Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.Cl.[F:16][C:17]1([F:22])[CH2:21][CH2:20][NH:19][CH2:18]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>>[Cl:14][C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[C:2]([N:19]2[CH2:20][CH2:21][C:17]([F:22])([F:16])[CH2:18]2)[N:3]=1
Reactant: FC1(F)CCNC1
Reactant: Clc1cc(-c2cccnc2)cc(Cl)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: FC1(F)CCN(c2cc(-c3cccnc3)cc(Cl)n2)C1
Temperature: 140 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-dichloro-4-(3-pyridyl)pyridine (48 mg, 0.21327 mmol) and 3,3-difluoropyrrolidine hydrochloride (153 mg, 5.0 equiv., 1.0663 mmol) in NMP (1.0 mL, 10 mmol) in a microwave vial was added DIPEA (0.26 mL, 7.0 equiv., 1.4929 mmol), and the reaction was maintained at 140° C. for 60 min then at 150° C. for 20 min in the microwave machine, while LCMS indicated the conversion was more than 95%. The crude was used without further treatment. LCMS: m/z 296 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:37][CH2:36][C:31]4(OCC[O:32]4)[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:40])[F:41])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:27])[N:28]3[CH2:29][CH2:30][C:31](=[O:32])[CH2:36][CH2:37]3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1cn(CC(=O)N2CCC3(CC2)OCCO3)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: O=C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)-2-oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.01 g, 1.72 mmol) in acetone (20 mL) was added p-toluenesulfonic acid (359 mg, 2.06 mmol) and refluxed for 6 hours. LC/MS (method 31) shows product and presence of minor amounts of starting material. The reaction was cooled to room temperature and quenched with water. This was then extracted with ethyl acetate, dried with solid anhydrous magnesium sulfate powder and filtered to give a red oil. This was then purified by ISCO with a silica column and eluted with 0-15% methanol in dichloromethane to afford 0.43 g (0.78 mmol) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-oxo-1-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a foamy off white solid. LC/MS (method 39) [M+H]+=544.1, RT=1.91 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]=[CH:14][C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]=[CH:14][C:15]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[O:17])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1nc(-c2ccc(F)cc2)cs1
Reactant: CC(C)NC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)C=Cc1nc(-c2ccc(F)cc2)cs1)C(C)C

Procedure:
98 mg (0.39 mmol) of 3-[4-(4-fluoro-phenyl)-thiazol-2-yl]-acrylic acid, 79.6 mg (0.78 mmol) of diisopropylamine, 119.35 mg (1.17 mmol) of triethylamine and 164.5 mg (0.43 mmol) of HATU in 5 ml of DMF were stirred at room temperature for 2 h. The reaction mixture was concentrated, and water and ethyl acetate were added. The organic phase was separated, washed and evaporated. The residue was purified by chromatography (RP18). Yield: 39 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][OH:14])[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.Cl>CC(O)C.ClC(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][O:14][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][O:16]3)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(CO)O2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2c(c1)CCC(COC1CCCCO1)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a stirred mixture of 38 parts of 3,4-dihydro-6-nitro-2H-1-benzopyran-2-methanol, 30 parts of 3,4-dihydro-2H-pyran and 750 parts of trichloromethane were added 3 drops of 2-propanol saturated with hydrogen chloride (slightly exothermic reaction). The whole was stirred for 3 hours in a water bath at room temperature. The whole was washed with a cold sodium hydroxide solution 10% and with water. The organic layer was dried, filtered and evaporated. The oily residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was solidified in petroleumether. The product was filtered off and dried, yielding 34 parts (64%) of 3,4-dihydro-6-nitro-2-[[(tetrahydro-2H-pyran -2-yl)oxy]methyl]-2H-1-benzopyran; mp. 66.4° C. (intermediate 9).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][CH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: Cc1sc(-c2ccccc2)nc1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)sc1CBr
Yield: 74.4 %

Procedure:
A solution of tert-butyl 5-methyl-2-phenylthiazole-4-carboxylate (1.0 g. 3.64 mmol), N-bromosuccinimide (NBS) (0.65 g 3.64 mmol), and benzoyl peroxide (BPO) (5.5 mg, 0.023 mmol) in CCl4 (30 ml) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography to give tert-butyl 5-(bromomethyl)-2-phenylthiazole-4-carboxylate as a light yellow solid (0.96 g, 75% yield).
Reaction SMILES: O[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([I:12])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:15]>CN(C)C=O>[Cl:15][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([I:12])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc(I)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(I)cnc1Cl
Temperature: 130 °C
Yield: 50 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis (diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Br:12][CH2:13][C:14](Br)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:12][CH2:13][C:14]([C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1)=[O:15]
Reactant: CS(=O)(=O)Nc1ccccc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Methanesulfonanilide as prepared in Preparation 1 (172.0 g, 1.0 mole), bromoacetylbromide (363.35 g, 1.8 mole), and 1 liter of carbon disulfide is combined under N2 with vigorous mechanical stirring. Anhydrous aluminum chloride (400.0 g, 3.0 mole) is added in portions to this mixture over 11/2 hour resulting in a deep red color and separation of the reaction mixture into two layers. Following the addition, the reaction is stirred at ambient temperature for 45 minutes and is then heated to reflux. After refluxing for 1 hour the oil bath is removed and the reaction is stirred at room temperature overnight. The two layers are allowed to separate and the upper layer is decanted. The viscous dark brown layer remaining is slowly poured over a mixture of crushed ice and 400 ml of concentrated HCl. This results in decomposition of the dark material with violent fuming, and yellow precipitate formation. The resulting precipitate is filtered then washed with H2O, a small volume of EtOH, and ether. The remaining solid is crystallized from large volumes of CH2Cl2 containing a small amount of MeOH to aid in solubility which yielded 3 crops of the title compound, m.p. 186°-188° C.; [according to the literature, R. H. Uloth, et al., J. Med. Chem. 9, p. 88 (1966), m.p. 190°-191° C. dec⟧
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[Cl:46][C:47]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:54][C:48]=1[CH2:49][NH:50][CH:51]1[CH2:53][CH2:52]1>>[Cl:46][C:47]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:54][C:48]=1[CH2:49][N:50]([CH:51]1[CH2:52][CH2:53]1)[C:24]([C:13]1[C@@H:14]2[NH:16][C@H:10]([CH2:11][C:12]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]3[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=3[Cl:45])=[CH:29][CH:28]=1)[CH2:9][NH:8][CH2:15]2)=[O:25]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Reactant: COCCCc1ccc(Cl)c(CNC2CC2)c1
Product: COCCCc1ccc(Cl)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (rac.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (WO 2005/040165) and N-[2-chloro-5-(3-methoxypropyl)benzyl]cyclopropanamine, as for compound L1, and as described for Example 1. MS (ESI, Q+) m/z 697.9.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O1CCCC1.CCCCCC>[OH:16][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of 8.2 g of acetonitrile in 200 ml of tetrahydrofuran is added dropwise to the solution of 14.08 g of butyl lithium in 125 ml of tetrahydrofuran and 125 ml of n-hexane while stirring at -70° under nitrogen and stirring is continued for 1 hour. Thereupon the solution of 36.4 g benzophenone in 200 ml of tetrahydrofuran is added dropwise and the mixture stirred for 20 minutes at room temperature. It is poured onto 300 g of ice and 100 ml of 3N hydrochloric acid, the organic layer separated and the aqueous phase extracted three times with 50 ml of diethyl ether. The combined organic solutions are dried, evaporated and the residue recrystallized from ethanol, to yield the β-hydroxy-β,β-diphenyl-propionitrile melting at 136°-138°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[CH:15][C:14]=2[F:27])[CH2:11][C:10]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[OH:29])=[N:9]1.ClC1C=CC=C(C(OO)=[O:46])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:26])=[O:46])[CH:20]=3)=[CH:15][C:14]=2[F:27])[CH2:11][C:10]([C:28]([C:30]([F:32])([F:31])[F:33])([C:34]([F:36])([F:37])[F:35])[OH:29])=[N:9]1
Reactant: CSc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c(F)c2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a mixture of 1-(2-chloro-phenyl)-5-(3-fluoro-3′-methylsulfanyl-biphenyl-4-yl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (31.0 mg, 0.06 mmol) prepared in Example 338 in dichloromethane (2.0 mL), was slowly added meta-chloroperbenzoic acid (77%, 22.8 mg, 0.12 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with dichloromethane three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1, 1/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[C:16]#[N:17].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:16]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)#[N:17]
Reactant: C1CNCCN1
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c(C#N)c1
Product: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c(C#N)c1

Procedure:
10.0 g (40.4 mmol) of 6-(4-chloro-3-cyano-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are reacted with 10 g of piperazine in a manner analogous to Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1nc2ccccc2s1
Product: FCc1cccc(C#CCCc2nc3ccccc3s2)n1
Yield: 38.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (266 mg, 1.40 mmol) and 2-(but-3-ynyl)benzo[d]thiazole (compound 35(A), 260 mg, 1.40 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 100/0 to 80/20 as eluent) to afford 160 mg of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzo[d]thiazole (Yield: 38%) as a beige powder (Mp=74-76° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[CH3:10][C:11](=[CH2:19])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:11]([CH3:19])([CH3:10])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: C=C(C)CCCC(=O)OC
Reactant: Oc1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CCCC(C)(C)c1cc(Cl)c(O)c(Cl)c1

Procedure:
12.8 Parts of 2,6-dichlorophenol, 14.2 parts of methyl 5-methyl-hex-5-enoate, 130 parts of 98% sulphuric acid, and 24 parts of methanol were stirred and heated on a steam-bath for 24 hours and the reaction mixture then worked up as in Example 25. Distillation gave methyl 5-(3,5-dichloro-4-hydroxyphenyl)-5-methyl-hexanoate b0.5 140°-60° C. and m.p. 101°-3° C., with the following percentage composition by weight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:30])[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2Sc2ccc(Cl)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Reaction time: 0.08 h

Procedure:
4-{5-[(4-Chlorophenyl)thio]-2-phenyl-1H-imidazol-4-yl}benzonitrile (Example 1, 222 mg, 0.57 mmol) was dissolve in THF (6 mL), to which was added NaH (60% wt, 27.5 mg, 0.687 mmol) at 0° C. After stirring for 5 min, MeI (0.05 mL, 0.86 mmol) was added. The reaction was stirred at 0° C. for 2 h, and then quenched with aq NH4Cl to adjust the pH to 6-8. The product was extracted with EtOAc and the organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was subject to silica column chromatography (0-20% EtOAc in hexanes) to give the title compound as the major region isomer. 1H NMR (500 MHz, (CD3OD): 8.18 (d, 2H), 7.77 (m, 2H), 7.76 (d, 2H), 7.68 (m, 3H), 7.34 (d, 2H), 7.09 (d, 2H), 3.70 (s, 3H). LCMS: m/z 402 (M+H)+. The minor region isomer was the title compound of Example 3.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[Cl:7][C:8]1[C:9]([CH3:36])=[C:10]([C:29]2[CH:30]=[N:31][C:32](F)=[CH:33][CH:34]=2)[C:11]([O:27][CH3:28])=[C:12]([CH:14]([N:16]2[C:20]3=[N:21][CH:22]=[N:23][C:24]([NH2:25])=[C:19]3[C:18]([CH3:26])=[N:17]2)[CH3:15])[CH:13]=1>>[NH2:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([CH:14]([C:12]3[C:11]([O:27][CH3:28])=[C:10]([C:29]4[CH:34]=[CH:33][C:32]([O:5][CH2:4][CH2:3][OH:6])=[N:31][CH:30]=4)[C:9]([CH3:36])=[C:8]([Cl:7])[CH:13]=3)[CH3:15])[N:17]=[C:18]([CH3:26])[C:19]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(F)nc1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(OCCO)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
Sodium hydride (20 mg, 0.5 mmol) was added to 1,2-ethanediol (0.5 mL, 9 mmol) and the mixture was stirred at room temperature for 10 min. At this time 1-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 mg, 0.023 mmol) was added and then the reaction was stirred at 110° C. overnight. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.8 mg, 17%). The product was isolated as a single enantiomer. LCMS calculated for C23H26ClN6O3 (M+H)+: m/z=469.2; Found: 469.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Cl:12][S:13](O)(=[O:15])=[O:14].S(Cl)(Cl)=O>>[Cl:12][S:13]([C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6])(=[O:15])=[O:14]
Reactant: COc1ccccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reaction time: 8 h
Yield: 94 %

Procedure:
Commercially available 2-methoxybenzoic acid (15.2 g, 0.1 mol) was added portionwise to chlorosulphonic acid (52.43 g) over 30 min with ice cooling. Thionyl chloride (11.9 g, 0.1 mol) was added and the reaction stirred overnight. The reaction was quenched onto ice/water (250 g/65 ml) and the precipitated product granulated for 1 hr, filtered, water washed and oven dried to give the title compound (23.56 g, 93.9%) as a white solid with m.p. 138-140° C. δ (CDCl3): 4.18 (3H, s), 7.23 (1H, d), 8.21 (1H, d), 8.78 (1H, s).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[N-:8]=[N+:9]=[N-:10].[Li+].O>CN(C)C=O>[N:8]([CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1OCCC1Br
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.56 g (10 mmol) of 2-bromo-γ-butyrolactone are dissolved in 2 ml of dimethylformamide and treated at 0° C. with 612 mg (12.5 mmol) of lithium azide. The mixture is stirred at room temperature for 2 h, treated with water and extracted three times with methylene chloride. The combined organic phases are washed three times with water, dried over sodium sulphate and concentrated. 1.10 g (86.6% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Br:30]N1C(=O)CCC1=O>O1CCOCC1>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Br:30])[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Product: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Yield: 62.6 %

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (4.20 g, 9.48 mmol) was refluxed in dry dioxane (25 mL) while freshly recrystallized N-bromosuccinimide (3.37 g, 18.9 mmol) was added all at once. After 5 minutes of reflux, volatiles were removed in vacuo. The residue was partitioned between water and chloroform. The chloroform layer was dried (sodium sulfate), and evaporated to an oil which was chromatographed on silica gel with elution by 1:1 hexanes-ethyl acetate. Resolidification from ethanol-water gave title compound as white powder (3.10 g, 63%), m.p. 157°-158.5° C.; 1H-NMR(DMSO-d6) identical to that of the sample described in Example 3.
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(O)(C)C>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:8](=[N:9][C:10]#[N:11])[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(N)cc1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: COc1ccc(NC(=NC#N)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.3 %

Procedure:
A slurry of diphenyl cyancarbonimidate (1 g) in isopropanol (10 mL) was treated with 4-methoxyaniline (517 mg). After stirring at room temperature for a further 2.5 hours the reaction mixture was filtered. The insoluble material was washed with isopropanol to give the title compound (778 mg) as a white solid, which was used without further purification.