Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH3:22])=[C:14]([CH:18]=1)[C:15]([OH:17])=O)(=[O:9])[CH3:8].[NH2:23][C:24]1[C:25]([C:39]([NH2:41])=[O:40])=[N:26][N:27]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:28]=1[CH2:29][CH2:30][CH3:31]>CN(C)C=O.ClCCl>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH3:22])=[C:14]([CH:18]=1)[C:15]([NH:23][C:24]1[C:25]([C:39]([NH2:41])=[O:40])=[N:26][N:27]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:28]=1[CH2:29][CH2:30][CH3:31])=[O:17])(=[O:9])[CH3:8]
Reactant: CCCc1c(N)c(C(N)=O)nn1Cc1ccccn1
Reactant: CCCOc1ccc(C(C)=O)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCOc1ccc(C(C)=O)cc1C(=O)Nc1c(C(N)=O)nn(Cc2ccccn2)c1CCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (1.6 ml, 18 mmol) was added to an ice-cooled solution of 5-acetyl-2-n-propoxybenzoic acid (WO 9312095) (2 g, 9 mmol) in N,N-dimethylformamide (0.2 ml) and dichloromethane (200 ml) under nitrogen. Once addition was complete the solution was allowed to warm to room temperature for 3 hours and the solvent was removed under reduced pressure. The intermediate acid chloride was dissolved in pyridine (50 ml) and 4-amino-5-propyl-1-(pyridin-2-ylmethyl)-1H-pyrazole -3-carboxamide (WO 9954333) (1.5 g, 5.8 mmol) and the reaction was stirred at reflux for 3 hours, then at room temperature for 18 hours. The mixture was partitioned between dilute sodium carbonate solution and dichloromethane, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (100:0 changing to 98:2 then 92:8) to afford the title compound as a beige solid, 1.5 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23].O>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:22](=[O:23])[O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(NC(=O)OCC(Cl)(Cl)Cl)cn2)CC1

Procedure:
To a solution of 6-(4-methylpiperazin-1-yl)pyridine-3-amine (1.00 g, 5.20 mmol) and pyridine (0.509 ml, 6.24 mmol) in tetrahydrofuran (17 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.509 ml, 6.24 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 349 mg (18.2%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:37]([NH:39][NH2:40])=O>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][N:31]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: NNC(=O)c1cnccn1
Reactant: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Cl)c1Cl)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[(2,3-dichloro-4-fluorophenyl)carbonyl]-2-piperazinone (I34) (0.210 g, 0.721 mmol) was dissolved in Dichloromethane (DCM) (3 mL), and to this was added triethyloxonium tetrafluoroborate (0.144 g, 0.757 mmol), the solution was stirred for 20 minutes before 2-pyrazinecarbohydrazide (commercially available from e.g. TimTec, J&W PharmLab or AKos Consulting, 0.120 g, 0.866 mmol) was added. The solution was then allowed to stir for an additional 30 minutes before the solvent was concentrated and n-butanol (3 mL) was added. The solution was then stirred, under argon and reflux, for 3 hours before being allowed to cool to room temperature. The solvent was then removed in vacuo and the remaining residue was purified by flash chromatography (Biotage SP4, 25M cartridge) with a gradient of 0-10% 2M NH3/MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo. The remaining residue was then further purified by mass-directed automated HPLC, and the solvent evaporated in vacuo. The remaining residue was then triturated with ether and dried in a vacuum oven to yield the product in 0.112 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:22]([N+:23]([O-])=O)=[CH:21][C:20]([F:26])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:22]([NH2:23])=[CH:21][C:20]([F:26])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(F)cnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
A mixture of 4-(benzyloxy)aniline (2.26 g), 2-chloro-5-fluoro-3-nitropyridine (2 g) and K2CO3 (3.13 g) in DMF (20 mL) was stirred at 120° C. for 5 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and collected by filtration. The obtained solid was dissolved in EtOH (20 mL), and Pt/C (2 g) was added. Under H2 atmosphere, the mixture was stirred for 1 h, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1>CS(C)=O>[O:9]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
A mixture of trimethylsulfoxonium iodide (50.2 mmol) and anhydrous dimethyl sulfoxide (DMSO) (50 mL) was stirred at room temperature for 1 h. The reaction was then cooled to 0° C. and 60% sodium hydride in mineral oil (60.2 mmol) was added in small portions over several minutes. The reaction was allowed to warm to room temperature and stirred for 2 h. The resulting white slurry was cooled to 0° C. then treated with solid 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (50.2 mmol) in one portion. The ice bath was removed and stirring continued at room temperature for 18 h. Ice cold water (150 mL) was added and the mixture was extracted into diethyl ether (3×). The extracts were washed with brine, dried (sodium sulfate) then evaporated under reduced pressure to a yellow oil. The oil was dissolved in ethyl acetate, treated with silica powder (˜20 g), and evaporated to dryness. This was placed on a short pad of silica in a sintered glass funnel and washed with hexanes (500 mL; the filtrate was discarded). The silica pad was then washed with 2:1 hexanes/ethyl acetate. The filtrate was evaporated in vacuo to give the title product (6.40 g, 57% yield) as a pale yellow oil that solidified upon standing. MS(ES)+ m/e 214.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 11 H) 1.72-1.87 (m, 2 H) 2.69 (s, 2H) 3.36-3.50 (m, 2 H) 3.63-3.83 (m, 2 H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([N+:31]([O-:33])=[O:32])=[C:27]([CH:30]=1)[CH2:28]Cl.[I-].[Na+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[OH:1][CH2:2][CH:3]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:28][C:27]1[CH:30]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=1[N+:31]([O-:33])=[O:32])[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])c(CCl)c1
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(CO)N(Cc1cc(C)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.3 %

Procedure:
A solution of 23.14 g (0.08 mol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 120 ml of dry N,N-dimethylformamide was added dropwise to a stirred suspension of 3.2 g (0.08 mol) of sodium hydride (57% in oil) in 120 ml of N,N-dimethylformide. When gas evolution ceased, the mixture was chilled in an ice bath and a solution of 16.4 g (0.084 mol) of 5-methyl-2-nitrobenzyl chloride in 100 ml of N N-dimethylformamide was added. To the mixture was added 12.6 g (0.084 mol) of anhydrous sodium iodide and the mixture was chilled in an ice bath and stirred for 20 minutes. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under vacuum and the residue diluted with 200 ml of H2O and extracted with 500 ml of ethyl acetate. The aqueous layer was extracted with an additional 200 ml of ethyl acetate. The combined extract was washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 41.18 g of crude product. The product was chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 8.14 g (RF 0.38) of product as a yellow semi-solid. From a small scale run (1 mmol) the product was chromatographed twice on thick silica gel plates with hexane-ethyl acetate (1:1) to give 0.12 g of a yellow semi-solid. Anal. for C19H22N2SO8 : Calc'd: C,52.0; H,5.1; N,6.4: Found: C,51.7; H,5.1; N,6.0.
Reaction SMILES: B(F)(F)F.CCOCC.CC(O[CH2:14][C:15]1[CH2:24][S:23][C@@H:18]2[C@H:19]([NH2:22])[C:20](=[O:21])[N:17]2[C:16]=1[C:25]([OH:27])=[O:26])=O.[OH:28][NH:29][C:30](=[O:44])[CH2:31][CH2:32][C:33]1(S)[CH:38]=[CH:37][N:36]2[NH:39][C:40]([CH3:42])=[N:41][C:35]2=[N:34]1.ClCCl.ClCCl.[S:51]1(CCCC1)(=O)=O>>[NH2:22][C@@H:19]1[C:20](=[O:21])[N:17]2[C@@H:18]1[S:23][CH2:24][C:15]([CH2:14][S:51][C:37]1[N:36]3[N:39]=[C:40]([CH3:42])[N:41]=[C:35]3[N:34]=[C:33]([CH2:32][CH2:31][C:30](=[O:44])[NH:29][OH:28])[CH:38]=1)=[C:16]2[C:25]([OH:27])=[O:26]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=S1(=O)CCCC1
Reactant: CC1=NC2=NC(S)(CCC(=O)NO)C=CN2N1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nc2nc(CCC(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Boron trifluoride diethyl etherate (2 ml) are added dropwise at 0° C. to a suspension of 305 mg (1.12 mmol) of 7-aminocephalosporanic acid and 318 mg (1.25 mmol of N-hydroxy-5-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-propionamide in 4 ml of dichloromethane/sulpholane (1:1 v/v). Subsequently, the mixture is stirred at room temperature for 16 hours. The solution is treated with 50 ml of dichloromethane. A beige substance crystallizes out. It is filtered off, washed with diethyl ether and dissolved in 5 ml of water. The solution is adjusted to about pH 4 with aqueous sodium hydrogen carbonate solution. The product is crystallized by the addition of about 100 ml of ethanol. The crystals are filtered off, washed with ethanol and dried at room temperature in a high vacuum. There are obtained 311 mg of (6R,7R)-7-amino-3-[[[5-[2-(hydroxycarbamoyl)ethyl]-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCCl>[C:19]([C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1)#[CH:20]
Reactant: C#Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: C#Cc1cccc(Nc2ncnc3ccc(NS(C)(=O)=O)cc23)c1

Procedure:
The title product of Example 8 (100 mg, 0.384 mmol), pyridine (140 μL, 1.68 mmol) and methanesulfonyl chloride (99 μL, 1.26 mmol) were refluxed in 10 mL of 1,2-dichloroethane for 7 hours. The reaction mixture was cooled and evaporated in a vacuo to a residue which was triturated in 10 mL of 1N HCl, filtered and dried in vacuo to yield (3-ethynylphenyl)-(6-methanesulfonylaminoquinazoline-4-yl)amine; 102 mg (78%) mp 248° C. dec.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][NH:7][C:8]([NH2:10])=[S:9].C(O)C.[CH3:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH:24]=O)[CH:22]=2)[NH:17][N:16]=1>O>[CH3:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH:24]=[N:6][NH:7][C:8]([NH2:10])=[S:9])[CH:22]=2)[NH:17][N:16]=1
Reactant: NNC(N)=S
Reactant: Cc1n[nH]c2ncc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2ncc(C=NNC(N)=S)cc12
Temperature: 80 °C

Procedure:
Sodium acetate (166 mg, 2.02 mmol), thiosemicarbazide (333 mg, 3.66 mmol), 100 ml ethanol and 2 ml distilled water were charged into a 250 ml round bottom flask. The resulting suspension was heated to 80° C. until it becomes a clear solution. The reaction was then cooled down to room temperature and the resulting mixture was added into a 250 ml round bottom flask containing 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (333 mg, 2.1 mmol). After the addition, the resulting mixture was heated to 80° C. for 16 hours. The mixture was cooled to room temperature and solid was precipitated out. The solid was filtered off and washed with ether (50 ml). The product (500 mg, y=95%) was used directly for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C@@H:16]3[C@@H:12]([CH2:13][O:14][CH2:15]3)[O:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][C:21]([F:34])([F:33])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:17][C:10]1[O:11][C@H:12]2[C@@H:16]([C@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:30]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:21]([F:34])([F:33])[F:20])=[CH:29][N:28]=4)=[O:31])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=1)[CH2:15][O:14][CH2:13]2
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21

Procedure:
The coupling of (3aS,7S,7aS)-7-(5-amino-2-fluoro-phenyl)-7-methyl-3,3a,7,7a-tetrahydro-1H-2,4-dioxa-6-aza-inden-5-ylamine and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (prepared as described in Banner D. et al., WO 2010/128 058) following procedure G yielded the title compound as a colorless solid. MS: m/z=469.2 [M+H]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH2:22][C:23]1[C:24]([C:30](O)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][N:28]=1.O.ON1C2C=CC=CC=2N=N1>C(#N)C>[NH2:22][C:23]1[C:24]([C:30]([NH:21][CH2:20][CH2:19][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][N:28]=1
Reactant: NCCN1CCOCC1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)NCCN1CCOCC1
Reaction time: 7 h
Yield: 68.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.68 g, 3.5 mmol) was added in one portion to a stirred suspension of 2-morpholin-4-ylethanamine (0.422 g, 3.2 mmol), 3-amino-6-bromopyrazine-2-carboxylic acid (0.64 g, 3.0 mmol; described in: Ellingson, R. C.; Henry, R. L. J. Am. Chem. Soc. 1949, 2798-2800), and 1-hydroxybenzotriazole hydrate (0.48 g, 3.5 mmol) in acetonitrile (25 mL) at 0° C. The cooling bath was removed and stirring was continued at room temperature for 7 h. The solid was filtered off, washed with acetonitrile and purified by column chromatography on silica using methylene chloride/methanol/triethyl amine, (95:5:0.1), to give 0.68 g (69% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 8.53 (m, 1H), 8.34 (s, 1H), 8.68 (br s, 2H), 3.57 (t, J=5 Hz, 4H), 3.37 (q, J=7 Hz, 2H), 2.47 (q, J=7 Hz, 2H), 2.40 (m, 4H); MS (ES) m/z 330 and 332 (M++1).
Reaction SMILES: [Na+].[OH:2][C:3]1[C:4]([S:20]([O-:23])(=O)=[O:21])=[CH:5][C:6]2[C:7](=[O:19])[C:8]3[C:13]([C:14](=[O:18])[C:15]=2[C:16]=1[OH:17])=[CH:12][CH:11]=[CH:10][CH:9]=3.[Cl:24]S(O)(=O)=O>>[OH:2][C:3]1[C:4]([S:20]([Cl:24])(=[O:23])=[O:21])=[CH:5][C:6]2[C:7](=[O:19])[C:8]3[C:13]([C:14](=[O:18])[C:15]=2[C:16]=1[OH:17])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1c2ccccc2C(=O)c2c1cc(S(=O)(=O)[O-])c(O)c2O
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)c2c1cc(S(=O)(=O)Cl)c(O)c2O
Temperature: 90 °C
Yield: 66 %

Procedure:
3,4-dihydroxy-9,10-dioxo-2-anthracenesulfonic acid sodium salt (1.4 g, 3.9 mmoles) was combined with 30 mL of chlorosulfonic acid and heated to 90° C. for 5 hours, after which the solution was cooled to 0° C. and poured into 100 g of ice. After the ice melted the solution was extracted with CH2Cl2 (3×100 mL), methylene chloride extracts were combined, dried with Na2SO4 and evaporated to produce 0.87 g of solid (Yield 66%).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].Cl[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[O:36][CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][C:27]=3[O:36][CH3:37])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc2ccccc2c1CCl
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (406 mg, 1.28 mmol) in DMF (3.21 ml) was added 1-(chloromethyl)-2-methoxynaphthalene (318 mg, 1.54 mmol) and cesium carbonate (1.25 g, 3.85 mmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (448 mg, 72%) as an off-white solid. MS m/z 509 (MNa)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCCCCCCCCCCCC1
Reactant: NCc1cccnc1
Product: c1cncc(CNC2CCCCCCCCCCCCCC2)c1

Procedure:
Following the general procedure of Example 33, but starting with 3-aminomethylpyridine and cyclopentadecanone, the title compound is produced, NMR (CDCl3, TMS) δ 8.58, 7.72, 7.25, 3.76, 2.56, 1.32.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.BrCCBr.[Mg].[C:15]1([C:25]#N)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.Cl.[OH-:28].[Na+]>O1CCCC1.CO>[C:15]1([C:25]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [OH-]
Reactant: COc1ccc(Br)cc1
Reactant: N#Cc1nccc2ccccc12
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: BrCCBr
Product: COc1ccc(C(=O)c2nccc3ccccc23)cc1
Temperature: 0 °C

Procedure:
4-Bromoanisol (15.3 ml, 122 mmol) and a catalytic amount of 1,2-dibromoethane as an initiator were added to a mixed solution of magnesium (3059 mg, 125.8 mmol) and tetrahydrofuran (20 ml) under nitrogen atmosphere, and this reaction mixture was stirred while heating under reflux for 45 minutes. The mixture was cooled to 0° C., a solution of 1-isoquinolinecarbonitrile (10.78 g, 69.9 mmol) in tetrahydrofuran (30 ml) was added dropwise thereto, and this reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled on ice, concentrated hydrochloric acid (24 ml) and methanol (120 ml) were added, and this mixture was heated under reflux for 1.5 hours. After cooling on ice, the mixture was adjusted to pH 8 by adding aqueous sodium hydroxide, extracted with ether, washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (15.87 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=O)=[CH:18][CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][C:17](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=4)=[CH:18][CH:19]=2)[CH:14]=[N:13]1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C1Nc2ccc(Br)cc2/C1=C\c1ccc2[nH]ncc2c1
Yield: 10.6 %

Procedure:
The title compound was synthesized according to the method described for Example A11B except substituting 5-bromooxindole (40 mg, 0.189 mmol) and 1H-indazole-5-carbaldehyde (30 mg, 0.208 mmol) to obtain the title compound (6.8 mg, 4.0%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.76-7.68 (m, 2H), 7.38 (d, J=8.59 Hz, 1H), 6.87 (d, J=8.59 Hz, 1H); MS ESI 340.1 [M+H]+, calcd for [C16H10BrN3O+H]+ 340.01.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([Cl:24])=[O:23]>O1CCOCC1>[ClH:24].[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[N:4]=[C:5]([NH:9][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][C:18]([F:17])([F:29])[F:30])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccccc3OC(F)(F)F)n2)CC1
Product: Cl
Yield: 88.5 %

Procedure:
Prepare according to procedure in Example 66 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol), 2-(trifluoromethoxy)benzoyl chloride (175 μL, 1.09 mmol), and 1,4-dioxane (10 mL) to yield 357 mg (88%) of the title compound: mass spectrum (ion spray): m/z=408.8 (M+1); Analysis calc'd for C20H24N4O2F3Cl.1.0H2O: C, 51.89; H, 5.66; N, 12.10. Found: 51.64; 5.50; 12.48. mp 102–4° C.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26]>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[C:26][C:2]2[N:6]3[CH:7]=[C:8]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]3=[N:4][CH:3]=2)[CH:28]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3c2)cc1
Reactant: C#Cc1cccnc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(C#Cc4cccnc4)n3c2)cc1

Procedure:
The title compound was prepared from 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18 step 6) (460 mg, 1 mmol) and commercially available 3-ethynylpyridine (105 mg, 1 mmol) according to general procedure II. Obtained as a white solid (330 mg, 75%). MS (ISP) 432.1 [(M+H)+]; mp 169-170° C.