Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=1)=[O:7])(C)(C)C.C([Li])(C)(C)C.C(OCC)(=O)[C:25](OCC)=[O:26].Cl>C1COCC1>[CH:16]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[C:10]=1[C:25](=[O:26])[C:6](=[O:7])[NH:8]2)([CH3:17])[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)Oc1cccc(NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cccc2c1C(=O)C(=O)N2
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of 3.78 g (25.0 mmol) of 3-isopropoxy aniline and di-tert-butyl dicarbonate in 25 mL of THF was heated to reflux for 2 h. The solution was cooled to ambient tempurature, and solvent was removed in vacuo. The residue was dissolved in 100 mL of EtOAc, and the solution was washed with three 50-mL portions of 0.5 M citric acid and 50 mL of brine. The solution was dried over MgSO4 and removal of solvent in vacuo afforded N-(t-butyloxy-carbonyl)-3-isopropoxyaniline as a white solid (5.75 g, 92%): mp 79-81°C.; 1H NMR (DMSO-d6): δ1.21 (d, J=6.0 Hz, 6H), 1.43 (s, 9H), 4.46 (septet, J=6 Hz, 1H), 6.47 (dd, J=2.1, 8.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.0-7.1 (m, 2H), 9.23 (s, 1H); APCI−MS: m/z 274 (M+Na)+. To a solution of 2.5 g (10 mmol) of N-(t-butyloxycarbonyl)-3-isopropoxyaniline in 15 mL of dry THF at −78° C. was added 15 mL (25 mmol) of 1.7 M t-butyllithium in hexanes. The mixture was stirred at −20° C. for 2 h. A solution of 1.84 g (12.5 mmol) of diethyl oxalate in 10 mL of dry THF was added slowly over 5 min, and the mixture was stirred at −20° C. for 2 h. The reaction mixture was then poured into 100 mL of 1.0 N HCl and extracted with two 100-mL portions of EtOAc. Solvent was removed in vacuo, and the residue was dissolved in 100 mL of a 1:1 mixture of EtOH and 6 N HCl and heated to reflux for 1 h. The mixture was cooled to ambient temperature and was extracted with four 100-mL portions of EtOAc. The combined extracts were evaporated to dryness to provide crude 4-isopropoxy-1H-indol-2,3-dione, which was dissolved in 10 mL of EtOH containing 0.50 g (2.2 mmol) of 4-sulfonamidophenylhydrazine hydrochloride. The solution was heated to 80° C. for 1 h and cooled to ambient temperature. The resulting solid was collected by vacuum filtration and purified by flash chromatography on silica gel (EtOAc/hexane 3:2) to afford the title compound as a yellow solid (0.052 g, 1.4%): mp>250° C.; 1H NMR (DMSO-d6): δ3.35 (d, J=6 Hz, 6H), 4.74 (septet, J=6 Hz, 1H), 6.48 (d, J=7.7 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 7.14-7.2 (m, 3H), 7.47 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 11.01 (s, 1H), 12.7 (s,1H); APCI−MS: m/z 373 (M−H)−. Anal. Calcd for C17H18N4O4S: C, 54.53; H, 4.85; N, 14.96; S, 8.56. Found: C, 54.46; H, 4.84; N, 14.90; S, 8.50.
Reaction SMILES: [CH3:1][C:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:13])[CH:9]=2)[NH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].P(Cl)(Cl)([Cl:21])=O.CN(C)C1C=CC=CC=1>>[Cl:21][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:13])[CH:9]=2)[N:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]=1[CH3:1]
Reactant: CCOC(=O)c1[nH]c2ccc(C)cc2c(=O)c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1nc2ccc(C)cc2c(Cl)c1C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a mixture of ethyl 1,4-dihydro-3,6-dimethyl-4-oxoquinoline-2-carboxylate (4.0 g) and phosphoryl chloride (10 g) was added N,N-dimethylaniline (3.95 g) at ambient temperate and the mixture was stirred for 1 hour. The solvent was removed in vacuo, and the residue was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-hexane-dichloromethane) to give ethyl 4-chloro-3,6-dimethylquinoline-2-carboxylate (3.17 g) as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9]([O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:5]2[N:4]=1.CO.[Br:23]N1C(=O)CCC1=O>C1COCC1>[Br:23][C:11]1[N:5]2[C:6]([CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]2)=[C:9]([O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncc2c(OCOCC[Si](C)(C)C)ccn2n1
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ncc2c(OCOCC[Si](C)(C)C)cc(Br)n2n1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
Into a 1-Neck round-bottom flask, 2-Methylsulfanyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazine (1.05 g, 3.37 mmol), Tetrahydrofuran (50 mL) and Methanol (25 mL) were added and stirred at room temperature. N-Bromosuccinimide (0.630 g, 3.54 mmol) in THF (20 mL) was added to the reaction mixture . The reaction was stirred at room temperature for 2 hours. LCMS suggested no SM. The solvent was removed under vacuum. The reaction was partitioned with water and Et2O. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant (5 to 20% EtOAc). The collected fractions afforded 7-Bromo-2-methylsulfanyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazine as an oil (1.10 g, 83%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH:22]=[O:23].[CH3:24][C@H:25]1[CH2:30][N:29]([CH:31]2[CH2:34][O:33][CH2:32]2)[C@H:28]([CH3:35])[CH2:27][N:26]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)=[N:40][CH:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:24][CH:25]1[CH2:30][N:29]([CH:31]2[CH2:34][O:33][CH2:32]2)[CH:28]([CH3:35])[CH2:27][N:26]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([N:8]4[C:20](=[O:21])[C:19]5[S:18][C:17]6[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=6[C:11]=5[CH:10]=[N:9]4)[C:3]=3[CH:22]=[O:23])[CH:48]=2)=[N:40][CH:41]=1
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC1CN(C2COC2)C(C)CN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 38.1 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 124a (200 mg, 0.58 mmol), 3-({5-[(2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 155a (1.0 g, 2.0 mmol), PdCl2(dppf) (47 mg, 0.060 mmol), K3PO4 (280 mg, 1.2 mmol), sodium acetate (95 mg, 1.2 mmol), acetonitrile (15 mL), and water (1.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified with silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 159a as a red solid (150 mg, 38%). MS-ESI: [M+H]+ 679
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]Br>C(OCC)C>[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1F
Solvent: CCOCC
Product: O=C(CBr)c1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of 1-(2-fluorophenyl)ethanone (5.00 g, 36.2 mmol) in diethyl ether (100 ml) was slowly added dropwise bromine (5.78 g, 36.2 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was distilled off under reduced pressure to give the desired product (5.89 g, 74.9%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CCCCCBr
Reactant: Nc1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCNc1ccccc1-c1ccccc1
Yield: 98.1 %

Procedure:
20.0 g of 2-aminobiphenyl, 15.3 g of ethyldiisopropylamine and 26.3 g of ethyl 6-bromocaproate are reacted, analogously to Example 47a), to obtain 36.0 g of ethyl 6-(biphenyl-2-yl)aminocaproate as a non-crystallizing oil. 18.0 g of this ester are reacted, analogously to Example 47b), with 7.5 g of ethyldiisopropylamine and 10.1 g of p-chlorobenzoyl chloride in 70 ml of benzene. The resulting reaction product is purified chromatographically over a silica gel column (eluent: methylene chloride) to obtain 11.5 g (44.2% of theory) of ethyl 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproate as a viscous non-distillable oil. Saponification of this ester yields 8.1 g (75.1% of theory) of 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproic acid, MP 93° to 95°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](C2C=CC(N)=CC=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CCOC(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 89.7 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 35, step (b) using 4-nitrophenylboronic acid (167 mg, 1.00 mmol) and 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in Example 13, step (a), 295 mg, 1.00 mmol). Silica gel chromatography (10% EtOAc in hexanes) afforded the title compound (273 mg, 90%) as an oil. 1H-NMR (CDCl3; 400 MHz): δ 8.19 (d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 6.23 (m, 1H), 4.12 (m, 2H), 3.66 (m, 2H), 2.54 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][C:12]2[N:16]([C:17]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][N:18]=3)[N:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[C:26](#N)C.O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][C:12]2[N:16]([C:17]3[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][N:18]=3)[N:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1Cl
Reactant: CC#N
Solvent: O
Product: CCc1ccc(COc2ccnn2-c2cc(C(=O)OC)ccn2)cc1Cl

Procedure:
The title compound was prepared from 2-[5-[(3-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 95) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.76 (2H, q, J=7.6 Hz), 3.97 (3H, s), 5.18 (2H, s), 5.75 (1H, s), 7.26 (2H, s), 7.45 (1H, s), 7.58 (1H,$), 7.78 (1H, d, J=8.0 Hz), 8.33 (1H, s), 8.72 (1H, d, J=0.8 Hz). LCMS (mobile phase: 20%-95% Acetonitrile-Water-0.02% NH4OH): purity is >95%, Rt=4.602 min.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:30])([F:29])[C:5]([NH:7][CH2:8][CH:9]1[CH2:14][N:13](CC2C=CC=CC=2)[CH2:12][CH2:11][N:10]1CC1C=CC=CC=1)=[O:6]>CO.[Pd].O>[F:29][C:4]([F:3])([F:30])[C:5]([NH:7][CH2:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1)=[O:6]
Reactant: O=C(NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C(NCC1CNCCN1)C(F)(F)F
Yield: 96.8 %

Procedure:
To a solution of 3.1 g (6.7 mmol) of 2-trifluoroacetylaminomethyl-1,4-diphenylmethyl piperazine dihydrochloride in 100 ml methanol was added a suspension of 0.5 g palladium on carbon in 2 ml water. The mixture was hydrogenized for 30 mn, the catalyst was filtered off and the solvent was removed, taken up in 10 ml absolute ethanol, evaporated again and crystallized in ether to yield 1.37 g of a white powder (72%) as title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]([N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])[C:6]([N:8]1[C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]1C(OCC1C=CC=CC=1)=O)=[O:7].[H][H]>C(O)C.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH:5]([N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])[C:6]([N:8]1[C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=[CH:10][NH:9]1)=[O:7]
Reactant: CC(C)(C)OC(=O)C1=CC=CN(C(=O)OCc2ccccc2)N1C(=O)C(CCCBr)N1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1=CC=CNN1C(=O)C(CCCBr)N1C(=O)c2ccccc2C1=O
Yield: 96.2 %

Procedure:
2.37 g of 1-benzyl 3-tert.butyl 2-(5-bromo-2-phthalimidovaleryl)-1,3-pyridazinedicarboxylate (2 diastereomers) were dissolved in 25 ml of ethanol and the solution was hydrogenated at atmospheric pressure over 50 mg of 10% palladium-on-carbon until the uptake of hydrogen had ceased. The catalyst was removed by filtration and the filtrate was evaporated to give 1.79 g (96%) of tert.butyl 2-(5-bromo-2-phthalimidovaleryl)-3-pyridazinecarboxylate (2 diastereomers) in the form of an oil.
Reaction SMILES: C12(COC3C=CC(C(N)=O)=CC=3C3C(OC)=NC=CC=3)CC3CC(CC(C3)C1)C2.[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:53][CH2:52]4)=[CH:49][C:45]([C:46]([NH2:48])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.CS(Cl)(=O)=O.[CH:60]1([S:64](Cl)(=[O:66])=[O:65])[CH2:63][CH2:62][CH2:61]1>>[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:52][CH2:53]4)=[CH:49][C:45]([C:46]([NH:48][S:64]([CH:60]4[CH2:63][CH2:62][CH2:61]4)(=[O:66])=[O:65])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:37][CH:36]3[CH2:38][CH:32]([CH2:33][CH:34]([CH2:35]3)[CH2:39]1)[CH2:31]2
Reactant: O=S(=O)(Cl)C1CCC1
Reactant: NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)Cl
Product: O=C(NS(=O)(=O)C1CCC1)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 38 step 4 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide and to replace methanesulfonyl chloride with cyclobutanesulfonyl chloride, the title compound was obtained as a colorless solid (0.05 g, 10%): 1H NMR (300 MHz, CDCl3) δ8.57-8.44 (m, 1H), 7.60-7.52 (m, 1H), 6.61-6.48 (m, 1H), 4.61-4.46 (m, 1H), 3.55 (s, 2H), 2.74-2.56 (m, 2H), 2.45-2.29 (m, 2H), 2.12-1.97 (m, 6H), 1.84-1.64 (m, 12H), 0.99-0.88 (m, 2H), 0.71-0.58 (m, 2H); MS (ES+) m/z 462.2 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[C:15]1[C:16]([S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([N:2]([CH2:3][C:4]2[CH:9]=[C:8]([C:10]3[O:11][CH:12]=[CH:13][N:14]=3)[CH:7]=[CH:6][C:5]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:22])=[O:23])[CH3:1])=[O:39])=[CH:40][CH:41]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (24.1 mg, 0.055 mmol, prepared as described in Step (A) of Example 28) and 4-chlorobenzoic acid (7.8 mg, 0.05 mmol) in 0.5 ml of CH2Cl2, 4-dimethylaminopyridine (6.7 mg, 0.055 mmol) was added and followed by 1,3-diisopropylcarbodiimide (6.9 mg, 0.055 mmol). The reaction was stirred at room temperature for 18 hrs and concentrated. The residue was dissolved in MeOH, neutralized to pH>8 with aq. NaHCO3, and filtered. The filtrate was acidified to pH<5 with NaHSO4, and filtered to provide the title compound of this Example (18 mg, 62%) as a white solid, m.p. 122°-132° C. (amorphous).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:19][C:20]#[CH:21])([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:23][OH:24].[K+].[Br-]>>[OH:24][NH:23][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:19][C:20]#[CH:21])[CH2:16][C:17]#[CH:18]
Reactant: NO
Reactant: C#CCC(CC#C)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C#CCC(CC#C)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 85 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from (4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of the product was isolate Yield 85%; white solid; mp 156° C.; MS: 321.9 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H), 3.90(s, 3H), 7.01 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H); IR (KBr, cm−1): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s; Anal. Calc'd for C15H15NO5S: C, 56.07; H, 4.70; N, 4.36. Found: C, 55.65; H, 4.67; N, 4.10.
Reaction SMILES: [Si]([O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]2[O:26][C:27]3[CH:33]=[C:32]([O:34][CH2:35][CH:36]4[CH2:38][CH2:37]4)[CH:31]=[CH:30][C:28]=3[N:29]=2)[CH2:21][CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:36]1([CH2:35][O:34][C:32]2[CH:31]=[CH:30][C:28]3[N:29]=[C:25]([C@H:22]4[CH2:23][CH2:24][C@H:19]([OH:18])[CH2:20][CH2:21]4)[O:26][C:27]=3[CH:33]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1

Procedure:
A solution of a solution (1.0 M, 2.72 mL) of 2-(trans-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl)-6-(cyclopropylmethoxy)-1,3-benzoxazole (714 mg) and tetrabutylammonium fluoride in THF in THF (5 mL) was stirred at room temperature overnight and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (311 mg).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:9]([Mg]Br)[CH3:10].[Cl-].[NH4+]>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:1]([OH:8])[CH2:9][CH3:10])[CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cccnc1
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of nicotinaldehyde (0.200 mL, 0.12 mmol) in THF (2.0 mL) was slowly added to ethylmagnesium bromide (1.0 mol/L solution in THF, 3.18 mL, 3.18 mmol) at 0° C. The mixture was stirred at the same temperature for 1 hour and a saturated aqueous ammonium chloride solution was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give Compound A19 (194 mg, 67% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@@H]1C(O)=O.Br[C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([N+:34]([O-:36])=[O:35])[CH:22]=1>[Cu]I.O.C(OCC)(=O)C.CS(C)=O>[N+:34]([C:23]1[CH:22]=[C:21]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([O-:36])=[O:35]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-n2cccn2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
1H-Pyrazole (0.14 g), potassium carbonate (0.46 g), D-proline (38 mg), and copper(I) iodide (32 mg) were added to a dimethyl sulfoxide (5 mL) solution of tert-butyl 4-bromo-2-nitrobenzoate (0.50 g), followed by stirring under a nitrogen atmosphere at 100° C. for 3 hours. After cooling the reaction mixture to room temperature, ethyl acetate and water were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.20 g of tert-butyl 2-nitro-4-(1H-pyrazol-1-yl)benzoate as a white solid.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:30]([CH:33]4[CH2:35][CH2:34]4)(=[O:32])=[O:31])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH:33]1([S:30]([N:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][C:18]([N:11]4[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[NH:8][CH2:9][CH2:10]4)=[N:19][CH:20]=3)[CH2:29][CH2:28]2)(=[O:32])=[O:31])[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(S(=O)(=O)C4CC4)CC3)cn2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(C1CC1)N1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
10.3 g of 4-[5-(4-(cyclopropylsulphonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in 204 ml of a 4N solution of hydrochloric acid in dioxane. The reaction mixture is stirred at ambient temperature for 1.5 h. It is subsequently evaporated under reduced pressure and then a saturated aqueous sodium hydrogencarbonate solution is added. The aqueous phase is extracted three times with dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated under vacuum. 7.96 g of 4-[5-(4-(cyclopropylsulphonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline are obtained.