Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[C:47]([CH2:52][CH2:53][N:54]1[CH2:58][CH2:57][CH2:56][C@H:55]1[CH3:59])[CH:46]=[CH:45]2>COCCOC.O.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>[CH3:59][C@@H:55]1[CH2:56][CH2:57][CH2:58][N:54]1[CH2:53][CH2:52][C:47]1[CH:46]=[CH:45][C:44]2[C:49](=[CH:50][CH:51]=[C:42]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[CH:43]=2)[N:48]=1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Reactant: OB(O)c1cccnc1
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: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3cccnc3)ccc2n1
Temperature: 80 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (28.8 mg, 0.025 mmol), 2-(dicyclohexylphosphino)biphenyl (35.0 mg, 0.10 mmol), 3-pyridinylboronic acid (0.375 mmol), and sodium carbonate (40.0 mg, 0.375 mmol) were combined in 1,2-dimethoxyethane (4 mL) and water (1.5 mL). The mixture was then treated with the product from Example 42D (80 mg, 0.25 mmol) and heated at 80° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (20 mL). The organic layer was separated, washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with HCl in IPA:ethyl acetate to give the trihydrochloride salt. mp 205-207° C.; MS (ESI) 318 (M+H)+; 1H NMR (DMSO-d6) δ 9.48 (1H, br, s), 9.05 (1H, d), 8.96 (1H, d), 9.00 (1H, d), 8.86 (1H, br, s), 8.60 (1H, d), 8.59 (1H, d), 8.32 (1H, dd), 8.23 (1H, d), 4.08 (1H, br, m), 3.90 (2H, br, m), 3.65 (2H, br, m), 3.46 (1H, q), 2.40 (1H, m), 2.19 (2H, m), 1.84 (1H, m), 1.58 (3H, d).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24].C1N2CCN(CC2)C1>CC#N>[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[O:24][CH:2]1[C:7]2=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][NH:3]1
Reactant: CC(C)c1ccn2ncnc(Cl)c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CC(C)c1ccn2c1C(Oc1ccc([N+](=O)[O-])cc1F)NC=N2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
To a mixture of 4-chloro-5-isopropylpyrrolo[2,1-f][1,2,4]triazine (0.038 g, 0.194 mmol, 1.0 equiv) and 2-fluoro-4-nitrophenol (0.062 g, 0.388 mmol, 2.0 equiv) in anhydrous CH3CN (2mL), stirred for five minutes under a nitrogen atmosphere then was added DABCO (0.044 g, 0.388 mmol, 2.0 equiv) and the reaction mixture was heated at 50° C. for 2 h. The mixture was cooled to room temperature and quenched with 1 N HCl. The solution was extracted with CH2Cl2 (3×30 ml), the combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography, eluting with 2/1 hexane/ethyl acetate, afforded the title compound (0.048 g, 79%). 1H NMR (CDCl3) δ 8.07-8.13 (m, 2H), 7.77 (s, 1H), 7.68-7.69 (m, 1H), 7.46-7.50 (m, 1H), 6.71-6.72 (m, 1H), 3.53-3.56 (m, 1H), 1.29-1.31 (m, 6H); HRMS(ESI), calc, 317.1050 (M+H)+ found, 317.1039.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[C:12]([CH2:13][S:14][CH2:15][C:16]([NH2:18])=[O:17])=[CH:11][CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1.[OH:21]O>C(O)(=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[C:12]([CH2:13][S:14]([CH2:15][C:16]([NH2:18])=[O:17])=[O:21])=[CH:11][CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: OO
Reactant: NC(=O)CSCc1cccc2oc3cc(Cl)ccc3c12
Solvent: CC(=O)O
Product: NC(=O)CS(=O)Cc1cccc2oc3cc(Cl)ccc3c12
Temperature: 50 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
To a suspension of 2-(7-chlorodibenzofuran-1-ylmethylsulfanyl)acetamide (Example 151 2.56 g, 8.38 mmole) in acetic acid (90 mL), were added 1.4 mL of 35% hydrogen peroxide (14.4 mmole). The mixture was heated at 50° C. for 30 minutes to give a solution, then stirred at RT for 24 hours to give a thick suspension which was filtered, washed by ethanol, ether, dried in vacuum to give 2 g of white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl[CH2:13]CCl.CO.S(=O)(=O)(O)O>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:13])=[O:6]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: ClCCCl
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc(O)c(F)c1
Yield: 91.6 %

Procedure:
10.0 g (64.1 mM) of 3-fluoro-4-hydroxybenzoic acid, 150 ml of 1,2-dichloroethane, 80 ml of methanol and 10 ml of concentrated sulfuric acid were mixed, followed by refluxing for 5.5 hours under stirring and further stirring for 12 hours at room temperature. After the reaction, a solution of salt was added to the reaction mixture, followed by sufficient shaking to separate the reaction mixture. The organic layer was recovered from the reaction mixture and the water layer was subjected to extraction with methylene chloride to be added thereto. The resultant organic layer was washed with a 5%-aqueous solution of sodium hydrogencarbonate in a solution of salt and further washed with a solution of salt, followed by drying with anhydrous sodium sulfate. The sodium sulfate was recovered by filtration and the filtrate was condensed into a solid. Hexane was added to the solid and subjected to filtration to obtain 9.98 g of methyl 3-fluoro-4-hydroxybenzoate (Yield: 91.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[O:13])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Cl)c(I)cc1NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(I)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetic acid (280 mg, 0.83 mmol) and tert-butyl piperazine-1-carboxylate (185 mg, 0.99 mmol) in DMF (10 mL) at room temperature, BOP (550 mg, 1.25 mmol) and DIEA (321 mg, 2.4 9 mmol) were added and the resulting mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=3:1) to afford the desired product (350 mg, 68.7% yield). ESI-MS m/z: 510.3[M+1]+.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-])=O.[CH:15]1([SH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH:15]1([S:21][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: SC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1NC(=O)c2cc(SC3CCCCC3)ccc21
Yield: 114.7 %

Procedure:
A mixture of 5-nitro-isoindole-1,3-dione (10.0 g), cyclohexanethiol (9.1 g) and potassium carbonate (18.7 g) in acetone (260 ml) was heated to reflux overnight. After cooling, the mixture was diluted with water (250 ml) and then acidified by 6 N HCl to pH=4. Precipitate was collected and dried in vacuo to give the intermediate 5-cyclohexylsulfanyl-isoindole-1,3-dione (15.6 g). This intermediate was dissolved in acetone (170 ml) and to the mixture was added bromo ethylacetate (10.6 g) and potassium carbonate (23.8 g). The mixture was refluxed overnight. After cooling, reaction mixture was filtered and rinsed with ethyl acetate. Filtrate was concentrated and purified by silica gel chromatography (10%-50% ethyl acetate in methylene chloride) to give the title compound (13.1 g). 1H NMR (200 MHz, CDCl3) δ 7.73 (m, 2H), 7.56 (dd, J=7.8, 1.6 Hz, 1H), 4.40 (s, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.37 (m, 1H), (m, 1H), 2.07-1.28 (m, 13H).
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40]O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1C=CC=CC=1>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][I:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(CI)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Imidazole (1.58 g, 23.2 mmol), triphenylphosphine (6.09 g, 23.2 mmol) and iodine (4.72 g, 18.6 mmol) were added to 1-(tert-butoxycarbonyl)piperidin-3-yl methanol (2.00 g, 9.29 mmol) in benzene (50 mL). The mixture was stirred at room temperature for 3 hours. Subsequently, the reaction mixture was filtered through Celite and the solvent was evaporated. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with brine and was dried over magnesium sulfate, followed by evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 2.91 g (96%) of the desired compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[N:20]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[CH:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[N:21]=[N:22][CH:23]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[CH:33]=[CH:34][N:30]([C:27]2[CH:26]=[CH:25][C:24]([N:20]3[N:21]=[N:22][CH:23]=[N:19]3)=[CH:29][CH:28]=2)[C:31]1=[O:35])[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2ncnn2)cc1
Product: C[C@@H](n1ccn(-c2ccc(-n3ncnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 26).
Reaction SMILES: Cl[CH:2]([C:12](=O)[CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]([NH2:32])=[S:31])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>C(O)C>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[Cl:10])[CH2:3][C:2]1[S:31][C:30]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:17]([O:16][CH3:15])[CH:18]=2)=[N:32][C:12]=1[CH3:13]
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CC(=O)C(Cl)Cc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: COc1cc(Nc2nc(C)c(Cc3ccc(Cl)c(Cl)c3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from crude 2-chloro-1-(3,4-dichloro-phenyl)-butan-3-one and 53 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea in ethanol (1 ml). The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 85 mg (93%) of the title compound as a brown solid. MS ISP (m/e): 4.59.3/461.2/460.3/462.2 (100/74/35/20) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.63 (s, 1H), 7.37 (d, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 7.15 (d, 1H), 7.03 (d, 1H), 6.89 (d, 1H), 6.86 (s, 1H), 3.93 (s, 2H), 3.83 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3]([NH2:5])=[O:4].[CH:7]([C:10]1[CH:16]=[CH:15][C:13](N)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].CNC>ClC1C=CC(Cl)=CC=1Cl>[CH:7]([C:10]1[CH:16]=[CH:15][C:13]([NH:5][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])=[CH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: CN(C)C(N)=O
Reactant: CC(C)c1ccc(N)cc1
Agent: CNC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CC(C)c1ccc(NC(=O)N(C)C)cc1
Temperature: 205 °C
Reaction time: 5.5 h

Procedure:
3.35 g (0.038 mol) of N,N-dimethylurea and 3.38 g (0.025 mol) of 4-isopropylaniline were added with stirring into 20 ml of 1,2,4-trichlorobenzene. The reaction mixture was heated to 205° C., dimethylamine being introduced from 120° C. After 5.5 hours, 8.8 g (0.19 mol) of dimethylamine had been introduced and the reaction was complete.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[CH:11]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1>ClCCl>[CH3:10][C:4]12[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH:3]1[CH:18]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: C1=CCCCCCC1
Solvent: ClCCl
Product: CC1(C)CC(=O)C2C3CCCCCCC3C2(C)C1
Reaction time: 7 h
Yield: 88 %

Procedure:
To a 5-liter flask equipped with a quartz immersion well and nitrogen bubbler was added, under nitrogen, 138 g. (1.0 mol.) of isophorone and 420 g. of freshly distilled cyclooctene. The flask was filled with dichloromethane and was bubbled with nitrogen for 1 hour. The solution was irradiated for 18.5 hours with an Hanovia 450 watt medium pressure mercury arc through a Corning 9700 glass filter. After 7 hours, an additional 82 g. of cyclooctene was added. The solution was concentrated in vacuo to obtain an oil which was distilled through a 45 cm. Vigreux-column to yield 218.4 g. (0.881 mol., 88% yield) of product, b.p. 106°-110° C./0.3 mm.Hg. The product by glpc consisted of 3 isomers in the approximate ratio of 75:12.5:12.5. IR: 1692 cm-1 confirmed the production of the desired product.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][C:11]#[CH:12])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:20]>C(O)(=O)C.O>[C:11]([CH2:10][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:8]=[O:9])(=[O:20])[CH3:12]
Reactant: O=S(=O)(O)O
Reactant: C#CCC(C=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)CC(C=O)(c1ccccc1)c1ccccc1
Yield: 103.9 %

Procedure:
A solution of 2,2-diphenyl-2-(2-propynyl)acetaldehyde (83.0 g) in acetic acid (83 ml) was added dropwise to a solution of mercuric acetate (3.1 g) and sulfuric acid (18.3 g) in a mixture of acetic acid (300 ml) and water (75 ml) over a period of 2 hours at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and aqueous solution of sodium bicarbonate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (5:1) as an eluent to give 3-acetyl-2,2-diphenylpropionaldehyde (48.9 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[C:9]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:10][CH:11]=[CH:12][CH:13]=2)[O:5][N:4]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1C=C(C2C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=CC=2)ON=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:2][C:3]2[CH:7]=[C:6]([C:8]3[C:9]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:10][CH:11]=[CH:12][CH:13]=3)[O:5][N:4]=2)=[CH:41][CH:42]=1
Reactant: OB(O)c1ccc(COc2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(CBr)no1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(-c2cccnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, to a mixture of di-tert-butyl {3-[3-(bromomethyl)isoxazol-5-yl]pyridin-2-yl}imidodicarbonate (68 mg, 0.15 mmol), {4-[(pyridin-2-yloxy)methyl]phenyl}boronic acid (34 mg, 0.15 mmol), potassium phosphate (35 mg, 0.17 mmol), triphenylphosphine (7.9 mg, 0.03 mmol), and toluene (1.0 mL) was added palladium acetate (1.7 mg, 5 mol %), which was stirred for 16 hours at 90° C. After cooling, ethyl acetate and water were added thereto, and the mixture was transferred to a separatory funnel and separated. The organic layer was washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography, so as to obtain a mixture of the titled compound, di-tert-butyl {3-[3-(bromomethyl)isoxazol-5-yl]pyridin-2-yl}imidodicarbonate, and di-tert-butyl [3-(3-methylisoxazol-5-yl)pyridin-2-yl}imidodicarbonate (54 mg:molar ratio of 53:36:11), as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[S:10][C:6]=2[CH:5]=1)([O-])=O.Cl[Sn]Cl.N.CO.C(Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[S:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc(NCCN3CCCC3)sc2c1
Agent: Cl[Sn]Cl
Agent: N
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: Nc1ccc2nc(NCCN3CCCC3)sc2c1
Yield: 65 %

Procedure:
A suspension of 6-nitro-2-(2-pyrrolidin-1-ylethylamino)benzothiazole (Example 11, 50 mg, 0.17 mmol) and SnCl2 (161 mg, 0.85 mmol) in 20 mL of ethanol (denatured) was heated at reflux for 4 hours. After cooling the mixture was partitioned between 50 mL of ethyl acetate and 20 mL of 1.0N aqueous NaOH. The organic layer was dried over sodium sulfate and concentrated to give a yellow residue which was subjected to silica gel column chromatography (5% 2M NH3/MeOH:95% CH2Cl2). Yield: 65%, 1H-NMR (CD3OD): δ 8.70 (d, 1H, J=8.3 Hz); 8.47 (d, 1H, J=2.0 Hz); 8.21 (dd, 1H, J=6.3, 1.9 Hz); 5.05 (t, 2H, J=6.3 Hz); 4.28 (t, 2H, J=6.8 Hz); 4.14 (m, 4H); 3.33 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:4]=2[NH:5][C:6]2[CH:12]=[C:11](F)[CH:10]=[CH:9][C:7]=2[N:8]=1.Cl.CN(C)CCNC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[F:42]C1C=CC2N=C(N(CCN(C)C)C)C3C4C=CC=CC=4SC=3NC=2C=1>CS(C)=O>[NH2:1][C:2]1[C:3]2[C:16]3[CH:17]=[CH:18][C:19]([F:42])=[CH:20][C:15]=3[S:14][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Reactant: CN(C)CCN(C)C1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Agent: CNCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Product: NC1=Nc2ccccc2Nc2sc3cc(F)ccc3c21

Procedure:
In the same manner as in Example 42 and using 12-amino-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1 hydrochloride (1.3 g), N,N,N′-trimethylethylenediamine (13 g), dimethyl sulfoxide (5 ml) and citric acid, 8-fluoro-12-[N-(2-dimethylaminoethyl)-N-methylamino]-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1 citrate 1 hydrate (289 mg) was obtained.
Reaction SMILES: [CH:1]([C:3]1[C:15]([O:16]C)=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[O:2].[I-].[Mg+2].[I-].Cl>O1CCCC1.CCOCC>[CH:1]([C:3]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[O:2]
Reactant: COc1cccc(OCCCCC#N)c1C=O
Agent: Cl
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCCCCOc1cccc(O)c1C=O

Procedure:
To a stirred solution of 5-(2-formyl-3-methoxyphenoxy)pentanonitrile (2.33 g, 0.01 M) in dry tetrahydrofuran (28 ml) was added dropwise a solution of magnesium iodide (4.17 g, 0.015 M) in dry ether (55 ml). The mixture was then stirred under reflux (51/2 hr). The cooled mixture was poured into 10% hydrochloric acid (50 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic solutions were washed with water and extracted quickly with 2 N sodium hydroxide solution (1×25 ml). The separated aqueous phase was immediately acidified with concentrated hydrochloric acid with cooling and the solid produced filtered off and washed with water to give 5-(2-formyl-3-hydroxyphenoxy)pentanonitrile, m.p. 66°-67° C. from benzene/petrol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]=[N+:13]=[N-:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of 4-chlorobenzenesulfonyl chloride (5.28 g) in tetrahydrofuran (25 mL) was added a solution of sodium azide (1.79 g) in water (12.5 mL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 4-chlorobenzenesulfonyl azide (4.27 g, yield: 78%) as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:4]=2[CH:3]=1.[CH3:13][S:14][CH2:15][S:16]([CH3:18])=[O:17]>>[NH2:12][C:11]([C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([CH3:1])=[CH:3][C:4]=2[CH:10]=1)=[C:15]([S:16]([CH3:18])=[O:17])[S:14][CH3:13]
Reactant: CSCS(C)=O
Reactant: Cc1cc2cc(C#N)ccc2o1
Product: CSC(=C(N)c1ccc2oc(C)cc2c1)S(C)=O

Procedure:
2-Methyl-5-cyanobenzo(b)furan (17.25 g., 0.11 mole) was treated with methyl methylthiomethyl sulphoxide as described in Example 8, Part B, to yield 1-amino-1-[2-methyl-5-benzo(b)furanyl]-2-methylsulphinyl-2-methylthioethylene (12.4 g.), m.p. 185°-186° C.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[S:21][C:20]([NH:22][C:23]([N:25]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])=[N:19][CH:18]=2)[CH2:12]1)=[O:10])C1C=CC=CC=1>[Pd].CO>[CH:32]1([N:25]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:23](=[O:24])[NH:22][C:20]2[S:21][C:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:11]([C:9]([OH:10])=[O:8])[CH2:12]3)=[CH:18][N:19]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=C(OCc1ccccc1)C1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)C1

Procedure:
1-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-pyrrolidine-3-carboxylic acid benzyl ester (30 mg, 0.057 mmol) was combined with palladium on carbon (20 mg) in MeOH. Vacuum was applied to degas the mixture. The reaction was subjected to hydrogen and vigorous stirring until no ester could be detected (24 h). After filtering and concentration, the pure acid was obtained by trituration.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[N+]=[N-]>[Pd]>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][NH2:1])[CH:12]=1
Reactant: [N-]=[N+]=NCc1ccccc1-c1cccnc1
Agent: [Pd]
Product: NCc1ccccc1-c1cccnc1

Procedure:
The product of Example 119B and Pd/C were processed according to the method of Example 115B to provide the product. MS (ESI+) m/z 185 (M+H)+.