Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][CH2:10][CH2:11][CH2:12][NH2:13].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1)#[N:15]>C(Cl)Cl>[Cl:9][CH2:10][CH2:11][CH2:12][NH:13][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=1)=[O:24]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: NCCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)NCCCCl)cc1
Yield: 53.7 %

Procedure:
Triethylamine (13.8 g; 137 mmole) was slowly added to a mixture of 3-chloropropylamine hydrochloride (17.8 g; 137 mmole), 4-cyanophenyl isocyanate (19.7 g; 137 mmole), and methylene chloride (200 ml). The resulting solution was stirred until the mild exothermic reaction had subsided and the solvent was removed in vacuo. The product was dissolved in ether, washed with water, dried, and part of the ether removed. The colorless crystals which precipitated out were filtered and dried to give 1-(3-chloropropyl)-3-(4-cyanophenyl)urea (17.5 g; 54% yield). A small portion of the product was recrystallized from water/acetone to give pure product, m.p. 95°-97° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)([CH3:3])[CH3:2].Br[CH2:43][CH2:44][OH:45].C(N(CC)CC)C>>[CH:1]([O:4][C:5]1[C:6]([NH:18][C:19]2[N:24]=[C:23]3[NH:25][N:26]=[C:27]([CH3:28])[C:22]3=[C:21]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=2)=[CH:7][C:8]([CH3:17])=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:43][CH2:44][OH:45])[CH2:13][CH2:12]2)[CH:10]=1)([CH3:3])[CH3:2]
Reactant: OCCBr
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(CCO)CC1
Temperature: 100 °C

Procedure:
The mixture of N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (20 mg, 0.035 mmol), 2-bromoethanol (0.1 N in DMF, 0.070 mmol, 0.70 mL) and triethylamine (0.1 N in DMF, 0.18 mmol, 1.75 mL) was heated at 100° C. for 10 min. The resulting reaction mixture was purified by RP-HPLC to afford 2-(4-(5-isopropoxy-4-(4-(2-(isopropylsulfonyl)phenylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenyl)piperidin-1-yl)ethanol. MS (ES+): 622.3 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30](=[O:42])[NH:31][CH:32]([C:34]1[S:35][CH:36]=[C:37]([C:39]([OH:41])=O)[N:38]=1)[CH3:33])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C.[NH:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1>CN(C=O)C>[C:25]([O:29][C:30](=[O:42])[NH:31][CH:32]([C:34]1[S:35][CH:36]=[C:37]([C:39]([N:52]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:55][CH2:54][CH2:53]2)=[O:41])[N:38]=1)[CH3:33])([CH3:26])([CH3:27])[CH3:28]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(NC(=O)OC(C)(C)C)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)OC(C)(C)C)c1nc(C(=O)N2CCCc3ccccc32)cs1
Reaction time: 18 h
Yield: 63.6 %

Procedure:
HBTU (306 mg, 0.81 mmol) was added to a solution of tert-butyl(1-(4-carboxythiazol-2-yl)ethyl)carbamate (200 mg, 0.73 mmol) in DMF (5 ml) at room temperature. Diisopropylethylamine (0.26 ml, 190 mg, 1.5 mmol) and 1,2,3,4-tetrahydroquinoline (0.11 ml, 117 mg, 0.88 mmol) were added and the mixture was stirred for 18 h. The mixture was partitioned between ethyl acetate and 1N hydrochloric acid and separated. The organic layer was washed with water and brine, dried and reduced. Chromatography (45% EtOAc/55% hexanes) afforded tert-butyl(1-(4-(1,2,3,4-tetrahydroquinoline-1-carbonyl) thiazol-2-yl)ethyl)carbamate (180 mg, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=[C:4]2[C:3]=1[NH:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][NH:13][C:3]1[C:4]2[N:5]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:23](=[O:25])[CH3:24]
Reactant: Cc1cccc(C)c1CNc1c(N)ccn2c(C)c(C)nc12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccn2c(C)c(C)nc2c1NCc1c(C)cccc1C
Temperature: 25 °C

Procedure:
7-amino-2,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[1,2-a]pyridine (example 77) (0.16 g, 0.53 mmol) was dissolved in methylene chloride (5 ml) and acetic anhydride (60 mg) was added. The mixture was stirred over night at ambient temperature. A small amount of triethylamine was added and the solvent was removed under reduced pressure. Chromatography first with methylene chloride:methanol, 95:5 and secondly with methylene chloride:ethyl acetate, 50:50 gave after trituration with diethyl ether 87 mg (47%) as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([C:13]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[O:12])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH3:10].[NH3:25]>CN1C(=O)CCC1.O.[Cu-]=O>[NH2:25][C:2]1[CH:3]=[C:4]([C:11]([C:13]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[O:12])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1ncc(C(=O)c2cn(C(C)C)c3ncncc23)cc1Br
Reactant: N
Agent: O=[Cu-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1ncc(C(=O)c2cn(C(C)C)c3ncncc23)cc1N
Temperature: 130 °C
Yield: 24 %

Procedure:
Copper(I) oxide (38.6 mg, 0.27 mmol) was added to (5-Bromo-6-ethoxy-pyridin3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 241, 350 mg, 0.89 mmol) in concentrated ammonia solution (6 mL) and NMP (1 mL). The mixture was heated in a sealed vessel at 130° C. for 17 hours. The reaction mixture was cooled to room temperature and diluted with water (10 ml). It was extracted with 20% i-PrOH in DCM (6×50 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (MeOH:DCM 5:95) to afford the title compound as a yellow solid in 24% yield, 70 mg. LCMS (system 10): Rt=2.99 min; m/z 326 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C:10](=[O:11])[O:9][C:7](=O)[CH2:6]1)(=[O:3])[CH3:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CC(C)=O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:18]2[C:7](=[O:9])[CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C:10]2=[O:11])=[CH:15][CH:14]=1
Reactant: CC(=O)N[C@@H]1CC(=O)OC1=O
Reactant: NCc1ccc(F)cc1
Solvent: CC(C)=O
Product: CC(=O)N[C@@H]1CC(=O)N(Cc2ccc(F)cc2)C1=O
Temperature: 100 °C
Yield: 86 %

Procedure:
Following the method of Witiak et al. (J. Med. Chem., 1971, 14(1), 24-30), N-acetyl-D-aspartic acid anhydride (2.19 g, 13.9 mmol) and para-fluorobenzylamine (1.74 g, 13.9 mmol) in acetone (12 mL) were heated together in a sealed tube at 100° C. for 1 h. The solvent was then removed under reduced pressure. Acetic anhydride (15 mL) was added to the residue and the mixture heated 50 min. at 100° C. The solvent was removed under reduced pressure and the residue purified by flash column chromatography (silica, 10% methanol in dichloromethane) to give the product as a foam (3.16 g, 85%). HPLC retention time 1.94 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>C(C(C)=O)C>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])[CH:19]=[CH2:18]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.5 g of 2-hydroxyphenylsulfonamide, 5.5 g of potassium carbonate and 1.7 ml of allyl bromide in 100 ml of methyl ethyl ketone is stirred, under nitrogen, for 1 hour at reflux temperature. The reaction mixture is cooled to room temperature, filtered, and evaporated to dryness. One recrystallisation from ethyl acetate yields 3.27 g of 2-allyloxyphenylsulfonamide with a melting point of 104°-105° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:14].N1C(C)=CC=CC=1C>C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7]([OH:14])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: O=S1CCC2(CC1)OCCO2
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: OC1CC2(CCS1)OCCO2
Temperature: 150 °C

Procedure:
A mixture of 0.88 g of product from Example 393, 5.0 ml of acetic anhydrideand 2.0 ml of lutidine is heated at 110°-115° C. for 2.5 hours, followed by increasing the temperature to 150° C. and then heated for 3 hours. The reaction mixture is diluted with ethyl acetate, washed 2 X with 1N hydrochloric acid, water, saturated sodium chloride, dried and concentrated in vacuo. The residue is dissolved in methylene chloride, filtered through a pad of hydrous magnesium silicate and reconcentrated in vacuo to give 0.569 g of the desired product.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].Cl[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:37]([F:40])([F:39])[F:38])[CH:26]=[C:27]([C:28]3[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=3)[C:21]=2[N:20]=1>>[CH3:1][NH:2][S:3]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:19]3[NH:20][C:21]4[C:27]([C:28]5[CH:29]=[C:30]([F:36])[C:31]([F:35])=[C:32]([F:34])[CH:33]=5)=[CH:26][C:25]([C:37]([F:40])([F:38])[F:39])=[CH:24][C:22]=4[N:23]=3)[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: CNS(=O)(=O)c1cccnc1N1CCNCC1
Product: CNS(=O)(=O)c1cccnc1N1CCN(c2nc3cc(C(F)(F)F)cc(-c4cc(F)c(F)c(F)c4)c3[nH]2)CC1

Procedure:
The piperazine from step (a) above (128 mg, 0.5 mmol) reacted with 2-chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (140 mg, 0.4 mmol, Example 51b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 571 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.Cl.[C:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:10]([O:14][C:15](=[O:19])[C@@H:16]([NH:17][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:8])[CH3:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ncc[nH]1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (0.179) in N,N-dimethylformamide (DMF) (3 mL) was added alanine tert-butyl ester hydrochloride (0.22 g), diisopropylethyl amine (0.27 mL) and HOBT (0.41 g) before cooling to 0° C. and the reaction mixture was then treated with EDC HCl (0.32 g). The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 18 hrs before being diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and concentrated at reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford the sub-title compound as a colourless oil (0.263 g, 73%): 1H NMR 400 MHz CDCl3 1.50 (9H, s), 1.51 (3H, d, J 7.2), 3.70 (1H, m), 7.28 (2H, s), 7.78 (1H, d, J 7.6), 11.49 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:7]=1)[C:8]([C:9](=[CH:20][N:21]([CH3:23])[CH3:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15]
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1OC
Temperature: 90 °C
Yield: 79.8 %

Procedure:
A stirred mixture of ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (10.02 mmol, 1 eq) and 1,1-dimethoxy-N,N-dimethylmethanamine (3.0 mL, 22 mmol, 2.2 eq) was heated at 90° C. for 2 hours. After evaporation of excess 1,1-dimethoxy-N,N-dimethylmethanamine, the crude product was purified by flash chromatography on silica gel (0 to 80% ethyl acetate in dichloromethane) to yield 2.493 g (80%) of ethyl 2-(5-chloro-2-methoxybenzoyl)-3-(dimethylamino)acrylate. LCMS (ESI) m+H=312.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH2:9]([NH2:11])[CH3:10]>CCOCC>[CH2:9]([NH:11][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH3:10]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCN
Solvent: CCOCC
Product: CCNS(=O)(=O)CCCCl
Yield: 100 %

Procedure:
To a solution of 3-chloropropylsulfonyl chloride 1(6.1 g,34.5mmol) in ether (25 ml) was added dropwise ethylamine (a 70% aqueous solution,4.4 g,68.3 mmol) with stirring under ice-cooling over 15 minutes. The resultant mixture was stirred for one hour at room temperature and concentrated in vacuo. Benzene (100 ml) was added to the residue and the solvent was distilled off in vacuo. To the residue was added ether (150 ml) and filtered to remove the insoluble material. The liltrate was distilled in vacuo to remove ether and 6.96 g (yield, about 100%) of crude N-ethyl-3-chloro propylsulfonamide (intermediate 3a) was obtained as colorless crystals (m.p.=30°-32° C.). To a solution of this intermediate 3a (6.96 g,34.5 mmol) in THF (50 ml) was slowly added sodium hydride (60% in oil,1.52 g,38.0 mmol) with stirring under ice-cooling over 15 minutes. The reaction mixture was stirred for another 30 minutes at room temperature. After the addition of ether (50 ml), the mixture was filtered to remove insoluble material and the filtrate was distilled in vacuo to remove solvent and to give 4.93 g (96%) of the objective compound 4a as a pale yellow oil.
Reaction SMILES: C=C.C(O)(=O)C.[CH2:7]=[CH:8][CH2:9][CH3:10].[F:11][C:12]([F:17])([F:16])[C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[F:11][C:12]([F:17])([F:16])[C:13]([O:15][CH:8]([CH2:9][CH3:10])[CH3:7])=[O:14]
Reactant: C=CCC
Reactant: O=C(O)C(F)(F)F
Agent: C=C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(C)OC(=O)C(F)(F)F

Procedure:
In addition, the esterification of olefins with carboxylic acids and subsequent ester hydrolysis of the alkyl esters formed to the corresponding alcohol with recovery of the acid is known. For instance, U.S. Pat. No. 4,384,148 describes the reaction of ethene with acetic acid to give ethyl acetate in an autoclave. The subsequent hydrolysis of the ethyl acetate removed by distillation with water in a molar ratio of 1:5 in an autoclave affords a mixture comprising ethyl acetate, ethanol and diethyl ether. GB 2 238 539 discloses the two-stage hydration of 1-butene by reaction with trifluoroacetic acid to give 2-butyl trifluoroacetate in the presence of a highly acidic ion exchange resin and subsequent hydrolysis of the ester to give 2-butanol.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11].O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)CCCCCBr
Yield: 95.3 %

Procedure:
A solution of 6-bromohexanoyl chloride (100 g, 468 mmol) in 350 ml of tetrahydrofuran was poured into a solution of diethylamine (1.08 moles, 79 g, 112 ml) in 800 ml of rapidly stirring water. The mixture was then extracted with 2×200 ml of CH2C12 and the pooled extracts were washed with 250 ml of brine. Drying over Na2SO4 and concentration under reduced pressure afforded 111.6 g (446 mmol, 100% yield) of product as a pale yellow oil: 1H NMR (Me2SO-d6, 300 MHz) δ 3.5 (t, J=6.7 Hz, 2 H ), 3.2°-3.3 (m, 4 H ), 2.3 (t, J=7.5 Hz, 2 H ), 1.8 (m, 2 H ), 1.3-1.6 (m, 4 H ), 1.1 (t, J=7.1 Hz, 3 H ), 0.99 (t, J=7.0 Hz, 3 H ).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:11]1[C:18](Cl)=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13]>CCOCC.C1C=CC=CC=1>[Cl:13][C:12]1[N:14]=[C:15]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:17]=[C:18]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Brc1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reaction time: 8 h
Yield: 134.2 %

Procedure:
The procedure used was based on the method of Jones et al, AD 229453, Sept. 1959. A stirred mixture of magnesium turnings (24.3 g, 0.935 mol) and a crystal of iodine in ether (150 ml), was added a solution of bromobenzene (155.3 g, 0.985 mol) in ether (100 ml) under a nitrogen atmosphere over a period of 3.75 hr at such a rate as to maintain a gentle reflux. Thereafter, the mixture was refluxed for 2.5 hr. The Grignard reagent thus prepared was then cooled and transferred to an addition funnel and added with stirring to a solution of cyanuric chloride (70 g, 0.38 mol) in benzene (500 ml) at 4°-15° C. (ice bath cooling) over a period of 1.25 hr. After stirring overnight the mixture was refluxed for 4 hr, cooled, and filtered. The filtrate was evaporated to dryness using a Rinco evaporator yielding 136.5 g of crude product mixture. This mixture was distilled in vacuo at 0.007 mm. The desired product, bp 140°-152° C., 63.5 g(62% yield), was crystallized three times from heptane yielding pure 2-chloro-4,6-diphenyl-s-triazine, 46.1 g (45% yield), mp 136°-138° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:18][CH2:17][CH:14]1[CH2:16][CH2:15]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1CC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Nitrophenyl chloroformate (0.56 g, 2.8 mmol) was added to a mixture of cyclopropyl carbinol (0.20 g, 2.8 mmol) and triethylamine (0.58 mL, 4.2 mmol) in methylene chloride (5 mL). The mixture was stirred at r.t. for 2 h. After removal of solvent, the residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:10])[C:7]=1[CH:8]=[O:9].[H-].[Na+].I[CH2:14][C:15]([NH2:17])=[O:16]>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:10][CH2:14][C:15]([NH2:17])=[O:16]
Reactant: O=Cc1c(O)cccc1Cl
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)COc1cccc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
3.1 1.0 g of 6-chlorosalicylaldehyde 9 is dissolved in 30 ml of DMF, 0.26 g of NaH (60% suspension in paraffin oil) is carefully added with cooling, and the mixture is stirred at RT for 45 min. 1.30 g of 2-iodoacetamide 2 are then added, and the reaction mixture is stirred overnight. The mixture is subsequently subjected to conventional work-up, giving 1.28 g (90%) of 2-(3-chloro-2-formylphenoxy)acetamide 10; MS-EI (M+)=213.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:27])([F:26])[C-:11]([C:22]([F:25])([F:24])[F:23])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[F:20][C:12]([F:21])([C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])[C:11]([C:22]([F:25])([F:24])[F:23])([C:10]([F:27])([F:26])[F:9])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 66 %

Procedure:
Benzyl bromide, 4.77 g (0.028 mol), was added dropwise to a solution of 15.0 g (0.031 mol) of tris(dimethylamino)sulfonium 1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-2-pentanide in 50 mL of acetonitrile at 25°, and the reaction mixture was stirred overnight and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were dried (MgSO4) and then distilled to give 7.5 g (66%) of 3,3,4,4,5,5,5-heptafluoro-2,2-bis(trifluoromethyl)pentylbenzene as a colorless liquid: b.p. 62°-63° (5 mm); 19F NMR (CDCl3) δ -62.7 ppm (t,t 6F), -80.7 ppm (t, 3F), -106.3 ppm (m, 2F) and -123.3 ppm (2F); 1H NMR (CDCl3) δ 3.52 ppm (s, 2H) and 7.27 ppm (s, 5H). Anal. Calcd. for C13H7F13 : C, 38.07; H, 1.72; F, 60.21. Found: C, 37.82; H, 1.73; F, 60.42.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH3:17][O:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.CN(C=O)C>CCOC(C)=O>[CH3:17][O:18][CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=2)[CH2:20]1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: COC1CCNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1CCN(c2nc(C(F)(F)F)ccc2C=CC(=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.2 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0.198 mmol) in 3-methoxy-pyrrolidine (40 mg, 0.396 mmol) was added DMF (1.0 ml). The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographed to yield the 3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (59 mg, 98%).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][Cl:5].[Cl:6][CH2:7][CH2:8][OH:9]>ClCCCl>[Cl:6][CH2:7][CH:8]([OH:9])[CH2:1][O:3][CH2:2][CH2:4][Cl:5]
Reactant: OCCCl
Reactant: ClC[C@H]1CO1
Solvent: ClCCCl
Product: OC(CCl)COCCCl
Temperature: 45 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
step 1—To a solution of R-(−)-epichlorohydrin (7 mL, 89.27 mmol) and DCE (280 mL) was added 2-chloroethanol (6.3 mL, 93.74 mmol) followed by a solution of BF3 Et2O (1.1 mL, 8.927 mmol) and DCE (20 mL). The pale yellow solution was stirred at 45° C. for 2 h. The reaction mixture was allowed to cool to RT, evaporated and dried in vacuo overnight (yield>95%) to afford 1-chloro-3-(2-chloro-ethoxy)-propan-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O:11][CH2:12][CH:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12]([OH:11])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:19]=[N:5]2)=[CH:7][CH:8]=1
Reactant: CCOCC(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(F)c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(F)ccc2c1O
Temperature: 100 °C
Yield: 67.6 %

Procedure:
Under a nitrogen atmosphere, 3-fluoroaniline (50.0 g, 0.45 mol) and diethyl ethoxymethylmalonate (91 mL, 0.45 mol) were combined and heated at 100° C. for 3 hours. The reaction was allowed to cool to ambient temperature and it solidified. Dowtherm A (200 mL) was added and the reaction mixture was heated at 240° C. for 4 hours. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, washed with hexane and then dried in a vacuum oven to provide 71.5 g of ethyl 7-fluoro-4-hydroxy-3-quinolinecarboxylate.