Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([CH3:8])=[N:5][CH:4]=1.[C-:9]#[N:10].[Na+].O>CN(C=O)C>[CH3:8][C:6]1[O:7][C:3]([CH2:2][C:9]#[N:10])=[CH:4][N:5]=1
Reactant: [C-]#N
Reactant: Cc1ncc(CBr)o1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc(CC#N)o1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 5-(bromomethyl)-2-methyl-oxazole CAS [82190-68-9] (15 g, 85 mmol) in DMF (150 mL) was treated with NaCN (10.4 g, 213 mmol) at room temperature and the mixture stirred at 70° C. for 1 h. After this time the mixture was poured onto ice-cooled water (300 mL) and extracted with CH2Cl2 (5×200 mL). The combined organic extracts were then washed with brine, dried with Na2SO4 for 30 min, and the mixture concentrated to afford crude 2-methyl-5-oxazoleacetonitrile product CAS [1159511-94-0] (10 g).
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][CH: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]([CH: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: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)c(Cl)c2)C3)cc1
Reactant: C1COCCN1
Product: Clc1ccc(C2Cc3cnc(Nc4ccc(CCN5CCOCC5)cc4)nc3-c3ccccc32)cc1Cl
Yield: 55 %

Procedure:
This product was synthesized as described in general procedure 2 except 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 6-(3,4-dichlorophenyl)-N-(4-(2-morpholinoethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine in 55% yield. M.p.=180-181° C. 1H NMR 400 MHz (CDCl3) δ 8.45-8.4 (m, 1H), 8.17 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.58-6.85 (m, 6H), 4.18-4.0 (m, 1H), 3.84-3.68 (m, 4H), 3.35-3.18 (m, 1H), 3.18-3.0 (m, 1H), 2.92-2.73 (m, 2H), 2.7-2.45 (m, 6H). LCMS m/e 532 (M+H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC#N>[N:20]1([C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:8]3[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6](=[O:19])(=[O:18])[C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:31][CH:32]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCCCCC2)cc1
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(Nc2ccc(N3CCCCCC3)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 53.4 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.500 mmol), (4-azepan-1-ylphenyl)amine (0.095 g, 0.500 mmol) and TEA (0.070 ml, 0.500 mmol) in MeCN (2 ml) was heated in a microwave reactor at 120° C. for 65 mins. TEA (0.070 ml, 0.500 mol) was added and the reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. The reaction mixture was filtered and the residue was purified by silica gel column chromatography using 15-20% EtOAc in petroleum ether 40-60° C. as eluent, to give the title compound (0.121 g, 53%). 1H NMR (500 MHz CDCl3): δ 7.16-7.04 (m, 5H), 7.00 (s, 1H), 6.53 (d, 2H), 6.23 (d, 2H), 3.33 (t, 4H), 1.77 (s, 9H), 1.73-1.61 (m, 4H), 1.50-1.45 (m, 4H); 13C NMR (125 MHz CDCl3): δ 160.4, 146.6, 131.8, 129.8, 128.5, 127.9, 125.4, 124.5, 124.3, 110.7, 108.3, 61.8, 49.7, 27.9, 27.3, 26.9; Mass Spectrum: M+H+ 454.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.46 g) in dichloromethane (7 ml) was added TFA (7 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH) yielded the title compound as a white solid (0.16 g, 31%). MS (ISP) 513.2 [(M+H)+]; mp 245.5° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=O)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:29](=[O:30])[O:28][CH2:27][C:26]=1[N:31]1[CH2:35][CH2:34][C:33]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:32]1=[O:41].[Na]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Si:1]([O:8][CH2:9][CH:10]([N:38]1[CH2:39][CH2:40][C:33]2([C:32](=[O:41])[N:31]([C:26]3[CH2:27][O:28][C:29](=[O:30])[C:25]=3[CH3:24])[CH2:35][CH2:34]2)[CH2:36][CH2:37]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Reactant: Cc1c(CC(=O)CO[Si](C)(C)C(C)(C)C)ccc2c1COC2=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na]
Solvent: CO
Product: CC1=C(N2CCC3(CCN(C(CO[Si](C)(C)C(C)(C)C)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-(3-((tert-butyldimethylsilyl)oxy)-2-oxopropyl)-4-methylisobenzo furan-1(3H)-one (0.50 g, 1.5 mmol) in methanol (20 mL) was added 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-17) (0.45 g, 1.8 mmol) and titanium(IV) isopropoxide (2.10 g, 7.5 mmol). After stirring at for room temperature 48 h, sodium cyanoborohyride (190 mg, 3.0 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with water (10 mL), and the resulting inorganic precipitate was filtered off and washed with methanol (50 mL). The filtrate was then concentrated and the crude product was dissolved in ethyl acetate, filtered to remove the remaining inorganic solids, and concentrated. The residue was purified by flash column chromatography (0-10% methanol in dichloromethane) to give the title compound. LC-MS (ESI, m/z): 569 [M+1]+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[O:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])(=[O:11])=[O:10])[CH:8]=1)#[N:2].Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.O>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[O:24][CH2:25][C:26]2[O:27][C:32](=[O:34])[NH:29][N:28]=2)(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)NN)c1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCc2n[nH]c(=O)o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
5-Cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide (0.258 g) was dissolved in 10 mL of tetrahydrofuran. To the stirred solution was added 0.177 g of triphosgene under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 0.26 g of 5-cyano-2-hydroxy-N-[2-[4-isopropyl-2-(5-oxo-4,5-dihydro[1,3,4]-oxadiazol-2-ylmethoxy)phenyl]ethyl]benzenesulfonamide.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10](O)=[O:11])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH2:58][NH2:59]>C1COCC1>[CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:59][CH2:58][C:57]2[CH:60]=[CH:61][CH:62]=[C:55]([F:54])[CH:56]=2)=[O:11])=[C:8]([C:13]([F:15])([F:14])[F:16])[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)O
Reactant: NCc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)NCc1cccc(F)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
To a solution of 170 mg (0.5 mmol) 2-(ethylsulfanyl)-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylic acid in THF (3 ml) were added 192 mg (0.5 mmol) HATU and 210 μl (1.5 mmol) NEt3 and the RM was stirred at 50° C. for 90 min. Then 69 μl (0.6 mmol) 3-fluorobenzylamine were added and stirring was continued at 50° C. for 5 d. After cooling to RT the mixture was partitioned between water and EtOAc. The organic layer was separated, washed with a 4N aq. NH4Cl sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 57 mg (0.13 mmol, 26%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylic acid amide (example 11). [M+H]+ 444.1.
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([C:18]2[S:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:21][CH:22]=2)[CH:15]=[CH:14][N:13]=1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:20]1[S:19][C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[N:17]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)C(C)Br
Reactant: NCCNc1nccc(-c2ccc(-c3cccs3)s2)n1
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C(C)NCCNc1nccc(-c2ccc(-c3cccs3)s2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 2-bromopropanoate (182 mg, 1.09 mmol) was added to a mixture of N-(2-amino-ethyl)-4-(5-(thiophen-2-yl)thiophen-2-yl)pyrimidin-2-amine (300 mg, 0.99 mmol) and N,N-diisopropylethylamine (153 mg, 1.19 mmol) in 1-methylpyrrolidine (8 mL) at rt. After stirring at rt for 24 h, water (50 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound. MS (M+H)+ 389.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[C:22][C:23]4[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=4)[CH:19]=3)[S:14][C:13]([CH3:35])([CH3:34])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[C:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=4)[CH:19]=3)[S:14][C:13]([CH3:35])([CH3:34])[CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)C=C(c2ccc(C(C)(C)C)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc2S1
Temperature: 45 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of ethyl 4-[[4-(4-tert-butylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 229, 65.0 mg, 0.135 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 45° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 33.0 mg (54%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.01 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.45 (4H, m), 7.24 (3H, m), 5.93 (1H, s), 1.47 (6H, s), 1.34 (9H, s).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=[O:3])[CH3:2].[N+:10]([C:13]1C=[CH:20][CH:19]=[CH:18][C:14]=1C(Cl)=O)([O-:12])=[O:11].O>C1(C)C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:18][CH:19]=[CH:20][C:2]=1[C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])=[O:3])([O-:12])=[O:11]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)C1CCOC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCCC1C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 372 %

Procedure:
A mixture of Mg(OEt)2 (63 g, 0.55 mole) in toluene, under N2, is treated with dihydro-3-acetyl-(3H)-furanone (141 g, 1.10 mole) at 7°-10° C. over a 15 minute period and stirred at 25°-30° C. for 2 hours. The resultant reaction mixture is treated with a solution of o-nitrobenzoyl chloride (185.7 g, 1.0 mole) in toluene at 25°-35° C. over a 45 minute period, stirred at ambient temperatures for 1.75 hours, treated with 400 mL H2O and heated at 60°-75° until reaction is complete by LC analysis. The resultant reaction mixture is cooled to room temperature and the phases are separated to give the title product as a toluene solution, 875 g, 18% desired product by LC analysis (67% yield). The product solution is used as is in Example 6.
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:16])=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl.O1CCOCC1.[Na]>O>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[CH2:15][CH:13]3[CH2:14][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1CC2CC(C1)c1cc(N)ccc12
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(C(C)C)C2)ncc1Cl
Temperature: 120 °C
Yield: 34.7 %

Procedure:
10-Isopropy-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (30 mg, 0.14 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (41 mg, 0.14 mmol) and 4N HCl in dioxane (28 μl, 0.15 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 8 g Isco basic alumina column using 0-2% methanol in methylene chloride as the eluent to yield 2-[5-chloro-2-(10-isopropyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (23.2 mg, 35%) as a red orange foam. 1H-NMR (CDCl3) δ 11.0 (s, 1H), 8.68 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.3 Hz, 1H), 7.37 (s, 1H), 7.21 (s, 1H), 7.06 (dd, J=3.3, 6.8 Hz, 2H), 3.10-3.0 (m, 4H), 2.75 (m, 2H), 2.55 (m, 4H), 2.27 (m, 1H), 1.68 (d, J=10.1 Hz, 1H), 0.85 (d, J=6.6 Hz, 6H); LC/MS (ESI+): 477 (M+H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]2[O:15][CH2:16][O:17][C:12]2=[CH:11][C:10]=1[CH:18]([CH3:23])[C:19](OC)=[O:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>COCCO>[CH3:23][CH:18]1[C:10]2[CH:11]=[C:12]3[O:17][CH2:16][O:15][C:13]3=[CH:14][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:26][NH:25][C:19]1=[O:20]
Reactant: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccccc1)OCO2
Reactant: NN
Solvent: COCCO
Solvent: O
Product: CC1C(=O)NN=C(c2ccccc2)c2cc3c(cc21)OCO3
Yield: 18 %

Procedure:
A mixture of methyl 2-(2-benzoyl-4,5-methylenedioxyphenyl)propionate, hydrazine hydrate (0.45 mL), and 2-methoxyethanol (6 mL) was heated to reflux for 20 h. The solvent was then removed in vacuo and the residue was purified by a flash chromatography (EtOAc:Hex=1:1.5) to yield the product as a white solid (62 mg, 18%), mp, 206°-209° C. 1H NMR (CDCl3) 8.45 (s, 1H), 7.62 (m, 2H), 7.45 (m, 3H), 6.88 (s, 1H), 6.63 (s, 1H), 6.05 (s, 1H), 6.00 (s, 1H), 3.29 (q,J=6.7, 1H), 1.62 (d,J=6.7, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C@:29]([OH:33])([C:31]#[CH:32])[CH3:30]>>[OH:33][C@@:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)([CH3:30])[C:31]#[C:32][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1ccccn1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@](C)(O)c3ccccn3)cc1-2
Yield: 6.1 %

Procedure:
10-bromo-N3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with (2R)-2-(2-pyridyl)but-3-yn-2-ol via General Procedure G to afford 3.4 mg (6.1%) of 10-[(3S)-3-hydroxy-3-(2-pyridyl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. M+1=432.0
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[N:20]=[C:19]2[C@H:28]([NH2:30])[CH3:29])=[CH:14][CH:13]=1)[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH2:9]([O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[N:20]=[C:19]2[C@H:28]([NH:30][CH2:7][CH:4]2[CH2:3][CH2:2][S:1][CH2:6][CH2:5]2)[CH3:29])=[CH:16][CH:17]=1)[CH3:10]
Reactant: CCOc1ccc(-n2c([C@@H](C)N)nc3cc(F)ccc32)cc1
Reactant: O=CC1CCSCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@@H](C)NCC3CCSCC3)nc3cc(F)ccc32)cc1
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Tetrahydro-thiopyran-4-carbaldehyde (35.80 g, 275.4 mmol) was added to a solution of compound A2 (80.73 g, 270 mmol) in dichloroethane (700 mL) at −20° C., followed by sodium triacetoxyborohydride (85.84 g, 405 mmol). The mixture was kept at that temperature for 4 h. The solution was diluted with dichloromethane, washed by saturated aqueous sodium bicarbonate, water, brine and dried over anhydrous sodium sulfate The solvent was evaporated and the residue was purified by flash column to yield A3 as a yellow solid (55 g). MS(ESI+) 414.1 (MH+).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]2[N:12]=[CH:13][C:14]([O:41][CH3:42])=[C:15]3[C:19]([C:20](=[O:40])[C:21]([N:23]4[CH2:28][CH2:27][N:26]([C:29]5[N:33]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[N:32]=[N:31][N:30]=5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][NH:17][C:16]=23)[N:10]=1.O.C(O)(C(F)(F)F)=O>>[CH3:42][O:41][C:14]1[CH:13]=[N:12][C:11]([C:9]2[N:10]=[C:6]([CH:2]=[O:1])[S:7][CH:8]=2)=[C:16]2[NH:17][CH:18]=[C:19]([C:20](=[O:40])[C:21](=[O:22])[N:23]3[CH2:24][CH2:25][N:26]([C:29]4[N:33]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:32]=[N:31][N:30]=4)[CH2:27][CH2:28]3)[C:15]=12
Reactant: COc1cnc(-c2csc(C3OCCO3)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(-c2csc(C=O)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 70 °C
Reaction time: 20 h
Yield: 36.4 %

Procedure:
To a suspension of 1-(7-(2-(1,3-dioxolan-2-yl)thiazol-4-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.305 g, 0.519 mmol) in H2O (2 mL, 111 mmol) was added TFA (1 mL, 12.98 mmol). The mixture was heated to 70° C. After 18 h of heating, the mixture was cooled to rt, and was stirred at rt for an additional 20 h. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and was partitioned with sat. NaHCO3. The mixture was extracted with dichloromethane (3×10 mL) and was dried with Na2SO4. The drying agent was removed by filtration. The organic solution was concentrated under reduced pressure, and the resulting mixture was purified by flash chromatography (0 to 5% methanol in dichloromethane gradient). The product, 4-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)thiazole-2-carbaldehyde (0.103 g, 0.189 mmol, 36.5% yield) was collected as a light-yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: c1c[nH]nn1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnn2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Fluorobenzonitrile (0.847 g, 7 mmol), 1H-[1,2,3]triazole (0.483 g, 7 mmol), Cs2CO3 (2.27 g, 7 mmol) and DMF (8 ml) and a magnetic stirrer were placed in a vial. The mixture was heated with stirring for 3 h at 80° C. Extractive work-up (EtOAc/H2O) and subsequent drying (Na2SO4) gave a crude product which was purified on silica giving 0.55 g (46%) of the title compound.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([S:28](Cl)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:28]([CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Product: CCCCS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 58.4 %

Procedure:
Following procedures essentially as described in Example 90, 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (50 mg, 0.168 mmol) and 1-butanesulfonyl chloride (158 mg, 1.01 mmol) affords 41 mg (58%) of the title compound as a colorless oil. MS (ES) 440 (M+Na); HPLC shows 99% purity.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:26])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:26])[N:9]([CH2:8][C:6]([OH:7])=[O:5])[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(=O)[nH]c2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
1.92 g (5.02 mmol) of tert-butyl 3-tert-butoxycarbonylmethyl-5-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIg) were dissolved in dichloromethane (40 ml) and, while stirring at room temperature, trifluoroacetic acid (15 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 1.50 g (100%) of white solid