Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:14]1([N:24]=[C:25]=[O:26])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:25]([NH:24][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:26])=[CH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C=Nc1cccc2ccccc12
Reactant: COc1cc2ccccc2cc1N
Solvent: ClCCl
Product: COc1cc2ccccc2cc1NC(=O)Nc1cccc2ccccc12
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of 2-amino-3-methoxynaphthalene (0.253 g, 1.50 mmol) in CH2Cl2 (3 mL) at room temp. was added a solution of 1-naphthyl isocyanate (0.247 g, 1.50 mmol) in CH2Cl2 (2 mL) and the resulting mixture was allowed to stir overnight. The resulting precipitate was separated and washed with CH2Cl2 to give the desired urea as a white powder (0.450 g, 90%): mp 235-236° C.; 1H-NMR (DMSO-d6) δ 4.04 (s, 3H), 7.28-7.32 (m, 2H), 7.38 (s, 1H), 7.44-7.72 (m, 6H), 7.90-7.93 (m, 1H), 8.05-8.08 (m, 1H), 8.21-8.24 (m, 1H), 8.64 (s, 1H), 9.03 (s, 1H), 9.44 (s, 1H); FAB-MS m/z 343 ((M+H)+). B1f. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate
Reaction SMILES: [H-].[Na+].[CH3:3]S(C)=O.[O:7]=[CH:8][C@@H:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.[Cl-].[Na+].O>[O:7]1[CH2:3][CH:8]1[C@@H:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCOCC1
Reactant: CS(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCOCC1)C1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A 100 mL flask was charged with NaH (116 mg, 2.9 mmol) and Me3S+OI− (639 mg, 2.9 mmol) under N2. Dry DMSO (6 mL) was added. The mixture was stirred at rt for 1 h. A second 100 mL flask was charged with (S)-tert-butyl 1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamate (500 mg, 1.9 mmol) dissolved in THF (5 mL) under N2. The solution of NaH and Me3S+OI− was added through a syringe. The resulting mixture was stirred for 1 h. at rt. Brine was added and the mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography to give tert-butyl (1S)-1-(oxiran-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethylcarbamate (150 mg, 29%). 1H NMR (CD3OD) δ 1.45 (s, 9H), 2.60 (b, 1 h), 2.75 (m, 1H), 3.0 (b, 1H), 3.35 (m, 2H), 4.0 (m, 3H), 4.30 (b, 1H), 5.30 (s, 2H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH:24]=[O:25])[CH3:19].Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]=[O:25])[CH:26]=[CH:27][C:28]=1[O:29][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH3:19]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: CCOc1cc(C=O)ccc1Oc1ccccc1CC(=O)OC
Yield: 92 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.02 mmol) of 3-ethoxy-4-hydroxybenzaldehyde was alkylated with 1.52 g (6.62 mmol) of methyl 2-bromophenylacetate to afford 1.74 g (92%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.CCCCCC>CN(C=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:2][C:3](=[O:5])[CH3:4])=[CH:15][CH:14]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(=O)CSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
1-Chloro-propan-2-one (1.0 g, 11.63 mmol) and potassium carbonate (2.9 g, 21.15 mmol) were added to a solution of 4-bromo-benzenethiol (2.0 g, 10.58 mmol) in DMF (5.0 mL) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (100% hexane). The reaction mixture quenched with ice and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to yield the crude product. Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 2.0 g of the product (80% yield).
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]2[S:15][C:14]([NH:16][C:17](=[O:26])[C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])=[N:13][C:12]=2[CH3:27])[CH:3]=1.[CH3:28][N:29](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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:28]([C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]2[S:15][C:14]([NH:16][C:17](=[O:26])[C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])=[N:13][C:12]=2[CH3:27])[CH:3]=1)#[N:29]
Reactant: CN(C)C=O
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cc(Br)c2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cc(C#N)c2c(c1)OCO2
Temperature: 100 °C

Procedure:
A degassed mixture of Compound 56 (80 mg, 0.18 mmol), zinc cyanide (26 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium (20.0 mg, 0.017 mmol) in DMF (2.0 mL) was heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate. The mixture was washed with a solution of saturated NaHCO3 then with brine, dried (Na2SO4), filtered and concentrated. The residue was purified on silica to provide Compound 58 (55 mg).
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>ClCCl>[N:10]1([CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1ccnc1
Yield: 54.9 %

Procedure:
To 1.95 g (0.013 mole) of pivaloyloxymethyl chloride, dissolved in 20 ml of dichloromethane, were added 1.76 g (0.026 mole) of imidazole. The reaction mixture was refluxed for 32 hours, then was cooled and filtered. The filtrate was concentrated in vacuo to give an oil which was triturated with 100 mL of ether. The ether was decanted and concentrated in vacuo to give 1.30 g (55% yield) of the desired ester: IR (neat) 1720 cm-1 (s) (C=O); NMR (CDCl3) δ 7.7 (s, 1, N=CH--N), 7.07 (s, 2, N--CH=CH--N), 5.9 (s, 2, N--CH2 --O2C), and 1.17 (s, 9, (CH3)3C).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[C:20]([Cu])#[N:21]>[Cl-].[NH4+]>[C:20]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)#[N:21]
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2I)cc1
Reactant: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Product: N#Cc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A solution of the iodide 77 (5.0 g, 13.66 mmol) and CuCN (1.65 g, 18.42 mmol) in 30 mL of anhydrous dimethiylsulfoxide was heated (180° C.) under an argon atmosphere. After 2 hr, the reaction mixture was added to a 0° solution of aqueous ammonium chloride (100 mL) and filtered through a Buchner funnel. The insoluble product was partitioned into methylene chloride and water. The separated or ganic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (1/1 Hexane/CH2Cl2 to 30%/69%/1% Hexane(CH2Cl2 /MeOH) to afford the nitrile 78 (3.3 g, 12.27 mmol, 90% from 77) as a light yellow solid. 1H NMR (DMSO-d6) δ8.69 (d, 1H, J=2.3), 8.56 (dd, 1H, J1 =8.6, J=2.3), 8.44-8.41 (m, 2H), 7.80-7.76 (m, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:21])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Benzoylbenzoic acid (226 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 3-benzoylbenzoyl chloride.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[CH:6]=1.[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:8]=[C:9]([CH3:23])[CH:10]=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[N:12]=3)[CH:6]=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1

Procedure:
N-tert-Butyl-4-{1-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyrimidine (example E.71) (0.43 g, 1.0 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.39 g, 1.5 mmol) according to the general procedure VI. Obtained as a light brown solid (0.2 g) which was subsequently deprotected.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]2=[C:4]([N:13]2[CH2:19][CH:18]3[O:20][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH:15]12[O:20][CH:18]([CH2:17][CH2:16]1)[CH2:19][N:13]([C:4]1[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)[N:7]=[C:6]3[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]=13)[CH2:14]2
Reactant: Nc1ccc(B(O)O)cc1
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Temperature: 25 °C

Procedure:
3-(6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (3.08 g, 10.5 mmol) was dissolved in toluene (95 mL) and ethanol (55 mL). 4-Aminophenylboronic acid, pinacol ester (2.53 g, 11.55 mmol) was added followed by the addition of a 2M aqueous solution of Na2CO3 (21 mL). The mixture was degassed by bubbling a stream of nitrogen through the solution and tetrakis(triphenylphosphine)palladium (606 mg) was added. The mixture was heated under reflux for 16 h, cooled to room temperature and concentrated. The mixture was dissolved in ethyl acetate and washed with brine. The organic phase was dried over MgSO4 and filtered over magnesol. The aqueous phase was extracted with ethyl acetate, which was dried over MgSO4. The combined organic phases were concentrated. The crude product was applied to a silica gel column and eluted with ethyl acetate in hexanes (30-100%) to give 3.6 g of the title compound. HRMS: 351.1925 [M+H]. For [M+H]+ mass error=−0.3 mDa or −0.92 ppm.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[O-:10][CH2:11][CH3:12].[Na+]>CO>[CH2:11]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:12]
Reactant: ClCc1ccccn1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOCc1ccccn1

Procedure:
2-(Chloromethyl)pyridine hydrochloride (16.3 g., 0.1 mole) is dissolved in 100 ml. of methanol. Sodium ethoxide (0.22 mole of sodium dissolved in 150 ml. of ethanol) is added dropwise. The resulting mixture is heated at reflux for 18 hours, then filtered. The filtrate is concentrated. Water and ether are added, the aqueous phase is extracted with ether and the combined ethereal phases are washed with water and saturated aqueous sodium chloride, then dried over magnesium sulfate, concentrated and distilled to give 2-(ethoxymethyl)pyridine.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([OH:19])[C:13]2[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=2)=[CH:8][C:7]=1[C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:4].[N-:36]=[N+:37]=[N-:38].[Na+]>CO>[N:36]([CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([OH:19])[C:13]2[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=2)=[CH:8][C:7]=1[C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:4])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(NC(=O)CBr)c(C(=O)c2cccc(Cl)c2)c1
Agent: [Na+]
Solvent: CO
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(NC(=O)CN=[N+]=[N-])c(C(=O)c2cccc(Cl)c2)c1

Procedure:
A mixture of intermediate (4) (0.0161 mol) and NaN3 (0.0161 mol) in methanol (25 ml) was stirred and refluxed overnight.The product was used without further purification, yielding 2-azido-N-[2-(3-chlorobenzoyl)-4-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]-acetamide (intermediate 5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1.Cl.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][NH:17][CH2:16]2.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:17]2[CH2:16][CH:15]3[O:22][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1
Reactant: C1CC2CNCC1O2
Reactant: CS(=O)(=O)Cc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Cc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A 2,4-dichloro-6-(methylsulfonylmethyl)pyrimidine (42, prepared as reported in WO2008/023159, 1.60 g, 6.64 mmoles) was dissolved in dichloromethane and cooled to 0° C. A solution of 8-oxa-3-azabicyclo[3.2.1]octane (2, 0.990 g, 6.64 mmoles) in dichloromethane and triethylamine (1.94 mL, 13.94 mmoles) was slowly added over 15 minutes. The solution was allowed to warm to room temperature over 30 minutes then heated to reflux for 1.5 hours. The reaction mixture was stirred at room temperature for an additional 18 hours, then concentrated and purified by chromatography on silica gel (eluting with 2-3% methanol in dichloromethane) to provide 3-(2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (43) as a white solid. Yield: 1.72 g (82%). HRMS; [M+H]+ Obs'd=318.0669, [M+H]+ Calc'd=318.0674.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([SH:13])[S:12][C:8]=2[CH:7]=1)[CH3:4].[N+:16]([C:19]1[CH:25]=[CH:24][C:23](Cl)=[CH:22][C:20]=1[NH2:21])([O-:18])=[O:17]>O.CN(C)C=O>[N+:16]([C:19]1[CH:25]=[CH:24][C:23]([S:13][C:11]2[S:12][C:8]3[CH:7]=[C:6]([O:5][CH2:3][CH3:4])[CH:15]=[CH:14][C:9]=3[N:10]=2)=[CH:22][C:20]=1[NH2:21])([O-:18])=[O:17]
Reactant: CCOc1ccc2nc(S)sc2c1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2nc(Sc3ccc([N+](=O)[O-])c(N)c3)sc2c1
Reaction time: 16 h

Procedure:
To a stirred solution of 0.15 moles of potassium hydroxide in a mixture of 15 ml of water and 300 ml of dimethylformamide add 0.15 moles of 6-ethoxybenzothiazole-2-thiol (L. B. Sebrell and C. E. Boord, J. Am. Chem. Soc., 45, 2390 (1923)) under a nitrogen atmosphere. After complete dissolution, add 2-nitro-5-chloroaniline (R. C. Fuson, R. A. Dauman, E. Howard, Jr., and E. N. Marvell, J. Org. Chem., 12, 084 (1947)) and heat the mixture under reflux and a positive nitrogen pressure for about 16 hours. Pour the mixture into 1000 ml of water and remove the resulting precipitate. Wash the precipitate with water and crystallize from acetonitrile to give the title compound having a melting point of 126°-129° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[CH:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)(C)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]#[CH:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: C#Cc1cccc(N)c1
Yield: 82 %

Procedure:
This experiment was carried out using 735 grams of 3-nitrophenylacetylene in isopropanol (6.6% wt. conc.) over 140 grams of the cobalt polysulfide paste from Example 11. After reaction time of 1.4 hours, analysis showed that 82% of feed had been converted, and that an 82% yield to desired 3-aminophenylacetylene was obtained. About 18% of product was polymeric in nature. This run is summarized in Table 1 below.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH2:25][CH3:26])=[CH:19]4)(=O)=O)=CC=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C:38]1[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=1>CS(C)=O.C(OCC)(=O)C>[CH2:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[C:17]1[O:27][CH:13]([CH2:12][N:41]3[CH2:42][CH:43]=[C:38]([C:32]4[C:31]5[C:35](=[CH:36][CH:37]=[C:29]([F:28])[CH:30]=5)[NH:34][CH:33]=4)[CH2:39][CH2:40]3)[CH2:14][O:15][C:16]1=[CH:24][CH:23]=2)[CH3:26]
Reactant: CCc1cc2c3c(ccc2[nH]1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)O3

Procedure:
A solution of 0.41 g (0.1.1 mmole) of [(2R)-8-ethyl-2,3-dihydro-7H-[1,4]-dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.71 g (3.3 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 25 mL of DMSO were heated at 75-80° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0-2% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with ether/hexane (1:1) to give 0.090 g of the (S)-enantiomer of the title compound as a yellow solid hydrate, m.p. 81-82° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:24])[C:6]=2[CH:25]=1.[Li+].C[Si]([N-:31][Si](C)(C)C)(C)C>>[NH2:31][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:24])[C:6]=2[CH:25]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Agent: [Li+]
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N)cc3c2C)c1
Yield: 37.2 %

Procedure:
The intermediate methyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate was prepared from methyl 3-{[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (45 mg, 0.1 mmol) and LiHMDS (1M in THF, 120 μL, 0.12 mmol) according to the General Procedure 4, described in Example 45, using a modified reaction time (130° C., 300 s, microwave reactor). The experiment was repeated four times giving 14 mg of methyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.CI.[CH2:25](I)[CH3:26]>>[CH2:25]([N:12]1[C:6]2[CH:5]=[C:4]([O:21][CH3:22])[C:3]([O:2][CH3:1])=[CH:20][C:7]=2[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][CH2:10][C:11]1=[O:13])[CH3:26]
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Reactant: CCI
Solvent: CI
Product: CCN1C(=O)CN=C(c2ccccc2)c2cc(OC)c(OC)cc21
Yield: 62 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-dimethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaa), and MeI by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 62%. M: 86–88° C. 1H-NMR (CDCl3, 200 MHz): d 1.15 (t, 3H, CH3), 3.80 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.03 (AB system, ? d=0.61, JAB=13.9, 2H, —NCH2), 4.30 (AB system, ? d=1.00, JAB=9.98, 2H, CH2), 6.71 (s, 1H Ar), 6.88 (s, 1H Ar), 7.40–7.69 (m, 5H Ar).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22](/[CH:28]=[CH:29]/[C:30]([NH:32][O:33]C5CCCCO5)=[O:31])[CH:23]=4)[O:18]3)[CH2:13]2)=[CH:3]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22](/[CH:28]=[CH:29]/[C:30]([NH:32][OH:33])=[O:31])[CH:23]=4)[O:18]3)[CH2:13]2)=[CH:3]1
Reactant: Cn1cc(CN2CCCC3(CC(=O)c4cc(/C=C/C(=O)NOC5CCCCO5)ccc4O3)C2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(CN2CCCC3(CC(=O)c4cc(/C=C/C(=O)NO)ccc4O3)C2)c2ccccc21
Yield: 86.2 %

Procedure:
(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (300 mg, 0.56 mmol) in DCM (10 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide (215 mg, hydrochloride salt) as a light brown solid.
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][C:4]([O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:5].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(O)(=O)C>C1C=CC=CC=1>[F:14][C:15]([F:23])([F:24])[C:16]1[CH:17]=[C:18]([NH:19][C:2]([CH3:13])=[CH:3][C:4]([O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:5])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)CC(=O)OCC[Si](C)(C)C
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=CC(=O)OCC[Si](C)(C)C)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 3.75 g (1.5 mmol) of the compound of Example 39A in 55 ml benzene are added 3 g (18.5 mmol) 3-(trifluoromethyl)aniline and 1.1 g (18.5 mmol) acetic acid. The mixture is stirred under reflux overnight using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 6). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([N:21]=[C:22]=[O:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>O1CCCC1>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[NH:1][C:22]([NH:21][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[O:23]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: Nc1nc2ccccc2[nH]1
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccccc2[nH]1)Nc1cccc2ccccc12
Reaction time: 0.5 h

Procedure:
A solution was prepared containing 5.32 g. of 2-aminobenzimidazole in 150 ml. of tetrahydrofuran (THF). A second solution containing 6.76 g. of naphthyl isocyanate in 100 ml. of THF was added with stirring over a 30 minute period. The reaction mixture was heated at refluxing temperature for 6 hours and then cooled N-(2-benzimidazolyl)-N'-naphthylurea precipitated and was separated by filtration. Recrystallization of the filter cake from acetone yielded purified N-(2-benzimidazolyl)-N'-naphthylurea melting at 327°-328° C.