Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[NH2:5][C:6]1[CH:26]=[C:25]([Cl:27])[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:16])(=[O:15])[CH2:14][C:8]=2[CH:7]=1.O>C(O)=O>[Cl:27][C:25]1[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:15])(=[O:16])[CH2:14][C:8]=2[CH:7]=[C:6]([NH:5][CH:1]=[O:2])[CH:26]=1
Reactant: O=C[O-]
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O

Procedure:
Sodium formate (0.308 g, 4.58 mmol) was added to a solution of compound of Example 2 (0.8 g, 2.26 mmol) in formic acid 85% (8 mL) and refluxed for 2 h. The reaction mixture was diluted using water (20 mL) and the solid obtained was filtered, washed with water and dried. The product was purified by crystalisation using DMF/methanol to obtain the title compound. Yield: 0.78 g, (91%); 1H NMR (DMSO-d6, 300 MHz): δ 2.64 (s, 3H, CH3), 5.31 (s, 2H, CH2), 7.70 (s, 1H, Ar), 7.87 (s, 1H, Ar), 7.93 (s, 1H, Ar), 8.08 (s, 1H, Ar), 8.31 (s, 1H, CHO), 10.57(s, 1H, NH); MS: m/e (ES−) 380 (M−1);
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[N:20]=[CH:19][C:18]2[C:17](SC)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=1.O>C(Cl)(Cl)Cl>[NH2:10][C:11]1[N:20]=[CH:19][C:18]2[C:17]([NH:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@@H](Nc1ncnc2cc(N)ncc12)c1ccccc1
Temperature: 180 °C
Yield: 10.9 %

Procedure:
A mixture of [R]-1-phenylethylamine (0.072 mL, 0.55 mmol) and 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (97 mg, 0.5 mmol) (described in a previous experimental) is heated at 180° C. under N2 for 1.5 hr. The reaction is then cooled to room temperature producing a precipitate. The mixture is added to water and CHCl3, sonicated and filtered. The phases are separated and the aqueous phase is extracted with CHCl3. The combined extracts are washed with water, saturated brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue purified by using preparative tlc (5% MeOH/CHCl3) and recrystallization from CHCl3 to give 7-amino-4-([R]-1-phenylethylamino)pyrido[4,3-d]pyrimidine (14.5 mg, 11%), mp 231.8-232.1° C. 1H NMR (DMSO) δ 9.23(1H, s), 8.50 (1H, d, J=8.0 Hz), 8.19 (1H, s), 7.41 (2H, d, J=7.0 Hz), 7.31 (2H, t, J=8.0 Hz, 7.21 (1H, tt, J=7.4, 1.2 Hz), 6.45 (2H, s), 6.33 (1H, s), 5.56 (1H, p, J=7.2 Hz), 1.55 (3H, d, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([OH:31])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: Oc1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3O)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromophenol. MS (ESI): mass calcd. for C16H12FN3O, 281.10; m/z found, 282.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.36 (s, 1H), 8.01 (d, J=1.4, 1H), 7.87 (m, 1H), 7.49 (dd, J=4.4, 1.3, 1H), 7.45 (s, 1H), 7.34 (dd, J=7.4, 1.3, 1H), 7.19 (m, 1H), 6.95 (d, J=7.3, 1H), 6.89 (m, 1H), 6.68 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Cc1ccc2c(Cl)ccnc2c1
Product: Cc1ccc2c(-c3c(C)[nH]c4ccc(C)cc34)ccnc2c1

Procedure:
The sub-title compound was prepared by the method of Example 1 step a) using 2,5-dimethyl indole and 4-chloro-7-methyl-quinoline.
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16](=O)[C:15]([CH3:21])([CH3:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C([BH3-])#[N:23].[Na+]>CO>[NH2:23][CH:16]1[CH2:17][CH2:18][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14][C:15]1([CH3:21])[CH3:20]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)C(C)(C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (700 g, 9.09 mol) was added to a stirred solution of 1-t-butyloxy carbonyl-3,3-dimethyl-4-piperidone (352 g, 1.55 mol) in methanol (1.0 L). The suspension was stirred for 3 hr at 20-30° C. The reaction mixture was cooled to 0° C. and sodiumcyanoborohydride (45 g, 0.71 mol) was added portion wise over 30 minutes. Cooling was removed and the suspension was stirred for 12 hr at 20-30° C. The reaction mixture was concentrated to dryness, stirred with water (2.0 L) and extracted with 1.0 L×3 dichloromethane. Combined organic extract was washed with water and dried over sodium sulfate. Evaporation of organic solvent afforded the product.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]=[CH:12][C:13]3[N:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:28])=[N:4][CH:3]=1>C(OCC)(=O)C.CO>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH2:18][C:19]([F:21])([F:20])[F:22])[N:16]=[C:15]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:28])=[N:4][CH:3]=1
Reactant: Cc1ncc(C)n2nc(C=Cc3nc(N4CCCC4)nn3CC(F)(F)F)nc12
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3nc(N4CCCC4)nn3CC(F)(F)F)nc12
Yield: 54.7 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 2 using 5,8-dimethyl-2-(2-(3-(pyrrolidin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrazine (20 mg, 51.0 μmol, Eq: 1.00) as starting material. The crude material was applied on a 5 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 5,8-dimethyl-2-{2-[5-pyrrolidin-1-yl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-ethyl}-[1,2,4]triazolo[1,5-a]pyrazine (11 mg/52.4%) as a white solid. MS: m/e=395.8 (M+H+)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:1][CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCc1nc2ccc(Cl)cc2n1CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCn2c(CCNC(=O)OC(C)(C)C)nc3ccc(Cl)cc32)cc1

Procedure:
A solution of 1.5 g. (4.6 mmole) of 1-(2-hydroxy ethyl)-2-(2-t-butoxycarbonylaminoethyl)-6-chlorobenzimidazole prepared in Step B. above and 1.0 g. (5.5 mmole) p-toluenesulfonyl chloride in 7.5 ml. of dry pyridine is heated at 50° C. for 2 hours. After cooling the reaction mixture is partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic extracts are dried with calcium sulfate and concentrated to remove solvent. The remaining pyridine is removed by azeotroping with toluene. The desired product, 1.6 g. (70%), is obtained as a crystalline solid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])#[CH:5]
Reactant: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ccccc1CC(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-(2-((trimethylsilyl)ethynyl)phenyl)acetate (I10) (4.63 g, 19.0 mmol) was dissolved in DCM (200 mL) and TBAF (1.0 M in THF) (28.5 mL, 28.5 mmol, 1.5 eq) was added at 0° C. The resulting solution was stirred at room temperature for 1 hour before washing with 10% NaHCO3 (100 mL). The organic layer was dried (MgSO4) then evaporated under reduced pressure to give a dark brown/black residue. The residue was adsorbed onto silica and then chromatographed on silica gel (0-10% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I4) (2.76 g, 83%) as a red liquid; 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J=7.6, 1.1 Hz, 1H), 7.43-7.16 (m, 3H), 3.88 (d, J=9.6 Hz, 2H), 3.77-3.52 (m, 3H), 3.28 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][C:19]([OH:21])=[O:20].[Na].[CH2:23](I)[CH3:24]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][C:19]([O:21][CH2:23][CH3:24])=[O:20]
Reactant: Nc1c(CC(=O)O)cc(Cl)cc1C(=O)c1ccc(Br)cc1
Reactant: CCI
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)cc(C(=O)c2ccc(Br)cc2)c1N
Yield: 91.3 %

Procedure:
A solution of 40.9 g (0.1 mole) of 2-amino-3-(4-bromobenzoyl)-5-chlorobenzeneacetic acid, sodium salt, monohydrate in 400 ml of dimethylformamide was treated with 32.0 g (0.2 mole) of ethyl iodide and the solution was let stand at ambient temperature overnight. The solution was poured in 3.5 liters of cold water and a solid gradually crystallized. The solid was collected by filtration, washed with water, and recrystallized from absolute ethanol to yield 36.2 g (91%) of title compound, a yellow solid, m.p. 92°-94° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([NH:9][C:17](=[O:18])[C:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][C:13]=1[O:20][CH3:21])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc(Br)ccc1C(=O)Cl
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)ccc1C(=O)NCCc1ccccc1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
Phenethylamine (0.79 mL, 6.31 mmol) was added slowly to a mixture of 4-Bromo-2-methoxy-1-benzenecarbonyl chloride (1.5 g, 6.01 mmol) and triethylamine (1.3 mL, 9.02 mmol) in dichloromethane (60 mL). After 2 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography using dichloromethane/ethyl acetate (97:3) as mobile to give N1-phenethyl-4-bromo-2-methoxybenzamide (1.81 g, 90%). 1H NMR (DMSO-d6) δ 2.83 (m, 2H), 3.50 (m, 2H), 3.84 (s, 3H), 7.31 (m, 7H), 7.65 (d, J=8.28 Hz, 1H), 8.15 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O1CCCC1>C(O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CC=C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CC=C(C)C)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid ethyl ester (6.2 g, 16 mmol) dissolved in ethanol (15 mL), 10 N sodium hydroxide (10 mL) and tetrahydrofuran (75 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2 g (21%). brown solid mp 196-197° C., MS: 367.9 (M+H)+.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[C:9](OS(C(F)(F)F)(=O)=O)[C:8]=2[CH:26]=1>C(OCC)C.[Cu]I>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([CH3:1])[C:8]=2[CH:26]=1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2cc(Br)ccc2CCC1
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C1=C(C)c2cc(Br)ccc2CCC1
Reaction time: 0.33 h
Yield: 106.6 %

Procedure:
To a suspension of CuI (760 mg, 4.0 mmol) in anhydrous diethyl ether (5 mL) was dropwise added a 1.6 M solution of methyllithium (8 mmol, 5 mL) in an ice-salt bath (−10° C.). After stirring for 20 min, a homogeneous 0.4 M (Me)2CuLi solution was ready for use. To a solution of (Z)-methyl 2-bromo-9-(trifluoromethylsulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from step B1 (52 mg, 0.121 mmol) in diethyl ether (0.5 mL) was dropwise added the above Me2CuLi solution (0.727 mmol, 1.82 mL) at −78° C. The mixture was stirred from −78° C. to −40° C. over 2 h. The reaction mixture was then quenched with 10 mL of water, and the mixture was extracted with diethyl ether (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (E)-methyl 2-bromo-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate (38 mg, 0.129 mmol, 106% yield). The material was used for the next step without purification. LCMS (M+H)+=297.0. 1H NMR (500 MHz, chloroform-d) δ 7.43 (d, J=1.8 Hz, 1H), 7.35 (dd, J=8.1, 2.0 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 3.82 (s, 3H), 2.56-2.49 (m, 2H), 2.38 (s, 3H), 2.17-2.07 (m, 4H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:9]2[C:10]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.[CH3:28][NH:29][CH3:30]>CN(C)C=O>[CH3:28][N:29]([CH3:30])[C:3](=[O:2])[CH2:4][C:5]1[N:9]2[C:10]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1
Reactant: CNC
Reactant: COC(=O)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 3, 8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetic acid methyl ester is reacted with dimethylamine in dimethylformamide to give N,N-dimethyl-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetamide.
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[CH:18][C:5]([O:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[N:8]=2)=[C:4]([F:21])[CH:3]=1>[Pd].CO>[NH2:1][C:2]1[C:19]([F:20])=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[N:8]=2)=[C:4]([F:21])[CH:3]=1
Reactant: CC(=O)Nc1nc(Cl)cc(Oc2cc(F)c(N)cc2F)n1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1nccc(Oc2cc(F)c(N)cc2F)n1
Temperature: 15 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
A mixture of N-[4-(4-amino-2,5-difluoro-phenoxy)-6-chloro-pyrimidin-2-yl]-acetamide (3.3 g, 10.5 mmol) and palladium on carbon (1.0 g, 10%) in methanol (100 mL) was stirred under H2 (1 atm) at 15° C. for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give N-[4-(4-amino-2,5-difluoro-phenoxy)-pyrimidin-2-yl]-acetamide (2.4 g, 82% yield) as a pale yellow solid. 1HNMR (400 MHz, DMSO-d6): δ10.37 (s, 1H), 8.44 (d, J=5.7 Hz, 1H), 7.15 (dd, J=11.4 Hz, J=4.8 Hz, 1H) 6.71 (d, J=5.7 Hz, 1H), 6.65 (dd. J=12.3 Hz, J=8.4 Hz, 1H), 5.40 (s, 2H), 1.99 (s, 3H); MS (ESI) m/z: 281.2[M+H]+.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[C:3](=[O:5])[CH3:4].[CH:8]([O:10][CH2:11][CH3:12])=[CH2:9]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[CH2:8]([O:10][CH:11]([O:7][C:2]([CH3:6])([CH3:1])[C:3](=[O:5])[CH3:4])[CH3:12])[CH3:9]
Reactant: C=COCC
Reactant: CC(=O)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)OC(C)(C)C(C)=O
Yield: 66.7 %

Procedure:
In a 200 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 15 gm (147 mmol) of 3-methyl-3-hydroxy-2-butanone, 500 mg (2.0 mmol) of pyridinium p-toluenesulfonate and 100 ml of anhydrous methylenechloride were mixed with stirring under nitrogen stream, and 11.7 gm (162 mmol) of ethyl vinyl ether was added dropwise at room temperature for 3 hours while stirring. After the reaction, the reaction mixture was washed with 5% aqueous sodium hydrogen carbonate, and then the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Distillation of the crude product afforded 17.09 gm of 3-(1-ethoxyethoxy)-3-methyl-butane-2-one (b.p. 38-40/l mmHg, yield: 66%).
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:33]([NH2:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>CN(C=O)C>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:42][C:33]([CH3:35])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:34])=[O:6]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)c1cccnc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccnc1Br)c1ccccc1
Yield: 76 %

Procedure:
In a similar manner to Step 1 of Example 137, 2-bromonicotinic acid (2.42 g, 12.0 mmol) was dissolved in DMF (48 mL), and the solution was treated with EDCI (3.45 g, 18.0 mmol), HOBT monohydrate (917 mg, 5.99 mmol) and cumylamine (3.40 mL, 24.0 mmol), followed by purification by flash column chromatography (chloroform/methanol=100/1 to 98/2) to obtain 2-bromo-N-(1-methyl-1-phenylethyl)nicotinamide (2.91 g, yield 76%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=O)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].Cl.Cl.Cl.[N:21]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:15]([C:12]3[S:11][C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]=4[CH:13]=3)=[O:17])[CH2:34][CH2:35]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: CC(C)COc1cccc2sc(C(=O)O)cc12
Agent: Cl
Product: CC(C)COc1cccc2sc(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized from compound 202 and amine 5 analogously to the method described in Example 178.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Product: Cc1ccc(C(OC2CCN(CCCOc3ccccc3[N+](=O)[O-])CC2)c2ccccc2)cc1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(4-methylphenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(4-methylphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[O:11]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:9]=[C:5]([CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:19]=1)[CH2:6][CH2:7][CH:8]1[NH:4][C:3](=[O:10])[CH2:2][CH2:1]1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: ClCc1cccc(Oc2ccccc2)c1
Product: O=C(CCC1CCC(=O)N1)Cc1cccc(Oc2ccccc2)c1
Yield: 61.1 %

Procedure:
Analogous to the procedure described for Compound 1B, Step A, tetrahydro-pyrrolizine-3,5-dione (650 mg, 4.68 mmol) and 3-phenoxybenzyl chloride (1.20 g, 5.49 mmol) were reacted over 3.5 h to provide 5-[3-oxo-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (924 mg). 1H NMR (CDCl3) δ 7.30 (m, 3H), 7.10 (m, 1H), 6.99 (m, 2H), 6.92-6.84 (m, 3H), 3.66 (s, 2H), 3.57 (m, 1H), 2.52 (t, 2H), 2.27 (m, 2H), 2.17 (m, 1H), 1.80-1.58 (m, 3H).
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:5]([O:7]C)=[O:6])(=[O:3])[NH2:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:14][CH:15]=1)[C:5]([OH:7])=[O:6])(=[O:3])[NH2:2]
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C(N)=O)C(=O)O)cc1
Reaction time: 15 h
Yield: 97.7 %

Procedure:
Methyl 2-carbamoyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (1.80 g, 4.41 mmol) obtained in Example 2 was dissolved in methanol (20 ml) and tetrahydrofuran (20 ml), and 2.5N aqueous sodium hydroxide solution (2.5 ml, 6.16 mmol) was added at room temperature. The mixture was stirred for 15 hr and the solvent was evaporated. To the residue was added 10% aqueous sodium hydroxide solution (50 ml) and the mixture was washed three times with ethyl acetate (30 ml). To the aqueous layer was added sodium chloride to saturate the same, and the mixture was acidified with 3N hydrochloric acid. The precipitated white solid was collected by filtration, washed with water, and dried to give the title compound (1.70 g, yield 98%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:14])[C:5]=2[S:4][CH:3]=1
Reactant: O=c1[nH]cnc2c(Br)csc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2c(Br)csc12
Temperature: 150 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
7-bromothieno[3,2-d]pyrimidin-4(3H)-one (5.9 g) was dissolved in POCl3 (20 mL) and the reaction mixture was stirred at 150° C. for 3 hours. The reaction mixture was cooled to room temperature, and remaining POCl3 was concentrated and placed in ice water. The solid thus obtained was washed with sodium bicarbonate and dried using nitrogen gas. The resulting compound was further dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound (1.0 g, 39%).