Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]=[CH2:18])=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:18]=[CH:17]/[C:14]2[CH:15]=[N:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:19])=[CH:5][CH:6]=3)=[N:12][CH:13]=2)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: C=Cc1cnc(Nc2ccc(OC(F)F)cc2)nc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: FC(F)Oc1ccc(Nc2ncc(/C=C/c3ccc(OCc4ccccc4)cc3)cn2)cc1
Temperature: 90 °C
Yield: 69.7 %

Procedure:
To a solution of N-(4-(difluoromethoxy)phenyl)-5-vinylpyrimidin-2-amine (0.102 g, 0.387 mmol) in ACN (3 mL) were added 1-(benzyloxy)-4-iodobenzene (0.1 g, 0.322 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.033 g, 0.032 mmol), tri-o-tolylphosphine (0.039 g, 0.129 mmol), and TEA (0.135 mL, 0.967 mmol). The reaction mixture was flushed with N2 and heated at 90° C. overnight. Solvent was evaporated, and the residue was dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified by flash chromatography on silica gel using 30% ethyl acetate in hexanes to give (E)-5-(4-(benzyloxy)styryl)-N-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine (0.1 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.14 (s, 2H), 6.93-7.30 (m, 7H), 7.34-7.52 (m, 2H), 7.78-7.80 (m, 2H), 8.71 (s, 2H), 9.82 (s, 1H). LCMS: RT 1.18 min, (M+H)+446.6.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH:33]=[CH2:34])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:50][C:51]([O:53][CH2:54][C:55]1[CH2:64][S:63][C@@H:58]2[C@H:59]([NH2:62])[C:60](=[O:61])[N:57]2[C:56]=1[C:65]([OH:67])=[O:66])=[O:52].Cl>O.C(N(CC)CC)C.C(Cl)Cl>[C:51]([O:53][CH2:54][C:55]1[CH2:64][S:63][C@@H:58]2[CH:59]([NH:62][C:27](=[O:28])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[S:22][CH:23]=3)=[N:30][O:31][CH2:32][CH:33]=[CH2:34])[C:60](=[O:61])[N:57]2[C:56]=1[C:65]([OH:67])=[O:66])(=[O:52])[CH3:50]
Reactant: C=CCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Yield: 168.7 %

Procedure:
A mixture of 470 mg of the product of Step C, 5 ml of methylene chloride and 130 ml of dicyclohexylcarbodiimide was rinsed with a little methylene chloride and the mixture was stirred for an hour at room temperature. The mixture was vacuum filtered to remove the dicyclohexylurea formed and the filtrate was cooled. A solution of 136 mg of 7-amino-cephalosporanic acid, 2.4 ml of methylene chloride and 0.14 ml of triethylamine was added to the filtrate under an inert atmosphere and the mixture sat for 11/2 hours at room temperature. 2 ml of 1 N hydrochloric acid and water were added thereto and the mixture was stirred and decanted. The organic phase was washed with water, dried and evaporated to dryness to obtain 610 mg of raw 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-propenyl) oxyiminoacetamido]-ceph-3-eme-4-carboxylic acid with a syn configuration.
Reaction SMILES: N[C@@H](CC)[C@H](O)[C:4](NC1CC1)=[O:5].[NH2:13][C@@H:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24]>>[NH2:13][C@@H:14]([CH2:18][CH2:19][CH3:20])[C@H:15]([OH:17])[C:4]([NH:24][CH2:23][C:22]([F:26])([F:25])[F:21])=[O:5]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: CCC[C@H](N)C(=O)O
Reactant: NCC(F)(F)F
Product: CCC[C@H](N)[C@H](O)C(=O)NCC(F)(F)F

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using (S)-2-aminopentanoic acid in the first step (step B1), and 2,2,2-trifluoro-ethylamine in the seventh step (step B7).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: BrC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)C(c1cccc(Cl)c1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
A solution of diisopropylamine (1.80 mL, 12.9 mmol) in dry tetrahydrofuran (6 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.4 M in hexanes, 5.4 mL, 12.9 mmol). The resulting solution was warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and treated, via cannula, with a solution of 3-chlorophenylacetic acid (1.0 g, 5.9 mmol) in tetrahydrofuran (6 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 45 minutes and was then re-cooled to −78° C. Cyclopentyl bromide (0.76 mL, 7.1 mmol) was then added via syringe, and the resulting mixture was stirred at −78° C. for 1 hour. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1×15 mL). The aqueous layer was then acidified to pH =1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×15 mL), and the combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the product was purified via Biotage Horizon (FLASH 25 M, silica, gradient from 0% EtOAc/hexane to 40% EtOAc/hexane) to yield 1.08 g (79%) (3-chlorophenyl)(cyclopentyl)acetic acid as a clear oil. HRMS: calcd for C13H15ClO2−H, 237.06823; found (ESI, [M−H]−), 237.0682
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:16]4[O:17][CH2:18][CH2:19][NH:20][C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:21]=1.Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][N:26]=1.ClC1C(Cl)=CC=CN=1>>[Cl:31][C:30]1[C:25]([N:20]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:9]4[NH:8][C:7]5[CH:21]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=[CH:5][C:6]=5[N:10]=4)[C:16]=3[O:17][CH2:18][CH2:19]2)=[N:26][CH:27]=[C:28]([Cl:32])[CH:29]=1
Reactant: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4)[nH]c2c1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: Clc1cccnc1Cl
Product: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4c3ncc(Cl)cc3Cl)[nH]c2c1
Yield: 89 %

Procedure:
The procedure of Example 6 was repeated except for using 8-(6-(trifloromethyl)-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine and 2,3,5-trichloropyridine instead of 4-(5-tert-butyl-1H-benzo[d]imidazol-2-yl)benzenamine and 2,3-dichloropyridine in Example 6 respectively to obtain the title compound (4.1 g, yield: 89%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[F:9][C:10]1[C:15](B(O)O)=[CH:14][C:13]([Br:19])=[CH:12][N:11]=1.B(O)O>C(#N)C.[F-].[K+].C(Cl)Cl.O>[Br:19][C:13]1[CH:14]=[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH2:8])[C:10]([F:9])=[N:11][CH:12]=1
Reactant: Nc1cnccc1I
Reactant: OB(O)c1cc(Br)cnc1F
Agent: OBO
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Nc1cnccc1-c1cc(Br)cnc1F
Temperature: 95 °C
Yield: 68.8 %

Procedure:
A mixture of 4-iodo-pyridin-3-ylamine (1.027 g, 4.67 mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.05 g, 9.33 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (191 mg, 0.233 mmol) in acetonitrile (12 mL) and 1N aqueous potassium fluoride solution (12 mL) was heated at 95° C. for 3 h. The reaction mixture was allowed to cool, treated with additional portions of the boronic acid (0.5 eq) and of catalyst (5.0 mol %), and heated under reflux overnight under a nitrogen atmosphere. The mixture was allowed to cool, diluted with DCM and water, and filtered to remove the solids. The filtrate layers were separated and the aqueous phase was extracted into DCM, and the combined organic phase concentrated in vacuo. The resultant residue was redissolved in 20% methanol in DCM and absorbed onto silica gel for purification by flash chromatography (silica, 100 g column, Biotage, 1-20% methanol in DCM) to afford the title compound as a brown solid (861 mg, 69%). 1H NMR (DMSO-D6, 400 MHz): 8.43 (d, J=1.1 Hz, 1H), 8.18 (dd, J=8.3 Hz, 2.5 Hz, 1H) 8.11 (s, 1H), 7.81 (d, J=4.8 Hz, 1H), 7.01 (d, J=4.8 Hz, 1H), 5.37 (s, 2H). LCMS (Method B): RT=0.95 min, M+H+=268/270.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:28])[N:19]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1.[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>N1C=CC=CC=1>[ClH:30].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=2[NH:9][C:10](=[O:29])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18](=[O:28])[N:19]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN(C)CCn1cccc(-c2ccc(C(=O)Nc3c(N)cccc3O)cc2)c1=O
Solvent: c1ccncc1
Product: CN(C)CCn1cccc(-c2ccc(C(=O)Nc3c(O)cccc3NC(=O)c3ccc(Cl)cc3)cc2)c1=O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2-amino-6-hydroxyphenyl)-4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzamide (276 mg) was dissolved in pyridine (6 mL), and with cooling with ice, 4-chlorobenzoyl chloride (99 μL) was added, followed by stirring overnight at room temperature. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol:ammonia=100:0:0 to 95:5:0.5). The purified product (250 mg) was dissolved in ethyl acetate, and 4 M hydrochloric acid/ethyl acetate solution (129 μL) was added, followed by stirring at room temperature for 1 hour. The precipitate formed was collected by filtration and dried at room temperature under reduced pressure to obtain 4-chloro-N-{2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzoyl)amino]-3-hydroxyphenyl}benzamide hydrochloride (157 mg) as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH:14]=O)[N:2]=1.CN(C)C=O.[CH3:21][N:22]([CH3:24])[NH2:23]>O>[CH3:21][N:22]([CH3:24])[N:23]=[CH:14][C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: O=Cc1cc2c(cn1)[nH]c1ccccc12
Reactant: CN(C)N
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)N=Cc1cc2c(cn1)[nH]c1ccccc12
Reaction time: 3 h

Procedure:
A mixture of 1.0 g of beta-carboline-3-carboxaldehyde, 10 ml of dimethyl-formamide and 3 ml of N,N-dimethyl hydrazine is introduced into a glass autoclave. The air is replaced by nitrogen. After stirring for 3 h, the reaction mixture is allowed to stand overnight at room temperature. After adding 25 ml of water, the reaction mixture is extracted with 100 and 50 ml of chloroform. The chloroform phase is dried using magnesium sulfate, then filtered. Then, the chloroform is evaporated. After adding 10 ml of ether, the reaction product is filtered off. 0.9 g of beta-carboline-3-carboxaldehyde-dimethylhydrazone with a m.p. of 203°-206° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:26]4[C:35]5[C:30](=[CH:31]C(Cl)=CC=5)N=CC=4)[CH2:18][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.BrCCCCBr.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][N:25]4[CH2:31][CH2:30][CH2:35][CH2:26]4)[CH2:20][CH2:21]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(NCCCN3CCN(CCCNc4ccnc5cc(Cl)ccc45)CC3)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: BrCCCCBr
Product: Clc1ccc2c(NCCCN3CCN(CCCN4CCCC4)CC3)ccnc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,4-bis{3-[N-(7-chloroquinolin-4-yl)amino]propyl}piperazine described in example 1 (0.15 g, 0.41 mmol), 1,4-dibromobutane (0.06 mL, 0.5 mmol) in DMF (5 mL), K2CO3 (287 mg, 2.07 mmol) is added. After stirring the mixture at room temperature for 48 h, the solvent was removed under reduced pressure. The residue was solubilized in CH2Cl2, washed with NaHCO3 1M and dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH/NH4OH: 80/20/2.7).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([CH2:40][CH2:41][OH:42])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[OH:42][CH2:41][CH2:40][N:34]1[CH2:39][CH2:38][N:37]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:36][CH2:35]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: OCCN1CCNCC1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCN(CCO)CC1
Yield: 2 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.2 equivalent of 2-(piperazin-1-yl)ethanol as secondary amine. The product was purified by preparative TLC (eluent: petrolether/DCM/MeOH 2:3:1 containing 2% of a 7 M NH3 solution in MeOH).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21]([O:23]CC)=[O:22])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:9]=1.O[Li].O>C1COCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([C:21]([OH:23])=[O:22])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[CH:9]=1
Reactant: CCOC(=O)c1nc(C)c(Cc2cccc(N3CCN(C)CC3)c2)s1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)O)sc1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
A solution of ethyl 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylate (270 mg, 0.72 mmol) was treated with LiOH.H2O (61 mg, 1.45 mmol) in THF (4 mL) and H2O (1 mL), and stirred at RT for 2 h. The solvents were removed under reduced pressure and the residue was purified by Combiflash (20% MeCN/H2O) to afford 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylic acid as a yellow solid (70 mg, 29%). MS (ES+) C17H21N3O2S requires: 331, found: 332[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][OH:23])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:24][S:25]([O:23][CH2:22][CH2:21][NH:20][C:19]1[C:15]([C:10]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=3)[C:13](=[O:14])[O:12][N:11]=2)=[N:16][O:17][N:18]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1onc(-c2nonc2NCCO)n1-c1ccc(F)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(3-bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (1.5 kg, 3.9 mol, containing also some of the corresponding bromo-compound) in ethyl acetate (12 L) was added methanesulfonyl chloride (185 mL, 2.4 mol) dropwise over 1 h at room temperature. Triethylamine (325 mL, 2.3 mol) was added dropwise over 45 min, during which time the reaction temperature increased to 35° C. After 2 h, the reaction mixture was washed with water (5 L), brine (1 L), dried over sodium sulfate, combined with 3 more reactions of the same size, and the solvents removed in vacuo to afford the desired product (7600 g, quantitative yield, containing also some of the corresponding bromo-compound, Caution: irritating dust!) as a tan solid. LCMS for C13H11BrFN5O6SNa (M+Na)+: m/z=485.9, 487.9. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.58 (t, J=8.7 Hz, 1H), 6.75 (t, J=5.9 Hz, 1H), 4.36 (t, J=5.3 Hz, 2H), 3.58 (dd, J=111.2, 5.6 Hz, 2H), 3.18 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:12][C:13]1[C:18]([B:19]([C:31]2[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=2[F:41])[C:20]2[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=2[F:30])=[C:17]([F:42])[C:16]([F:43])=[C:15]([F:44])[C:14]=1[F:45].[CH2:46]([N:64]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH3:65])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>C1(C)C=CC=CC=1>[F:37][C:36]1[C:31]([B:19]([C:18]2[C:13]([F:12])=[C:14]([F:45])[C:15]([F:44])=[C:16]([F:43])[C:17]=2[F:42])[C:20]2[C:21]([F:30])=[C:22]([F:29])[C:23]([F:28])=[C:24]([F:27])[C:25]=2[F:26])=[C:32]([F:41])[C:33]([F:40])=[C:34]([F:39])[C:35]=1[F:38].[F:37][C:36]1[C:31]([B:19]([C:18]2[C:13]([F:12])=[C:14]([F:45])[C:15]([F:44])=[C:16]([F:43])[C:17]=2[F:42])[C:20]2[C:21]([F:30])=[C:22]([F:29])[C:23]([F:28])=[C:24]([F:27])[C:25]=2[F:26])=[C:32]([F:41])[C:33]([F:40])=[C:34]([F:39])[C:35]=1[F:38].[CH2:66]([NH+:64]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH3:65])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83].[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][N-:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: CCCCCCCCCCCCCCCCCCN(C)CCCCCCCCCCCCCCCCCC
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC[NH+](C)CCCCCCCCCCCCCCCCCC
Product: Cc1cc2nc[n-]c2cc1C

Procedure:
5,6-dimethylbenzimidazole (0.2855 g, 1.953 mmol), tris(pentafluorophenyl)borane (2.0000 g, 3.9063 mmol) and dioctadecylmethylamine (1.0469 g, 1.9531 mmol) were placed in a 50 mL flask, taken up in 21 mL of toluene and refluxed under argon for 16 hours. The volatiles were then stripped under vacuum. Yield, 3.060 g, 91.84 percent.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[C:21]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][CH:36]([N:39]5[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]5)[CH2:35][CH2:34]4)=[C:29]([C:46]#[N:47])[CH:28]=3)=[O:25])[CH:20]=[N:19]2)=[CH:14][CH:13]=1.[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]([CH3:23])=[C:21]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][CH:36]([N:39]5[CH2:40][CH2:41][C:42](=[O:45])[CH2:43][CH2:44]5)[CH2:35][CH2:34]4)=[C:29]([C:46]#[N:47])[CH:28]=3)=[O:25])[CH:20]=[N:19]2)=[CH:16][CH:17]=1
Reactant: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCC(O)CC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCC(=O)CC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of oxalyl chloride (0.1 ml) and dimethyl sulfoxide (0.2 ml) in methylene chloride (30 ml) were added under ice-cooling 1-(4-chlorophenyl)-N-[3-cyano-4-[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]phenyl]-5-methylpyrazole-4-carboxamide synthesized in Example 189 and triethylamine (0.9 ml), and the mixture was stirred at the same temperature for 1 h. To a reaction mixture was added aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform:methanol=20:1) to give the title compound (0.2 g), melting point: 213° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[N:8]=1.CN([CH:19]=[O:20])C>C1COCC1>[CH:13]1([C:9]2[N:8]=[C:7]([CH:19]=[O:20])[CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:14]1
Reactant: Brc1cccc(C2CC2)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(C2CC2)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A flame dried flask was charged with dry THF (75 mL) and chilled to −78° C. To this was added n-BuLi (9.90 mL, 24.7 mmol, 2.5 M in hexanes), followed by the slow addition of a THF (25 mL) solution of the 2-bromo-6-cyclopropylpyridine (4.90 g, 24.7 mmol) over a 15 minute period). The mixture was stirred at −78° C. for 15 minutes, and neat DMF (2.87 mL, 37.1 mmol) was added. The mixture was stirred for 15 minutes at −78° C., then quenched with saturated ammonium chloride solution (50 mL) and allowed to warm to ambient temperature. The mixture was diluted with water, extracted with EtOAc, dried over sodium sulfate and concentrated to 3.5 g (96%) of an orange oil/liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:17](=[O:18])[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:6][CH:5]=[C:4]([Cl:26])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:33][CH:34]([F:37])[CH2:35]Br>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([C:8]2[C:17](=[O:18])[N:16]([CH2:35][CH:34]([F:37])[F:33])[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:6][CH:5]=[C:4]([Cl:26])[N:3]=1
Reactant: FC(F)CBr
Reactant: CC(C)(C)C(=O)Oc1c(-c2ccc(Cl)nc2Cl)c(=O)[nH]c2nccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Oc1c(-c2ccc(Cl)nc2Cl)c(=O)n(CC(F)F)c2nccnc12
Temperature: 120 °C

Procedure:
To s suspension of 2,2-dimethyl-propionic acid 7-(2,6-dichloro-pyrid-3-yl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 1.7) (0.064 g) in dry N,N-dimethylformamide (3 ml) was added successively potassium carbonate (0.068 g) and difluoro-ethyl bromide (0.063 g). The reaction mixture was heated in a microwave for 20 minutes at 120° C. The reaction mixture was cooled to ambient temperature, and then diluted with ethyl acetate and water. The phases were separated and organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated to give Compound No. A16 of Table A as a pale yellow solid (0.006 g).