Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:35][O:36][C:37]1[CH:47]=[CH:46][C:45](/[CH:48]=[CH:49]/[C:50](=[O:63])[C:51]2[CH:56]=[C:55]([O:57][CH3:58])[C:54]([O:59][CH3:60])=[C:53]([O:61][CH3:62])[CH:52]=2)=[CH:44][C:38]=1[O:39][CH2:40][C:41](O)=[O:42]>ClCCl.O>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:41](=[O:42])[CH2:40][O:39][C:38]3[CH:44]=[C:45](/[CH:48]=[CH:49]/[C:50](=[O:63])[C:51]4[CH:52]=[C:53]([O:61][CH3:62])[C:54]([O:59][CH3:60])=[C:55]([O:57][CH3:58])[CH:56]=4)[CH:46]=[CH:47][C:37]=3[O:36][CH3:35])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2nc(N)sc2c1
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc2nc(NC(=O)COc3cc(/C=C/C(=O)c4cc(OC)c(OC)c(OC)c4)ccc3OC)sc2c1
Yield: 781.2 %

Procedure:
To a solution of 6-ethoxy-2-aminobenzothiazole (194 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9h) (452 mg, 80% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]#[N:10])[N:3]=1.[CH3:11][N:12]1[C:16]([OH:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][N:12]1[C:16]([O:17][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]#[N:10])[N:3]=2)=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]1
Reactant: Cc1cc(Br)nc(C#N)c1
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#N)nc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 74.4 %

Procedure:
7.6 g 2-bromo-6-cyano-4-methylpyridine, 9 g 1-methyl-3-trifluoromethyl-5-hydroxypyrazole and 9.7 g potassium carbonate were mixed in 30 ml N,N-dimethylformamide and heated to reflux for 5 hours. After cooling, the reaction mixture was poured into 300 ml water and the aqueous layer extracted three times each with 100 ml ethyl acetate. The combined extracts were dried with anhydrous magnesium sulphate and the solvent removed in vacuo. Purification by silica gel column chromatography using hexane/ethyl acetate 7:3 afforded 8.1 g (50%) of the title compound as a pale brown solid of melting point 88° C.
Reaction SMILES: [F:1]/[C:2](=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)/[CH:3]=O.Cl[C:25](Cl)([F:30])[C:26]([O:28][CH3:29])=[O:27]>>[F:30]/[C:25](=[CH:3]\[C:2](\[F:1])=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)/[C:26]([O:28][CH3:29])=[O:27]
Reactant: O=C/C(F)=C/CCCCCCCOc1ccc2ccccc2n1
Reactant: COC(=O)C(F)(Cl)Cl
Product: COC(=O)/C(F)=C/C(F)=C/CCCCCCCOc1ccc2ccccc2n1

Procedure:
(Z)-2-Fluoro-10-(2-quinolinyloxy)dec-2-ene-1-al, prepared as in compound 45 was reacted with methyl dichlorofluoroacetate as in compound 40 to give (2Z,4Z) methyl 2,4-difluoro-12-(2-quinolinyloxy)dodeca-2,4-dienoate. The latter was converted to the title compound an analogy with compound 33.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[O:11][C:12]1[CH:17]=CC=C[C:13]=1C=CC(=O)C>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][C:12](=[O:11])[CH3:17]
Reactant: COc1ccccc1C=CC(C)=O
Reactant: O=Cc1ccccc1F
Product: CC(=O)C=Cc1ccccc1F

Procedure:
The title compound was prepared from 2-fluoro-benzaldehyde (6.2 g, 50.0 mmol), following the procedure describing the synthesis of 4-(2-methoxy-phenyl)-but-3-en-2-one (example 1/a stage 1).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 59 %

Procedure:
2-[2-(2-Methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one is prepared by following the procedure described in example 1a (step 5a) using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 510 mg of 2-methyl-2,3-dihydro-1H-indole and 487 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.308 ml of pyridine and 8 ml of N,N-dimethylformamide. 400 mg of 2-[2-(2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[C:15]3=[O:25])=[CH:10][C:9]=2[O:26][CH3:27])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:28][O:29][CH2:30][C:31](=O)[CH3:32]>>[OH:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:25])[N:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH:31]([CH3:32])[CH2:30][O:29][CH3:28])[CH2:3][CH2:2]3)=[C:9]([O:26][CH3:27])[CH:10]=1)[CH2:23][CH2:22]2
Reactant: COc1cc(N2CCc3cc(O)ccc3C2=O)ccc1N1CCCNCC1
Reactant: COCC(C)=O
Product: COCC(C)N1CCCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2OC)CC1

Procedure:
2-(4-[1,4]Diazepan-1-yl-3-methoxy-phenyl)-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one and 1-methoxy-propan-2-one were reacted according to Method J1. In this way the product was obtained with molecular weight 439.56 (C25H33N3O4); MS (ESI): 440 (M+H+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]([CH2:25][O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]2[O:14][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=3)=[N:11][N:12]=2)=[CH:27][CH:28]=1
Reactant: Oc1ccccc1-c1nnc(Nc2cccc(C(F)(F)F)c2)o1
Reactant: ClCc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccccc3OCc3ccnc4ccccc34)o2)c1
Temperature: 60 °C
Yield: 27.2 %

Procedure:
To a solution of 2-(5-(3-trifluoromethylphenylamino)-1,3,4-oxadiazol-2-yl) phenol (100 mg, 0.31 mmol; Reference Compound 9-(1)) and 4-chloromethylquinoline (55 mg, 0.31 mmol) in N,N-dimethylformamide (1.0 mL) was added potassium carbonate (86 mg, 0.62 mmol) at room temperature and then the mixture was stirred at 60° C. over night. The reaction solution was cooled to a room temperature and diluted with ethyl acetate (100 mL). The ethyl acetate solution was washed with a saturated brine solution (30 mL), dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The residue was purified with a silica gel column chromatography (hexane/ethyl acetate) to give 39 mg (27%) of the titled compound as a colorless solid.
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)C.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[CH2:5][C:4](=[O:16])[N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:24]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: NNc1ccccc1
Solvent: CCO
Product: COc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1
Yield: 77.5 %

Procedure:
Using General Procedure A; ethyl-4-methoxybenzoylacetate (7.00 g, 27.8 mmol, 1.1 equ.) in ethanol (100 mL) was treated at 0° C. with phenylhydrazine (2.50 mL, 25.3 mmol, 1.0 equ.) to give 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (5.21 g, 19.6 mmol, 78%) after crystallization (ethanol) as a light yellow solid. 1H-NMR (400 MHz) CDCl3: 7.99-7.97 (d, 1H), 7.66-7.64 (d, 2H), 7.44-7.40 (t, 2H), 7.22-7.18 (t, 1H), 6.94-6.92 (d, 2H), 3.82 (s, 3H), 3.68 (s, 3H), 13C-NMR (100 MHz) CDCl3: 170.1, 161.5, 154.4, 138.2, 128.8, 127.5, 125.0, 123.5, 118.8, 114.2, 55.3, 39.6; LC/MS-MS: 267.0→77.2 m/z; GS1 and GS2 at 30, DP=81, CE=65, CXP=4, tR=4.15 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH3:2].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH:10][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1cccc(N)n1
Product: CCOC(=O)C(=CNc1cccc(OCC)n1)C(=O)OCC
Temperature: 95 °C

Procedure:
A mixture of 6-ethoxypyridin-2-amine (8.0 g) and diethyl ethoxymethylenemalonate (12.5 g) was heated at 95° C. under vacuum for 3 hours and then heated at 95° C. at atmospheric pressure for 18 hours. The mixture was cooled to ambient temperature, diluted with petroleum ether b.p. 40°-60° C. and filtered to give diethyl (6-ethoxy-2-pyridylamino)methylenemalonate, m.p. 58°-60° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:7]=1.[C:14]([N:22]=[C:23]=[S:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[C:14]([NH:22][C:23]([NH:13][C:4]1[CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:7]=[C:2]([Br:1])[CH:3]=1)=[S:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cc(Br)cc(-n2cccn2)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)cc(-n2cccn2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To the solution of 3-bromo-5-pyrazol-1-yl-phenylamine (0.18 g, 0.76 mmol) in anhydrous acetone (5.0 mL) was added benzoylisothiocyanate (0.14 g, 0.83 mmol) and the reaction mixture was stirred at room temperature for 30 min. Acetone was distilled off and the crude residue was washed with hexane to obtain desired compound (0.27 g, 89%).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][C:12]([NH2:15])([CH3:14])[CH3:13]>O1CCOCC1>[Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5]([NH:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[N:6][CH:7]=1
Reactant: CSc1nc(Cl)ncc1Br
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: CSc1nc(NC(C)(C)C)ncc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To 5-bromo-2-chloro-4-(methylthio)pyrimidine (3 g, 12.53 mmol) in dioxane (12.53 mL) was added 2-methylpropan-2-amine (7.93 mL, 75 mmol). The mixture was stirred at 100° C. overnight in a sealed vessel. The solvent was removed under reduced pressure and the residue was dissolved in 100 mL ethyl acetate and washed with 50 mL of a 1M aqueous solution of sodium hydrogen phosphate. The aqueous layer was back-extracted with 50 mL ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give 5-bromo-N-tert-butyl-4-(methylthio)pyrimidin-2-amine (3.4 g, 12.31 mmol, 98% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61-8.72 (m, 1H), 8.08 (s, 1H), 6.95-7.17 (m, 1H), 2.48 (s, 2H), 1.38 (s, 9H). MS (ESI) m/z 276.0 [M+1]+ and 278.2 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:18]=[C:17]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=[O:28])[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[CH:16]=[CH:15][C:14]=2[CH3:31])[C:3]1=[O:32].O1CCCCC1O[NH2:40].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:21]=[C:22]([C:23]4[S:24][CH:25]=[CH:26][N:27]=4)[O:28][N:40]=3)[CH:16]=[CH:15][C:14]=2[CH3:31])[C:3]1=[O:32]
Reactant: NOC1CCCCO1
Reactant: CS/C(=C\C(=O)c1nccs1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3cc(-c4nccs4)on3)ccc1C)c(=O)n2C
Temperature: 150 °C

Procedure:
The mixture of (Z)-1,7-dimethyl-3-(2-methyl-5-(1-(methylthio)-3-oxo-3-(thiazol-2-yl)prop-1-enylamino)phenyl)-1,6-naphthyridin-2(1H)-one 32 (462 mg, 1.0 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (293 mg, 2.5 mmol) and K2CO3 (415 mg, 3.0 mmol) in 1,4-dioxane (5 mL) in a sealed vial was heated at 150° C. for 30 h. The mixture was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-(thiazol-2-yl)isoxazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (D9). 1H NMR (400 MHz, d6-DMSO) δ 10.73 (s, 1H), 9.19 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.87 (d, J=3.2 Hz, 1H), 7.74 (d, J=3.2 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.61 (s, 1H), 7.53 (dd, J=2.4, 8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 3.72 (s, 3H), 2.78 (s, 3H), 2.10 (s, 3H). MS m/z 430.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH:38]=[O:39])[CH2:34][CH2:33]2)[C:26]=1[CH3:40])=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][N:32]2[CH2:33][CH2:34][N:35]([CH:38]=[O:39])[CH2:36][CH2:37]2)[C:26]=1[CH3:40])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCN(C=O)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCN(C=O)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (178 mg) was condensed with 4-(5-formyl-2,4-dimethyl-1H-pyrrol-3-ylmethyl)-piperazine-1-carbaldehyde (125 mg) using piperidine (cat. amount) in ethanol at 80° C. for 4 hours to give the titled compound.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([C:12]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[O:16][CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7]1)=[O:5].[Br-].O.Cl>O1CCCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:12]2([C@@H:9]3[CH2:8][CH2:7][C@H:6]([C:4](=[O:5])[CH2:8][CH2:7][CH:6]=[CH2:4])[CH2:11][CH2:10]3)[O:13][CH2:14][CH2:15][O:16]2)=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](C2(c3ccc(Cl)cc3)OCCO2)CC1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)[C@H]1CC[C@@H](C2(c3ccc(Cl)cc3)OCCO2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 168.3 %

Procedure:
While under a nitrogen atmosphere, a solution of cis-4-[2-(4-chlorophenyl)-[1,3]-dioxolan-2-yl]-cyclohexanecarboxylic acid, methoxy-methyl amide (1.36 g, 3.85 mmol), in tetrahydrofuran (10 mL) was cooled to 0° C. and treated with 4-butenylmagnesiun bromide (0.5 M in THF, 19.24 mL, 9.62 mmol) in a dropwise manner. The solution was stirred for 1 hour at 0° C. then allowed to warm to room temperature overnight. The resulting solution was poured into water, acidified to pH 3-4 with 1 N hydrochloric acid, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-25% ethyl acetate in heptane) gave cis-1-{4-[2-(4-chlorophenyl)-[1,3]-dioxolan-2-yl]-cyclohexyl}pent-4-en-1-one as a colorless oil (1.13 g, 84%); 1H NMR (CDCl3, 300 MHz) δ 7.31 (d, J=7.5 Hz, 2H), 7.27 (d, J=7.5 Hz, 2H), 5.78 (m, 1H), 4.96 (m, 2H), 3.94 (m, 2H), 3.68 (m, 2H), 2.50 (m, 3H), 2.30 (m, 2H), 2.15 (dd, J=13, 3 Hz, 2H), 1.76 (tt, J=11, 3 Hz, 1H), 1.36-1.56 (m, 4H) and 1.25 (td, J=13, 3 Hz, 2H); MS (+CI): m/z for C20H25ClO3: expected 348.2. found 349.2 (M+H)+.
Reaction SMILES: [C:1]([C:8]([NH2:32])([CH2:12][CH2:13][CH2:14][C:15]1([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH2:35])=[N-]>C(Cl)Cl>[C:1]([C:8]([NH2:32])([CH2:12][CH2:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([O:11][CH3:35])=[O:10])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)C(N)(CCCC1(CC(=O)OCc2ccccc2)CCCCC1)C(=O)O
Solvent: ClCCl
Product: COC(=O)C(N)(CCCC1(CC(=O)O)CCCCC1)C(=O)OC(C)(C)C

Procedure:
The Boc-benzyl ester (J) (4 mmol) is dissolved in methylene chloride and treated with excess ethereal diazomethane at room temperature. The residual diazomethane is quenched with acetic acid and the solution is evaporated at reduced pressure. The crude diester is dissolved in methanol and hydrogenated over 10% palladium-on- carbon to give, after flash chromatography (silica gel), the titled compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC>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.CN(C)C=O>[C:18]([C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:20])[CH3:19]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(C)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1C(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a N,N-dimethylformamide (8.5 mL) solution of methyl 2-bromo-5-methylbenzoate (752 mg), tributyl(1-ethoxyethenyl)stannane (1.22 mL) and bis(triphenylphosphine)palladium(II) dichloride (115.1 mg) were added, and the resultant was stirred at 100° C. for 1 hour. The reaction solution was allowed to cool to room temperature and then filtered through Celite, and the filtrate was concentrated under reduced pressure. Acetone (10 mL) and a 1 mol/L aqueous hydrochloric acid solution (3.0 mL) were added to the obtained residue, and the resultant was stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction operation twice using chloroform. Organic layers were separated from aqueous layers using a phase separator. The organic layers were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=86/14→65/35) to obtain the title compound (0.49 g) as a pale yellow oil.
Reaction SMILES: C([Mg]Br)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=1.Br[CH2:21][CH2:22][O:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>O1CCCC1>[CH2:31]([O:30][C:28]([C:27]1[CH:33]=[CH:34][C:24]([O:23][CH2:22][CH2:21][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)=[CH:25][CH:26]=1)=[O:29])[CH3:32]
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Reactant: CCOC(=O)c1ccc(OCCBr)cc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCCc2c(-c3cccnc3)[nH]c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 12.0 ml of a 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0°-5° is added dropwise over 20 minutes a solution of 4.0 g of 2-(3-pyridyl)indole in 20 ml of tetrahydrofuran. The mixture is stirred for 0.5 hours at 0°-5° and then is added a solution of 5.06 g of ethyl p-(2-bromoethoxy)benzoate [for preparation see U.S. Pat. No. 2,790,825 (1957)] in 30 ml of tetrahydrofuran. The suspension is stirred at 0°-10° for 1 hour and at room temperature for 0.5 hour, poured into ice-water and extracted with ether. The ether extract is separated, dried over MgSO4, and concentrated to give 3-[2-(4-ethoxycarbonylphenoxy)-ethyl]-2-(3-pyridyl)-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[C:4]([F:13])[CH:3]=1.CCN(CC)CC.[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1>CC#N>[Cl:21][C:22]1[N:27]=[C:26]([N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][C:4]=3[F:13])[CH2:8]2)[N:25]=[CH:24][N:23]=1
Reactant: Fc1cc(Cl)ccc1OC1CNC1
Reactant: Clc1ncnc(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1cc(Cl)ccc1OC1CN(c2ncnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
To a solution of 3-(4-chloro-2-fluorophenoxy) azetidine (3.6 g, 18.0 mmol) in CH3CN (60 mL, 3 mL/mmol) was added Et3N (7.2 mL, 50.0 mmol) and 2, 4-dichloro-1, 3, 5-triazine (3.0 g, 20.0 mmol) and the reaction mixture was stirred at RT for 1 h. Then the reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography to obtain 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 20%) as a solid. Observed mass (M+1): 315.0
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]2C2CCCCO2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>CO>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[NH:13]2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
2-{[(1S)-1-Methylbutyl]oxy}-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (6 g, 17.89 mmol) (for example as prepared for Intermediate 6) was dissolved in methanol (50 mL). Trifluoroacetic acid (20.67 mL, 268 mmol) was added dropwise, and the mixture stirred at 20° C. for 72 hours under an atmosphere of nitrogen. The solvent was removed in vacuo, and the resulting solid was washed with ethyl acetate and filtered. The filtrate was stripped and the residue washed with ethyl acetate. The combined solid residues were dried in the vacuum oven for 2 hours to give the title compound as an off white solid (5.3 g).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+]>C1COCC1.O>[C:1]1([CH:7]([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CN1CCC(C(c2ccccc2)c2cccc(C)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C(c2ccccc2)C2CCN(CC(=O)O)C2)c1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
To a solution of methyl 2-(3-(phenyl(m-tolyl)methyl)pyrrolidin-1-yl)acetate (1.5 g, 4.64 mmol) in THF at 0° C. was added a solution of lithium hydroxide (0.58 g, 13.8 mmol) in water and the reaction mixture was stirred for 4 h. The reaction mixture was concentrated under reduced pressure. To the residue was added water, the pH of the aqueous layer was adjusted to 3 using dil.HCl and extracted with 30% methanol in chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 0.72 g of the title compound.