Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]=2[N:7]([CH3:16])[C:6]1=[O:17].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH2:35]1[CH2:40][O:39][CH:38]=[CH:37][CH2:36]1.O>C(Cl)Cl>[CH3:16][N:7]1[C:8]2[S:14][CH:13]=[C:12]([CH3:15])[C:9]=2[C:10](=[O:11])[N:5]([CH2:4][CH2:3][CH2:2][O:1][CH:38]2[CH2:37][CH2:36][CH2:35][CH2:40][O:39]2)[C:6]1=[O:17]
Reactant: C1=COCCC1
Reactant: Cc1csc2c1c(=O)n(CCCO)c(=O)n2C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: Cc1csc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
To a solution of 3-(3-hydroxypropyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9 g, 35.4 mmol) and PPTS (900 mg, 3.54 mmol) in DCM (90 mL) at 0° C. was added DHP (8.96 g, 0.106 mol) dropwise. The reaction was stirred at RT for 18 h, poured into water (30 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography and eluted with PE/EA (4:1) to give 1,5-dimethyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (11.2 g, 93.4% yield) as a yellow oil. LCMS: [MH+-THP] 255 and TR=1.473 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].ClCCl.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[CH3:12][S:13]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:15])=[O:14]
Reactant: OCCc1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccs1
Reaction time: 1 h

Procedure:
A mixture of 12.8 g. of 2-(2-thienyl)ethanol, 450 ml. of dichloromethane and 20.2 g. of triethylamine is chilled to -10° C. and 12.8 g. of cold methanesulfonyl chloride is added dropwise over 30 minutes. After stirring for 1 hour, the mixture is washed with 300 ml. of cold water, 300 ml. of cold 10% hydrochloric acid, 300 ml. of cold saturated sodium bicarbonate, and 300 ml. of cold saturated sodium chloride solution. The organic layer is dried over magnesium sulfate and concentrated under vacuum to give the product as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31])=O>>[C:30]([C:29]1[CH:28]=[C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)[CH:34]=[CH:33][CH:32]=1)#[N:31]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: N#Cc1cccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)c1
Yield: 56 %

Procedure:
4-[4-(3-Cyano-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (150 mg, 56%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3-(2-bromoacetyl)benzonitrile (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.59 (d, J=1.6 Hz, 1H), 8.54 (s, 1H), 8.51 (s, 1H), 8.44 (d, J=7.7 Hz, 1H), 8.31 (dd, J=8.0, 1.6 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 7.64-7.88 (m, 4H), 7.43-7.49 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[CH2:29][O:30][C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[CH2:24][CH2:23]1>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:35]([C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][C:28]([N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)=[O:39])=[CH:38][CH:37]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN1CCN(C(=O)COc2ccc(C=O)cc2)CC1
Product: CN1CCN(C(=O)COc2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cc2)CC1
Yield: 26 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (1 eq.) and 4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)benzaldehyde (58) (1.1 eq) were reacted in an analogous manner as compound CCXXIII to yield the desired product (26%) as an off white solid. NMR: δ (1H, 400 MHz, DMSO-d6): 1.38 (1H, d, J=8 Hz), 2.19 (3H, s), 2.20-2.35 (5H, m), 2.62 (1H, d, J=8.4 Hz), 2.78 (1H, s), 2.89 (1H, s), 3.40-3.50 (4H, m), 4.91 (2H, s), 5.16 (1H, t, J=8 Hz), 6.36-6.40 (2H, m), 7.08 (2H, d, J=8.4 Hz), 7.11-7.14 (1H, m), 7.22 (1H, bs), 7.76 (1H, bs), 7.92 (1H, s), 8.05 (2H, d, J=8.4 Hz).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C@@H:15]3[C@@H:19]([C:20]4[NH:24][N:23]=[N:22][N:21]=4)[O:18][C:17](=[O:25])[NH:16]3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC>O1CCCC1>[CH3:26][N:22]1[N:23]=[N:24][C:20]([C@H:19]2[O:18][C:17](=[O:25])[NH:16][C@@H:15]2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:10]=2)=[N:21]1
Reactant: O=C([O-])[O-]
Reactant: O=C1N[C@H](c2cccc(C#Cc3ccccc3)c2)[C@@H](c2nnn[nH]2)O1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nnc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)n1
Reaction time: 6 h
Yield: 11785.7 %

Procedure:
To a solution of (4R,5S)-4-(3-(phenylethynyl)phenyl)-5-(1H-tetrazol-5-yl)oxazolidin-2-one (18.6 mg, 0.056 mmol) in tetrahydrofuran (5 mL) was added potassium carbonate (38.8 mg, 0.281 mmol) and iodomethane (0.035 mL, 0.561 mmol) and the reaction mixture was held at 50° C. for 6 hours. The reaction mixture was concentrated and purified by Preparative HPLC Method 16 providing (4R,5S)-5-(2-methyl-2H-tetrazol-5-yl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one (2.4 mg, 6.60 mmol, 11.76% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 4.43 (s, 3H) 5.27 (s, 1H) 5.75 (s, 1H) 7.39-7.46 (m, 4H) 7.49 (t, J=7.63 Hz, 1H) 7.55-7.62 (m, 3H) 8.69 (s, 1H). Mass spec.: 344.11 (M−H)−.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-methoxybenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[OH:9].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.[N+:31]([C:34]([CH3:36])=[CH2:35])([O-:33])=[O:32]>C(#N)C.O1CCCC1>[N+:31]([CH:34]([CH3:36])[CH2:35][O:9][CH:3]1[C:4]([CH3:8])([CH3:7])[CH2:5][CH2:6][C:2]1([CH3:10])[CH3:1])([O-:33])=[O:32]
Reactant: C=C(C)[N+](=O)[O-]
Reactant: CC1(C)CCC(C)(C)C1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(COC1C(C)(C)CCC1(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2,5,5-Tetramethyl-1-cyclopentanol is added to a dry flask under argon at 0° C. Dry tetrahydrofuran is added with a syringe. Sodium hydride (60% dispersion in oil) is added quickly in one portion and the contents of the flask are stirred for one hour at room temperature. A 10 mM solution of 18-crown-6-ether in acetonitrile is added with a syringe and the flask cooled to 0° C. A tetrahydrofuran solution of 2-nitropropene is added with vigorous stirring over a 10 minute period. After completion of the reaction as judged by thin layer chromatography, it is quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield 1-(2-nitropropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:21])[C:15]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:21])[C:15]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)C(=O)NCC(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To a solution of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-1-yl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-[N-(tert-butoxycarbonylmethyl)carbamoyl]propyl]acetamide (0.20 g) in ethanol (1 mL) and tetrahydrofuran (2 mL) was added 10% (v/v) palladium on carbon (0.075 g), and the mixture was shaken under a hydrogen atmosphere (3 bar) for 2.5 hours. The mixture was filtered through diatomaceous earth and evaporated. Chromatography, with chloroform:methanol (96:4) as the eluent, gave material which was precipitated from dichloromethane and hexane to yield the title compound as a white solid (0.128 g); TLC: Rf =0.35, chloroform:methanol (96:4); MS: m/z=498(M+1). Analysis for C24H31F2N5O6.0.3 H2O: Calculated: C, 55.51; H, 5.89; N, 12.95; Found: C, 55.65; H, 5.73; N, 12.60.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[NH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Nc1ccncc1
Product: c1cc(NC2CCCNC2)ccn1

Procedure:
Reaction of tert-butyl 3-oxopiperidine-1-carboxylate and 4-aminopyridine using the method of Example 3 followed by deprotection using the method of Example 4 affords the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([OH:17])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([O:17][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: On1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2c(-c3ccncc3)n(OCCN3CCOCC3)c3cccnc23)cc1
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]-pyridine (0.20 g, 0.65 mmol) and 2-chloroethylmorpholine hydrochloride (0.24 g, 6.56 mmol) in dimethylformamide (5 ml) was added sodium hydride (100 mg, 60% in oil). The reaction mixture was stirred overnight and quenched with 10% HCl (2 ml). The pH was adjusted to pH=8-9 by the addition of saturated sodium bicarbonate solution and the product was extracted into ethyl acetate. The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an oil. Purified by flash column chromatography (50%-80% ethyl acetate/hexanes, followed by 95/5% methylene chloride/methanol gradient) gave 3-(4-fluorophenyl)-1-[2-(morpholin-4-yl)ethoxy]-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine (180 mg) which recrystallized from hexanes/ethyl acetate to give a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.CC(C)(O)[C:14]#[N:15]>>[CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([OH:8])([C:14]#[N:15])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC(C)(O)C#N
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Product: CC1(C)CC(O)(C#N)CC(C)(C)N1

Procedure:
A solution of 97 g 2,2,6,6-tetramethyl-4-piperidone and 67 g of acetone cyanohydrin were stirred at room temperature for 30 hours to precipitate the desired cyanohydrin. The precipitate was collected, washed with petroleum ether and air dried to yield 70 g (61.4%); mp 129°-132° C.
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10](=[O:41])[C@@H:11]([C@H:33]1[C:37](=[O:38])[O:36][C:35]([CH3:40])([CH3:39])[O:34]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[CH:20][CH:19]=1)[C:5]([CH3:8])([CH3:7])[CH3:6])(O)=[O:2].[C:42]1([C@H:48]([NH2:50])[CH3:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(OCC)(=O)C>[CH3:39][C:35]1([CH3:40])[O:34][C@@H:33]([C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)=[CH:20][CH:19]=2)[C:10]([NH:9][C@H:4]([C:1]([NH:50][C@@H:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:49])=[O:2])[C:5]([CH3:6])([CH3:7])[CH3:8])=[O:41])[C:37](=[O:38])[O:36]1
Reactant: COc1cccc(-c2ccc(CCCCCC[C@@H](C(=O)N[C@H](C(=O)O)C(C)(C)C)[C@@H]3OC(C)(C)OC3=O)cc2C)c1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccc(CCCCCC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c3ccccc3)C(C)(C)C)[C@@H]3OC(C)(C)OC3=O)cc2C)c1
Yield: 70.8 %

Procedure:
According to the method of Example 25(a), (2R)-N-[(1S)-1-(carboxy)-2,2-dimethylpropyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-5-[(3′-methoxy-2-methylbiphen-4-yl)propyl]pentanamide (Preparation 34)(150 mg, 0.28 mmol) was reacted with (R)-1-phenylethylamine (35 μl , 0.28 mmol) at room temperature for 2.5 h. The mixture was poured into ethyl acetate (75 mL) and washed with 0.5M aqueous sodium dihydrogenphosphate (2×50 mL) and 5% aqueous sodium bicarbonate (50 mL) (solid sodium chloride was added to give phase separation). The organic solution was dried (Na2SO4) and concentrated under reduced pressure. The residual oil was purified by flash chromatography (eluting with hexane:ethyl acetate=35:65) to give (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-N-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]-5-[(3′-methoxy-2-methylbiphen-4-yl)propyl]pentanamide as a white solid (133 mg, 76%).
Reaction SMILES: CO[C:3](OC)(OC)[CH2:4][CH2:5][CH2:6][CH3:7].[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:20][CH:19]=[CH:18][CH:17]=2>C1(C)C=CC=CC=1>[CH2:4]([C:3]1[N:23]([CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Reactant: CCCCC(OC)(OC)OC
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 50.8 %

Procedure:
Trimethylorthovalerate (5.9 g, 36.4 mmol) was added with stirring to a solution of 1,1-dimethylethyl N-{2-[(3-aminoquinolin-4-yl)amino]ethyl}carbamate (10.0 g, 33.1 mmol) in anhydrous toluene (100 mL). The reaction mixture was heated to reflux. A 10 mL portion of toluene was removed using a Dean Stark trap and the reaction mixture was maintained for 36 hours. An additional 40 mL of toluene was removed and then the reaction was allowed to cool to ambient temperature with continued stirring. The resulting precipitate was isolated by filtration and dried to provide 6.2 g of 1,1-dimethylethyl N-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a tan solid. Thin layer chromatography (silica gel; 10% methanol in dichloromethane) analysis indicated that the material was pure.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[Cu][C:13]#[N:14]>CN(C)C=O.N1C=CC=CC=1>[C:13]([C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4])#[N:14]
Reactant: N#C[Cu]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1ccc([N+](=O)[O-])cc1N
Temperature: 160 °C
Yield: 70.4 %

Procedure:
To a solution of 2-bromo-5-nitroaniline (5.0 g, 23 mmol) in dimethylforamide (100 ml) and pyridine (20ml) was stirred with copper(I) cyanide (2.05 g, 64 mmol). The mixture was then heated to 160° C. for 48 hrs. The reaction was then cooled to room temperature and filtered through celite, the celite was washed with ethyl acetate. The solvent was evaporated and chromatography of the resulting solid on silica gel (25%EtOAc/Hexane) gave the desired product (2.64 g, 70%). 1H NMR (CD3COCD3): δ7.75 (s, 1H), 7.70 (d, 1H), 7.44 (dd, 1H), 6.25(bs, 2H).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([N+:13]([O-])=O)[CH:7]=1)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[H][H]>[Pd].C(O)C>[NH2:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([C:3]1[CH:2]=[CH:19][CH:18]=[C:17]([NH2:20])[CH:16]=1)=[O:5]
Reactant: [H][H]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1

Procedure:
In an autoclave there are added 32.5 g (0.1 moles) of 2-chloro-4'-fluoro-5,3'-dinitro benzophenone, 15.9 g (0.15 moles) of sodium carbonate, 2 g of 5% palladium/alumina catalyst (from Nihon-Engelhardt Co.) and 100 ml of ethanol. With the mixture being stirred at 30°-35° C., there is introduced hydrogen into the autoclave, at a constant pressure of 10 Kg/cm2. G, to carry out the reaction for ten hours. After the completion of the reaction, the reaction mixture is heated up to filter out the catalyst and the inorganic salt. Then, on cooling the mixture there is obtained 3,3'-diamino benzophenone in the form of yellow needle-like crystals. The crystals are filtered, washed with 10 ml of ethanol and dried. Yield 16.2 g (76.3%). M.P. 149°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]#[N:6].OO.C(=O)([O-])[O-:23].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]([NH2:6])=[O:23]
Reactant: N#Cc1cc(F)c(Oc2ccc(C=O)cc2)c(F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(Oc2ccc(C=O)cc2)c(F)c1
Yield: 99 %

Procedure:
Hydrolysis of the compound of step 1 using hydrogen peroxide and potassium carbonate in DMSO as described previously afford the above compound in 99% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=CCc1ccc(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCCc1ccc(F)c(F)c1
Reaction time: 8 h

Procedure:
Into a 1 liter three-necked flask equipped with a stirrer, 33.29 g (213 mmol) of (3,4-difluorophenyl) acetaldehyde and 426 ml of ethanol were charged, to which 8.85 g (234 mmol) of sodium borohydride were added, and the mixture was stirred overnight. Ethanol was distilled off, and 1N hydrochloric acid and ether were added. An organic layer and an aqueous layer were separated, the aqueous layer was extracted with ether, the extract combined with the organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the solvent was distilled off and condensed, the concentrate was purified by vacuum distillation to obtain 17.59 g (52%, bp 110-121° C./16-22 Torr.) of the title compound as oily product.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19]([S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C@H:4]1[S:3]2>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19]([S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Sc3ccccc3)[C@H]1S2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)Sc3ccccc3)[C@H]1S2
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(phenylthio)carbonylaminopenam-3-carboxylate (1.04 g.) in a mixture of dimethylformamide (7 ml.) and acetic acid (2.2 ml.) was added zinc powder (1.8 g.) under ice-cooling, and the mixture was stirred for 1.5 hours. After the reaction, zinc powder was filtered off and the filtrate was poured into a mixture of ethyl acetate (30 ml.) and ice-water (30 ml.) containing 2% hydrochloric acid (2 ml.), extracted and then the aqueous layer was further extracted with ethyl acetate (10 ml.) The combined extract was washed with water and a saturated sodium chloride aqueous solution in turn, dried over magnesium sulfate and then the solvent was removed under reduced pressure. The obtained residue was crystallized by adding a small amount of acetonitrile to give 2-methyl-2,3-methylene-6-(phenylthio)carbonylaminopenam-3-carboxylic acid (0.43 g.), mp 116° to 119°C (dec.).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:25])[CH3:24]
Reactant: O=C1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC1(c2ccc(F)cc2)CCC(=O)CC1
Reaction time: 20 h
Yield: 57 %

Procedure:
The 4-hydroxymethyl-4-(4-fluorophenyl)cyclohexanone is dissolved in 50 ml. of pyridine and 30 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is pured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed sucessively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution and brine, and evaporated to dryness. The solid residue is recrystallized from ether to give 9.77 g. (57% yield) of 4-acetoxymethyl-4-(4-fluorophenyl)cyclohexanone, having a melting point of 80° to 84°C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.Cl[CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]>C1COCC1.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=1
Reactant: COCCOCCl
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCOc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
Sodium hydride (6.55 g) was added in small portions to a solution of 4-bromo-2-(trifluoromethyl)phenol (32.9 g) in THF (150 ml). After stirring at room temperature for 10 minutes, 1-(chloromethoxy)-2-methoxyethane (17 g) was then added by syringe. The mixture was stirred at room temperature for 24 hours then diluted with ethyl acetate (300 mL) and washed with water. Organics were dried over sodium sulphate and solvent evaporated under reduced pressure. The resulting residue was columned on silica gel using heptane as eluant to afford 4-bromo-1-((2-methoxy-ethoxy)methoxy)-2-(trifluoromethyl)benzene (78% yield).