Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[C:6]1([CH:12]2[CH2:17][CH2:16][C:15]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Product: C1=C(N2CCCC2)CCC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
36.8 g (0.517 mole) of pyrrolidine dissolved in 170 ml of n-hexane were added dropwise to 30.0 g (0.172 mole) of 4-phenylcyclohexanone dissolved in 860 ml of n-hexane, and the solution was cooled to 0° C. in an ice bath. 18.0 g (0.095 mole) of titanium tetrachloride dissolved in 140 ml of n-hexane were added dropwise within one hour at 0° C.-10° C., stirred for a further two hours at RT, following which the suspension was filtered. The filtrate was concentrated by evaporation on a rotary evaporator (500 to 10 mbar), and the remaining oil was purified by distillation at a pressure of less than 1 mbar; the main fraction boiled at 135° C. 22.2 of crude product were obtained, which on account of incomplete conversion underwent, in the cold, the addition of 27.2 g (0.379 mole) of pyyrolidine dissolved in 125 ml of n-hexane and 13.1 g (0.069 mole) of titanium tetrachloride dissolved in 140 ml of n-hexane, and the mixture was then heated under reflux for two hours. 20.2 g of 1-(4-phenylcyclohex-1-enyl)pyrrolidine (51.7% of theory) were obtained in this way.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:25]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:24]4[N:25]=[C:21]([CH3:20])[S:22][CH:23]=4)[CH:27]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.71 min.; [M+H]+: 423.95 g/mol.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OCCOC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCCOC1CCCCC1)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A solution of 2-cyclohexyloxyethanol (4.56 g, 32 mmol) and triethylamine (22 mL, 160 mmol) in dichloromethane (225 mL) was stirred under nitrogen. A saturated solution of 4-bromobenzenesulfonyl chloride (9.0 g, 35 mmol) in dichloromethane was added dropwise at 0° C., and the reaction mixture was stirred overnight under nitrogen. The reaction mixture was then washed with 1N aqueous hydrochloric acid (2×200 mL) and the organic layer separated. The organic layer was washed sequentially with water (200 mL) and brine (200 mL), dried (MgSO4) and then concentrated in vacuo to give a white solid. The crude solid was dissolved in the minimum amount of dichloromethane and purified by passing through a plug of silica, which was eluted with ethyl acetate:hexane (50:50), ethyl acetate (100%) and finally methanol:ethyl acetate (10:90). The title compound was obtained as a yellow oil (4.3 g, 41%).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[CH2:20][CH2:21][CH3:22]
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: CCCCBr
Product: CCCCn1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-(n-Butyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and n-butyl bromide.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([O:9][C:10]([C:12]1[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][C:25]=3[C:17]=2[C:16]([CH3:28])([CH3:27])[CH2:15][N:14]([C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:13]=1)=[O:11])[CH3:8].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([O:26][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[CH:23]=[CH:24][C:25]=3[C:17]=2[C:16]([CH3:28])([CH3:27])[CH2:15][N:14]([C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(O)ccc21
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OC(=O)N(C)C)ccc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
Dimethylcarbamoyl chloride (0.2 mL, 2.17 mmol) was added dropwise to a stirred solution of 3-(4-fluorobenzoyl)-8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (199 mg, 0.47 mmol), 4-dimethylaminopyridine (DMAP) (20 mg), and triethylamine (0.8 mL, 5.74 mmol) in anhydrous DCM (15 mL) at 0° C. under nitrogen, and the resulting mixture was stirred at 50° C. for 5 hours. The solvents were removed in vacuo, and the residue was purified by chromatography on silica gel eluting with DCM-20% MeOH/DCM (90:10) to give the title compound (171 mg, 74%); 1H-NMR (CDCl3): δ 10.62 (1H, s), 7.78 (s, 1H), 7.74 (1H, d), 7.63-7.59 (2H, m), 7.16-7.10 (3H, m), 6.84 (1H, dd), 4.24 (2H, q), 4.08 (2H, brs), 3.14 (3H, s), 3.03 (3H, s), 1.59 (6H, s), 1.23 (3H, t); MS (ES): 494 (MH+).
Reaction SMILES: C(O[C:4](=[O:12])[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:13][CH:14]([C:18]([NH2:20])=[O:19])[C:15]([NH2:17])=[O:16].[OH-].[Na+].C(O)C>O>[OH:16][C:15]1[C:14]([C:18]([NH2:20])=[O:19])=[N:13][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:12])[N:17]=1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: NC(=O)C(N)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc(C(N)=O)c(O)nc1O
Reaction time: 0.67 h

Procedure:
In 2.0 mL of water are suspended 0.65 mL of diethyl-2-oxomalonate and 0.5 g of 2-aminomalonamide. Under ice-cooling, 0.85 mL of 5 mol/mL sodium hydroxide is added thereto. The resulting solution is stirred for 40 minutes. Then, at ambient temperature, 2.55 mL of 5 mol/mL sodium hydroxide is added to the solution, which is then stirred for an additional 30 minutes. Ethanol is added to the reaction mixture and the precipitate is collected by filtration to obtain 0.24 g of 3,5-dihydroxy-6-ethoxycarbonyl-2-pyrazinecarboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH3:21])[CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH3:21])[CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(Cc1ccncc1)C(=O)Nc1ccc(N)cc1
Reaction time: 8 h

Procedure:
To a mixture of 5.72 gms. (0.02 mole) of 1-(p-nitrophenyl)-3-methyl-3-(4-pyridylmethyl)urea (see U.S. Pat. No. 3,700,678), 200 ml. of ethanol and 65 ml. of hydrazine hydrate there is added with stirring 0.5 gms. of 5 percent palladium-on-carbon in 50 ml. of ethanol. The resulting mixture is allowed to stand overnight at room temperature and then is refluxed for 2 to 3 hours. The hot reaction mixture is then filtered and the filtrate evaporated to remove solvent. The residue is 1-(p-aminophenyl)-3-methyl-3-(4-pyridylmethyl)urea.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[CH2:11]([O:13][C:14](=[O:22])[C:15](=O)[CH2:16][C:17](=O)[CH2:18][CH3:19])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH2:18][CH3:19])[N:9]=[C:8]([S:7][CH3:6])[N:10]=1)=[O:22])[CH3:12]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc(CC)nc(SC)n1
Yield: 56.1 %

Procedure:
A solution of S-methylisothiourea sulphate (874 mg, 4.65 mmol) and 2,4-dioxohexanoic acid ethyl ester (800 mg, 4.65 mmol) in ethanol (4 mL) is heated to 80° C. for 48 h. The reaction mixture is then filtered, evaporated and purified by prep. TLC (using heptane/EA 1/1 as eluent) to give 590 mg of 6-ethyl-2-methylsulfanyl-pyrimidine-4-carboxylic acid ethyl ester as a yellow oil; LC-MS: tR=0.91 min, [M+H]+=227.22. 1H NMR (D6-DMSO): δ 1.24 (t, J=7.5 Hz, 3H), 1.34 (t, J=7.0 Hz, 3H), 2.56 (s, 3H), 2.81 (q, J=7.5 Hz, 2H), 4.37 (q, J=7.0 Hz, 2H), 7.58 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1/[CH:14]=[CH:15]/[Si](C)(C)C.[Cl:20]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1/[CH:14]=[CH:15]/[Cl:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1/C=C/[Si](C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)c(F)c(N)c1/C=C/Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
To a solution of (E)-methyl 4-amino-6-chloro-5-fluoro-3-(2-(trimethylsilyl)vinyl)picolinate (176 mg, 0.581 mmol) in DMF (2.3 mL) was added N-chlorosuccinimide (116 mg, 0.872 mmol). The reaction mixture was stirred at 60° C. After 4 h, the observed conversion was ˜50%. At this point, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (SiO2, hexane/EtOAc gradient) to afford the title compound (75 mg, 0.283 mmol, 48.7% yield) as an orange solid: mp 128-130° C.; 1H NMR (400 MHz, CDCl3) δ 6.97 (d, J=14.1 Hz, 1H), 6.45 (d, J=14.1 Hz, 1H), 4.73 (s, 2H), 3.93 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −138.17; ESIMS m/z 265 ([M]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chloro-4-hydroxyphenyl acetic acid (20 mmol) in methanol (50 mL) was added concentrated HCl solution (5 mL), and stirred for 1 h at 50° C. After excess solvents were removed under vacuum, the residue was dissolved in EtOAc (50 mL) and washed with sat. NaHCO3 solution (2×30 mL), brine (30 mL) and dried over anhydrous Na2SO4. This afforded methyl 3-chloro-4-hydroxy acetate 3 as a colorless oil (4.0 g, 99%). 1H NMR (CDCl3) 6.9-7.0 (d, 1H), 6.8-6.9 (d, 1H), 5.4 (s, 1H), 3.6 (s, 3H), 3.4 (s, 2H).
Reaction SMILES: Br[CH:2]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=2[CH3:22])=[N:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH3:25][CH2:26][OH:27]>>[CH2:26]([O:27][CH:2]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=2[CH3:22])=[N:8][CH:7]=1)[CH2:3][CH2:4][CH3:5])[CH3:25]
Reactant: CCCC(Br)c1cnc(-c2c(C)ccc(O)c2C)c2ccccc12
Reactant: CCO
Product: CCCC(OCC)c1cnc(-c2c(C)ccc(O)c2C)c2ccccc12

Procedure:
A mixture of 3-[4-(1-bromo-butyl)-isoquinolin-1-yl]-2,4-dimethyl-phenol (110 mg, 0.29 mmol) and c-HCl (30 uL) in EtOH (12 ml) is heated at reflux for 18 h. After removal of solvent, the residue is diluted with DCM and neutralized with 1N—NaOH. The layers are separated and the aqueous layer is extracted with DCM. The combined organic layers are dried over Na2SO4 and concentrated. The residue is chromatographed on silica gel to give 19 mg of 3-[4-(1-Ethoxy-butyl)-isoquinolin-1-yl]-2,4-dimethyl-phenol along with the unreacted starting material (80 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Cl)([O-:9])=[O:8].C(OCC)C>C1(C)C=CC=CC=1>[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O-:9])=[O:8]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A solution of morpholine (4.57 mL) in toluene (10 mL) at 5° C. was treated with a solution of 3-nitrobenzyl chloride (4.29 g) in toluene (10 mL). After stirring at 85° C. for 2 hours the reaction mixture was allowed to cool to room temperature and then left to stand overnight. The reaction mixture was treated with diethyl ether (100 mL), then washed three times with water (50 mL), then three times with brine (50 mL), dried over magnesium sulfate and then evaporated. The residue was subjected to column chromatography on silica eluting with ethyl acetate to give the title compound (2.86 g) as a white solid, m.p. 48–50° C. 1H NMR [(CDCl3]: δ 8.24 (s, 1H), 8.13 (d, 1H), 7.70 (d, 1H), 7.50 (t, 1H), 3.74 (t, 4H), 3.60 (s, 2H) and 2.48 (s, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: Clc1ccccc1I
Reactant: C#Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2ccccc2Cl)c1
Temperature: 70 °C

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (63.2 mg, 0.090 mmol), copper (I) iodide (34.3 mg, 0.180 mmol), and 5-ethynylnicotinonitrile (242 mg, 1.89 mmol), (prepared essentially as described in PREPARATION 4), to a solution of 1-chloro-2-iodobenzene (0.22 mL, 1.77 mmol) in triethylamine (3.60 mL, 25.8 mmol) and heat to 70° C. in a sealed tube for 1.5 h. Cool to room temperature and dilute with ethyl acetate. Wash with a saturated aqueous solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient from 95:5 to 80:20 (90:10 hexanes:ethyl acetate):dichloromethane, to give the title compound as a yellow solid. Further purify the title compound by recrystallizing from cyclohexane (20 mL) to give a white solid (95 mg, 22%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:5]2=[N:6][CH:7]=1.[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O.O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[C:4]3[N:10]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:5]3=[N:6][CH:7]=2)=[CH:28][CH:29]=1)=[O:20]
Reactant: CS(=O)(=O)NCc1nc2cc(Br)cnc2s1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NCc1nc2cc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)cnc2s1
Temperature: 70 °C
Yield: 25.2 %

Procedure:
A mixture of N-((6-bromothiazolo[5,4-b]pyridin-2-yl)methyl)methanesulfonamide (236 mg, 0.732 mmol), 2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (300 mg, 0.0.732 mmol) and tris(2-furyl)phosphine (34 mg, 0.146 mmol) and Tris(dibenzylideneacetone) dipalladium(0) (68 mg, 0.0732 mmol) in dimethylformamide (3 mL) is heated at 70° C. for 5 hours under nitrogen. The mixture is then cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). Extracts are dried over Na2SO4 and concentrated to get crude product. Obtained product purified by HPLC to give the title compound (90 mg): 1H NMR (DMSO-d6): 3.07 (s, 3H), 4.27-4.39 (m, 1.5H), 4.40-4.48 (m, 0.5H), 4.52-4.60 (m, 0.5H), 4.64-4.71 (m, 2.5H) 4.88-4.94 (m, 1H), 6.22 (t, 1H), 7.50 (d, 2H), 7.83 (d, 2H), 8.22-8.33 (m, 1H), 8.62 (bs, 1H), 8.85 (d, 1H), 8.94 (s, 1H). m/z (CI) M+H 489.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([NH:16][C:17]([NH:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[NH:21])=[NH:18])[CH:7]=1.[CH3:31][C:32]([CH3:34])=O>>[ClH:3].[ClH:3].[NH2:18][C:17]1[N:16]([C:8]2[CH:7]=[N:6][C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:32]([CH3:34])([CH3:31])[N:21]=[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:19]=1
Reactant: CC(C)=O
Reactant: CCCCCCCCNC(=N)NC(=N)Nc1cnc2ccccc2c1
Agent: Cl
Solvent: CO
Product: CCCCCCCCNC1=NC(C)(C)N(c2cnc3ccccc3c2)C(N)=N1

Procedure:
150 ml of methanol, 120 ml of acetone and 0.5 ml of concentrated hydrochloric acid were added to 7.0 g (18.6 mmol) of N1-(3-quinolyl)-N5-octyl-biguanide dihydrochloride. The mixture was refluxed for 26 hours, and 1.8 ml of concentrated hydrochloric acid was further added thereto. The mixture was refluxed for 22 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1)) to obtain 5.3 g of a pale yellow powder.
Reaction SMILES: [OH-].[K+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[SH:19][CH2:20][CH2:21][OH:22].[CH:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1)=[CH2:24]>C(O)C>[OH:22][CH2:21][CH2:20][S:19][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([CH:23]=[CH2:24])=[CH:26][CH:27]=1
Reactant: C=Cc1ccc(CCl)cc1
Reactant: OCCS
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1ccc(CSCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of potassium hydroxide (86 g, 1.3 moles) and 2,6-di-tert-butyl-p-cresol (1 g) in ethanol (1 liter) at room temperature was added under nitrogen atmosphere 2-mercaptoethanol (100 g, 1.3 moles), over fifteen minutes. Following addition the solution was stirred an additional hour at room temperature and then p-vinylbenzyl chloride (198 g, 1.3 moles) was added at room temperature over one hour. After addition, the mixture was allowed to reach ambient temperature overnight. The mixture was filtered and the solvent removed on a rotary evaporator. To the residue was added dichloromethane (1.2 liter) and the solvent was washed with water (3×200 ml), then with saturated NaCl solution (200 ml), dried over anhydrous magnesium sulfate, filtered and the solvent removed on a rotary evaporator. To the residue was added diethyl ether (200 ml) and petroleum ether (800 ml). The product crystallized and was then filtered to give a white solid: m.p. of 44°45.5° C. Yield of 85%. Analysis calculated for C11H 14 OS: C. 68.0, H, 7.26, S, 16.50. Found: C, 67.7, H, 6.98, S, 15.37.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:13]([OH:14])=[CH:12][C:11]2[O:15][C:16]3[C:22](=[N:23][C:10]=2[CH:9]=1)[CH:21]=[CH:20][C:18](=[O:19])[CH:17]=3.C(=O)([O-])[O-].[K+].[K+].O>COCCOCCN(CCOCCOC)CCOCCOC.O1CCOCC1>[CH3:5][O:14][C:13]1[CH:8]=[CH:9][C:10]2[N:23]=[C:22]3[C:16]([O:15][C:11]=2[CH:12]=1)=[CH:17][C:18](=[O:19])[CH:20]=[CH:21]3
Reactant: O=c1ccc2nc3ccc(O)cc3oc-2c1
Reactant: COS(=O)(=O)OC
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2nc3ccc(=O)cc-3oc2c1
Reaction time: 2 h
Yield: 59.5 %

Procedure:
12.1 ml of dimethyl sulphate were added at room temperature while stirring well to a suspension of 20.0 g (85.0 mmol) of resorufin, 17.6 g of freshly powdered potassium carbonate and 10 drops of tris-[2-(2-methoxyethoxy)ethyl]amine in 150 ml of dioxan. The reaction mixture was subsequently stirred at 100° for 2 hours, cooled and then treated with 150 ml of water. The solid was filtered off, washed with water and dried over phosphorus pentoxide. 11.5 g (59.5%) of resorufin methyl ether of m.p. 240°-244° (dec.) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=2[CH:27]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[F:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][C:39]=1[C:47]([O:49][CH2:50][CH3:51])=[O:48]>>[CH2:50]([O:49][C:47]([C:39]1[CH:40]=[C:41]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:28])[C:9]([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=4[CH:27]=3)([OH:14])[C:10]([F:12])([F:13])[F:11])=[C:2]([Cl:1])[CH:3]=2)[CH:42]=[CH:43][C:38]=1[F:37])=[O:48])[CH3:51]
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C(F)(F)F)cc21
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(CC)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 64, step 7, trifluoromethanesulfonic acid 3-chloro-4-[2-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 64, step 6) was reacted with 4-fluoro-3-(ethoxycarbonyl)phenylboronic acid (70° C., 5 h) to give title compound as a white solid. MS (m/e)=580.3 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:33]([F:35])[F:34])[N:3]=1.[CH3:36][N:37]([CH3:49])[CH2:38][CH2:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41].CCN(CC)CC>C1COCC1>[F:35][CH:33]([F:34])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([N:46]3[CH2:47][CH2:48][N:43]([S:40]([CH2:39][CH2:38][N:37]([CH3:49])[CH3:36])(=[O:42])=[O:41])[CH2:44][CH2:45]3)[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CN(C)CCS(=O)(=O)N1CCNCC1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 293 mg (0.57 mmol) of tert-butyl 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (Example 9), 152 mg (0.69 mmol) of N,N-dimethyl-2-(1-piperazinylsulfonyl)ethanamine (Example 83), and 87 mg (0.86 mmol) of Et3N in 20 mL THF was stirred at room temperature for 2 hrs. The solvent was removed under vacuum. After dilution with water, the residue was extracted into CH2Cl2 and dried. Removal of the solvent gave a white solid which was recrystallized from methanol to give 0.27 g, (68% yield) of tert-butyl 2-(difluoromethyl)-1-[4-(4-{[2-(dimethylamino)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazol-6-ylcarbamate: mp 200-202° C.; 1H NMR (CDCl3) δ 8.63 (br s, 1H), 7.44 (t, JHF=53.6 Hz, 1H), 6.62 (br s, 1H), 6.36 (d, J=1.6 Hz, 1H), 4.12-3.77 (m, 15H), 3.40 (m, 4H), 3.10 (dd, J=8.2, 6.4 Hz, 2H), 2.77 (dd, J=8.2, 6.4 Hz, 2H), (s, 6H), 1.52 (s, 9H); Anal. Calcd. for C29H42F2N10O6S: C, 50.0; H, 6.1; N, 20.1. Found: C, 50.3; H, 6.15; N, 20.1%.