Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([NH:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[C:3]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1c(NCc2ccccc2)ccnc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
4-chloro-3-nitro-2-pyridone (5 g, 28.65 mmol) was suspended in 150 mL of acetonitrile then benzylamine (3.15 mL, 28.65 mmol) was added followed by potassium carbonate (4 g, 28.65 mmol) and the mixture was stirred at 60° C. overnight. The solvent was removed in vacuo and the residue was suspended in water (200 mL). A solution of HCl 2M was added until pH˜6. The precipitate was filtered and dried in vacuo to give 4.75g of the title compound as a beige solid. A second crop from the mother liquids provided 1.4 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26]>>[C:25]([O:28][CH:8]1[C:7]2[CH:19]=[N:20][CH:21]=[N:22][C:6]=2[C:5]2[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:9]1)(=[O:27])[CH3:26]
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc2C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1N=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc21

Procedure:
A mixture of 2.5 g (7.4 mmols) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide and 50 ml of acetic anhydride was heated on the steambath for 24 hours. The reaction mixture was concentrated at reduced pressure to dryness and the residue was crystallized from a mixture of methylene chloride and ether to give the crude product, m.p. 197°-198° C. Recrystallization from a mixture of methylene chloride and ether gave the pure product as cream colored prisms, m.p. 200°-201° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[OH:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1.Cl>CCCCCC.O1CCCC1>[C:24]([CH2:23][CH2:22][C:21]([O:20][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:27])([OH:26])=[O:25]
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)Oc1c(Cc2ccccc2)ccc2ccccc12
Yield: 68.7 %

Procedure:
Sodium hydride (60% in mineral oil; 1.32 g, 0.33 mol) was washed free of mineral oil by stirring in hexane and decanting the solvent. Tetrahydrofuran (75 mL) was added and the suspension was stirred at 0°. A solution of 2-phenylmethyl1-naphthol (7.00 g, 0.030 mol) in tetrahydrofuran (100 mL) was added dropwise. After the mixture was stirred for two hours, a solution of succinic anhydride (3.30 g, 0.033 mol) in tetrahydrofuran (80 mL) was added dropwise. After stirring for one hour at 0°, 1 N hydrochloric acid was added slowly until the mixture was acidic. The tetrahydrofuran was removed on a rotary evaporator and the residue was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water and brine and was dried over MgSO4. Concentration provided a yellow solid, which was recrystallized (1-chlorobutane) to provide the title compound (6.89 g, 69%) as white crystals: mp 139.5°-140.5°; NMR (CDCl3) 7.79 (m, 2H), 7.66 (d, J=7 Hz, IH), 7.47 (m, 2H), 7.3-7.2 (m, 6H), 4.02 (s, 2H), 3.01 (t, J=6 Hz, 2H), 2.81 (t, J=6 Hz, 2H); IR (mull) 3200-2400, 1745, 1714; Calcd. for C21H18O4 : C-75.43 H-5.43; Found C-75.13 H-5.42.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH3:15])[C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[O:22]=[S:19]1[CH2:20][CH2:21][N:16]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH3:15])[C:6]=3[N:7]=[C:2]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:3]=2)[CH2:17][CH2:18]1
Reactant: CCCNc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CCCNc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analagous to Example 123 from 2-chloro-4-(1-oxido-thiomorpholino)-8-propylamino-pyrimido-[5,4-d]-pyrimidine (m.p.: 174°-176° C.) and piperazine.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](Cl)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1.O>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
To a mixture consisting of 19.4 g. of L-leucine, 15.7 g. of sodium carbonate, and 500 ml. of water, cooled to 0° C., is added a solution of 19.1 g. of 9-fluorenylmethylchloroformate in 200 ml. of tetrahydrofuran, and the resulting mixture is stirred at 0° C. for one hour and at room temperature for 15 hours. The mixtue is then acidified with 3 N hydrochloric acid and concentrated to remove the solvent. The residue is extracted with ethyl acetate, and the extract is washed with 100 ml. of 10% hydrochloric acid and with 100 ml. of water, dried, and evaporated to dryness to give a residue of N-9-fluorenylmethoxycarbonyl-L-leucine, which is slurried with n-hexane, isolated, and dried; m.p. 76°-79° C.; [α]D25 -28.7° (1.01% in methanol). To a mixture consisting of 15.2 g. of this intermediate product, 37 g. of pentachlorophenol, and 300 ml. of N,N-dimethylformamide, cooled to 5° C., is added 9.8 g. of dicyclohexylcarbodiimide, and the resulting mixture is kept at 4° C. for 2 days. It is then filtered, and the filtrate is evaporated to dryness to give a residue of N-9-fluoroenylmethoxycarbonyl-L-leucine pentachlorophenyl ester, which is triturated with n-hexane, isolated and dried; m.p. 119°-121° C.; [α]D25 -35.4° (1.00% in methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (70 mg, 59%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:15][S:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][C@@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6].N1C=CN=C1.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].O>CN(C=O)C>[Si:41]([O:1][C@@H:2]([CH2:15][S:16][C:17]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][C@@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC[C@H](C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3.72 g (7.88 mmol) of the crude product of Example 21 dissolved in 10 mL of DMF was added 2.68 g (0.039 mol) of imidazole followed by 2.85 g (0.019 mol) of t-butyldimethylsilyl chloride. The reaction mixture was stirred at room temperature for 2 h and then poured into 200 mL of H2O. The resulting solution was extracted with ether and the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 10mL of methanol/THF (1:1) and 5.0 mL of 1N NaOH solution was added. After stirring for 0.75 h at room temperature the reaction mixture was acidified with 5% HCl solution to pH 5 and then extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 4.76 g (100%) of the desired product as a colorless oil. Electrospray Mass Spec: 603.5 (M-H)-.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.N1C=CN=C1.[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35]>C(Cl)Cl>[Si:37]([O:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]=[CH2:21])=[CH:18][CH:19]=2)[CH3:13])[CH2:7][CH2:6]1)([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=Cc1ccc([C@H](C)N2CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c3ccccc3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 0.137 mmol) and imidazole (11.2 mg 0.165 mmol) in CH2Cl2 (10 mL) was added a solution of TBSCl (24.6 mg, 0.164 mmol) in CH2Cl2 (15 mL) dropwise at 0° C. The mixture was stirred overnight at rt. The mixture was filtered, and the solvent was evaporated to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (40 mg, 60%). 1H NMR (CDCl3): 0.02 (s, 6H), 0.87 (m, 9H), 1.23 (m, 1H), 1.52 (d, 3H), 1.62 (m, 1H), 1.98 (m, 2H), 2.14-2.38 (m, 3H), 2.97 (m, 1H), 3.58 (m, 2H), 5.28 (m, 1H), 5.71 (m, 1H), 6.68 (m, 1H), 6.88 (m, 1H), 7.16 (m, 1H), 7.22-7.38 (m, 7H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH3:8][O:9][C:10]1[CH:46]=[CH:45][C:13]([C:14]([O:29][CH2:30][C@H:31]2[O:35][C@@H:34]([N:36]3[CH:43]=[CH:42][C:40](=[O:41])[NH:39][C:37]3=[O:38])[CH2:33][C@@H:32]2[OH:44])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:46]=[CH:45][C:13]([C:14]([O:29][CH2:30][C@H:31]2[O:35][C@@H:34]([N:36]3[CH:43]=[CH:42][C:40](=[O:41])[N:39]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[CH:1])[C:37]3=[O:38])[CH2:33][C@@H:32]2[OH:44])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C#CCCCCO
Product: C#CCCCCn1c(=O)ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)O2)c1=O
Yield: 86 %

Procedure:
5-Hexynol was allowed to react with 2′-deoxy-5′-O-(4,4′-dimethoxytrityl)uridine under Mitsunobu conditions described in example 1. Purification on silica gel (eluent diethyl ether) yielded the title compound as a solid (86%) Compound 9:
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:19][CH3:20])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#[N:2].I([O-])(=O)(=O)=[O:22].[Na+].CO>O>[C:1]([N:3]=[C:4]([NH:19][CH3:20])[NH:5][CH2:6][CH2:7][S:8]([CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)=[O:22])#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CNC(=NC#N)NCCSCc1nsc(NC(=N)N)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=NC#N)NCCS(=O)Cc1nsc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[2-(2-cyano-3-methylguanidino)-ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole (0.626 g.), sodium metaperiodate (0.428 g.), methanol (20 ml.) and water (70 ml.) was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue extracted with absolute ethanol (120 ml.). The extract was filtered and evaporated to dryness. The residue was crystallised from methanol (with charcoal treatment) to give 3-[2-(2-cyano-3-methylguanidino)-ethylsulphinylmethyl]-5-guanidino-1,2,4-thiadiazole as a white powder, m.p. 185°-186°.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13].[CH3:14][NH:15][CH:16]([OH:18])[CH3:17]>C(O)CCC>[NH2:13][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[C:10]=1[N:11]=[CH:12][N:4]2[CH2:3][CH2:2][N:15]([CH:16]([OH:18])[CH3:17])[CH3:14]
Reactant: CNC(C)O
Reactant: Nc1ncnc2c1ncn2CCCl
Solvent: CCCCO
Product: CC(O)N(C)CCn1cnc2c(N)ncnc21
Yield: 95.9 %

Procedure:
0.6 g (3 mmol) 9-(chloroethyl)-6-amino-9H-purine (Chemistry of Heterocyclic Compounds, 1996, 32, 333–337) was dissolved in 10 ml n-butanol and treated with 0.684 g (9 mmol) of N-methylaminoethanol at 110° C. for 18 h. The solvent was evaporated under reduced pressure and the crude mixture purified by flash chromatography on silica gel with a gradient of 0 to 25% methanol in dichloromethane to yield 0.68 g (94%) of a light orange solid. MS (ISP): 237.3 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[O:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:46]=[C:47]([NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)[CH2:41][CH2:40]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:49]4[CH:48]=[C:47]([NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[CH:46]=[C:45]([N:42]5[CH2:41][CH2:40][O:39][CH2:44][CH2:43]5)[CH:50]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc(N3CCOCC3)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc(N5CCOCC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 43.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (45 mg, 0.08 mmol) was treated with N-(3-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (44 mg, 0.12 mmol), sodium carbonate (22 mg, 0.21 mmols) and bis(triphenylphosphine)palladium(II) dichloride (21 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl ether) to give 27 mg (32% yield) of the title compound. Purity 70%.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH:11]1[CH2:12][CH:13]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:14]2)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH:11]1[CH2:12][CH:13]([CH2:19][C:20]([OH:22])=[O:21])[CH2:14]2)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC1CC2CCCC(C1)N2C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCCC1CC(CC(=O)O)C2
Temperature: 25 °C

Procedure:
10 ml of 1M aqueous NaOH are added to a solution of 3-ethoxycarbonylmethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in 20 ml of THF and the mixture obtained is stirred at RT. To the mixture obtained 10 ml of brine and 70 ml of EtAc are added, and the mixture obtained is washed with 1M aqueous HCl. The organic layer obtained is dried and solvent is evaporated. 3-Carboxymethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in the form of an oil is obtained. 13C-NMR: 178.47, 177.28, 155.61, 154.50, 79.70, 79.63, 47.39, 45.88, 43.39, 40.31, 36.92, 32.22, 31.98, 31.37, 30.99, 30.74, 30.64, 30.08, 29.59, 29.20, 21.15, 20.60, 14.05.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[S:15][C:14]2[C:13](=[O:16])[NH:12][C:11]([C@@H:17]3[C@@H:22]4[CH2:23][C@@H:19]([CH2:20][CH2:21]4)[N:18]3C(OC(C)(C)C)=O)=[N:10][C:9]=2[CH:8]=1.Cl.C(OCC)(=O)C>CO>[C@H:19]12[CH2:23][C@H:22]([CH2:21][CH2:20]1)[C@@H:17]([C:11]1[NH:12][C:13](=[O:16])[C:14]3[S:15][C:7]([C:3]4[CH:4]=[N:5][NH:6][C:2]=4[CH3:1])=[CH:8][C:9]=3[N:10]=1)[NH:18]2
Reactant: Cc1[nH]ncc1-c1cc2nc([C@@H]3[C@H]4CC[C@H](C4)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1[nH]ncc1-c1cc2nc([C@H]3N[C@@H]4CC[C@H]3C4)[nH]c(=O)c2s1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
To a solution of tert-butyl(1R,3S,4S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate (690 mg) in methanol (10 mL) was added 4M hydrochloric acid/ethyl acetate solution (2.0 mL) with stirring at room temperature. The reaction system was stirred with heating at 50° C. for 30 min, and the mixture was concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate. Insoluble material was removed by filtration. The mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate), and the obtained colorless solid was crystallized from methanol/ethyl acetate to give the title compound (220 mg) as a colorless solid. The optical purity was 86% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK OD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: methanol, flow rate: 0.5 mL/min, column temperature: 30° C., detection 254 nm).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[Cl:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:12]2[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CC(C)n1nc2c(c1-c1ccc(Cl)c(Cl)c1)CCNCC2
Yield: 39.5 %

Procedure:
The title compound (60 mg) was prepared according to Example 189 using 200 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 268 mg of 3,4-dichlorophenylboronic acid. MS (ESI): exact mass calculated for C16H19Cl2N3, 323.10; found, m/z 324.4 [M+H]+, 326.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.72-7.71 (m, 1H), 7.53-7.52 (m, 1H), 7.29-7.27 (m, 1H), 4.64 (br s, 2H), 4.32 (m, 1H), 3.86-3.57 (m, 2H), 3.31-3.08 (m, 2H), 2.84-2.75 (m, 2H), 1.39 (d, J=6.6 Hz, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20](Cl)=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.O>C(O)(=O)C>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1Cl)=NC2
Reactant: C1CCNC1
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]nc2n1-c1ccc(N3CCCC3)nc1C(c1ccccc1Cl)=NC2

Procedure:
20 grams of 1-keto-6-(o-chlorophenyl)-8-chloro-1,2-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine were boiled with 60 ml. of pyrrolidine for 1 hour under reflux. Then the mixture was poured into 1 liter of water and acidified with glacial acetic acid whereupon the reaction product crystallized out. This was dissolved in alcohol, the alcoholic solution concentrated to about 70 ml. and ether added. The crystallized material was recrystallized from methanol. M.P. 228°-230° C.; Yield 8 grams.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:14].Cl.[NH2:16][CH:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1>>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[CH:17]([NH:16][C:11]([C:8]1[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:6][CH:7]=1)=[O:13])[CH2:18]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1ccc2cccnc2c1
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1ccc2cccnc2c1
Yield: 71.1 %

Procedure:
Prepared in analogy to the method for Example 1 starting from 183 mg of quinoline-7-carboxylic acid (Seibert et al. J. Am. Chem. Soc. 1946, 68, 2721) and 200 mg of 3-aminoquinuclidine dihydrochloride. 227 mg (71% yield) of the hydrochloride were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14](OCC)=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[NH3:21]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:21])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Product: NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Temperature: 122.5 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A suspension of ethyl 9-bromo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (compound 61-4, page 196, WO 2011/036280) (0.3 g, 0.89 mmol) in 7 M ammonia solution (in methanol, 4 ml) was heated in a microwave apparatus to 120-125° C. for 2.5 hours. After cooling the mixture was left at room temperature for 18 hours before the solvent was removed in vacuo and the residue was then taken up in tetrahydrofuran and pre-absorbed onto a small amount of silica. Purification by FCC (silica, 20-100% ethyl acetate in heptane) gave 245 mg (89%) of the title compound. 1H NMR (250 MHz, DMSO-d6) 8 ppm 3.18 (2H, t, J=5.79 Hz), 4.46 (2H, t, J=5.79 Hz), 6.71 (1H, s), 7.18 (1H, dd, J=8.60, 0.69 Hz), 7.39 (1H, br, s.), 7.51 (1H, ddd, J=8.68, 2.44, 0.76 Hz), 7.84 (1H, br. s.), 8.19 (1H, dd, J=2.44, 0.76 Hz)); M+1=308/310.