Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH:15](O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.S(Cl)([Cl:24])=O>>[Cl:24][CH:15]([CH2:14][C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(O)Cc1ccc(C2CCCCC2)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(Cl)Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 232 g. (0.747 mole) of ethyl β-(3-chloro-4-cyclohexylphenyl)lactate is stirred with 106.67 g. (0.895 mole) of thionyl chloride at room temperature for 24 hours and then heated to reflux for 6 hours. The cold reaction mixture is poured into 1125 ml. of ice-cold water with stirring. The mixture is extracted with 800 ml. of ether. The ethereal solution is washed with 450 ml. of cold saturated sodium hydrocarbonate solution followed by washing twice, each time with 250 ml. of cold water. The ethereal solution is dried over anhydrous sodium sulfate and filtered. The solvent is removed in vacuo to obtain ethyl α-chloro-β-(3-chloro-4-cyclohexylphenyl)propionate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[H-].[Na+].[CH3:15]I.[Cl-].[NH4+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[N:7]([CH3:15])[C:6]=2[CH:12]=1
Reactant: CI
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1C(=O)CSc2ccc(N)cc21
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
4.5 g 6-Amino-4H-benzo[1,4]thiazin-3-one in 50 ml DMF was treated in portions with 0.695 g 95% sodium hydride at room temperature. After 30 min, 3.548 g methyl iodide were added dropwise at 0° C. and stirring was continued for another 30 min. The mixture was poured into ice and ammonium chloride solution and extracted with CH2Cl2. Chromatography on silica yielded 3.1 g crude product, which was further purified by trituration with diethyl ether.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[Br:11]Br>C(OCC)C>[Br:11][CH:3]1[CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][O:9][C:10]=2[C:2]1=[O:1]
Reactant: O=C1CCCc2ccoc21
Reactant: BrBr
Solvent: CCOCC
Product: O=C1c2occc2CCC1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 100 ml of diethyl ether, 1.09 g of 7-oxo-4,5,6,7-tetrahydrobenzofuran was dissolved, and 0.41 ml of bromine was added. The mixture was stirred at room temperature for one hour. The solvent was then evaporated, and the residue was subjected to silica gel column chromatography, whereby 1.13 g of 6-bromo-7-oxo-4,5,6,7-tetrahydrobenzofuran was obtained as the oil form from the fraction eluted with hexane-ethyl acetate (10:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:13][C:11]=2[NH2:12])[CH:6]=[CH:7][CH:8]=1.[CH:26](=O)[CH3:27].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:10]2[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:26]([CH3:27])=[N:12][C:11]=2[CH:13]=1
Reactant: CC=O
Reactant: COc1cccc(Nc2ccc(-c3nc4ccccc4o3)cc2N)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-n2c(C)nc3cc(-c4nc5ccccc5o4)ccc32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a solution of 2-(2-(3-methoxyphenyl)aminoanilin-5-yl)benzoxazole (see Working Example 31-1) (55.0 mg, 0.166 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 31.2 μL, 0.405 mmol) and oxone (66.3 mg, 0.108 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (17.3 mg, 29% yield) as light brown crystals.
Reaction SMILES: [C:1](=[O:37])([O:8][CH2:9]/[C:10](/[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)=[C:11](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)\[CH2:12][O:13][Si](C(C)(C)C)(C)C)[O:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7]>CC#N.C1(C)C=CC=CC=1>[C:1](=[O:37])([O:8][CH2:9]/[C:10](/[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=1)=[C:11](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)\[CH2:12][OH:13])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\COC(=O)OCCCCBr)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCBr)=C(/CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A mixture of 5.7 g of 4-bromobutyl (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate and 5 mL of PyHF in 100 mL of MeCN was stirred at rt for 2 h, diluted with 500 mL of toluene, filtered through a pad of silica gel, evaporated, and purified by flash chromatography to afford 4.3 g of the titled compound. 1H NMR (acetone-d6, 500 MHz): δ 7.70 (d, 2 H), 7.36 (d, 2 H), 7.18–7.10 (m, 5 H), 5.30 (s, 2 H), 4.68 (d, 2 H), 4.15 (t, 1 H, OH), 4.13 (t, 2 H), 3.53 (t, 2 H), 3.07 (s, 3 H), 1.93–1.87 (m, 2 H), 1.80–1.70 (m, 2 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[C:8]([CH3:14])[CH:7]=2)=[CH:2]1.CO>O1CCCC1.[C].[Pd]>[CH3:12][C:10]1[CH:11]=[C:6]([CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[CH:7]=[C:8]([CH3:14])[C:9]=1[OH:13]
Reactant: Cc1cc(-c2ccoc2)cc(C)c1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C2CCOC2)cc(C)c1O
Reaction time: 18 h
Yield: 52 %

Procedure:
4-(furan-3-yl)-2,6-dimethylphenol (Compound 6-5) (110 mg, 0.74 mmol) were dissolved in tetrahydrofuran:methanol=1 mL:1 mL. Palladium carbon (15 mg, 15%) was added thereto, followed by stirring under hydrogen balloon for 18 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain 2,6-dimethyl-4-(tetrahydrofuran-3-yl)phenol (74 mg, 72%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]([F:16])=[C:10]([NH:12]C(=O)C)[CH:11]=1.S(=O)(=O)(O)[OH:18].NC(N)=O.[OH-].[Na+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:12][C:10]1[CH:11]=[C:6]([OH:18])[CH:7]=[CH:8][C:9]=1[F:16]
Reactant: CC(=O)Nc1cc(N)ccc1F
Reactant: O=S(=O)(O)O
Agent: [Cu+2]
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: O
Product: Nc1cc(O)ccc1F
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A solution of sodium nitrite (17.3 g) in water (40 mL) was added dropwise to a mixture of N-(5-amino-2-fluorophenyl)acetamide (36.7 g), sulfuric acid (50 mL) and water (270 mL) at 0-10° C. The mixture was stirred at 0-10° C. for 20 minutes and then a solution of urea (2.0 g) in water (20 mL) was added and the resulting mixture stirred at 0-10° C. for a further 20 minutes. The mixture was added dropwise over a period 75 minutes to a stirred solution of copper sulfate pentahydrate (131 g) in water (110 mL) at 130° C. and the resulting mixture heated at 130° C. for 2.5 hours. The mixture was cooled in an ice bath and the pH of the solution adjusted to 14 by the addition of 30% aqueous sodium hydroxide solution. The mixture was filtered through hyflo, washing with water. The pH of the filtrate was acidified by the addition of concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to afford title compound as a brown solid, 22.1 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1>[Pd].COCCOCCOCCOC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1cc2c(ccc3ccccc32)c2c1CCCC2
Agent: [Pd]
Solvent: COCCOCCOCCOC
Product: Cc1cc2c3ccccc3ccc2c2ccccc12
Temperature: 210 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
A mixture of palladium on carbon (10%, 5.0 g) and 6-methyl-7,8,9,10-tetrahydro-chrysene (64.0 g, 0.24 mol) in triglyme (290 mL) was heated at 210° C. under a slow nitrogen stream. The progress of the reaction was monitored by NMR analysis that showed the reaction was 72% complete after 4 hours. The heating was discontinued after 18 hours when essentially all of the starting material had been consumed. The mixture was cooled to 100° C. and filtered to remove the catalyst. The solution was then cooled further to 0° C., and filtered to give 42.9 g (68% yield) of 6-methylchrysene. The filtrate was diluted with water (300 mL) and filtered to give an additional 15.5 g (93% combined yield) of 6-methylchrysene. 1H NMR (CDCl3) 2.86 (s, 3 H), 7.6 (m, 4 H), 7.9 (m, 2 H), 8.1 (m, 1 H), 8.55 (s, 1 H), 8.65 (m, 1 H), 8.8 (m, 2 H).
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[Cl:21])=[N+]=[N-]>C1(C)C=CC=CC=1>[Br:20][C:16]1[CH:17]=[C:18]([Cl:19])[C:13]([N:12]2[CH:11]=[C:5]3[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]3=[N:1]2)=[C:14]([Cl:21])[CH:15]=1
Reactant: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc(Br)cc1Cl
Solvent: Cc1ccccc1
Product: Fc1cncc2cn(-c3c(Cl)cc(Br)cc3Cl)nc12
Yield: 66.9 %

Procedure:
A solution of [1-(4-azido-5-fluoropyridin-3-yl)meth-(E)-ylidene]-(4-bromo-2,6-dichlorophenyl)amine (˜60 mmol) in toluene (200 mL) was heated at 105° C. for 2 hours. The resultant mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solid obtained was collected by filtration and dried to afford the title compound (14.5 g, 67% yield over two steps). 1H NMR (400 MHz, DMSO-d6): δ 9.25 (d, J=2.7 Hz, 1H), 9.20 (d, J=2.6 Hz, 1H), 8.28 (dd, J=3.8, 0.5 Hz, 1H), 8.19 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11](#[N:14])[CH:12]=[CH2:13].C1N2CCN(CC2)C1>[OH-].[Na+]>[F:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][CH2:13][C:12]([C:11]#[N:14])=[CH:7]2
Reactant: C=CC#N
Reactant: O=Cc1cc(F)ccc1O
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Product: N#CC1=Cc2cc(F)ccc2OC1
Yield: 288 %

Procedure:
A solution of 5-fluoro-2-hydroxybenzaldehyde (1.00 g, 8.92 mmol) and acrylonitrile (9.40 mL, 143 mmol) was refluxed overnight with DABCO (1.00 g, 8.92 mmol). The mixture was cooled and 1 M NaOH (10 mL) was added. The mixture was extracted with EtOAc (20 mL), and the organic layer was dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography (elution with 10% EtOAc/hexanes) to provide the title compound (4.50 g) as yellow crystals. 1H NMR (300 MHz, CDCl3) δ 7.13 (m, 1H), 6.98 (td, J=8.5, 3.0 Hz, 1H), 6.89-6.80 (m, 2H), 4.80 (d, J=1.4 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[Cl:8].C(O)(=[O:17])C>>[Cl:8][C:7]1[C:2](=[O:17])[NH:3][N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1
Reactant: Clc1cc(-c2ccccc2)nnc1Cl
Reactant: CC(=O)O
Product: O=c1[nH]nc(-c2ccccc2)cc1Cl

Procedure:
A mixture of 3,4-dichloro-6-phenylpyridazine (0.53 g) and acetic acid (2.6 mL) was heated under reflux for 5 hr, and the solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate solution. The obtained solid was collected by filtration and recrystallized from ethanol to give the title compound (0.20 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[S:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Product: CNC(=S)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by a similar method to Example 20 from N2-methyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxamide [see Preparation 43] and Lawesson's reagent. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 25:75 (in 5% increments), by volume, ethyl acetate:hexane, to afford N2-methyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarbothioamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][CH:12]([CH3:14])[CH2:11][CH:10]([C:15]3[NH:20][C:19]4=[CH:21][CH:22]=[N:23][C:18]4=[CH:17][N:16]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC[O:26]C(C)=O.[ClH:30]>CO>[OH2:26].[ClH:30].[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][CH:12]([CH3:14])[CH2:11][CH:10]([C:15]3[NH:20][C:19]4=[CH:21][CH:22]=[N:23][C:18]4=[CH:17][N:16]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Agent: CC1CC(c2ncc3nccc-3[nH]2)CC(c2cccc(F)c2)N1
Agent: Cl
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing [1-(3-fluorophenyl)vinyl]pyrrolidine (freshly prepared before use) (1.10 g, 5.81 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.21 g, 5.81 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (0.9 mL, 5.81 mmol), piperidine (Aldrich Chemical Company) (0.9 mL, 9.3 mmol), NEt3 (Aldrich Chemical Company) (1.0 mL) and SnCl2 (Aldrich Chemical Company) (17 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 82 mg (5%) of the free base as a beige colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.65 (br S, 4), 2.42 (s, 3), 3.72 (br s, 4), 6.85 (s, 1), 7.22 (m, 1), 7.51 (m, 1), 7.75-7.81 (m, 2), 10.97 (s, 1). MS m/z: 311 (M+1). To a hot (near boiling) solution of 6-(3-fluorophenyl)-2-methyl-4-piperidylpyrrolo[3,2-d]pyrimidine (82.0 mg, 0.26 mmol) in 10:1 EtOAc: MeOH (30 mL) was added 1M etheral HCl (Aldrich Chemical Company) (265 mL, 0.26 mmol). Crystallization occurred as the mixture cooled and the precipitate was collected by filtration, washed with Et2O (2×5 mL) and dried under vacuum to give 82 mg (91%) of the title compound as beige colored small needles. Mp: >285° C. 1H HMR (DMSO-d6; 400 MHz): δ 1.71 (br s, 6), 2.57 (s, 3), 4.06 (br s, 4), 6.99 (s, 1), 7.35 (t, 1, J=8.5), 7.60 (q, 1, J=7.7), 7.83 (d, 1, J=7.6), 7.91 (d, 1, J=10.2), 11.99 (s, 1), 14.34 (s, 1). MS m/z: 311 (M+1). Anal. Calcd for C18H19FN4.HCl.H2O: C, 59.17; H, 6.09; N, 15.34; Cl, 9.70. Found C, 59.17; H, 6.09; N, 15.21; Cl, 9.81.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=O.Cl.O[NH2:13]>C(O)=O.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:13]
Reactant: NO
Reactant: O=Cc1c(Br)cncc1Br
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: N#Cc1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-dibromoisonicotinaldehyde (2.0 g, 0.0075 mol) in formic acid was added hydroxyl amine hydrochloride (14 mL) and concentrated sulfuric acid (5 drops) under argon atmosphere. The reaction mixture was heated to reflux for 8 h. After 8 h, the mixture was cooled to room temperature and concentrated. The residue was dissolved in diethyl ether, washed diethyl ether with saturated solution of sodium bicarbonate, water, saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated to afford the title compound. 1H NMR (400 MHz, CdCl3) δ 8.81 (s, 2H).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:41]=[CH:42][C:43]([N:46]5[CH2:47][CH2:48][O:49][CH2:50][CH2:51]5)=[CH:44][CH:45]=4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(N2CCOCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: OCCO
Product: COC1=C(C)C(c2ccc(N3CCOCC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.500 g, 1.28 mmol, 1 eq) and MeOH (10 ml), the product was purified by prep TLC using 4% methanol in chloroform as eluent; yield: 0.100 g (19.34%); MS m/z: 405.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.37 (s, 1H), 8.13 (d, 1H), 7.68-7.64 (m, 1H), 7.50-7.48 (m, 1H), 7.38 (m, 1H), 7.25-7.22 (m, 1H), 7.08-7.06 (m, 2H), 6.82-6.80 (m, 2H), 5.68 (d, 1H), 3.93 (s, 3H), 3.66-3.63 (m, 4H), 3.17-3.01 (m, 4H), 1.66 (s, 3H); HPLC (METHOD [A]): rt 9.33 min (96.37%)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=1>>[CH:14]1([CH2:13][N:12]2[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=[C:8]2[C:7]2[C:2]([O:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Fc1cc2nc(-c3cccnc3Cl)n(CC3CCCCC3)c2cc1F
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-(2-chloro-pyridin-3-yl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (Ex. 1, intermediate a) and (4-methoxy-phenyl)-methanol (CAS Reg. No. 105-13-5). Colorless solid (31%). MS (Turbo Spray): m/z=464.2 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[C:29](=[O:30])[N:4]2[C:5]([C:13]([O:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[C:6]([CH:9]=[CH:10][CH2:11][Cl:12])[CH2:7][S:8][C@H:3]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Cl.[NH2:44][C:45]1[S:49][N:48]=[C:47]([C:50](=[N:54][O:55][CH3:56])[C:51](Cl)=[O:52])[N:46]=1>C(Cl)Cl>[NH2:44][C:45]1[S:49][N:48]=[C:47]([C:50](=[N:54][O:55][CH3:56])[C:51]([NH:1][CH:2]2[C:29](=[O:30])[N:4]3[C:5]([C:13]([O:15][CH:16]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:14])=[C:6]([CH:9]=[CH:10][CH2:11][Cl:12])[CH2:7][S:8][C@H:3]23)=[O:52])[N:46]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCCl)CS[C@H]12
Reactant: CON=C(C(=O)Cl)c1nsc(N)n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCCl)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of XVIII (Z isomer) (20 g, 42 mmole) in CH2Cl2 (420 ml) containing N,O-bis(trimethylsilyl)acetamide (34 ml, 125 mmole) was added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl chloride hydrochloride (15.2 g, 59 mmole) in three portions over a period of 30 minutes at -10° to 0° C. The mixture was stirred for 30 minutes at 0°-5° C. and concentrated under reduced pressure. The residual brown oil was dissolved in ethyl acetate (420 ml) and the solution was washed successively with saturated aqueous NaHCO3 (3×15 ml), saturated aqueous NaCl (15 ml), 10% HCl (15 ml) and saturated aqueous NaCl (15 ml), and concentrated to about 50 ml of the volume. To the concentrate was added n-heptane (200 ml) to give 28.5 g (90% pure) of the title compound VIII-1 (Z-isomer) as a colorless powder. M.p. >150° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][NH2:10].C(N(C(C)C)CC)(C)C.[C:20]1([CH:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][NH:10][C:27](=[O:28])[CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:30][CH3:31]
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: Cc1ccc(F)c(CN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C(=O)NCc1cc(C)ccc1F)c1ccccc1

Procedure:
A solution of (2-fluoro-5-methylphenyl)methanamine (1-f, 50 mg, 0.26 mmol, Oakwood Products, Inc., West Columbia, S.C.) and diisopropylethylamine (88 uL, 0.52 mmol) in dichioromethane (1 mL) was treated at room temperature with 2-phenylbutanoyl chloride (1-a, 47 mg, 0.26 mmol). The reaction mixture was stirred for 30 mm, partitioned between dichloroinethane and 0.1N—NaOH. The aqueous layer was removed and the organic layer was washed with 0.1N—HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was evaporated in vacuo to give the desired product (1-2); HRMS (M+1)=286.1586.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cccc(C2CC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(C2CC2)n1
Temperature: 25 °C
Yield: 62 %

Procedure:
To 6-cyclopropylpicolinaldehyde (3.5 g, 23.8 mmol) in methanol (95 mL) chilled to 0° C. was added sodium borohydride (2.70 g, 37.8 mmol). Once addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. The mixture was concentrated under reduced pressure and the resulting residue was taken up in water, extracted with EtOAc, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (100% EtOAc as the eluent) of the crude material afforded 2.20 g (62%) of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[Cl:15][C:10]1[C:11]([F:14])=[CH:12][CH:13]=[C:8]2[C:9]=1[C:4](=[O:3])[NH:5][CH2:6][CH2:7]2
Reactant: CCOC(=O)NCCc1ccc(F)c(Cl)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2ccc(F)c(Cl)c21
Yield: 21.9 %

Procedure:
Using the same reaction procedure and workup as described in Example 1, [2-(3-chloro-4-fluoro-phenyl)-ethyl]-carbamic acid ethyl ester (I-34c: 1.4 g, 5.7142 mmol) in POCl3 (11.4 mL) was reacted with P2O5 (1.62 g, 11.4285 mmol) at 110° C. for 2 hours to afford the crude product. Purification by column chromatography on silica gel (35% ethylacetate in hexane) afforded 250 mg of the product (21.98% yield).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:13]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CON(C)C(=O)c1cccnn1
Product: CC(O)c1cccnn1
Yield: 157.4 %

Procedure:
According to a similar synthesis of compound 4 described in Example 346, compound 1 (500 mg, 1.17 mmol) was alkylated with 1-Bromo-2-methoxy-ethane (180 mg, 1.3 mmol) to give compound 2 (360 mg, 65%) as a white solid. Compound 2 (200 mg, 0.43 mmol) was reacted with Lawesson's Reagent (190 mg, 0.47 mmol) to give compound 3 (84 mg, 50%) as a white solid. And compound 3 (80 mg, 0.17 mmol) was converted to hydantoin 4 (55 mg, 70%) as a white solid.