Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:16]([C:18]3[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:17]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=NC(=O)c1ccc(Cl)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 61 %

Procedure:
N-(1-ethoxy-ethylidene)-4-chloro-benzamide 472 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(4-chloro-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (446 mg, yield: 61%) was obtained as a solid phase.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[CH:21][CH:22]=2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CC(CCc1ccc(N)cc1)c1cccc(C#N)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)CC(CCc1ccc(NS(=O)(=O)c2ccccc2)cc1)c1cccc(C#N)c1
Reaction time: 1 h
Yield: 41 %

Procedure:
Part A. methyl 3-(3-cyanophenyl)-5-(4-aminophenyl)pentanoate (0.100 gm, 0.325 mmol) was dissolved in dioxane and 0.5 mL of 1 N NaOH was added, followed by benzenesulfonyl chloride. The solution was stirred for 1 hour, quenched in 1 N HCl and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over MgSO4. The solvent was removed under vacuum and the residue was chromatographed on silica gel eluting ethyl acetate:toluene (20:80, v:v) to give methyl beta-[3-(cyano)phenyl]-4-[(phenylsulfonyl)amino]benzenepentanoate as an oil 0.060 gm (41%). MS: (M+NH4)+ 466; 1H NMR (CDCl3): 1.9 (m, 2H), 2.35 (m, 2H), 2.6 (m, 2H), 3.15 (m, 1H), 3.55 (s, 3H), 6.95 (s, 4H), 7.45 (m, 5H), 7.55 (m, 2H), 7.75 (d, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:15][N:16]=2)=[CH:4][N:3]=1.[C:24]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)#[N:25].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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].O>[CH:9]([NH:8][C:6]1[C:5]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:15][N:16]=2)=[CH:4][N:3]=[C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[CH:7]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(CN2CCOCC2)o1
Reactant: N#Cc1ccc(N)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Nc1cc(Nc2ccc(C#N)cc2)ncc1-c1nnc(CN2CCOCC2)o1
Temperature: 110 °C

Procedure:
To solution of 2-chloro-N-isopropyl-5-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)pyridin-4-amine (47) (100 mg, 0.2 mmol) in dioxane (5 mL): H2O (1 mL), 4-cyano aniline (0.3 mmol, 1.1 equiv.), xanthphos (0.1 mmol, 0.5 equiv.) and Na2CO3 (0.8 mmol, 3 equiv.) were added and degassed for 10 min. To the reaction mixture Pd2(dba)3 (0.1 mmol, 0.5 equiv.) was added and degassed again for 10 min. It was then heated at 110° C. for overnight. The reaction mass was cooled and filtered through small pad of celite. The filtrate obtained was concentrated to provide crude material. The crude material was purified by column chromatography through silica gel and MeOH: DCM as eluent. The material obtained was repurified on preparative TLC to afford 4-((4-(isopropylamino)-5-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)amino)benzonitrile. 1H NMR: 400 MHz, CD3OD: δ 1.37 (d, J=6.40 Hz, 6H), 2.67 (t, J=4.8 Hz, 4H), 3.77 (t, J=4.4 Hz, 4H), 3.87 (q, J=6.4 Hz, 1H), 3.94 (s, 2H), 6.24 (s, 1H), 7.61-7.64 (m, 2H), 7.72 (d, J=6.4 Hz, 1H), 7.77-7.80 (m, 2H), 8.57 (s, 1H). LC/MS: XBridge Phe 8, 4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.595 min; LCMS (ES-API), m/z 420.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.964 min; Purity: 95.1%.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([CH3:14])[C:6]1=[O:15].[H][H]>CO.[Pt](=O)=O>[NH2:11][C:9]1[CH:8]=[C:7]([CH3:14])[C:6](=[O:15])[N:5]([CH2:4][C:3]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:2]=2[CH3:1])[CH:10]=1
Reactant: [H][H]
Reactant: Cc1ccc(Cn2cc([N+](=O)[O-])cc(C)c2=O)c(C)c1
Agent: O=[Pt]=O
Solvent: CO
Product: Cc1ccc(Cn2cc(N)cc(C)c2=O)c(C)c1
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution containing 0.2 g (0.73 mmol) of 1-(2,4-dimethylbenzyl)-3-methyl-5-nitropyridin-2(1H)-one in 50 ml of methanol was added 0.017 g (0.073 mmol) of platinum (IV) oxide (Adam's catalyst). The flask was fitted with a balloon of hydrogen and allowed to stir for 1 h. The reaction was filtered through GF/F paper and the filtrate concentrated under reduced pressure to afford 0.11 g (62%) of product.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[C:3]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 4-bromo-7-chloro-3-(4-chloro-benzenesulfonyl)-quinoline (0.42 g, 1 mmol), 4-fluorophenylboronic acid (0.21 g, 1.5 mmol) and tetrakis-(triphenylphosphin)palladium(0) (0.08 g, 0.07 mmol) in 30 ml 1,2-dimethoxyethane and 8 ml of 2M aqueous sodium carbonate solution was stirred for 2 hours at 70° C. After cooling the mixture was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform) and crystallized from methanol to obtain 0.29 g of the title compound in 67% yield.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]([CH2:15][C:16]1[N:17]=[N:18][N:19]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)=[C:23]([F:34])[CH:22]=2)[CH:20]=1)=[N+:13]=[N-:14].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[N:12]([CH2:15][C:16]1[N:17]=[N:18][N:19]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([N:28]3[CH2:33][CH2:32][S:31](=[O:6])[CH2:30][CH2:29]3)=[C:23]([F:34])[CH:22]=2)[CH:20]=1)=[N+:13]=[N-:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [N-]=[N+]=NCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=NCc1cn(-c2cc(F)c(N3CCS(=O)CC3)c(F)c2)nn1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
m-Chloroperoxybenzoic acid (75%, 545 mg, 2.36 mmol) was added to a solution of 4-[4-(4-azidomethyl-[1,2,3]triazol-1-yl)-2,6-difluoro-phenyl]-thiomorpholine (800 mg, 2.36 mmol), obtained in Example 13, in dichloromethane (10 mL) at 0° C. and allowed to stir for 1 h. The reaction mixture was then diluted with dichloromethane (20 mL) and a solution of sodium sulfite was added. Aqueous layer was separated and the dichloromethane layer was washed with water followed by brine and dried over sodium sulfate. Removal of volatiles produced the title sulfoxide (800 mg, 95%).
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CCO.[Pd]>[C:1]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=Cc1cccc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccc2ccccc12

Procedure:
A solution of 7 (12 g, 53.1 mmol) in 95% EtOH (180 mL) was hydrogenated over 10% Pd.C (600 mg) at room temperature using an H2 filled balloon (overnight). The reaction mixture was filtered and taken to dryness to give a 8 as a clear oil80 (11.9 g, 98%). 1H NMR (CDCl3) δ 8.05 (1H, d, J=7.8 Hz), 7.86 (1H, dd, J=2.7, 7.6 Hz), 7.75 (1H, d, J=7.6 Hz), 7.35˜7.58 (4H, m), 4.17 (2H, q, J=7.1 Hz), 3.44 (2H, t, J=8.1 Hz), 2.77 (2H, t, J=8.3 Hz), 1.26 93H, t, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]([C:15]#[N:16])[C:12]3[N:17]=[CH:18][NH:19][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:29][CH3:30]>C(#N)C.ClCCl.O>[CH2:29]([N:19]1[C:11]2[CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=3)[N:14]=[C:13]([C:15]#[N:16])[C:12]=2[N:17]=[CH:18]1)[CH3:30]
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc2[nH]cnc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCn1cnc2c(C#N)nc(-c3cccc(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
To a stirring solution of 6-(3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (50 mg, 0.17 mmol) in acetonitrile (1 ml) was added cesium carbonate (62 mg, 0.19 mmol) and iodoethane (15 μl, 0.19 mmol). The resulting suspension was stirred at room temperature overnight. Reaction mixture was diluted with dichloromethane (5 ml) and water (5 ml) and filtered through a hydrophobic frit and concentrated in vacuo. Residual orange oil was triturated with ether (5 ml) and resulting precipitate was filtered and dried to give the title compound as a pale yellow solid (4 mg). 1H NMR (MeOD): δ 8.56 (s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 8.41 (d, 1H), 7.71-7.74 (m, 2H), 4.46-4,51 (q, 2H), 1.57-1.61 (t, 3H). MS m/z 317.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](B(O)O)=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:11]=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=4[C:21]4[CH2:20][N:19]([CH3:22])[CH2:18][CH2:10][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[CH:25][N:24]=1
Reactant: OB(O)c1cncc2ccccc12
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cncc4ccccc34)c2)CCN(C)C1
Temperature: 90 °C

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-isoquinolineboronic acid (96.8 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was heated at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(isoquinolin-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 9.5 (s, 1H), 8.57 (s, 1H), 8.4 (d, 1H), 8.09 (d, 1H), 8.0 (dd, 1H), 7.8-7.95 (m, 2H), 7.7 (d, 1H), 7.6 (m, 2H), 7.37 (s, 1H), 7.21 (d, 1H), 7.07 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.81 (m, 1H), 3.61 (m, 1H), 3.1-3.3 (m, 5H), 2.4 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12]C)=[CH:6][CH:5]=2.B(Br)(Br)Br.[OH-].[Na+]>O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([OH:12])=[CH:6][CH:5]=2
Reactant: COc1ccc2[nH]c(C)c(C)c2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]c2ccc(O)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 2,3-dimethyl-5-methoxyindole (175 mg, 1 mmol), (J. Chem. Soc. 1957, 3175-3180) in methylene (5 ml) cooled at −60° C. was added boron tribromide (210 μl, 2.2 mmol) dropwise. After completion of addition, the mixture was left to warm up to ambient temperature and was stirred for 1 hour. Water was added and the pH was adjusted to 6 with 2N sodium hydroxide. The mixture was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give 2,3-dimethyl-5-hydroxyindole (124 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([NH2:10])[CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=O.N1CCCCC1.C(O)C>ClCCl>[C:14]([C:12]1[CH:11]=[CH:8][C:7]2[C:6](=[CH:5][CH:4]=[N:3][C:2]=2[Cl:1])[N:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(=O)C(C)(C)C
Reactant: Nc1ccnc(Cl)c1C=O
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc2c(Cl)nccc2n1

Procedure:
A mixture of 15.7 g (100 mmol) of 2-chloro-3-formyl-4-aminopyridine [338452-92-9], 37.6 ml (300 mmol) of tert-butyl methyl ketone, 1.0 ml (10 mmol) of piperidine and 100 ml of ethanol is heated under reflux for 60 h. After cooling, the reaction mixture is diluted with 500 ml of dichloromethane, washed five times with 500 ml of water each time, dried over magnesium sulfate, and the solvent is removed in vacuo. The residue is recrystallised from ethanol. Yield: 8.2 g (37 mmol), 37%. Purity: >95% according to 1H-NMR.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH3:27][O:28][C:29]1([O:35][CH3:36])[CH2:32][CH:31]([CH2:33]O)[CH2:30]1>C(Cl)Cl>[I:25][CH2:33][CH:31]1[CH2:32][C:29]([O:35][CH3:36])([O:28][CH3:27])[CH2:30]1
Reactant: COC1(OC)CC(CO)C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1(OC)CC(CI)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
In a round bottom flask was placed triphenylphosphine (2.42 g, 9.25 mmol) and imidazole (1.26 g, 18.49 mmol) in methylene chloride (20 ml) and it was cooled to 0° C. in an ice bath. To this cooled solution was added iodine (2.35 g, 9.25 mmol). Once the iodine dissolved a solution of (3,3-dimethoxy-cyclobutyl)-methanol (1.04 g, 7.11 mmol) in methylene chloride (10 ml) was added. The reaction was stirred at 0° C. for 30 min and then at 25° C. for 2 h. After this time the reaction was poured into ice cold water (50 ml) and extracted with methylene chloride (2×30 ml). The combined organic layers were washed with 1.0 N sodium thiosulfate (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (Merck Silica gel 60, 230-400 mesh, 30% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded 3-iodomethyl-1,1-dimethoxy-cyclobutane (1.34 g, 74%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.72-1.81 (m, 2H, CH2), 2.28-2.53 (m, 3H, CH2 and CH), 3.14 (s, 3H, OCH3), 3.16 (s, 3H, OCH3), 3.29 (d, J=7.7 Hz, 2H, ICH2).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[CH3:29][C:30]([C:33]1[N:38]=[CH:37][C:36]([C:39](=O)[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][N:34]=1)([CH3:32])[CH3:31].O>C(OCC)C.CCCCCC>[CH3:29][C:30]([C:33]1[N:38]=[CH:37][C:36]([C:39](=[C:2]([CH3:3])[CH3:1])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][N:34]=1)([CH3:32])[CH3:31]
Reactant: CCOC(=O)C(=O)c1cnc(C(C)(C)C)nc1
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)C(=C(C)C)c1cnc(C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.5 molar solution of n-butyl lithium in hexanes (5.5 cm3) was added in portions to a suspension of isopropyltriphenylphosphonium iodide (6 g) in dry diethyl ether, whilst the temperature was maintained between -10° and -20° C. After stirring for 1 hour at this temperature, a solution of ethyl 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-2-oxo-acetate (3 g) in dry diethyl ether (15 cm3) was added in portions. The stirred reaction mixture was allowed to warm to the ambient temperature, and allowed to stir for 16 hours. The reaction mixture was poured into water and extracted into ethyl acetate. The combined organic extracts were washed, dried over anhydrous magnesium sulphate, and concentrated by removal of the solvent under reduced pressure to give a dark brown oil, which was subjected to chromotography on silica gel, using hexane containing 10% ethyl acetate (by volume), as eluent to give ethyl 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoate (0.4 g) as a clear oil.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].Cl.CN.[CH2:21]([N:23](CC)CC)C>CN(C)C=O>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:23][CH3:21])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.65 ml) was added to a solution containing 4-chloro-3-nitrobenzoic acid (1.50 g) in N,N-dimethylformamide (15 ml) and stirred for 30 minutes at room temperature. Methylamine hydrochloride (1.21 g) and triethylamine (3.11 ml) were added to the reaction mixture. After being stirred for 1 hour at room temperature, the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with water, 1N sodium hydroxide aqueous solution, 1N hydrochloric acid aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The yellow solid residue was purified by silica gel column chromatography (silica gel 10 g, chloroform:methanol=1:0-10:1), thereby yielding the entitled compound (0.97 g) as pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:24]=[CH:25][C:18]=23)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:4]1[N:3]=[C:2]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:27])=[O:28])[CH:24]=[CH:25][C:18]=23)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(F)n4)ccnc32)cc1

Procedure:
In a 20 mL microwave tube, 2-Bromo-6-fluoropyridine (L) (682 mg, 3.3 mmol, 1.2 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (B)(1.1 g, 2.8 mmol, 1 equiv.) and Pd(PPh3)4 (323 mg, 0.28 mmol), 0.1 equiv.) were suspended in a mixture of DME (10 mL) and aqueous Na2CO3 2M (3 mL). The container was sealed and the reaction mixture was exposed to microwave irradiation for 30 min at 160° C. The resulting mixture was diluted in ethyl acetate, washed with water and dried over anhydrous Na2SO4. The crude material was purified by flash chromatography on silica gel, eluting with hexanes/ethyl acetate mixtures (90:10 to 60:40). The title compound J was isolated as a pale yellow solid (2.1 g, 50%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].C(N(CC)CC)C.[S:14](Cl)([CH3:17])(=[O:16])=[O:15].C(=O)(O)[O-].[Na+]>C1COCC1.C(Cl)Cl>[CH3:17][S:14]([O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])(=[O:16])=[O:15]
Reactant: [N-]=[N+]=NCCO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of compound 2-azidoethanol (1.00 g, 11.49 mmol) in THF (25 mL) and triethylamine (Et3N) (2.418 mL, 17.24 mmol) was added mesyl chloride (1.328 mL, 17.24 mmol) at 0° C., and the mixture was allowed to warm to room temperature. Stirring continued for 3 h, during which TLC revealed a quantitative conversion into a higher Rf product. CH2Cl2 (70 mL) and saturated sodium bicarbonate (50 mL) were added, and the two layers were separated. The organic layer was washed with sodium bicarbonate (2×50 mL), saturated brine (45 mL) and dried over Na2SO4. Solvent was evaporated off to give crude compound 156a (1.70 g) as a colorless oil, which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:23][C:22]=3F)=O)=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:18][NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:23][CH:22]=3)=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(-c2nnn[nH]2)cc1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Solvent: C1CCOC1
Product: Clc1ccc(-n2nc3c(c2C(CNc2ccc(-c4nnn[nH]4)cc2)C2CCCCC2)CCCC3)cc1

Procedure:
In analogy to the procedure described in example 29.1, [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)-phenyl]-acetamide (example 58) was reduced using borane-dimethylsulfide complex in THF to give the title compound as brown solid. MS: m/e=502.0 [M+H+]1.