Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.[C:26]([N:28]=[C:29](SC)[S:30][CH3:31])#[N:27].CCN(CC)CC>CC#N>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:29](=[N:28][C:26]#[N:27])[S:30][CH3:31])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CSC(=NC#N)SC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSC(=NC#N)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A 25 mL flask was charged with (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (3 g, 8.15 mmol) and dimethyl cyanocarbonimidodithioate (1.2 g, 8.15 mmol) dissolved in 50 mL of MeCN, and 1 mL Et3N was added and the mixture was stirred for overnight. The mixture was evaporated in vacuo and the residue was purified by chromatography to give desired (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-((cyanoimino)(methylthio)methylamino)ethoxy)methyl)-piperidine-1-carboxylate (2.2 g, 58%). 1H NMR (CDCl3, 400 MHz) δ 7.28 (m, 2H), 7.23 (m, 1H), 7.16 (m, 1H), 4.10 (m, 2H), 3.86 (m, 1H), 3.68 (m, 2H), 3.22 (m, 2H), 2.72 (m, 2H), 1.62 (m, 2H), 1.46 (s, 9H), 1.40-1.10 (m, 4H).
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:9]1[CH2:10][CH:8]1[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1ccccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CC1c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the t-butyl ester from Step 1 (0.52 g, 0.0022 mole) in dichloromethane at 0° C. was added trifluoroacetic acid and the mixture stirred at rt for 30 min. The reaction was concentrated in vacuo to give the title compound as an oil. Analysis of the acid by chiral HPLC (Chirapak AD, 250×4.6 mm) using 95/5(A/B), 0.2% trifluroacetic acid in hexane(A) and ethanol(B), 1 mL/min, showed the material to have a purity of ≧94% EE. M.S.(M+1): 181.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.C(Cl)(Cl)Cl>[ClH:17].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: Nc1ncccc1OCc1ccc(F)cc1
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccc(F)cc1
Yield: 9.4 %

Procedure:
A mixture of 2-amino-3-(4-fluorobenzyloxy)pyridine (5.42 g, 24.2 mmol) and ethyl phenylacetimidate hydrochloride (6.28 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was taken up in chloroform, filtered to remove an insoluble white solid, and purified by flash chromatography (chloroform/methanol) to obtain the product (0.85 g), m.p. 175°-178° C.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@H:15]1[CH2:23][N:22]2[C@H:17]([CH2:18][C:19](=[O:24])[CH2:20][CH2:21]2)[CH2:16]1.O>ClCCl>[Si:6]([O:14][C@H:15]1[CH2:23][N:22]2[C@H:17]([CH2:18][C:19](=[O:24])[CH2:20][CH2:21]2)[CH2:16]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCN2C[C@H](O)C[C@H]2C1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CC(=O)CCN2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
1.70 g (24.9 mmol) of imidazole and 1.88 g (12.5 mmol) of t-butyldimethylsilyl chloride were added to a solution of 1.30 g (8.1 mmol) of (2R,8aS)-2-hydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one [obtained as described in Preparative Example 2(i)′ above] in 30 ml of dichloromethane and the resulting mixture was stirred for 20 hours at room temperature. At the end of this time, water was added and the reaction mixture was extracted with dichloromethane. The organic extract was washed with water and concentrated by evaporation under reduced pressure, and the resulting residue was then purified by chromatography on an alumina column using a 9:1 by volume mixture of hexane and ethyl acetate as the elaunt to afford 1.98 g (yield: 88%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[N+:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[N+:30]([C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:27][C@H:19]2[CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:18]2[NH:17][C:12]2[C:11]([CH2:28][CH3:29])=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:14]([CH2:15][CH3:16])[N:13]=2)=[O:38])=[CH:40][CH:41]=1)([O-:32])=[O:31]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@H]1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of (1S,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (321 mg, 0.75 mmol), 4-nitrobenzoic acid (552 mg, 3.3 mmol), and triphenylphosphine (964 mg, 3.7 mmol) in benzene (19 mL) was purged with nitrogen and cooled to 0° C. The resulting yellow suspension was treated with diethylazodicarboxylate (0.58 mL, 3.7 mmol) becoming lighter in color with gradual warming to RT. After 18 hours, the volatiles were removed under reduced pressure with the resulting crude residue being absorbed on 6 g silica gel and purified by Biotage MPLC (40 g column, 15% ethyl acetate/heptane) to afford the title compound as a light yellow solid. IR (diffuse reflectance) 1725, 1568, 1550, 1527, 1498, 1467, 1392, 1372, 1349, 1320, 1273, 1119, 1103, 836, 719 cm−1; OAMS supporting ions at: ESI+ 576.8; MS (CI) m/z 577 (MH+); HRMS (FAB) calcd for C30H26CL2N4O4+H1 577.1409, found 577.1417.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]3[CH2:12][S:13][CH2:14][C:10]3=[C:9]([C:15]#[N:16])[CH:8]=2)[CH:2]=1.[Br:17]N1C(=O)CCC1=O>>[Br:17][C:8]1[C:9]([C:15]#[N:16])=[C:10]2[CH2:14][S:13][CH2:12][N:11]2[C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cc(-c2cccnc2)n2c1CSC2
Reactant: O=C1CCC(=O)N1Br
Product: N#Cc1c(Br)c(-c2cccnc2)n2c1CSC2
Yield: 30.7 %

Procedure:
6-Bromo-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carbonitrile is prepared as in Example 9, from 5 g of 5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carbonitrile and 4.1 g of N-bromosuccinimide. 2.07 g of 6-bromo-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carbonitrile are thus obtained in the form of white powder melting at 190° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.N12CCN(CC1)CC2.[CH3:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])[C:24]=2[N:23]=[N:22]1>C(#N)C.O>[CH3:1][C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH:8][C:34]([NH:33][S:30]([C:29]2[C:24]3[N:23]=[N:22][N:21]([CH3:20])[C:25]=3[CH:26]=[CH:27][CH:28]=2)(=[O:31])=[O:32])=[O:35])[N:7]=1
Reactant: Cc1nc(N)nc2c1CCO2
Reactant: Cn1nnc2c(S(=O)(=O)N=C=O)cccc21
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CC#N
Product: Cc1nc(NC(=O)NS(=O)(=O)c2cccc3c2nnn3C)nc2c1CCO2
Reaction time: 4 h

Procedure:
To a stirred solution of 5,6-dihydro-4-methylfuro(2,3-d)pyrimidin-2-amine (0.08 g) and 1,4-diazabicyclo[2,2,2]octane (catalytic amount) in acetonitrile (5 mL) was added 0.125M 1-methyl-1H-benzotriazole-4-sulfonylisocyanate in acetonitrile (4.0 mL) under a nitrogen atmosphere. After stirring for 4 hours, the reaction was diluted with water (20 mL) and the precipitate was filtered, washed with water and ether, and dried to give 0.09 g of the title compound as a white solid. m.p. 234°-240° C. with decomposition.
Reaction SMILES: C(N(CC)C(CCCC(NF)C)CC)C.CCN([C:21]1[CH:26]=[CH:25][C:24]2[C:27]3([C:37]4[CH:43]=[C:42](Cl)[CH:41]=[CH:40][C:38]=4[O:39][C:23]=2[CH:22]=1)OC(=O)C1C3=CC=CC=1)CC.CC1C=C2OC3C=C(N4CCCCC4)C=CC=3C3(OC(=O)C4C3=CC=CC=4)C2=CC=1NC1C=CC=CC=1>>[CH:43]1[C:37]2[CH2:27][C:24]3[C:23](=[CH:22][CH:21]=[CH:26][CH:25]=3)[O:39][C:38]=2[CH:40]=[CH:41][CH:42]=1
Reactant: CCN(CC)c1ccc2c(c1)Oc1ccc(Cl)cc1C21OC(=O)c2ccccc21
Agent: CCC(CCCC(C)NF)N(CC)CC
Agent: Cc1cc2c(cc1Nc1ccccc1)C1(OC(=O)c3ccccc31)c1ccc(N3CCCCC3)cc1O2
Product: c1ccc2c(c1)Cc1ccccc1O2

Procedure:
Rhodamine B anilinolactam, Rhodamine B-p-chloroanilinolactam, 3-diethylamino-7-dibenzylamino-fluoran, 3-diethylamino-7-octylaminofluoran, 3-diethylamino-7-phenylfluoran, 3-diethylamino-7-chlorofluoran, 3-diethylamino-6-chloro-7-methylfluoran, 3-diethylamino-7-(3,4-dichloroanilino).=uoran, 3-diethylamino-7-(2-chloroanilino)fluoran, 3-diethylamino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tolyl)amino-6-methyl-7-anilinofluoran, 3-piperidino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tolyl)amino-6-methyl-7-phenethylfluoran, 3-diethylamino-7-(4-nitroanilino)fluoran, 3-dibutylamino-6-methyl-7-anilinofluoran, 3-(N-methyl-N-propyl)amino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-isoamyl)amino-6-methyl-7-anilinofluoran, 3-(N-methyl-N-cyclohexyl)amino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tetrahydrofuryl)-amino-6-methyl-7-anilinofluoran, etc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[Br:10]Br>[Fe].ClCCl>[Br:10][C:7]1[C:2]([Cl:1])=[C:3]([CH3:9])[C:4]([F:8])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: Cc1c(F)cccc1Cl
Agent: [Fe]
Solvent: ClCCl
Product: Cc1c(F)ccc(Br)c1Cl
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
2-chloro-6-fluorotoluene (5.00 g, 34.6 mmol) and iron (0.1 g, 0.17 mmol) was stirred in a 100 mL flask. Bromine (6.08 g, 38.1 mmol) was added slowly in 3 portions with 1 min between each addition. The reaction was stirred for additional 15 min. Then dichloromethane (50 ml) was added, the reaction mixture transferred to a separation funnel and washed with a sodium thiosulphate solution (10%, 30 mL) until it had turned colorless. The layers were separated and the organic layer was washed with sat. sodium hydrogen carbonate (30 mL), dried and evaporated to give the title compound as a colorless oil (7.57 g, 98%) containing 15% 3-bromo-5-chloro-2-fluorotoluene (calc. by 1H-NMR). The compound was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:34][CH3:35])[C:16]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C1COCC1.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:16]2[C:15]([O:34][CH3:35])=[CH:14][CH:13]=[C:12]3[C:17]=2[CH2:18][CH:19]([C:20]([O:22][CH3:23])=[O:21])[N:10]([C:8](=[O:9])[CH:7]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11]3)=[CH:26][CH:27]=1
Reactant: COC(=O)C1Cc2c(ccc(OC)c2Oc2ccc([N+](=O)[O-])cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1Cc2c(ccc(OC)c2Oc2ccc(N)cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 0.80 g (1.45 mmole) of the nitrobenzene derivative of Example 43 in 50% methanol-THF is reduced with 5% palladium-on-carbon catalyst. The filtered solution is concentrated at reduced pressure to give 0.75 g of pure product as a solid foam; mass spectrum (EI) 522 (M+) .
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[Li][CH2:12]CCC.CI>C(OCC)C>[CH2:1]([C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1)[CH3:12]
Reactant: Cc1cc2cccnc2[nH]1
Reactant: [Li]CCCC
Solvent: CI
Solvent: CCOCC
Product: CCc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-methyl-7-azaindole (1.32 g, 10 mmol) in dry diethyl ether (60 ml) at room temperature under an inert atmosphere is added n-BuLi (18.8 ml of a 1.6 M solution in hexanes, 30 mmol) followed by f-BuOK (2.24 g, 20 mmol). The reaction mixture is stirred at room temperature for 40 minutes and then cooled to −70° C. whereupon methyl iodide (1.25 ml, 20 mmol) is added dropwise. Stirring continues for a further 2 hours after which time, the reaction mixture is quenched with water (2 ml) and is allowed to slowly warm to room temperature. The cooled solution is poured onto water (200 ml), neutralized with 1N HCl and then extracted with diethyl ether (80 ml). The organic portion is washed with water (2×60 ml), dried (Na2SO4) and concentrated in vacuo to yield the titled compound as orange crystals. [MH+CH3CN]+=188)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10]=[O:11].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.Cl>C(#N)C>[OH:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH:10]=[O:11]
Reactant: C=O
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C=O)c(O)c1
Yield: 84.5 %

Procedure:
A mixed solution of 3,5-dimethylphenol (20.0 g, 164 mmol), paraformaldehyde (14.8 g, 492 mmol), magnesium chloride (23.4 g, 246 mmol) and triethylamine (80 mL, 573 mmol) in acetonitrile (500 mL) was heated under reflux for 4 hours. The reaction solution was acidified with hydrochloric acid, which was extracted with diethyl ether. The organic layer was washed with a saturated sodium hydrogen carbonate solution and a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 20.8 g (yield 84%) of the title compound. Melting point: 48-49° C. (hexane).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:23]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:22]=[CH:21][CH:20]=4)[CH:17]=3)[C:12]([CH2:30][CH3:31])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]2[C:19]([C:16]3[CH:17]=[C:18]4[C:13]([C:12]([CH2:30][CH3:31])=[N:11][N:10]4[CH:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)=[CH:14][CH:15]=3)=[CH:20][CH:21]=[N:22]2)[CH2:25][CH2:26]1)(=[O:3])[CH3:2]
Reactant: CCc1nn(C2CCCC2)c2cc(-c3ccnn3C3CCNCC3)ccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nn(C2CCCC2)c2cc(-c3ccnn3C3CCN(C(C)=O)CC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
Acetyl chloride (7.8 μL, 0.11 mmol) was slowly added to a mixture of 1-cyclopentyl-3-ethyl-6-(1-piperidin-4-yl-1H-pyrazol-5-yl)-1H-indazole (20 mg, 0.055 mmol), triethylamine (15 μL, 0.11 mmol) in methylene chloride (2 mL), and the reaction was stirred for 16 hours at room temperature. Methylene chloride was added and the organic layer was washed with saturated sodium bicarbonate, water, then brine, dried, filtered and concentrated. The residue was dissolved in ethyl acetate and purified by silica gel column chromatography using 100% ethyl acetate as the eluent to afford 18 mg (81%) of 6-[1-(1-acetylpiperidin-4-yl)-1H-pyrazol-5-yl]-1-cyclopentyl-3-ethyl-1H-indazole. LC/MS (EI) tR 4.29 (Method C), m/z 406.3 (M++1).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([N:12]([CH2:14][C:15](O)=[O:16])[CH3:13])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(=O)(O)[O-].[Na+].O>C(O)C>[C:8]([O:7][C:5](=[O:6])[N:12]([CH2:14][C:15](=[O:16])[NH:4][CH2:1][CH:2]=[CH2:3])[CH3:13])([CH3:11])([CH3:9])[CH3:10]
Reactant: C=CCN
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCNC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
Allylamine (0.377 ml, 5.03 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) (1.89 g, 6.04 mmol) were added to a solution of Boc-sarcosine (1.0 g, 5.29 mmol) in ethanol, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction solution, followed by extraction with ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give allylcarbamoylmethyl-methyl-carbamic acid tert-butyl ester (712 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[N:4]=1)[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:44](C)=O.[Na+]>C(Cl)Cl.CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][CH:27]4[CH2:31][CH2:30][N:29]([CH3:44])[CH2:28]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[N:4]=1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NC5CCNC5)ccn34)c12
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NC5CCN(C)C5)ccn34)c12
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To N3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-N7-(pyrrolidin-3-yl)imidazo[1,2-a]pyridine-3,7-dicarboxamide (5 mg, 0.0096 mmol; prepared as in Example 46) in DCM/MeOH (1 mL/1 mL) was added HCHO as a 35% aqueous solution (16 mg, 0.19 mmol) and NaBH(OAc)3 (10 mg, 0.048 mmol). The reaction mixture was stirred for one hour, concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (4 mg). MS (ES+APCI) m/z=537 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:11]([O:13]CC)=[O:12])=[CH:6][CH:5]=1.[CH3:23]I>CN(C=O)C.CCOC(C)=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)([CH3:23])[C:11]([OH:13])=[O:12])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C(=O)O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
A solution of NaH (60% dispersion in mineral oil) (2.1 g, 53 mmol) in DMF (100 mL) in a 500 mL round bottom flask was cooled 0° C. A solution of ethyl 2,2-bis(4-chlorophenyl)acetate (5.47 g, 18 mmol) and MeI (3.3 mL, 53 mmol) in DMF (50 mL) was added dropwise over 15 minutes. The mixture was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stirred for 20 hours. A mixture of products was observed by LC/MS. The solution was diluted with EtOAc (200 mL), and then washed with 10% HCl(aq) (200 mL), with deionized water (200 mL), and then with brine (100 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give 10.11 g crude product which was purified by flash column chromatography (silica, 0-100%, hexane/EtOAc) to give 2,2-bis(4-chlorophenyl)propanoic acid (3.05 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH2:17]Cl)[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>ClC(Cl)CCl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:25])[Cl:26])=[O:21])=[C:15]([CH3:19])[CH2:17][S:16][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCC(Cl)Cl
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 25.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2-methyl-2-chloromethylpenam-3-carboxylate (0.50 g.) in 1,1,2-trichloroethane (7 cc) and pyridine (0.16 g.) was heated under reflux for 3.5 hours. After cooling, the reaction mixture was washed with water, dried and then concentrated under reduced pressure. The residue was subjected to chromatography on silica gel and eluated with chloroform. The eluate was concentrated and the residue was crystallized with ether to yield crystals (0.12 g.) of 2,2,2-trichloroethyl 7-(2-phenylacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 161°-162° C.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[O:16][C:15]([C:17]2[S:21][C:20]([CH2:22][N:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:14][N:13]=1>N1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[O:16][C:15]([C:17]2[S:21][C:20]([CH2:22][N:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:14][N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1nnc(-c2ccc(CN3CCCCCC3)s2)o1
Solvent: c1ccncc1
Product: O=C(NCc1ccccc1)Nc1nnc(-c2ccc(CN3CCCCCC3)s2)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
0.14 ml (1.1 mmol) of benzyl isocyanate was added to 20 ml of pyridine solution containing 278 mg (1.0 mmol) of the compound of Example 43, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under a reduced pressure, and the resulting residue was subjected to a silica gel column chromatography, which was eluted with chloroform-methanol (50:1) to give 406 mg of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]=[CH:8]1.[Br:18]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:18][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:16])([CH3:17])[CH3:1])[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]=1
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Temperature: 60 °C
Yield: 43.6 %

Procedure:
To a stirred solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (5.0 g, 19.5 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (3.47 g, 19.5 mmol) and AIBN (160 mg, 5 mol %) at room temperature. The reaction mixture was heated at 60° C. for 3 h, cooled to room temperature, and filtered through a small pad of CELITE®. The filtrate was concentrated in vacuo to give light yellow colored residue which was dissolved in EtOAc and washed with 10% NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated to give crude compound. The crude material was purified by flash chromatography (gradient from 20 to 30% EtOAc/hexanes), to provide the title compound (2.85 g, 43%). 1H NMR (CDCl3) δ 7.76 (s, 1H), 5.30 (s, 2H), 3.90 (s, 3H), 3.55 (t, J=8.0 Hz, 2H), 0.92 (t, J=8.0 Hz, 2H), 0.01 (s, 9H); MS(ESI+) m/z 335.0 (M+H)+.