Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:36][C:35]3[CH:34]=[N:33][N:32]([CH3:37])[C:31]=3[NH:30][C:29]3[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:28]2=3)=[O:26])=[CH:21][C:20]=1[F:43]>ClCCl>[CH3:37][N:32]1[C:31]2[NH:30][C:29]3[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:28]=3[N:27]([C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:13]([CH:10]4[CH2:12][CH2:11]4)=[O:14])=[C:20]([F:43])[CH:21]=3)=[O:26])[CH2:36][C:35]=2[CH:34]=[N:33]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
DIEA (0.08 ml, 0.46 mmol) and cyclopropanecarbonyl chloride (0.013 ml, 0.14 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E98.2 (57 mg, 0.14 mmol) in dichloromethane (10 ml) at 0° C. The mixture was stirred for 90 min at room temperature then diluted with dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (33 mg, 54%).
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][CH2:29]C(O)=O.CN(C([O:42]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1>[F:26][C:27]([F:34])([F:33])[CH2:28][C:29]([CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)=[O:42]
Reactant: O=C(O)CCC(F)(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CC(F)(F)F)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 8 h

Procedure:
A mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 66 mg, 0.17 mmol), 3-trifluoromethylpropionic acid (23 mg, 0.18 mmol), HATU (75 mg, 0.2 mmol) and triethylamine (87 mg, 0.86 mmol) in THF (7 mL) was stirred overnight. The resulting mixture was partitioned between etyl acetate and water, and the organic layer was washed sequentially with NaHCO3 (sat'd) and brine, then dried (Na2SO4) and concentrated. The residue was purified by reverse-phase chromatography (CH3CN/H2O-TFA) to yield 3,3,3-trifluoro-1-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)propan-1-one.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[N:6]1[C:7]2[N:8]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:9]=[CH:10][C:11]=1O>ClCCCl.CN(C=O)C>[Br:3][C:11]1[CH:10]=[CH:9][N:8]2[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=[C:7]2[N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1ccn2c(n1)nc1ccccc12
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Brc1ccn2c(n1)nc1ccccc12
Temperature: 100 °C
Yield: 100 %

Procedure:
Phosphorus oxybromide (25 g, 87 mmol) was added to a suspension of benzo[4,5]imidazo[1,2-a]pyrimidin-2-ol (5.2 g, 28.1 mmol) in DCE (Ratio: 1.000, Volume: 93 ml) and DMF (Ratio: 0.01, Volume: 0.927 ml). Heated the reaction mixture to 100° C. for 3 hours. Cooled the reaction to room temperature and concentrated. Diluted with ice water and quenched to pH ˜8 with concentrated ammonium hydroxide. The resulting residue was filtered and washed with water followed by ethyl ether. Dried under vacuum to afford crude 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (6.97 g, 28.1 mmol, 100% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[N:7][C:6]([C:9]([O:11]CC)=O)=[CH:5][CH:4]=1.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:14][N:2]([CH3:1])[C:3]1[N:8]=[N:7][C:6]([C:9](=[O:11])[CH2:16][C:15]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(N(C)C)nn1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccc(N(C)C)nn1
Temperature: 20 °C
Reaction time: 60 h
Yield: 83.8 %

Procedure:
Ethyl 3-(6-dimethylaminopyridazin-3-yl)-3-oxopropionate can be obtained by adding, over the course of 10 minutes at a temparature of about 30° C., a solution of ethyl (6-dimethylaminopyridazin-3-yl)carboxylate (39 g) and of ethyl acetate (35.2 g) in anhydrous toluene (480 cc) to a suspension of sodium tert.-butoxide (38.4 g) in anhydrous toluene (350 cc). The reaction mixture is then stirred for 60 hours at a temperature of about 20° C., after which 12N hydrochloric acid (35 cc) and distilled water (600 cc) are added. The aqueous phase is removed by decantation and washed with methylene chloride (2 × 200 cc). The combined organic fractions are dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. Ethyl 3-(6-dimethylaminopyridazin-3-yl)-3-oxopropionate (39.7 g) is thus obtained in the form of a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=O)=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C1COCC1>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH2:21])=[CH:22][CH:23]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCOc1ccc(C(N)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(CN)cc1
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a stirred suspension of lithium aluminum hydride (1.928 g, 52.23 mmol) in THF (150 ml) at room temperature under nitrogen was added a suspension of 4-(heptyloxy)benzamide (6.146 g, 26.117 mmol). After refluxing for 22 h, reaction was cooled in an ice bath and quenched in the following order: water (2.09 ml), 15% NaOH (2.09 ml) and water (6.26 ml). The mixture was stirred for 3 h followed by the addition of Na2SO4. The mixture was filtered and concentrated in vac. The residue was taken up in Et2O, filtered, concentrated, and the resulting residue taken up in hexane, filtered, concentrated, and dried to give the desired product as a hazy yellow oil (4.872 g, 84%): 1H NMR (400 MHz, DMSO-d6) δ0.86 (t, J=7 Hz, 3H), 1.22-1.42 (m, 8H), 1.64-1.72 (m, 2H), 1.82 (broad s, 2H), 3.13 (s, 2H), 3.89 (t, J=6.6 Hz, 2H), 6.80-6.84 (m, 2H), 7.17-7.21 (m, 2H); IR (film) 2940, 2850, 1510, 1250 cm−1; mass spectrum [(+)ESI], m/z 222 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[C:9]([Cl:11])[CH:10]=1)[C:6]([OH:8])=O.[NH:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)C(=O)C1=O.OO.ClC1C=CC=C(C(O)=O)C=1N.NOC1CCCCCC=1>C1(C)C=CC=CC=1>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]2[C:5]=1[C:6](=[O:8])[N:13]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:23]1=[N:12]2
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Nc1cc(Cl)cc(Cl)c1C(=O)O
Agent: NOC1=CCCCCC1
Agent: Nc1c(Cl)cccc1C(=O)O
Agent: OO
Solvent: Cc1ccccc1
Product: O=c1c2c(Cl)cc(Cl)cc2nc2n1CCCCC2
Temperature: 25 °C

Procedure:
To a stirred suspension of 15 g of 4,6-dichloroanthranilic acid (prepared from the corresponding isatine: T. Sandmeyer Helv. Chim. Acta, 2:234 (1919), by oxidation with alkaline hydrogen peroxide, following the procedure described by Baker et al., J. Org. Chem., 17:141 (1952) for the synthesis of 3-chloroanthranilic acid) in 100 mL of toluene was added 20 g of 1-aza-2-methoxy-1-cycloheptene. The mixture was stirred for an hour at room temperature, followed by heating under reflux for 18 hours. Then the mixture was concentrated in vacuo and volatile material was removed at 130° C. at 1 torr. The dark brown residue was chromatographed using 8:1 chloroform-ethyl acetate to give 9 g of the desired material as a crystalline solid, m.p. 110° C.-112° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[CH2:34][C:35]#[N:36].CN(C)C=O.[H-].[Na+]>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH2:34][C:35]#[N:36])=[CH:4][CH:5]=1
Reactant: N#CCc1c(O)ccc2ccccc12
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc3ccccc3c2CC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (4.52 g), 2-(2-hydroxy-1-naphthyl)acetonitrile (0.58 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.14 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.11 g, 76%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 178-179° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH3:11][C:12]1([NH2:15])[CH2:14][CH2:13]1.C[O-].[Na+]>CN1C(=O)CCC1.O>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:15][C:12]2([CH3:11])[CH2:14][CH2:13]2)[CH:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC1(N)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(Nc2cc(Cl)nc(N)n2)CC1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
2-amino-4,6-dichloropyrimidine (508 mg, 3.1 mmol) was added to a suspension of 1-methylcyclopropylamine hydrochloride (1.0 g, 9.3 mmol) and sodium methoxide (502mg, 9.30 mmol) in NMP (3 ml). The resulting mixture was heated at 90° C. for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water (20 ml) and the resulting precipitate filtered off, washed with further water (20 ml) and dried in vacuo to give the title compound as a colourless solid (280 mg, 15%).
Reaction SMILES: S1[CH:5]=[CH:4][CH:3]=[CH:2]1.[F-:6].[Cs+].ClCCl.S1[CH:15]=[CH:14][CH:13]=[C:12]1[SnH3:16]>C1(C)C=CC=CC=1.[Pd].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>[Sn:16]([F:6])([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: c1ccsc1
Reactant: [SnH3]c1cccs1
Reactant: [F-]
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC[Sn](F)(CCCC)CCCC
Temperature: 120 °C
Reaction time: 12 h

Procedure:
Introduction of the thiophene-unit to the squarylium dye framework was achieved by palladium catalyzed Stille coupling reaction. Under inert atmosphere, to a mixture of brominated squarylium dye 12, Pd(PPh3)4, 2 equivalents of CsF in toluene, thienyl-stannane was added. The reaction mixture was stirred at 120° C. for 12 h. After cooling to room temperature, dichloromethane was added. The white salt (Bu3SnF) formed during the reaction was filtered off and the solvent removed under reduced pressure. Purification of the crude product was performed by column chromatography on silica gel with (2/8) dichloromethane/ethylacetate to give the pure thiophene derived squarylium dye 13 as green solid.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:10]([CH2:12]N)[OH:11]>O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:1]([C:8]1[O:11][CH2:10][CH2:12][N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCC#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Product: CCCCCCCC1=NCCO1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of about 100.0 grams (0.774 mole) of heptylcyanide, about 47.3 grams (0.774 mole) ethanolamine, and about 4.8 grams (0.019 mole) cadmium acetate dihydrate is heated to about 120 degrees C. to about 130 degrees C. for about 2 days. The mixture is distilled under vacuum and the fraction boiling at about 109 degrees C. to about 116 degrees C. at about 28 mmHg is collected for later use.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[SH:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[C:29](=[O:32])([O-])[O-:30].[K+].[K+].CN(C)C=O>C(O)(=O)C.O>[C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[S:19][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([S:19][C:20]4[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=4[C:29]([OH:30])=[O:32])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)([OH:24])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccccc1S
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1Sc1cccc2c1C(=O)c1cccc(Sc3ccccc3C(=O)O)c1C2=O
Temperature: 125 °C
Yield: 91.7 %

Procedure:
A mixture of 1,5-dichloroanthraquinone (13.8 grams, 0.05 mole), o-mercapto benzoic acid (15.4 grams, 0.10 mole), potassium carbonate (13.8 grams, 0.10 mole), and N,N-dimethylformamide (200 ml) was heated at approximately 125° C. for four hours. The reaction mixture was allowed to cool to room temperature and then drowned into water (500 ml) and acidified with acetic acid to a pH of about 5.0. The dye was collected by filtration, washed with hot water, and then dried in air to yield 23.5 grams of 1,5-bis(2-carboxyphenylthio)anthraquinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]SCC(C)C(Cl)=S)=[CH:5][CH:4]=1.[SH:17][CH2:18][CH:19]([S:36][CH3:37])[C:20]([N:22]1[C@H:32]([C:33]([OH:35])=[O:34])[CH2:31][C:24]2(C(=O)CCC2=O)[CH2:23]1)=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][S:17][CH2:18][CH:19]([S:36][CH3:37])[C:20]([N:22]2[C@H:32]([C:33]([OH:35])=[O:34])[CH2:31][C:24]3([S:36][CH2:19][CH2:18][S:17]3)[CH2:23]2)=[O:21])=[CH:7][CH:8]=1
Reactant: COc1ccc(CSCC(C)C(=S)Cl)cc1
Reactant: CSC(CS)C(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O
Product: COc1ccc(CSCC(SC)C(=O)N2CC3(C[C@H]2C(=O)O)SCCS3)cc1

Procedure:
The 3-[[(4-methoxy)phenylmethyl]thio]-2-methylthiopropionyl chloride from part (a) is reacted with 4,4-ethylenedithio-L-proline according to the procedure of Example 9 (d) to yield [8S]-7-[3-[[(4-methoxy)phenylmethyl]thio]-2-methylthio-1-oxopropyl]-7-aza-1,4-dithiaspiro[4.4]nonane-8-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[N:11]=1
Reactant: C1CCNC1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCCC2)nc(Cc2cccc(Cl)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 244 mg (3.43 mmol) of pyrrolidine to give 29 mg (27% of theory) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][OH:5].[NH2:7][C:8]([NH2:10])=[S:9].[CH3:11][CH2:12][OH:13]>>[NH2:7][C:8]1[S:9][CH:2]=[C:3]([CH2:4][O:5][C:12](=[O:13])[CH3:11])[N:10]=1
Reactant: O=C(CO)CCl
Reactant: NC(N)=S
Reactant: CCO
Product: CC(=O)OCc1csc(N)n1

Procedure:
1-Chloro-3-hydroxy-propan-2-one (15.06 g) and thiourea (8.36 g) were dissolved in EtOH (55 mL) and heated at reflux over 30 min. The reaction mixture was concentrated under reduced pressure to afford the desired product.
Reaction SMILES: [CH3:1][C:2]([N+:23]([O-])=O)([CH3:22])[CH:3]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)=O.[C:26](O)(=[O:28])[CH3:27].C(OC(=O)C)(=O)C>[Zn].N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[N:23]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:26](=[O:28])[CH3:27])=[CH:9][CH:8]=2)[CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: CC(=O)O
Reactant: CC(C)(C(CC(=O)c1ccc([N+](=O)[O-])cc1)c1ccncc1)[N+](=O)[O-]
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C2=NC(C)(C)C(c3ccncc3)C2)cc1
Reaction time: 1 h

Procedure:
18 G. of zinc powder are added to a solution of 18.0 g. of 4-methyl-4,4'-dinitro-3-(4-pyridyl)-valerophenone in 500 ml. of glacial acetic acid while stirring. After one hour, an additional 18 g. of zinc powder are added and the reaction mixture is left to react overnight. Then the reaction mixture is filtered, the filter residue is washed with dilute acetic acid and the filtrate evaporated under reduced pressure. The resulting residue is treated with dilute ammonia solution and extracted with ethyl acetate. The extract is dried over sodium sulfate and evaporated under reduced pressure to obtain a residue, which is then treated with a mixture of 70 ml. of acetic anhydride and 35 ml. of pyridine. After 1 hour, the crystals which precipitate are filtered off and washed with ethyl acetate to yield 4'-[5,5-dimethyl-4-(4-pyridyl)-1-pyrrolin-2-yl]-acetanilide, which is recrystallized from methanol to give a product with a melting point of 227°-228° C.
Reaction SMILES: [C:1]([O:6][CH2:7]CCl)(=[O:5])C(C)O.[C:10]([O:14][CH3:15])(=[O:13])[CH2:11][OH:12].[C:16](C1C=CC=CC=1)(C)(C)C>C(OCC)C>[C:10]([O:14][CH2:15][C:1]([O:6][CH3:7])=[O:5])(=[O:13])[CH:11]([CH3:16])[OH:12]
Reactant: CC(O)C(=O)OCCCl
Reactant: COC(=O)CO
Reactant: CC(C)(C)c1ccccc1
Solvent: CCOCC
Product: COC(=O)COC(=O)C(C)O

Procedure:
A 6.5 mL aliquot of an ethyl ether solution containing 0.25 M 2-chloroethyl lactate (prepared as described in Example 1a), 0.25 M methyl glycolate, and 0.125% tert-butylbenzene was added to 0.5 g Lipase P30. After mixing for 48 hr at room temperature, the conversion of 2-chloroethyl lactate to the title compound was estimated (by GC, Method A) to be 40%. In identical reactions substituting Lipase AK, Lipase G, Lipase MAP10, Protease M, Lipase AP12, or porcine pancreatic lipase for Lipase P30, the relative values for conversions at 48 hr (Lipase P30 =100) were 101, 90, 44, 43, 32, and 13, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)#[N:19]>CO.C(Cl)Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([C:18]#[N:19])[N:21]=2)=[O:34])=[C:3]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)[CH:4]=1)(=[O:7])[NH2:8]
Reactant: NC(=O)c1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(N)=O)cc1C1=CCCCC1
Yield: 98 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (f) using 4-amino-3-cyclohex-1-enyl-benzamide (as prepared in the previous step, 100 mg, 0.462 mmol) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 155 mg, 0.509 mmol). Silica gel chromatography (1-2% MeOH/DCM) afforded the title compound (210 mg, 98%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C24H31N5O3Si, 466.2 (M+H), found 466.1.
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.C(=O)([O-])[O-].[K+].[K+].[F:36][C:37]1[CH:38]=[C:39]([SH:44])[CH:40]=[CH:41][C:42]=1[F:43]>CN(C=O)C.C(OCC)(=O)C>[F:36][C:37]1[CH:38]=[C:39]([S:44][C:2]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]3[C:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[O:21][C:20]([CH3:22])=[N:19][CH:18]=5)=[C:13]([O:23][CH3:24])[CH:12]=4)=[N:9][N:10]=[C:3]23)[CH:40]=[CH:41][C:42]=1[F:43]
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: Fc1ccc(S)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Sc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a mixture of ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (500 mg) and potassium carbonate (497 mg) in DMF (6.0 mL) was added 3,4-difluorobenzenethiol (0.133 mL), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (491 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7]/[C:8](=[N:33]\[OH:34])/[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH:20][C:21]([C:23]2[NH:27][C:26]3[S:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]=2)=[O:22])[C:11]1=[O:32].C1COCC1.Cl>N1C=CC=CC=1.CCOC(C)=O>[NH2:7]/[C:8](=[N:33]\[O:34][C:2]([O:4][CH2:5][CH3:6])=[O:3])/[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH:20][C:21]([C:23]2[NH:27][C:26]3[S:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]=2)=[O:22])[C:11]1=[O:32]
Reactant: CCOC(=O)Cl
Reactant: N/C(CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21)=N\O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)O/N=C(\N)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Temperature: 100 °C

Procedure:
Ethyl chloroformate (60 μL, 0.63 mmol) was added to a suspension of N-{1-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 31; 200 mg, 0.48 mmol) in dry pyridine (1 mL) under an inert atmosphere then stirred heated to 100° C. for 30 minutes. On cooling THF (10 mL) and added followed by EtOAc (50 mL) and 1M HCl aq. (20 mL). The organic was separated and dried (Na2SO4), filtered and evaporated to give a clear orange oil. This was used in the next stage without characterization or purification.
Reaction SMILES: [O-:1][CH2:2]C.[Na+].[O:5]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]CC)=O)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:24][C:25]([NH2:27])=[O:26]>C(O)C>[O:5]([C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[C:19](=[O:21])[NH:27][C:25](=[O:26])[NH:24][C:2]2=[O:1])=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC[O-]
Reactant: CCOC(=O)Cc1ccc(Oc2ccccc2)cc1
Reactant: NC(N)=O
Agent: [Na+]
Solvent: CCO
Product: O=C1NC(=O)C(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A soultion of sodium ethoxide (0.27 g) in 3 ml of anhydrous ethanol is added with 0.657 g of ethyl (4′-phenoxyphenyl)acetate dissolved in 5 ml of ethanol, then with urea (0.18 g). The reaction mixture is refluxed for 2 hours 30 minutes, then it is cooled to room temperature and the suspended solid is filtered. The solid is redissolved in 8 ml of water and the solution is acidified with 1 N hydrochloric acid. The solid which separates is recovered by filtration to give 0.165 g of the product, m.p. >240° C.