Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][C:20]([F:25])([F:24])[CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8]>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][C:20]([F:24])([F:25])[CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCCC(F)(F)C2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Cl)c(OCC2CCCC(F)(F)C2)cc1F
Reaction time: 2 h

Procedure:
A solution of tert-butyl 5-chloro-4-((3,3-difluorocyclohexyl)methoxy)-2- fluorobenzoate (64.4 mg) in dichloromethane (0.34 mL) and trifluoroacetic acid (0.17 mL) was stirred at 0° C. for 10 min then at rt for 2 h. The contents were concentrated. The residue was re-dissolved with dichloromethane and concentrated. The crude was dried under vacuum and used directly.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:10]=[CH:9][C:7]([NH2:8])=[N:6][C:4]1=[O:5].Cl[CH2:12][O:13][CH2:14][O:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:23]([O:22][P:17]([CH2:16][O:15][CH2:14][O:13][CH2:12][N:3]1[CH:10]=[CH:9][C:7]([NH2:8])=[N:6][C:4]1=[O:5])([O:19][CH2:20][CH3:21])=[O:18])[CH3:24]
Reactant: CCOP(=O)(COCOCCl)OCC
Reactant: Nc1cc[nH]c(=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCOCn1ccc(N)nc1=O)OCC
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a suspension of 60% sodium hydride in mineral oil (700 mg, 17 mmol) in DMF (50 mL) was added cytosine (1.9 g, 17 mmol) and the mixture was heated at 80° C. for 2 hr under nitrogen. To the resulting yellow solution was added dropwise a solution of chloromethoxy(diethylphosphonomethoxy)methane [prepared from diethylphosphate (2.4 g, 17 mmol) and bis-(chloromethoxy)methane (12.5 g, 86 mmol)] in DMF (10 mL) under nitrogen. After stirring 15 hr at 25° C., the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (120 mL) and water (30 mL). The organic phase was washed with brine and dried (MgSO4). After removal of the solvent in vacuo, the residual oil was chromatographed on silica gel using CH2Cl2 /10% MeOH as eluent to give the title compound as a white oil: yield 1.2 g (22%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:18](=[C:6]3\[C:5](=[O:28])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N2CCN(C)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(4-methyl-piperazin-1-yl)-aniline Rf value: 0.3 (aluminium oxide, ethyl acetate) C29H30N4O3
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH2:48])[CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)C>CN(C=O)C>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][C@H:41]([NH:48][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=[CH:38][CH:39]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CCN(CC)C[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCN(CC)C[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](CC(C)C)NC(=O)N1CCCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A solution of 53 mg (0.20 mmol) of (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (Example 1, Step B) and 0.079 mL (7.2 mmol) 4-methylmorpholine in 4 mL DMF was stirred at 25° C. for 0.5 hour, and 82 mg (0.21 mmol) 0-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate was added. The resulting solution was cooled in an ice-bath and stirred 30 minutes, after which 64 mg (0.20 mmol) of (S)-3-(4-benzyloxy-phenyl)-N1,N1-diethyl-propane-1,2-diamine in 2 mL DMF was added. The resulting solution was warmed to 25° C. and stirred for 30 minutes. The mixture was then poured into 30 mL diethyl ether, and washed with 25 mL each of 5% HCl solution, brine, saturated aqueous sodium bicarbonate solution, and finally twice with brine. The mixture was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a clear, colorless oil that was purified by preparative thin-layer chromatography on a 500 μm silica gel plate using 50:50:1 ethyl acetate:hexane:methanol as eluant to give 21.2 mg (19%) of the title compound as a clear, colorless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(OCC)C>[OH:1][C@H:2]1[CH2:6][N:5]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
35.6 g (0.27 mol) of (2S,4R)-4-hydroxyproline were dissolved in 300 ml (0.60 mol) of 2N sodium hydroxide in a 750 ml sulphonation flask which was provided with stirrer, dropping funnel, thermometer and condenser. Thereupon, within 10 minutes there was added dropwise thereto a solution of 63 g (0.33 mol) of p-toluenesulphonyl chloride in 180 ml of diethyl ether. The temperature was held at 16°-20° C. by means of a water bath. After intensive stirring at room temperature for 16 hours, the reaction has finished. The aqueous phase (pH about 7) was separated and back-washed with 250 ml of diethyl ether. The ether phases were back-washed a further twice with 100 ml of deionized water each time. The combined aqueous phases were acidified to pH 2 with 25 ml of concentrated hydrochloric acid (27%) while cooling with ice at 5° C. and stirred for 1.5 hours at 5° C. The separated crystals were filtered off under suction, washed with 1 liter of deionized water and dried for 16 hours in a vacuum drying oven at 40° C./17 mbar. The resulting product (76.2 g of white crystals of melting point (142°-145° C.) was, for purification, dissolved in 200 ml of hot ethanol/water (1:4, v/v) and recrystallized while stirring and slowly cooling to 5° C. The white crystals obtained after drying (73.4 g) were again recrystallized from 150 ml of ethanol/water (1:4, v/v) as previously described and dried in a vacuum drying oven at 50° C./17 mbar. There were obtained 69.4 g (89.6%) of (2S,4R)-4-hydroxy-1-(p-tolylsulphonyl)-2-pyrrolidinecarboxylic acid of melting point 146°-147° C. [α]D20 =-87.6° (c=1 in ethanol).
Reaction SMILES: [P:1]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])([O:3]CC)=O.[C:12](Cl)(=[O:14])[CH3:13].C(Cl)C>>[C:12]([P:1](=[O:3])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: CCOP(=O)(OCC)OCC
Agent: CCCl
Product: CCOP(=O)(OCC)C(C)=O
Yield: 97.7 %

Procedure:
166.2 grams (1 mole) triethyl phosphate was added dropwise with stirring to 78.4 grams (1 mole) of acetyl chloride over a period of 30 minutes at a temperature of 30° to 35° C. maintained by cooling. Ethyl chloride was evolved. The temperature was increased to 60° C. over the next 1 hour and 15 minutes, at which time the evolution of ethyl chloride was complete. The product was distilled under vaccum yielding 176 grams of diethyl acetylphosphonate (DEAP) in 98% yield, B.P. about 80° C. at 5 mm. and having a refractive index of 1.4240 at 200° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4].[C:15]([C:17]1[CH:18]=[C:19]([S:23]([N:26]2[C@H:31]([CH3:32])[CH2:30][NH:29][CH2:28][C@@H:27]2[CH3:33])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1)#[N:16]>>[C:15]([C:17]1[CH:18]=[C:19]([S:23]([N:26]2[C@@H:31]([CH3:32])[CH2:30][N:29]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:7]=3[CH3:14])=[O:4])[CH2:28][C@H:27]2[CH3:33])(=[O:24])=[O:25])[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: Cc1ccc(C#N)cc1NC(=O)CCl
Reactant: C[C@@H]1CNC[C@H](C)N1S(=O)(=O)c1cccc(C#N)c1
Product: Cc1ccc(C#N)cc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(C#N)c2)[C@@H](C)C1

Procedure:
The title compound was prepared from the product of step (i) (0.19 g) and the product from Example 80 step (ii) (0.2 g) by the method of Example 80 step (iii) as a white solid. Yield: 0.25 g
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[C:13]3[CH:14]=[C:15]([C:17](O)=[O:18])[O:16][C:12]=3[CH:11]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[CH:5][CH:4]=1.[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:30].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNC>CN(C=O)C.O>[F:1][CH:2]([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[C:13]3[CH:14]=[C:15]([C:17]([N:29]([CH3:30])[CH3:28])=[O:18])[O:16][C:12]=3[CH:11]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C(=O)O)oc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C(=O)N(C)C)oc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a solution of 4-[4-(difluoromethyl)phenoxy]-6-(ethoxycarbonyl)-1-benzofuran-2-carboxylic acid (300 mg, 0.80 mmol) in DMF (10 mL) was added HATU (606 mg, 1.59 mmol), DIEA (515 mg, 4.0 mmol) and the solution was stirred at 0° C. for 15 min. Dimethylamine hydrochloride (97.5 mg, 1.20 mmol) was added and the solution was warmed gradually to room temperature and stirred for 14 h. Water was added to the reaction and the product was extracted with CHCl3. The combined organic layers were washed with water twice, dried over MgSO4, and concentrated. The product was purified via gradient silica gel chromatography using CHCl3/MeOH (100/0 to 95/5) to give the title compound (240 mg, 70%) as a light yellow solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 3.13 (s, 3 H) 3.32 (s, 3 H) 4.38 (q, J=7.16 Hz, 2 H) 6.64 (t, J=56.61 Hz, 1 H) 7.09 (d, J=8.48 Hz, 2 H) 7.16 (s, 1 H) 7.50 (d, J=8.48 Hz, 2 H) 7.55 (s, 1 H) 8.05 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH:13]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:20][C:21]#[N:22]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[C:20](=[CH:13]/[C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:12][N:11]=2)/[C:21]#[N:22])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cc(-c2ccc(F)cc2)on1
Product: COc1ccc(/C(C#N)=C/c2cc(-c3ccc(F)cc3)on2)cc1OC
Yield: 41 %

Procedure:
5-(4-Fluorophenyl)-isoxazole-3-carboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (185 mg) through Method A (production step 2), to thereby yield the target product (yield: 150 mg, 41%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:23]=3)[O:20][C:19](=[O:38])[NH:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:39]1[O:41][CH2:40]1.[Cl-].C[NH3+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:23]=3)[O:20][C:19](=[O:38])[N:18]2[CH2:39][CH2:40][OH:41])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc([C@H]2NC(=O)O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: C1CO1
Agent: C[NH3+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2[C@H](c3ccc(OC)c(OCc4ccccc4)c3)OC(=O)N2CCO)cc1OCc1ccccc1

Procedure:
Mixture: 100 mg of rel-(4R,5S)-4,5-bis(3'-benzyloxy-4'-methoxyphenyl)oxazolidin-2-one, 5 ml of ethylene oxide, 15 ml of tetrahydrofuran, 5 mg of methylammonium chloride.
Reaction SMILES: [O-]CC.[Na+].Cl.[CH:6]([NH2:8])=[NH:7].C(O[C:12](=[O:24])[CH:13]([C:22]#[N:23])[CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])C>C(O)C>[NH2:23][C:22]1[N:7]=[CH:6][NH:8][C:12](=[O:24])[C:13]=1[CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: N=CN
Reactant: CCOC(=O)C(C#N)CC(OCC)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(Cc1c(N)nc[nH]c1=O)OCC
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 45.2 mmol of sodium ethoxide (made in situ from sodium and absolute ethanol) in 40 mL of absolute ethanol was added formamidine hydrochloride (1.74 g, 21.5 mmol) and 2-cyano-4,4-diethoxy-butyric acid ethyl ester (2.47 g, 11 mmol, literature reference: Davoll, J., J. Chem. Soc. 131-138 (1960)). The mixture was refluxed for 6 hours, cooled to room temperature and filtered. The solid was washed with hot acetonitrile. The filtrate was neutralized with acetic acid to pH 6.5 and then evaporated to half of the volume. Ethyl acetate (50 mL) was added to the resultant filtrate. The precipitate was filtered, washed with EtOAc to give 1.6 g (66%) of 6-amino-5-(2,2-diethoxy-ethyl)-3H-pyrimidin-4-one as a white solid which was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, br, 1H, NH), 7.68 (s, 1H), 6.07 (s, br, 2H, NH2), 4.54 (t, J=6.0 Hz, 1H, CH(OCH2CH3)2), 3.53-5.62 (m, 2H, CH(OCH2CH3)2), 3.31-3.49 (m, 2H, CH(OCH2CH3)2), 2.50 (m, 2H, CH2), and 1.05 (t, J=6.93 Hz, 6H, CH(OCH2CH3)2).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6](Cl)=[O:7].[CH2:23]([OH:25])[CH3:24]>CC1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]([O:25][CH2:23][CH3:24])=[O:7]
Reactant: O=C(Cl)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 30 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetyl chloride, 9.3 parts of ethanol and 90 parts of methylbenzene was stirred overnight at room temperature. The reaction mixture was evaporated, the residue was taken up in ethanol and the latter was evaporated again. The residue was taken up in 2,2'-oxybispropane. The whole was washed with a saturate sodium hydrogen carbonate solution and with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and hexane (50:50 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 19.6 parts of ethyl α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetate as a residue (intermediate 18).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[OH-].[Na+].CN([CH:29]=[O:30])C>>[F:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:29]=[O:30])=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc3cc[nH]c3cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3c(C=O)c[nH]c3cc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Phosphorous oxychloride (185.0 mg, 1.20 mmol) was added to DMF (2 mL) at 0° C. and the reaction mixture was stirred for 15 minutes. To this solution was added 6-fluoro-5-(4-methoxy-phenyl)-1H-indole (147.0 mg, 0.61 mmol) in DMF (2 mL) and the reaction mixture was stirred at 95° C. for 20 minutes. The reaction mixture was cooled to room temperature, treated with 1N aqueous NaOH (3 mL) and heated to 100° C. for 1 minute. The reaction mixture was cooled to room temperature and filtered. The collected solids were air dried to give the title compound (106 mg, 65% yield). MS (ES+) 270.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([CH2:13][C:14]([OH:16])=[O:15])#[N:12].C([O-])(=O)C.[NH4+].N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[C:11]([C:13](=[CH:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[C:14]([OH:16])=[O:15])#[N:12]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: N#CC(=Cc1c(Cl)cccc1Cl)C(=O)O
Yield: 4.9 %

Procedure:
A stirred mixture of 2,6-dichlorobenzaldehyde (609 mmol, 106.5 g), cyanoacetic acid (609 mmol, 51.8 g), ammonium acetate (122 mmol, 9.38 g), pyridine (1065 mmol, 86 ml, 84 g) and toluene (468 ml) was stirred at reflux using a Dean-Stark apparatus until one equivalent of water was collected (NB Oil bath temperature should not exceed 120° C. to avoid decarboxylation at this stage—lag Dean-Stark well). The reaction mixture was allowed to cool and the solid precipitate filtered and stirred with 10% aqueous HCl. The solid was again collected by filtering to afford pure 2-cyano-3-(2,6-dichlorophenyl)acrylic acid (7.21 g). The filtrate was concentrated in vacuo to give the crude 2-cyano-3-(2,6-dichlorophenyl)acrylic acid (˜135 g). Recrystallisation from toluene afforded pure 2-cyano-3-(2,6-dichlorophenyl)acrylic acid (101 g).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]([C@@H:17]3[CH2:21][C@H:20]([CH:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)[CH2:19][N:18]3C(OC(C)(C)C)=O)=[N:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:4].[ClH:39]>O1CCOCC1>[ClH:39].[CH3:31][S:28]([N:25]1[CH2:24][CH2:23][CH:22]([C@@H:20]2[CH2:19][NH:18][C@H:17]([C:15]3[NH:16][C:12]([C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])=[CH:11][CH:10]=4)=[CH:13][N:14]=3)[CH2:21]2)[CH2:27][CH2:26]1)(=[O:29])=[O:30]
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)OC(C)(C)C)[nH]2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of the compound prepared in Example 64 (0.447 g, 0.811 mmol) in 1,4-dioxane was added 4 M HCl in 1,4-dioxane (5.0 mL) and the reaction mixture stirred at room temperature for 1 h. The mixture was concentrated and the residue was purified by trituration with 1:1 dichloromethane/hexanes to afford the title compound (0.46 g, 99%) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH2:11][CH2:12][N:13]=1.C(N(C(C)C)CC)(C)C.[C:25](Cl)(Cl)=[S:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:15]=[C:25]=[S:26])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH2:11][CH2:12][N:13]=1
Reactant: CN1CCN=C1Sc1ccc(N)cc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN=C1Sc1ccc(N=C=S)cc1Cl
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a stirred solution of 3-chloro-4-(1-methyl-4,5-dihydro-1H-imidazol-2-ylsulfanyl)-phenylamine (5.0 g, 21 mmol) and diisopropylethylamine (5.37 g, 41.6 mmol) in dry tetrahydrofuran at 0° C. under N2 inert atmosphere, thiophosgene (2.39 g, 21 mmol) in tetrahydrofuran was added dropwise and stirred for 20 minutes. When the reaction was completed, the reaction mixture was concentrated at room temperature and taken in dichloromethane (100 mL), washed with water (2×50 mL) and dried over anhydrous MgSO4 to get the product as a brown solid (5.8 g, 99%). TLC: pet ether/ethyl acetate (8/2) Rf-0.4. LCMS (method A): mass found (M+H+, 282.0), Rt (min): 3.43, area % 71.5 (max); 1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, J=2.16 Hz, 1H), 7.57 (s, 1H), 7.31 (m, 1H), 7.28 (m, 1H), 6.43 (d, J=8.56 Hz, 1H), 3.61 (s, 3H).
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]O)([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[BrH:38].S(=O)(=O)(O)O>O>[C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Br:38])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 29.0 g (0.049) of CF3(CF2)7(CH2)10CH2OH and 250 mL of 48 percent by weight aqueous hydrobromic acid was slowly added 25 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 18 hr and poured into 1 liter of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solution was concentrated to a dark liquid, which was eluted through 3 inches (8 cm) of silica with hexanes. Concentration of the eluent yielded 20.2 g of CF3(CF2)7(CH2)10CH2Br as a nearly white solid, which was used without further purification.
Reaction SMILES: [N:1]([C:3]1[CH:7]=[N:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[NH2:14])=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>CCO>[C:8]1([N:5]2[C:4]([NH2:14])=[C:3]([NH2:1])[CH:7]=[N:6]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1c(N=O)cnn1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnn(-c2ccccc2)c1N
Temperature: 60 °C
Yield: 27.1 %

Procedure:
To a suspension of 4-nitroso-2-phenyl-2H-pyrazol-3-ylamine (100 mg, 0.53 mmol) in EtOH (1 mL) is added SnCl3-2H2O (240 mg, 1.06 mmol). The mixture is then heated to 60° C. for 30 min. After cooling down the mixture, it is poured into a mixture of EtOAc (20 mL) and saturated aqueous NaHCO3 solution (20 mL). The solid is removed by filtration through Celite. The filtrate is put into separatory funnel to collect the organic layer, which is washed with brine and dried over MgSO4. After filtering off the drying agent, the filtrate is concentrated to provide the crude 2-phenyl-2H-pyrazole-3,4-diamine (˜25 mg) and used immediately for next step.