Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CCCCCC.C([Li])CCC.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]1([O:50][Si:51]([CH2:56][CH3:57])([CH2:54][CH3:55])[CH2:52][CH3:53])[C:33]2[C:28](=[CH:29][C:30](I)=[CH:31][C:32]=2[C:34]([F:37])([F:36])[F:35])[N:27]([CH2:39][C@H:40]2[CH2:43][C@H:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[CH2:41]2)[C:26]1=[O:49].O>O1CCCC1>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]1([O:50][Si:51]([CH2:56][CH3:57])([CH2:52][CH3:53])[CH2:54][CH3:55])[C:33]2[C:28](=[CH:29][C:30]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:31][C:32]=2[C:34]([F:36])([F:35])[F:37])[N:27]([CH2:39][C@H:40]2[CH2:41][C@H:42]([N:44]([CH2:45][CH3:46])[CH2:47][CH3:48])[CH2:43]2)[C:26]1=[O:49]
Reactant: c1cocn1
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3ccc(Cl)cc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3ccc(Cl)cc3Cl)c3c2cc(-c2ncco2)cc3C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxazole (150 mg, 2.17 mmol) in tetrahydrofuran (4 mL) was added 2.67 M n-butyl lithium hexane solution (0.8 mL, 2.14 mmol) at −78° C. under nitrogen, and the mixture was stirred for 15 minutes. To the reaction solution was added 1.0M zinc chloride diethyl ether solution (2.2 mL, 2.2 mmol) at −78° C., and the mixture was stirred for 15 minutes. The reaction solution was allowed to warm to 0° C., and then thereto was added a solution of the compound of Example 14-1 (310 mg, 0.418 mmol) and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 1 hour, and then the mixture was heated to stir at 60° C. for 3 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with saturated saline, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (chloroform/methanol=20/1) to give the titled compound (160 mg, 56%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:23]2([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[C:31]3[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=3)[NH:25][C:24]2=[O:33])[CH2:15][C:16](=[O:22])[NH:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:28]1[CH:27]=[C:26]2[C:31]([C:23]([N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][C:16]([NH:17][CH:18]3[CH2:19][CH2:20][CH2:21]3)=[O:22])([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[C:24](=[O:33])[NH:25]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(CC(=O)NC2CCC2)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CN(C1CCNCC1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)NC1CCC1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
At room temperature, 4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 1.17 mmol) was dissolved a mixture solution of CF3COOH and CH2Cl2. After stirred 0.5 h, the solution was concentrated and the organic layer was washed with NaOH aqueous solution. The organic layer was dried, concentrated to obtain crude product. The crude product was purified by chromatography to obtain 200 mg rac-2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-4-yl-amino}-N-cyclobutyl-acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=2[CH3:23])=[CH:9][C:8]=1[CH3:24])[CH3:2].[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:32][C:31]3[CH:33]=[CH:34][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:29][CH:30]=3)=[CH:17][C:16]=2[CH3:23])=[CH:9][C:8]=1[CH3:24])[CH3:2]
Reactant: CCOC(=O)COc1cc(C)c(Sc2ccc(C=O)cc2C)cc1C
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)COc1cc(C)c(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a stirred solution of compound 21.4 (13.5 g, 37.7 mmol) in CHCl3 (135 mL) was successively added 4-(trifluoromethyl)aniline (6.07 g, 37.7 mmol) and AcOH (3.24 mL). After stirring at room temperature for 30 min, the reaction was cooled to 0° C., sodium triacetoxyborohydride (12.0 g, 56.6 mmol) was added, and the reaction was stirred at room temperature for 3 h. The reaction mixture was poured into 150 mL of ice-water and the product was extracted with 2×50 mL CHCl3. The organics were sequentially washed with 150 mL aqueous NaHCO3 and 150 mL brine, dried over MgSO4, and concentrated to a yellow oil, which was purified with flash chromatography (SiO2 gel 60 N, eluted with 10% EtOAc/hexanes—20% EtOAc/hexanes). The fractions containing the desired product were combined and concentrated to yield a colorless solid (18.7 g). 1H NMR (400 MHz) (CDCl3) δ 7.38 (2H, d, J=8.5 Hz); 7.20 (1H, s); 7.14 (1H, s); 6.97 (1H, d, J=8.1 Hz); 6.70-6.50 (4H, m); 4.66 (2H, s); 4.40-4.20 (5H, m); 2.38 (3H, s); 2.30 (3H, s); 2.22 (3H, s); 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH:38]1([CH2:43][CH2:44][C:45](Cl)=[O:46])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:45](=[O:46])[CH2:44][CH2:43][CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CC(C)(Cc1c(C(=O)CCC2CCCC2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using 3-cyclopentylpropanoyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[C:28]([F:30])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([F:31])[CH:3]=1.Cl[CH2:33][C:34]1[C:39]([F:40])=[CH:38][C:37]([CH3:41])=[CH:36][N:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:29]=[C:28]([F:30])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:33][C:34]4[C:39]([F:40])=[CH:38][C:37]([CH3:41])=[CH:36][N:35]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([F:31])[CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(O)cc2n1Cc1c(F)cc(Br)cc1F
Reactant: Cc1cnc(CCl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(OCc3ncc(C)cc3F)cc2n1Cc1c(F)cc(Br)cc1F
Temperature: 100 °C

Procedure:
To a mixture of racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-hydroxy-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate (110 mg, 0.22 mmol), 2-(chloromethyl)-3-fluoro-5-methylpyridine (35 mg, 0.22 mmol) in acetonitrile (5 mL) was added Cs2CO3 (79 mg, 0.24 mmol) and heated at 100° Celsius. After 1 hr the mixture was concentrated to dryness and the residue was purified by FCC to provide racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-((3-fluoro-5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate. To the resulting ethyl ester was added MeOH (2 mL), and NaOH (1 mL, 1 N). The mixture was heated to 110° Celsius. After 1 h the mixture was concentrated to dryness and purified by FCC to provide the title compound and the trans-isomer see Example 124. MS (ESI): mass calcd. for C28H25BrF3N3O3, 587.10; m/z found, 588.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.22 (5, 1H), 7.52-7.45 (m, 2H), 7.28 (d, J=7.6, 2H), 6.99 (d, J=2.0, 1H), 6.88 (dd, J=8.7, 2.3, 1H), 5.54 (two d, J=16.4, 2H), 5.18 (5, 2H), 3.79 (d, J=4.6, 1H), 2.78-2.63 (m, 1H), 2.40 (s, 3H), 2.36-2.20 (m, 1H), 2.12-1.86 (m, 3H), 1.86-1.67 (m, 2H), 1.51-1.39 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.[Cl:34][C:35]1[CH:36]=[C:37]([O:46][CH2:47][CH:48]=[C:49]([Cl:51])[Cl:50])[CH:38]=[C:39]([Cl:45])[C:40]=1[O:41][CH2:42][CH2:43][NH2:44]>ClCCl>[Cl:34][C:35]1[CH:36]=[C:37]([O:46][CH2:47][CH:48]=[C:49]([Cl:51])[Cl:50])[CH:38]=[C:39]([Cl:45])[C:40]=1[O:41][CH2:42][CH2:43][NH:44][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 62.6 %

Procedure:
To a solution of 0.15 g of 4-trifluoromethylcinnamic acid and 0.07 g of triethylamine dissolved in 5 ml of dichloromethane was added 0.14 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride, while stirring under ice cooling. After stirring for 30 minutes, a solution of 0.20 g of 3,5-dichloro-4-(2-aminoethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene dissolved in 5 ml of dichloromethane was added dropwise. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.20 g of 3,5-dichloro-4-(2-(4-trifluoromethylcinnarnamido)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (63% yield), m.p., 109.4° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=CN2CCC(CO)CO)=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([O:27][C:28](=[O:30])[CH3:29])(=O)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:28]([O:30][C:9]12[N:18]=[C:23]([CH2:22][CH2:21][CH:20]([CH2:24][O:27][C:28](=[O:30])[CH3:29])[CH3:19])[N:6]=[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[N:10]2)(=[O:27])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: Nc1ncc2ncn(CCC(CO)CO)c2n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC(C)CCC1=NC2(OC(C)=O)N=C(N)N=CC2=N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
23.73 g (0.1 mole) of 2-amino-9-(4-hydroxy-3-(hydroxymethyl)but-1-yl)purine was suspended in 300 ml of tetrahydrofuran. To the suspension, 24.52 g (0.31 mole) of pyridine, 1.22 g (0.01 mole) of 4-dimethylaminopyridine and 21.44 g (0.21 mole) of acetic acid anhydride were added, and the mixture was stirred for five hours at room temperature. After completion of the reaction, the reaction product was concentrated under reduced pressure. The remaining concentrate was added to 300 ml of purified water and then extracted four times with 400 ml portions of chloroform. The organic layer was collected, and dried with anhydrous magnesium sulfate, followed by filtration and washing. The resulting filtrate was concentrated under reduced pressure and crystallized from butanol, thereby giving 24.10 g (75% yield) of white 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl-2-aminopurine (famciclovir).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([OH:22])=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1C=CC=CC=1>[CH3:24][S:25]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([O:22][S:25]([CH3:24])(=[O:27])=[O:26])=[C:8]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=3)[O:9]2)=[CH:4][CH:3]=1)(=[O:27])=[O:26]
Reactant: COC(=O)c1ccc(-c2oc3cc(N)ccc3c(=O)c2O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Product: COC(=O)c1ccc(-c2oc3cc(NS(C)(=O)=O)ccc3c(=O)c2OS(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
2.5 g of methyl 7-amino-3-hydroxy-4'-flavonecarboxylate are put in suspension in 25 cc of anhydrous benzene. The mixture is cooled to 0° C., and 10 cc of methanesulfonic acid chloride are added drop by drop. The mixture is stirred at ambient temperature until the reaction is complete. The reaction is checked by thin-layer chromatography (benzene (90)-dioxane (25)-acetic acid (4) elution solvent). The mixture is poured into 300 cc of ice water. The precipitate is filtered, washed with water and dried. The resulting product is purified by open silica column chromatography. MP=250° C. NMR in DMSO(D6): δ=3.3 ppm, 3H, singlet, CH3 methanesulfonamido; δ=3.6 ppm, 3H, singlet, CH3L methanesulfonyloxy; δ=3.9 ppm, 3H singlet, CH3 methyl ester; δ=7.1-8.4 ppm, 7H, complex multiplet, aromatic protons; δ=10.7 ppm, 1H, dome, NH; (interchangeable with D2O).
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[NH:12][N:11]=1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:27](=[O:28])[N:26]([C:29]3[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=3)[CH:25]=[N:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:27](=[O:28])[N:26]([C:29]3[S:30][C:31]([C:35]([NH:16][CH2:15][C:13]4[NH:12][N:11]=[C:10]([CH3:9])[CH:14]=4)=[O:36])=[C:32]([CH3:34])[N:33]=3)[CH:25]=[N:24]2)=[CH:20][CH:19]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1cc(CN)[nH]n1
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(-n3cnn(Cc4ccc(F)cc4)c3=O)nc2C)[nH]n1
Yield: 31 %

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (3-methyl-1H-pyrazol-5-yl)methanamine to react with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid instead of (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as an off-white solid in 31% yield: mp 234-235° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.76 (s, 1H), 8.67 (t, J=5.5 Hz, 1H), 7.41-7.36 (m, 2H), 7.27-7.16 (m, 2H), 5.91 (s, 1H), 5.00 (s, 2H), 4.37-4.31 (m, 2H), 2.55 (s, 3H), 2.19-2.12 (m, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.7 (d, 1JC-F=244 Hz), 160.7, 151.2, 150.5, 149.7, 149.6, 138.7, 132.2 (d, 4JC-F=3 Hz), 132.1, 130.0 (d, 3JC-F=8 Hz), 122.9, 115.4 (d, 2JC-F=22 Hz), 102.3, 47.7, 37.3, 16.9, 10.4; MS (ES+) m/z 427.8 (M+1), MS (ES−) m/z 425.8 (M−1).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]([NH2:18])([CH2:16][CH3:17])([CH3:15])[CH3:14]>>[C:13]([NH:18][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH2:16][CH3:17])([CH3:15])[CH3:14]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCC(C)(C)N
Product: CCCCCCC/C=C/C(=O)NC(C)(C)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and tert-amylamine as starting materials to give the aimed compound.
Reaction SMILES: [ClH:1].[NH2:2][C:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]1[C:12](=[O:30])[C:13]([O:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:4]21.Cl.[H][H].[C:34](OCC)(=O)C>C(O)C.[Pd]>[ClH:1].[CH3:34][NH:2][C:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]1[C:12](=[O:30])[C:13]([O:21][C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:4]21
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N)CC1
Reactant: CCOC(C)=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC)CC1
Yield: 90 %

Procedure:
To a mixture of ethyl 10-amino-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate hydrochloride (6 g, 11.96 mmol) in ethyl acetate (100 mL) and ethanol (100 mL) was added 1N HCl (12.56 mL, 12.56 mmol) followed by Pd/C (1.273 g, 1.196 mmol) and the mixture stirred under 1 atm of hydrogen for 2 h. The mixture was then filtered (filter paper) and the solid thoroughly washed with ethyl acetate. The filtrate was concentrated under reduced pressure and dried under high vacuum overnight to afford the title compound (4.8 g, 90% yield)as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.15 (2 H, d, J=7.28 Hz), 7.62-7.67 (1 H, m), 7.47-7.52 (2 H, m), 4.26 (2 H, q, J=7.03 Hz), 4.11 (2 H, d, J=3.76 Hz), 2.76 (3 H, s), 2.56 (1 H, brs), 2.16-2.25 (2 H, m), 2.00-2.13 (4 H, m), 1.68-1.82 (3 H, m), 1.12 (3 H, t, J=7.03 Hz). LCMS (M+H)=412.78.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1cnc2ccccc21

Procedure:
Using general procedure 2 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.125 g, 0.48 mmol) and benzimidazole (0.067 g, 0.57 mmol) gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([NH2:21])=[C:18]([NH2:20])[N:19]=2)=[N:6]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[NH2:20][C:18]1[N:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:15]=[N:16][C:17]=1[NH:21][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 72 h

Procedure:
200 mg (0.595 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5,6-diamine were admixed with 8 ml of dichloromethane and cooled to 0° C. 545 mg (4.757 mmol) of methanesulphonyl chloride and 481 mg (4.757 mmol) of triethylamine were added and the mixture was stirred at RT for 72 h. The mixture was diluted with dichloromethane and the precipitate was filtered off with suction. The filtrate was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 57 mg (18% of theory) of the target compound.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:50][CH2:51][CH:52]4[CH2:54][CH2:53]4)=[C:29]([NH:32][C:33](=[O:49])[CH:34]=[CH:35][CH2:36][N:37]([CH2:43][C:44]([O:46]CC)=[O:45])[CH2:38][C:39](O)([CH3:41])[CH3:40])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20].C(OCC)(=O)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:50][CH2:51][CH:52]4[CH2:54][CH2:53]4)=[C:29]([NH:32][C:33](=[O:49])[CH:34]=[CH:35][CH2:36][N:37]4[CH2:43][C:44](=[O:46])[O:45][C:39]([CH3:41])([CH3:40])[CH2:38]4)[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: CCOC(=O)CN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CN(CC=CC(=O)Nc2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc2OCC2CC2)CC(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
15 mg of p-toluenesulphonic acid monohydrate are added to 150 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline in 2.5 ml of acetonitrile. The solution formed is stirred first for three hours at ambient temperature, then refluxed for a further two hours until the reaction is complete. For working up, the reaction mixture is combined with 30 ml of ethyl acetate. The organic phase is separated off, washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The oily yellow residue is stirred with diethylether, whereupon a light yellow solid crystallises out, which is filtered off and dried. Yield: 85 mg (61% of theory), Melting point: 140-142° C. Mass spectrum (ESI+): m/z=554, 556 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]2[N:11]([C:12]3[N:13]=[C:14]4[C@H:23]([CH3:24])[O:22][CH2:21][C:15]4=[CH:16][C:17]=3[CH2:18]2)[C@H:10]([CH3:25])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH3:8].[CH3:24][C@H:23]1[C:14]2[C:15](=[CH:16][C:17]3[CH2:18][C@H:19]4[N:11]([C:12]=3[N:13]=2)[C@H:10]([CH3:25])[CH2:9][NH:8][CH2:20]4)[CH2:21][O:22]1
Reactant: C[C@@H]1OCc2cc3c(nc21)N1[C@H](C3)CN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1OCc2cc3c(nc21)N1[C@@H](CNC[C@H]1C)C3
Product: N

Procedure:
The product of step 1 was treated with trifluoroacetic acid at 0° C. for 30 minutes. The mixture was evaporated under aspirator vacuum and the residue was partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was mixed with dichloromethane. The pH of this mixture was adjusted to 12.00 by addition of 28% aqueous sodium hydroxide. The phases were separated and the organic phase was washed with half concentrated brine dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel with methylenechloride:methanol:ammonia=90:10:1 to yield the title compound (3S,5R,8aR)-3,5-Dimethyl-1,3,5,6,7,8,8a,9-octahydro-2-oxa-4,4b,7-triaza-cyclopenta[b]fluorene as slightly yellow crystals m.p.: 90-91° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:21]3[CH:22]=[CH:23][S:19][CH:20]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: OB(O)c1ccsc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccsc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-thiophen-3-yl-isoquinolin-3-yl)-amine. LC-MS m/e 307(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8](Cl)[N:7]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)[N:7]=1
Reactant: COc1ccc(Br)c(CNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CCCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Br)c(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 80 °C
Yield: 82.8 %

Procedure:
To a solution of N-(2-bromo-5-methoxybenzyl)-2,5-dichloropyrimidin-4-amine (4.0 g, 11 mmol) and 3-(3-aminophenyl)propan-1-ol (2.3 g, 15 mmol, prepared according to Example 12, Step B) in 1,4-dioxane (90 mL) was added p-toluenesulfonic acid monohydrate (0.31 g, 1.6 mmol). The mixture was heated at 80° C. over two days and the reaction was complete. After cooling, the mixture was filtered under vacuum. The cake was washed with cold EtOAc to give the desired product as an off-white powder (4.35 g, 83%). LCMS for C21H22BrClN4O2 (M+H)+: m/z=477.0, 479.0.