Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[N:38]=[C:39]([CH3:42])[S:40][CH:41]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[N:38]=[C:39]([CH3:42])[S:40][CH:41]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2csc(C)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (0.63 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.94 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:6]1[C:7]2[CH:8]=[C:9]([CH2:12][O:13][CH3:14])[O:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COCc1cc2cccc(OC)c2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COCc1cc2c(Br)ccc(OC)c2o1
Reaction time: 48 h
Yield: 110.7 %

Procedure:
A solution of 7-methoxy-2-methoxymethylbenzofuran (13.32 g) in acetonitrile (500 ml) was stirred at room temperature. N-bromosuccinimide (11.04 g) was added and stirring continued for 2 days after which the solvent was removed in vacuo. The resulting oil was partitioned between ethyl acetate (100 ml) and sodium metasulfite solution (50 ml), the organic extract washed with more sodium metasulfite solution (2×50 ml), followed by brine (50 ml). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound as a yellow oil (18.61 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 4-benzylpiperidine (10.5 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (13.4 mg). Calcd for C23H21F3N2O2: 414.1555, found 414.1544.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=CC=C2C=1C(C#N)=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: COc1ccc(Br)c2cn[nH]c12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ncc12

Procedure:
Compound CXCVII was prepared from 4-Bromo-7-methoxy-1H-indazole using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:12]=2)[CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:12]=[C:11]([C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=3)[NH:28][CH:27]=[C:26]4[CH:35]3[CH2:36][CH2:37][N:38]([S:41]([CH2:44][CH3:45])(=[O:42])=[O:43])[CH2:39][CH2:40]3)[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2cncc(CNCC3CC3)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Temperature: 150 °C
Reaction time: 0.13 h

Procedure:
To a CEM microwave tube containing (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (21 mg, 0.0725 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), dioxane (0.75 mL), a solution of potassium carbonate (60 mg, 0.434 mmol) in H2O (0.25 mL), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C. and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 65° C. to give impure title compound, which was repurified on the Agilent MDAP as shown above to give 25 mg of the title compound (70%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH2:14].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 93.7 %

Procedure:
A solution of 2,4-dichloro-quinazoline obtained in step A of example 1 (125 g, 628 mmol) in THF (1 L) was cooled to 4° C. and 40% aqueous MeNH2 (136 mL, 1.57 mol) was added. The mixture was stirred at ambient temperature for 80 min. The solution was alkalized with saturated aqueous NaHCO3 (pH=9) and concentrated. The precipitate was collected by filtration, washed with H2O and hexane, and dried at 80° C. to give (2-chloro-quinazolin-4-yl)-methyl-amine (114 g, 94%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:3][C:4]([C:6]1[S:37][C:9]2[N:10](C(OC(C)(C)C)=O)[N:11]=[C:12]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[C:8]=2[CH:7]=1)=[O:5]>CO>[CH3:1][N:2]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:3][C:4]([C:6]1[S:37][C:9]2[NH:10][N:11]=[C:12]([NH:13][C:14](=[O:29])[C:15]3[CH:16]=[CH:17][C:18]([CH2:21][N:22]4[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]4)=[CH:19][CH:20]=3)[C:8]=2[CH:7]=1)=[O:5]
Reactant: CN1CCN(Cc2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4sc(C(=O)NN(C)c5ccccc5)cc34)cc2)CC1
Solvent: CO
Product: CN1CCN(Cc2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN(C)c5ccccc5)cc34)cc2)CC1
Yield: 66.8 %

Procedure:
A solution of 0.14 g (232 μmol) of tert-butyl 5-(N′-methyl-N′-phenylhydrazinocarbonyl)-3-[4-(4-methylpiperazin-1-ylmethyl)benzoylamino]-thieno[2,3-c]pyrazole-1-carboxylate in 8 mL of methanol is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 20 minutes, and then for two further periods of 15 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 35° C. The residue is taken up in 15 mL of diisopropyl ether, triturated, filtered on a sinter funnel, washed twice with 5 mL of diisopropyl ether, suction-filtered and then dried in an oven under vacuum (0.01 kPa) at a temperature in the region of 60° C. 78 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-ylmethyl)benzamide are thus obtained in the form of an off-white solid melting at 246° C. LC-MS-DAD-ELSD: 504(+)=(M+H)(+); 502(−)=(M−H)(−).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=[O:22])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=[O:38]>O1CCCC1>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=[O:22])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][C:36]([C:37]([OH:39])=[O:38])([CH3:41])[CH3:40])=[O:7]
Reactant: CCC1CCC(=O)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: CC(C)(O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC1CCC(=O)C=C1c1ccc(OCC(=O)OC(C)(C)C(=O)O)c(Cl)c1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid (2.06 g, 0.006 mole) under nitrogen in tetrahydrofuran (THF) (50 ml) was added 1,1'-carbonyldiimidazole (0.97 g, 0.006 mole). The solution was stirred for 1 hour then 2-hydroxy-2-methylpropanoic acid (0.62 g, 0.006 mole) in THF (25 ml) was added and stirring was continued overnight. The THF was evaporated in vacuo and the residue chromatographed on silica (300 g) eluting with CH2Cl2 -THF-AcOH (100:2:1). Evaporation of the pertinent fractions gave 1-carboxy-1-methylethyl [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetate which melted at 167°-168° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])=O.[CH3:9][S:10][C:11]1[N:20]=[C:19]([N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)N=CC)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.Cl.O>CCOCC>[CH3:32][O:31][C:28]1[CH:27]=[C:26]2[C:25](=[CH:30][CH:29]=1)[N:21]([C:19]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([S:10][CH3:9])[N:20]=1)[C:2]([CH3:1])=[C:4]2[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(=O)CCC(=O)O
Reactant: CC=NN(c1ccc(OC)cc1)c1nc(SC)nc2ccccc12
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1nc(SC)nc2ccccc12

Procedure:
A mixture of laevulinic acid (7 g.), acetaldehyde N1 -(2-methylthioquinazolin-4-yl)-p-methoxyphenylhydrazone (3.5 g.) and a saturated solution of hydrogen chloride in ether (2 ml.) was heated at 95° - 100° C. for 22 hours. The mixture was poured into water (300 ml.), and the precipitated brown solid was collected by filtration and dissolved in chloroform (100 ml.). The solution was filtered and the filtrate was extracted with 2 N- ammonia solution (4 × 50 ml.). The extracts were combined and acidified to pH3 with glacial acetic acid. The mixture was filtered, and the solid crystallised from methanol to give 5-methoxy-2-methyl-1-(2-methylthioquinazolin-4-yl)indol-3-ylacetic acid, as a pale yellow crystalline solid, m.p. 175°-178° C.
Reaction SMILES: [F:1]/[C:2](=[CH:6]\[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)/[C:3]([OH:5])=O.[C:13]1([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1]/[C:2](=[CH:6]\[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)/[C:3]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[CH:28][CH:27]=1)=[O:5]
Reactant: O=C(O)/C(F)=C/c1cccnc1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)/C(F)=C/c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
The mixture of (Z)-2-fluoro-3-(pyridin-3-yl)acrylic acid (100 mg, 0.598 mmol),4-(phenylsulfonyl)aniline (140 mg, 0.598 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (341 mg, 0.897 mmol), DIEA (232 mg, 1.795 mmol) in DMF (Volume: 10 ml) was stirred at RT for overnight, removed DMF, extracted with EtOAc, washed with 1N NaOH, brine, dried and the biotage purification afforded the product (51 mg, 23%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:15][CH3:16])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:16][O:15][CH:5]([O:4][CH3:3])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[CH:10][CH:9]=1
Reactant: COC(CNc1ccc(O)cc1)OC
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(CNc1ccc(OCCN(C)C)cc1)OC
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.57 g) was added to a solution of 4-(2,2-dimethoxyethyl-amino)phenol (4.3 g) in dimethylformamide (25 mL). After 30 minutes, 2-dimethylaminoethyl chloride (hydrochloride, 3.14 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated. The residue was purified by MPLC (eluent: dichloromethane/methanol/ammonia solution 95:4.9:0.1). The product with the molecular weight of 268.36 (C14H24N2O3); MS (ESI): 269 ([M+H]+), was obtained in this way.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](=[C:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:11])[CH3:10].N1C=CN=C1>CCOC(C)=O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([C:12](=[C:9]([CH3:10])[CH3:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:19])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)Nc1ccc(F)cc1)=C(C)C
Temperature: 200 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
To a solution of 4-fluoroaniline (2 g, 18 mmol) in diethyl isopropylidenemalonate (10 g, 50 mmol) is added 1H-imidazole (0.25 g, 3.67 mmol). The reaction mixture is stirred at 200° C. under N2 for 3 hours. After the reaction is cooled, silica gel is added. The mixture is loaded onto a silica gel column, and eluted first with PE and then PE:EtOAc (3:1) to give the product (1.85 g, 39% yield). MS (m/z): 266.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
(S)-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (10 g, 0.05 mol) was taken into anhydrous pyridine (51 mL). The reaction was cooled to 0° C. and p-toluenesulfonyl chloride (10.42 g, 0.055 mol) in anhydrous pyridine (25 mL) was added dropwise over 10 min. The reaction ran at 0° C. for 2 h. and then allowed to warm to room temperature overnight. The mixture was concentrated to dryness and the residue was taken into ethyl acetate (200 mL) and washed with 0.5N HCl (50 mL). The ethyl acetate was then washed with aqueous sodium bicarbonate (100 mL), brine, dried over sodium sulfate and concentrated to dryness to obtain the title product (17.55 g, 0.049 mol, 99% yield); MS; m/z 355, found 356 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 1.28 (s, 9H), 1.72 (s, 3H), 1.90 (s, 1H), 2.42 (s, 3H), 3.14-3.23 (m, 2H), 3.84 (s, 1H), 3.97-4.06 (m, 2H), 7.49 (d, J=8.0, 2H), 7.78 (d, J=8.0, 2H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:22])C2C=C(C)C=CC=2C2C=NN(C)C=2)[C@@H:3]1[CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].[Br:35][C:36]1[C:37](C(O)=O)=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=1>>[Br:35][C:36]1[C:37]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:23][N:24]2[C:25](=[O:34])[C:26]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]2=[O:33])=[O:22])=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=1
Reactant: Cc1ccc(Br)c(C(=O)O)n1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Product: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)n1

Procedure:
The title compound was prepared following the same general protocol as described for 2-(((2S,3R)-3-methyl-1-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoyl)piperidin-2-yl)methyl)isoindoline-1,3-dione in Example A1, using 3-bromo-6-methylpicolinic acid. ESI-MS (m/z): 456, 458 [M]+[M+2]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]#[N:15])=[C:12]([C:16]([O:18]CC)=[O:17])[CH:11]=[N:10]1.[OH-:21].[K+]>C(O)C>[C:16]([C:12]1[CH:11]=[N:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:13]=1[C:14]([NH2:15])=[O:21])([OH:18])=[O:17]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccc(Cl)cc1Cl

Procedure:
A 2.5 g. portion of ethyl 1-(2,4-dichlorophenyl)-5-cyano-4-pyrazolecarboxylate was reacted with 1 g. of potassium hydroxide in 60 ml. of 50% aqueous ethanol to obtain 1.2 g. of purified product, m.p. 239°-240° , with the following elemental analysis.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=1[C:2](=[O:3])[CH3:1])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(O)c1C(C)=O

Procedure:
A mixture of 2,6-dihydroxyacetophenone (40 g), ethyl bromoacetate (48 g) and potassium carbonate (58 g) in acetone (500 ml) was refluxed for 3 hours. The mixture was cooled and filtered. The solution was evaporated to dryness and the crude solid extracted with boiling hexane. Upon cooling, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.C(NC(C)C)(C)C.[C:31]1([CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[CH:13]=[CH:12]2)=[C:4]([NH:39][CH2:38][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:3]=1
Reactant: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C2)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2,6-Dichloro-9-[(1R,4S)-4-(5-ethyl-tetrazol-2-yl)-cyclopent-2-enyl]-9H-purine (step 1) (0.2 g, 0.57 mmol) is dissolved in THF (5 ml) under an atmosphere of argon. Diisopropylamine (0.088 g, 0.68 mmol) is added followed by 2,2-diphenylethylamine (0.123 g, 0.63 mmol) and the reaction mixture is stirred at 50° C. for 4 hours. The solvent is removed in vacuo and residue is partitioned between dichloromethane (20 mL) and 2M HCl (20 mL). The organic layer is washed with sat. NaHCO3 (20 mL), water (20 ml) and brine (20 ml), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 8.20 (br s, 1H), 7.30-7.10 (m, 10H), 6.30 (m, 1H), 6.20 (m, 1H), 5.95 (m, 1H), 5.80 (m, 1H), 4.35 (m, 1H), 4.20 (m, 2H), 3.35 (m, 1H), 2.85 (q, 2H), 2.20 (m, 1H), 1.30 (t, 3H), MS (ES+) m/e 512 (MH+).
Reaction SMILES: N#[C:2][Br:3].C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:31]=[CH:30][C:14]2[O:15][C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[CH2:18][CH:19]([S:20][CH2:21]CN(C)C)[C:13]=2[CH:12]=1.CCCCCC>C(Cl)(Cl)Cl>[Br:3][CH2:2][CH2:21][S:20][CH:19]1[CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[O:15][C:14]2[CH:30]=[CH:31][C:11]([F:10])=[CH:12][C:13]1=2
Reactant: N#CBr
Reactant: CN(C)CCSC1Cc2ccccc2Oc2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Fc1ccc2c(c1)C(SCCBr)Cc1ccccc1O2
Reaction time: 0.33 h

Procedure:
To a mixture of 2.3 g of cyanogen bromide and 5.0 g of potassium carbonate in 40 ml of chloroform is added portion-wise over a 50 minutes span a solution of 4.8 of 2-fluoro-10,-11-dihydro-11-[β-(dimethylamino)ethylthio]dibenz[b,f]oxepin, free base of Example 32, in 85 ml of chloroform. After total addition, the mixture is stirred for 20 minutes before being filtered. The filtrate is evaporated to leave an oil which is treated with three portions of boiling hexane. The combined hexane portions are evaporated leaving an oil which is chromatographed through a silica gel column with an eluant of methylene chloride and is recrystallized from cold hexane to give a white powder, mp 46°-48° C. of 11-[β-(bromo)ethylthio]-2-fluoro-10,11-dihydrodibenz [b,f]oxepin.
Reaction SMILES: CN([CH:4]=[O:5])C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][C:8]=1[F:14].C([O-])([O-])=O.[K+].[K+].CI>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:5][CH3:4])=[CH:9][C:8]=1[F:14]
Reactant: CN(C)C=O
Reactant: Oc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz).