Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>O1CCCC1>[C:21]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(NC(=O)c2ccncc2)nc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a mixture of ethyl 2-amino-4-methylthiazole-5-carboxylate (5.70 g, 30.60 mmol) and triethylamine (10.0 mL, 71.80 mmol) in tetrahydrofuran (100 mL) was added isonicotinoyl chloride hydrochloride (6.00 g, 32.00 mmol). The reaction mixture was stirred at ambient temperature for 2 days. The solvent was removed by evaporation and the resulting white solid was washed sequentially with water, 10% sodium bicarbonate solution, and water, then dried to afford the title compound in 90% yield (8.10 g); 1H NMR (DMSO-d6, 300 MHz) δ 8.77 (d, J=6.0 Hz, 2H), 8.77 (d, J=6.0 Hz, 2H), 4.23 (q, J=7.2 Hz, 2H), 2.34 (s, 3H). 1.27 (t, J=7.2 Hz, 3H); MS (ES+) m/z 292.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:17][N:18]([CH3:30])[CH2:19][CH2:20][N:21]([CH3:29])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([N:21]([CH2:20][CH2:19][N:18]([CH3:30])[CH3:17])[CH3:29])=[CH:27][CH:26]=1)=[O:8]
Reactant: CN(C)CCN(C)c1ccc(N)cc1
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Product: CN(C)CCN(C)c1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
The product was prepared according to general working method I from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and N-(2-dimethylamino-ethyl)-N-methylbenzene-1,4-diamine (141b).
Reaction SMILES: C(OC([NH:8][C:9]([NH:29][C:30](OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1C1OCCO1)=O)(C)(C)C.[ClH:37]>C(O)C>[ClH:37].[ClH:37].[NH2:8][C:9]1[N:29]=[CH:30][C:12]2[C:11](=[CH:16][C:15]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[N:10]=1
Reactant: Cc1ccnc(-c2ccc(C3OCCO3)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc(-c2ccc3cnc(N)nc3c2)c1
Reaction time: 6 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(2-(1,3-dioxolan-2-yl)-5-(4-methylpyridin-2-yl)phenyl)guanidine (190 mg) in ethanol (2 ml) was added hydrochloric acid (36%, 1 ml), and the mixture was stirred for 6 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (50 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 2-amino-7-(4-methylpyridin-2-yl)quinazoline dihydrochloride (92 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:2].Br[C:14]1[CH:15]=[CH:16][C:17]2[O:21][CH2:20][CH2:19][C:18]=2[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:11][CH3:12])=[CH:5][CH:6]=3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: Brc1ccc2c(c1)CCO2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(Nc2ccc3c(c2)CCO3)cc1
Temperature: 80 °C
Yield: 87 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added N,N-diethyl-1,4-phenylenediamine (3.35 grams, 20.4 mmoles), 5-bromo-2,3-dihydrobenzofuran (3.4 grams, 17.1 mmoles), tris(dibenzylideneacetone)dipalladium (0) (0.39 grams, 0.43 mmoles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (2.1 grams, 3.4 mmoles), sodium tert-butoxide (0.71 grams, 1.28 mmoles) and anhydrous toluene (90 mL). The contents of the flask were heated to 80° C. for two days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (200 mL). The combined organic layers were concentrated in vacuo to yield a dark blue oil. The oil was chromatographed on silica gel, eluting with a hexane/ethyl acetate gradient to afford 4.2 grams of the desired product as a brown oil. 1H NMR (CDCl3) δ 6.6-7.0 (m, 7H), 5.15 (bs, 1H), 4.5 (t, 2H), 3.05-3.2 (m, 6H), 1.1 (t, 6H).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].C(OC(S)=S)C.[K].[OH-].[Na+].[Cl:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>O>[Cl:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:6][OH:7])=[O:21]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: NO
Agent: CCOC(=S)S
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: O
Product: CC(C)(CCl)C(=O)NO

Procedure:
A two liter resin kettle was equipped with two inlet tubes, a thermometer, stirring paddle, pH probes and a cooling jacket. A solution of hydroxylamine sulfate (264 g, 1.61 moles) and ethyl xanthic acid, potassium salt (0.5 g, 0.003 mole) in 700 ml of water was added to the kettle and the stirrer started. One of the inlet tubes was connected through a metering pump to a reservoir containing an aqueous 50% sodium hydroxide solution. The addition of base to the reaction mixture was regulated by an electronic pH meter/controller connected to the pump and pH probe and set for pH of 7.2. Aqueous base was delivered to the reactor until that pH was attained. The other inlet tube was connected through a metering pump to a reservoir containing 3-chloro-2,2-dimethylpropionyl chloride (286 g, 1.84 moles). The acid chloride was added to the reaction mixture during a period of 2.5 hours at a temperatue of 28° C., maintaining a pH of 7.2 by simultaneous addition of base. The reaction slurry was then vacuum filtered and the filter cake dried. The dried filter cake weighted 293 g. An aliquot of the filter cake was dissolved in a mixture of DMF and toluene. Analysis of the extract using GLPC indicated the yield of 3-chloro-N-hydroxy-2,2-dimethylpropanamide, based on the amount of 3-chloro-2,2-dimethylpropionyl chloride, was 85%.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH3:20])[C:12]([S:21]([NH:24][C:25](=[O:33])[NH:26][C:27]3[S:28][C:29]([Br:32])=[CH:30][N:31]=3)(=[O:23])=[O:22])=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>>[Br:32][C:29]1[S:28][C:27]([NH:26][C:25]([NH:24][S:21]([C:12]2[C:13]3[C:18](=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)(=[O:22])=[O:23])=[O:33])=[N:31][CH:30]=1
Reactant: COc1cccc2c(S(=O)(=O)NC(=O)Nc3ncc(Br)s3)cn(S(=O)(=O)c3ccccc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc2c(S(=O)(=O)NC(=O)Nc3ncc(Br)s3)c[nH]c12
Temperature: 70 °C

Procedure:
A suspension of 1-(benzenesulfonyl)-N-[(5-bromo-1,3-thiazol-2-yl)carbamoyl]-7-methoxy-1H-indole-3-sulfonamide (cf. Ex. 43iii), 0.072 g) in 1 n sodium hydroxide (5 mL) was heated to 70° C. for 4 h. The reaction mixture was cooled down and acidified with 1N HCl to pH 4-5. The precipitate was filtered off, washed with water and dried to obtain the title compound as light brown solid. MS (ISN): m/e 429.3, 431.3 (M−H)−
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:5]([O:4][C:2]([NH:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCC(C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NC1CCC(C(=O)O)CC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
Benzyl chloroformate (2.2 mL, 15.4 mmol) was added to a solution of 4-amino-cyclohexanecarboxylic acid (2 g, 14.0 mmol) in a mixture of 1,4-dioxane (5 mL) and saturated sodium bicarbonate aqueous solution (5 mL). The mixture was stirred at 0° C. for 3 hours. Dioxane was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate solution was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2.3 g (59%) of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid as yellow oil. MS (ESP−) m/z 276.39 (M−1). 1H NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 5.09 (s, 2H), 2.24 (m, 1H), 2.04 (m, 2H), 1.83 (m, 2H), 1.44 (m, 3H), 0.97 (m, 2H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.O.C[N:21]([CH:23]=[O:24])C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:23]([C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1)(=[O:24])[NH2:21]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Cn1nc(I)c2ccncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1nc(C(N)=O)c2ccncc21
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 2-(3-iodo-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (3.76 g, 10.5 mmol), Zn(CN)2 (1.35 g, 11.5 mmol), Pd(dppf)Cl2 (855 mg, 1.05 mmol), Pd2(dba)3 (959 mg, 1.05 mmol), water (4 mL) and DMF (30 mL) was stirred at 100° C. for 16 h under argon. The reaction mixture was diluted with EtOAc and then was successively washed with water, sat. aq. NaHCO3 (2×) and brine, dried (Phase separator) and concentrated under vacuum. The residual oil was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:1 then 100% EtOAc). MS (LC/MS): 259.0 [M+H]+; tR (HPLC conditions k): 3.10 min. Further elution of the column with CH2Cl2/MeOH 8:2 and subsequent purification by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40×250 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) afforded tert-butyl 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate as a side-product. MS (LC/MS): 277.0 [M+H]+; tR (HPLC conditions k): 2.39 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([CH3:15])[C:11]=3[CH:16]=2)=[C:4]([CH2:19]Cl)[CH:3]=1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([CH3:15])[C:11]=3[CH:16]=2)=[C:4]([CH2:19][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:3]=1
Reactant: Cn1nnc2ccc(Cc3ccc(Cl)cc3CCl)cc21
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1nnc2ccc(Cc3ccc(Cl)cc3Cn3cncn3)cc21
Yield: 51.8 %

Procedure:
A suspension of 6-[4-chloro-2-(chloromethyl)benzyl]-1-methyl-1H-benzotriazole (0.11 g) from Example 78, 1H-1,2,4-triazole (37 mg) and cesium carbonate (0.18 g) in acetonitrile (2 ml) was refluxed for 30 minutes. After removal of the solvent, the resulting residue was purified by chromatography on a silica gel column (methylene chloride:methanol=99:1), to give the title compound (63mg; 52%). The purity of the compound was 96.7% by HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[CH3:28][NH2:29]>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:29][CH3:28])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: CN
Solvent: O
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1CCN2c1ccccc1C
Temperature: 180 °C

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(392 mg, 1.0 mmol) was dissolved in aqueous solution of methylamine(40%, 5.0 ml) and the reaction mixture was refluxed at 180° C. for 15 hours in the pressure tube. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:1) to obtain 290 mg of desired compound as solid in 75% of yield.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].CN(N=O)/C(/N)=N/[N+]([O-])=O.[OH-].[K+].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>CCOCC>[N+:1](=[CH:3][C:23]([C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=1)=[O:24])=[N-:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(N=O)/C(N)=N/[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
The ethereal diazomethane solution [prepared by adding 12.5 g n-methyl-n-nitro-n-nitroso guanidine to potassium hydroxide (50%, 20 ml) and ether (200 ml) at 0°, stirring for 1 hr, and decanting the ether layer; 65% presumed yield] is treated with TEA (7.7 ml) at 0°, then dropwise with p-nitrobenzoyl chloride (10.21 ml) in ether (25 ml). After stirring for 19 hrs, the reaction is filtered through celite and concentrated to give the title compound.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[NH:47][C:30]4[N:31]=[CH:32][N:33]=[C:34]([O:35][C:36]5[C:37]([F:46])=[C:38]6[C:42](=[CH:43][CH:44]=5)[NH:41][C:40]([CH3:45])=[CH:39]6)[C:29]=4[CH:28]=3)=[CH:23][CH:22]=2)=O)[CH2:15][CH2:14]1)[CH3:12].[NH4+].[Cl-].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O>[CH2:11]([N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[NH:47][C:30]4[N:31]=[CH:32][N:33]=[C:34]([O:35][C:36]5[C:37]([F:46])=[C:38]6[C:42](=[CH:43][CH:44]=5)[NH:41][C:40]([CH3:45])=[CH:39]6)[C:29]=4[CH:28]=3)=[CH:23][CH:22]=2)[CH2:17][CH2:18]1)[CH3:12]
Reactant: CCN1CCN(C(=O)c2ccc(-c3cc4c(Oc5ccc6[nH]c(C)cc6c5F)ncnc4[nH]3)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCN(Cc2ccc(-c3cc4c(Oc5ccc6[nH]c(C)cc6c5F)ncnc4[nH]3)cc2)CC1
Reaction time: 3 h

Procedure:
1.56 ml of diisobutyl-aluminium hydride (1 M in THF) are added to a solution of 130 mg (0.26 mMol) of (4-ethyl-piperazin-1-yl)-{4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}methanone in 13 ml of THF at −15° C. under a N2-atmosphere. After 3 h, 4 ml of EtOAc are added to the solution, followed by 0.2 ml of a saturated solution of NH4Cl in water. After adding solid Na2SO4, the reaction mixture is filtered through Celite. The filtrate is concentrated together with 3 g of SiO2. The resulting powder is put on top of a chromatography column (SiO2) and then eluted with EtOAc/methanol 4:1 and finally EtOAc/methanol/NEt3 80:20:1, yielding the title compound; HPLC (conditions see Examples 67-78) tR=10.5 min; MS-ES+: (M+H)+=485.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:13](=O)[O:12][C:10](=O)[C:9]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:8]23)=[CH:4][CH:3]=1.CSC1[NH:24][CH2:25][CH2:26][N:27]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:8]3[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:12])[N:24]3[CH2:25][CH2:26][N:27]=[C:13]23)=[CH:19][CH:20]=1
Reactant: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Reactant: CSC1=NCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1c2ccccc2N(Cc2ccc(F)cc2)C2=NCCN12
Reaction time: 4 h

Procedure:
A solution of 5.4 g. of N-(p-fluorobenzyl)isatoic anhydride, 2.5 g. of 2-methylmercapto-imidazoline and one pellet (about 100 mg.) sodium hydroxide in 75 ml. of dioxane is refluxed with stirring for 4 hours. The resulting mixture is evaporated to dryness, the residue dissolved in methylene chloride, washed with water and extracted twice with 1N hydrochloric acid. The combined aqueous extracts are washed with methylene chloride and then with diethyl ether and made basic with sodium bicarbonate. The resulting precipitate is filtered off, washed thoroughly with water, dried by suction, dissolved in methylene chloride, dried with sodium sulfate, treated with charcoal and the methylene chloride exchanged for methanol to crystallize 10-(4'-fluorobenzyl)-2,3-dihydro-imidazo[2,1-b]quinazolin-5(10H)-one, m.p. 192°-195°C.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][CH2:12][NH:13][C:14]2[C:15]([CH3:31])=[N:16][C:17]([N:20]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:29][CH2:28][CH2:27][C@@H:26]4[CH3:30])[CH2:21]3)=[CH:18][CH:19]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:31][C:15]1[C:14]([N:13]2[CH2:12][CH2:11][C:5]3([CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)[C:3]2=[O:2])=[CH:19][CH:18]=[C:17]([N:20]2[CH2:24][CH2:23][C@@H:22]([N:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:30])[CH2:21]2)[N:16]=1
Reactant: COC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCOCC2)C1=O
Temperature: 60 °C
Yield: 20 %

Procedure:
To a solution of 4-{2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamino]-ethyl}-tetrahydro-pyran-4-carboxylic acid methyl ester (92 mg, 0.21 mmol) in tetrahydrofuran (2 mL) was added 1 M solution of potassium-tert-butoxide in tetrahydrofuran (0.4 mL, 0.4 mmol). The resulting mixture was heated to 60° C. for 3 hours with stirring. The reaction was cooled to rt and then added NaHCO3 (aq) (20 mL), extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford a crude solid which was then purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to provide 16.8 mg (20% yield, two steps) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:9])([S:5]([O-:8])(=[O:7])=[O:6])[CH2:3]O.[CH2:10]([N+:17]([CH3:20])([CH3:19])[CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(S([O-])(=O)=O)CO.C1([S+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:49][CH2:50][CH2:51][CH2:52]C(Cl)=O.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[Cl:49][CH2:50][CH2:51][CH2:52][CH2:3][C:2]([F:9])([F:1])[S:5]([O-:8])(=[O:7])=[O:6].[CH2:10]([N+:17]([CH3:20])([CH3:19])[CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCCCl
Reactant: O=S(=O)([O-])C(F)(F)CO
Agent: CN(C)c1ccncc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)([O-])C(F)(F)CCCCCl
Reaction time: 4 h
Yield: 78.5 %

Procedure:
In 60 g of methylene chloride were dissolved 16 g of benzyltrimethylammonium 1,1-difluoro-2-hydroxyethanesulfonate which had been prepared with reference to the synthesis of triphenylsulfonium 1,1-difluoro-2-hydroxyethanesulfonate described in JP-A 2009-258695 (U.S. Pat. No. 8,114,570), 7.6 g of triethylamine, and 0.6 g of 4-dimethylaminopyridine. Under ice cooling, a mixture of 8.5 g chlorobutyryl chloride and 20 g methylene chloride was added dropwise to this solution, followed by 4 hours of stirring. At the end of stirring, 50 g of 5 wt % dilute hydrochloric acid was added to quench the reaction. The organic layer was separated, washed with water, and concentrated in vacuum. To the concentrate, 100 g of MIBK was added. This was concentrated in vacuum again. The residue was washed with diisopropyl ether, obtaining 15 g of the target compound, benzyltrimethylammonium 2-(3-chloropropyl)-1,1-difluoroethanesulfonate as oily matter. Yield 74%.
Reaction SMILES: O[CH2:2][CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]([OH:6])=[O:5]>P(=O)(O)(O)O>[CH2:7]([C:3](=[CH2:2])[C:4]([OH:6])=[O:5])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCC(CO)C(=O)O
Agent: O=P(O)(O)O
Product: C=C(CCCCCCCCCCCCCC)C(=O)O
Yield: 77 %

Procedure:
A 34.25 g sample of α-hydroxymethylpalmitic acid (0.119 mole) and 17 drops of phosphoric acid (85%) were placed in a distillation flask and the mixture heated to 245°-255° C. in an oil bath under vacuum. The product, 2-tetradecylacrylic acid, distilled over at 155°-160° C. at 0.10 mm Hg (24.80 g; 77% yield) and was crystallized from acetone, m.p. 53°-55° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[CH:21]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1)[CH3:27])[CH3:26]
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4-Cyclohexylphenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[Cl:9]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: CN1CCN(CCO)CC1
Product: CN1CCN(CCOc2ccc(Br)c(Cl)c2)CC1

Procedure:
4-Bromo-3-chlorophenol was reacted with 1-methyl-4-(2-hydroxyethyl)piperazine under the Mitsunobu conditions to provide 1-[2-(4-bromo-3-chlorophenoxy)ethyl]-4-methyl-piperazine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccccc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and phenylboronic acid according to Method C (Example 178). Yield: 190 mg (82%).