Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)CCO.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][O:33][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCO)ccc23)CC1
Solvent: CCN(CC)CC
Solvent: OCCCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCOS(C)(=O)=O)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[7-(-Hydroxy-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared as described in Example 33 using propane-1,3-diol in place of 3-hydroxypropylpiperidine. To a solution of 4-[7-(-hydroxy-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.3 mmol) in anhydrous DCM, was added Et3N (0.6 mmol) and methanesulfonyl chloride (0.6 mmol) and the mixture was stirred at rt for 2 h. It was then washed with water (3×), dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 4-[7-(3-methanesulfonyloxy-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester. This (0.05 mmol) was dissolved in anhydrous dioxane together with 1-ethyl-piperazine (0.1 mmol) and the mixture was stirred at 100° C. overnight and then concentrated in vacuo, then diluted with water and extracted with DCM. The DCM extract was washed with water (3×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3M HCl/MeOH (1 mL) and the mixture was stirred at rt for 2 h and then concentrated in vacuo and the residue was dissolved in a 1:1 mixture of DCM:MeOH, neutralized with excess Et3N and treated with (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.06 mmol), which was prepared as described in Example 66a. The mixture was stirred at rt overnight and then concentrated in vacuo and partitioned between water and DCM. DCM layer was drawn off, washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH; 90:9:1) to obtain 9.4 mg (32%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.13 (s, 1H), 8.04 (d, 1H), 7.35-7.22 (m, 4H), 6.88 (d, 2H), 6.33 (s, 1H), 4.32-4.15 (m, 4H), 3.89-3.81 (m, 4H), 3.74-3.60 (m, 1H), 3.20-3.04 (m, 7H), 2.66-2.35 (m, 12H), 2.22-1.88 (m, 5H), 1.10 (t, 3H). LC/MS (ESI): 588.1 (MH)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([C:29]([OH:32])([CH3:31])[CH3:30])[N:23]=[C:22]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[CH2:33]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([C:29]([OH:32])([CH3:30])[CH3:31])[N:23]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(C(C)(C)O)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(C(C)(C)O)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that describe in Example 45(d), but using 185 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxamide [prepared as described in step (a) above] and 10 ml of a 4N solution of hydrogen chloride in dioxane, 88 mg of the hydrochloride of the title compound were obtained as an amorphous solid, melting at 130°-138° C. (with softening).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[OH:8][CH2:7][C:6]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:5]=1[CH2:4][CH2:1][OH:2]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a Tetrahydrofuran (THF) (220 mL) solution of 2-carboxymethyl-4-nitro-benzoic acid (10.0 g, 44.4 mmol) was added sodium borohydride (5.06 g, 133 mmol) in portions. The contents were cooled to 0° C., and boron trifluoride diethyl etherate (21.3 mL, 133 mmol) was added dropwise over 1 hr. The contents were allowed to warm to 25° C. and stirred for 16 hrs. The reaction was cooled to 0° C. and cautiously quenched with aqueous sodium hydroxide (1 N, 178 mL). The contents were stirred for 3 hrs, THF was removed under vacuum, the resulting aqueous suspension was cooled to 0° C. and the product was filtered off. After drying, the product was obtained as a white solid 7.78 g (89%, mp 79-81° C.). IR 3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170, 1134, 1089, 1067 cm-1.1H NMR (CD3)2SO δ8.05 (d,J=9 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J=9 Hz, 1H), 5.42 (t,J=5 Hz, 1H), 4.74 (t, J=5 Hz, 1H), 4.64 (d, J=5 Hz, 2H), 3.63 (m, 2H), 2.80 (t, J=6 Hz, 2H). 13C NMR (CD3)2SO δ149.1, 146.6, 139.2, 127.8, 124.3, 121.3, 61.2, 60.6, 34.9. Anal. Calcd for C9H11NO4 :C, 54.82; H, 5.62; N, 7.10. Found: C, 54.54; H, 5.49; N, 7.07.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1.CO.[H][H]>[C].[Pd].O1CCCC1>[O:11]=[C:10]1[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[C:6]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[C:7]=2[CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1c(Oc2ccc([N+](=O)[O-])cc2)ccnc1N
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3c2CCC(=O)N3)cc1
Yield: 16.8 %

Procedure:
Ethyl (E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate (330 mg), palladium-carbon (10%, aqueous, 100 mg), methanol (5 ml) and tetrahydrofuran (5 ml) were stirred overnight at under a hydrogen atmosphere at 1 atmosphere. The palladium-carbon was filtered off, the filtrate was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography (ethyl acetate, followed by ethyl acetate:methanol=5:1) to obtain 43 mg of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][CH:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])[CH2:19][CH2:20][OH:21])[CH3:16])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][CH:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])[CH2:19][CH:20]=[O:21])[CH3:16])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: Cc1cc(F)ccc1C(CCO)CN(C)C(=O)c1cc(C#N)cc2c1CCCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cc1cc(F)ccc1C(CC=O)CN(C)C(=O)c1cc(C#N)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
3-Cyano-N-[2-(4-fluoro-2-methylphenyl)-4-hydroxybutyl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide (350 mg, 0.89 mmol) was dissolved in CH2Cl2 (15 mL) together with Dess-Martin periodinane (410 mg, 098 mmol) and the mixture was stirred at room temperature for 4 h. Sodium thiosulfate (0.84 g, 5.2 mmol), dissolved in a saturated solution of NaHCO3 aq, was added and the mixture was then stirred vigorously for 1 h. The organic layer was washed with NaHCO3 aq and then brine. The solution was dried over Na2SO4 and the solvent was removed by evaporation. There was obtained 310 mg (89%) of 3-cyano-N-[2-(4-fluoro-2-methylphenyl)-4-oxobutyl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil. 1H NMR (300 MHz, CDCl3): 1.0-4.5 (cm, 19H), 6.6-7.4 (cm, 5H), 9.8 (s, 1H). LCMS: m/z 391 (M−1)−.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21]O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:25][NH:26][CH2:27][CH2:28][OH:29]>>[CH3:25][N:26]([CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:1])[F:23])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:27][CH2:28][OH:29]
Reactant: OCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNCCO
Product: CN(CCO)CCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 19.1, 4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and 2-Methylaminoethanol were converted to yield 2-(Methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amino)-ethanol as yellow oil, MS: 405 (MH+).
Reaction SMILES: OC[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:23][OH:24])([C:12]2[C:21](O)=[CH:20][C:15]3[N:16]=[C:17]([CH3:19])[S:18][C:14]=3[CH:13]=2)[C:4]1=[O:25].C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O.N.Cl>O1CCCC1>[CH3:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]3[C:5]4([CH2:23][O:24][C:21]3=[CH:20][C:15]=2[N:16]=1)[C:6]1[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:3][C:4]4=[O:25]
Reactant: Cc1nc2cc(O)c(C3(CO)C(=O)N(CO)c4ccccc43)cc2s1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a cooled (−78° C.) solution of 1,3-bis(hydroxymethyl)-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one (1.70 g, 4.7 mmol) in anhydrous tetrahydrofuran (30 mL) was added tri-n-butylphosphine (0.80 mL, 5.7 mmol), followed by diethyl azodicarboxylate (1.05 mL, 6.7 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 2 h. The reaction mixture was cooled to 0° C. and a 28% aqueous solution of ammonia (10 mL) was added. The reaction mixture was stirred for 1 h at 0° C. and was acidified to pH 6 by the dropwise addition of 10% aqueous hydrochloric acid. The reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic solution was washed with brine (2×50 mL), dried over sodium sulfate, filtered and concentrated. The resultant solid was triturated with diethyl ether (50 mL), collected by vacuum filtration, washed with diethyl ether (20 mL) and dried under high vacuum to afford 2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one (1.03 g, 70%): mp>250° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ10.75 (br s, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.26-7.19 (m, 1H), 7.10 (d, J=8.6 Hz, 1H), 7.02-6.86 (m, 3H), 4.86-4.74 (m, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.7, 160.1, 148.9, 141.7, 138.5, 132.7, 128.6, 128.0, 123.4, 122.7, 122.1, 119.9, 109.7, 108.3, 80.9, 57.8, 20.0; MS (ES+) m/z 309.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[Cu][C:14]#[N:15].CN(C=O)C>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5]([C:14]#[N:15])=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(Br)cnc1N
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(C#N)cnc1N
Temperature: 25 °C
Yield: 32.4 %

Procedure:
3-Amino-6-bromo-N-methylpyrazine-2-carboxamide (2.0 g, 8.7 mmol) and copper (I) cyanide (3.9 g, 43.5 mmol) were taken into DMF (20 mL) and the mixture was heated to reflux for two hours. The mixture was allowed to cool to room temperature then diluted with ethyl acetate (250 mL). The insoluble residue was removed by filtration and the filtrate partitioned with water. The organic layer was separated and washed with water (2×) then brine and dried over anhydrous magnesium sulfate. Filtration and concentration afforded 3-amino-6-cyano-N-methylpyrazine-2-carboxamide (500 mg, 33% yield) as a white solid: 1H NMR (400 MHz, d6-DMSO): 8.84 (br m, 1H), 8.67 (br s, 1H), 8.65 (s, 1H), 2.77 (d, 3H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>Cl>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:8]2[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)c1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Yield: 74.5 %

Procedure:
Compound 114 (1.0 g, 2.82 mmol) was suspended in 3 N HCl (15 mL) and the suspension heated to reflux for 30 min. Following neutralization with saturated aqueous Na2CO3 solution, the precipitated product was collected by filtration, washed with water (70 mL), and dried under vacuum. The residue was crystallized from MeOH to give the product (655 mg, 2.1 mmol, 74%) as a solid, mp 220-221° C.; 1H NMR (500 MHz, DMSO) δ 1.28 (9, s), 5.91 (2, br s), 6.60 (2, d, J=7.0 Hz), 7.45 (2, d, J=7.0 Hz), 13.95 (1, br s); 13C NMR (125 MHZ, DMSO) δ 29.3, 36.0, 112.6, 127.3, 127.7, 152.5, 166.1, 166.6; MS (LCQ, ESI+) Calculated for C12H17N4O2S2 313.1. found 313.0 (M+H)+; HRMS (FAB+, m/z) Calculated for C12H17N4O2S2 313.0793. found 313.0793 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]1[C:17]([CH2:22][CH3:23])=[N:18][O:19][C:20]=1[CH3:21])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:22]([C:17]1[C:16]([C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:24])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:20]([CH3:21])[O:19][N:18]=1)[CH3:23]
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCN(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1CCCN(C)C

Procedure:
A mixture of 5.0 grams (0.015 mole) of 3-dimethylamino-1-[2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indol-3-yl]-1-propanone in 120 milliliters of tetrahydrofuran is added dropwise to a refluxing mixture of 2.0 grams of lithium aluminum hydride (0.053 mole) and 200 ml. of tetrahydrofuran under nitrogen. The combined mixture is refluxed for one hour, cooled in an ice bath and quenched by the cautious addition of 7 milliliters of water. The mixture is then filtered through celite and the solvent evaporated in vacuo to yield an oil, which slowly crystallizes. The crystals are triturated with ether to give 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-(3-dimethylaminopropyl)-indole, m.p. 131°-133° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].O.O.[Sn](Cl)Cl.Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[NH2:9]
Reactant: Cc1c(Br)ccc(F)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: Cc1c(Br)ccc(F)c1N
Temperature: 40 °C
Yield: 98 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1-bromo-4-fluoro-2-methyl-3-nitrobenzene (700 mg, 2.58 mmol), tin(11) chloride dihydrate (2.62 g, 11.6 mmol), hydrochloric acid (6.5 mL) and methanol (6.5 mL), and the reaction mixture was heated at 40° C. for 2 h. After this time, potassium carbonate was added to adjust the pH of the solution to 12, and the resulting suspension was extracted with methylene chloride (2×50 mL). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 3-bromo-6-fluoro-2-methylaniline in a 98% yield (598 mg) as a yellow solid: mp 49-50° C.; 1H NMR (500 MHz, CDCl3) δ 6.91 (dd, 1H, T=9.0, 5.0 Hz), 6.76 (dd, 1H, J=10.0, 9.0 Hz), 3.77 (bs, 2H), 2.28 (s, 3H); MS (ESI+) m/z 203.9 (M+H).
Reaction SMILES: [Cu][C:2]#[N:3].[ClH:4].[CH3:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O>CCOCC>[ClH:4].[C:2]([C:8]1[CH:7]=[C:8]2[C:7](=[CH:10][CH:9]=1)[CH2:5][NH:6][CH2:10][CH2:9]2)#[N:3]
Reactant: N#C[Cu]
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: CCOCC
Product: N#Cc1ccc2c(c1)CCNC2
Yield: 85 %

Procedure:
As an alternative procedure to that contained within Description 7, a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (6.0 g, 24 mmol) and triethylamine (7.4 ml, 5.36 g, 53 mmol) in dichloromethane (100 ml) was treated with trifluoroacetic anhydride (3.7 ml, 5.54 g, 26.4 mmol) with ice cooling. Mixture was stirred at 20° C. for 1.5 h. then partitioned between saturated aqueous NaHCO3 (250 ml) and dichloromethane (3×50 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid (8.3 g). A mixture of the latter with copper (I) cyanide (5.1 g, 56.6 mmol) in 1-methyl-2-pyrrolidinone (100 ml) was heated at reflux under argon for 4 h, then cooled and partitioned between water (300 ml), 0.880 aqueous ammonia (100 ml) and dichloromethane (5×200 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. The latter was dissolved in ether and treated with ethereal HCl to give the title compound (4.47 g, 85%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:10]=2)=[CH:14][CH:15]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)c1nc(-c2ccc(CO)cc2)[nH]c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(-c2nc(C(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3)[nH]2)cc1

Procedure:
tert-Butyl 5-(4-chlorophenyl)-2-(4-hydroxymethylphenyl)-imidazole-4-carboxylate is dissolved in pyridine and reacted with acetic anhydride to give the objective tert-butyl 2-(4-acetoxymethylphenyl)-5-(4-chlorophenyl)imidazole-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][N:4]=1.[CH3:25][N:26]1[C:30]([S:31](Cl)(=[O:33])=[O:32])=[CH:29][CH:28]=[N:27]1.N1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:31]([C:30]2[N:26]([CH3:25])[N:27]=[CH:28][CH:29]=2)(=[O:33])=[O:32])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:5][N:4]=1
Reactant: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1N
Reactant: Cn1nccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1NS(=O)(=O)c1ccnn1C
Temperature: 25 °C

Procedure:
To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 111 mg (0.61 mmol) 1-methyl-1H-pyrazole-5-sulfonyl chloride and 72 μL (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 32 mg (22%). HPLC-MS: M+H=470; tR=0.78 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>>[CH3:1][C:2]1[N:3]([S:33]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1[nH]ccc1C=O
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Product: Cc1c(C=O)ccn1S(=O)(=O)c1cccnc1

Procedure:
By a similar reaction as in Reference Example 44 and using 2-methyl-1H-pyrrole-3-carbaldehyde (1.10 g), sodium hydride (60% in oil, 1.20 g), 15-crown-5 (6.0 mL) and pyridin-3-ylsulfonyl chloride hydrochloride (3.22 g), the title compound was obtained as white crystals (yield 1.10 g, 44%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Br:15][C:16]1[CH:17]=[CH:18][C:19](I)=[N:20][CH:21]=1.CCOC(C)=O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:12][CH:10]2[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Brc1ccc(I)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)cn2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
1-Boc-3-hydroxyazetidine (4.0 g, 23 mmol) was dissolved in DMF (30 mL) and cooled to 0° C. To this was added NaH (60% suspension, 0.83 g, 34 mmol) and it was stirred for 15 min. Finally, a solution of 5-bromo-2-iodopyridine (6.5 g, 23 mmol) in DMF (20 mL) was added to it and the reaction mixture was stirred at 70° C. for 5 h. It was, then, cooled to room temperature and diluted using EtOAc (200 mL). The organic layer was washed with water (150 mL×2), brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (10% EtOAc in hexane) to provide Va-2-I (4.5 g, 59% yield). LCMS: m/z; 329.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[NH:17]1[C:25]2[C:20](=[CH:21][C:22]3[CH2:28][CH2:27][CH2:26][C:23]=3[CH:24]=2)[C:19](=[O:29])[C:18]1=[O:30].Cl>C(OCC)C.C(OCC)(=O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1([OH:29])[C:20]2[C:25](=[CH:24][C:23]3[CH2:26][CH2:27][CH2:28][C:22]=3[CH:21]=2)[NH:17][C:18]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc3c(cc2C1=O)CCC3
Reactant: Brc1ccccc1OCc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2cc3c(cc2C1(O)c1ccccc1OCc1ccccc1)CCC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
Several drops of a 6 mL diethyl ether solution of 5.3 g of 2-benzyloxybromobenzene were added to a suspension of 583 mg of magnesium in 2 mL of diethyl ether under a nitrogen atmosphere to initiate the reaction, after which the rest was gradually added dropwise at a rate at which heating reflux was maintained. Upon completion of the dropping, the reaction mixture was heated and refluxed for 2 hours in an oil bath, and then cooled to room temperature. A reagent prepared as above was gradually added dropwise under ice cooling and a nitrogen atmosphere to an 11 mL tetrahydrofuran solution of 1.5 g of 1,5,6,7-tetrahydrocyclopenta[f]indol-2,3-dione. Upon completion of the dropping, the temperature was raised to room temperature, and then the reaction mixture was stirred for 16 hours at that temperature. A 1 mol/L hydrochloric acid aqueous solution was poured into the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate, and the drying agent was then filtered off and the solvent was distilled off under reduced pressure. The residue was refined by column chromatography (silica gel 60, mobile phase: ethyl acetate/hexane=1/2; v/v) to obtain 1.10 g of the titled compound (colorless powder).