Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:14])=[CH:5][N:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH3:2].[H-].[Na+].[CH2:17](I)[CH:18]=[CH2:19].O>CN(C=O)C>[CH2:1]([C:3]1[C:4]([F:14])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH2:19][CH:18]=[CH2:17])[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCc1c(F)cnc2ccc(=O)[nH]c12
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2ncc(F)c(CC)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
8-Ethyl-7-fluoro-1,5-naphthyridin-2(1H)-one (0.810 g, 4.22 mmol) was suspended in dry DMF (12.5 mL) under argon at 0° C., this was then treated with sodium hydride (0.371 g of a 60% w:w dispersion in oil, 2.2 eq.) added in portions. The suspension was allowed to warm to rt; after stirring for 30 mins at rt, the mixture was treated with allyl iodide (0.858 ml, 2.2 eq). It was then stirred for a further 30 mins before addition of water (10 ml). The mixture was then extracted with 10% MeOH/DCM (3×20 ml). The organic extracts were combined, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give a brown oil. This residue was then purified by column chromatography on silica gel (50 g) eluting with 0-100% EtOAc in hexane gradient to give title compound as a brown oil (0.9588 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:42][O:43][CH2:44][C:45](Cl)=[O:46]>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([C:45](=[O:46])[CH2:44][O:43][CH3:42])[C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:23])([F:24])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:4][CH:3]=1
Reactant: COCC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Cl)cn1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1ncc(Cl)cn1
Yield: 71.7 %

Procedure:
In a solution of 0.27 g of N-(5-chloro-2-pyrimidinyl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 11, 0.08 g of triethylamine and a catalytic amount of 4-(dimethylamino)pyridine in 5 mL of tetrahydrofuran, 0.08 g of methoxyacetyl chloride was added at room temperature with stirring, and stirred at the same temperature for 0.5 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was passed through short-pass silica gel column that was eluated with ethyl acetate, and thereby insoluble material was removed. The solvent was distilled off under reduced pressure, and purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (3:7) to obtain 0.22 g of the aimed product as colorless resinous substance.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH2:37][CH2:38][NH2:39]>>[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH2:37][CH2:38][NH:39][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CN1CCCC1CCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC3CCCN3C)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine by the procedure analogous to Example 1. MS (APCI, m/z): 472 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][CH3:3].[H-].[Na+].[CH:10](OCC)=[O:11].O>O1CCCC1>[CH3:3][CH:2]([CH:10]=[O:11])[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC=O
Reactant: CCOC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
Into a 500-mL 3-neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl propionate (11.3 mL, 97.9 mmol) in tetrahydrofuran (160 mL). The solution was cooled to 0° C., then sodium hydride (4.1 g, 103 mmol, 60% dispersion in mineral oil) was added in portions. The mixture was stirred at 0° C. for 10 min, then ethyl formate (7.92 mL, 98.5 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction was carefully quenched water (100 mL) by drop-wise addition and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure (50 mm Hg) and the fraction between 70-80° C. was collected to obtain the title compound as a colorless liquid (3.0 g, 24%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[CH:12]=O.Cl.[NH2:15]O.C([O-])=O.[Na+].C(O)=O>O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[C:12]#[N:15]
Reactant: O=Cc1coc2ccccc2c1=O
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1coc2ccccc2c1=O

Procedure:
A mixture of 26.1 g. (0.15 mole) of 4-oxo-4H-1-benzopyran-3-carboxaldehyde, 13.1 g. (0.19 mole) of hydroxylamine hydrochloride, 18.4 g. (0.27 mole) of sodium formate and 250 ml of 99% formic acid was heated with stirring at reflux for 21/2 hours. Water was added to 1-liter volume. The separated solid was filtered from the cooled mixture, washed well with water and dried to give 13 g. (51%) of crude nitrile melting at 138°-145°C. Recrystallization from ethylacetate gave pure, white crystals melting at 174°-176°.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(S([S:21][CH2:22][CH:23]([N:35]([CH3:37])[CH3:36])[CH2:24][S:25]S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:25][CH2:24][CH:23]([N:35]([CH3:37])[CH3:36])[CH2:22][S:21]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CN(C)C(CSS(=O)(=O)c1ccccc1)CSS(=O)(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(C(=O)OCC)SCC(N(C)C)CS1
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To 20 ml of chloroform were added 1.6 g (0.01 mole) of diethyl malonate and 4.3 g (0.01 mole) of 1,3-bis(benzenesulfonylthio)-2-(N,N-dimethylamino)propane, and then 2.1 g (0.02 mole) of triethylamine was added thereto at room temperature. After completion of addition, the reaction was allowed to proceed at 40° C. for 4 hours. The reaction mixture was washed with two 20-ml portions of water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was heated in 20 ml of ether-hexane (1:1) for dissolution and the solution was allowed to stand in the cold overnight. The resulting crystalline precipitate was collected by filtration to give 2.7 g (90%) of 2,2-diethoxycarbonyl-5-(N,N-dimethylamino)-1,3-dithiane as light-yellow crystals melting at 38°-39° C.
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([Cl:16])[CH3:10])=[CH:7][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc(C(F)(F)Cl)nc1
Solvent: ClCCl
Product: CC(Cl)c1ccc(C(F)(F)Cl)nc1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of 1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethanol (0.78 g, 3.77 mmol) in CH2Cl2 (40 mL) was added thionyl chloride (0.54 mL, 7.54 mmol) dropwise at room temperature. After 1 hr, the reaction was quenched slowly with saturated NaHCO3 aqueous solution and the two phases were separated. The organic layer was dried over Na2SO4, filtered, concentrated, and dried in vacuum to give 0.83 g of the crude 2-[chloro(difluoro)methyl]-5-(1-chloroethyl)pyridine (D) as brown oil in 98% yield, which was directly used for the next step reaction. GC-MS: mass calcd for C8H7Cl2F2N [M]+ 225. Found 225.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:18][CH2:17]1)[CH:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(OCC)(=O)C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:17][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 21.4 %

Procedure:
A mixture of 2.4 g of ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluorobutyrate (a mixture of diastereomers) and 6.4 g of 1,2,4-triazole was subjected to reaction at 90°-100° C. for 8 hours. To the reaction mixture were then added 10 ml of ethyl acetate and 5 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain 650 mg of ethyl 3-(2,4-difluorophenyl)-2-fluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate (one of the diastereomers).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:57])[CH2:39][N:40]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53](O)=[O:54])[CH:49]=[N:50][C:44]=3[NH:43][C:42](=[O:56])[CH2:41]2)[CH2:34][CH2:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:53](=[O:54])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[CH2:41][N:40]([CH2:39][C:38]([N:35]3[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]3)=[O:57])[CH2:46][C:45]=2[CH:47]=1
Reactant: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(/C=C/C(=O)O)cc3C2)CC1
Reactant: CNCc1sc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CC(=O)N2CCN(C)CC2)CC(=O)N3)sc2ccccc12
Yield: 53 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-{4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl}acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.18 g, 53%) was prepared as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 10.91 (br s, 1H), 10.55 (br s, 1H), 8.61 (s, 1H), 8.18 (s, 1H), 7.88-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.61-7.52 (m, 1H), 7.42-7.28 (m, 3H), 5.14-4.89 (m, 2H), 4.42-4.38 (m, 1H), 4.01 (br s, 3H), 3.65 (s, 4H), 3.39 (br s, 4H), 3.16 (s, 2H), 3.04-2.94 (m, 3H), 2.74 (br s, 3H), 2.42 (s, 3H); MS (ESI) m/e 547 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]([CH3:15])[S:11](Cl)(=[O:13])=[O:12].[CH3:16][O:17][C:18](=[O:31])[C@H:19]([C@@H:21]([CH3:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:31])[C@H:19]([C@@H:21]([CH3:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:20][S:11]([N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH3:15])(=[O:13])=[O:12]
Reactant: CN(CCc1ccccn1)S(=O)(=O)Cl
Reactant: COC(=O)[C@@H](N)[C@@H](C)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NS(=O)(=O)N(C)CCc1ccccn1)[C@@H](C)OCc1ccccc1

Procedure:
To the resulting compound from Example 87 (1 mmol) and (O-benzyl)threonine methyl ester (1 mmol) in CH2Cl2 was added triethylamine (2.0 mmol). After 1 h the product was isolated as described in Example 80.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:19].O>C1(C)C=CC=CC=1>[CH2:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1)[CH3:19]
Reactant: CCN1CCNCC1
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Solvent: Cc1ccccc1
Solvent: O
Product: CCN1CCN(c2cc(-c3ccccc3)c3ccccc3n2)CC1
Yield: 86.8 %

Procedure:
A solution of 2-chloro-4-phenylquinoline (2.0 g) and 1-ethylpiperazine (2.7 g) in toluene (15 ml) is heated under reflux for 10 hours. To the reaction mixture is added water and the resulting mixture is extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (25 g) using chloroform as an eluent. Fractions containing the title compound are pooled and concentrated to give the title compound (2.3 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.[CH3:45][N:46]1[C:50]([C:51]2[CH:52]=[C:53]([NH2:66])[CH:54]=[CH:55][C:56]=2[O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)=[CH:49][CH:48]=[N:47]1>C1COCC1>[CH3:45][N:46]1[C:50]([C:51]2[CH:52]=[C:53]([NH:66][C:38](=[O:40])[C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:43])=[CH:42][CH:41]=3)[CH:54]=[CH:55][C:56]=2[O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)=[CH:49][CH:48]=[N:47]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)cc2)ccc1OCCN1CCOCC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 28.5 %

Procedure:
A solution of HATU (98.0 mg, 0.260 mmol), triethylamine (55.7 μl, 0.400 mmol) and 4-trifluoromethyl-benzoic acid (49.0 mg, 0.260 mmol) in THF (1.0 mL) was stirred at room temperature. After 15 min, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (60.0 mg, 0.200 mmol) was added, and the mixture was stirred at 100° C. for 10 minutes in microwave. The mixture was purified by HPLC to give title compound as a white solid (TFA salt, 27 mg, 28%). 1H NMR (DMSO-d6, 400 MHz) δ 2.96-3.10 (m, 2H), 3.16-3.19 (m, 2H), 3.52-3.60 (m, 4H), 3.70 (s, 3H), 3.84-3.87 (m, 2H), 4.39 (t, J=5.05 Hz, 2H), 6.31 (d, J=1.77 Hz, 1H), 7.28 (d, J=9.09 Hz, 1H), 7.51 (d, J=1.77 Hz, 1H), 7.75 (d, J=2.78 Hz, 1H), 7.94 (d, J=8.34 Hz, 2H), 8.16 (d, J=8.84 Hz, 2H), 8.89 (s, 1H), 10.5 (s, 1H). Exact mass calculated for C24H25F3N4O3 474.2, found 475.4 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pt]=O.C(O)C>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([NH2:12])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCCCc1ccc(N)c(N)c1

Procedure:
4-n-Butyl-2-nitroaniline (12.5 g, 0.065 mole), platinum oxide (0.75 g) and ethanol (125 ml) were mixed together and shaken in an atmosphere of hydrogen at atmospheric pressure and laboratory temperature. After six hours 5.2 liters of hydrogen had been absorbed. The mixture was filtered and ethanol removed from the filtrate by distillation. Benzene (40 ml) was added to the residual oil and this was then also removed by distillation. The crude 4-n-butyl-1,2-phenylenediamine thus obtained was used directly in the preparation of 1,2-bis-(3-methoxycarbonyl-2-thioureiddo)-4-n-butylbenzene.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34].Cl>O1CCCC1.C(OCC)(=O)C>[OH:34][C:30]1([C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:32][CH2:33][CH:29]1[CH2:28][C:27]1[CH:35]=[CH:36][CH:37]=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: COc1cccc(CC2CCCC2=O)c1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(CC2CCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,5-diphenyloxazole in tetrahydrofuran (100 ml) at -78° C. under nitrogen was added n-butyllithium (in hexane, 1,7N, 12 ml). After 30 minutes, at the same temperature a solution of 2-(3-methoxybenzyl)cyclopentanone (3.8 g) in tetrahydrofuran (10 ml) was added dropwise thereto. After being stirred for 1 hour at 0° C., the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and 1N-hydrochloric acid (50 ml). The organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed (n-hexane--ethyl acetate:5:1-2:1) on silica gel to afford 1-hydroxy-1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cyclopentane (8.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH2:24]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:24][CH3:23])[N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc(Oc2ccc(OCc3ccccc3)cc2)n1
Reactant: CN
Solvent: CS(C)=O
Product: CNc1nccc(Oc2ccc(OCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Benzyloxy-phenoxy)-2-chloro-pyrimidine (Step A, 2.03 g, 6.49 mmol) was dissolved in 10 mL DMSO in a sealed tube at 0° C. 2 N CH3NH2 (in THF) was added (4.9 mL, 9.7 mmol), and the tube was sealed, warmed first to RT for 2 h, then to 70° C. for 2 h with stirring. The reaction was cooled to RT and concentrated in vacuo to a DMSO solution. The crude solution was diluted into Et2O and 1 N NaOH (aq) was added. The layers were separated, and the organic layer was washed several times with water then brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography using a hexanes/EtOAc gradient to yield the title compound as a white solid. MS (MH+)=308.3; Calc'd 307.36 for C18H17N3O2.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37]>>[C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:42]4[CH2:43][CH2:44][N:39]([C:36](=[O:38])[CH3:37])[CH2:40][CH2:41]4)=[CH:19][C:18]=3[C:24]([F:26])([F:27])[F:25])(=[O:15])=[O:16])[CH2:11][CH:10]2[C:28]([N:30]2[CH2:33][C:32]([F:34])([F:35])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(=O)N1CCNCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: CC(=O)N1CCN(c2ccc(S(=O)(=O)C3CC(C(=O)NC4(C#N)CC4)C(C(=O)N4CC(F)(F)C4)C3)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 127 using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118) and 1-acetyl-piperazine. White solid. MS (EI): 632.2 (M+H)+.
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH2:44]([NH:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[C:54]([O:58][CH3:59])[NH:55]2)=[C:51]([NH2:60])[N:50]=1)[CH2:45][CH2:46][CH3:47].Br[CH2:62][CH2:63][CH2:64][CH2:65][CH:66]1[CH2:71][CH2:70][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1>>[NH2:60][C:51]1[N:50]=[C:49]([NH:48][CH2:44][CH2:45][CH2:46][CH3:47])[N:57]=[C:56]2[C:52]=1[N:53]=[C:54]([O:58][CH3:59])[N:55]2[CH2:62][CH2:63][CH2:64][CH2:65][CH:66]1[CH2:67][CH2:68][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)=[O:73])[CH2:70][CH2:71]1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt and phenylmethyl 4-(4-bromobutyl)-1-piperidinecarboxylate. LCMS (System B): tRET=2.64 min; MH+ 510
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[CH3:4][S:1]([O:20][CH:17]1[CH2:18][CH2:19][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH2:6])=[CH:10][CH:11]=2)[CH2:16]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OC1CCN(c2ccc(N)cc2)C1
Yield: 106.3 %

Procedure:
40 ml (0.516 mol) of mesyl chloride was added dropwise at 5° C. to 83.3 g (0.4 mol) of N-(4-nitrophenly)-3-hydroxypyrrolidine (1) dissolved in 625 ml of anhydrous THF and 72.7 ml (0.6 mol) of triethylamine. The mixture was allowed to return to room temperature and was then poured onto ice. After filtering off the precipitate by suction and drying, 109 g of yellow powder (2) was obtained.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]1[O:9][CH2:8]1>[Fe]>[OH:9][CH2:8][CH2:7][O:5][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C1CO1
Agent: [Fe]
Product: C=C(C)C(=O)OCCO
Temperature: 70 °C

Procedure:
The procedure of Example 4 is repeated, except with less catalyst (1.9 g, 46% iron), with methacrylic acid (2.0 g) used in place of acrylic acid, and slightly less ethylene oxide added (3.8 g). The reactor is heated to 70° C. for 1 hour. The results for the product hydroxyethylmethacrylate (HEMA) are presented in Table 2.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][OH:21])[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3[N:15]=[N:16][N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2].OCCNC(=O)OC(C)(C)C.Br[CH2:34][C:35]#[C:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(Br)C#C>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:34][C:35]#[C:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3[N:15]=[N:16][N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCO
Reactant: BrCC#Cc1ccccc1
Agent: C#CCBr
Agent: CC(C)(C)OC(=O)NCCO
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCC#Cc1ccccc1

Procedure:
The general method described in Part A of Example 81 was followed, using 2-(8-ethoxymethyl-5,6-dimethyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)ethanol (4.51 g, 15.5 mmol) in lieu of tert-butyl 2-hydroxyethylcarbamate and 3-bromo-1-phenylpropyne, prepared as described in Part A of Example 7, in lieu of propargyl bromide. The crude product was triturated with diethyl ether, isolated by filtration, and dried under reduced pressure to provide 5.93 g of 8-ethoxymethyl-5,6-dimethyl-7-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine as a yellow solid.