Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:25].CN(C=O)C.[N-:34]=[N+:35]=[N-:36].[Na+].N(CC)(CC)CC.Cl>CCOC(C)=O>[CH2:13]([C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:26])[C:2]([CH3:1])([CH3:27])[CH3:28])=[C:7]([CH3:25])[CH:8]=1)([C:17]1[CH:18]=[CH:19][C:20]([C:21]2[NH:36][N:35]=[N:34][N:22]=2)=[CH:23][CH:24]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(CC)(c1ccc(C#N)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(-c2nnn[nH]2)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 110 °C
Yield: 66.7 %

Procedure:
To a mixture of 4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzonitrile (0.50 g, 1.32 mmol), and DMF (5 mL) is added NaN3 (0.26 g, 3.95 mmol) and Et3N.HCl (0.54 g, 3.95 mmol). The slurry is heated at 110° C. overnight. The slurry is diluted with EtOAc (50 mL), washed with 1M HCl (40 mL) water (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (20%-40% [89% EtOAc: 10% MeOH: 1% ACOH] gradient) to furnish the title compound (0.37 g, 0.88 mmol, 66%).
Reaction SMILES: C(O[C:4]([CH2:6][C:7]1[NH:8][C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][C:10]=2[N:25]=1)=O)C.Cl.[NH2:27][C:28]1[CH:29]=[C:30]([NH:35][C:36]([NH2:38])=[NH:37])[CH:31]=[CH:32][C:33]=1[NH2:34].[CH3:39]N(C)C=O>C(#N)C>[NH:35]([C:30]1[CH:31]=[CH:32][C:33]2[NH:34][C:39]([CH:6]([C:7]3[NH:8][C:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[O:16])[CH2:11][C:10]=4[N:25]=3)[CH3:4])=[N:27][C:28]=2[CH:29]=1)[C:36]([NH2:38])=[NH:37]
Reactant: CCOC(=O)Cc1nc2c([nH]1)CCN(C(=O)OCc1ccccc1)C2
Reactant: CN(C)C=O
Reactant: N=C(N)Nc1ccc(N)c(N)c1
Agent: Cl
Solvent: CC#N
Product: CC(c1nc2c([nH]1)CCN(C(=O)OCc1ccccc1)C2)c1nc2cc(NC(=N)N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture comprising benzyl 2-ethoxycarbonylmethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (1.7 g, 4.8 mmol), N-(3,4-diaminophenyl)guanidine hydrochloride (0.8 g, 4.0 mmol) and dimethylformamide (2 mL) heated in an oil bath at 185° C. and stirred under a nitrogen atmosphere for 2.5 hours. The mixture was cooled to room temperature and poured into stirring acetonitrile ( 150 mL) to give a precipitate. The precipitate was washed with additional acetonitrile and diethyl ether (150 mL), collected by filtration and dried in vacuo to give an off white solid. The solid was purified by preparative reverse phase HPLC to provide benzyl 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate as a white solid (1.0 g, 55% yield); LRMS(ESI): Calculated for C24H26N8O2: 458.5; Found (MH+): 459.2.
Reaction SMILES: C(O[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=C.[OH2:14]>CO>[C:12]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=2)[C:11]([OH:14])=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: O
Reactant: C=COc1cccc2ccccc12
Solvent: CO
Product: Oc1ccc2ccccc2c1-c1cccc2ccccc12
Temperature: -10 °C
Reaction time: 5 h
Yield: 11 %

Procedure:
62.4 mg (0.20 mmol) of O-vinylnaphthol and 1.3 mg (0.002 mmol) of Co (OAc) (L3) were dissolved in 50 μl of methanol under the atmosphere, 18 μl (1.0 mmol) of water was added to the mixture, and the mixture was then stirred at −10° C. After 5 hours, the reaction solution was analyzed by HPLC, to find that 89% of the O-vinylnaphthol was left with an optical purity of 10% ee. Further, the reaction solution was purified by silica gel column chromatography to obtain the reaction product binaphthol in a yield of 11%. Also, the kre1 value showing the selectivity of reactions at this time was 11.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[O:13][CH2:12]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:17]1[CH2:18][CH2:19][C:14]2([O:21][CH2:11][CH2:12][O:13]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)c1sccc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.5 %

Procedure:
A suspension of 3-amino-thiophene-2-carboxylic acid methyl ester (5.0 g, 31.85 mmol) in dry THF (9 mL) is treated with 1,4-cyclohexanedione monoethylene ketal (5.0 g, 32.05 mmol), followed by dibutyltin dichloride (482 mg, 1.59 mmol). After 5 min, phenyl silane (4.3 mL, 34.96 mmol) is added and the reaction mixture is stirred overnight at room temperature. After concentration, the residue is dissolved in EtOAc and washed with NaHCO3 followed by brine. The organic layer is separated, dried (Na2SO4), filtered and concentrated. The residue is purified by column chromatography using 30% ethyl acetate in hexane as eluent to give 3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (4.5 g, 47% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:41])=[O:40]>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:11]2[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([C:27]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:50][CH2:49]3)=[O:28])[C:8]([C:6]3[C:5]([O:30][CH2:31][CH3:32])=[CH:4][C:3]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[C:2]([Cl:1])[CH:7]=3)=[N:12]2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 744.4 [(M+H)+]
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]4)=[N:6][CH:7]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: CN(C)C1CCN(c2ccc(I)cn2)C1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CN(C)C1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)C1

Procedure:
Prepared according to general working method I from [1-(5-iodo-pyridin-2-yl)-pyrrolidin-3-yl]-dimethyl-amine (160 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (108 mg, 0.50 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH2:9].[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:21])=[CH:15][CH:14]=1)[CH3:11]
Reactant: CCOc1ccc(N=C=O)cc1
Reactant: NCCc1ccccn1
Product: CCOc1ccc(NC(=O)NCCc2ccccn2)cc1
Yield: 95 %

Procedure:
Prepared in a similar manner to example 158 using 2-(pyridine-2-yl)ethanamine and 1-ethoxy-4-isocyanatobenzene. Yield: 95%. mp: 163-164° C. 1H NMR (500 MHz, CDCl3): δ 1.43 (t, 3H), 3.03 (t, 2H), 3.68 (t, 2H), 4.03 (q, 2H), 5.69 (br s, 1H), 6.45 (br s, 1H), 6.84 (m, 2H), 7.14 (m, 3H), 7.20 (d, 1H), 7.64 (dt, 1H), 8.43 (dd, 1H). MS (M+H, 286).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][NH:14][CH2:13]2.[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH:27]=[C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[C:25](=[O:33])[NH:24][C:23]1=[O:34].O>CN(C=O)C>[ClH:18].[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][N:14]([CH2:19][CH2:20][CH2:21][N:22]1[CH:27]=[C:26]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:25](=[O:33])[NH:24][C:23]1=[O:34])[CH2:13]2
Reactant: O=c1[nH]c(=O)n(CCCCl)cc1-c1cccs1
Reactant: Fc1cc(C(F)(F)F)ccc1[C@@]12CNC[C@@H]1C2
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3F)C2)cc1-c1cccs1
Temperature: 100 °C

Procedure:
A mixture of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (29 mg, prepared following a similar procedure to that reported in WO 2005080382), 1-(3-chloropropyl)-5-(2-thienyl)-2,4(1H,3H)-pyrimidinedione (Prep15, 35 mg) and TEA (0.034 mL) in DMF (1.5 mL) was heated at 100° C. for 24 hours. Water was then added and the solution was extracted with dichloromethane. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude obtained was loaded over a SCX cartridge and eluted with ammonia (1M in methanol). The resulting product was further purified by silica flash chromatography (DCM/MeOH 98:2) to obtain 13 mg of the title compound as free base. To a solution of this product (13 mg) in dichloromethane (0.5 mL), HCl (1M in Et20, 1 eq) was added, the solvent was evaporated in vacuo and the material thus obtained triturated with Et2O to give 13 mg of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C@H:14]([CH2:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].C(N(CC)CC)C.O([Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])S(C(F)(F)F)(=O)=O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C@H:14]([CH2:15][CH:16]([O:23][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(O[Si](C)(C)C(C)(C)C)CC[C@@H]4[C@H]3CC[C@]12C
Reaction time: 0.42 h
Yield: 87.4 %

Procedure:
To a solution of 17β-acetyloxy-5α-estran-3-one (1.595 g, 5 mmol) in dry dichloromethane (30 mL) was added with stirring at ice-water bath temperature, triethyl amine (2 mL) followed by t-butyldimethylsilyl triflate (2.64 g, 10 mmol). The solution was stirred for 25 min, then diluted with dichloromethane (20 mL) and washed with satd.aq. NaHCO3 (30 mL), brine (30 mL) and dried over Na2SO4. The solvent was removed to yield a solid, which was purified by chromatography (silica gel, dichloromethane, pretreated with 1% triethyl amine in hexanes) to get 1.9 g (87%) of pure product as colorless crystals, m.p. 89°-90° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[N:12]1([CH2:17][CH2:18][O:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[Br:1][C:2]1[C:10]2[C:9]([N:24]3[CH2:25][CH2:26][CH:21]([CH2:20][O:19][CH2:18][CH2:17][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[CH2:22][CH2:23]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Reactant: Clc1ncnc2scc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Brc1csc2ncnc(N3CCC(COCCN4CCCC4)CC3)c12
Temperature: 110 °C
Yield: 93.4 %

Procedure:
5-Bromo-4-chlorothieno[2,3-d]pyrimidine (828 mg 3.33 mmol) in dry acetonitrile (13 mL) was treated with 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (1.057 g, 5.0 mmol,) and potassium carbonate (687 mg, 5.0 mmol) and heated at 110° C. for 30 min in a microwave. The reaction was then poured into ethyl acetate (50 mL) and water (30 mL) and the ethyl acetate layer separated, dried over sodium sulphate and concentrated in vacuum to give 5-bromo-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (1.322 g, 3.11 mmol, 93%). LCMS RT=2.91 min. M+1=427.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]3[C:18](=[O:20])[NH:19][C:5]([C:6]=23)=[CH:4][CH:3]=1.Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[H-].[Na+].CCOC(C)=O>CN(C=O)C.O>[Br:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]3[C:18](=[O:20])[N:19]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:5]([C:6]=23)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccc1)CO3
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(CCN2CCOCC2)c2ccc(Br)c3c2n1C(c1ccccc1)CO3
Yield: 8.7 %

Procedure:
To a 0° C. mixture of 7-bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.065 g, 0.20 mmol) from Example 1, step 4 and 4-(2-chloroethyl)morpholine hydrochloride (0.12 g, 0.63 mmol) in DMF (1 mL) was added NaH in mineral oil (0.048 g, 1.2 mmol). The reaction mixture was stirred over a weekend. EtOAc and water were added. The organic layer was washed with water and brine, dried over Na2SO4 and evaporated to dryness to give an orange oil. The crude was purified by LCMS (C18 column eluting with a gradient MeCN/H2O containing 0.15% NH4OH at 5 mL/min.) and gave a white solid (7.7 mg, 9% yield). 1H NMR (400 MHz, CD3OD/CDCl3): d 7.31 (3H, m); 7.18 (3H, m); 6.65 (1H, d); 5.19 (1H, m); 4.61 (1H, m); 4.43 (1H, m); 3.99 (2H, m); 3.6 (4H, m); 2.65 (2H, m); 2.51 (4H, m). LCMS calc. for C26H29N4O4 (M+H)+: m/z=. found: 444.1, 446.1.
Reaction SMILES: C1(=O)CCCCC1.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28]([OH:32])(=[O:31])[CH:29]=[CH2:30]>>[CH:20]([CH:30]=[CH:29][C:28]([OH:32])=[O:31])=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=Cc1ccccc1
Reactant: C=CC(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O=C1CCCCC1
Product: O=C(O)C=CC=Cc1ccccc1
Reaction time: 2 h

Procedure:
432 g of cyclohexanone and 3 g of azobisisobutyronitrile were poured into a five-necked reaction vessel having a capacity of one litter. Then, while introducing nitrogen gas into the reaction vessel, the resultant mixture was heated to 80° C. Then, a mixed liquid constituted by 98.9 g of styrene and 9.1 g of acrylic acid was added drop-wise to the above mixture taking two hours. 30 minutes after finishing of the dropping of the mixed liquid, 3 g of azoisobutyronitrile was added to the resultant mixture and the mixture thus obtained was heated for 5 hours to obtain a styrene-acrylic acid copolymer. The weight average molecular weight of the styrene-acrylic acid copolymer thus obtained was 6900.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9]CC(=C)C=2[CH:31]=1.C[N+]1([O-])CC[O:36]CC1.S([O-])(O)=O.[Na+].[C:45]([OH:49])([CH3:48])([CH3:47])[CH3:46]>N1C=CC=CC=1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:47][C:45]([CH2:48][OH:36])([OH:49])[C:46]=2[CH:31]=1
Reactant: CC(C)(C)O
Reactant: C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)(CO)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-5-methylidene-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.28 g) in t-butanol (3 ml), pyridine (0.2 ml) and water (1.2 ml) is added 4% aqueous osmium tetraoxide solution (0.2 ml), and further thereto is added 4-methylmorpholine N-oxide (0.1 g). The mixture is refluxed for 5 hours, and cooled. Saturated aqueous sodium hydrogen sulfite solution is added to the reaction mixture, and the mixture is stirred at room temperature for 30 minutes. Water is added to the reaction solution, and the mixture is extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-hydroxymethyl-5-hydroxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.14 g) as colorless amorphous.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]([C:12]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)[CH:15]=[CH:14][C:13]=1[OH:28])(=O)[CH3:10].C(Cl)(Cl)Cl>O.CO>[OH:3][N:2]=[C:9]([C:12]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)[CH:15]=[CH:14][C:13]=1[OH:28])[CH3:10]
Reactant: CC(=O)c1cc(CN2CCN(CCO)CC2)ccc1O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=NO)c1cc(CN2CCN(CCO)CC2)ccc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
Hydroxylamine hydrochloride (63 mg, 0.9 mmol) and sodium bicarbonate (76 mg, 0.9 mmol) were dissolved in distilled water (1 ml). 2-Acetyl-4-[4-(2-hydroxyethyl)-piperazin-1-yl-methyl]phenol (85 mg, 0.3 mmol) in absolute methanol (2 ml) was added and the reaction mixture was stirred at 65° C. for 24 h. CHCl3 (20 ml) was then added, the organic phase washed with water followed by brine, dried over Na2SO4, filtered and evaporated to obtain the title product (52 mg, 81%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH:36]N)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: CS(=O)(=O)c1cccc(NN)c1
Product: CS(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (3-methanesulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=477.0 (M+H)+
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[CH3:12])C.[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23]CC(N(OC)C)=O>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH:12]=[C:14]([CH2:15][CH2:23][N:19]1[CH2:20][CH2:21][CH2:22][C@@H:18]1[CH2:17][OH:16])[NH:3][C:4]2=[O:13]
Reactant: CON(C)C(=O)CCN1CCC[C@@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(Cl)c1C
Product: O=c1[nH]c(CCN2CCC[C@@H]2CO)cc2c(Cl)cccc12
Yield: 14.2 %

Procedure:
In the same manner as in Example 16b and using N,N-diethyl-3-chloro-2-methylbenzamide (3.35 g) and (R)-3-(2-hydroxymethylpyrrolidin-1-yl)-N-methoxy-N-methylpropanamide (3.22 g), (R)-5-chloro-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one (645 mg) was obtained.
Reaction SMILES: [OH:1][C@H:2]([CH2:12][O:13]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][N:4]1[CH:11]=[N:10][C:8]([NH2:9])=[N:7][C:5]1=[O:6].S(O[CH2:44][P:45](=[O:54])([O:50]C(C)C)[O:46]C(C)C)(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+].Br[Si](C)(C)C>CN(C=O)C.C(O)(=O)C>[OH:13][CH2:12][C@@H:2]([O:1][CH2:44][P:45]([OH:54])([OH:50])=[O:46])[CH2:3][N:4]1[CH:11]=[N:10][C:8]([NH2:9])=[N:7][C:5]1=[O:6]
Reactant: Nc1ncn(C[C@H](O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)n1
Reactant: Cc1ccc(S(=O)(=O)OCP(=O)(OC(C)C)OC(C)C)cc1
Agent: C[Si](C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1ncn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-[(2S)-2-hydroxy-3-(triphenylmethoxy)propyl]-5-azacytosine (934 mg, 2.18 mmol) and diisopropyl tosyloxymethylphosphonate (1.05 g, 3 mmol) in DMF (30 ml) was cooled to −20° C. and 60% oil dispersion of NaH (240 mg, 6 mmol) was added. The mixture was stirred at −20° C. for 15 min, then the temperature was let to rise to approx. 25° C. (room temperature) and the stirring continued for additional 15 h. Acetic acid was added drop wise to pH 7, the mixture evaporated and the residue coevaporated with toluene (2×50 ml). Acetonitrile (30 ml) was added, followed by bromotrimethylsilane (2.7 ml, 20 mmol), the resulting suspension stirred in dark at room temperature for 48 h and evaporated. The residue was coevaporated with acetonitrile (3×50 ml). 90% Aqueous solution of methanol (50 ml) was added and the solution neutralized to pH 7.0 with 0.2 M triethylammonium hydrogencarbonate. The solution was concentrated to minimal volume (approx. 5 ml) and partitioned between water (100 ml) and ether (100 ml). An aqueous layer was concentrated to a volume 5 ml and applied onto a column of Dowex 1 (AcO− form, 60 ml). Elution was performed with water (300 ml), then with a linear gradient of acetic acid (0.5-1 M, 1 l) and lastly, the pure product was eluted with 1 M formic acid. UV absorbing fractions were taken down in vacuo and the residue coevaporated several times with water till a complete removal of acid. The residue was crystallized from aqueous ethanol, crystals collected by suction, washed with ethanol and ether and dried in vacuo. Yield: 200 mg (33%) of pure HPMP-5-azaC.
Reaction SMILES: [OH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.Cl.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]2=[O:49])[CH2:35][CH2:34]1.[O:50]1CCC[CH2:51]1>>[O:49]=[C:40]1[N:39]([CH:36]2[CH2:35][CH2:34][N:33]([C:51]([O:1][CH:2]3[N:8]=[C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:6]4[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=4[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]3=[O:24])=[O:50])[CH2:38][CH2:37]2)[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41]1
Reactant: O=C1C(O)N=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Reactant: C1CCOC1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(OC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-Hydroxy-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (40 mg, 0.12 mmol) and p-nitrophenylchloroformate (24.1 mg, 0.12 mmol) were dissolved in tetrahydrofuran (1 mL) under argon, and cooled to 0° C. Triethylamine (15 uL, 0.11 mmol) was added and the reaction stirred for 1.5 h. Additional triethylamine was added (33 uL, 0.24 mmol) along with 3-(4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride (32 mg, 0.12 mmol). The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and the residue triturated with methanol. The triturated solid was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution), to yield the title compound (29 mg). MS 592.2181 (M+1)