Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15]C(C)([O-])C.[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:15])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
1-tert-Butoxycarbonyl-3-oxopiperazine (see Tetrahedron Lett. (1980), 21(32), 3019-20 for outline of synthesis, 5 g) was dissolved in dry DMF (75 ml) and potassium tert-butoxide (3.08 g) was added. The mixture was stirred at ambient temperature for 1 hour, then iodomethane (3.9 g) was added, and stirring continued at the same temperature for 2.5 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 100% ethyl acetate in iso-hexane. Relevant fractions were combined and evaporated to give 1-tert-butoxycarbonyl-4-methyl-3-oxopiperazine (3.92 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[CH2:22]([N:29]1[CH2:34][CH2:33][C:32](=[CH:35][C:36](OCC)=[O:37])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:22]([N:29]1[CH2:30][CH2:31][C:32]2([N:6]3[N:5]=[C:4]([C:7]4[CH:8]=[CH:9][C:10]([O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[CH:11][CH:12]=4)[C:3]([C:20]#[N:21])=[C:2]3[NH:1][C:36](=[O:37])[CH2:35]2)[CH2:33][CH2:34]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C=C1CCN(Cc2ccccc2)CC1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)CC21CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Yield: 53.9 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (1.0 g, 3.6 mmol), ethyl 2-(1-benzylpiperidin-4-ylidene)acetate (1.1 g, 4.3 mmol) and K2CO3 (745 mg, 5.4 mmol) in DMF (20 mL) was heated to 80° C. for 16 hr under N2. The reaction was quenched with water (20 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel using 30% of EA in PE as eluant to give the product (950 mg, 54.9%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.48-7.40 (m, 2H), 7.36-7.29 (m, 4H), 7.27-7.23 (m, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.15-7.07 (m, 4H), 3.55 (s, 2H), 3.01 (s, 2H), 2.81-2.73 (m, 2H), 2.39-2.27 (m, 2H), 2.26-2.16 (m, 2H), 1.83-1.74 (m, 2H). MS (ESI, m/e) [M+1]+ 489.9.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH3:13][C:14]1[N:15]=[C:16]([CH2:19][C:20](=[O:23])[CH2:21][CH3:22])[S:17][CH:18]=1.N1CCCCC1.C(O)(=O)C>ClCCl>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[C:19]([C:16]1[S:17][CH:18]=[C:14]([CH3:13])[N:15]=1)[C:20](=[O:23])[CH2:21][CH3:22])[C:7]#[N:8]
Reactant: COc1cc(C#N)ccc1C=O
Reactant: CCC(=O)Cc1nc(C)cs1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCC(=O)C(=Cc1ccc(C#N)cc1OC)c1nc(C)cs1

Procedure:
400 mg (2.48 mmol) of the compound from example 3A and 924 mg (2.73 mmol, 50% purity) of the compound from example 5A are dissolved in 10 ml of dichloromethane, and 0.245 ml (2.48 mmol) of piperidine and 0.142 ml (2.48 mmol) of acetic acid are added. The reaction mixture is heated under reflux with an inverse water trap overnight. The volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 657 mg (83% of theory) of the title compound are obtained as a mixture of the E/Z isomers.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:32]2[CH:31]=[N:30][C:29]([O:28][CH3:27])=[N:34][CH:33]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(Br)c1
Product: COc1ncc(-c2cccc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cn1

Procedure:
By carrying out the operation analogously to example 3, starting from 3-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 2-methoxy-5-pyrimidineboronic acid, the expected product is obtained and is reacted further without additional purification in order to obtain the nonacetylated xyloside.
Reaction SMILES: [CH:1]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:2]=1.Br[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([F:30])=[CH:23][C:22]=1[F:31].C([Sn](CCCC)(CCCC)C=C)CCC.[F-].[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)C>[F:30][C:24]1[CH:23]=[C:22]([F:31])[C:21]([CH:1]=[CH2:2])=[CH:26][C:25]=1[N+:27]([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=Cc1cc([N+](=O)[O-])c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 385.6 %

Procedure:
A mixture of Pd2 dba3 (1.924 g, 2.101 mmol), and PPh3 (2.204 g, 8.404 mmol) was dissolved in toluene (200 mL), degassed and then stirred 10 minutes at ambient temperature. A solution of 1-bromo-2,4-difluoro-5-nitrobenzene (10 g, 42.02 mmol) in toluene (200 mL) was then added to the above solution, followed by tributyl(vinyl)stannane (18.40 mL, 63.03 mmol). The mixture was refluxed for 2 hours, then poured into a mixture of aqueous NaF and diethyl ether. The residue was purified using silica gel column chromatography with 5-10-20% acetone in hexanes to provide 1,5-difluoro-2-nitro-4-vinylbenzene (6 g, 32.41 mmol, 77.13% yield) as yellow oil.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27]>CN1C(=O)CCC1>[NH2:27][CH2:26][CH2:25][NH:28][C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(Cl)c23)c(C)c1
Reactant: NCCN
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(NCCN)c23)c(C)c1

Procedure:
Heat a solution of 4-chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizine (0.3 g, 0.89 mmol), and ethylene diamine (0.6 mL, 8.93 mmol) in dry NMP (3 mL) at 100° C. for 14 h. Pour the cooled mixture onto water (30 mL) and extracted twice with EtOAc (30 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (20% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:16]=1)[C:3]1[N:8]=[C:7]([S:9][C:10]#[N:11])[C:6]([N+:12]([O-])=O)=[CH:5][N:4]=1>C(O)(=O)C>[NH2:11][C:10]1[S:9][C:7]2[N:8]=[C:3]([N:2]([CH3:1])[C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)[N:4]=[CH:5][C:6]=2[N:12]=1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Solvent: CC(=O)O
Product: CN(c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1)c1ncc2nc(N)sc2n1
Temperature: 100 °C
Yield: 25.4 %

Procedure:
To a solution of 2-[methyl(3-{[3-(trifluoromethyl)benzoyl]amino}phenyl)amino]-5-nitropyrimidin-4-yl thiocyanate (1.79 g, 3.76 mmol) in acetic acid (100 mL) was added reduced iron (5.50 g, 98.5 mmol), and the mixture was stirred with heating at 100° C. for 1.5 hr. The reaction solution was allowed to cool to room temperature, and the insoluble material was filtered off and the residue was washed with acetic acid. The combined filtrate and washing solution were concentrated under reduced pressure, and the residue was diluted with tetrahydrofuran (50 mL) and ethyl acetate (250 mL). This liquid was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL), saturated aqueous ammonium chloride solution (150 mL) and saturated brine (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and recrystallized from ethyl acetate and tetrahydrofuran to give N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(trifluoromethyl)benzamide (compound of Example D1) (424 mg, 26%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>Cl.CC(O)C>[F:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1ccc(-c2ccnc(Cl)c2)cc1F
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc(-c2ccnc(N3CCN(C)CC3)c2)cc1F
Temperature: 180 °C

Procedure:
To a microwave tube was added 2-chloro-4-(3-fluoro-4methyl-phenyl)-pyridine (30 mg, 0.14 mmol), 1-methylpiperazine (50 mg, 0.5 mmol), 2-propanol (0.6 mL) and 1 drop concentrated HCl. The resulting mixture was heated at 180° C. for 60 minutes using the microwave instrument. The resulting mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.S(Cl)(Cl)=O.[Mg].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1.C(OCC)C.C(Cl)(Cl)(Cl)Cl.CCO>[CH3:6][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)([CH3:1])[C:3]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:22]([O:30][CH2:31][CH3:32])=[O:29])=[O:5]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1ccc(C(F)(F)F)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of 2-methyl-2-(4-(trifluoromethyl)phenyl)propanoic acid (1325 mg, 5706 μmol) in thionyl chloride (4162 μL, 57063 μmol) was heated at reflux under nitrogen. After 2 hours, the reaction was cooled to 23° C. and concentrated in vacuo to afford the crude acid chloride. In an oven-dried round-bottomed flask, magnesium (208 mg, 8559 μmol) and diethyl malonate (1293 μL, 8559 μmol) were added to EtOH (15 mL) and CCl4 (0.2 mL). The reaction was stirred at 23° C. for 30 minutes followed by the addition of THF (15 mL). The reaction was heated to reflux under nitrogen. After 1 hour, a solution of the crude acid chloride in THF (10 mL) was added in a drop wise fashion. After 30 minutes, the reaction was cooled to 23° C., diluted with diethyl ether (150 mL), and washed with water (150 mL). The aqueous layer was extracted with diethyl ether (150 mL). The combined ether layers were washed with brine (100 mL), dried over MgSO4, concentrated in vacuo, and purified on silica gel (eluant: 5-20% EtOAc/hexane) affording 1115 mg of the title compound. MS m/e=375.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[S:10](=[O:12])(=[O:11])[NH2:13])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1cc(F)cc(F)c1S(N)(=O)=O
Product: NS(=O)(=O)c1c(F)cc(F)cc1NS(=O)(=O)c1cccc(Cl)c1Cl
Yield: 7 %

Procedure:
The title compound was synthesized as described for Example 194 a) in 7% yield, starting from 2-amino-4,6-difluorobenzenesulfonamide and 2,3-dichlorobenzene-1-sulfonyl chloride (1.5 equiv.). Purification by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]=[C:26]1[CH2:35][CH2:34][CH2:33][C:32]2[C:31]([OH:36])=[CH:30][CH:29]=[CH:28][C:27]1=2>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:36][C:31]3[C:32]4[CH2:33][CH2:34][CH2:35][C:26](=[CH2:25])[C:27]=4[CH:28]=[CH:29][CH:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: C=C1CCCc2c(O)cccc21
Product: C=C1CCCc2c(Oc3nc(C(=O)NC(C)c4cc(F)c(NS(C)(=O)=O)c(F)c4)co3)cccc21
Yield: 79.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 5-methylene-5,6,7,8-tetrahydro-naphthalen-1-ol (43 mg, 0.26 mmol, example 39) to give the title compound (52 mg, 85%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]2[C:12]([F:26])=[C:13]([CH:22]=[CH:23][C:24]=2[F:25])[O:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.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]>[F:26][C:12]1[C:11]([NH:10][CH2:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=3)[CH:3]=2)=[C:24]([F:25])[CH:23]=[CH:22][C:13]=1[O:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1cc(Br)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)cc(-c2cccc(F)c2)c1
Yield: 78.9 %

Procedure:
To a solution of isopropyl 2-[3-[(3-bromo-5-methyl-phenyl)methylamino]-2,4-difluoro-phenoxy]acetate (176 mg, 0.4 mmol, 1.0 eq) in acetonitrile (15 mL) was added 3-fluorophenylboronic acid (86 mg, 0.61 mmol, 1.5 eq), K2CO3 (142 mg, 1.03 mmol, 2.5 eq) and Pd(dppf)Cl2 (15 mg, 0.02 mmol, 0.05 eq). The mixture was heated at reflux overnight then the solvent was removed in vacuo. The residue was diluted with CH2Cl2, washed with water, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ether: EtOAc, 150:1 to 60:1) to give the title compound as an oil (140 mg, 77%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([OH:21])=[C:6]([Cl:20])[C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:8]=2[CH:19]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:21][C:5]1[C:4]([Cl:3])=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[N:10][O:11][C:7]=2[C:6]=1[Cl:20])[CH3:28]
Reactant: Oc1c(Cl)cc2c(-c3ccccc3F)noc2c1Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(Cl)cc2c(-c3ccccc3F)noc2c1Cl
Temperature: 45 °C

Procedure:
1.4 g NaH is suspended in 50 ml DMF with stirring. A solution of 7.2 g of 5,7-dichloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole in 50 ml DMF is added dropwise. The solution is heated to 45° C. for one hour. Ethyl bromoacetate (4.0 g) in 20 ml DMF is added dropwise and the reaction is stirred at 40° C. for two hours. The solution is poured into 1 l of water, stirred and extracted with ethylacetate. The organic extracts are washed with saturated NaCl solution and the solvent removed in vacuo affording ethyl{[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetate, mp 105°-106° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].F[B-](F)(F)F.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+]#N)[CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[C:15]([O:32][CH3:33])[CH:14]=1)=[O:12].C(OCC)(=O)C.O>CN(C)C=O>[C:1]([C:27]1[CH:28]=[C:29]2[C:24]([CH:23]=[CH:22][CH:21]=[C:20]2[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14][C:15]=2[O:32][CH3:33])=[CH:25][CH:26]=1)#[N:2]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc([N+]#N)cc23)c(OC)c1
Reactant: [C-]#N
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cccc3ccc(C#N)cc23)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
A mixture of cuprous cyanide (2.52 g), sodium cyanide (1.68 g), and dimethylformamide (50 ml, distilled over CaH2) was stirred for 1 h. The homogeneous solution was cooled to 0° C. and a solution of 1-(4-methoxycarbonyl-2-methoxyphenylmethyl)naphthalene-7-diazonium tetrafluoroborate (2.62 g), in dimethylformamide (12 ml, distilled over CaH2) was added. The reaction was stirred for 15 min at 0° C. and then at room temperature for 16 h. The mixture was added to ethyl acetate (200 ml) and water (300 ml) and filtered through diatomaceous earth with ethyl acetate washes. The organic layer was washed (water, brine), dried (MgSO4), and evaporated. Flash chromatography of the residue, eluting with methylene chloride, and trituration of the product with hot ether afforded methyl 4-(7-cyanonaphth-1-ylmethyl)-3-methoxybenzoate (1.04 g, 56%) as a pale yellow solid; mp 138.5°-139.5° C.; MS(CI), m/e=33Z(M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][N:49]([CH3:54])[S:50](Cl)(=[O:52])=[O:51]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([S:50]([N:49]([CH3:54])[CH3:48])(=[O:52])=[O:51])[CH2:42][CH2:41]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 38 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and dimethylsulfamoyl chloride as starting materials in 38% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.36 (s, 1H), 9.29 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.76 (s, 1H), 7.21 (d, 1H), 7.05 (m, 2H), 6.89 (d, 1H), 6.79 (d, 1H), 3.58 (d, 2H), 2.88 (m, 6H), 2.76 (s, 6H), 2.30 (d, 2H), 1.91 (m, 1H), 1.76 (m, 2H), 1.21 (m, 2H). LCMS for C27H33ClN7O3S (M+H)+: m/z=570.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:15]=1[NH2:16])([O-:13])=[O:12].C(N(CC)CC)C.O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:14]=2[N+:11]([O-:13])=[O:12])=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-chloronicotinoyl chloride (100 mg, 0.6 mmol) and 2-nitro-4-trifluoromethylaniline (117 mg, 0.6 mmol) in THF (10 ml) was added triethylamine (0.16 ml, 1.1 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. Water was added to dissolve the precipitate and the organic phase was separated and washed with water, then dried over anhydrous sodium sulfate. The product was purified by column chromatography to give the title compound as a pale yellow solid. 1H NMR (DMSO-d6): 11.27 (s, 1H), 8.97 (d, J=2.7, 1H), 8.38-8.35 (m, 2H), 8.19 (d, J=8.4, 1H), 7.96 (d, J=8.7, 1H), 7.78 (d, J=8.1, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:24]([NH:23][S:20]([C:15]1[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([N:1]([S:20]([CH3:15])(=[O:22])=[O:21])[S:39]([CH3:38])(=[O:41])=[O:40])=[CH:7][N:6]=3)=[C:9]([F:28])[CH:10]=2)=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:22])=[O:21])([CH3:25])([CH3:27])[CH3:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N(S(C)(=O)=O)S(C)(=O)=O)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 17.25 h

Procedure:
To a 20 mL vial were added a stir-bar, 4′-(5-aminopyrazin-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide (49 mg, 0.12 mmol), dry DCM (2.0 mL), DIPEA, (0.10 mL, 0.58 mmol), and methanesulfonyl chloride (0.020 mL, 0.25 mmol). The mixture was stirred at rt for 17.25 h before subjecting it to FCC to give impure title compound. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([CH2:9][NH:10][C:11]([NH2:13])=[S:12])=[CH:7][CH:6]=1)=[O:4].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=O.C(=O)(O)[O-].[Na+].O>C(#N)C.CCCCCC>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:13]=[C:11]([NH:10][CH2:9][C:8]3[CH:14]=[CH:15][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[S:12][CH:17]=2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccc(CNC(N)=S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1ccc(CNc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a suspension of 1-(4-methoxycarbonylbenzyl)-2-thiourea (138.0 g, 0.554 mol) obtained in Example 1(1) in acetonitrile (1380 ml, 10.0 v/w) were successively added 2-bromo-4′-nitroacetophenone (124.1 g, 0.554 mol) and sodium bicarbonate (46.9 g, 0.559 mol), and the mixture was heated under reflux for 2 hr. After cooling to room temperature, water (1380 ml, 10.0 v/w) and n-hexane (690 ml, 5.0 v/w) were successively added and the mixture was stirred for 1 hr. The precipitated crystals were collected by filtration, washed successively with water (1000 ml) and n-hexane (500 ml) and dried in vacuo to give the title compound (183.9 g, yield 89.9%) as a yellow solid.