Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:17][OH:18])[CH2:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.Cl[Si](C)(C)C.[C:24](Cl)(=[O:26])[CH3:25].CO>N1C=CC=CC=1>[C:24]([NH:16][C:9]1[NH:10][C:11](=[O:15])[C:12]2[N:13]=[CH:14][N:6]([CH2:5][CH2:4][CH:3]([CH2:17][OH:18])[CH2:2][OH:1])[C:7]=2[N:8]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Reaction time: 0.25 h

Procedure:
To a suspension of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (0.23 g, 0.9 mmol) in pyridine (3 ml) was added chlorotrimethylsilane (0.25 ml, 2.0 mmol) and the mixture was stirred for 15 minutes. To this mixture was added acetyl chloride (0.085 ml, 1.2 mmol) and the mixture was stirred for 30 minutes. Methanol (2 ml) was the added and the mixture was stirred for a further 30 minutes. The solvent was removed and the residue purified by column chromatography on silica gel eluting with chloroform-methanol mixtures (4:1, 5:2) to give the title compound as its hydrochloride salt. This was dissolved in methanol and stirred with potassium carbonate. The solution was filtered and the solvent removed. The residue was taken up in water and passed through C18-Sep-pak cartridges. Fractions containing product were pooled and the solvent removed to afford N2-acetyl-9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (0.11 g, 41%), m.p. 143-146° C.; λmax (H2O) 260 (15,100) nm; νmax (KBr) 3420, 3200, 2940, 1685, 1615, and 1560 cm−1; δH [(CD3)2SO] 1.46 (1H, m, 3′-H), 1.77 (2H, q, J 7.1 Hz, 2′-H), 2.18 (3H, s, CH3), 3.3-3.5 (4H, m, 2×4′-H), 4.13 (2H, t, J 7.4 Hz, 1′-H), 4.42 (2H, br.t, J 5 Hz, D2O exchangeable, 2×OH), 7.98 (1H, s, 8-H), and 11.83 (2H, br, D2O exchangeable, 1-H and 2-NH).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21])#[N:16].C1CCN2C(=NCCC2)CC1>CN1CCCC1=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([C:15]#[N:16])[CH:18]=2)=[N:4][N:3]=1
Reactant: COc1ccc(CN)cc1C#N
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1C#N

Procedure:
1,4-Dichlorophthalazine-6-carbonitrile and 3-cyano-4-methoxybenzylamine were stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, whereby 1-chloro-4-[(3-cyano-4-methoxybenzyl)amino]-6-phthalazine carbonitrile was obtained as a less polar product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([OH:19])=O)=[CH:8]1)=[O:5])[CH3:2].Cl.[NH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34](=[O:47])[C@@H:35]([CH2:37][CH2:38][CH2:39][NH:40][C:41]([NH2:46])=[N:42][N+:43]([O-:45])=[O:44])[NH2:36])=[CH:28][CH:27]=1)=[O:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][NH:33][C:34](=[O:47])[C@@H:35]([CH2:37][CH2:38][CH2:39][NH:40][C:41]([NH2:46])=[N:42][N+:43]([O-:45])=[O:44])[NH:36][C:17](=[O:19])[CH2:16][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=2)=[CH:30][CH:31]=1)=[O:23]
Reactant: CCOC(=O)Cn1cc(CC(=O)O)c2ccccc21
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCOC(=O)Cn1cc(CC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc2ccc(CNC(N)=O)cc2)c2ccccc21
Yield: 56 %

Procedure:
Prepared analogously to Example 69a) from 1-(ethoxycarbonylmethyl)-1H-indole-3-acetic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 56% of theory.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][O:7][C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11](Cl)=[N:10][N:9]=1>CO>[CH3:6][O:7][C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]([S:5][CH2:2][CH:3]=[CH2:4])=[N:10][N:9]=1
Reactant: C=CCS
Reactant: COc1nnc(Cl)c2c1CCCC2
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OC)c2c1CCCC2

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.99 g(0.01 mol) of 1-methoxy-4-chloro-5,6,7,8-tetrahydro-phthalazine obtained from Preparation 6. The reaction solution was refluxed for one hour and then treated according to the same manner as Example 1 to obtain the title compound as a freezing pale white crystal.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[NH2:6]>C(O)(=O)C>[Br:1][C:9]1[CH:8]=[C:7]([CH3:11])[C:5]([NH2:6])=[C:4]([CH3:3])[CH:10]=1
Reactant: Cc1cccc(C)c1N
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(C)c1N
Temperature: 40 °C
Reaction time: 2 h

Procedure:
21.3 ml (66.1 g, 0.413 mol) of bromine were added dropwise, while vigorously stirring, over ca. 20 minutes to a solution of 50.0 g (0.413 mol) of 2,6-dimethylaniline in 1200 cm3 of glacial acetic acid. This mixture was stirred for 2 hours at 40° C. The precipitate formed was filtered off, washed with 50 ml of acetic acid, and dried in air. Then, this white solid was added to a solution of 100 g of sodium hydroxide in 600 ml of water. This mixture was stirred for 30 minutes. The crude product was extracted with 3×100 ml of dichloromethane. The combined organic fractions were dried over Na2SO4 and evaporated to dryness. Fractional distillation gave a yellow liquid, bp 82-85° C./1 mm Hg. Yield 61.7 g (75%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[C:10](SC)=[N:11][CH2:12][CH2:13][C:8]=2[N:7]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=1)=[O:4].[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH2:31]>CO>[CH3:1][O:2][C:3]([C:5]1[C:9]2[C:10]([NH:31][CH2:30][CH:29]([O:32][CH3:33])[O:28][CH3:27])=[N:11][CH2:12][CH2:13][C:8]=2[N:7]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cn(CCc2ccc([N+](=O)[O-])cc2)c2c1C(SC)=NCC2
Reactant: COC(CN)OC
Solvent: CO
Product: COC(=O)c1cn(CCc2ccc([N+](=O)[O-])cc2)c2c1C(NCC(OC)OC)=NCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a round bottom flask are 4-Methylsulfanyl-1-[2-(4-nitro-phenyl)-ethyl]-6,7-dihydro-1H-pyrrolo[3,2-C]pyridine-3-carboxylic acid methyl ester (25.33 mmol), amino acetaldhyde dimethyl acetal (63.32 mmol) and 125 mL MeOH combined (a part “oiled-out” that later went into solution) and stirred at RT for 20 hours. The solvent is evaporated in vacuo yielding 4-(2,2-Dimethoxy-ethylamino)-1-[2-(4-nitro-phenyl)-ethyl]-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid methyl ester, 11.56 g, as a yellow oil/solid that is used without purification.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[O:20]1C[CH2:23][CH2:22][CH2:21]1.C(Cl)(=O)C=C>O>[C:21]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:20])[CH:22]=[CH2:23]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a mixture of 10 mmole of 1,3-adamantanediol, 15 mmole of triethylamine, and 100 ml of tetrahydrofuran, 13 mmole of acrylic chloride was added drop wise over about 30 minutes. After the completion of addition, the resulting mixture was stirred at 50° C for 1.5 hours. Water was added to the reaction mixture; the mixture was then extracted with ethyl acetate; the organic layer was concentrated; and the concentrate was subjected to column chromatography on a silica gel to yield the title compound in a yield of 63%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[C:5]2[I:12].[H-].[Na+].[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[N:6]=[C:5]2[I:12]
Reactant: Fc1cc2[nH]nc(I)c2cc1Br
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc2c(cc1Br)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of 3.0 g of 5-bromo-6-fluoro-3-iodo-1H-indazole in N,N-dimethylformamide in 150 mL was added 0.42 g of sodium hydride at room temperature, and the resultant solution was stirred for 15 minutes, added with 2.45 g of trityl-chloride, and stirred at this temperature for 1 hour. After adding water and diluting with ethyl acetate, washing successively with aqueous ammonium chloride and saturated brine and drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:30-1:5), and the resultant product was added with n-hexane. Then the precipitated crystals were washed with diethyl ether:n-hexane=1:10, to afford 3.79 g of the title compound as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[CH3:27][C:25]1[N:26]=[C:21]2[CH:20]=[C:19]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)=[N:23][N:22]2[CH:24]=1
Reactant: Cc1cn2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cn2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc2n1
Temperature: 25 °C
Yield: 76 %

Procedure:
100 mg (0.22 mmol) {1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, (intermediate example int-2-2), were stirred with 7.5 mL 4M hydrogen chloride in dioxane over night at room temperature. After evaporation of the solvent the residue was treated with a mixture of methyl-tert. butylether and dichloromethane (1:1) and stirred over night at room temperature. The precipitate was filtered off yielding 132 mg (76%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2)=[O:6].[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][N:2]([CH2:3][CH2:4][C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]2=3)=[O:6])[CH3:1])=[CH:26][CH:25]=1
Reactant: CNCCC(=O)N1c2ccccc2NC(=O)c2ccccc21
Reactant: Cc1ccc(CCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(CCN(C)CCC(=O)N2c3ccccc3NC(=O)c3ccccc32)cc1

Procedure:
A mixture of 5-(3-methylaminopropionyl)-10,11-dihydrodibenzo [b,e][1,4]diazepin-11-one (0.20 g) (J. Med. Chem., 1963, 6, 255), 4-methylphenethyl bromide (0.14 g) and sodium hydrogen carbonate (60 mg) in acetonitrile (20 ml) was heated under reflux for 16 hours and evaporated. The residue was partitioned between water and dichloromethane and the organic layer washed with brine, dried over MgSO4 and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-20% methanol as eluant. Appropriate fractions were combined and evaporated and the residue crystallised from ether to give the title compound as a colourless solid, 60 mg (21%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:23])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:23])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][CH:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[CH:20][CH:21]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Product: CN1CCC(Nc2ccc(-c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)cc2)CC1

Procedure:
Cyclopentyl-[2-(4-aminophenyl)-5-chloro-1H-indol-7-yl]-amine prepared in Example 82 and 1-methyl-piperidin-4-one were reacted according to the same procedure as Step B of Example 1 to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([CH3:12])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:3][CH:4]=2)([CH3:12])[CH2:9][NH:10][CH3:11])=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CNCC(C)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CNCC(C)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
[2,2-Bis-(4-chloro-phenyl)-propyl]-methyl-amine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LCMS (PS-A3) Rt 6.94 min [M+H]+ 326. 1H NMR (Me-d3-OD) δ 1.86 (3H, s), 2.77 (3H, s), 3.89 (2H, s), 7.26-7.33 (4H, m), 737-7.40 (21-1, m), 7.68 (2H, d). 8.35 (2H, s).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([N:25](C(OCC4C=CC=CC=4)=O)[C:24](=[O:36])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO.[Pd]>[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([NH:25][C:24](=[O:36])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@]2(CCC(=O)N2C(=O)OCc2ccccc2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CCC(=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
phenylmethyl (5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-oxo-1,8-diazaspiro[4.5]decane-1-carboxylate (Intermediate 33 70 mg, 0.101 mmol) was dissolved in Methanol (3 ml) and to the solution was added Pd/C (10.74 mg, 10.09 μmol) The suspension was left stirring under H2 atmosphere for 30 mins. The palladium was filtered out and the solvent removed in vacuo obtaining the title compound (53.6 mg, 0.096 mmol, 95% yield); UPLC: Rt=0.81 mins, m/z=560 [M+H]+; MS: m/z=560 [M+H]+ and 582 [M+Na]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:14][C:15]([CH3:31])([CH2:18][N:19]1[N:23]=[C:22]2[C:24]([Cl:30])=[CH:25][C:26]([Cl:29])=[C:27]([Cl:28])[C:21]2=[N:20]1)[C:16]#[N:17]>C1COCC1>[C:16]([C:15]([NH:14][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)([CH3:31])[CH2:18][N:19]1[N:23]=[C:22]2[C:24]([Cl:30])=[CH:25][C:26]([Cl:29])=[C:27]([Cl:28])[C:21]2=[N:20]1)#[N:17]
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=476, RT=0.72 min.
Reaction SMILES: I[C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([SH:29])[CH:18]=[C:19]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:20]=1>>[CH3:11][N:6]1[C:5]2[CH:12]=[CH:13][C:2]([S:29][C:17]3[CH:18]=[C:19]([C:21]4([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:20]=[C:15]([F:14])[CH:16]=3)=[CH:3][C:4]=2[N:8]([CH3:9])[C:7]1=[O:10]
Reactant: COC1(c2cc(F)cc(S)c2)CCOCC1
Reactant: Cn1c(=O)n(C)c2cc(I)ccc21
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)n(C)c(=O)n4C)c2)CCOCC1
Yield: 60 %

Procedure:
Using a similar procedure to that described in Example 1, 5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one was reacted with 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran to give 4-[3-(1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylthio)-5-fluorophenyl]-4-methoxytetrahydropyran in 60% yield, m.p. 128°-130° C.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=CC=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCCC(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
5,5-Diphenylpenta-2,4-dienoic acid (0.90 g) was dispersed in methanol (15 mL), and 5% palladium-carbon (90 mg) was added thereto. The mixture was subjected to catalytic reduction for two hours under hydrogen. The insoluble matter was separated through filtration and washed with methanol. The filtrate was subjected to distillation under reduced pressure, to thereby yield 0.89 g of the product of interest (yield 97.3%).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].Cl>C(OCC)C.CCCCCC.O>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18](=[NH:3])[NH2:19]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: N#Cc1ccccc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: N=C(N)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a solution of hexamethyldisilazane (19.4 g, 120 mmol) in diethyl ether (200 ml) was added dropwise a 1.6 N solution (75.0 ml, 120 mmol) of n-butyllithium in hexane under ice-cooling. Thereto 2-fluorobenzonitrile (7.01 g, 57.9 mmol) was added, followed by stirring at room temperature for 2 hours. Thereto 3 N hydrochloric acid (80 ml) was added dropwise under ice-cooling, and the reaction mixture was stirred at room temperature for 0.5 hour. Water (200 ml) was added thereto, and the ether layer was removed. The aqueous layer was basified with an aqueous 3 N sodium hydroxide solution, and then extracted with chloroform. The extracts were dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 5.17 g (64.7%) of the desired product as a solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4]/[C:3](=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8])/[CH2:2]1.[NH3:12]>O1CCOCC1.CO>[NH2:12][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: CCOC(=O)/C=C1/CCOC1
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)CC1(N)CCOC1
Temperature: 150 °C

Procedure:
Ethyl (2Z)-dihydrofuran-3(2H)-ylideneacetate (Preparation 36, 1.29 g, 8.25 mmol) was stirred in 1,4-dioxane (7 mL) in a microwave vial. A solution of 7M ammonia in methanol (5 mL) was added and the reaction heated for 4 hours at 150° C. in a Biotage Initiator™ microwave. The reaction was concentrated in vacuo, but later deemed not to have reached completion. A solution of 7M ammonia in methanol (7 mL) was added and the reaction heated again for 3 hours at 150° C. in the microwave. A further portion of 7M ammonia in methanol (3 mL) was added and the reaction heated for a further 2 hours. The reaction was concentrated in vacuo to afford the title compound along with the methyl ester where trans-esterification had occurred. The material was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([C:26]2[CH2:27][CH2:28][O:23][CH2:24][CH:25]=2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
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: Cc1ccccc1
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C2=CCOCC2)c(Br)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 462 mg, 1.11 mmol), 2-(3,6-dihydro-2h-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (262 mg, 1.22 mmol), Pd(Ph3P)4 (64.1 mg, 0.056 mmol), Na2CO3 (3 mL of 2 M, 5.99 mmol), EtOH (1 mL) and toluene (3 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 70° C. for 18 h. The RM was diluted with EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 12 g, n-heptane/EtOAc, from 10% B to 100% EtOAc) to afford the title compound. HPLC (Condition 3) tR=6.04 min, UPLC-MS (Condition 2) m/z=443.1 [M+H]+.
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)C(OCOC(=O)CC)=O)(=O)C.[C:36](Cl)(=[O:47])[O:37][CH2:38][O:39][C:40](=[O:46])[CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43]>ClCCl>[O:34]=[S:30]1(=[O:33])[CH2:29][CH2:28][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:36]([O:37][CH2:38][O:39][C:40](=[O:46])[CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:47])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:32][CH2:31]1
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Reactant: CC(C)(C)CC(=O)OCOC(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)CC(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 46 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (589.0 mg, 1.72 mmol) in dichloromethane (14 mL) and 3,3-dimethyl-butyroxymethyl carbonochloridate (7 g) gave the titled product in 46% yield (407.2 mg, 0.79 mmol). 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H), 7.24 (t, 1H), 7.16 (dd, 1H), 5.73 (q, 2H), 5.26 (t, 1H), 4.75-4.82 (m, 1H), 4.05 (t, 1H), 3.78 (dd, 1H), 3.68 (ddd, 1H), 3.56 (dt, 1H), 3.13-3.19 (m, 4H), 3.10 (dt, 1H), 2.35-2.46 (m, 2H), 2.16-2.25(m, 4H), 1.00 (s, 9H).