Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[S:10][C:11]([CH3:14])=[N:12][N:13]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(N(CC)CC)C>[C:15]([NH:8][C:9]1[S:10][C:11]([CH3:14])=[N:12][N:13]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nnc(N)s1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nnc(C)s1
Yield: 89.1 %

Procedure:
To a mixture of toluene (20 ml) and triethylamine(2.63 g) was added 2-amino-5- methyl-1,3,4-thiadiazole (3.0 g) and acetic anhydride (3.2 g). The mixture was heated under reflux for 2.5 hours. After cooling, the precipitated solid was filtrated, washed with water and dried. The title compound(3.65 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])#[N:2].[NH3:16]>CO>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH2:16])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])#[N:2]
Reactant: COC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Reactant: N
Solvent: CO
Product: N#Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Yield: 32.6 %

Procedure:
2 g (9.71 mmol) Methyl 4-cyano-3-nitrobenzoate (Compound II-8) and 60 ml methanol were added into a reaction flask, stirred, and ammonia gas was passed through for 1 hour, then reacted for 8 hours at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure to evaporate most of the methanol. Then the mixture was extracted with 100 ml ethyl acetate, and the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 1.1 g (5.76 mmol) crude product, which was recrystallized from ethyl acetate-n-hexane to obtain 4-cyano-3-nitrobenzamide (compound I-8), 0.6 g, yield 32.6%.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.O>[C:13]([O:1][CH:2]1[O:10][C@H:9]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:7]([O:8][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:5]([O:6][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:3]1[O:4][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC[C@H]1OC(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1

Procedure:
100 g of D-glucose (555 mmol; 1 eq) are dissolved in 2 l of pyridine and the reaction medium is heated under reflux for 1 hour before 387 ml (3,330 mmol; 6 eq) of benzoyl chloride are added thereto in the hot. After addition, the medium is diluted with water, the product precipitates and is filtered off and rinsed with water to neutrality. After drying, it is purified by recrystallisation from ethyl acetate.
Reaction SMILES: [C:1]([C:3](=[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)SC)[C:4]#[N:5])#[N:2].O.[NH2:20][NH2:21]>CO>[NH2:2][C:1]1[NH:21][N:20]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: NN
Reactant: CCOc1ccc(NC(SC)=C(C#N)C#N)cc1
Solvent: CO
Solvent: O
Product: CCOc1ccc(Nc2n[nH]c(N)c2C#N)cc1

Procedure:
A mixture of 21.5 g (82.9 mmol) of 2-cyano-3-(4-ethoxy-phenylamino)-3-methylmercapto-acrylonitrile, 4.31 ml (87 mmol) of hydrazine hydrate and 110 ml of methanol is heated under reflux for 7 hours and then concentrated by evaporation in vacuo. Recrystallization of the residue from ethyl acetate/hexane yields the title compound; m.p. 166-167° C.
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[N:5]=[C:6]([S:26](Cl)(=[O:28])=[O:27])[N:7]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:8]=1[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>CC(C)=O.C1COCC1>[Cl:3][C:4]1[N:5]=[C:6]([S:26]([NH2:2])(=[O:28])=[O:27])[N:7]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:8]=1[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: [NH4+]
Reactant: CC(C)(C)[Si](C)(C)OCc1c(Cl)nc(S(=O)(=O)Cl)n1COCC[Si](C)(C)C
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1c(Cl)nc(S(N)(=O)=O)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Ammonium hydroxide (5.0 mL, 128 mmol) was added to a 0° C. solution of 4-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonyl chloride (1.33 g, 2.8 mmol) in acetone (4.5 mL) and THF (2.5 mL). The reaction mixture was stirred at RT for 30 min and evaporated. The residue was taken up in EtOAc and washed with brine. The organic phase was dried (Na2SO4), filtered, evaporated, and purified by silica gel chromatography (0-25% EtOA/hexanes) to give the title compound (0.95 g, 74%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.71 (s, 2H), 5.37 (br. s., 2H), 4.75 (s, 2H), 3.59-3.70 (m, 2H), 0.92-0.97 (m, 2H), 0.91 (s, 9H), 0.11 (s, 6H), 0.02 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][CH:20]([OH:24])[CH2:21][C:22]#[CH:23]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:23]#[C:22][CH2:21][CH:20]([OH:24])[CH3:19])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C#CCC(C)O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CCC(C)O)cc1
Temperature: 70 °C
Yield: 91.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 4-pentyne-2-ol (0.47 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and a half-saturated aqueous sodium chloride solution (1×20 mL). The aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were washed with a half-saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-propionic acid methyl ester (578 mg, 92%) as an amber oil: EI-HRMS m/e calcd for C20H26O3 (M+) 314.1881, found 314.1888.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)=[O:6].[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([Sn](CCCC)(CCCC)CCCC)=[N:31][CH:32]=1.C1(C)C=CC=CC=1>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>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([C:2]2[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:18]=2)[C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=2)=[O:6])=[N:31][CH:32]=1
Reactant: Cc1ncc(CNC(=O)c2cc(Br)cc(C(=O)N3CCCC3)c2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCCC3)c2)nc1

Procedure:
A mixture of 3-bromo-N-((2-methylpyrimidin-5-yl)methyl)-5-(pyrrolidine-1-carbonyl)benzamide (25 mg, 0.059 mmol), 5-methyl-2-(tributylstannyl)pyridine (40 mg, 0.10 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.0043 mmol), and toluene (1 mL) under nitrogen was subjected to microwave irradiation at 120° C. for 1 hour. After cooling, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and concentrated. The residue was purified by flash chromatography to afford the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][C:28]1([CH2:31][OH:32])[CH2:30][CH2:29]1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:31][C:28]2([CH3:27])[CH2:30][CH2:29]2)[CH:7]=1
Reactant: CC1(CO)CC1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CC1(COc2cc(F)ccc2-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)CC1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and 1-methylcyclopropanmethanol (76.3 mg; 0.841 mmol), example 49 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Cl[C:2]1[C:3]([C:19]#[N:20])=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35]C(=O)OC(C)(C)C)O1>>[C:11]1([CH3:18])[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=1[C:9]#[C:8][C:6]1[CH:5]=[N:4][C:3]2[C:2]([CH:7]=1)=[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]1=[N:35][C:19]=2[NH2:20]
Reactant: Cc1cc(C)c(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1cc(C)c(C#Cc2cnc3c(N)nc4ccccc4c3c2)c(C)c1

Procedure:
2-(Mesitylethynyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 3-chloro-5-(mesitylethynyl)picolinonitrile (Example 77/Step 1) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (commercially available) following the procedures described for Example 45/Step 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>CCO>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[CH:13][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Yield: 99.1 %

Procedure:
To a solution of 4-aminoanisole (50 g, 0.406 mol) in EtOH (500 mL) was added diethyl ethoxymethylenemalonate (81 mL, 0.406 mol). The reaction solution was refluxed for 4 h; LCMS showed complete reaction. The reaction solution was concentrated under reduced pressure to give the desired product (118 g, 100%) as a crystalline solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C(O)=CC4C[CH2:22][O:23]C=4C=3)C2=O)C=CC=CC=1.[OH:34][C:35]1[C:36]([CH:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][C:51]=3[O:53][CH3:54])[N:46]([CH2:55][C:56]3[O:57][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:60]=3)[C:45]2=[O:65])=[CH:37][C:38]2[O:42][CH2:41][O:40][C:39]=2[CH:43]=1>>[OH:34][C:35]1[C:36]([C:44]2([CH2:22][OH:23])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][C:51]=3[O:53][CH3:54])[N:46]([CH2:55][C:56]3[O:57][C:58]([C:61]([F:63])([F:62])[F:64])=[CH:59][CH:60]=3)[C:45]2=[O:65])=[CH:37][C:38]2[O:42][CH2:41][O:40][C:39]=2[CH:43]=1
Reactant: O=C1C(c2cc3c(cc2O)CCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1C(c1cc3c(cc1O)OCO3)C(=O)N2Cc1ccc(C(F)(F)F)o1
Product: COc1cccc2c1C(CO)(c1cc3c(cc1O)OCO3)C(=O)N2Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 26C, and making non-critical variations to replace 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one with 3-(6-hydroxy-1,3-benzodioxol-5-yl)-4-methoxy-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one, the title compound was obtained (64%): MS (ES+) m/z 500.4 (M+23).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.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.C(O)C>CCCCCC>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[CH:14][NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20]
Reactant: CCOc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OCC)cc1)C(=O)OCC

Procedure:
The preparation was the same as in example 1. But one equivalent of p-Phenetidine was used instead of p-Anisidine and one equivalent of diethyl ethoxymethylenemalonate was used instead of dimethyl methoxymethylenemalonate. Ethanol was replaced by hexane. 21 g of the title compound was obtained which is a white solid melting at 55-56° C., UV 329 nm (E=802).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH:11][CH3:12]>CCOCC>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:11]([CH3:12])[CH3:10])[N:7]=1
Reactant: CNC
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCOCC
Product: CN(C)c1nc(Cl)nc(Cl)n1
Temperature: 0 °C

Procedure:
A suspension of cyanuric chloride (27.6 g.) in anhydrous ether (600 ml.) was kept at -30° C. and treated with dimethylamine (13.5 g.). Following the addition the mixture was allowed to warm to 0° C. and poured on to ice. The ether layer was separated, dried, kand evaporated and the residue crystallised from light petroleum to give the product (26.0 g.) having a melting point of 123°-124° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].[I-:36].[Na+]>C(C(C)=O)C>[I:36][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCCCl)OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCCI)OC
Yield: 85.9 %

Procedure:
To a solution of 197 mg (0.354 mM) of 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIIa6 in 7 ml of methyl ethyl ketone is added 265 mg (1.77 mM) of sodium iodide and the mixture is heated under refluxing for 3 hours with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (3:1) mixture as an eluent to give 197 mg (0.304 mM) of 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIa6 in 86% yield.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=O)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.ON1C2C=CC=CC=2N=N1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:34]([NH:41][C:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)=[O:23])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)O)c3)cc2)S1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)NCc4ccccc4)c3)cc2)S1
Reaction time: 24 h
Yield: 60.3 %

Procedure:
600 mg (1.84 mmol) of 4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-carboxylic acid (prepared in Example 23(c)), 5 ml of dimethylformamide, 340 mg (2.5 mmol) of 1-hydroxybenzotriazole and 250 μl (2.3 mmol) of benzylamine are introduced into a three-necked flask under a stream of nitrogen. At 0° C., 480 mg (2.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride are added portionwise. The mixture is stirred for 24 hours while allowing the temperature to rise. The reaction medium is immersed in water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The residue obtained is washed with dichloromethane and filtered. 460 mg (60%) of the desired product are obtained.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>C(O)(=O)C>[ClH:1].[ClH:1].[CH3:9][C:8]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1[nH]cnc1CO
Agent: Cl
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CSCCN
Yield: 184.6 %

Procedure:
A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30 g) and cysteamine hydrochloride (23 g) in acetic acid (200 ml) was heated under reflux for 10 hours. Following cooling to 15°-20° C, the solid which crystallised was collected and washed with isopropyl alcohol to give 2[(5-methylimidazol-4-yl)methyl]thioethylamine dihydrochloride (45.5 g), m.p. 189°-192° C.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][O:22]S(C)(=O)=O)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[O:27]1[C:35]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[CH:29]=[C:28]1[CH2:36]O>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][O:22][CH2:36][C:28]2[O:27][C:35]3[CH:34]=[CH:33][N:32]=[CH:31][C:30]=3[CH:29]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: OCc1cc2cnccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOCc2cc3cnccc3o2)CC1
Temperature: 20 °C

Procedure:
t-BuOK (45 mg, 401 μmol) and 4-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butyl ester (134 mg, 436 μmol) were added to a stirred solution of furo[3,2-c]pyridin-2-ylmethanol (Preparation 4, 50 mg, 336 μmol) in anhydrous THF (5 mL). The reaction was heated under reflux for 6 h, before being cooled to 20° C. and quenched with saturated aqueous NH4Cl. The mixture was extracted twice with EtOAc, then the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography (EtOAc-MeOH, 1:0 to 50:1) to furnish the title compound: RT=2.86 min; m/z (ES+)=361.3 [M+H]+.
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([C:14]2[S:15][C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:24]=3)=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=2)[N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+].Cl>CO.O>[N:30]1([CH2:29][C:25]2[N:24]=[C:23]([NH:22][C:16]3[S:15][C:14]([C:12]4[N:11]=[N:10][NH:9][CH:13]=4)=[CH:18][C:17]=3[C:19]([NH2:21])=[O:20])[CH:28]=[CH:27][CH:26]=2)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)C(=O)OCn1cc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1cc(-c2c[nH]nn2)sc1Nc1cccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of [4-(4-(aminocarbonyl)-5-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}-2-thienyl)-1H-1,2,3-triazol-1-yl]methyl pivalate (70 mg, 0.14 mmol) in MeOH (1.5 mL) and water (1.0 mL) was added NaOH (1.0 M, 0.310 ml, 0.31 mmol). The mixture was stirred at room temperature for 45 min (the suspension became a clear orange solution). The reaction was neutralized with 2 N HCl (0.150 ml), diluted with water, and extracted with 5:1 CH2Cl2:MeOH (3×). The combined organic extracts were dried (MgSO4), filtered, combined with silica gel, and evaporated to dryness. Flash chromatography (dry load, 0-10% MeOH/CH2Cl2) yielded the title compound as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26](=O)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:23])C1C=CC=CC=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:26]2[O:23][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:21])[CH3:20])=[N:24][CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCC(=O)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)OCCn2c1nc(-c1ncc(Cc3ccc(F)cc3)o1)c(O)c2=O

Procedure:
A mixture of 3-(benzyloxy)-N-(3-(4-fluorophenyl)-2-oxopropyl)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.16 g, 0.3337 mmol) and POCl3 (2 mL) in toluene (15 mL) was heated at reflux for 5 h, then cooled, concentrated and the resulting residue taken up in EtOAc (50 mL), washed with water (2×10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated to give a yellow residue. Purification by preparative HPLC on C18 column using water/MeOH containing 0.1% TFA provided the title as a white solid which was crystallized from MeOH/H2O to afford colorless needles. 1HNMR (500 MHz, CDCl3) δ: 11.04-10.92 (1H, br s), 7.26 (2H, dd, J=8.6, 5.5 Hz), 7.04 (2H, t, J=8.6 Hz), 6.86 (1H, s), 4.10 (2H, s), 4.07-4.02 (4H, m), 1.65 (6H, s). HRMS (M+H) calcd for C19H19N3O4F: 372.1360. found: 372.1356. Anal calcd for C19H18N3O4F: C, 61.45; H, 4.88; N, 11.31. found: C, 61.19; H, 4.74; N, 11.14.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:27])[CH3:26].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCCCl
Reactant: CC(C)(C)c1nc(C2CC2)cc(N2CCNCC2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCCN1CCN(c2cc(C3CC3)nc(C(C)(C)C)n2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2.9 g of 2-tert-Butyl-4-piperazin-1-yl-6-cyclopropyl-pyrimidine (11.1 mmol), 1.8 g acetic acid 3-chloro-propyl ester (13.2 mmol), 1.38 g of triethylamine (13.7 mmol), and a spatula tip of sodium iodide were dissolved in 50 ml of dimethylformamide and stirred for 8 h at 80° C. After cooling to room temperature, the dimethylformamide was evaporated. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product (3.7 g) was directly used in the subsequent reaction step.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH3:30]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH3:30])[CH2:20]1
Reactant: CCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and iodoethane.