Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([O:8][C@H:9]1[CH2:17][CH2:16][C@@H:15]2[C@@H:11]([CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[C@@H:10]1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=O.[CH2:41]1COCC1>C1(C)C=CC=CC=1.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[F:39][C:2]([F:40])([F:1])[C:3]1[CH:4]=[C:5]([C:6]([O:8][C@H:9]2[CH2:17][CH2:16][C@@H:15]3[C@@H:11]([CH2:12][N:13]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14]3)[C@@H:10]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH2:41])[CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](OC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3)[C@@H]2C1
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Solvent: Cc1ccccc1
Product: C=C(O[C@H]1CC[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution 9.5 g (14.0 mmol) of the crude intermediate of step C in dry THF under nitrogen atmosphere at 0° C. was added 66 mL (33 mmol.) of a 0.5 M solution of Tebbe reagent in toluene. The resulting mixture was stirred at 0° C. for 2 hr then carefully quenched by the dropwise addition of 7.5 mL water, then 7.5 mL of 5.0 N aq. NaOH. The resulting suspension was stirred at RT for 0.5 hr and the solids filtered. The resulting filtrate stirred with 5 mL of 5.0 N aq. NaOH for 16 hr and the solids filtered through filter aid. The solvent was evaporated under vacuum and the residue purified by column chromatography eluting with EtOAc/hexanes (1/3) to give the title compound. 1H-NMR (CDCl3): δ: 7.73 (1H, s), 7.55 (2H, s), 7.30–7.18 (2H, m), 7.03 (2H, m), 4.67 (1H, s), 4.37 (1H, s), 4.25 (1H, m), 3.55–3.30(3H, m), 3.27–3.15 (2H, m), 2.81(1H, t, J=12.7 Hz), 2.60 (1H, m), 2.40–30 (2H, m), 1.98 (1H, m), 1.83 (1H, m), 1.55, 1.47 (9H, two singlets)
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH2:6][CH2:7][CH3:8])[CH2:4][SH:5].CO[C:13](OC)(OC)[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]23[S:5][CH2:4][C:3]([CH2:6][CH2:7][CH3:8])([CH2:9][O:10]2)[CH2:2][O:1]3)=[CH:15][CH:16]=1
Reactant: COC(OC)(OC)c1ccc(Br)cc1
Reactant: CCCC(CO)(CO)CS
Product: CCCC12COC(c3ccc(Br)cc3)(OC1)SC2

Procedure:
Using a method analogous to that described in stage iv of Example 5 2,2-di-hydroxymethyl-pentan-1-thiol and trimethyl 4-bromo-orthobenzoate were reacted together to give 1-(4-bromophenyl)-4-n-propyl-2,6-dioxa-7-thiabicyclo[2,2,2]octane (colourless solid).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:40])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][C:31]([CH3:39])([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]4)=[N:26][CH:27]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2].[Li+].[OH-]>C1COCC1>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:22]3[CH:27]=[N:26][C:25]([N:28]4[CH2:29][CH2:30][C:31]([CH3:39])([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)=[N:24][CH:23]=3)=[CH:11][C:9]=2[N:10]=1)=[O:40])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3cc(C)ccn3)c2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(-c3cc(C)ccn3)c2s1
Temperature: 65 °C
Yield: 36.2 %

Procedure:
To an ice-cold solution of ethyl 1-(5-(2-(3-ethylureido)-7-(4-methylpyridin-2-yl)benzothiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (0.015 g, 0.026 mmol) in THF was added aqueous LiOH (0.006 g, 0.134 mmol dissolved in minimum amount of H2O) and the mixture heated up to 65° C. for 3 h. After reaction completion (by TLC), the solvent was concentrated and 10 mL of water added and washed with EtOAc (2×50 mL). The organic layer was discarded and the pH of the aqueous layer was adjusted up to 4-5 then extracted with hot EtOAc (3×50 mL) and the combined organic layer dried over Na2SO4 and solvent evaporated under reduced pressure. The residue thus obtained was triturated with ether to afford the desired product as an off-white solid (0.005 g, 35%). 1H NMR (DMSO-d6): δ 1.11 (t, J=7.20 Hz, 3H), 1.19 (s, 3H), 1.41 (m, 2H), 2.07 (m, 2H), 2.45 (s, 3H), 3.17-3.24 (m, 4H), 4.32 (m, 2H), 6.93 (br s, 1H), 7.27 (d, J=4.80, 1H), 7.94 (s, 1H), 8.23 (s, 1H), 8.35 (s, 1H), 8.65 (d, J=4.8 Hz, 1H), 8.91 (s, 2H) and 10.60 (br s, 1H). MS: 530.21 [M−H]−.
Reaction SMILES: C1(C2C=CC(C(O)=O)=NC=2OCC2CC2)CC1.[CH:18]1([CH2:21][C@H:22]([NH:28][C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]3CCO[CH2:39][CH2:38]3)=[C:33]([O:43][CH2:44][CH:45]3[CH2:47][CH2:46]3)[N:32]=2)=[O:30])[C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][C@H:22]([NH:28][C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:39][CH2:38]3)=[C:33]([O:43][CH2:44][CH:45]3[CH2:47][CH2:46]3)[N:32]=2)=[O:30])[C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[CH2:19][CH2:20]1
Reactant: O=C(N[C@@H](CC1CC1)c1nccs1)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: O=C(N[C@@H](CC1CC1)c1nccs1)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine (Example 59 b) as starting materials, MS (LC/MS): m/e=384.3 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[S:28](=[O:32])(=[O:31])([OH:30])[OH:29]>C(O)(C)C>[CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[S:28]([O-:32])([O-:31])(=[O:30])=[O:29]
Reactant: O=S(=O)(O)O
Agent: OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Solvent: CC(C)O
Product: O=S(=O)([O-])[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Quetiapine free base (5.0 g) was dissolved in isopropyl alcohol (50 ml) at room temperature. This was followed by addition of 98% sulfuric acid (1.28 g) at 30 to 35° C. The resulting gummy mass was heated to reflux and maintained for 15 minutes. The resulting mass was cooled at 25-30° C. and stirred for 1 hour. The precipitated product was collected by filtration, washed with isopropyl alcohol (25 ml) and dried to give the title compound as off white powder (5.88 g).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH:3]([OH:7])[C:4]([O-:6])=[O:5].[Na+:10].Cl[O-].[Na+]>O.[Ru](=O)=O.O>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[O:7])[C:4]([O-:6])=[O:5].[Na+:10]
Reactant: CC(C)(C)C(O)C(=O)[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: CC(C)(C)C(=O)C(=O)[O-]

Procedure:
Sodium 3,3-dimethyl-2-hydroxybutyrate and ruthenium dioxide hydrate are added to water, the pH rendered alkaline, and sodium hypochlorite is slowly added to produce sodium 3,3-dimethyl-2-oxobutyrate in high yield and purity. The solid catalyst is filtered off and may be re-used while the filtrate can be directly used in further synthesis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:35][CH3:36])=[C:17]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:34])/[CH:28]=[CH:29]\[C:30]([O:32]C)=[O:31])[CH2:23][CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:37])=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:35][CH3:36])=[C:17]([O:20][CH:21]4[CH2:22][CH2:23][N:24]([C:27](=[O:34])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31])[CH2:25][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)/C=C\C(=O)N1CCC(Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2OC)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CCN(C(=O)/C=C\C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.2 %

Procedure:
0.1 g of the compound obtained in Example 83 was diluted in 2 ml of tetrahydrofuran, and 0.1 ml of a 3M lithium hydroxide solution was added thereto at 0° C. The resulting mixture was stirred at room temperature for two hours and extracted with chloroform. The aqueous layer was acidified with a 1N HCl and extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was purified by column chromatography (methylene chloride:methanol=5:1) to obtain the title compound (118 mg, 48%).
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([N:7]1[CH:11]=[CH:10][N:9]([C:12](=[O:14])[CH3:13])[C:8]1=[O:15])(=[O:6])[CH3:5]>CCOCC.C(OCCCC)CCC>[C:12]([N:9]1[CH:10]=[CH:11][N:7]([C:4](=[O:6])[CH3:5])[C:8]1=[O:15])(=[O:14])[CH3:13].[C:12]([N:9]1[C:8](=[O:15])[N:7]([C:4](=[O:6])[CH3:5])[CH:11]2[CH:10]1[CH2:3]2)(=[O:14])[CH3:13]
Reactant: C=[N+]=[N-]
Agent: CC(=O)n1ccn(C(C)=O)c1=O
Solvent: CCOCC
Solvent: CCCCOCCCC
Product: CC(=O)N1C(=O)N(C(C)=O)C2CC21
Yield: 20 %

Procedure:
A solution of diazomethane in ether (prepared from 200 g of N-nitrosomethylurea) is introduced in portions over the course of 3 days into a solution of 25.0 g (0.15 mol) of 1,3-diacetyl-4-imidazolin-2-one and 5.0 g of copper-I chloride in 250 ml of di-n-butyl ether at 80°-90°. The solution is then filtered, the residue is repeatedly eluted with benzene and the combined filtrates are concentrated in vacuo. Chromatography of the crude product on silica gel gives 10.3 g of unconverted 1,3-diacetyl-4-imidazolin-2-one and 3.6 g (about 20%) of 2,4-diacetyl-2,4-diaza-bicyclo[3,1,0]hexan-3-one as colourless crystals of melting point 134°-136° C. (from ether).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:3]=12.Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: CSc1nc(Cl)c2c(-c3ccccc3Cl)n[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2c(-c3ccccc3Cl)nn(COCC[Si](C)(C)C)c2n1
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
4-Chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (10.0 g, 0.032 mol) was added to 100 mL of dry DMF, and the resulting solution was cooled to 0° C. (2-Chloromethoxy-ethyl)-trimethyl-silane (6.8 mL, 0.038 mol) was added dropwise, and the reaction mixture was stirred for five minutes. Sodium hydride (1.40 g, 0.0333 mol) was then added, and the reaction mixture was stirred for 30 minutes at 0° C. The reaction mixture was partitioned between water and ethyl acetate. The layers were separated, and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with brine, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 10% hexanes in EtOAc) to afford 8.55 g of 4-Chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[NH:17][C:18]([C:20]1[NH:24][C:23]2[S:25][C:26]([Cl:28])=[CH:27][C:22]=2[CH:21]=1)=[O:19])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[NH:17][C:18]([C:20]1[NH:24][C:23]2[S:25][C:26]([Cl:28])=[CH:27][C:22]=2[CH:21]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 134.1 %

Procedure:
tert-Butyl((1R,2R)-2-{[(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)carbamate (Method 22, 10.6 g, 24.5 mmol) was suspended in DCM (200 mL), TFA (20 mL) added and the reaction stirred at ambient temperature for 20 hours. The volatiles were removed by evaporation under reduced pressure and the residue triturated with DCM (50 mL) then filtered and dried to give the title compound (10.9 g, 100%) as the trifluoroacetic acid salt.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].COC(=O)C1C=CC(C(OC)=O)=CC=1Br.BrC1C=C(C=O)C=CC=1C=O>>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[CH2:4][OH:5])[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Agent: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Agent: O=Cc1ccc(C=O)c(Br)c1
Product: O=C(O)c1ccc(CO)c(Br)c1

Procedure:
A more general access to 3-alkyl-4-formyl-benzoic acids is given in the following section: Commercially available 2-bromo-terephthalic acid or 2-bromo-terephthalic acid dimethyl ester is transformed to 2-bromo-terephthalaldehyde via a reduction-oxidation sequence in analogy to litereture procedures (e.g. K. R. Roesch, H. Zhang, R. C. Larock, J. Org. Chem. (2001), 66, 8042-8051 (supporting information); T. Ise, D. Shiomi, K. Sato, T. Takui, Chemistry of Materials (2005), 17, 4486-4492; S, Narsimhan, K. G. Prasad, S. Madhavan, Synthetic Commun. (1995), 25, 1689-1697). 2-Bromo-terephthalaldehyde is then subjected to a Cannizzaro reaction according to a literature procedure (S. E. Hazlet, G. Bosmajian, J. H. Estes, E. F. Tallyn, J. Org. Chem. (1964), 29, 2034-2036) to give 3-bromo-4-hydroxymethyl-benzoic acid which is then oxidised for instance by treatment with MnO2 (lit. e.g. T. Ise, D. Shiomi, K. Sato, T. Takui, Chemistry of Materials (2005), 17, 4486-4492; S. Goswami, et al. Chem. Letters (2005), 34, 194-195) to 3-bromo-4-formyl-benzoic acid. This compound is then elaborated to the desired 3-alkyl-4-formyl-benzoic acid by either treating it with the appropriate alkenyl boron derivative (e.g. 2,4,6-trivinyl-cyclotriboroxane) under Suzuki conditions (Lit.: e.g. F. Kerins, D. F. O'Shea, J. Org. Chem. (2002), 67, 4968-4971) followed by catalytic hydrogenation or by reacting it with the appropriate alkyl-Zn reagents under Negishi conditions (e.g. H. Matsushita, E. Negishi, J. Org. Chem. (1982), 47, 4161-4165). The 4-formyl-group and the carboxylic acid function may require protection e.g. as an acetal and ester, respectively, during these transformations.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]2[N:11]=[N:12][NH:13][N:14]=2)=[O:8])=[CH:5][CH:4]=1)=O.[CH:17]1([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C.COC(OC)OC.CO>[CH:17]1([C:23]2[CH:24]=[CH:25][C:26]([NH:27][CH2:1][C:3]3[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]4[N:11]=[N:12][NH:13][N:14]=4)=[O:8])=[CH:5][CH:4]=3)=[CH:28][CH:29]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: O=Cc1ccc(C(=O)Nc2nn[nH]n2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(Nc1nn[nH]n1)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above resin bound 4-formyl-N-(2H-tetrazol-5-yl)benzamide (50 mg) was treated with a 0.5 M solution of 4-cyclohexylaniline (0.25 mmol, 41.25 mg) in a mixture of DMF and trimethylorthoformate (1:1, 0.5 mL) and glacial acetic acid (50 μL) for 1 hour at 25° C. followed sodium cyanoborohydride (250 μmol, 16 mg) dissolved in a mixture of DMF and methanol (1:1, 0.25 mL). Shaking at 25° C. for 4 hours followed by filtration and washing with a mixture of DMF and methanol (1:1, 2×1 mL), 3×1 mL DMF and 2×1 mL dichloromethane afforded the desired product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]1[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([Cl:21])[C:14]=1[NH2:22])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=O>ClCCCl>[Si:1]([O:8][CH2:9][C@@H:10]([N:12]1[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([Cl:21])[C:14]=2[N:22]=[C:32]1[CH2:31][Cl:30])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc(Cl)c(N)c(N[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1C
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1nc(Cl)c2nc(CCl)n([C@@H](C)CO[Si](C)(C)C(C)(C)C)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
N4-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-5,6-dimethylpyridine-3,4-diamine (2.85 g, 8.29 mmol) was dissolved in 100 mL of dry 1,2-dichloroethane and the solution was cooled to 0° C. as it stirred under an atmosphere of N2. Triethylamine (2.3 mL, 16.58 mmol) and chloroacetyl chloride (0.92 mL, 11.60 mmol) were added sequentially. After 30 minutes, the reaction mixture was allowed to warm to ambient temperature and stirred for 3 days followed by heating to 70° C. for 2 days. The reaction mixture was allowed to cool to ambient temperature and was washed with saturated NaHCO3 solution (2×100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as a brown solid. Chromatography (SiO2, 20-50% ethyl acetate/hexanes) gave 1-((1S)-2{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-4-chloro-2-(chloromethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridine (0.44 g) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[S:19][C:20]2[C:21]([N:26]=1)=[N:22][CH:23]=[CH:24][CH:25]=2.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[S:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:26]=[C:18]1[O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(O)cc1
Reactant: Clc1nc2ncccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: OCCc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of 4-hydroxyphenethyl alcohol (1.16 g, 8.4 mmol, 1.2 equiv.) and K2CO3 (1.94 g, 14.06 mmol, 2 equiv.) in CH3CN (12 mL) was added 2-chloro[1,3]thiazolo[4,5-b]pyridine (1.2 g, 7.03 mmol, 1 equiv.). The reaction mixture was heated to 80° C. and stirred for 16 h. Satd. aq. Na2CO3 (25 mL) was added to the reaction mixture, which was then extracted with isopropyl acetate (2×30 mL). The combined organic layers were dried, filtered, and concentrated. The crude material was purified by column chromatography (50% EtOAc/hexanes-100% EtOAc), which afforded the title compound as a light orange oil (74%). MS (ESI): mass calcd. for C14H12N2O2S, 272.32; m/z found, 273.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=7.9, 1.7, 1H), 7.37-7.29 (m, 4H), 7.22 (dd, J=7.9, 4.8, 1H), 3.88 (dd, J=12.5, 6.5, 2H), 2.91 (t, J=6.6, 2H), 2.03 (t, J=5.9, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:18]=[CH2:19]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[CH2:10][C:11](=[O:12])[CH2:19][CH2:18]2)[CH3:2]
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Reactant: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc2c(c1)CCC(=O)C2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
39.1 g (0.20 mol) of 4-ethoxyphenylacetyl chloride in 200 ml of dichloromethane were added dropwise in the course of 1 hour at −78° C. to 53.4 g (0.4 mol) of aluminum chloride in 800 ml of dichloromethane. A vigorous stream of ethylene was subsequently passed in in the course of 15 minutes, and the mixture was allowed to come to room temperature and stirred for a further 3 hours. The dark red solution was cooled to 0° C. and carefully treated with 300 ml of ice-water. After phase separation, the organic phase was washed with 2N HCl (3×) and saturated sodium hydrogen carbonate solution, dried and evaporated on a rotary evaporator. After purification by column chromatography with petroleum ether/ethyl acetate (9:1, 8:2), 20.9 g (56% of theory) of a yellow syrup were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1.[NH:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:28](O)=[O:29])=[CH:27][C:22]=2[N:21]=[CH:20]1>>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:28]([C:26]3[CH:25]=[CH:24][C:23]4[NH:19][CH:20]=[N:21][C:22]=4[CH:27]=3)=[O:29])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:4]=1
Reactant: COc1nn(-c2ccccc2)c2cc(N)ccc12
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1nn(-c2ccccc2)c2cc(NC(=O)c3ccc4[nH]cnc4c3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 66 reacting 3-methoxy-1-phenyl-1H-indazol-6-ylamine and 1H-Benzoimidazole-5-carboxylic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:11][CH:10]=1.[C:36]([O:39][CH2:40][CH2:41]Br)(=[O:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:31][CH2:32][N:33]([CH2:41][CH2:40][O:39][C:36](=[O:38])[CH3:37])[CH2:34][CH2:35]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:11][CH:10]=1
Reactant: O=C(NN1CCNCC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCN1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
5-(4-Chloro-phenyl)-N-piperazin-1-yl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxamide trifluoroacetate (1:1) (200 mg, 378 μmol, example 13b) was combined with acetonitrile (10 mL) to give a yellow solution. To this solution 2-bromoethyl acetate (760 mg, 500 μl, 4.55 mmol) and K2CO3 (157 mg, 1.13 mmol) were added successively. The reaction mixture was heated to 60° C., stirred for 20 h, filtered through a Celite® pad after cooling to ambient temperature and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 20 g, 0% to 50% methanol in ethyl acetate) to give the title compound (107 mg, 57%) as white solid; LC-MS (UV peak area/ESI) 97.8%, 501.1510 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15].[Cu][C:20]#[N:21]>N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[C:20]([C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15])#[N:21]
Reactant: CC(=O)c1cc(Br)c(Sc2ccc(Cl)cc2Cl)s1
Reactant: N#C[Cu]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: CC(=O)c1cc(C#N)c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a CEM microwave tube, was charged with 1-[4-bromo-5-(2,4-dichlorophenyl)sulfanyl-2-thienyl]ethanone as prepared in example 21 (0.6 g, 1.6 mmol), copper(I) cyanide (0.85 g, 9.4 mmol), and pyridine (5 mL) as solvent. The mixture was subjected to microwave irradiation (200 W) on a CEM Discovery™ microwave machine at 150° C. for 30 minutes. After the irradiation, the mixture was cooled to ambient temperature and treated with 20 mL of saturated copper(II) sulfate aqueous solution and extracted with ethyl acetate. The combined organic layer was separated, washed with water, dried (Na2SO4) and concentrated. The crude was purified by silica gel chromatography using a 96:4 mixture of hexane and ethyl acetate as eluent to afford the title product (0.515 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ: 7.69 (1H, s), 7.56 (1H, m), 7.53 (1H, m), 7.33 (1H, m), 2.51 (3H, s). MS m/z: 326.2 [M+H]+.