Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[O:8][C:9]([CH2:22][CH2:23][C:24](OC)=[O:25])=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=2)[CH:4]=[CH:5][N:6]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH2:24][OH:25])=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(C(F)(F)F)cc1
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(C(F)(F)F)cc2)c(CCCO)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Methyl 2-(2-methyl-1-imidazolyl)-4-(4-trifluoromethylphenyl)-5-oxazolepropionate (1.00 g) was dissolved in toluene (15 mL). To the obtained solution was added dropwise a mixture of a 70% solution (1.20 g) of sodium bis(2-methoxyethoxy)aluminum hydride in toluene and toluene (5 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was carefully added a 10% aqueous solution (50 mL) of potassium sodium (+)-tartrate tetrahydrate, and the mixture was stirred at room temperature for 1 h. The precipitated crystals were collected by filtration, washed successively with a 10% aqueous solution of potassium sodium (+)-tartrate tetrahydrate, pure water and isopropyl ether, and air-dried to give the title compound as crystals (0.75 g, 81%). Recrystallization from ethyl acetate-isopropyl ether gave pale-yellow prism crystals. melting point: 127-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7](O[Si](C(C)(C)C)(C)C)=[CH:6][C:3]=1[CH2:4][OH:5].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:47][N:48](C)C=O>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:47]#[N:48])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CO)c1
Agent: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: N#Cc1ccc(Br)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2 (20.0 mmol), (methoxymethyl)triphenylphosphonium chloride (8.49 g, 24.0 mmol), and potassium tert-butoxide (2.83 g, 24.0 mol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for overnight. The reaction was quenched with 6 N HCl, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (×2) and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced. To the residue were added tetrahydrofuran (60 mL) and 6 N HCl, and the mixture was heated at reflux for 8 h. Water was added, and the mixture was extracted with ether. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 16.6 mmol of 9.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1cccc(Cl)c1
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccc(Cl)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (3-chlorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 2.20 (s, 3H), 4.51 (d, J=3.0 Hz, 2H), 6.91 (d, J=6.8 Hz, 1H), 7.02-7.15 (m, 2H), 7.20 (t, J=6.4 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.55 (bs, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.78 (s, 1H), 8.10 (s, 1H), 8.49 (d, J=3.8 Hz, 1H); MS (ESI) m/z 340.1 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:22][CH2:21]3)=[CH:16][C:15]=2[CH:23]2[CH2:25][CH2:24]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(OCC)C>ClCCl>[CH:23]1([C:15]2[CH:16]=[C:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1cc(N2CCNCC2)c(C2CC2)cc1C1CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 68.5 %

Procedure:
A mixture of 1-(2,4-dichlorophenyl)piperazine (3 g), di-tert-butyl dicarbonate (3.23 g), triethylamine (5.5 mL) and methanol (30 mL) was stirred at room temperature for 5 hr. Water and ethyl acetate were added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(2,4-dichlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g). To a solution of 4-(2,4-dichlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g) in tetrahydrofuran (15 mL) were added 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (809 mg), palladium acetate (442 mg), tripotassium phosphate (11 g) and cyclopropylboronic acid (2.54 g), and the mixture was refluxed for 7 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(2,4-dicyclopropylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g). 4-(2,4-Dicyclopropylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g) was dissolved in dichloromethane (20 mL), 4N hydrogen chloride/dioxane (10 mL) was added, and the mixture was stirred at room temperature for 3.5 hr. Diethyl ether (100 mL) was added, and the precipitate was collected by filtration. To the obtained precipitate were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated to give 1-(2,4-dicyclopropylphenyl)piperazine (1.6 g). By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (237 mg) and 1-(2,4-dicyclopropylphenyl)piperazine (300 mg), the title compound (500 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1)=[O:9]
Reactant: COC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.6 %

Procedure:
2-Chloropyridine-4-carbonyl chloride (1.58 g, 9.0 mmol) in DCM (10 ml) was added dropwise to a solution of methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (1.81 g, 7.5 mmol) and triethylamine (3.13 ml, 22.5 mmol) in DCM (10 ml) at 0° C. The reaction was stirred at room temperature for 20 h, the solvent evaporated under vacuum and the residue partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The aqueous was extracted with ethyl acetate (50 ml) and the combined organic phases washed with brine (50 ml), dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/ethanol/ammonia (300:8:1). The solvents were evaporated under vacuum to give methyl 5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylate (1.73 g, 61%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CC(N2CCOCC2)CCN1
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method described for Preparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene and 4-(piperidin-4-yl)morpholine. The residue was purified using silica gel column chromatography eluting with 80-100% DCM in cyclohexanes.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3cnccn3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
2-Amino-4,6-dichloropyrimidine (15 g, 91 mmol) was treated with 1-methylpiperazine (10.1 g, 100 mmol), treated with Et3N (90 mL, 0.64 mol), treated with EtOH (185 mL), heated to 80° C. over night, cooled, concentrated and partitioned between CH2Cl2 (100 mL) and 1 M NaOH (125 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (4×100 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated and crystallized from EtOAc to provide 14.9 g (71%) of the title compound. 1H NMR (CDCl3) δ 2.34 (s, 3H), 2.45 (m, 4H), 3.60 (m, 4H), 4.82 (s, 2H), 5.96 (s, 1H); MS (DCl—NH3) m/z 228 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]2)=[CH:53][C:52]=1[CH3:63]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:59]3[CH2:60][CH2:61][C:57]([C:54]4[CH:55]=[CH:56][C:51]([F:50])=[C:52]([CH3:63])[CH:53]=4)([OH:62])[CH2:58]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: Cc1cc(C2(O)CCNC2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(F)c(C)c3)C2)cc1Cl
Yield: 40.6 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(4-fluoro-3-methylphenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (7 mg). MS (ESI, pos. ion) m/z: calcd for C22H20ClFN2O4: 430.1096, found 430.1094.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1Br)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1.[F:46][C:47]1[C:52]([CH:53]([CH3:55])[CH3:54])=[CH:51][C:50](B(O)O)=[C:49]([O:59][CH3:60])[CH:48]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O>[F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1[C:50]1[CH:51]=[C:52]([CH:53]([CH3:55])[CH3:54])[C:47]([F:46])=[CH:48][C:49]=1[O:59][CH3:60])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: COc1cc(Br)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)c(-c2cc(C(C)C)c(F)cc2OC)cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-4,5-dimethoxy-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (150 mg) is dissolved in 1,4-dioxane (3 ml) and thereto are added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (128 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (32 mg) and cesium carbonate (196 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4′-fluoro-5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (140 mg). MS (m/z): 796 [M+H]+
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=O)=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C1C2C3C(C(=O)N2CC[NH:25]1)=CC=CC=3.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)S(N)(=O)=O.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O.CN(C1C=CN=CC=1)C.CC(N(C)C)=O.C(N(CC)CC)C>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:25])=[O:21])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Reactant: O=C1c2ccccc2C2CNCCN12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)S(N)(=O)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 6-carboxylic acid (200 mg, 0.48 mmol), 1,2,3,4-tetrahydropyrazino[2,1-a]isoindol-6(10bH)-one hydrochloride (130 mg, 0.58 mmol) and triethylamine (0.20 mL) in DMF (3 mL) was added HATU (220 mg, 0.58 mmol). The reaction mixture was stirred at rt for 1 h, diluted with H2O (˜5 mL) stirred for 30 min, and the solids (288 mg) collected by filtration and flushed with H2O. The crude solids were dissolved into MeOH/THF (1:1, 4 mL) and treated with 1M aqueous NaOH (0.75 mL). The reaction mixture was stirred and heated at 80° C. with microwave irradiation for 15 min in a sealed tube. The clear solution was diluted with H2O (5 mL), neutralized with 1M aqueous HCl (0.75 mL) and concentrated to remove organic solvents. The resultant solids (247 mg) were collected by filtration and washed with H2O. To a stirred solution of the crude solids (150 mg, 61% of total collected, ˜0.25 mmol), N,N-dimethylsulfamide (155 mg, 1.25 mmol) and DMAP (150 mg, 1.25 mmol) in dimethylacetamide (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 1.0 mmol). The reaction solution was stirred at 50° C. for 2h, diluted with water (5 mL) and the resulting solids were collected by filtration. The mother liquor was concentrated and the solids and the mother liquor were independently purified by preparative HPLC (MeOH/2O with NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[(3,4,6,10b-tetrahydro-6-oxopyrazino[2,1-a]isoindol-2(1H)-yl)carbonyl] (71 mg total, 27 mg from solids and 44 mg from mother liquor, 0.09 mol, 36% over 3 steps) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.96 (br s, 1H), 8.15 (s, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.83 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.57-7.38 (m, 7H), 6.96 (s, 1H), 5.20 (br s, 1H), 4.44 (br s, 1H), 4.38-3.70 (m, 3H), 3.23-2.66 (m, 5H), 2.98 (s, 6H), 2.11-1.17 (m, 10H). LCMS: m/e 676 (M−H)−, ret time 1.61 min, column A, 2 minute gradient.
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[N+:14]([O-])([O-:16])=[O:15].[K+].C([O-])([O-])=O.[Na+].[Na+]>OS(O)(=O)=O>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)C1Cc2ccc([N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a solution of 2-tert-butylindoline (9.7 g) in H2SO4(98%, 80 mL) was slowly added KNO3(5.6 g, 56 mmol) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 h. The mixture was carefully poured into cracked ice, basified with Na2CO3 to pH 8 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-butyl-6-nitroindoline (4.0 g, 31% over two steps). 1 H NMR (300 MHz, CDCl3) δ 7.52(dd, J=1.8, 8.1 Hz, 1 H), 7.30(s, 1 H), 7.08(d, J=7.8 Hz, 1 H), 3.76(t, J=9.6 Hz, 1 H), 2.98-3.07(m, 1 H), 2.82-2.91(m, 1 H), 0.91(s, 9 H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:58]=[C:49]3[CH2:50][N:51]([CH2:54][CH2:55][O:56][CH3:57])[CH2:52][CH2:53][N:48]3[N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=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>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:58]=[C:49]3[CH2:50][N:51]([CH2:54][CH2:55][O:56][CH3:57])[CH2:52][CH2:53][N:48]3[N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: COCCN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COCCN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (198 mg, 0.50 mmol), 296f (190 mg, 0.50 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), Pd(dppf)Cl2 (21 mg, 0.025 mmol), acetonitrile (8 mL), and water (0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane (20 mL) and water (10 mL). The water layer was extracted with dichloromethane (2×20 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 296g (163 mg, 50%) as a yellow solid. MS-ESI: [M+H]+ 654.9
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:11][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOc1ncc(Br)cc1N
Solvent: c1ccncc1
Product: CCOc1ncc(Br)cc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5-bromo-2-(ethyloxy)-3-pyridinamine (1.45 g) in anhydrous pyridine (15 ml) was treated with benzenesulfonyl chloride (1.03 ml) then stirred at RT for 20 hr. The reaction was evaporated to dryness and the residue was purified by column chromatography on silica, eluting with 30% hexanes in DCM, to give the title compound (1.86 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si]([O:32][CH2:33][CH2:34][C:35]1[C:36]([F:53])=[C:37]([CH:50]=[CH:51][CH:52]=1)[CH2:38][N:39]1[CH2:49][CH2:48][C:42]2([O:47][CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40]1)(C(C)(C)C)(C)C.[CH2:54]([C:56]1[S:60][CH:59]=[C:58]([C:61](O)=[O:62])[CH:57]=1)[CH3:55].C(N(CC)CC)C>CN(C=O)C>[CH2:54]([C:56]1[S:60][CH:59]=[C:58]([C:61]([N:44]2[CH2:43][C:42]3([CH2:41][CH2:40][N:39]([CH2:38][C:37]4[CH:50]=[CH:51][CH:52]=[C:35]([CH2:34][CH2:33][OH:32])[C:36]=4[F:53])[CH2:49][CH2:48]3)[O:47][CH2:46][CH2:45]2)=[O:62])[CH:57]=1)[CH3:55]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CCc1cc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.316 g) was added in one portion to a solution at 0° C. of 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.271 g) and 5-ethylthiophene-3-carboxylic acid (0.1 g) and triethylamine (0.36 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in THF (20 mL) and treated with tetrabutylammonium fluoride (1M in THF, 1.921 mL). The reaction mixture was allowed to stand at 20° C. for 18 hours and the solvent was then removed under reduced pressure. The crude product was purified by flash silica chromatography using 2% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.12 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCCCBr)cc1

Procedure:
A solution of methyl 4-hydroxyphenylacetate (20.0 g, 0.12 mol), 1,3-dibromopropane (97.2 g, 0.48 mol) and cesium carbonate (43.1 g, 0.13 mol) in dry DMF (250 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with methylene chloride/hexane (2:1) to afford the title compound.