Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[C:24](Br)=[CH:23][N:22]=[C:21]([NH2:26])[N:20]=2)[N:16]([CH3:27])[CH:15]=1)=[O:13])[CH3:2].[CH3:28][Al](C)C>C1COCC1.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>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[C:24]([CH3:28])=[CH:23][N:22]=[C:21]([NH2:26])[N:20]=2)[N:16]([CH3:27])[CH:15]=1)=[O:13])[CH3:2]
Reactant: C[Al](C)C
Reactant: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(N)ncc2Br)n(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(N)ncc2C)n(C)c1
Temperature: 65 °C

Procedure:
To a solution of 5-(2-Amino-5-bromo-pyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide (83.7 mg, 0.1954 mmol) in 4 mL of dry THF, AlMe3 (1M in toluene, 0.488 mL, 0.977 mmol) and Pd(PPh3)4 (22.6 mg, 0.0195 mmol) were added under argon. The mixture was heated at 65° C. for 1 h. After dilution with water and extraction with CH2Cl2 the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was treated with Et2O affording 58.8 mg (83%) of the desired product.
Reaction SMILES: [Na].C(O)C.[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([Cl:27])=[CH:15][C:14]=1[C:28](=[O:30])[CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:31](OCC)(=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(O)(=O)C>[CH2:35]([O:34][C:32](=[O:33])[C:31]([OH:37])=[CH:29][C:28]([C:14]1[CH:15]=[C:16]([Cl:27])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:13]=1[O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:30])[CH3:36]
Reactant: CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(O)=CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
Sodium metal (1.35 g, 0.058 mol) was added in small pieces over a period of 20 minutes to stirred anhydrous ethanol under a nitrogen atmosphere. The reaction mixture was then stirred for a further 10 minutes until all the sodium had reacted to give a homogeneous solution. 1-(2,4-bis-benzyloxy-5-chloro-phenyl)-ethanone (10.0 g, 0.027 mol) was added in portions over 2-3 minutes and the resulting suspension was stirred for 5 minutes prior to addition of diethyl oxalate (6 ml, 0.043 mol) which afforded a thicker, yellow precipitate. The reaction mixture was heated to reflux (giving homogeneous brown solution) for 4 hours, then allowed to cool to room temperature and acetic acid (6 ml) was added. The resulting which solid forms was triturated, filtered, washed with ethanol and dried to give a yellow solid (12.0 g, 95%). 1H NMR (400 MHz, CDCl3) δ 1.2 (t, 3H), 4.19 (q, 2H), 5.05 (s, 2H), 5.10 (s, 2H), 6.50 (s, 1H), 7.22-7.41 (m, 10H), 7.97 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: C1CNCCN1
Reactant: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)CCS2

Procedure:
To one gram of 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)quinoline-4-carboxylic acid (33 mmol) were added 2.87 grams (33 mmol) of anhydrous piperazine and 30 ml of pyridine and the resulting suspension was heated to reflux for twelve hours in an oil bath. Pyridine was evaporated therefrom under reduced pressure, water was added to the residue, and the mixture was again concentrated under reduced pressure. Water was added to the resulting residue, then 4 ml of 2 N aqueous solution of sodium hydroxide was added thereto, and the mixture was warmed to prepared uniform solution. Then this was adjusted to pH nearly seven with 1 N hydrochloric acid. Crystals separated out therefrom were collected by filtration, washed with water, washed with acetone and ether, and air dried to give the title product as powdery crystals. Yield 997.8 mg (90.7 percent). Melting point 287° to 288° C. (decomposition). Elementary analysis calculated as C16H16FN3O3S.3H2O: C 47.64, H 5.50, N 10.41; Found: C 47.60, H 5.42, N 10.63.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C-:32]#[N:33].[Na+].O>CS(C)=O>[C:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:33]
Reactant: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
1-(7-Bromoheptyl)-2,4,5-triphenylimidazole (7 g) in dry dimethylsulphoxide (15 ml) was added over 20 minutes to a mixture of sodium cyanide (0.87 g) in dimethyl-sulphoxide (25 ml). The reaction was stirred at 40° C. for 1 hour. The cooled reaction mixture was poured into water (800 ml) and extracted with diethyl ether (4×100 ml). The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from dichloro-methane/hexane gave 1-(7-cyanoheptyl)-2,4,5-triphenylimidazole (3.7 g,60%) as a white solid, m.p. 93°-94°; Found: C, 82.35; H, 6.90; N, 9.96%; C29H29N3 1% CH2Cl2 requires C, 82.43; H, 6.91; N, 9.91%.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C:13]([CH2:15]Br)=[C:12]([CH2:17]Br)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:26](#[N:28])[CH3:27]>C(N)C>[CH2:26]([N:28]1[CH2:15][C:13]2[CH2:14][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:19])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:11][C:12]=2[CH2:17]1)[CH3:27]
Reactant: CC#N
Reactant: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CBr)C2)cc1
Agent: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN1CC2=C(C1)CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of 1-p-toluene sulfonyl-3,4-bis (bromomethyl)-3-pyrroline (3.41 g) in acetonitrile (43 ml), 0.73 ml of 70% ethylamine and anhydrous potassium carbonate (8 g) were added and stirred at room temperature for one hour. The solid was filtered off and the filtrate was purified by silicagel column chromatography (CHCl3 --MeOH) to give 3-ethyl-7-p-toluene sulfonyl-3,7-diazabicyclo [3.3.0]oct-1(5)-ene (0.95 g, yield 39%). 0.9 g of this compound was hydrolysized in 20 ml of 48% hydrobromic acid with 1 g of phenol. The hydrolysate was washed with chloroform (30 ml×3) and decolorized with active carbon. The solvent was concentrated and washed with ethanol to give the title compound (0.57 g, yield 62%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:11])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3]1.[Br:23]Br>CN(C=O)C>[Br:23][C:3]1[N:2]([CH3:1])[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:14])([F:16])[F:15])[C:10](=[O:11])[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: Cn1cc(-c2ccccc2)c2c(=O)n(CC(F)(F)F)cnc21
Solvent: CN(C)C=O
Product: Cn1c(Br)c(-c2ccccc2)c2c(=O)n(CC(F)(F)F)cnc21
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a stirring solution of 7-methyl-5-phenyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (825 mg, 2.68 mmol) in anhydrous DMF (6 ml) at 0° C. was added bromine (0.152 ml, 2.95 mmol) and the mixture stirred for 30 min. The mixture was partitioned between ethyl acetate (50 ml) and an aqueous mixture (water, saturated sodium hydrogen carbonate solution and 20% w/w sodium thiosulfate solution, 3:1:4; 100 ml). The aqueous phase was separated and extracted using ethyl acetate (3×25 ml). The combined ethyl acetate fractions were washed with brine/water (1:1, 4×25 ml), dried (anhydrous sodium sulfate), filtered and reduced in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-40% ethyl acetate in cyclohexane) to afford the title compound (0.97 g, 94%). LCMS RT=1.40 min, M+H+=385.9/388.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:18]=[N:17][C:16]([Br:19])=[CH:15][N:14]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:19][C:16]1[N:17]=[CH:18][C:13]([NH:12][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])=[N:14][CH:15]=1
Reactant: Nc1cnc(Br)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cnc(Br)cn1)c1c(F)cccc1F
Temperature: 0 °C
Yield: 52.8 %

Procedure:
To a 0° C. cooled and stirred, solution of 2,6-difluorobenzoyl chloride (5.7 g, 36.2 mmol, 0.9 eq) in DCM (200 mL) was added drop wise a solution of 2-amino-5-bromopyrazine (7.0 g, 40.2 mmol, 1.0 eq) in DCM (50 mL) followed b pyridine (3.1 g, 36.2 mmol, 0.9 eq). The resulting mixture was stirred at room temperature for 15 h. The reaction was diluted with DCM (100 mL), and washed with 10% hydrochloric acid (100 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexane) to afford 6.0 g of the title product as a yellow solid. 1HNMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.62 (s, 1H, D2O exchangeable), 8.24 (s, 1H), 7.53-7.45 (m, 1H), 7.03 (t, J=8.0 Hz, 2H); ESI-MS (m/z) 314, 316 [(MH)+ Br79,81].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[S:11][CH:12]=1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][CH3:34])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][CH3:34])=[CH:28][CH:27]=3)=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: CCC(=O)c1ccc(F)cc1
Reactant: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(O)cc1
Product: CCC(=O)c1ccc(Oc2ccc(-c3scc(-c4ccccc4Cl)c3CC(=O)OC)cc2)cc1

Procedure:
Methyl [4-(2-chlorophenyl)-2-(4-hydroxyphenyl)thien-3-yl]acetate was reacted as in Example 9, Step 2 with p-fluoropropiophenone (0.213 g, 1.40 mmol) to yield methyl {4-(2-chlorophenyl)-2-[4-(4-propionylphenoxy)phenyl]thien-3-yl}acetate (0.398 g). This material was reacted as in Example1, Steps 7 and 8 to yield N″-({4-(2-chlorophenyl)-2-[4-(4-propionylphenoxy)phenyl]thien-3-yl}acetyl)guanidine (0.151 g) as a white solid. mp 123-124° C.; 1H NMR (500 MHz, DMSO-d6) δ: 1.04 (t, 3H, J=7.2 Hz), 2.98 (q, 2H, J=7.2 Hz), 3.23 (s, 2H), 7.08 (d, 2H, J=8.9 Hz), 7.14 (d, 2H, J=8.7 Hz), 7.31 (m, 4H), 7.47 (d, 1H, J=8.1 Hz), 7.59 (d, 2H, J=8.7 Hz), 7.96 (d, 2H, J=8.9 Hz). MS (ES) m/z 518.10 ([M+H]+).
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S@:12]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[O:13])[C:6]=1[CH3:23])(=O)=O.[CH2:24]([OH:29])[C:25]([F:28])([F:27])[F:26]>>[CH3:23][C:6]1[C:7]([CH2:11][S@:12]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[O:13])=[N:8][CH:9]=[CH:10][C:5]=1[O:29][CH2:24][C:25]([F:28])([F:27])[F:26]
Reactant: OCC(F)(F)F
Reactant: Cc1c(S(C)(=O)=O)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Product: Cc1c(OCC(F)(F)F)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1

Procedure:
In accordance with yet another embodiment of the present invention, there is provided a process for producing (R)-(+)2-([3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl)-1H-benzimidazole comprising reacting 4-chloro-2,3-dimethyl-pyridine-1-oxide with sodium methane thiolate to give 2,3-dimethyl-4-methylsulfanyl-pyridine-1-oxide followed by oxidation using a suitable oxidizing agent to obtain (4-methanesulfonyl-2,3-dimethyl-pyridine)-1-oxide, chlorinating the resultant in the presence of suitable chlorinating agent to obtain 2-chloromethyl-4-methanesulfonyl-3-methylpyridine, condensing the 2-chloromethyl-4-methanesulfonyl-3-methylpyridine in presence of a suitable base in a solvent, optionally in the presence of a phase transfer catalyst with 2-mercaptobenzimidazole to obtain 2-(4-methanesulfonyl-3-methyl-pyridine-2-ylmethylsulfonyl)-1-H-benzimidazole, stereoselective oxidation of the 2-(4-methanesulfonyl-3-methyl-pyridine-2-ylmethylsulfonyl)-1-H-benzimidazole using an optically active compound in presence of a metal catalyst and a suitable solvent to obtain (R)-2-(4-methanesulfonyl-3-methyl-pyridin-2-ylmethanesulfinyl)-1H-benzimidazole and subsequently reacting the (R)-2-(4-methanesulfonyl-3-methyl-pyridin-2-ylmethanesulfinyl)-1H-benzimidazole with trifluoroethanol to obtain the (R)-(+)2-([3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl)-1H-benzimidazole.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:13][CH2:12]1.I[CH3:36]>O1CCCC1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH:21]([O:26][CH3:36])[C:22]([F:24])([F:23])[F:25])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:13][CH2:12]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(O)C(F)(F)F)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 88.3 mg, 2.21 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (0.68 g, 1.47 mmol) and iodomethane (92.0 μL, 1.47 mmol) in tetrahydrofuran (20 mL) at 0° C. After 2 h, the mixture was allowed to warm to ambient temperature. After 2 h, additional iodomethane (92.0 μL, 1.47 mmol) and sodium hydride (60% dispersion in mineral oil; 10.0 mg, 0.27 mmol) were added. After 1 h, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→30% ethyl acetate/dichloromethane) gave the title compound (195 mg). MS 476.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].CCN(C(C)C)C(C)C.[CH2:28]([O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][N:35]=[C:36]=[O:37])[CH3:29]>C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH:17][C:15]1[S:16][C:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([F:1])[CH:3]=2)=[C:13]([CH3:18])[N:14]=1)=[O:37])[CH3:29]
Reactant: CCOC(=O)CCCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1

Procedure:
5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72), (0.1 g, 0.31 mmol) DIPEA (0.039 ml, 0.34 mmol), ethyl-4-isocyanatobutyrate (0.046 ml, 0.31 mmol) in DCM (2 ml) are heated together at reflux overnight. The reaction mixture is diluted with DCM (20 ml) and washed with 1M hydrochloric acid (15 ml), water (2×15 ml), brine (15 ml), dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:20]12[CH2:26][CH:23]([CH:24]=[CH:25]1)[CH2:22][CH:21]2[C:27](Cl)=[O:28]>>[CH:20]12[CH2:26][CH:23]([CH:24]=[CH:25]1)[CH2:22][CH:21]2[C:27]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:28]
Reactant: O=C(Cl)C1CC2C=CC1C2
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(C1CC2C=CC1C2)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Following the procedure of Example 8, 19.53 g. of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g. of sodium carbonate and 5-norbornene-2-carbonyl chloride are reacted to give the product as a light brown-yellow oily gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH2:13])=[CH:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:20]I>O1CCCC1.O>[I:20][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH2:13]
Reactant: COc1ccc2ccc(N)cc2c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2ccc(N)c(I)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a mixture of 7-methoxynaphthalen-2-amine (5 g, 29 mmol) and sodium carbonate (6.1 g, 57.6 mmol) in tetrahydrofuran (200 ml) and water (20 ml) was added iodine (7.0 g, 27.67 mmol) in portions at 0° C. The resulting solution was stirred overnight at room temperature and then diluted with water (250 ml), extracted with ethyl acetate (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 5% ethyl acetate in petroleum ether to afford 1-iodo-7-methoxynaphthalen-2-amine as a yellow solid (5.2 g, 60%). (ES, m/z): [M+H]+ 300.1; 1H NMR (300 MHz, CDCl3): δ 7.54 (dd, J=8.7, 5.4 Hz, 2H), 7.30 (d, J=2.4 Hz, 1H), 6.91 (dd, J=8.7, 2.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.04 (br s, 2H), 3.96 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]#[C:16]/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]([C:54]([O:56]C)=[O:55])[CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[O:53])/[CH:37]=[CH:38]/[C:39]#[C:40][C:41]4[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=4)[CH2:32][CH2:31]3)[CH2:23][CH2:22]2)=[O:20])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].Cl>CO>[CH3:52][O:51][C:43]1[CH:42]=[C:41]([C:40]#[C:39]/[CH:38]=[CH:37]/[C:36]([N:33]2[CH2:32][CH2:31][CH:30]([CH2:29][CH:28]([C:54]([OH:56])=[O:55])[CH2:27][CH:24]3[CH2:25][CH2:26][N:21]([C:19](=[O:20])/[CH:18]=[CH:17]/[C:16]#[C:15][C:7]4[CH:6]=[C:5]([O:4][CH3:3])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=4)[CH2:22][CH2:23]3)[CH2:35][CH2:34]2)=[O:53])[CH:46]=[C:45]([O:47][CH3:48])[C:44]=1[O:49][CH3:50]
Reactant: COC(=O)C(CC1CCN(C(=O)/C=C/C#Cc2cc(OC)c(OC)c(OC)c2)CC1)CC1CCN(C(=O)/C=C/C#Cc2cc(OC)c(OC)c(OC)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C#C/C=C/C(=O)N2CCC(CC(CC3CCN(C(=O)/C=C/C#Cc4cc(OC)c(OC)c(OC)c4)CC3)C(=O)O)CC2)cc(OC)c1OC
Reaction time: 1 h
Yield: 34.4 %

Procedure:
A 5N aqueous sodium hydroxide (2 ml; 10 mmol) was added to a solution in methanol (2 ml) of methyl 1,3-bis[1-[(E)-5-(3,4,5-trimethoxyphenyl)-2-penten-4-ynoyl]-4-piperidinyl]-2-propanecarboxylate (136 mg; 0.18 mmol) synthesized by the above process, and the mixture was stirred for 1 hour in a bath controlled at 65° C. The reaction mixture was made acidic by addition of 1N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 46 mg (yield: 35%) of the title compound as a pale yellow amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(=[O:18])[C:11](N1C=CN=C1)=[O:12]>O1CCCC1>[OH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[NH:1][C:10](=[O:18])[C:11](=[O:12])[NH:8]2
Reactant: Nc1cccc(O)c1N
Reactant: O=C(C(=O)n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(O)c2[nH]c1=O

Procedure:
A solution of 2,3-diaminophenol (50 g) and 1,1′-oxalyldiimidazole (92 g) and tetrahydrofurane (1.2 L) is refluxed 30 minutes. The solvent is removed under reduced pressure and the remaining solid taken into ethyl acetate. The organic phase is washed with 1M aqueous hydrochloric solution, dried over sodium sulphate and concentrated under vacuum. The crude solid obtained is recrystallised from dimethylformamide; yield: 14.8 g; MS: 177.1 (M−1); 1H NMR (DMSO-d6, 300 MHz): δ [ppm] 6.61 (m, 2H); 6.91 (ss, 1H), 10.21 (s (1H); 11.05 (s, 1H); 11.85 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].[H-].[Na+].Br[CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[CH:13]=[CH:12][C:11]=1[C:21]1[C:22]([S:27]([N:30]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[C:38]=2[CH3:43])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])(=[O:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>CN(C=O)C.O>[CH3:42][C:39]1[C:38]([CH3:43])=[C:37]([N:30]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:27]([C:22]2[C:21]([C:11]3[CH:12]=[CH:13][C:14]([C:16]4[O:17][CH:18]=[CH:19][N:20]=4)=[CH:15][C:10]=3[CH2:9][S:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:29])=[O:28])[O:41][N:40]=1
Reactant: CC(C)CS
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CSCC(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 5 equiv. of 2-methyl-1-propanethiol (125 mg, 1.39 mmol) in 1 ml of dry DMF was added 2.5 equiv. of 60% sodium hydride under an argon atmosphere at room temperature. The reaction mixture was stirred for 0.5 hrs. and then a solution of the title compound of Step (B) (160 mg, 0.278 mmol) in 1 ml of DMF was added. The reaction was stirred for 1 hr, diluted with 15 ml of water and extracted with ethyl acetate (3×20 ml). The ethyl acetate extract was washed with 5% lithium chloride (2×30 ml), brine and dried over sodium sulfate. The crude material was purified on a Merck silica column eluting with 40% ethyl acetate/hexane yielding 118 mg (68%) of the title compound of this step as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl.[C:22](=N)(OCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(-c3ccccc3)n1-2

Procedure:
A solution of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 1.8 parts of ethyl benzimidate hydrochloride in 30 parts by volume of chloroform is stirred at room temperature for 24 hours and then washed with water.The chloroform layer is dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with diethyl ether yields 8-chloro-1,6-diphenyl-4H-s-triazolo-[4,3-a] [1,4] benzodiazepine as crystals. Recrystallisation from a mixture of ethyl acetate and n-hexane yields colorless needles melting at 192° C to 193.5° C.