Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].O.Cl.[OH:6][C:7]1[C:8]([CH3:24])=[C:9]([CH3:23])[C:10]2[O:15][C@:14]([CH3:20])([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][C:11]=2[C:21]=1[CH3:22]>CO>[OH:6][C:7]1[C:8]([CH3:24])=[C:9]([CH3:23])[C:10]2[O:15][C@@:14]([CH3:20])([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][C:11]=2[C:21]=1[CH3:22]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CC(=O)O)O2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(CC(=O)O)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This crude enriched (R)-ester (1.1 g) was dissolved in MeOH (8 mL) and treated with NaOMe (2.7 mL of a 25 wt % solution in MeOH, 12 mmol). This solution was heated at reflux for 24 h when H2O (2 mL) was added to the hot solution and reflux was maintained for an additional 30 min. The solution was cooled to room temperature, 1M HCl (15 mL) was added, and the mixture was stirred vigorously for 1 h. The solid was isolated by filtration, washed with H2O (2×5 mL), and air-dried overnight to give 0.70 g (70% yield; essentially 1:1/(R):(S), Method A) of (R,S)-acid of Formula (XI) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:18])[CH:3]=1.S(Cl)(Cl)=O.Cl.CN.C[CH2:27][N:28](C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([NH:28][CH3:27])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:18])[CH:3]=1
Reactant: O=C(O)c1cnccc1-c1cc(F)c(Cl)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1cnccc1-c1cc(F)c(Cl)cc1F
Temperature: 65 °C
Reaction time: 7 h
Yield: 41.9 %

Procedure:
4-(4-chloro-2,5-difluorophenyl)nicotinic acid (170 mg, 0.630 mmol) was taken in thionyl chloride (0.14 mL, 1.89 mmol) and heated at 65° C. for 1 h. The solvent was evaporated under reduced pressure to afford a crude oil which was dissolved in dichloromethane and added to a mixture of methanamine hydrochloride (63.9 mg, 0.946 mmol) and DIEA (0.11 mL, 0.63 mmol) in DCM (8 mL) dropwise at 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 7 h. The reaction mixture was diluted with DCM (5 mL) and washed with water (3×5 mL) followed by brine (1×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to provide the crude product which was purified by preparative thin layer chromatography (3:2 Ethyl acetate:hexane) to afford 4-(4-chloro-2,5-difluorophenyl)-N-methylnicotinamide (90 mg, 0.264 mmol, 42% yield) as a white solid. LC/MS (ESI) m/e 283.0 [(M+H)+, calcd for C13H10ClF2N2O 283.0]; LC/MS retention time (method A): tR=1.46 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].N1C=CC=CC=1>COCCOC>[CH:30]([O:29][C:27](=[O:28])[NH:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1)([CH3:32])[CH3:31]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cnc2nc(-c3cc(NC(=O)N4CCCC4)ccc3Cl)oc2c1
Solvent: c1ccncc1
Solvent: COCCOC
Product: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)N4CCCC4)ccc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-[6-amino-[1,3]oxazolo[4,5-b]pyridin-2-yl]-4-chlorophenyl)pyrrolidine-1-carboxamide (100 mg, 0.28 mmol, 1.00 equiv), propan-2-yl chloroformate (68.3 mg, 0.56 mmol, 1.99 equiv), pyridine (111 mg, 1.40 mmol, 5.02 equiv) in ethylene glycol dimethyl ether (15 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated under vacuum. This resulted in 60.8 mg (49%) of propan-2-yl N-[2-(2-chloro-5-[[(pyrrolidin-1-yl)carbonyl]amino]phenyl)-[1,3]oxazolo[4,5-b]pyridin-6-yl]carbamate (75) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:26]=[C:24]([C:23]3[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=3)[O:25][CH:15]=2)[CH:9]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Product: O=C(O)COc1ccc(Br)cc1-c1coc(-c2ccc(Cl)cc2)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 4-chlorobenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.90 min, m/z 407.7 [M+H]+; 1H NMR (CDCl3): δ 4.89 (s, 2H), 7.09 (d, 1H), 7.48 (d, 1H), 7.64 (d, 2H), 8.08 (d, 2H), 8.20 (s, 1H), 8.89 (s, 1H), 13.2 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[C:7]2[OH:12].Cl[S:17]([C:20]1[CH:21]=[C:22]([S:28]([F:31])(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27])(=[O:19])=[O:18].CN(C)C1C=CC=CC=1.Cl>CN(C)C(=O)C>[F:31][S:28]([C:22]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([S:17]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[C:7]3[OH:12])(=[O:18])=[O:19])[CH:21]=1)(=[O:29])=[O:30]
Reactant: COc1ccc(S(=O)(=O)F)cc1S(=O)(=O)Cl
Reactant: Nc1cccc2c(O)c(C(=O)O)ccc12
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)c1ccccc1
Product: COc1ccc(S(=O)(=O)F)cc1S(=O)(=O)Nc1cccc2c(O)c(C(=O)O)ccc12
Temperature: 22 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
5-Amino-1-hydroxy-2-naphthoic acid (10.2 g, 50 mmol) and 3-chlorosulfonyl-4-methoxybenzenesulfonylfluoride (14.4 g, 50 mmol) as prepared as in 1A were suspended in N,N-dimethylacetamide (100 ml). N,N-Dimethylaniline (15.1 g, 125 mmol) was added, the mixture was stirred at room temperature (22° C.) for 16 hours, and was then poured into ice water (750 ml) acidified with concentrated hydrochloric acid (25 ml). The mixture was extracted with three portions of ethyl acetate (500 ml each). The combined extracts were dried over anhydrous magnesium sulfate, the salts were removed by filtration, and the filtrate was decolorized with acidic alumina. The alumina was separated and the solvent was removed under reduced pressure to yield 8.3 g, (36.4%) of product.
Reaction SMILES: [OH:1][C@@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].N1CCCCC1>CCO.C(O)(=O)C>[OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:23]2[S:19][C:20](=[O:25])[NH:21][C:22]2=[O:24])=[CH:7][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OC[C@@H](O)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(OCC(O)c3ccccc3)cc2)S1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
To a stirring solution of 4-[(2S)-2-hydroxy-2-phenylethoxy]benzaldehyde (2.63 g, 10.8 mmol) in absolute EtOH (75 mL) was added 2,4-thiazolidinedione (1.27 g, 10.8 mmol) and piperidine (0.54 mL, 5.4 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight. The reaction mixture was allowed to cool to RT. No precipitate formed. The pH of reaction mixture was ca. 5. Acetic acid (20 drops) was added, and the reaction was evaporated in vacuo. The material was adsorbed onto silica gel and chromatographed eluting with 30-40% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to give 3.18 g (86%) of the title compound as a light yellow solid. MS (ESI−) for C18H15NO4S m/z 340.1 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]2[N:13]([N:20]=[CH:21][CH:22]=2)C(=O)[C:15]=1[CH2:16][CH2:17]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O.C(N(CC)CC)C.[CH:35]([Cl:38])(Cl)Cl>>[CH2:1]([O:8][CH2:9][C:10]1[C:15]([CH2:16][CH2:17][Cl:25])=[C:35]([Cl:38])[N:13]2[N:20]=[CH:21][CH:22]=[C:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: O=c1c(CCO)c(COCc2ccccc2)[nH]c2ccnn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: ClCCc1c(COCc2ccccc2)nc2ccnn2c1Cl
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
To 0.52 g of 5-benzyloxymethyl-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one were added 4.0 ml of phosphorus oxychloride and 0.55 ml of triethylamine, and the mixture was stirred for 1 hour and 20 minutes in an oil bath heated to 100-110° C. Excess phosphorus oxychloride was distilled off under reduced pressure, and the residue was poured into ice water and extracted with chloroform. After the chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The thus-obtained crude product was subjected to column chromatography on silica gel (elution solvent: chloroform alone) to obtain 0.37 g (yield: 63.4%) of the intended product.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@H:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)C.O>>[NH2:23][C@@:22]([C@@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH2:18]1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@@H]([C@]2(C)COC(=O)N2)C3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@@H]([C@@](C)(N)CO)C3)CC1

Procedure:
The mixture of (R)-4-((R)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (46.6 mg, 0.000121 mol) (from isomer 3) and lithium hydroxide (31.8 mg, 0.00133 mol) in ethanol (0.77 mL, 0.013 mol) and water (0.26 mL, 0.014 mol) was heated to reflux for overnight. LCMS showed SM was consumed and peak Rf=1.65 left. The solvent was removed under vacuum and the residue was partitioned between water and dichloromethane. The aqueous was extensively extracted with dichloromethane and the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into dichloromethane and subjected to chromatography purification with dichloromethane/MeOH (10:90 to 80:20) to give the product (21.2 mg, 49% yield). LCMS 360.42 ([M+1], 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.89 (s, 9H), 1.06 (s, 3H), 1.04-1.40 (m, 6H), 1.77-1.88 (m, 3H), 1.97 (m, 1H), 2.15 (m, 2H), 2.56 (dd, J=15.8, 12.1 Hz, 1H), 2.71-2.84 (m, 3H), 3.47 (d, J=10.9 Hz, 1H), 3.51 (d, J=10.9 Hz, 1H), 4.07 (m, 1H), 6.58 (d, J=2.5 Hz, 1H), 6.63 (dd, J=8.2, 2.5 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43]>C1(C)C=CC=CC=1.C(O)C>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43].[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]([NH:44][C:45]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][N:18]=2)=[CH:28][CH:29]=1)=[S:46])=[O:43]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 73%).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25]CC)=[O:24])[CH:16]=[N:15]3)[N:9]=2)=[CH:6][C:5]([CH3:28])=[CH:4][N:3]=1.[CH3:29][C:30]1[CH:31]=[C:32]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[CH:33]=[CH:34][C:35]=1[CH2:36][OH:37]>>[CH3:28][C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:18]([C:19]([F:21])([F:22])[F:20])=[C:17]([C:23]([OH:25])=[O:24])[CH:16]=[N:15]3)[N:9]=2)[C:2]([O:37][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)=[CH:31][C:30]=2[CH3:29])=[N:3][CH:4]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)cnc3F)n2)c1C(F)(F)F
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Product: Cc1cnc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C)c(-c2cccc(-n3ncc(C(=O)O)c3C(F)(F)F)n2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 237 Step B, by reaction of the title compound from Example 238 Step B with [3-methyl-4′-(trifluoromethyl)biphenyl-4-yl]methanol (PCT Publication WO2005118542): LCMS m/z 612.9 [M+H]+; 1H NMR (500 MHz, acetone-d6) δ 8.18 (m, 2H), 7.91 (d, J=8.2 Hz, 2H), 7.80 (m, 3H), 7.63 (m, 2H), 5.66 (s, 2H), 2.51 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1](C(CCCC)CN)C.C(N)CC.[CH2:14]([CH:16]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][NH:18][C:19](=[O:25])[O:20][CH:21](C)[CH2:22][OH:23])[CH3:15]>>[CH2:14]([CH:16]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][NH:18][C:19](=[O:25])[O:20][CH2:21][CH:22]([OH:23])[CH3:1])[CH3:15]
Reactant: CCCCC(CC)CNC(=O)OC(C)CO
Reactant: CCCCC(CC)CN
Solvent: CCCN
Product: CCCCC(CC)CNC(=O)OCC(C)O

Procedure:
When example 6 is followed except that a chemically equivalent amount of 2-ethylhexylamine is substituted for n-propylamine, an isomeric mixture of 1-hydroxy-2-propyl 2-ethyl-1-hexylcarbamate and 2-hydroxy-1-propyl 2-ethyl-1-hexylcarbamate is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][CH2:68][CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:67][CH2:68][CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300 mg, 0.67 mmol), HATU (280 mg, 0.74 mmol) and N,N-diisopropylethylamine (190 mg, 1.47 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of tert-butyl (2-aminoethyl)carbamate (128 mg, 0.80 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate as white solid. Yield: 355 mg, 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:31])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:32][C:33]1[CH:34]=[C:35]([OH:41])[CH:36]=[CH:37][C:38]=1[C:39]#[N:40].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[O:31])[CH:8]=[CH:7][C:3]=1[C:4]([O:41][C:35]1[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[C:33]([Cl:32])[CH:34]=1)=[O:5]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)Cl)c(Cl)c3)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)Oc4ccc(C#N)c(Cl)c4)c(Cl)c3)cc2)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 2-chloro-4-{[p-(p-hexylphenyl)benzoyl]oxy}benzoyl chloride obtained was dissolved in 125 ml of benzene and then added dropwise to a solution of 4.0 g of 3-chloro-4-cyanophenol in 100 ml of pyridine. The mixture was stirred at a bath temperature of 65° C. overnight, then poured into ice-cold, dilute hydrochloric acid and extracted with diethyl ether. The extract was washed several times with 3N hydrochloric acid, then washed neutral with water, dried and evaporated. The crude 4'-hexyl-4-biphenylcarboxylic acid 3-chloro-4-[(3-chloro-4-cyanophenoxy)carbonyl]phenyl ester obtained was chromatographed on silica gel with toluene/dichloromethane (1:1). The fractions (8.2 g) which were practically pure according to thin-layer chromatography were recrystallized once from ethyl acetate and once from ethyl acetate and a small amount of hexane; m.p. (C-N) 95° C., cl.p. (N-I) 235° C.
Reaction SMILES: N1C2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=C1.[H-].[Na+].I[CH3:16].[CH3:17][N:18]([CH:20]=O)[CH3:19]>>[CH3:16][O:12][C:10]([C:6]1[CH:5]=[C:4]2[C:19](=[CH:8][CH:7]=1)[N:18]([CH3:17])[CH:20]=[CH:3]2)=[O:11]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc2c(ccn2C)c1
Yield: 93 %

Procedure:
A solution of 1H-indole-5-carboxylic acid (1.6 g, 10 mmol), sodium hydride (1.2 g, 30 mmol), iodomethane (6.2 mL, 100 mmol) and DMF (40 mL) was stirred and room temperature for 24 hr. The reaction mixture was then quenched with water (5 mL) and diluted with ether (150 mL) and ethyl acetate (50 mL). After washing with aq. NH4Cl (100 mL), water (100 mL) and then brine (100 mL), the organic layer was dried over MgSO4, filtered and concentrated. The remaining material was subjected to flash chromatography (ethyl acetate/hexane 1:4) to provide 1-methyl-1H-indole-5-carboxylic acid methyl ester as a crystalline solid (1.77 g, 93% yield). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.94 (d, 1H, J=9.0 Hz), 7.34 (d, 1H, J=9.0 Hz), 7.12 (d, 1H, J=2.9 Hz), 6.60 (d, 1H, J=2.9 Hz), 3.94 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(N(CC)C(C)C)(C)C.[CH3:38][C:39]([CH3:59])=[CH:40][CH2:41][CH2:42]/[C:43](/[CH3:58])=[CH:44]/[CH2:45][CH2:46]/[C:47](/[CH3:57])=[CH:48]/[CH2:49][S:50][CH2:51][C@H:52]([NH2:56])[C:53]([OH:55])=[O:54]>C(Cl)Cl.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([NH:56][C@@H:52]([CH2:51][S:50][CH2:49]/[CH:48]=[C:47](\[CH3:57])/[CH2:46][CH2:45]/[CH:44]=[C:43](\[CH3:58])/[CH2:42][CH2:41][CH:40]=[C:39]([CH3:59])[CH3:38])[C:53]([OH:55])=[O:54])=[O:10]
Reactant: O=C(O)CCc1ccco1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CCc1ccco1)C(=O)O
Reaction time: 0.17 h

Procedure:
To a solution of 3-(2-furyl) propionic acid (168 mg, 1.2 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 332 mg, 1.2 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol). After stirring for 10 min, S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added slowly. The solution was stirred at room temperature overnight and then diluted with ethyl acetate (60 mL). The solution was washed by 0.5 N HCl (10 mL×1), H2O (10 mL×1) and brine (10 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (333 mg, 74%) to yield Compound N-96. 1H-NMR (500 MHz, CD3OD): δ 1.50 (s, 6H), 1.57 (s, 3H), 1.59 (s, 3H), 1.86-1.89 (m, 2H), 1.95-2.06 (m, 6H), 2.51 (t, J=8.0 Hz, 2H), 2.57-2.62 (m, 1H), 2.83-2.869 (m, 3H), 3.05 (dd, J=7.5, 13.5 Hz, 1H), 3.12-3.16 (m, 1H), 4.49 (dd, J=4.5, 8.0 Hz, 1H), 4.99-5.01 (m, 2H), 5.13 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, CD3OD): δ 16.15, 16.24, 17.80, 24.96, 25.95, 27.39, 27.79, 30.11, 33.41, 35.08, 40.79, 40.89, 53.30, 106.28, 111.19, 121.61, 125.14, 125.46, 132.12, 136.27, 140.49, 142.36, 155.72, 174.00, 174.78; ES-MS: mass calcd for Chemical Formula: C25H37NO4S 447.63. Found (M+1) m/z 448.3, (M+23) m/z 470.2.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Sb](Cl)(Cl)Cl.[O:14]1[CH:18]=[CH:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[O:14]1[CH2:15][CH2:16][CH2:17][CH:18]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([CH:15]2[CH2:16][CH2:17][CH2:18][O:14]2)[C:5]1=[O:8].[O:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Agent: Cl[Sb](Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Product: O=c1c(F)cn(C2CCCO2)c(=O)n1C1CCCO1
Yield: 68 %
Yield: 27 %

Procedure:
In a sealed tube, 780 mg (6 m mole) of 5-fluorouracil, 5 ml of pyridine, 100 mg (0.44 m mole) of antimony trichloride and 1.26 g (18 m mole) of 2,3-dihydrofuran were heated at 100° C for 3 hours. The reaction mixture was further admixed with 800 mg (11.5 m mole) of 2,3-dihydrofuran and the mixture was heated for 17 hours. After the reaction, pyridine was distilled off under a reduced pressure and the residue was dissolved in chloroform and the insoluble matters were separated by a filtration. Chloroform was distilled off from the filtrate and the residue was purified by a column chromatography using a silica gel column (mixture of chloroform and acetone = 8 : 1 (V/V) as a developing medium) to obtain 1.10 g of N1,N3 -bis(2-tetrahydrofuryl)-5-fluorouracil (yield: 68.0%) and 325 mg of N1 -(2-tetrahydrofuryl)-5-fluorouracil (yield: 27%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[C:11](=[O:20])[NH:12][C:13]([NH:16][N+]([O-])=O)=[N:14][CH:15]=2)[CH:5]=[N:6][C:7]=1[CH3:8].N[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>C(O)C>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:16][C:13]1[NH:12][C:11](=[O:20])[C:10]([CH2:9][C:4]2[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:15][N:14]=1
Reactant: NCCCCCO
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Solvent: CCO
Product: Cc1cc(Cc2cnc(NCCCCCO)[nH]c2=O)cnc1C

Procedure:
5-(5,6-Dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone is reacted with 5-aminopentanol in refluxing ethanol to give 2-(5-hydroxypentylamino)-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone which is reacted with cyanamide and hydrogen chloride to give 2-[5-(O-isoureido)pentylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone.