Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.Br[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:30][CH2:29][CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[N:27]1([S:24]([C:21]2[CH:20]=[CH:19][C:18]([C:4]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=3[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:23][CH:22]=2)(=[O:25])=[O:26])[CH2:28][CH2:29][CH2:30]1
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCC1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1-c1ccc(S(=O)(=O)N2CCC2)cc1)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from example 151 step (iv), 1-[(4-bromophenyl)sulfonyl]azetidine and THF as solvent. Yield 0.028 g.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[NH3:13]>[Ni]>[NH2:13][CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: N
Agent: [Ni]
Product: CC(N)c1ccc(C(=O)O)cc1

Procedure:
4-Acetylbenzoic acid (4.1 g) is dissolved in 50 mL ammonia-saturated methanol. Raney nickel catalyst (1.5 g; activity grade III) is then added and the mixture reduced under hydrogen atmosphere (4750 psi) at 80° C. for 17 hrs. After removal of the catalyst by suction filtration, the filtrate is evaporated and the residue dissolved in H2O. The solution is passed through a 2.5×15 cm column of Dowex 50X8-400 resin (H+ form) and eluted with 1N NH4OH. Evaporation of the eluate leaves a residue (2.9 g) which is recrystallized from H2O/acetone and characterized as 4-(1-aminoethyl)benzoic acid, m.p.>300° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].C([Li])CCC.[CH:16]([CH:18]=[CH2:19])=[O:17].OS(O)(=O)=O>CCOCC.CCCCCC>[CH:18]([CH:16]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10])[OH:17])=[CH2:19]
Reactant: C=CC=O
Reactant: Fc1cc(F)c(F)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C=CC(O)c1cc(F)cc(F)c1F
Temperature: -73 °C
Reaction time: 0.03 h

Procedure:
A solution of 4.1 g (0.0194 mol) of 1-bromo-2,3,5-trifluorobenzene in 50 ml of anhydrous ether is cooled to -76 ° C. under a nitrogen atmosphere. 12.1 ml (0.0194 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise over 15 minutes at a temperature below -72° C. The mixture is stirred for 2 minutes at -73° C. and then a solution of 1.15 g (0.0205 mol) of acrolein in 5 ml of anhydrous ether is added dropwise. The mixture is stirred for 30 minutes at -70° C. and is then allowed to return to room temperature. The mixture is poured onto a mixture of 100 g of ice and 10 g of concentrated H2SO4. Extraction with ether, washing with water, drying over Na2SO4, filtration and concentration under vacuum are carried out. The residue obtained is used without other purification in the following stage. Weight obtained: 3.1 g (Yd.=86%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[C:13]1[C:14]([C:28]2([CH3:33])[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:15][C:16]2[N:17]([C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][N:21]=2)[N:18]=1>CN(C)C=O>[CH3:33][C:28]1([C:14]2[C:13]([O:1][CH2:2][C:3]3[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=3)=[N:18][N:17]3[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[N:20][N:21]=[C:16]3[CH:15]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cccnc1CO
Reactant: CC1(c2cc3nnc(-c4ccccc4)n3nc2Cl)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccnc1COc1nn2c(-c3ccccc3)nnc2cc1C1(C)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Hydroxymethyl-3-methylpyridine (43 mg) was dissolved in dimethylformamide (2 ml) under N2. Sodium hydride (60% w/w in oil, 14 mg) was added followed after 5-10 minutes by 6-chloro-7-(1-methylcyclopentyl)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (100 mg). Reaction was stirred at room temperature for 18 hours, partitioned between ethyl acetate and water, organic phase separated, dried (MgSO4) and evaporated to dryness. Recrystled from ethyl acetate to give pure product. 1H NMR (360 MHz, CDCl3) δ1.30 (3 H, s), 1.77 (6 H, m), 1.93 (2 H, m), 2.44 (3 H, s), 5.62 (2 H, s), 7.25 (1 H, m), 7.50 (3 H, m), 7.58 (1 H, d, J=7.8 Hz), 7.92 (1 H, s), 8.42 (2 H, d, J=6.4 Hz), 8.50 (1 H, m), ms (ES+) m/e 400 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C[O:12][P:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1>CC(C)=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([P:13]1(=[O:12])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1)=[O:5]
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CC(C)=O
Product: Cc1ccccc1C(=O)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 115 °C

Procedure:
61.8 g (0.4 mol) of 2-methylbenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 92 g (0.4 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]-oxaphosphorin were added dropwise over the course of two to three hours while stirring. The temperature was then increased in steps to 115° C. When the reaction was complete, 50 ml of acetone were added at room temperature. After crystallization, 103 g (77% of theory) of the above-mentioned compound of melting point 102° to 104° C. were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12]([Cu])#[N:13]>CN1CCCC1=O>[Cl:11][C:4]1[N:3]=[C:2]([C:12]#[N:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (40 g, 207 mmol) and CuCN (22.32 g, 248 mmol) in 1-methyl-2-pyrrolidinone (160 ml) was quickly heated to 180° C. for 25 minutes. The mixture was cooled to room temperature and the deep brown solution was poured into ice water (1200 ml) and stirred for 30 min. The aqueous solution was extracted with ethyl acetate and boiling toluene, the organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (5% to 25% Ethyl Acetate gradient in Pentane) to give 6-chloro-3-nitropicolinonitrile as a yellow solid. (15.75 g, 41.4% yield)
Reaction SMILES: [NH2:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:24]1([S:30]([NH:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]2[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCCCC(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
224.5 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in 2 ml of DMF and cooled to 0° C. 207 mg of benzenesulfonyl chloride and 303 mg of diisopropylethylamine were added and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was cooled to −25° C. for 16 hours and then warmed to room temperature. The reaction was quenched by the addition of water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/water/acetic acid (9/1/0.1/0.1). Yield 98 mg. MS (ES+): m/e=464.1 (M+H)+; 408.1.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:17]4[S:21][CH:20]=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:22])[CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23]1(=[N:27][S:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29])[CH2:26][CH2:25][CH2:24]1>O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:17]4[S:21][C:20]([C:23]5([NH:27][S:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29])[CH2:24][CH2:25][CH2:26]5)=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:22])[CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)S(=O)N=C1CCC1
Reactant: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cncs2)c1
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)CCC3)s2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added IDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:14][C:15](=[NH:18])[NH:16][CH3:17])=[O:13])[CH3:2].[CH3:19]N(C(OC)OC)C.[ClH:27].CO>CC#N>[ClH:27].[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[N:11]1[CH:17]=[N:16][C:15]([NH:18][CH3:19])=[N:14][C:12]1=[O:13])[CH3:10]
Reactant: CCc1cccc(CC)c1NC(=O)NC(=N)NC
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: CCc1cccc(CC)c1-n1cnc(NC)nc1=O
Yield: 47 %

Procedure:
To a suspension of 22.8 g (80.0 mmol) of 1-(2,6-diethylphenyl)-3-methylamidinourea in CH3CN (100 ml) were added 19.1 g (160.0 mmol) of DMF-DMA and the reaction mixture was heated at reflux for 3 hours. The CH3CN was removed under reduced pressure and the residue partitioned between CHCl3 and H2O. The layers were separated and the aqueous layer extracted with CHCl3 (1×100 ml), dried (MgSO4) and concentrated under reduced pressure to give an off-white solid, which by NMR confirmed the desired free base. The solution was dissolved in H2OH and acidified with HCl/MeOH and the MeOH removed under reduced pressure to give an off-white solid which was crystallized from CH3CN to give after vacuum drying the weekend (105° C., house vacuum) 16.7 g (71%) of crude product. The material was recrystallized from CH3CN (a hot filtration was necessary to remove some undissolved solid) to give 11.0 g (47%) of desired product as a white crystalline solid:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[CH3:18][C:19]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([C:21]1[N:22]=[CH:23][O:24][CH:25]=1)[CH3:20]>N1C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:19]([CH3:20])([C:21]3[N:22]=[CH:23][O:24][CH:25]=3)[CH3:18])=[CH:31][CH:30]=2)(=[O:33])=[O:34])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1cocn1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)c3cocn3)cc2)cn1

Procedure:
Following the general procedure for synthesis of N-arylbenzenesulfonamides, 63 mg (0.26 mmol) of (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 50 mg (0.1 7 mmol) of 4-(1-Methyl-1-oxazol-4-yl-ethyl)-benzenesulfonyl chloride were combined in 0.8 ml of anhydrous pyridine at 60° C. to give, after purification, the title product as a pale yellow solid: 1H NMR (CDCl3): δ (ppm): 1.54 (s, 6H), 2.63 (s, 3H), 7.22-7.30 (m, 2H), 7.32 (m, 2H), 7.55 (m, 1H), 7.61-7.63 (m, 2H), 7.70-7.80 (m, 3H), 8.49 (d, 1H), 9.95 (s, 1H); MS: (M+H)/z=496.0.
Reaction SMILES: OC(CN(C)C)COC1C=CC(N[C:10]2[N:15]=[C:14]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17]3)[C:13](C)=[CH:12][N:11]=2)=CC=1.[OH:32][CH:33]([CH2:58][N:59]([CH3:61])[CH3:60])[CH2:34][O:35][C:36]1[CH:57]=[CH:56][C:39]([NH:40]C2N=C(N3C4C(=CC=CC=4)CC3)C=CN=2)=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[OH:32][CH:33]([CH2:58][N:59]([CH3:61])[CH3:60])[CH2:34][O:35][C:36]1[CH:57]=[CH:56][C:39]([NH:40][C:12]2[N:11]=[CH:10][N:15]=[C:14]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH:13]=2)=[CH:38][CH:37]=1
Reactant: Cc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1-n1ccc2ccccc21
Reactant: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCc4ccccc43)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(C)CC(O)COc1ccc(Nc2cc(N3CCc4ccccc43)ncn2)cc1
Yield: 32.9 %

Procedure:
A solution of 4-chloro-6-(indolin-1-yl)pyrimidine (Method 15, 220 mg, 0.95 mmol) and 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 1, 229 mg, 0.81 mmol) in NMP (5 ml) was heated to 150° C. for 1 hour. Sodium bicarbonate solution (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The extracts were washed with water (2×10 ml) and dried. Silica (1 g) was added and volatile material removed by evaporation. The residue was purified by column chromatography, eluting with 0-8% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (108 mg). NMR: 2.18 (s, 6H), 2.32 (m, 2H), 3.17 (m, 2H), 3.86 (m, 5H), 4.78 (d, 1H), 5.96 (s, 1H), 6.85 (m, 3H), 7.16 (m, 2H), 7.44 (d, 2H), 8.26 (m, 2H), 9.02 (s, 1H); MS (MH+): 406.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].[C:33]([C:36]1[C:44]2[CH:43]=[C:42](B(O)O)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)([OH:35])=[O:34]>O1CCOCC1>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:9]1[C:8]([CH2:7][O:6][C:5]2[CH:24]=[CH:25][C:2]([C:42]3[S:41][C:40]4[CH:39]=[CH:38][CH:37]=[C:36]([C:33]([OH:35])=[O:34])[C:44]=4[CH:43]=3)=[C:3]([CH3:26])[CH:4]=2)=[C:12]([CH:13]([CH3:15])[CH3:14])[O:11][N:10]=1
Reactant: O=C(O)c1cccc2sc(B(O)O)cc12
Reactant: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1cc2c(C(=O)O)cccc2s1
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a 60° C. suspension of 4-(4-Bromo-3-methyl-phenoxymethyl)-3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazole (0.90 mmol; 410 mg) in a 2M solution of sodium carbonate (7.20 mmol; 3.6 mL) and 1.5 mL of deoxygenated dioxane under a nitrogen atmosphere is slowly added a solution of 4-carboxy-benzo[b]thiophen-2-boronic acid (1.08=mol; 240 mg) in 3.5 mL of deoxygenated dioxane over 1 h via an addition pump. The mixture is stirred for 1 h. The organic solvent is removed under reduced pressure and the residue is acidified with 1N HCl to pH 4. The resulting solution is extracted with dichloromethane. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is chromatographed using a gradient from 100% dichloromethane to 100% ethyl acetate to obtain a solid which is washed with acetonitrile to yield the title compound (135 mg, 27%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:23])([CH3:22])[CH3:21])[N:15]=2)[CH:3]=1.CO.[NH3:26]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:26])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:23])([CH3:22])[CH3:21])[N:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)O)n1
Reactant: N
Solvent: CO
Product: CC(C)(O)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.3 %

Procedure:
In a 50 mL round bottom flask, ethyl 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate (792 mg, 2.35 mmol) was suspended in ammonia 7M in methanol (7.87 g, 10.0 mL, 70.0 mmol). Sealed and stirred at room temperature for 5 h. The solvents were evaporated and the residue purified by flash chromatography (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to give 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (241 mg, 33.3% yield) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 11.64 (s, 1H), 8.96 (s, 1H), 8.18 (br. s., 1H), 7.71 (t, J=7.9 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 5.70 (br. s., 1H), 1.64 (s, 6H); LC-MS 308.0, 310.0 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:21]CCBr.CO>C1COCC1>[C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Br:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: O=C(Nc1ccccc1)c1ccncc1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccncc1Br
Temperature: -69 °C
Reaction time: 8 h

Procedure:
As described in Synthetic Communications 1997, 27, 1075-1086, a 4-necked RBF equipped with an overhead stirrer and a J-Kem internal temperature probe was placed N-phenylisonicotinamide (35.7 g, 0.18 mol) and anhydrous THF (700 ml). All material appeared to go into solution. This mixture was cooled to −69° C. in a dry ice/IPA bath. To this was slowly added nBuLi (158 ml of a 2.5 M solution in Hexanes) in three portions. While adding the first equivalent of nBuLi, an exotherm was observed raising the temperature to ca. −41° C. The orange reaction mixture was slightly heterogeneous. This was allowed to slowly warm to −5 to 0° C. over 1.5 hrs in a ice/brine bath. The reaction mixture was recooled to −72° C. and 1,2-dibromoethane (36 g, 0.189 mol) in 15 ml of THF was added. A slight exotherm was observed rising to −62° C. The reaction mixture was allowed to stir overnight. The reaction mixture was poured into a flask containing 10 vol. SiO2. Methanol (100 ml) was added and the mixture was concentrated under reduced pressure. The dried silica gel was then placed on top of a bed of silica gel. The plug of silica gel was washed with 40% ethyl acetate/Hexane as eluent. Concentration of 10 liters of solvent afforded an off-white solid. The material was placed in vacuum drying at 60° C. overnight to provide 34 g (68% th) of an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][C:28]6[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=6)[CH:26]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.C(OO)(=[O:37])C>C(Cl)Cl>[CH3:1][C:2]1([CH3:34])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][C:28]6[CH:29]=[N+:30]([O-:37])[CH:31]=[CH:32][CH:33]=6)[CH:26]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CC(=O)OO
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(-c5cnn(Cc6cccnc6)c5)cc43)sc2C(=O)N1
Solvent: ClCCl
Product: CC1(C)Cc2nc(N3CCOc4ccc(-c5cnn(Cc6ccc[n+]([O-])c6)c5)cc43)sc2C(=O)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
To a stirred solution of Example 323 (0.013 g, 0.028 mmol) in DCM (1.0 mL) was added peracetic acid (0.010 mL, 36-40 wt % in acetic acid, 0.055-0.061 mmol). The reaction mixture was stirred at r.t. for 150 minutes and then additional peracetic acid (0.040 mL, 36-40 wt % in acetic acid, 0.214-0.238 mmol) was added. After 46 h, the reaction mixture was concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.003 g, 20%) as a white solid. δH (CDCl3) 8.19-8.13 (2H, m), 7.98 (1H, d, J 1.9 Hz), 7.78 (1H, s), 7.66 (1H, s), 7.32-7.27 (1H, m), 7.20-7.14 (2H, m), 6.97 (1H, d, J 8.5 Hz), 5.42 (1H, s), 5.33 (2H, s), 4.37-4.31 (2H, m), 4.23-4.17 (2H, m), 2.89 (2H, s), 1.41 (6H, s). LCMS (ES+) 489 (M+H)+, RT 2.48 minutes (Method 1).
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([OH:11])=O.[NH2:34][OH:35]>>[OH:35][NH:34][C:9]([C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[N:2]([CH3:1])[S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])=[O:11]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@@H]3CCCC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 77 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 111 mg of trans-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-anecarboxylic acid with hydroxylamine provided 71 mg of trans-N-hydroxy-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxamide in 77% yield. MS: 484.1 (M+H)+
Reaction SMILES: Cl.C(OC([N:9]1[CH2:22][C:12]2=[C:13]3[N:18]([N:19]=[C:11]2[CH2:10]1)[C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=[N:14]3)=O)(C)(C)C>CC(O)=O.C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[N:14][C:13]2[N:18]([N:19]=[C:11]3[CH2:10][NH:9][CH2:22][C:12]3=2)[C:17]=1[CH3:20]
Reactant: Cc1c(Cl)cnc2c3c(nn12)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1c(Cl)cnc2c3c(nn12)CNC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A 32% solution of HCl (0.14 mL) was added to a solution of 6-chloro-7-methyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (140 mg; 0.44 mmol; 1 eq.) in AcOH (0.5 mL) and the reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with DCM, washed with 1M NaOH (2×), dried over sodium sulfate and concentrated in vacuo to afford the title compound (80 mg, 86%) as a yellow solid. 1H NMR (DMSO-d6) δ 8.48 (s, 1H), 4.12-4.03 (m, 4H), 3.73-3.57 (m, 1H), 2.80 (s, 3H). HPLC (max plot) 99.6%, Rt 1.33 min. UPLC/MS: (MS+) 209.1 ([M+H]+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[C:22]1([CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][C:30](Cl)=[O:31]>O1CCCC1>[Cl:2][C:3]1[C:4]([CH2:13][NH:14][C:30](=[O:31])[CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:33])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: Cc1ccccc1CCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1CCC(=O)NCc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (1 mmol, 0.247 g) in tetrahydrofuran (5 ml) was added triethylamine (2 mmol, 0.202 g) at room temperature and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate added to a solution of 3-(2-tolyl)propionyl chloride (1.1 mmol, 0.2 g) in tetrahydrofuran (5 ml) at room temperature. After 4 hours stirring at room temperature the solvent was evaporated and the residue washed with water. The solid was filtered and washed with diethyl ether/light petroleum (1:20) to give the title product, m.p. 152-3° C.