Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[Cu](C#N)[C:15]#[N:16].CN1CCCC1=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:15]#[N:16])[CH:7]=1)[CH3:2]
Reactant: N#C[Cu]C#N
Reactant: CCOC(=O)Cc1cccc(Br)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(C#N)c1
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of (3-bromo-phenyl)-acetic acid ethyl ester (9.15 g, 37.6 mmol), copper cyanide (5.06 g, 56.5 mmol), and 1-methyl-2-pyrrolidinone (80 mL) was placed into an oil bath heated at 120° C. behind a protective shield. The reaction was heated to 200° C. for 1 h and additional copper cyanide (spatula tip) was added. After heating for an additional 0.5 h, the reaction was cooled to room temperature. The reaction was diluted with EtOAc and the organic solution was washed with water/ammonium hydroxide solution (2:1 v/v) until the aqueous solution was no longer blue. The organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc) provided (3-cyano-phenyl)-acetic acid ethyl ester (6.31 g) as a clear oil which solidified on standing. 1H NMR (400 MHz, CDCl3) 6 7.57-7.50 (m, 3H), 7.42 (m, 1H), 4.15 (q, 2H), 3.63 (s, 2H), 1.24 (t, 3H).
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[C:26]([Cl:32])[CH:25]=1>C1COCC1.CCCCCC>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:10]2[CH2:11][CH2:12][N:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:14])[CH2:7][CH2:6]3)[C:9]2=[O:13])=[C:26]([Cl:32])[CH:25]=1
Reactant: O=C1CCCN1C1CCC(F)(F)CC1
Reactant: Clc1cc(Br)ccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCC(F)(F)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one (190 mg, 0.94 mmol) in 10 mL dry THF, add 1.04 mL of 1.5M LDA (1.5 eq.) in hexane dropwise at −78° C. Then, add 0.59 g of 4-bromo-1-bromomethyl-2-chloro-benzene (1.5 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NaCl and extract with Et2O. Wash the organic layer with water, then brine, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 407 (M+1).
Reaction SMILES: [ClH:1].Cl.[F:3][CH:4]([F:32])[C:5]1[N:9]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]([NH:22][C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[N:11]=2)[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1.CN(C)C=O.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]Br.C(=O)([O-])[O-].[K+].[K+]>O>[ClH:1].[ClH:1].[F:32][CH:4]([F:3])[C:5]1[N:9]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]([NH:22][C@H:23]3[CH2:27][CH2:26][N:25]([CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[CH2:24]3)[N:11]=2)[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1
Reactant: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(N[C@H]2CCNC2)n1
Reactant: CN(C)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN1CC[C@H](Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine dihydrochloride (75 mg) and N,N-dimethylformamide (1.5 mL) were added 2-(dimethylamino)ethyl bromide (26 mg) and potassium carbonate (85 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50-0:100, and subsequently chloroform:methanol=100:0-80:20). Desired fractions are combined and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (0.5 mL) and a 4 M solution (80 μL) of hydrogen chloride in 1,4-dioxane was added thereto. Diisopropyl ether (10 mL) was further added thereto. The resulting powder was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{(3S)-1-[2-(dimethylamino)ethyl]pyrrolidin-3-yl}-6-morpholin-4-ylpyrimidin-2-amine dihydrochloride (10 mg) as a white powder.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([CH3:22])=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])[N:18]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[C:38](OC(=O)C)(=O)C>N1C=CC=CC=1>[C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([C:17]2[C:21]([CH3:22])=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])[N:18]=2)=[O:16])[CH2:12][CH2:13]1)(=[O:7])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)N1CCC(NC(=O)c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1
Yield: 81 %

Procedure:
tert-Butyl-4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate (1 eq, 34 mg, 0.073 mmol) was stirred in pyridine (1 mL) and acetic anhydride (1 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure N-(1-acetylpiperidin-4-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide (30 mg, 81%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.28-1.49 (m, 2H) 1.87-2.13 (m, 5H) 2.30 (s, 3H) 2.62-2.82 (m, 1H) 3.05-3.24 (m, 1H) 3.75 (d, J=13.56 Hz, 1H) 3.98-4.25 (m, 1H) 4.49 (d, J=13.37 Hz, 1H) 6.80 (d, J=8.01 Hz, 1H) 6.99 (d, J=8.48 Hz, 2H) 7.13-7.29 (m, 4H) 7.36 (d, J=1.51 Hz, 1H).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][C:31]([C:32]([OH:34])=[O:33])=[C:8]3[C@H:7]2[CH2:35][CH3:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:49](O)[CH:50]=[CH2:51]>CN(C=O)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][C:31]([C:32]([O:34][CH2:51][CH:50]=[CH2:49])=[O:33])=[C:8]3[C@H:7]2[CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCO
Reactant: CC[C@@H]1c2c(C(=O)O)ncn2-c2cnc(Nc3ccc(C(=O)NC)cc3OC)nc2N1C1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ncn2c1[C@@H](CC)N(C1CCCC1)c1nc(Nc3ccc(C(=O)NC)cc3OC)ncc1-2
Temperature: 42.5 °C
Reaction time: 0.67 h
Yield: 77.3 %

Procedure:
(R)-5-cyclopentyl-6-ethyl-3-(2-methoxy-4-(methylcarbamoyl)phenylamino)-5,6-dihydroimidazo[1,5-f]pteridine-7-carboxylic acid 1-2 (44 mg, 0.09 mmol) in DMF (0.5 mL) was treated with carbonyldiimidazole (19 mg, 0.12 mmol) and stirred at 40-45° C. for 40 minutes. Allyl alcohol (1 ml, 14.7 mmol) was then added and the reaction mixture was stirred at 40° C. for 18 hours. The mixture was partitioned between an aqueous solution of sodium carbonate and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and concentrated to give the desired compound as a pale brown solid (37 mg, 77% yield); LC/MS M+1 (obs.) 532.68, LC/MS M−1 (obs.) 530.81.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1S.COC1C=C(S)C=CC=1.COC1C=CC=CC=1[S:27][Cl:28].COC1C=C(SCl)C=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:27][Cl:28])=[CH:5][CH:4]=1
Reactant: COc1ccccc1SCl
Reactant: COc1ccccc1S
Agent: COc1cccc(S)c1
Agent: COc1cccc(SCl)c1
Product: COc1ccc(SCl)cc1

Procedure:
By the same procedure or by the procedure of Example 13, o-methoxythiophenol and m-methoxythiophenol are converted, respectively, to o-methoxybenzenesulfenyl chloride and m-methoxybenzenesulfenyl chloride.
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH2:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCC[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-isohexyl-6-methylpiperidine (1.4 g, 5.50 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-isohexyl-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 155.0-156.0° C.; 1H NMR (250 MHz) δ 9.17 (s, 2H), 3.50 (s, 1H), 3.25 (s, 1H), 1.94-1.15 (m, 16H), 0.82 (d, 6H); 13C NMR (62.7 MHz) δ 51.7 (s), 47.9 (s), 38.4 (s), 30.9 (s), 28.8 (s), 27.8 (s), 26.1 (s), 23.5 (s), 22.5 (s), 22.3 (s), 17.3 (s), 16.8 (s) ppm. FT-IR (neat): 3430, 2948, 1615, 1589, 1557, 1472, 1436, 1418, 1362, 1102, 895. Elemental Analysis for C12H26NCl: C, 65.56%; H, 11.95%; N, 6.37%. Found: C, 64.90%; H, 11.89%; N, 6.26%.
Reaction SMILES: O[C@@H:2]([CH2:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29]C)[N:27]=2)[CH2:22][CH2:21][C:20]1=[O:31])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.CS(OS(C)(=O)=O)(=O)=O.[I-].[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[O:29]=[C:26]1[CH:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20](=[O:31])[N:19]3[CH2:18][CH:2]([CH2:3][N:4]4[CH2:5][CH2:6][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:8][CH2:9]4)[N:27]1[C:28]=23
Reactant: COc1ccc2c(n1)N(C[C@H](O)CN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CC2
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(CC2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Temperature: 80 °C
Yield: 50.7 %

Procedure:
A solution of 1,1-dimethylethyl (1-{(2R)-2-hydroxy-3-[7-(methyloxy)-2-oxo-3,4-dihydro-1,8-naphthyridin-1(2H)-yl]propyl}-4-piperidinyl)carbamate (3.9 g, 8.97 mmol) in chloroform (150 ml) and triethylamine (3.1 ml) under argon was treated with methanesulfonic anhydride (3.1 g, 17.94 mmol) at room temperature and then heated at reflux for 2.5 h. The solvents were evaporated and the residue dissolved in acetonitrile (150 ml) and treated with sodium iodide (6.7 g, 44.85 mmol) and heated at 80° C. After 45 minutes acetonitrile was evaporated and the residue was partitioned between water (250 ml) and 20% methanol/dichloromethane (250 ml); the layers were separated and the aqueous layer was extracted with 20% methanol/dichloromethane (4×250 ml). The combined organic extracts were dried on magnesium sulphate, filtered and evaporated. The crude was purified by silica chromatography using a 0-10% methanol/dichloromethane gradient to provide the desired compound as a bright orange foam (1.83 g; 57%, impure with triethylamine residues). The aqueous layer was evaporated and then treated with chloroform; the solid was filtered off and the chloroform was evaporated to give 2.77 g of a yellow solid. The solid was dissolved in methanol and loaded onto a SCX cartridge which was pre-wet with methanol. The cartridge was washed with methanol (50 ml) and then with 2M ammonia in methanol (50 ml). The 2M ammonia in methanol was evaporated to afford the pure product as a white solid (220 mg), presumed 2:1 mixture of R:S).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH3:12])=[C:6]([N:26]2[CH:30]=[CH:29][CH:28]=[CH:27]2)[CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH3:12])=[C:6]([N:26]2[CH:30]=[CH:29][CH:28]=[CH:27]2)[CH:5]=1
Reactant: CN(CCOc1ccc([N+](=O)[O-])cc1-n1cccc1)CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCOc1ccc(N)cc1-n1cccc1)CCc1ccc(N)cc1
Yield: 99 %

Procedure:
1-[4-Nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(4-nitrophenethyl)-N-methylamino]ethane (0.71 g, 1.73 mmol) was dissolved in 80 ml of a 1:1 solvent system of ethyl acetate and methanol and, after slowly adding 10% Pd/C (0.2 g), the solution was stirred at an ordinary temperature for 3 h as hydrogen gas was injected. Thereafter, the reaction mixture was filtered through Celite and the filtrate was evaporated to yield the compound 1-[4-amino-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(4-aminophenethyl)-N-methylamino]ethane (0.6 g) as a dark brown oil. The compound was dissolved in pyridine (30 ml) and, thereafter, the solution was cooled at 0° C. and methanesulfonyl chloride (0.344 ml, 4.45 mmol) was slowly added. Thereafter, the mixture was stirred at an ordinary temperature for 20 h and ethanol was added; the solvent pyridine was evaporated under vacuum and the resulting residue was added to an aqueous solution of 10% sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was washed with water twice, dried with magnesium sulfate, and the solvent was evaporated. The residue was purified by being subjected to column chromatography on silica gel using, as an eluent, ethyl acetate containing 5% methanol. The fractions containing the product were collected and the solvent was evaporated to yield the titled compound 1-[4-methanesulfonamido-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(4-methanesulfonamidophenethyl)-N-methylamino]ethane (0.43 g) as a pale yellow substance.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([CH3:16])[C:13](=O)[NH:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>N1C=CC=CC=1.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([CH3:16])[C:13](=[S:20])[NH:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1Oc2ccc(-c3ccccc3)cc2NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: CC1Oc2ccc(-c3ccccc3)cc2NC1=S
Yield: 100 %

Procedure:
1.62 g of 6-phenyl-2-methyl-1,4-benzoxazin-3-one is heated with 0.5 g of phosphorus pentasulfide in 6 ml of pyridine p.a. The product is diluted with water, extracted 3 times with ethyl acetate, the organic phase is washed with brine and dried with magnesium sulfate. It is concentrated by evaporation. The crude product corresponds to a yield of 100%. Column chromatography with a hexane/ethyl acetate mixture yields pure product.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21]>CN(C=O)C>[C:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:22])[CH3:16])[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCCN
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(Cl)n1
Solvent: CN(C)C=O
Product: CN(C)CCCNc1nc(C(C)(C)C)cn2c(=O)[nH]nc12
Reaction time: 16 h

Procedure:
A solution of 23 mg of 6-tert-butyl-8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one and 41 mg of 3-(dimethylamino)propylamine in DMF (0.5 mL) was heated to 80° C. After 16 h, the product was purified on a Shimadzu reverse-phase HPLC (Shimadzu LC-8A Preparatory LC; Waters Symmetry 30×50 mm column; solvent gradient=15-100% acetontrile/1% aqueous formic acid; flow rate=40 mL/min.) to provide the title compound as a white solid. MS (M+H+)=293.2.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.O.[SH2:12].[Na].Cl>CN(C)C=O>[S:8]1[C:7]2[C:2](=[S:12])[NH:3][CH:4]=[CH:5][C:6]=2[CH:10]=[CH:9]1
Reactant: Clc1nccc2ccsc12
Reactant: S
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: S=c1[nH]ccc2ccsc12
Temperature: 0 °C

Procedure:
(adc) 4.85 g of 7-chloro-thieno[2,3-c]pyridine were dissolved in 15 ml of dimethylformamide and 3.18 g of sodium hydrogen sulfide monohydrate were added under argon. The mixture was heated to 110°-115° for one hour, an additional 1.06 g of sodium hydrogen sulfide monohydrate were added and the mixture was held at the temperature indicated above for an additional hour. The mixture was poured on to 150 ml of ice-water and acidified with 1N aqueous hydrochloric acid solution. After stirring at 2° for a short time, the yellowish crystals were removed by filtration. After recrystallization from a toluene/ethyl acetate mixture, there was obtained pure thieno[2,3-c]pyridine-7(6H)-thione, m.p. 187°-189°.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])C1C=CC=CC=1.CN(C)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(Cl)Cl>[F:21][C:16]([F:22])([C:17]([F:18])([F:19])[F:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: FC(F)(F)C(F)(F)CCCCCCCOCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: OCCCCCCCC(F)(F)C(F)(F)F
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
16 g of 1-benzyloxy-8,8,9,9,9-pentafluoro-nonane is dissolved in 700 ml of absolute methylene chloride, mixed with 18.4 ml of N,N-dimethylaniline at 0° C. and stirred for 5 minutes. Then, 26.4 g of aluminum trichloride is added in portions, and the reaction mixture is heated for 45 minutes to 50° C. For working-up, the batch is allowed to come to room temperature, it is stirred into 2N hydrochloric acid, extracted 3 times with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient. 8.6 g of 8,8,9,9,9-pentafluoro-nonan-1-ol is obtained as an oil.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Li+].Cl>CO.O>[C:14]([C:11]1[CH:12]=[CH:13][C:4]([C:3]([OH:16])=[O:2])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])#[N:15]
Reactant: COC(=O)c1ccc(C#N)c(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Cyanoisophthalic acid dimethyl ester 203 (1.70 g, 7.76 mmol) was dissolved in methanol (100 mL) and then treated with an aqueous solution of lithium hydroxide (2.0 g, 46.5 mmol) in 50 mL of water. The basic solution was stirred at ambient temperature for 1.5 hour. It was then poured into a 10% HCl solution. The solution was extracted with ethyl acetate and the combined extracts were dried over Na2SO4. Removal of solvent gave quantitative yield of 4-cyanoisophthalic acid 204: 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J=8 Hz, 1H), 8.33 (dd, J=1.7 Hz, J=8 Hz, 1H), 8.73 (d, J=1.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:27]=1.BrC1C=CC2C3CC(C3)N3C(C(O)C4N(C)N=CC=4)=C(C(OC)=O)N=C3C=2C=1.CS(Cl)(=O)=O.[H][H]>[Pd]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:27]=1
Reactant: [H][H]
Reactant: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: [Pd]
Agent: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1ccc(Br)cc1-2
Agent: CS(=O)(=O)Cl
Product: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1ccc(Br)cc1-2

Procedure:
methyl 10-bromo-3-((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly to methyl 10-bromo-9-fluoro-3((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. Methyl 10-bromo-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with methanesulfonyl chloride followed by palladium on carbon and hydrogen to afford 140 mg (98% crude yield) of the titled crude product which was carried forward without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.CN1CCOCC1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([NH:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: Nc1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(-c2cnn(-c3cccnc3)c2)n1
Reaction time: 8 h

Procedure:
146 mg (585 μmol) of 6-[1-(pyridin-3-yl)-1H-pyrazol-4-yl]pyridine-2-amine and 54.0 μl (701 μmol) of N-methylmorpholine were initially charged in 10 ml of dichloromethane, and methanesulphonyl chloride was added at room temperature. The mixture was stirred overnight and the reaction mixture was filtered through silica gel (eluent: ethyl acetate). After concentration, the crude product was purified by chromatography (dichloromethane/methanol).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:12][NH:13][S:14]([C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20](O)=[O:21])(=[O:16])=[O:15])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:57]1[C:61]2([CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:60][NH:59]/[C:58]/1=[N:67]\[C:68]([C:70]1[C:75]([NH2:76])=[N:74][C:73]([NH2:77])=[C:72]([Cl:78])[N:71]=1)=[O:69]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1([CH2:12][NH:13][S:14]([C:17]2[CH:25]=[CH:24][CH:23]=[C:19]([C:20]([N:64]3[CH2:65][CH2:66][C:61]4([NH:57]/[C:58](=[N:67]/[C:68]([C:70]5[C:75]([NH2:76])=[N:74][C:73]([NH2:77])=[C:72]([Cl:78])[N:71]=5)=[O:69])/[NH:59][CH2:60]4)[CH2:62][CH2:63]3)=[O:21])[CH:18]=2)(=[O:15])=[O:16])[CH2:9][CH2:10][CH2:11]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)O)c2)CCC1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(1-tert-butoxycarbonyl-cyclobutylmethyl)-sulfamoyl]-benzoic acid (Int. AC) (1.37 g, 3.71 mmol) in DMF (20 ml) was treated with N-methylmorpholine (1.631 ml, 14.83 mmol) and HATU (1.41 g, 3.71 mmol) followed by 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide (1.27 g, 3.89 mmol). The reaction mixture was stirred at RT for 2 h and then partitioned between EtOAc and water. The organic portion was separated and washed with 0.5M aqueous 1,5,7-triazabicyclo[4.4.0]dec-5-ene solution, brine, dried over MgSO4 and concentrated in vacuo. Purification of the resulting oil by chromatography on silica eluting with 5-8% MeOH in iso-hexane afforded the title compound; LC-MS Rt 1.03 mins; 676.4 [M+H]+, Method 2minLC_v003.