Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:19])=[C:10]([OH:18])[C:11]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.[OH-].[K+]>CS(C)=O>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:9]([F:19])[C:10]=2[O:18][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(O)c2F)cn1
Reactant: Fc1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cnc(-c2ccc(C3CCC3)c(OCc3ccc(F)cc3)c2F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50 mg, 0.19 mmol) and 1-(bromomethyl)-4-fluorobenzene (36 μL, 0.29 mmol) in DMSO (1 mL) was added 1 pellet (˜125 mg) of potassium hydroxide. The reaction was stirred for 16 hours at room temperature before filtering and purifying by HPLC to give 5-{4-cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazin-2-amine (37 mg, 39%). MS (ESI): mass calcd. for C21H19F2N3O, 367.15; m/z found, 368.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.30 (d, J=1.3, 1H), 8.22 (s, 1H), 7.58 (m, 1H), 7.50-7.43 (m, 2H), 7.20 (d, J=8.0, 1H), 7.15-7.07 (m, 2H), 5.01 (s, 2H), 3.83-3.68 (m, 1H), 2.31-2.21 (m, 2H), 2.18-1.93 (m, 3H), 1.87-1.78 (m, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH:26]=3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:32])([F:33])[C:28]([F:30])([F:31])[F:29])=[N:11]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(C3=CCNCC3)c2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.5 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[2-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-4-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 190, triethylamine (42.0 uL, 0.30 mmol) and methanesulfonyl chloride (7.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][CH:15]1[CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]1[NH2:22]>N1C=CC=CC=1>[CH3:14][CH:15]1[CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]1[NH:22][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: CC1CCCC(N)C1C
Solvent: c1ccncc1
Product: CC1CCCC(NC(=O)c2cnc3ccccc3n2)C1C
Yield: 58.8 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 2,3-dimethylcyclohexylamine (115 mg, 0.90 mmol), and pyridine (5 mL) yielding 150 mg (59%) of (163):
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:27][CH2:26][C:14]2([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:12][CH2:13][C:14]3([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][CH2:15]3)[CH2:26][CH2:27]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (585.5 g, 3.59 mmol) and tert-butyl 8-amino-2-azaspiro[4.5]decane-2-carboxylate (1.08 g, 4.24 mmol) in EtOH (10 mL) was added Et3N (722.3 mg, 7.14 mmol) and the reaction mixture was stirred at rt for 48 h then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as yellow oil (1.04 g, 76.0%).
Reaction SMILES: [CH:1]1([C:8]2[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]2[CH2:23]1.C1(C)C=CC=CC=1>O1CCCC1>[CH:1]1([C:8]2[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[CH2:23][C:24]4[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=4[C:26]([OH:28])=[O:27])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1

Procedure:
A solution of 2.1 g of (E)-3-[2-[4-(cycloheptyl)-2-thiazolyl]ethenyl]benzeneamine, 1.25 g of homophthalic anhydride and 30 ml of toluene was heated to reflux for 0.5 hr. Cooling and filtration yielded 2.31 g of (E)-2-[2-[3-[2-[4-(cycloheptyl)-2-thiazolyl]ethenyl]phenyl=amino]-2-oxoethyl]benzoic acid; m.p. 189°-190° C. from tetrahydrofuran.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[BrH:18]>O.ClCCl>[C:6]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:1][CH2:2][CH2:3][Br:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Reactant: Br
Solvent: ClCCl
Solvent: O
Product: BrCCC=C(c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
At 0° C., cyclopropyl-diphenyl-carbinol (10.0 g) is dissolved in a hydrogen bromide solution 48% (40 ml). After being subjected to agitation for 5 hours at 0° C., the medium is diluted with water and dichloromethane, then the organic phase is washed three times with water. The organic phase is dried on MgSO4, filtered and concentrated to obtain the expected product as an orange oil (11.89 g).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[N+:16]([O-])([O-:18])=[O:17].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:16]([C:15]1[C:2]([OH:1])=[C:3]([CH:12]=[CH:13][CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(c1ccccc1)c1ccccc1O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 43.6 %

Procedure:
2-Hydroxybenzophenone (3.00 g, 15.1 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.42 g, 16.7 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.60 g, 44%). 1H NMR (CD3COCD3): δ 8.30 (d, 1H), 7.86 (m, 3H), 7.71 (m, 1H), 7.78 (d, 1H), 7.56 (dd 2H), 7.24 (t, 1H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:28]CCC.CI>C1COCC1>[CH3:28][C:13]1[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:17][CH:16]=2
Reactant: [Li]CCCC
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole (1.6 g, 4.4 mmol, synthesized as described in Example 22A) in THF (10 mL), under N2, at −78° C., was added n-BuLi (2.5 M solution in hexanes, 2.15 mL, 5.37 mmol) dropwise. After stirring at −78° C. for 30 min, methyl iodide (0.94 g, 6.6 mmol) was added. After 30 min, the −78° C. bath was removed. The solution was warmed to rt. 5% HCl (10 mL) was then added and the mixture was partitioned between EtOAc and water. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (20-70% EtOAc-hexanes gradient) to afford the title compound (0.8 g, 77% yield): MS (ES) m/z 478 (M+1).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=1)[CH2:18][N:19]1[CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:18][C@@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: N#Cc1ccc([C@H](N)CN2CCC2)cc1Cl
Agent: Cl
Product: N#Cc1ccc([C@@H](CN2CCC2)Nc2ncnc3c(C(N)=O)ccnc23)cc1Cl

Procedure:
Compound 47 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with 4-((S)-1-Amino-2-azetidin-1-yl-ethyl)-2-chloro-benzonitrile hydrochloride to give the title compound as a white solid. LC/MS [409 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.16 (d, 1H), 9.03 (d, 1H), 8.56 (s, 1H), 8.40 (d, 1H), 8.18 (s, 1H), 7.93 (d, 1H), 7.66 (d, 1H), 5.35 (s, 1H), 3.27-2.97 (m, 2H), 2.88 (d, 2H), 2.01-1.83 (m, 4H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].[Na+].[I-]>C1COCC1>[C:48]([O:47][C:45](=[O:46])[CH2:44][N:18]([CH2:17][CH2:16][CH:14]1[O:13][C:12](=[O:33])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1)([CH3:51])([CH3:50])[CH3:49]
Reactant: COc1ccc2nccc(CCNCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nccc(CCN(CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)CC(=O)OC(C)(C)C)c2n1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A solution of the compound of Example 72 (0.2 g, 0.44 mmol) in THF (3 mL) was treated with DIPEA (0.147 mL, 2 eq.), tert-butyl bromoacetate (0.129 g, 1.5 eq.) and NaI (0.067 g, 1 eq.). The mixture was heated at 80° C. for 2 h, partitioned between EA and water. The org. phase was dried over MgSO4 and concentrated. The residue was purified by FC (EA) to give the title compound as a yellowish oil (0.17 g, 67% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][C:7]=1[Cl:36].C(N(CC)C(C)C)(C)C.[C:46]([O:50][C:51](=[O:59])[NH:52][CH2:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:46]([O:50][C:51](=[O:59])[NH:52][CH2:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH:56][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:34]=[CH:35][C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[C:7]([Cl:36])[CH:8]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:33][CH:32]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a 100 mL round-bottom flask charged with the 4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid prepared above (13.0 mmol) was added CH2Cl2 (65 mL), and then N,N-diisopropylethylamine (7.95 mL, 45.5 mmol). The flask was cooled with a 0° C. bath. To the solution was added tert-butyl(3-amino-2,2-dimethylpropyl)carbamate (3.16 g, 15.6 mmol), and then 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 6.43 g, 16.9 mmol). The bath was removed and the solution was allowed to warm to room temperature with stirring for 1 h. The solution was transferred to a 1 L separatory funnel and was diluted with EtOAc (500 mL). The solution was washed with aq. 2M HCl (2×100 mL), and then with sat. aq. NaHCO3 (100 mL), and then with sat. aq. NaCl (100 mL). The organic solution was dried over MgSO4; filtered; and then concentrated in vacuo. The resulting solid residue was subjected to SiO2 chromatography (hexanes:EtOAc, 1:1) to afford tert-butyl(3-(4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate as a colorless solid (8.77 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.5 Hz, 2H), 7.76-7.66 (m, 1H), 7.62 (dd, J=15.6, 8.5 Hz, 2H), 7.35 (s, 1H), 7.22-7.15 (m, 1H), 6.96-6.89 (m, 1H), 5.16-5.04 (m, 1H), 4.73 (dq, J=12.2, 8.4 Hz, 2H), 4.57 (d, J=5.3 Hz, 2H), 4.19-4.14 (m, 2H), 3.69-3.61 (m, 2H), 3.28-3.18 (m, 2H), 3.00-2.92 (m, 2H), 2.36 (sxt, J=5.8 Hz, 2H), 1.46 (d, J=2.0 Hz, 9H), 0.91 (d, J=3.3 Hz, 6H); MS m/z=774.25 (M+1)+.
Reaction SMILES: COC[N:4]1[C:9]2[C:10]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[N:11][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[S:5]1(=[O:32])=[O:31].Cl.C(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[N:21]1([C:19]([C:10]2[C:9]3[NH:4][S:5](=[O:31])(=[O:32])[C:6]4[CH:30]=[CH:29][CH:28]=[CH:27][C:7]=4[C:8]=3[N:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=2)=[O:20])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: COCN1c2c(C(=O)N3CCOCC3)nn(-c3ccccc3)c2-c2ccccc2S1(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(c1nn(-c2ccccc2)c2c1NS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 10.3 %

Procedure:
To a solution of 4-(methoxymethyl)-3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazine 5,5-dioxide (85 mg; 0.19 mmol; 1.00 eq.) in 1,4-dioxane (3 mL) is added HCl (0.75 mL; 1 M; 0.75 mmol; 4.00 eq.) after which reaction mixture is stirred at 100° C. for 90 min under microwave irradiation (*2). DCM is added to the reaction mixture that is neutralized to pH 6 with NaHCO3, extracted with DCM, dried over MgSO4 and purified by MD-Autoprep to give 8 mg (10%) of the title compound as an off white solid. 1H NMR (300 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.00-7.91 (m, 1H), 7.71-7.50 (m, 7H), 6.99-6.86 (m, 1H), 3.83-3.55 (m, 8H). HPLC (max plot) 97.4%; Rt 3.27 min. MS (ESI+) 411.2.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)(=O)=O.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)#[N:26]
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccccc2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)cc(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Zinc cyanide (1.1 g) and Pd(PPh3)4 (281 mg) were added to a DMF (45 mL) solution of methyl 5-{[(trifluoromethyl)sulfonyl]oxy}biphenyl-3-carboxylate (1.68 g), and stirred at 90° C. for 1 hour and 30 minutes. The reaction liquid was filtered through Celite, the solvent was partly evaporated away, and the residue was diluted with ethyl acetate, aqueous ammonia was added to it, and the solution was extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated away. The residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Reaction time: 16 h

Procedure:
A mixture of 2.4 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], Example 23 b, 5.4 g of 2-fluoronitrobenzene and 1.0 g of sodium bicarbonate is stirred at 160°-165° C. under nitrogen, for 16 hours. Thereafter, the mixture is permitted to cool before sequentially being quenched with water and extracted thrice with ether. The combined ether extracts are shaken with a large excess of 1 N hydrochloric acid. The acidified layer is basified providing a reddish oil which upon drying over magnesium sulfate and then cooling leaves an orange solid. The solid is recrystallized from an etherpentane mixture to provide prisms, mp 130°-131° C. of 6-chloro-1'-methyl-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine].
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:32][C:27]1[CH:26]=[C:25]([C@@H:20]2[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:13][CH:12]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@@H](c2ccc(Cl)c(Cl)c2)C3)cc1
Product: Clc1ccc([C@H]2Cc3cnc(Nc4ccc(CCN5CCOCC5)cc4)nc3-c3ccccc32)cc1Cl
Yield: 45 %

Procedure:
This product was synthesized as described in general procedure 2 except (R)-4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and morpholine was used instead of piperidine to afford the title compound in 45% yield. M.p.=166-167° C. 1H NMR 400 MHz (CDCl3) δ 8.41 (dd, J=1.6 Hz, 7.6 Hz, 1H), 8.18 (s, 1H), 7.65-7.61 (m, 2H), 7.49-7.39 (m, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.25-7.19 (m, 3H), 7.09 (s, 1H), 7.03-6.99 (m, 1H), 6.91 (dd, J=2.4 Hz, 8.4 Hz, 1H), 4.29-4.24 (m, 1H), 3.79-3.74 (m, 4H), 3.21 (dd, J=6.0 Hz, 15.6 Hz, 1H), 3.04 (dd, J=7.2 Hz, 15.6 Hz, 1H), 2.83-2.77 (m, 2H), 2.64-2.51 (m, 6H). LCMS m/e 531 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.COC1C2CCCC(=O)NC=2C=CC=1[N+:29]([O-:31])=[O:30]>>[CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[NH:8][C:7]=2[C:6]([N+:29]([O-:31])=[O:30])=[CH:5][CH:4]=1
Reactant: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2
Reactant: COc1cccc2c1CCCC(=O)N2
Product: COc1ccc([N+](=O)[O-])c2c1CCCC(=O)N2

Procedure:
Analogous to procedure 107b, 6-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (700 mg, 3.66 mmol) was converted to 6-Methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (380 mg, 44%), purified by ISCO chromatography. 1H-NMR (CDCl3) δ 8.12 (s, 1H), 7.79 (d, J=8.6 Hz, 1H). 6.85 (d, J=8.6 Hz, 1H), 3.95 (s, 3H), 2.95 (t, J=7.2 Hz, 2H), 2.44 (t, J=7.3 Hz, 2H), 2.31 (quint, J=7.2 Hz, 2H); LC/MS (ESI-pos) m/z 237.11 (M+H). Analogously, 6-Methoxy-9-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was also isolated.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1.Cl>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:40])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.296 mL, 0.296 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 51-(1); 54.8 mg, 0.106 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at 60° C. for two hours. The reaction mixture was then poured into 0.5 N hydrochloric acid aqueous solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (52 mg, 98%).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:10][C:9]=12)=[NH:4].[S:28]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=1)(=[O:31])(=[O:30])[NH2:29]>>[F:17][C:14]([F:15])([F:16])[C:13]1[N:8]2[N:7]=[CH:6][C:5]([C:3]3[N:4]=[C:36]([C:35]4[CH:34]=[CH:33][C:32]([S:28]([NH2:29])(=[O:31])=[O:30])=[CH:40][CH:39]=4)[O:1][N:2]=3)=[C:9]2[N:10]=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH:12]=1
Reactant: N=C(NO)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Product: NS(=O)(=O)c1ccc(-c2nc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)no2)cc1

Procedure:
The title compound was prepared from N-hydroxy-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxamidine (example B.1) (195 mg, 0.5 mmol) and commercially available 4-sulfamoyl-benzoic acid (101 mg, 0.5 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (155 mg, 56%). MS (ISN) 553.3 [(M−H)−]; mp 292° C.