Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[OH:23][CH:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:22][NH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCCc1ccc(C(N)=O)s1
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(CCCNCC(O)COc2ccccc2)s1

Procedure:
921 mg of 5-(3-aminopropyl)-2-thiophenecarboxamide and 0.68 ml of 2,3-epoxypropyl phenyl ether were heated to 90° in 15 ml of dimethylsulfoxide for 14 hours. The reaction mixture was poured into water and extracted with methylene chloride. The dried methylene chloride solutions were evaporated in vacuo and the residue was chromatographed on silica gel, whereby there were obtained 800 mg of 5-[3-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]propyl]-2-thiophenecarboxamide, m.p. 129°-130°, ε276 =12130.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28]([NH2:30])=O)[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:28]([C:26]1[N:27]=[C:23]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:31]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:22]=[CH:21][CH:20]=2)[O:24][CH:25]=1)#[N:30]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C(N)=O)co3)c1)C2=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C#N)co3)c1)C2=O
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
(S)-2-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxamide (211 mg, 0.483 mmol) obtained in Step 1 was dissolved in pyridine (3 mL), and the mixture was stirred at 90° C. for 3.5 hours after adding p-toluenesulfonyl chloride (395 mg, 2.07 mmol). The mixture was diluted by addition of chloroform, and washed with 1 mol/L hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give (S)-5-[3-(4-cyano-1,3-oxazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (155 mg, 77%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][CH3:17])[C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCNCC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1[N+](=O)[O-]

Procedure:
1-Benzyl-4-[N-ethylamino]methylpiperidine (EXAMPLE 175, 7.59, 32.64 mmol), 2-chloro-3-nitropyridine (5.17 g, 32.64 mmol) and potassium carbonate (5.41 g, 39.17 mmol) in acetonitrile (0.25M) are refluxed 48 hr. The mixture is diluted with water and extracted with ethyl acetate and then dichloromethane. The combined extracts are dried over sodium sulfate, concentrated and chromatographed (silica gel column, 300 g; eluting with 15-80% ethyl acetate/hexane), to give the title compound, NMR (300 MHz, CD3OD) 8.43, 8.20, 7.42, 6.90, 3.61, 3.52, 3.49, 3.00, 2.10, 1.80, 1.37 and 1.25δ.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:39][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCCC4)ncnc32)[C@]1(C)F
Yield: 74 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.50 g, 1.08 mmol) in ethanol (about 5 ml) was added cyclohexylamine (about 1.48 ml, 12.9 mmol) and refluxed for about 30 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 6% methanol in dichloromethane as eluent furnished title compound (0.42 g) as a colorless solid. Yield: 74%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.38 (s, 1H), 8.06-7.96 (m, 3H), 7.58-7.42 (m, 3H), 6.54 (d, 1H, J=23.1 Hz), 5.77 (d, 1H, J=8.1 Hz), 4.83-4.78 (m, 2H), 4.48-4.41 (m, 1H), 2.16 (s, 3H), 2.13-1.77 (m, 14H), 1.45 (d, 3H, J=23.1 Hz); ES Mass: [M+1]+ 512 (20%), [M+Na] 534 (100%); IR cm−: 3414, 2926, 2854, 1724, 1618, 1229, 1063, 950, 712; HPLC: 98%.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[N:13]=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:11]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: O=C(O)c1cnn(-c2nc(NC3CC3)c3cc(N4CCCCC4)ccc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI/CI): predicted mass C20H22N6O2, 378.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+].Cl>O>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(=O)c2c(C)cc(CC(=O)O)n2C)cc1

Procedure:
A suspension of 8.5 g. (0.0284 mole) of ethyl 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate in 29 ml. of 1N sodium hydroxide solution is heated under reflux for 20 minutes. The yellow solution is diluted with water and added to dilute hydrochloric acid. The precipitated solid is collected, dried in vacuo, and recrystallized from 2-propanol to give 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid as a white solid, m.p. 160-161° C. Anal. Calcd. for C16H17NO3 : C, 70.83; H, 6.32; N, 5.16%. Found: C, 70.90; H, 6.39; N, 5.25%.
Reaction SMILES: C[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([OH:10])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:21][CH:20]=1>CN(C=O)C>[O:26]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][O:23][C:22]1[CH:33]=[CH:34][C:19]([CH2:18][O:10][C:4]2[N:3]=[CH:2][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)=[CH:20][CH:21]=1
Reactant: O=C(COc1ccc(CBr)cc1)c1ccccc1
Reactant: Cc1nc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(OCC(=O)c3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of methyl 6-hydroxypyridine-3-carbaldehyde. (0.25 g, 2 mmol) in DMF (10 mL) was added cesium carbonate (0.97 g, 3 mmol) and stirred at RT for 30 min then added 2-[4-(bromomethyl)phenoxy]-1-phenylethanone (0.61 g, 2 mmol) this resulting mass was stirred at 80° C. for 12 h, reaction quenched with water and extracted with ethyl acetate, Organic layer was washed with water and brine solution dried over anhydrous Na2SO4 and concentrated to afford crude product which was purified by column chromatography to get pale brown solid as product (0.4 g, Yield: 60%); 1H NMR (300 MHz, CDCl3): δ 9.59 (s, 1H) 7.95-8.02 (m, 2H), 7.67-7.78 (m, 3H), 7.54-7.59 (m, 2H), 7.30-7.33 (d, 2H), 6.93-6.96 (d, 2H), 6.49-6.53 (d, 1H), 5.57 (s, 2H), 5.11 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].O[Li].O.O>C1COCC1.O>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 60 °C
Yield: 98.7 %

Procedure:
Ethyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (100 mg, 0.2 mmol, 1.0 eq) was dissolved in a mixture of THF (15 mL) and H2O (10 mL). LiOH.2H2O (55 mg, 0.8 mmol, 4.0 eq) was added and the solution heated at 60° C. overnight. The THF was removed under reduced pressure and the aqueous phase extracted with EtOAc. The organic extract was discarded and the aqueous layer acidified with 1M HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound (I(b)) as a white solid (80 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH2:21])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(N(CC)C(C)C)(C)C.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH:21][S:34]([CH:31]4[CH2:33][CH2:32]4)(=[O:36])=[O:35])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.7 %

Procedure:
A solution of (rac)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-ylamine (example 89) (40 mg, 0.14 mmol) and N,N-diisopropylethylamine (0.071 mL, 0.41 mmol) in DMF (0.5 mL) was treated with cyclopropanesulfonyl chloride (0.021 mL, 0.20 mmol) and the reaction mixture stirred at room temperature overnight. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.5 mg (3%) of the title compound as a light brown oil. MS: 401.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1[CH2:34][CH2:35][CH2:36][OH:37].[F:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[C:42](B1OC(C)(C)C(C)(C)O1)[NH:43]2.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2].O>[F:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[C:42]([C:2]1[N:7]=[C:6]([C:8]3[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])=[CH:10][C:11]4[O:15][C:14]([C:16]5[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=5)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=4[CH:27]=3)[CH:5]=[CH:4][C:3]=1[CH2:34][CH2:35][CH2:36][OH:37])[NH:43]2
Reactant: CC1(C)OB(c2cc3c(F)cccc3[nH]2)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCCO)c(Cl)n3)cc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCCO)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Temperature: 90 °C

Procedure:
To a mixture of 5-(6-chloro-5-(3-hydroxypropyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (180 mg, 0.330 mmol), 4-fluoroindole-2-boronic acid pinacol ester (129 mg, 0.494 mmol), cesium carbonate (215 mg, 0.659 mmol) and dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium (II) (21.49 mg, 0.033 mmol) was added 1,4-dioxane (3 mL) and H2O (0.3 mL). A steady stream of N2 was bubbled through the reaction mixture for 5 minutes then the mixture was heated to 90° C. for 3 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc/CH2Cl2 as eluent. The residue was triturated with CH2Cl2 to provide the title compound as a white solid. 1H NMR δ (ppm) (CHCl3-d): 10.30 (1H, br s), 8.07 (1H, s), 8.00 (2H, dd, J=8.56, 5.31 Hz), 7.78 (1H, d, J=7.88 Hz), 7.69 (1H, s), 7.50 (1H, d, J=7.85 Hz), 7.27˜7.23 (3H, m), 7.17˜7.13 (2H, m), 6.81˜6.78 (1H, m), 5.93˜5.87 (1H, m), 3.89 (2H, d, J=5.37 Hz), 3.24 (2H, t, J=7.86 Hz), 3.16 (3H, s), 3.02 (3H, d, J=4.90 Hz), 2.92 (3H, s), 2.13 (2H, t, J=7.43 Hz). MS (M+H)+: 645.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)=[C:14]=[O:15]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(=O)oc2cc(N=C=O)ccc12

Procedure:
A round bottom flask was charged with 7-amino-4-methyl-coumarin (50 mg, 0.285 mmol) under argon and treated with a 20% phosgene in toluene solution (2 ml) under. The reaction mixture was heated at reflux for 15 hrs under argon during which time a white solid precipitated out of solution. After cooling, the excess phosgene was removed by bubbling argon gas through from the solution for 10 minutes. The reaction mixture was then evaporated to afford the product as white solid, which was used directly in the next step. Yield: 50 mg (87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]1>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:19][C:16]2[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=2)=[N:3][CH:4]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)COc1ccc(Br)nc1
Reactant: Cn1ccc(N)n1
Agent: CN(C)c1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1COCCO1
Product: CC(C)COc1ccc(Nc2ccn(C)n2)nc1
Temperature: 80 °C
Yield: 33 %

Procedure:
2-Bromo-5-isobutoxy-pyridine (0.38 mmol), sodium-tert.-butylate (1.4 eq.), and 1-methyl-1H-pyrazole-3-amine (1.2 eq.) are dissolved in degassed dioxane (2 ml) and heated to 80° C. Chloro-(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium (II) (3 mg) in degassed dioxane (1 ml) is added and the reaction is heated for 1 hour at 150° C. in the microwave. The reaction is quenched with ethylacetate methanol (30 ml, 9:1) and filtrated over celite. The solvent of the filtrate is removed in vacuo. (5-Isobutoxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)amine (“A26”) is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as colorless powder in a yield of 33%; HPLC (method C): 1.57 min; LC-MS (method A): 0.936 min, 247.15 (M+H+);
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[N:6]([CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=2)[N:7]=1.C([O-])=O.[NH4+]>C(Cl)Cl.[Pd]>[O:20]1[CH2:19][CH2:18][N:17]([C:4]2[C:5]3[N:6]([CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=3)[N:7]=[CH:2][CH:3]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)Cc1cn2nc(Cl)cc(N3CCOCC3)c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOC(=O)Cc1cn2nccc(N3CCOCC3)c2n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Compound 28b (1.00 g, 3.08 mmol) and 10% Pd on activated carbon (164 mg, 0.154 mmol) were placed in a 40 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry THF (10 mL) was added followed by ammonium formate (388 mg, 6.16 mmol) and then the reaction was stirred at 70° C. for 1 h. The reaction was cooled to rt and diluted with DCM (200 mL). The solids were removed by filtration and then washed with DCM (2×50 mL). The combined filtrates were concentrated under reduced pressure to afford compound 28c. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.96 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 6.02 (d, J=5.1 Hz, 1H), 4.21 (q, J=6.8 Hz, 2H), 3.85-4.01 (m, 8H), 3.83 (s, 2H), 1.29 (t, J=6.8 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C14H18N4O3: 291.2 (M+H). Found: 291.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:16]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([Cl:18])=[N:7][C:6]=2[CH:16]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)NC(=O)c1cscc1O2
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N=C(Cl)c1cscc1O2

Procedure:
A 4.62 g. portion of 7-methyl-thieno[3,4-b][1,5]benzoxazepin-10(9H)-one is reacted with 4.60 g. of phosphorus pentachloride in 88 ml. of toluene as described in Example 7, to give 7-methyl-10-chloro-thieno[3,4-b][1,5]benzoxazepine. To this is added 40 ml. of dry toluene, 4.8 g. of N-ethylpiperazine and 10 ml. of triethylamine. The reaction is heated at 100° C. overnight, concentrated to a thick oil and treated as described in Example 3 giving the base compound which is then converted to the hemifumarate, m.p. 208°-209° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[C:20](Cl)(=[O:22])[CH3:21].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[C:20](=[O:22])[CH3:21])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(=O)Cl
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine (120 mg) in dichloromethane (2 ml) was added acetyl chloride (31.4 μL) and triethylamine (61.6 μL). The reaction mixture was stirred at room temperature for 3.5 hours, then diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvents removed in vacuo to give a crude residue. This was purified by flash chromatography to yield N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-acetamide (110 mg).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH2:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH:50]1[C:59]([OH:61])=O>>[CH2:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH:50]1[C:59]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:61]
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C2CCc3ccccc3C2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 1,2,3,4-tetrahydro-2-naphthoic acid, mp 137°-139° C.
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=O)C.[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.Cl.O.[S-2].[Na+].[Na+]>C(O)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[N:18]1[CH:23]=[CH:22][C:21]([C:24]2[NH:1][C:2]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][C:12]=3[N:13]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cccc(N)c1N
Reactant: O=Cc1ccncc1
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(-c3ccncc3)[nH]c12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
1 g (5.5 mmol) of ethyl 2,3-diaminobenzoate and 0.7 ml (11.3 mmol) of acetic acid were dissolved in 15 ml of ethanol. Then 0.77 g (7.2 mmol) of pyridine-4-carbaldehyde, dissolved in 25 ml of ethanol was added dropwise over the course of 30 minutes. A solution of 1.44 g (7.2 mmol) of copper(II) sulfate in 20 ml of water was then rapidly added dropwise. The mixture was boiled under reflux for 2 hours. The reaction solution was then allowed to cool to 50° C. 2.25 ml of 32% strength hydrochloric acid were then added. A solution of 2.13 g (8.9 mmol) of sodium sulfide hydrate and 25 ml of water was then cautiously added dropwise while hot. The mixture was stirred for 10 minutes. The reaction mixture was then poured into ice-water, and the resulting precipitate was filtered off. The filtrate was made alkaline with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated in vacuo. 1.15 g of the product were obtained.
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:95]2[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NC4C=NC(OC)=CC=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:81]2[CH2:85][C@H:84]([N:86]3[N:90]=[N:89][C:88]([CH2:91][CH3:92])=[N:87]3)[C@@H:83]([OH:93])[C@H:82]2[OH:94])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH:101]1[C:105]([C:106]2[CH:107]=[C:108]([NH2:112])[CH:109]=[CH:110][CH:111]=2)=[N:104][N:103]=[N:102]1>>[ClH:45].[C:95]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:112][C:108]4[CH:109]=[CH:110][CH:111]=[C:106]([C:105]5[NH:101][N:102]=[N:103][N:104]=5)[CH:107]=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:81]2[CH2:85][C@H:84]([N:86]3[N:90]=[N:89][C:88]([CH2:91][CH3:92])=[N:87]3)[C@@H:83]([OH:93])[C@H:82]2[OH:94])[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6ccc(OC)nc6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6cccc(-c7nnn[nH]7)c6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-Diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-(6-methoxy-pyridin-3-yl)-urea hydrochloride (Example 156) by replacing (6-Methoxy-pyridin-3-yl)-carbamic acid phenyl ester with 3-(1H-tetrazol-5-yl)-phenylamine (first step a).