Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([CH2:29][CH2:30]O)[C:16]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Br:2][CH2:30][CH2:29][C:17]1[C:16]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=2)[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=1
Reactant: CCOC(=O)c1c(CCO)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(CCBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
Phosphorus tribromide (1.0 g) was added dropwise to a solution of ethyl 4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)-6,7-dimethoxyquinoline-3-carboxylate (1.7 g) in benzene (50 ml) at room temperature. The mixture was stirred at 80° C. for 1 hour, poured into ice-cold water, neutralized with an aqueous saturated solution of sodium bicarbonate, and then extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (1:1, v/v) gave ethyl 2-(2-bromoethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (0.49 g, 26%). This was recrystallized from ethyl acetate-hexane. Colorless prisms, mp. 132°-133° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>N1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=2[F:24])[O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[O:34])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 70 °C
Reaction time: 12 h
Yield: 68.3 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol) produced in Example 16(vi) was dissolved in pyridine (3.0 ml), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (145 mg, 0.65 mmol) was added, and the mixture was stirred at 70° C. for 12 hr. 1-Chloro-4-isocyanato-2-(trifluoromethyl)benzene (70 mg, 0.32 mmol) was added to the reaction mixture, and the mixture was further stirred at 70° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and tetrahydrofuran (1 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (5 mL), and the suspension was stirred at room temperature for 10 min. The solid was collected by filtration, and washed successively with ethyl acetate and n-hexane to give the title compound (170 mg, 70%) as a colorless powder.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH2:5][CH2:6][CH3:7].C[O-].[Na+]>CO>[CH2:5]([CH:4]1[NH:8][S:9](=[O:11])(=[O:10])[NH:12][C:3]1=[O:2])[CH2:6][CH3:7]
Reactant: CCCC(NS(N)(=O)=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC1NS(=O)(=O)NC1=O
Yield: 105.7 %

Procedure:
A solution of 2-(aminosulfonylamino)pentanoic acid methyl ester (24.6 g, 0.11 mol) in methanol (150 ml) was added to a solution of sodium methoxide (8.86 g, 0.164 mol) in 150 ml of methanol and the resulting reaction mixture was refluxed for 18 hours. The mixture was cooled, neutralized with BIO-RAD® 50W-X8 H+ ion exchange resin, and filtered. The filtrate was concentrated in vacuo to yield an oil which was crystallized from methanol/hexane to afford 20.73 g (theory) of 4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =propyl; R2 =R3 =H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[C:9](OCC)(=[O:13])[C:10]([NH2:12])=[O:11].O.Cl>O1CCCC1.C(O)C>[Cl:1][C:2]1[C:3]([Cl:8])=[CH:4][CH:5]=[CH:6][C:7]=1[C:9](=[O:13])[C:10]([NH2:12])=[O:11]
Reactant: CCOC(=O)C(N)=O
Reactant: Clc1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)C(=O)c1cccc(Cl)c1Cl
Temperature: -60 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
n-Butyl chloride (55.5 g, 0.6 mol) was added dropwise to a stirred suspension of lithium slices (8.30 g, 1.2 mol) in dried ether (300 ml) under N2 so as to maintain gentle reflux. After heating under reflux for a further 33/4 hours the mixture was cooled to room temperature and stirred overnight. (Previous analyses indicate that this procedure affords a 66% yield of butyl lithium (≡0.4 mol). The mixture was then cooled to -60° C. and held at this temperature during the following operations. Dried tetrahydrofuran (400 ml) was added, then a solution of 1,2-dichlorobenzene (58.8 g, 0.4 mol) in dried tetrahydrofuran (300 ml) was added dropwise over 40 mins. After stirring the mixture for 1 hour a solution of ethyl oxamate 23.4 g, 0.2 mol) in warm tetrahydrofuran (300 ml) was added dropwise over 1 hour and the mixture stirred for a further 1 hour at -60° C. After allowing to warm to 0° C., water (300 ml) was added cautiously and the mixture acidified to pH 6 within hydrochloric acid. The yellow organic phase was separated, washed with brine (2×300 ml), dried (magnesium sulphate) and evaporated to give a pale yellow solid. This was slurried with ethanol (250 ml), filtered and dried to give crude 2,3-dichlorophenylglyoxylamide (22.5 g, 52%) m.p. 214-215° C. (ref. 215-218° C.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[N:4]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[N:4]=1
Reactant: ClCc1cccc(SCC2CC2)n1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Product: O=C(O)CCc1ccc(OCc2cccc(SCC3CC3)n2)c(Cl)c1
Yield: 63.5 %

Procedure:
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (43 mg, 0.20 mmol) obtained in Step D of Preparation Example 20 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (51 mg, 0.22 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (48 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:9]=1[C:24](OCC)=[O:25]>C1(C)C=CC=CC=1>[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][C:9]=1[C:24]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:25]
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Nc1nccs1
Solvent: Cc1ccccc1
Product: O=C(Nc1nccs1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Yield: 67.1 %

Procedure:
A solution of 4.08 g of 2-aminothiazole and 8.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 250 ml of toluene was refluxed for 30 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 1:25 ethyl acetate-dichloromethane as the eluent). The resulant solution was degassed and evaporated. Recrystallization of the residue from diethyl ether yielded 6.35 g (67%) of 1,2-dihydro-4-hydroxy-1-phenyl-N-(2-thiazolyl)-3-quinolinecarboxamide, m.p. 220° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C([O:12][C:13](=[O:31])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1/[CH:23]=[C:24]1/[C:25](=[O:30])[NH:26][C:27](=[O:29])[S:28]/1)C>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([OH:31])=[O:12])=[C:17]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:25]2=[O:30])[CH:18]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1/C=C1\SC(=O)NC1=O
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(CN2C(=O)SC(Cc3cc(Br)ccc3OCC(=O)O)C2=O)cc1

Procedure:
Prepared from 4-methylbenzylbromide and 4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acid ethyl ester according to GP13, GP14 and GP16 (yield: 14 mg, 21%): LC/MS (an10p8): Rt 2.5 min, m/z 462 [M−H]−. 1H NMR (DMSO-d6): δ 2.98-3.07 (m, 1H), 3.53-3.59 (m, 1H), 4.63 (s, 2H), 4.74 (s, 2H), 5.07-5.13 (m, 1H), 6.89-6.91 (m, 1H), 7.11-7.16 (m, 4H), 7.38-7.43 (m, 2H), 13.11 (br s, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][N:37]([C:34](=[O:36])[CH3:35])[CH2:38][CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1CCNCC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: CC(=O)N1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 1-acetylpiperazine. A yellow solid 125 was obtained (0.010 g, 19%). 1H-NMR (CDCl3, 400 MHz) δ 2.17 (s, 3H), 3.67–3.72 (m, 2H), 3.73–3.77 (m, 2H), 3.83–3.88 (m, 2H), 3.94–3.98 (m, 2H), 4.28–4.34 (m, 4H), 6.93 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.02 (d, J=5.8 Hz, 1H), 7.05 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.83 (s, 1H), 8.29 (d, J=6.2 Hz, 1H); MS (APCI) m/z 516 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:8][CH:7]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc2c[nH]c3ccccc23)cc1
Yield: 70.5 %

Procedure:
A solution of 3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester (12.6 g, 37.7 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (12.8 g, 53.6 mmol), (i-Pr)2NEt, (7.42 g, 57.4 mmol) in DMSO (100 mL) is heated to 50° C. After 8 hours the mixture is partitioned with CH2Cl2/H2O. The organic layer is dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel to produce 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (13.1 g). A solution of KOH (12.9 g (87% pure), 0.2 mol) in MeOH (100 mL) is added to a solution of HONH2.HCl (13.9 g, 0.2 mol) in MeOH (200 mL) and a precipitate results. After 15 minutes the mixture is filtered, the filter cake washed with MeOH and the filtrate evaporated under vacuum to approximately 75 mL. The mixture is filtered and the volume adjusted to 100 mL with MeOH. The resulting solution 2M HONH2 is stored under N2 at −20° C. for up to 2 weeks. Then 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (5.4 g, 11 mmol) is added to 2 M HONH2 in MeOH (90 mL, 180 mmol) followed by a solution of KOH (720 mg (87% pure), 11.2 mmol) in MeOH (5 mL) and the mixture stirred overnight. Dry ice is added to the reaction and the mixture diluted with H2O resulting in the formation of a precipitate. The liquid was decanted and the solid was dissolved in MeOH and filtered. The filtrate is evaporated to afford N-hydroxy-3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}methyl)-phenyl]-(2E)-2-propenamide (5.1 g,) which is used without further purification. The hydroxamic acid (5.0 g, 13.3 mmol) is then dissolved in 95% TFA/H2O (59 mL) and heated to 40-50° C. for 4 hours. The mixture is evaporated and the residue purified by reverse phase HPLC to produce N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide as the trifluoroacetate salt (m/z 380 [MH+]).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:41])[C:12](=[CH:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:42]>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:41])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:42]
Reactant: Cc1c2n(c3ccc(Cl)cc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CC1CCc2c(C)c3cc(Cl)ccc3n2C1=O
Yield: 91.2 %

Procedure:
To a solution of 2-chloro-8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (0.95 g) in acetic acid (47.5 ml) was added zinc powder (1.09 g) and the mixture was refluxed for 2.5 hours. The resulting precipitates were filtered off, and the filtrate was evaporated in vacuo. The residue was diluted in chloroform, washed with aqueous sodium bicarbonate, solution, water, and brine, dried over sodium sulfate, and chromatographed on silica gel eluted by chloroform-methanol (0-5% V/V), to give 2-chloro-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.50 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[C:11]([O:13]C)=[O:12].[OH-].[Na+].O.CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C1CC1c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CC1c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-(2-fluorophenyl)cyclopropanecarboxylate (4.8 g, 24.72 mmol) in tetrahydrofuran (25 mL), was added 10 M sodium hydroxide solution (approximately 2 mL), a small amount of water, and sufficient methanol to achieve a homogeneous reaction mixture. The reaction mixture was then allowed to stir at rt for approximately 2 h. After concentrating the reaction mixture, 1N HCl was added until the mixture was acidic. The organic layer was extracted twice with ethyl acetate, then washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the title compound. M.S. (M+1): 181.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.[Br:14][C:15]1[C:22]([F:23])=[CH:21][C:18]([CH2:19]Br)=[C:17]([F:24])[CH:16]=1>>[CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[C@@H:7]([CH2:19][C:18]2[CH:21]=[C:22]([F:23])[C:15]([Br:14])=[CH:16][C:17]=2[F:24])[N:8]=1
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1
Reactant: Fc1cc(CBr)c(F)cc1Br
Product: COC1=N[C@H](Cc2cc(F)c(Br)cc2F)C(OC)=N[C@H]1C(C)C
Yield: 88 %

Procedure:
The title compound (1.61 g) was prepared from 0.865 g (4.7 mmol) of (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine and 1.5 g (5.2 mmol) of 4-bromo-2,5-difluorobenzyl bromide using the procedure described for Intermediate 2, Step A. 1H NMR (400 MHz, CDCl3) δ 7.21 (m, 1H), 6.97 (m, 1H), 4.25 (m, 1H), 3.78 (s, 3H), 3.70–3.64 (m, 4H), 3.25–3.18 (m, 1H), 2.96–2.90 (m, 1H), 2.25–2.16 (m, 1H), 1.01 (d, 3H, J=8 Hz), 0.65 (d, 3H, J=8 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH2:20])[C:18](=[O:21])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.C(Cl)Cl.[N:25]([CH2:28][CH2:29][O:30][N:31]=[C:32]([C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)[C:33](O)=[O:34])=[N+:26]=[N-:27].ON1C2C=CC=CC=2N=N1.Cl>O.C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:33](=[O:34])[C:32]([C:36]4[N:37]=[C:38]([NH:41][C:42]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)([C:55]5[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=5)[C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[S:39][CH:40]=4)=[N:31][O:30][CH2:29][CH2:28][N:25]=[N+:26]=[N-:27])[C:18](=[O:21])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: [N-]=[N+]=NCCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.652 g of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7-amino-ceph-3-eme-4-carboxylic acid, 6.5 ml of methylene chloride and 0.56 ml of triethylamine was stirred at room temperature for 15 minutes and then 1.29 g of 1-hydroxy-1H-benzotriazole 2-(2-azidoethoxyimino)-2-(2-tritylamino-4-thiazolyl)-acetate were added thereto. The mixture was stirred at room temperature for 20 hours and then 10 ml of water and 3 ml of 2 N hydrochloric acid were added thereto. The decanted organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was taken up in 5 ml of ethyl acetate and 10 ml of ether were added thereto. The mixture was stirred for 30 minutes at room temperature and was vacuum filtered to obtain 1.416 g of raw syn isomer of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]#[CH:22])[CH:18]=[CH:19][CH:20]=1>CO>[C:21]([C:17]1[CH:16]=[C:15]([NH:14][C:2]2[C:3]3[C:10]([C:11]([OH:13])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:20]=[CH:19][CH:18]=1)#[CH:22]
Reactant: O=C(O)c1c[nH]c2ncnc(Cl)c12
Reactant: C#Cc1cccc(N)c1
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3[nH]cc(C(=O)O)c23)c1
Temperature: 125 °C
Yield: 56.7 %

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (0.38 g, 1.9 mmol) in dry methanol (4ml) was added m-aminophenyl acetylene (0.47 g, 4.0 mmol). The suspension was heated in a sealed pressure tube at 125° C. for 18 hours. The reaction mixture was cooled to ambient temperature, filtered with methylene chloride washes and dried in vacuo to afford the title compound as a tan powder (0.30 g, 54%). TS-MS: 278 (MH+); anal. RP18-HPLC RT: min.
Reaction SMILES: C[O:2][CH:3]1[CH2:35][C:7]2[NH:8][C:9]([C:11]3[C:12]([CH3:34])=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])=[N:10][C:6]=2[CH2:5][CH2:4]1.C(#N)C.Cl[Si](Cl)(Cl)Cl.[I-].[Na+]>ClCCl>[OH:2][CH:3]1[CH2:35][C:7]2[NH:8][C:9]([C:11]3[C:12]([CH3:34])=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)=[O:17])=[N:10][C:6]=2[CH2:5][CH2:4]1
Reactant: COC1CCc2nc(-c3cc(C(=O)N4CCC(c5ccc(C#N)cc5)CC4)c(C)cc3C)[nH]c2C1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc(C)c(-c2nc3c([nH]2)CC(O)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
Into around-bottom flask, was placed a solution of 4-(1-(5-(6-methoxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 459, 80 mg, 0.17 mmol, 1.0 equiv) in a solvent mixture of acetonitrile and dichloromethane (10/10 mL). Tetrachlorosilane (32 mg, 0.19 mmol, 1.1 equiv) and sodium iodide (28 mg, 0.19 mmol, 1.1 equiv) were added to the reaction and the resulting mixture was stirred overnight at 20° C. The reaction was quenched with aqueous sodium bicarbonate (10 mL) and the aqueous was extracted with ethyl acetate (3×10 mL). The combined organics was dried (Na2SO4), filtered and concentrated in vacuo and the residue was purified by silica gel chromatography with ethyl acetate as the eluent to obtain the title compound as a yellow solid (7.1 mg, 9%). m/z (ES+) 455 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].[CH3:36]O>>[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:6]([N:8]3[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]3[C:16]([O:18][CH3:36])=[O:17])=[O:7])=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CO
Reactant: O=C(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccc(Cl)c(Cl)c3)cc2)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid, and methanol, the title compound was isolated as a mixture of two isomers in 91.9% purity by HPLC.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28]>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: NCCc1ccccn1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccccn3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (2-pyridin-2-yl-ethyl)-amine to afford the title compound. MS: m/e=363 (M+H).