Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][NH:9][CH3:10].[C:11]([O:15][C:16]([NH:18][S:19](N1C=CC(=[N+](C)C)C=C1)(=[O:21])=[O:20])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[O:2]1[CH2:7][CH2:6][O:5][CH2:4][C@H:3]1[CH2:8][N:9]([CH3:10])[S:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])(=[O:20])=[O:21]
Reactant: CNCC1COCCO1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C[C@@H]1COCCO1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride (0.760 g, 4.55 mmol), N-[1-{[(tert-butoxycarbonyl)amino]sulfonyl}pyridin-4(1H)-ylidene]-N-methylmethanaminium (1.51 g, 5.00 mmol), and triethylamine (1.55 mL, 11.4 mmol) were slurried in 50 mL dichloromethane and stirred at ambient temperature. After 12 hours, the solution was concentrated in vacuo and purified by silica chromatography (50-100% ethyl acetate/hexanes gradient) to afford the title compound. LRMS (APCI) calc'd for (C11H22N2O6SNa) [M+Na]+, 333.1; found, 333.1.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:15])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CC#N>[CH:12]1([NH:15][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.7 mL, 6.3 mmol) in anhydrous CH3CN (10 mL) were added cyclopropylamine (0.4 mL, 6.3 mmol) and DIPEA (1.1 mL, 6.3 mmol). The reaction mixture was stirred at RT for 18 h then evaporated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% EtOAc in cyclohexane) to afford the title compound as a yellow solid (6.3 mmol, quantitative). 1H NMR (CDCl3, 300 MHz): δ 8.26-8.09 (2H, m), 6.95 (1H, dd, J=11.43, 2.68 Hz), 6.46-6.35 (1H, m), 2.60-2.50 (1H, m), 0.98-0.89 (2H, m), 0.71-0.63 (2H, m).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:24][S:25]([N:28]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:29]1)(=[O:27])=[O:26].CCN(CC)CC>C(Cl)(Cl)Cl.CCOC(C)=O>[CH3:24][S:25]([N:28]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30]2([CH2:31][CH2:32][N:33]([C:14]([NH:13][C:10]3[CH:9]=[N:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][N:11]=3)=[O:22])[CH2:34][CH2:35]2)[CH2:29]1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2ccccc21
Yield: 92.9 %

Procedure:
A mixture of phenyl N-(5-phenyl-2-pyrazinyl)carbamate 1-2 (7,350 mg, 1.20 mmol), 1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride 1-3 (400 mg, 1.32 mmol) and Et3N (0.5 mL, 3.6 mmol) in CHCl3 (6 mL) was heated to reflux for 3 h. After cooling, the mixture was diluted with EtOAc, washed with 10% citric acid, sat. NaHCO3 and brine, dried over MgSO4, and concentrated under reduced pressure to start precipitation. The precipitate was collected by filtration and dried in vacuo to give 100 (517 mg, 93%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[C:13]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:21][CH3:22])=[O:8])([OH:15])=[O:14]
Reactant: CCO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1C(=O)O

Procedure:
A mixture of 3-nitrophthalic acid (35 g) in ethanol (300 ml) containing conc. sulfuric acid (20 ml) was heated under reflux for 24 hours. The solvent was evaporated in vacuo and the residue was poured into cold water. (700 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with water and shaken with an aqueous solution of potassium carbonate. The aqueous layer was made acidic with hydrochloric acid and the mixture was extracted with methylene chloride. The organic layer was washed with water, then dried, followed by evaporation of the solvent. The resultant solid (29 g, 74%) was used for the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:51]1[CH:55]=[CH:54][N:53]=[C:52]1[NH:56][C:57]([C:59]1[C:67]2[NH:66][C:65]([NH2:68])=[N:64][C:63]=2[CH:62]=[CH:61][CH:60]=1)=[O:58]>O.CN(C=O)C>[NH:53]1[CH:54]=[CH:55][N:51]=[C:52]1[NH:56][C:57]([C:59]1[C:67]2[N:66]=[C:65]([NH:68][C:14]([C:13]3[CH:12]=[N:11][CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:17]=3)=[O:16])[NH:64][C:63]=2[CH:62]=[CH:61][CH:60]=1)=[O:58]
Reactant: O=C(O)c1cncc(OCc2ccccc2)c1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cncc(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
0.07 g (0.30 mmol) of 5-benzyloxy-nicotinic acid and 0.12 g (0.32 mmol) of HBTU were combined in a flask charged with 2 mL DMF and 0.25 mL of DIEA. This reaction mixture was then treated with 0.05 g (0.20 mmol) of 2-Amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B) and stirred at 80° C. for 1 h. The reaction mixture was diluted with water, and the resultant solid precipitate was filtered and washed with saturated NaHCO3. The solid was dissolved with MeOH, evaporated onto silica gel and isolated by flash column chromatography (500 mL DCM/20 mL NH3/MeOH) to yield 10 mg (10%) of 2-[(5-benzyloxy-pyridine-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 455.0 (M+1)+.
Reaction SMILES: [OH:1][N:2]([CH3:11])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C1COCC1.C(N(CC)CC)C>C(Cl)Cl>[S:18]([O:1][N:2]([CH3:11])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CN(O)C(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)ON(C)C(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 66.8 %

Procedure:
N-Tosyloxy-N-methylbenzamide was prepared by the following procedure. To a flask equipped with a stirrer were added N-hydroxy-N-methylbenzamide (1.39 g, 0.010 mol) from above, p-toluenesulfonyl chloride (1.91 g, 0.010 mol), 25 mL of THF and 2 mL of triethylamine. After 30 min at 0° followed by 1 h at room temperature, the reaction mixture was diluted with 50 mL of methylene chloride, and the solution was washed with water (4×50 mL) and dried. Evaporation of the solvent left 2.84 g of a golden oil which soon crystallized. Recrystallization from methylene chloride-hexane gave 2.04 g (69.4%) of fluffy white N-tosyloxy-N-methylbenzamide: mp 98°-99.5°; nmr (CDCl3) 7.8-7.0 (A2B2 and singlet at 7.36, 9H), 3.53 (s, 3H), 2.38 (s, 3H); ir (KBr) 1684 (vs), 1370 (s), 1180 (s), 1170 (s), 880 (m), 805 (m), 735 (m), 695 (s), 651 (m), 540 (s): uv (CH3CN) 227 (19,200), 265 (sh, 2020), 273 nm (sh, 1500); mass spectrum 305.0720 (calcd for C15H15O4NS: m+, 305.0720). Anal. Calcd for C15H15O4NS: C, 59.00; H, 4.95; N, 4.59; S, 20.96; O, 10.50. Found: C, 58.87, 58.75; H, 4.98, 5.02; N, 4.52, 4.43.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[N:17]#[C:18][NH2:19].CC(C)([O-])C.[K+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)=[O:29]>C(#N)C.C(O)(C)(C)C>[NH2:17][C:18]1[N:19]=[C:2]([NH:1][C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)=[CH:8][CH:9]=2)[S:3][C:27]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)=[O:29]
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Reactant: N#CN
Reactant: O=C(CBr)c1ccc(N2CCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC#N
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(N5CCCC5)cc4)s3)cc2)CC1
Reaction time: 0.5 h
Yield: 4 %

Procedure:
tert-Butanol (4 mL) and then 1-(4-isothiocyanatophenyl)-4-methyl piperazine (of Example 1; 219 mg, 1 mmol) were added to a solution of cyanamide (44 mg, 1.05 mmol) in acetonitrile (5 mL). Potassium t-butoxide (1 M in tert-butanol; 1 mL, 1 mmol) was added and the solution was stirred for 30 min. 2-Bromo-1-[4-(1-pyrrolidinyl)phenyl]ethanone (257 mg, 1 mmol) (Lancaster) was added, and the solution was stirred at room temperature for 2 days. The yellow-brown solid was filtered off and washed with cold acetonitrile, water and then cold acetonitrile (weight of solid: 271 mg). A portion of this crude product (50 mg) was purified by chromatography (10% methanol/dichloromethane) to give [4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone (18.5 mg).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=1)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][C:21]=1[F:27])[CH3:16].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:28])=[C:21]([F:27])[CH:22]=2)[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1cccc(C(=O)OC(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(C#Cc2cccc(C(=O)OC(C)C)c2)cc1F

Procedure:
Following General Procedure B and using 3-ethynyl-benzoic acid isopropyl ester (Intermediate 137, 0.099 g, 0.53 mmol), 2-fluoro-4-iodo phenyl acetic acid ethyl ester (0.164 g, 0.53 mmol), triethyl amine (3 mL), copper(I)iodide (0.01 g, 0.05 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.035 g, 0.5 mmol) followed by flash column chromatography over silica gel (230-400 -mesh) using 7-10% ethyl acetate in hexane as the eluent, the title compound was obtained as a light orange oil (0.08 g, 92%).
Reaction SMILES: C([Li])CCC.O1CCOCC1.[CH3:12][N:13]([CH3:24])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1)=[O:15].Cl.[CH:26]([N:29]([CH:33]([CH3:35])[CH3:34])[CH2:30][CH2:31]Cl)([CH3:28])[CH3:27]>CCCCCC.C(O)C>[CH3:12][N:13]([CH3:24])[C:14]([N:16]([CH2:31][CH2:30][N:29]([CH:33]([CH3:35])[CH3:34])[CH:26]([CH3:28])[CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1)=[O:15]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CN(C)C(=O)Nc1cccc(N)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)N(CCN(C(=O)N(C)C)c1cccc(N)n1)C(C)C
Temperature: -25 °C

Procedure:
Under a nitrogen atmosphere, n-butyl lithium solution (15.5 ml., 0.025 mole) is added dropwise with stirring to a dioxane (50 ml.) solution of N,N-dimethyl-N'-(6-amino-2-pyridyl)urea (4.5 g., 0.025 mole) at 10° C. Then 2-diisopropylaminoethyl chloride hydrochloride (55.5 g., 0.275 mole) is added followed by another portion of n-butyl lithium (15.5 ml., 0.025 mole). The mixture is heated at reflux over night. Ethanol (30 ml.) is added with cooling and the mixture is filtered and concentrated in vacuo. The residue is treated with ether and is filtered to remove salts. Removal of the ether in vacuo gives 5.1 g. of viscous oil. The crude oil is taken up in hexane, filtered and cooled to -25° C. Filtration gives 1.5 g. of white solid, m.p. 86°-88° C.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH3:8].C=O.[S:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.CN.ClC1C=[C:33](C=CC=1Cl)[CH2:34][N:35](C)C(C1CN(C)C(=O)C=1O)=O>>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][N:7]([CH3:8])[C:6]([C:5]1[CH:34]([CH3:33])[N:35]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: c1ccsc1
Agent: C=O
Agent: CN
Product: CC1C(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C(=O)N1c1cccs1
Yield: 28 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and methylamine thiophene as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (58.7 mg, 28% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (d, 1H, J=8.05), 7.33 (d, 1H, J=1.83), 7.26 (m, 1H), 7.08 (dd, 1H, J=8.05, J=1.83), 6.97 (m, 2H), 4.85 (s, 2H), 4.57 (s, 2H), 4.11 (s, 2H), 3.00 (s, 3H). HRMS (M−H) calcd for C18H15SN2Cl2O3: 409.0180. found: 409.0190.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N+:16]#[C-:17].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>Cl(O)(=O)(=O)=O>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH:16][C:17]1[N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]2=[N:1][C:22]=1[C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[O:19][CH3:18]
Reactant: COc1ccccc1C=O
Reactant: Nc1cnccn1
Reactant: [C-]#[N+]c1c(C)cccc1C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1ccccc1-c1nc2cnccn2c1Nc1c(C)cccc1C

Procedure:
Compound (15) was prepared in accordance with general instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml 2,6-dimethylphenyl isocyanide solution (0.2 M, MC), 0.500 ml 2-methoxybenzaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.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>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:47]=[CH:48][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[O:54])=[CH:50][CH:51]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CN(C)CCCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)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: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCCN(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, 3-(dimethylamino)propyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded 3-(dimethylamino)propyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]([CH3:55])[CH2:50][C:51](=[O:54])[NH:52][N:53]=2)=[CH:44][C:43]=1[OH:56]>O.CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]([CH3:55])[CH2:50][C:51](=[O:54])[NH:52][N:53]=3)=[CH:44][C:43]=2[OH:56])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccc(C#N)cc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
403 mg (2.74 mmol) 4-cyano-benzoic acid and 967 mg (3.01 mmol) TBTU are added to 40 ml DMF and the mixture is stirred for 30 min at RT, then 791 μl (5.47 mmol) diisopropylamine and 600 mg (2.74 mmol) 6-(4-amino-3-hydroxy-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one are added and the mixture is stirred overnight. The reaction mixture is mixed with water and extracted with DCM. The org. phase is again washed with water, dried on sodium sulphate and concentrated by rotary evaporation i. V. The residue is extracted with methanol, filtered off, washed with methanol and then dried in the vacuum dryer at 50° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.Cl.[CH3:18][N:19](C)C=O>>[C:18]([C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1)#[N:19]
Reactant: O=c1c2cc(Br)ccc2ccn2cccc12
Reactant: CN(C)C=O
Agent: Cl
Product: N#Cc1ccc2ccn3cccc3c(=O)c2c1
Reaction time: 0.5 h

Procedure:
A stirred mixture of 1 gm. of 9-bromo-11H-pyrrolo[2,1-b][3]benzazepin-11-one, 1 gm. of cuprous cyanide and 5 ml. of dimethylformamide is heated to reflux for 5 hr. The mixture is then poured into a solution of 4 gm. of ferric chloride hydrate in 25 ml. of 2N hydrochloric acid. After stirring the resulting mixture at 60° for 30 min., it is extracted with 3 × 50 ml. of ethyl acetate, the organic extracts washed with 3 × 100 ml. of water and dried over Na2SO4. Evaporation of the dried solution yields 9-cyano-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:12][Mg]Br>CCOCC>[OH:10][C:9]1([CH3:12])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH2:11]1
Reactant: C[Mg]Br
Reactant: O=C1CCCc2ccccc21
Solvent: CCOCC
Product: CC1(O)CCCc2ccccc21
Yield: 84.6 %

Procedure:
A solution of 98.0 g (0.670 mol) of α-tetralone in 800 ml of anhydrous ether was added over 30 min to a solution of 285 ml (0.855 mol) of 3.0M methyl magnesium bromide in ether under N2 whilst stirring magnetically. After completion of the addition, the reaction was heated to reflux for 30 min, allowed to cool, then quenched with 120 ml of saturated ammonium chloride solution. The ether layer was decanted from an offwhite solid, washed with water (400 ml), then with saturated sodium chloride solution, dried (K2CO3) and evaporated in vacuo to leave 91.9 g (85%) of an orange solid. NMR δ(CDCl3) 1.57 (3H, s), 1.77 (1H, s), 1.80-2.00 (4H, m), 2.80 (2H, m), 7.08 (1H, d of d), 7.18 (1H, t of d), 7.23 (1H, t of d), 7.60 (1 H, d of d).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:27])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:26])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28][C@H:29]([OH:32])[C:30]#[CH:31]>C1COCC1.CCOC(C)=O.[Cu]I>[Cl:26][C:22]1[N:23]=[CH:24][NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:31]#[C:30][C@@H:29]([OH:32])[CH3:28])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:27])=[O:20]
Reactant: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Reactant: C#C[C@H](C)O
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](O)C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 44.3 %

Procedure:
A solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (86 mg, 0.174 mmol), (2S)-3-butyn-2-ol (30.5 mg, 0.436 mmol), palladiumbisdichlorobistriphenylphosphine (12.23 mg, 0.017 mmol), copper(I) iodide (1.659 mg, 8.71 μmol) and TEA (0.121 ml, 0.871 mmol) in THF (3 ml) was irradiated in the microwave for 10 minutes at 120° C. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(3S)-3-hydroxy-1-butyn-1-yl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide (37 mg, 0.077 mmol, 44% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.54-7.94 (m, 1H), 7.26-7.47 (m, 2 H), 7.11 (s, 1H), 6.89 (s, 1H), 6.74 (s, 1H), 4.24-4.71 (m, 3H), 1.41 (d, 3H). LC-MS (ES+) m/z 481.95, [M+H].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=[O:21]>C1COCC1>[S:1]1[C:5]([CH:20]([OH:21])[C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: COc1ccc(C=O)cc1OC
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc3ccccc3s2)cc1OC

Procedure:
a-(2-benzo[b]thienyl)-3,4-dimethoxybenzyl alcohol was prepared in the same manner as described in Example 40A. Reaction of benzo[b]-thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 m, 97 mmoles, 5.7 ml) and 3,4-dimethoxybenzaldehyde (8.9 mmoles, 1.5 g) in THF (20 ml) yielded, after flash chromatography using 30% ethyl acetate/hexanes, 2.25 g (≈100%) of a white gummy solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](=[O:17])[O:11][C:12]([CH3:16])=[CH:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(O)(=[O:22])C>C1(C)C=CC=CC=1.C(O)C>[CH2:1]([S:8]([C:9]1[C:10](=[O:17])[O:11][C:12]([CH3:16])=[CH:13][C:14]=1[OH:15])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1cc(O)c(SCc2ccccc2)c(=O)o1
Agent: OO
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(S(=O)Cc2ccccc2)c(=O)o1
Yield: 69 %

Procedure:
3-Benzylthio-4-hydroxy-6-methyl-2-pyrone (7.45 g., 0.0282 mol) and 30% hydrogen peroxide (3.7 g., 0.033 mol) were combined in 30 ml. glacial acetic acid and stirred at room temperature for 20 hours. The solution was then diluted with a mixture of toluene and ethanol (5:1) and warmed in vacuo to codistil the acetic acid. The recovered tan solid was recrystallized from toluene (DARCO) to give 5.4 g. (69 percent) of the desired product: m.p. 150°-153°C. One additional recrystallization from toluene gave the pure compound: m.p. 155°-156°C.