Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O1CCCC1.[Cl-].[NH4+]>[Fe].C(O)C>[NH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([I:1])[CH:9]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc(N)cc1I
Yield: 96.8 %

Procedure:
A mixture of compound 489B (4.60 g, 16.8 mmol), tetrahydrofuran (75 mL), ethanol (100 mL), ammonium chloride solution (1.51 g, 28.3 mmol, dissolved in 100 mL of water), and iron (325 mesh, 4.21 g, 75.4 mmol) was mechanically stirred. The reaction mixture was heated to reflux for 3 h or until all starting material was consumed. The reaction mixture was cooled, filtered through Celite and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with 1N sodium hydroxide (2×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield 3.97 g (97%) of compound 489C as a dark solid. HPLC: 95% at 1.877 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 245.13 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[C:16](=O)[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]1)=O.[CH3:25][C:26]1[N:27]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH2:40])=[NH:39])=[CH:33][CH:32]=2)[CH:28]=[CH:29][N:30]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[C:11]2[CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15][C:16]=2[N:40]=[C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([N:27]3[CH:28]=[CH:29][N:30]=[C:26]3[CH3:25])=[CH:32][CH:33]=2)[N:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)Cc2ccccc2F)C1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 130 °C

Procedure:
tert-Butyl 3-(2-(2-fluorophenyl)acetyl)-4-oxopiperidine-1-carboxylate, (0.88 mmol) together with 1 eq 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine and 2 eq of potassium carbonate were slurrified in 4 ml EtOH. The reactions were heated in the microwave oven to 130° C. for 3 h. DCM and water were added and the organic phases were separated, dried with MgSO4 and the solvent was removed under reduced pressure tert-butyl 4-(2-fluorobenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (292 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([N:17]3[CH:21]=[CH:20][C:19]([CH3:22])=[N:18]3)=[C:12]([C:14]([OH:16])=O)[CH:13]=2)[CH:5]=[N:6][CH:7]=1.[CH3:23][N:24]1[C:33]2[C:28](=[CH:29][C:30]([CH2:34][NH2:35])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1.CCCP(O)(O)=O.CCN(C(C)C)C(C)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([N:17]3[CH:21]=[CH:20][C:19]([CH3:22])=[N:18]3)=[C:12]([C:14]([NH:35][CH2:34][C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[N:24]([CH3:23])[CH2:25][CH2:26][CH2:27]4)=[O:16])[CH:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN1CCCc2cc(CN)ccc21
Reactant: Cc1cncc(-c2cnc(-n3ccc(C)n3)c(C(=O)O)c2)c1
Agent: CCCP(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cncc(-c2cnc(-n3ccc(C)n3)c(C(=O)NCc3ccc4c(c3)CCCN4C)c2)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxylic acid (5-2, 0.025 g, 0.085 mmol) and 1-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methanamine (0.015 g, 0.085 mmol) in ACN (0.85 mL) was added 1-propylphosphonic acid cyclic anhydride (T3P, 0.15 mL, 0.255 mmol) followed by Hunig's base (0.089 mL, 0.51 mmol) and the system was stirred at 40° C. for 1 h in an oil bath. The reaction mixture was cooled and partitioned between EtOAc and water, washed with saturated sodium bicarbonate and dried over magnesium sulfate. The reaction mixture was filtered, concentrated and purified via normal phase chromatography (0→10% MeOH in EtOAc) to afford the title compound (5-3) as a bone powder. 1H NMR (500 MHz, CDCl3) δ 8.68 (m, 1H), 8.51 (m, 1H), 8.29 (m, 1H), 8.22 (m, 1H), 7.72 (m, 1H), 7.12 (m, 1H), 7.0 (m, 1H), 6.90 (m, 1H), 6.54 (m, 1H), 6.27 (m, 1H), 4.46 (m, 2H), 3.22(m, 2H), 2.88 (s, 3H), 2.74 (m, 2H), 2.44 (s, 3H), 2.28 (s, 3H), 1.97 (m, 2H). HRMS [M+H] C27H28N6O calc'd 453.2391, found 453.2397.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)=[CH:12][C:11]([C:25](O)=[O:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:23])([F:22])[F:24])[CH:15]=3)=[CH:12][C:11]([C:25]([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=[O:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(OC(F)(F)F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 78A in analogy to the synthesis of the compound of Example 1. 53 mg (91% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=O)[CH:4]=[C:5]([CH3:7])[N:6]=1.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[Li]>>[C:23]([O:22][C:19](=[O:21])[CH2:20][C:11]([C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([N:3]2[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]2[CH3:1])[CH:9]=1)=[O:13])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cccc(-n2cc(C)nc2C)c1
Agent: [Li]
Product: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)n1

Procedure:
Prepared from ethyl 3-(2,4-dimethyl-imidazol-1-yl)-benzoate [prepared by reaction of ethyl 3-aminobenzoate with ethyl acetimidate hydrochloride in EtOH at 0° C., direct treatment with 2-aminopropionaldehyde dimethyl acetal in EtOH at 23° C., follwed by addition of conc. H2SO4 and refluxing.] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a yellow-brown oil (6.00 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:20])[N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
6-Amino-9-benzyl-2-methylthiopurine (100 mg, 0.37 mmol) and bromine (0.5 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 3 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (10 mg, yield 8%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=1)=[CH:10][C:9]([NH:27][C:28](=[O:35])/[CH:29]=[CH:30]/CN(C)C)=[CH:8][CH:7]=2)#[N:2].C(N(CC)CC)C.C(Cl)(=O)C=C.NC1C=C2C(=CC=1)N=CC(C#N)=C2NC1C=CC(OC2C=CC=CC=2)=CC=1>C1COCC1.O>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=1)=[CH:10][C:9]([NH:27][C:28](=[O:35])[CH:29]=[CH2:30])=[CH:8][CH:7]=2)#[N:2]
Reactant: CN(C)C/C=C/C(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1
Agent: C=CC(=O)Cl
Agent: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Example 3 was prepared as an off-white solid using a procedure similar to that described for the synthesis of compound 21 (Example 2). Triethylamine (1.03 g, 10.2 mmol, 1.2 eq) and acryloyl chloride (926 mg, 10.2 mmol, 1.2 eq) were added to an ice cold solution of 6-amino-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile (3.0 g, 8.5 mmol, 1.0 eq) in THF (50 mL) under nitrogen. The reaction was stirred at rt for 2 hours. The water was added. The water layer was extracted with EA, dried over anhydrous sodium sulfate. The crude product was purified by column chromatography on silica gel to give N-(3-cyano-4-((4-phenoxyphenyl)amino)quinolin-6-yl)acrylamide as an off-white solid 1.2 g.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33]1[C:42]([OH:43])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH:35]=[CH:36][N:37]=[CH:38]2.[C:44]([O:48][C:49](=[O:58])[NH:50][C@H:51]1[CH2:56][CH2:55][C@H:54](O)[CH2:53][CH2:52]1)([CH3:47])([CH3:46])[CH3:45].C(N(CC)CC)C>ClCCl>[C:44]([O:48][C:49](=[O:58])[NH:50][C@H:51]1[CH2:52][CH2:53][C@@H:54]([O:43][C:42]2[C:33]([Br:32])=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH:38]=[N:37][CH:36]=[CH:35]3)[CH2:55][CH2:56]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: Oc1ccc2cnccc2c1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3cnccc3c2Br)CC1
Reaction time: 0.25 h
Yield: 23.9 %

Procedure:
4.33 mL (5.75 g, 33 mmol) of diethyl azo dicarboxylate were added to 18 g (68.75 mmol) of triphenylphosphine in 500 mL of dichloromethane at 0° C. and stirred for 15 min. 6.16 g (27.5 mmol) 5-bromo-isoquinolin-6-ol (2), 5.92 g (27.5 mmol) (trans-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester and 3.81 mL (33 mmol) triethyl amine were added. The mixture was stirred for 4 days. The precipitate was removed by filtration, washed with dichloromethane and the solvents were distilled off. The crude product was purified by flash chromatography using ethyl acetate/n-heptane as eluent to give 2.77 g (24%) of 85. Rt=1.37 min (Method #1). Detected mass: 421.1/423.1 (M+H+).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][CH:9]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)C=CC=CC=1.[ClH:39]>CC(C)=O>[ClH:39].[O:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[NH2:8])=[N:17]1
Reactant: Fc1ccc(CC(N=C(c2ccccc2)c2ccccc2)c2ccccc2-c2noc3ccccc23)cc1
Agent: Cl
Solvent: CC(C)=O
Product: NC(Cc1ccc(F)cc1)c1ccccc1-c1noc2ccccc12
Reaction time: 8 h

Procedure:
To a stirred suspension of 2.23 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde and 2.6 g of magnesium sulfate in 25 ml of methylene chloride was added 1.7 ml of diphenylmethanamine and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give 3.9 g crude N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine as a gum which slowly solidified. A stirred solution of 0.75 g of N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine in 15 ml tetrahydrofuran was cooled to −65° C. and 2.5 ml of a 1M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 5 min then 4-fluorobenzyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction was diluted with 25 ml of water then extracted with 100 ml then 50 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate then evaporated to give 1.18 g of crude N-(diphenylmethylidene)-2-(1,2-Benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine which was not characterised due to instability. To a solution of 1.1 g of N-(diphenylmethylidene)-2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine in 20 ml of acetone was added 9 ml of 1M hydrochloric acid. The solution was stirred overnight then evaporated and 15 ml of 4M sodium hydroxide solution added. The solution was extracted with 100 ml then 50 ml of methylene chloride. The organic extracts were dried and evaporated to an oil which was purified by flash chromatography eluting with a 19:1 mixture of methylene chloride-methanol to yield the pure amine free base which was dissolved in methanol and acidified with a solution of hydrogen chloride in methanol, evaporated and crystallised from methanol-ether to yield 0.18 g of 2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine hydrochloride, melting at 238-241° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl>[C:13]1([CH2:12][CH2:11][NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Yield: 97.5 %

Procedure:
1-Chloro-2-nitrobenzene (2 g, 12.7 mmol), phenethylamine (5.1 mL, 40.6 mmol), and N,N-diispropylethylamine (2.8 mL, 15.3 mmol) were dissolved in 1,2-dichloroethane (20 mL) and heated at reflux for 16 hrs. The mixture was concentrated to an oil which was dissolved in EtOAc (200 mL), washed with dilute HCl (3×50 mL), dried over Na2SO4, filtered and concentrated to dryness to give the title compound (3.0g, 97%): 1H NMR (400 MHz, CDCl3) δ 3.0-3.1 (2H, t), 3.5-3.65 (2H, q), 6.65-6.7 (1H, t), 6.85-6.9 (1H, d), 7.25-7.4 (5H, m), 7.45-7.5 (1H, t), 8.15-8.2 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:17]=3)[C:12]=2[NH:28][C:29]([C@H:31]2[CH2:36][CH2:35][C@H:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][C:38]3=[O:43])[CH2:33][CH2:32]2)=[O:30])=[O:10])=[N:6][CH:7]=1.Cl.O1CCOCC1>CO>[ClH:1].[NH2:20][C:15]1[N:14]=[C:13]2[C:12]([NH:28][C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][C:38]4=[O:43])[CH2:33][CH2:32]3)=[O:30])=[C:11]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[O:19][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCOCC4=O)CC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCOCC4=O)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl [2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridin-5-yl]carbamate (5.55 g) obtained in Example 94 is suspended in methanol (20 ml), and thereto is added 4N hydrogen chloride-dioxane solution (50 ml) under ice-cooling. The mixture is stirred at room temperature for 8 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is suspended in diethyl ether. The precipitates are collected by filtration to give the title compound (4.67 g).
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]O)(=[O:8])[CH3:7]>C(Cl)Cl.CCOC(C)=O.CO>[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][Cl:5])(=[O:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1cccc(CO)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulphonyl chloride (0.15 ml) was added to a stirred solution of 3-acetylaminobenzylalcohol (260 mg) and TEA (0.26 ml) in DCM (2 ml) at 0° C. The reaction was allowed to warm to room temperature and stirred for two hours. The mixture was diluted with EtOAc (20 mL) and MeOH (1 ml) and stirred for 5 minutes. The mixture was then washed with water (30 ml), organic layer was dried over sodium sulphate and solvent evaporated. The residue was columned on silica gel using DCM then ethyl acetate as eluant to give 3-acetylaminobenzylchloride (210 mg). 1H NMR (CDCl3) δ: 7.59 (s, 1H), 7.41 (d, 1H), 7.31 (t, 1H), 7.14 (d, 1H), 4.56 (s, 2H), 2.18 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](C3CCCCO3)[N:13]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCCC1.CO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2ncn(C3CCCCO3)n2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2nnc[nH]2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 18.8 %

Procedure:
To a 20 mL vial was added a solution of 4-{4-(4-chlorobenzyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyridine (0.2245 g, 0.635 mmol) in anhydrous tetrahydrofuran (2.000 mL) and methanol (2.000 mL). 4.0 M Hydrochloric acid in 1,4-dioxane (1.0 mL, 4.0 mmol) was added and the reaction mixture was allowed to stir at 50° C. for 18 hours. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by HPLC to afford the product (0.0423 g, 45%) as an off white solid. LC/MS (AA) ES+ 354. 1H NMR (400 MHz, d6-DMSO) δ: 14.48 (s, 1H), 8.71 (dd, J=4.4, 1.2 Hz, 2H), 7.89-7.87 (m, 2H), 7.38-7.32 (m, 4H), 4.67 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[O:28][CH2:29][CH2:30][OH:31])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[O:28][CH2:29][CH2:30][O:31][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:35][CH:36]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCO)c3)cc2)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CI
Product: CCOC(=O)COCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 92B and ethyl iodoacetate were processed as described in Example 116A to provide the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[NH2:16][C:17]1[S:21][N:20]=[C:19]([C:22](=[N:53][O:54][CH2:55][C:56]([OH:58])=[O:57])[C:23]([NH:25][C@@H:26]2[C:51](=[O:52])[N:28]3[C:29]([C:35]([O:37]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:36])=[C:30]([CH2:33][Cl:34])[CH2:31][S:32][C@H:27]23)=[O:24])[N:18]=1.C(OC(C)C)(C)C>C(Cl)Cl.CCCCCC>[NH2:16][C:17]1[S:21][N:20]=[C:19]([C:22](=[N:53][O:54][CH2:55][C:56]([OH:58])=[O:57])[C:23]([NH:25][C@@H:26]2[C:51](=[O:52])[N:28]3[C:29]([C:35]([OH:37])=[O:36])=[C:30]([CH2:33][Cl:34])[CH2:31][S:32][C@H:27]23)=[O:24])[N:18]=1
Reactant: Nc1nc(C(=NOCC(=O)O)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)ns1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=NOCC(=O)O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CCl)CS[C@H]23)ns1
Reaction time: 2 h
Yield: 106 %

Procedure:
To a solution of trifluoroacetic acid (20 ml) and anisole (10 ml) in methylene chloride (50 ml) was added benzhydryl 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (7.0 g) at 0°~-5° C. under stirring. The stirring was continued for 2 hours at the same temperature. The reaction mixture was poured into a cold mixture of diisopropyl ether (400 ml) and n-hexane (200 ml). The resulting precipitates were collected by filtration to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid (syn isomer) (5.5 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:15]=[CH:14][N:13]2[C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:33])=[C:23]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:24]=3)=[CH:17][N:18]=[C:12]2[N:11]=1>CN(C)C=O>[F:33][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[N:13]3[CH:14]=[CH:15][C:10]([CH2:9][N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)=[N:11][C:12]3=[N:18][CH:17]=2)=[CH:24][C:23]=1[C:25]1[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(CBr)ccn23)ccc1F
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(Cn4cncn4)ccn23)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-[1,2,4]triazole (30 mg, 0.435 mmol) in N,N-dimethylformamide was added sodium hydride (17 mg, 0.435 mmol) as a 60% dispersion in oil and the reaction stirred at ambient temperature for 0.5 h. To this mixture was added the previously prepared solution of 5′-(7-bromomethylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile in N,N-dimethylformamide in a dropwise manner. This mixture was allowed to stir at ambient temperature for 16 h before removal of the reaction solvent in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of dichloromethane, methanol and ammonia (90:5:0.5) to give 2′-fluoro-5′-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile: δH (360 MHz, CDCl3) 5.57 (2H, s), 6.89 (1H, d, J 7.1), 7.41 (3H, t, J 9.5 ), 7.52-7.62 (4H, m), 7.68-7.73 (1H, m), 7.82-7.85 (1H, m), 7.92 (1H, s), 8.01 (1H, s), 8.32 (1H, s), 8.80 (1H, s); m/z (ES+) 396 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([I:26])[S:25][C:18]=12.O>CS(C)=O>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([I:26])[S:25][C:18]=12)[NH2:1]
Reactant: Clc1ccnc2cc(I)sc12
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a solution of 4-amino-2-fluorophenol (1.83 g, 14.38 mmol) in DMSO (30 mL) was added potassium tert-butoxide (1.61 g, 14.38 mmol). After 15 min, 7-chloro-2-iodothieno[3,2-b]pyridine (2.5 g, 8.46 mmol, Ragan J. A. et al, Organic Process Research and Development, 2003, 7. 676-683) was added and the reaction mixture was heated at 100° C. for 60 min. The mixture was cooled down to RT then poured into water (250 mL) at 40-45° C. and stirred for 30 min. The precipitate was collected by filtration, washed with water, dried and purified by flash column chromatography on silica gel (eluent 60% EtOAc in Hexane) to afford title compound 268 (1.06 g, 32% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.41 (d, J=5.4 Hz, 1H), 7.75 (s, 1H), 7.03 (t, J=9.0 Hz, 1H), 6.57-6.45 (m, 3H), 3.83 (s, 2H).