactant: COc1ccc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)nc1
Reactant: CC(C)(N)CO
Product: COc1ccc(-n2nc(C(=O)NC(C)(C)CO)c3c2[C@@H]2C[C@@H]2C3)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Method G using (1aR,5aR)-2-(5-methoxy-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=343.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46 (td, J=4.7, 3.3 Hz, 1H), 1.24 (td, J=8.0, 4.8 Hz, 1H), 1.40 (s, 3H), 1.41 (s, 3H), 2.23-2.29 (m, 1H), 2.72-2.76 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.00 (dd, J=16.6, 6.2 Hz, 1H), 3.69 (s, 2H), 3.91 (s, 3H), 4.83 (bs, 1H), 6.95 (s, 1H), 7.36 (dd, J=9.0, 3.0 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 8.15 (d, J=2.9 Hz, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][N:16]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[N:17]1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][N:16]([CH3:15])[N:17]=1)=[O:22]
Reactant: Cn1ccc(C(=O)Cl)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)n1
Yield: 64.5 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0443 g, 0.188 mmol), 1-methyl-1H-pyrazole-3-carbonyl chloride (0.028 g; 0.188 mmol), and triethylamine (0.066 mL; 0.470 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.0367 g (65%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-methyl-1H-pyrazole-3-carboxamide as a solid.
Reaction SMILES: [CH3:1][O:2][S:3]([CH3:6])(=[O:5])=[O:4].[Li]CCCC.[CH2:12]([O:14][P:15](Cl)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13].[NH4+].[Cl-]>C1COCC1.CCCCCC.O>[CH3:1][O:2][S:3]([CH2:6][P:15]([O:16][CH2:17][CH3:18])([O:14][CH2:12][CH3:13])=[O:19])(=[O:5])=[O:4]
Reactant: CCOP(=O)(Cl)OCC
Reactant: COS(C)(=O)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(CS(=O)(=O)OC)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
Methanesulfonic acid methyl ester (0.43 mL, 5.0 mmol) is dissolved in THF (10 mL) and it is cooled down to −78° C. 1.6 M n-BuLi (3.4 mL, 5.5 mmol) in hexane is added into it dropwise and the mixture is stirred for 30 min at −78° C. Then Phosphorochloridic acid diethyl ester (0.41 mL, 2.8 mmol) is added dropwise into the mixture and it is then gradually warmed up to −50° C. in 2 hrs. 5 mL of sat. NH4Cl and 20 mL of water are added and it is further warmed up to room temperature. The mixture is extracted with EtOAc (3×40 mL) and the organic layers are combined, dried (Na2SO4) and concentrated to give crude product. Purification by flash column chromatography affords 350 mg (53%) of (Diethoxy-phosphoryl)-methanesulfonic acid methyl ester.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:13]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]I.[OH-].[K+].Cl>O.CC(C)=O>[CH3:23][N:8]1[C:9]2[C:14](=[CH:13][C:12]([CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[CH2:15][CH2:16][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(c1ccccc1)N2
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CN1c2ccc(CC(=O)O)cc2CCC1c1ccccc1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
The compound (3 g) of Example 2 was dissolved into acetone and, after methyl iodide (0.8 ml) and potassium hydroxide (3.7 g) were added, the mixture was stirred at 40° C. for 20 hours under heat. After water was added and the reaction mixture was acidified with hydrochloric acid, it was extracted with methylene chloride. The residue obtained by drying methylene chloride layer over anhydrous sodium sulfate and then concentrating under reduced pressure was recrystallized from ethanol-hexane to obtain aimed product (1.25 g) as pale yellow powdery crystals. Melting point: 110°-111° C.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:62])[C@@H:24]([NH:25][C:26](=[O:61])/[C:27](/[C:48]4[N:49]=[C:50]([NH:53]C(OC(C)(C)C)=O)[S:51][CH:52]=4)=[N:28]\[O:29][C:30]([C:32]([O:34]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:33])=[CH2:31])[C@H:21]3[S:20][CH2:19][C:18]=2[S:63][CH:64](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:53][C:50]1[S:51][CH:52]=[C:48](/[C:27](=[N:28]/[O:29][C:30]([C:32]([OH:34])=[O:33])=[CH2:31])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:62])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:63][CH2:64][S:65][C:66]4[N:67]=[N:68][NH:69][CH:70]=4)[CH2:19][S:20][C@H:21]23)=[O:61])[N:49]=1
Reactant: C=C(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: O
Product: C=C(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCSc3c[nH]nn3)CS[C@H]12)c1csc(N)n1)C(=O)O
Reaction time: 0.83 h
Yield: 77.1 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-(1-diphenylmethoxycarbonylvinyloxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (910 mg: 0.723 mMol.) in a mixture of anisole (3 ml) and nitromethane (12 ml) at -40° C. is added a solution of aluminum chloride (0.77 g: 5.79 mMol.) in anisole (3 ml), and the mixture is stirred at -30° to -40° C. for 50 minutes. The reaction mixture is mixed with 1N-hydrochloric acid (5.8 ml), diluted with water, washed with ethyl acetate, and concentrated under reduced pressure to remove the remaining organic solvents. The resulting aqueous solution is subjected to chromatography over styrene divinylbenzene copolymer (methanol: water=4:1), and resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxyvinyloxyimino)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (326 mg) as pale yellow white powder. Yield: 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)#[N:14]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:16]4[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=4[C:13]#[N:14])[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: N#Cc1ccc(F)cc1N1CCNCC1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 63.5 %

Procedure:
Following the general procedure of Example 39, Step 2, and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.298 g), 1-(2-cyano-5-fluorophenyl)piperazine (0.309 g), and THF (2 mL) are converted to product, which is then chromatographed on silica gel using methanol/dichlormethane (2/98 to 4/96). Crystallization from dichloromethane/hexane, gives 0.348 g of material, which is recrystallized from ethyl acetate/dichloromethane to give 0.201 g of the title compound; mp 149-150° C.; MS m/z 369, 371; IR (mineral oil) 1625, 1260, 2221, 1514, 1332 cm-1 ; 1H NMR (CDCl3) δ2.69, 3.37, 3.76, 3.53, 6.61, 7.13, 7.39, 7.52, 7.53, 8.14.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(Cl)sc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cl)sc1CBr
Temperature: 25 °C
Yield: 31.1 %

Procedure:
Ethyl 2-chloro-5-methyl-1,3-thiazole-4-carboxylate (Intermediate 179, 2.8 g; 13.6 mmol) was dissolved in CCl4 (25 ml). NBS (2.3 g; 13 mmol) and AIBN (2.12 g; 13 mmol) were added in a single portion and the resultant reaction mixture was heated to reflux for 24 hours. Additional NBS (690 mg; 0.3 equiv.) and AIBN (636 mg; 0.3 mmol) were added to push the reaction to completion. Continued to heat for another 4 hours. Cooled to room temperature, filtered and concentrated the mother liquor. Redissolved in minimal DMSO (7 ml) and purified by Gilson HPLC (5-95% ACN/0.1% TFA; run time=35 min). Isolated 1.15 g of desired product in 29% yield MS (ES) MH+: 284, 286, 288 for C7H7BrClNO2S.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1.C([Si]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH:46]2[CH2:48][O:47]2)=[CH:40][CH:39]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:47][C@@H:46]([CH2:48][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)[CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([OH:37])=[CH:39][CH:40]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=[N+]([O-])c1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1
Yield: 6.3 %

Procedure:
N-[4-(2-Aminoethyl)phenyl]-3-nitro-2-pyridinamine (0.87 g, 3.37 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (1.36 g, 3.36 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.59 g, 0.21 mmol).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C[Si](C)(C)[C:13]1[S:14][CH:15]=[CH:16][N:17]=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)c1nccs1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1nccs1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
4-fluorobenzoyl chloride (3 mL, 25.4 mmol) was added to 2-(trimethylsilyl)thiazole (2 mL, 12.7 mmol) in dichloromethane (70 mL). The reaction mixture was stirred over night at rt. Dichloromethane was evaporated under reduced pressure, and the crude product purified on a normal phase silica-gel column with 0-40% ethyl acetate in hexane to afford the title compound as white amorphous solid (2.050 g, 77% yield); MS (M+H)+ 208.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:8]2[CH:7]=[C:6]([CH2:4][OH:3])[S:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(Br)cc2s1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc2ccc(Br)cc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A −78° C. solution of 6-bromo-benzo[b]thiophene-2-carboxylic acid ethyl ester (5.75 g; 20.2 mmol) in THF (200 mL) is treated with diisobutylaluminum hydride (50.4 mL; 1.0 M) dropwise. The mixture is stirred at 0° C. for 10 minutes and quenched with HCl (1 M, 50 mL). The mixture is extracted with EtOAc (150 mL). The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography eluting with 25% EtOAc/Hexanes. The appropriate fractions are combined and concentrated under reduced pressure to afford the title compound (2.92 g, 60%). 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.68 (d, 1H), 7.42 (d, 1H), 7.18 (s, 1H), 4.90 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
A solution of 6-Bromoindole (1 g, 5 mmol) in DMF (3 ml) was added to a suspension of NaH (134.7 mg, 5.6 mmol) in DMF (98 ml) at 0° C. and stirred for 15 mins. Triisopropylsilyl chloride (1.082 g, 5.6 mmol) was added dropwise, and the reaction mixture stirred for 2 h before being poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, concentrated in vacuo and the crude product passed through a silica gel column, eluting with hexanes, to give the title compound (406.7 mg, 23%) as a colourless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C>C(Cl)Cl.Cl.CCOCC>[ClH:33].[ClH:33].[NH2:7][C@H:8]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2cnc3ccccn23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2cnc3ccccn23)CC1
Yield: 91.2 %

Procedure:
A solution of (R)-[1-(4-chlorobenzyl)-2-(4-imidazo[1,2-a]pyridin-3-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (350 mg, 0.72 mmol) in DCM (3 mL) and 2.0N HCl in Et2O (2 mL) was stirred for 12 hours. The mixture was concentrated in vacuo and the resulting material was chromatographed (SiO2) using 10% MeOH/DCM followed by 10% (7N NH3 in MeOH)/DCM as eluent. This material was dissolved in MeOH followed by the addition of 2.0N HCl in Et2O, and then concentrated in vacuo. The resulting gum was tripped from isopropyl alcohol, and then from acetonitrile to give 2-(R)-amino-3-(4-chlorophenyl)-1-(4-imidazo[1,2-a]pyridin-3-yl-piperazin-1-yl)-propan-1-one dihydrochloride as a white solid (100 mg). 1H NMR (DMSO-d6, 400 MHz) δ 8.66 (d, J=6.8 Hz, 1H), 8.49 (bs, 3H), 7.89 (m, 3H), 7.45 (m, 1H), 7.38 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 4.69 (bs, 1H), 3.49 (m, 6H), 3.08 (m, 1H), 2.94 (m, 3H), 2.85 (m, 1H). LCMS (APCI+) m/z 384, 386 [m+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc([N+](=O)[O-])c(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-methyl-2-nitroaniline (4 mmol) and pyridine (8 mmol) in dry dichloromethane (15 mL) was added dropwise benzoyl chloride (8 mmol). The reaction mixture was stirred at room temperature for 8 h. The solvent was evaporated in vacuum, and the residue was subjected to flash chromatography on silica gel using a mixture of hexanes and CH2Cl2 (7:3) as eluent to afford N-(5-methyl-2-nitrophenyl)benzamide as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCO.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C=C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)CC1CCN(Cc2ccccc2)CC1
Yield: 92.9 %

Procedure:
To a solution of 1 g of ((1-benzyl)piperidin-4-ylidene)acetic acid, t-butyl ester (from EXAMPLE 163, Step A) in 10 mL of EtOH was added 100 mg of platinum oxide at rt. The solution was hydrogenated for 3 h under one atmosphere of hydrogen gas. After filtering through celite, the filtrate was concentrated under reduced pressure to give 936 mg of the title compound as a viscous oil.