Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:12]([N:19]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:12]([N:19]1[CH:23]=[C:22]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc2cccc(-c3cnn(Cc4ccccc4)c3)n2n1
Temperature: 150 °C

Procedure:
A vial was charged with 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.00 g, 9.39 mmol), 1-benzylpyrazole-4-boronic acid, pinacol ester (3.20 g, 11.3 mmol), potassium phosphate (4.00 g, 18.8 mmol) and tetrakis(triphenylphosphine)palladium (1.10 g, 0.94 mmol). Dimethylacetamide (24 ml) and water (8 ml) were added and the reaction mixture was heated under microwave irradiation to 150° C. for 10 min. The mixture was partitioned between ethyl acetate and water, and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed several times with water, once with brine, dried over magnesium sulfate and concentrated in vacuo. Trituration in the minimum amount of dichloromethane and diethyl ether afforded an orange solid which required no further purification. Yield: 1.82 g, 67%; LCMS method: 2, RT: 2.37 min, MI: 291 [M+1].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[O:13]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[CH:23]=[N+:24]([CH3:26])[CH3:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:23]([N:24]([CH3:26])[CH3:25])[C:22]1[CH:27]=[CH:28][CH:29]=[C:20]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:21]=1)[CH3:2]
Reactant: CCc1cccc2cc[nH]c12
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: CCc1cccc2c(C(c3cccc(Oc4ccccc4)c3)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:8]([O:10]CC)=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH-].[K+].CCOC(C)=O.Cl>CCO>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:1])[C:8]([OH:10])=[O:9])[CH3:7]
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)(C)C(=O)O
Yield: 77.4 %

Procedure:
Diethyl dimethylpropanedioate (10 g, 53 mmol) in 170 mL EtOH was treated with 3.00 g (53 mmol) KOH at ambient temperature for 4 days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The aqueous phase was isolated, combined with fresh EtOAc and the pH adj to 2 with 6N HCl. The organic phase was isolated and the aqueous portion extracted twice with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated to give 6.56 g (41 mmol) 3-(ethyloxy)-2,2-dimethyl-3-oxopropanoic acid as a clear oil. 1H NMR (300 MHz, CDCl3) d 4.20 (q, J=7.1 Hz, 2H), 1.46 (s, 6H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:2].C1CCCCC=1.B(Br)(Br)Br>ClCCl>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[C:8]([C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:25]([C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH3:2]
Reactant: CCC1c2ccccc2-c2cc(-c3cccc(OC)c3)ccc2N1S(=O)(=O)c1ccc(O)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CCC1c2ccccc2-c2cc(-c3cccc(O)c3)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A stirred and cooled solution of 4-{[6-ethyl-2-(3-methoxyphenyl)phenanthridin-5(6H)-yl]sulfonyl}phenol (0.645 g, 1.36 mmol) and cyclohexene (1.1 mL, 10.9 mmol) in dichloromethane (5 mL) was treated drop-wise under nitrogen at −30° C. with boron tribromide (1.03 mL, 10.9 mmol). After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for four hours. The reaction was cooled to −30° C. and quenched with methanol (1 mL). The solvent was removed in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:3); to yield the title compound (0.473 g, 1.03 mmol, 76%), which was characterized by LCMS (ES+, FA, CV=20 or 5), m.p. 105° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=3)[C:21]([OH:23])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH:36](O)([CH3:38])[CH3:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=3)[C:21]([O:23][CH:36]([CH3:38])[CH3:37])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: CC(C)(F)C(c1cc(F)cc(C(=O)O)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Product: CC(C)OC(=O)c1cc(F)cc(C(C2CN(C(c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1

Procedure:
Prepared from 3-(1-{1-[(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzoic acid and isopropanol according to the procedure described in Preparation 21; Mass Spectrum: m/e=537 (M+1, 35Cl), 539 (M+1, 37Cl).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33](C(O)=O)=[C:32]([O:40][CH3:41])[CH:31]=1>>[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:27])[CH2:11]2)=[O:7])=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)C2CCCCC2)C1

Procedure:
4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (1.00 g) as starting compound was reacted and treated in the same manner as in Example 1 using cyclohexanecarbonyl chloride (0.49 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.74 g) to give 4-amino-5-chloro-N-(1-(4-cyclohexanecarbonylaminobutyl)pyrrolidin-3-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1.[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1)#[N:15]
Reactant: CN(C)C=O
Reactant: CCc1cc(Br)ccc1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCc1cc(C#N)ccc1C(=O)OC
Temperature: 100 °C
Yield: 40 %

Procedure:
Charged methyl 4-bromo-2-ethylbenzoate (1.9 g, 7.85 mmol), Zn(CN)2 (1.48 g, 12.56 mmol), Pd(PPh3)4 (1.0 g, 0.94 mmol) and DMF (30 mL) to a flask, the system was then purged with nitrogen and heated at 100° C. for 6 h. The reaction mixture was then filtered. The filtrate was extracted with ethyl acetate and concentrated the organic phase for flash column chromatograph to give 0.6 g of the title compound (40%). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.6 Hz), 2.99 (2H, q, J=7.6 Hz), 3.92 (3H, s), 7.52-7.54 (1H, m), 7.57 (1H, s), 7.90 (1H, d, J=8.0 Hz).
Reaction SMILES: CS(C1C=C(C2N=[C:15]([O:17]C)N=C(NCCC3C=CC(OC)=CC=3)C=2)C=CC=1)(=O)=O.[Cl:30]C1C=C(Cl)C=CC=1CCNC1N=C(OC)N=C(C2C=C(C=CC=2)OCC#N)C=1.[Cl:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[C:61]=1[CH2:67][CH2:68][NH:69][C:70]1[N:75]=[C:74]([O:76][CH3:77])[N:73]=[C:72]([C:78]2[CH:79]=[C:80]([CH:87]=[CH:88][CH:89]=2)[O:81][CH2:82][C:83]([NH:85][OH:86])=[NH:84])[CH:71]=1.ClC1C=C(Cl)C=CC=1CCNC1N=C(OC)N=C(C2C=C(C=CC=2)OCC(NO)=N)C=1>>[ClH:30].[Cl:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[C:61]=1[CH2:67][CH2:68][NH:69][C:70]1[N:75]=[C:74]([O:76][CH3:77])[N:73]=[C:72]([C:78]2[CH:79]=[C:80]([CH:87]=[CH:88][CH:89]=2)[O:81][CH2:82][C:83]2[NH:84][C:15](=[O:17])[O:86][N:85]=2)[CH:71]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(C)(=O)=O)c3)nc(OC)n2)cc1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(OCC#N)c2)n1
Reactant: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(OCC(=N)NO)c2)n1
Agent: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(OCC(=N)NO)c2)n1
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(OCc3noc(=O)[nH]3)c2)n1
Product: Cl

Procedure:
By proceeding in a similar manner to Example 34(a) above but: (i) substituting (3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-acetonitrile [164 mg, Example 22(f)] for (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-acetonitrile there is prepared 2-(3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-N-hydroxy-acetamidine (166 mg, 94%), (ii) substituting 2-(3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-N-hydroxy-acetamidine for 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-N-hydroxy-acetamidine, and (iii) subjecting the product to silica gel chromatography eluting with 0 to 7% MeOH in DCM there is prepared 3-(3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxymethyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride [Example 34(c)] as a solid. LC/MS: RT=2.4 minutes, MS: 472 (M+H). 1H NMR (300 MHz, (CD3)2SO): □12.82 (1H, br s), 7.18-7.55 (7H, m), 6.6 (1H, s), 5.18 (2H, s), 4 (3H, s), 3.68 (2H, m), 3.08 (2H, m). IC50=0.3 nM
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][O:10][CH:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C:22](=[O:39])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[CH:25][CH:24]=3)[CH2:14][CH2:13][CH2:12]2)=[O:8])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:48])C=1.S([O-])(O)=O.[Na+]>ClCCl>[O:48]=[S:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][O:10][CH:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C:22](=[O:39])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[CH:25][CH:24]=3)[CH2:14][CH2:13][CH2:12]2)=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)N3CCSCC3)c3ccccc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)N3CCS(=O)CC3)c3ccccc32)cc1
Temperature: -8 °C
Yield: 77.7 %

Procedure:
To a solution of 5-(thiomorpholinocarbonylmethoxy)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.40 g) in dichloromethane (40 ml) is added 80% m-chloroperbenzoic acid (175 mg) with stirring at -8° C., and the mixture is stirred at -8° C. for 1 hour. To the reaction solution is added 20% aqueous sodium hydrogensulfite solution (40 ml) and the mixture is stirred at room temperature for 30 minutes. The dichloromethane layer is collected, washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichlpromethane:methanol=20:1) to give 5-[(1-oxothiomorpholino)carbonylmethoxy]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.32 g) as colorless amorphous.
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.Br[CH2:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13]>>[CH3:1][S:2][CH:3]1[N:6]([CH2:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])[C:5](=[O:7])[CH2:4]1
Reactant: CSC1CC(=O)N1
Reactant: CC(=O)CC(=O)CBr
Product: CSC1CC(=O)N1CC(=O)CC(C)=O

Procedure:
4-Methylthioazetidin-2-one (6.66 g., 57 mmole) and 1-bromopentan-2,4-dione (11.25 g., 63 mmole) were converted into the title compound using the process described in Example 1.1. The title compound was obtained as a colourless gum (3.13 g., 25% yield). νmax (CHCl3): 3400 (br.) (enol OH), 1760 (β-lactam C=O), 1720 (sh.) (ketone C=O), 1630 (sh.) and 1605 (enolic β-diketone C=O) cm-1. δ(CDCl3): 2.03 (s, 6H, COCH3 and SCH3), 2.97 (dd, J 16, J' 2 Hz, 1H, β-lactam CHH), 3.41 (dd, J 16, J' 5 Hz, 1H, β-lactam CHH), 3.60 (s, 0.4H, COCH2CO), 3.65 (d, J 17 Hz, 1H, NCHH), 4.18 (d, J 17 Hz, 1H, NCHH), 4.78 (dd, J 5, J' 2 Hz, 1H, β-lactam CH), 5.68 (s, 0.8H, olefinic H for enol), ca 14(v.broad, 0.8H, enolOH).
Reaction SMILES: [CH2:1]([CH:9]1[C:14]2=[C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]3=[N:17][C:13]2=[C:12]([C:22]([C:24]2[O:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=2)=[O:23])[CH:11]=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:31]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:42][OH:43]>>[CH3:42][O:43][CH:29]([O:30][CH3:31])[C:27]1[O:28][C:24]([C:22]([C:12]2[CH:11]=[CH:10][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14]3[C:13]=2[N:17]=[C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=32)=[O:23])=[CH:25][CH:26]=1
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCCCC1C=CC(C(=O)c2ccc(C=O)o2)=C2N=C3CCCCC3=C21
Product: CCCCCCCCC1C=CC(C(=O)c2ccc(C(OC)OC)o2)=C2N=C3CCCCC3=C21

Procedure:
A mixture of 11.2 g of aldehyde from Example 155, and 1.0 g of p-toluenesulfonic acid in 150 mL of methanol was refluxed for 2 hours. After evaporation of the solvent the residue was poured into a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The material obtained as an orange-brown oil (11.9 g; 95%) was used without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4]1.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([NH:18][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4]1)[CH3:17]
Reactant: CCN
Reactant: CC(c1ccccc1)N1CCC(CCl)C1
Product: CCNCC1CCN(C(C)c2ccccc2)C1
Yield: 98 %

Procedure:
A solution of 4.0 g (15.4 mmol) [3R-(R*,R*)]-3-(chloromethyl)-1-(1-phenylethyl)pyrrolidine in 60 ml 70% ethylamine was heated in a pressure bottle on the steam bath overnight. The mixture was cooled, filtered, and evaporated to a thick syrup which was treated with 50 ml 2N sodium hydroxide and extracted with 3×30 ml dichloromethane. The combined organic layer was dried (MgSO4) and evaporated to afford 3.49 g (98%) of the title compound as a syrup, [α]D +45.6° C. (C, 1.04, methanol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[O:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:6]([CH3:21])[C:5]2=[O:22].C([O-])(=O)C.[Na+].[H][H]>[C].[Pd].C(O)(C)C>[CH3:21][C:6]1[C:5](=[O:22])[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=[CH:2][CH:3]=2)[O:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)O)cc(Cl)cc2c1=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc2c1=O
Reaction time: 6 h
Yield: 92.8 %

Procedure:
Into a pressure reactor were placed 3.15 g (0.01 mole) of 6-chloro-3-methylflavone-8-carboxylic acid, 4.0 g (0.03 mole) of sodium acetate, 150 ml of isopropanol and 0.2 g of 5% palladium-carbon catalyst. After the atmosphere was replaced with hydrogen gas, reaction was performed at a pressure of 5.0 kg/cm2G at 70° C. for 6 hours. Then the reaction mixture was treated in the same manner as in Example 13, affording 2.6 g (93%) of 3-methylflavone-8-carboxylic acid which was recrystallized from alcohol, giving a product melting at 230° to 233° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][NH:7][C:6]=2[N:16]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>CC(N(C)C)=O>[CH2:17]([N:7]1[CH2:8][C:9]([CH3:14])([CH3:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[N:16][C:6]1=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CN1C(=O)C(C)(C)CNc2nc(Cl)ncc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(C)CN(Cc2ccccc2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
2-Chloro-8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (50 mg, 0.21 mmol) and benzylbromide (30 μl, 0.25 mmol) in DMA (0.5 ml) was treated with sodium hydride 60% oil dispersion (9 mg, 0.23 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc in hexanes, loaded on silica, ˜50 mL silica) to give the title compound as a white solid (63 mg, 91%). NMR DMSO D61.00 (6H, s), 3.22 (3H, s), 3.53 (2H, s), 4.91 (2H, s), 7.28-7.39 (5H, m), 8.12 (1H, s); MS (ES+) 331.
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10].S(=O)(=O)(O)O.O.[OH-].[Na+].C(#[N:22])C>>[NH2:22][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: CC#N
Reactant: O[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 0 °C

Procedure:
Cis-1,2-indandiol (1.5 g) was dissolved in acetonitrile (25 mL) cooled to 0° C, and concentrated sulfuric acid (1.1 mL) was added. The mixture was gradually warmed to 20° C. and aged to 3 hours. Water (2 mL) was added and the mixture heated to reflux. Concentrated aqueous sodium hydroxide was added to adjust the pH to 12. The resulting solid was removed by filtration to provide an aqueous acetonitrile solution of cis-1-amino-2-indanol.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10]C.[Cl:12][C:13]1[C:18]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1.ICCCCCI>O.C(COC)OC>[Cl:12][C:13]1[C:18]([C:19]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CCCCCC
Reactant: O=S(=O)(Cc1cccnc1Cl)c1ccc(Cl)cc1
Agent: ICCCCCI
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cccnc2Cl)CCCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
At −78° C., butyl lithium (a 1.57M hexane solution; 0.66 ml, 1.03 mmol) was added dropwise to a dimethoxyethane (5 ml) solution of the 2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (156 mg, 0.516 mmol) obtained in Example 98. At −78° C., the resulting mixture was stirred for 20 minutes, followed by the addition of 1,5-diiodopentane (0.092 ml, 0.619 mmol). The temperature of the reaction mixture was gradually elevated to room temperature, at which stirring was performed for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the 15% ethyl acetate/hexane eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (72 mg, 38%) as a white solid. The resulting solid was washed with hexane-ether and then collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [CH2:1]([NH:3]/[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:5]1\[C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[S:9]\1)[CH3:2].[OH:21]O>C(O)(=O)C>[CH2:1]([NH:3]/[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:5]1\[C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[S:9]\1=[O:21])[CH3:2]
Reactant: CCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: OO
Solvent: CC(=O)O
Product: CCN/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1

Procedure:
Prepared analogous to Example 1 from (E)-2-[(ethylamino)phenylmethylene]-benzo[b]thiophen-3(2H)-one and aqueous hydrogen peroxide in glacial acetic acid.
Reaction SMILES: N1([C:6](N2C=NC=N2)=[O:7])C=NC=N1.[NH2:13][C:14]1[CH:21]=[C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])[C:17]([C:18]#[N:19])=[CH:16][N:15]=1.[CH3:27][O:28][CH:29]([O:49][CH3:50])[C:30]1[C:39]([CH2:40][N:41]2[CH2:48][CH2:47][CH2:46][C:42]32[CH2:45][O:44][CH2:43]3)=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[CH2:43]1[C:42]2([CH2:46][CH2:47][CH2:48][N:41]2[CH2:40][C:39]2[CH:38]=[C:37]3[C:32](=[N:31][C:30]=2[CH:29]([O:28][CH3:27])[O:49][CH3:50])[N:33]([C:6]([NH:13][C:14]2[CH:21]=[C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])[C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[O:7])[CH2:34][CH2:35][CH2:36]3)[CH2:45][O:44]1
Reactant: COC(OC)c1nc2c(cc1CN1CCCC13COC3)CCCN2
Reactant: O=C(n1cncn1)n1cncn1
Reactant: COCCNc1cc(N)ncc1C#N
Solvent: CN(C)C=O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCCC45COC5)c(C(OC)OC)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
A solution of di(1H-1,2,4-triazol-1-yl)methanone (320 mg, 1.95 mmol) in DMF (7 ml) was added to a mixture of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 375 mg, 1.95 mmol) in anhydrous DMF (1.5 ml) at 0° C. After stirring for 2.5 h at room temperature a solution of 5-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-2-oxa-5-azaspiro[3.4]octane (intermediate 230C, 260 mg, 0.78 mmol) in DMF (3 ml) was added. The reaction mixture was stirred for 17.5 h at room temperature, then partitioned between saturated aqueous NaHCO3 solution and EtOAc, the EtOAc phase washed with brine, dried over MgSO4 and evaporated. The residue was applied to a silica column and purified by normal phase chromatography, eluting with EtOAc then a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as a pale yellow solid. (UPLC-MS 3) Rt=0.92 min; MS m/z [M+H]+ 552.