Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=O)=[CH:18][CH:17]=1>>[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[O:11][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)=[N:12][N:13]=2)=[CH:18][CH:17]=1
Reactant: CSc1ccc(CCC(=O)O)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: CSc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(4-methylthiophenyl)propionic acid (197 mg; 1 mmol) as described in method 2;
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]([CH2:18][C:19](=[O:21])[NH2:20])[C:15]([OH:17])=[O:16])[C:8]2=[O:13])([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]([CH2:18][C:19](=[O:21])[NH2:20])[C:15]([OH:17])=[O:16])[C:8]2=[O:13]
Reactant: NC(=O)CC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: NC(=O)CC(C(=O)O)N1C(=O)c2cccc(N)c2C1=O

Procedure:
A mixture of 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-3-carbamoylpropanoic acid (7.5 mmol) and 10% Pd/C (200 mg) in 20 ml of dimethylformamide is treated with 60 psi of hydrogen in a Parr shaker to afford 2-(4-amino-1,3-dioxoisoindolin-2-yl)-3-carbamoylpropanoic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:14][NH:15][C:16]([NH2:18])=[S:17])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)CCCCc1ccccc1
Reactant: NNC(N)=S
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)CCCCc1ccccc1

Procedure:
A mixture of 9.9 g. of 5-phenylvaleroylchloride and 4.6 g. of thiosemicarbazide was stirred in 20 ml. of dimethylformamide for 6 hours at 22° C. The solvent was evaporated and 10 ml. of water and 10 ml.of ether were added to the residue. The precipitate was filtered off to give the intermediate 1-(5-phenylvaleroyl)-3-thiosemicarbazide, m.p. 140°-141° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH:38]1([OH:42])[CH2:41][CH2:40][CH2:39]1>>[CH:38]1([O:42][C:5]2[N:10]=[C:9]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])[N:6]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OC1CCC1
Agent: [Li]CCCC
Product: Clc1ccc(-c2c(Oc3cccnc3)nc(OC3CCC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (30 mg, 0.06 mmol) with 2 equivalents each of n-butyl lithium and cyclobutyl alcohol by the procedure described in Reference Examples 6 and 7 to afford 2-(2-cyclobutyloxy-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: HPLC/MS: m/e=498 (M++1); Rt4.16 min. 1H-NMR 400 MHz (CDCl3): δ 1.70-1.85 (m, 2H), 2.16-2.28 (m, 4H), 4.93 (m, 1H), 7.14-7.38 (m, 7H), 7.40-7.42 (m, 1H), 7.55-7.58 (m, 1H), 8.52-8.54 (m, 2H).
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[NH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:7](=[O:9])[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)([OH:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:25][CH2:26]1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC1CCN(C(=O)C(O)(c2ccccc2)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
To a stirred solution of (R)-cyclopentylhydroxyphenyl acetic acid (1.0 g, 4.54 mmol) in DCM (50 mL) was added t-butoxycarbonyl-4-aminopiperidine (0.9 g, 4.5 mmol). DIPEA (2.4 mL, 1.4 mmol) and HOBt (1.0 g, 6.8 mmol) were added to the mixture, followed by EDCI (1.0 g, 5.5 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then washed with 1N NaOH (50 mL), 1N HCl (50 mL), and then saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed by rotary evaporation. To the crude material was added a solution of 20% TFA/DCM and the reaction was stirred for 2 hours at room temperature. The solvent was removed by rotary evaporation. DCM (50 mL) was added and the mixture was then washed with saturated sodium bicarbonate (50 mL). The organic layer was removed, dried over MgSO4 and filtered. The crude material was purified by silica gel chromatography (10% MeOH/DCM with 1% NH3 (aq)) to afford the title compound as a white powder (920 mg, 3.0 mmol).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13][N:14](C)C=O>[Zn].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)#[N:14]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyamide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (100 mL) was purged with nitrogen and the mixture stirred at 80° C. overnight. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The solid was purified on silica gel using 1:5 ethyl acetate/hexane to afford the title compound (6.1 g, 80%). MS (DCI): m/z 180 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cn1cc(Br)cn1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]2=[CH:5][CH:4]=[C:3]1[C:16]([OH:18])=O)=[CH:14][CH:13]=[CH:12][CH:11]=3.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:41]([NH:49][C:16]([C:3]1[C:2](=[O:1])[N:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]2=[CH:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:18])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)c1ccc2n(c1=O)CCc1ccccc1-2
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)c1ccc2n(c1=O)CCc1ccccc1-2
Reaction time: 18 h
Yield: 77.4 %

Procedure:
To a solution of 4-oxo-6,7-dihydropyrido[2,1,a]isoquinoline-3-carboxylic acid (3-101-03) (76 mg) in DMF (2.0 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric acid salt (EDC, 83 mg), 1-hydroxybenzotriazole (HOBt, 58 mg), and phenethylamine (80 mg) at room temperature. After the reaction mixture was stirred for 18 h, the reaction was quenched with 0.5 mol/L hydrochloric acid. To the reaction mixture was added ethyl acetate and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude crystal was recrystallized to give 4-oxo-6,7-dihydropyrido[2,1,a]isoquinoline-3-carboxylic acid phenethylamide (3-101) (84 mg, 74%) as an yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([F:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]([O:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19])(=[O:15])[CH3:14].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([S:9]([F:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:18](=[O:19])[C:17]([O:16][C:13](=[O:15])[CH3:14])([CH3:22])[CH3:21]
Reactant: Nc1ccc(S(=O)(=O)F)cc1Cl
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C)(C)C(=O)Nc1ccc(S(=O)(=O)F)cc1Cl
Yield: 49.2 %

Procedure:
A solution of 2-chloro-4-fluorosulphonylaniline (2.5 g, 12 mmol), 2-acetoxyisobutyryl chloride (2.35 g, 14 mmol) and pyridine (1.2 ml, 14.5 mmol), in DCM (50 ml) was stirred at ambient temperature for 18 h. The mixture was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography using 25% EtOAc/isohexane and the oily product, the title compound (2.0 g, 5.9 mmol), solidified on standing. MS: 336.
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([O:14][CH2:15][CH:16]1[O:18][CH2:17]1)(=[O:13])[CH:11]=[CH2:12]>>[C:10]([O:14][CH2:15][CH:16]1[O:18][CH2:17]1)(=[O:13])[CH2:11][CH2:12][S:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CC(=O)OCC1CO1
Reactant: CCCCCCCCS
Product: CCCCCCCCSCCC(=O)OCC1CO1

Procedure:
1-Octanethiol, 71 g (0.5 mole), was reacted with glycidyl acrylate, 62 g (0.5 mole), at 50°-70° C., to give glycidyl 4-thialaurate according to the following reaction: ##STR3##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[O:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][C:24]=1[C:21]1[O:22][CH:23]=[C:19]([CH2:18][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)=[CH:4][CH:3]=2)[N:20]=1
Reactant: Oc1ccc(CCCCn2cncn2)cc1
Reactant: ClCc1coc(C2=Cc3ccccc3CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=C(c2nc(COc3ccc(CCCCn4cncn4)cc3)co2)CCc2ccccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 49 %

Procedure:
A mixture of 1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole (450 mg), 4-chloromethyl-2-(3,4-dihydro-2-naphthyl) oxazole (565 mg), potassium carbonate (290 mg) and N,N-dimethylformamide (10 ml) was stirred for 6 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. A crystalline product obtained from the fraction eluted with chloroform-methanol (50:1, v/v) was recrystallized from ethyl acetate-hexane to give 1-[4-[4-[2-(3,4-dihydro-2-naphthyl)-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole as colorless prisms, mp 96-97° C. The yield was 49%.
Reaction SMILES: [Cl:1][C:2]1([Cl:22])[CH2:4][C:3]1([CH2:6][S:7][C:8]1[CH:21]=[CH:20][C:11]2[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=2[CH:9]=1)[CH3:5].ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)(Cl)Cl.C(O)(=O)C>[Cl:22][C:2]1([Cl:1])[CH2:4][C:3]1([CH2:6][S:7]([C:8]1[CH:21]=[CH:20][C:11]2[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=2[CH:9]=1)=[O:28])[CH3:5]
Reactant: COC(=O)Nc1nc2cc(SCC3(C)CC3(Cl)Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2cc(S(=O)CC3(C)CC3(Cl)Cl)ccc2[nH]1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
To a solution of 7.2 g (0.2 mole) of [5-[[(2,2-dichloro-1-methylcyclopropyl)methyl]thio]-1H-benzimidazol-2-yl]carbamic acid, methyl ester in 120 ml of CHCl3 and 120 ml of acetic acid at -15° C there is added 4.2 g (0.02 mole) of 85% m-chloroperoxybenzoic acid and 40 ml of CHCl3 and with stirring is allowed to warm to room temperature. The mixture is stirred for an additional 2 hours. The CHCl3 is removed in vacuo and the remaining solution is neutralized with aqueous NaHCO3. The resulting solid is filtered off, dried, and crystallized from acetonitrile to yield 3.4 g of the title compound, m.p. 231-233° C.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[CH:39]=[CH:38][C:37](=[O:40])[N:36]=[CH:35]1)(=O)C1C=CC=CC=1.C[O-].[Na+].CO>N1C=CC=CC=1>[C@@H:11]1([N:34]2[CH:39]=[CH:38][C:37](=[O:40])[N:36]=[CH:35]2)[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: O=C(OC[C@H]1O[C@@H](n2ccc(=O)nc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cn1

Procedure:
Referring to FIG. 9, 1-(2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl)-1,4-dihydropyrimidine-4-one (3) was synthesized in accordance with Niedballa et al., J. Org. Chem 1974, 39, 3668-3671. 1-(β-D-Ribofuranosyl)-1,4-dihydropyrimidine-4-one (5) was prepared by standard NaOMe/MeOH deprotection of derivative 3 with nearly quantitative yield. 1-(5-O-Dimethoxytrityl-β-D-Ribofuranosyl)-1,4-dihydropyrimidine-4-one (6) was prepared by standard dimethoxytritylation of 5 in pyridine (rt., overnight) resulting in a yield of 83%. 1-(5-O-Dimethoxytrityl-2-O-tert-butyldimethylsilyl-β-D-Ribofuranosyl)-1,4-dihydropyrimidine-4-one was prepared using standard silylation procedure (Hakimelahi et al., Can. J. Chem. 1982, 60, 1106-1113). 1-[5-O-Dimethoxytrityl-2-O-tert-butyidimethylsilyl-3-O-2cyanoethyl-N,N-diisopropylaminophosphoramidite-β-D-Ribofuranosyl]-1,4-dihydro-pyrimidine-4-one (7) was prepared by phosphitylation using standard phosphitylation procedure (Tuschl et al., Biochemistry 1993, 32, 11658-11668).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33]([N:36]=[N+:37]=[N-:38])[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(Cl)ncn5)ccc43)cc2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(N=[N+]=[N-])ncn5)ccc43)cc2)CC1
Reaction time: 2.5 h

Procedure:
To a solution of 218 mg (0.44 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-amide in 2.5 ml DMF, 57 mg (0.88 mMol) NaN3 are added at rt. After 2.5 h at 68° C., the resulting red solution is poured into water and extracted three times with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: MS: [M+1]+=500; HPLC: AtRet=10.5.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22]([CH2:24][S:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].[N-:38]=[N+:39]=[N-:40].[Na+]>>[NH:38]1[C:19]([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:21]=[C:22]([CH2:24][S:25][C:26]5[CH:35]=[CH:34][C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=5)[N:23]=[C:8]4[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)=[N:20][N:40]=[N:39]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CSc4ccc5ccccc5n4)cn23)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: c1ccc2nc(SCc3cn4c(-c5ccc(-c6nnn[nH]6)nc5)cnc(N5CCOCC5)c4n3)ccc2c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Compound 75c (54.9 mg, 0.114 mmol) NH4Cl (9.20 mg, 0.172 mmol), and NaN3 (11.2 mg, 0.172 mmol) were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with Argon gas. Dry DMF (1 mL) was added via syringe and then the mixture was stirred at 120° C. for 2 h. The reaction was cooled to rt, diluted with water (5 mL), and adjusted to pH 2 with 2M HCl. The precipitate was collected by filtration and then the solid was washed with water (2×5 mL). The solid was dissolved in a mixture of DCM (20 mL) and MeOH (10 mL), dried over Na2SO4, and filtered. The solvent was removed under reduced pressure. The residue was triturated with MeOH (5 mL) and the solid was collected by filtration. The residual solvent was removed under reduced pressure to afford the title compound 70. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.98 (s, 1H), 8.30 (s, 2H), 8.17 (d, J=8.6 Hz, 1H), 8.07 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 4.68 (s, 2H), 4.15-4.27 (m, 4H), 3.69-3.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H22N10OS: 523.2 (M+H). found: 523.3.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]([CH3:28])=[CH:26][S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[C:27]([CH3:28])=[CH:26][S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)csc3n2)cc1
Reactant: NCc1ccc(F)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3c(C)csc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: CN1CCOCC1.[CH3:8][C:9]([CH3:25])([O:11][C:12]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([OH:19])=O)=[O:13])[CH3:10].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:17](=[O:19])[C:16]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:15]=2[NH:14][C:12]([O:11][C:9]([CH3:8])([CH3:10])[CH3:25])=[O:13])=[CH:28][CH:29]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2c(C)cccc2NC(=O)OC(C)(C)C)cc1
Temperature: 18 °C
Reaction time: 16 h

Procedure:
Firstly N-methylmorpholine (6.15 mL. 5.64 g, 55.8 mmol) and then O-(benzotriazol-1-yl N,N,N′N′-tetramethyluronium hexalfuorophosphate (10.15 g, 26.8 mmol) are added to a stirred mixture of 2-{([(1,1-dimethylethoxy)carbonyl]amino}-6-methylbenzoic acid (5.60 g, 22.3 mmol) and p-toluidine 4.78 g, 44.6 mmol) in dry dimethylformamide (110 mL) under an argon atmosphere, and stirred at 18° C. for 16 hours. The solvent is evaporated off under reduced pressure to give a residue which is treated with aqueous sodium hydrogen carbonate solution (200 mL of 10%) and extracted with dichloromethane (3×100 mL). The combined extracts are washed with aqueous citric acid solution (100 mL of 10%), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 20% ethyl acetate in hexane, and recrystallised from tert-butyl methyl ether-hexane to give the title compound as a colourless crystalline solid, m.p. 250° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:3]([NH:11][C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12
Reactant: Nc1nn2cccnc2c1Br
Reactant: O=C(O)Cc1ccc(F)cc1
Product: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1Br

Procedure:
The product from Example 110A and 4-fluorophenylacetic acid were processed using the method analogous to that described in Example 137 to provide the title compound. MS (APCI) m/z 349/351 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:23])[C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[C:15]([NH2:17])=[O:16])=[CH:6][CH:5]=1.BrC[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[NH2:17])=[CH:13][C:12]=1[C:11](=[O:23])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:25])[F:1])=[CH:5][CH:6]=1)[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 3-N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamide and ethyl bromoacetate by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[Li+].[BH4-]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1C#N
Temperature: 70 °C

Procedure:
4-Cyano-3-methoxy-benzoic acid methyl ester from step 1 (4.7 g, 25 mmol) was dissolved in THF (125 ml). LiBH4 in THF (2 M, 25 ml, 50 mmol) was added. The reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was quenched carefully with 3N HCl and then extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired product.
Reaction SMILES: [C:1]([NH2:6])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[C:1]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCCO1
Reactant: CCC(C)(C)N
Solvent: C1CCOC1
Product: CCC(C)(C)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of tert-amylamine (2.0 g, 23.3 mmol) in tetrahydrofuran (15 mL) was added 1,3-propane sultone (2.76 g, 22.2 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with acetone (2×25 mL), and dried in vacuo, to afford compound DG (3.3 g, 73%): 1H NMR (D2O, 500 MHz) 8 ppm 3.04 (t, 2H, J=7.8 Hz), 2.89 (t, 2H, J=7.8 Hz), 2.87 (t, 2H, J=7.3 Hz), 1.97 (m, 2H), 1.55 (m, 2H), 1.18 (s, 6H), 0.82 (t, 6H, J=7.3 Hz). 13C NMR (D2O, 125 MHz) 8 ppm 60.42, 48.17, 39.88, 30.81, 22.23, 21.98, 7.25. ES-MS 208 (M−1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH3:17]>O1CCOCC1>[NH2:17][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: N
Reactant: FC(F)(F)c1cc(Cl)c2ccc(Cl)cc2n1
Solvent: C1COCCO1
Product: Nc1cc(C(F)(F)F)nc2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
A solution of 4,7-dichloro-2-trifluoromethylquinoline (2 g, 7.52 mmol) in dioxane (10 mL) and NH3 (2 mL) are mixed at −78° C. in a sealed tube. After sealing and warming up to room temperature, the reaction is heated at 60–70° C. for 19 hours and at 120° C. for 3 hours. The sealed tube is cooled to −78° C. before it is opened and the contents are concentrated by rotary evaporator. 4-Amino-7-chloro-2-trifluoromethylquinoline is obtained as a solid by trituration of the residue with ether.