Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1
Reactant: COCn1c(-c2nccs2)cc2cccc(NS(=O)(=O)c3cccs3)c21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(c1cccc2cc(-c3nccs3)n(COC)c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-[1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (0.68 g), ethyl bromoacetate (0.23 mL), potassium carbonate (0.35 g) and N,N-dimethylformamide (6 mL) was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.82 g, quantitative) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 124-125° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Li+].O1CCCC1>O>[C:13]1([C:12]#[C:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cnc(C#Cc2ccccc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(C#Cc2ccccc2)s1
Yield: 97.1 %

Procedure:
A solution of 2-phenylethynyl-thiazole-5-carboxylic acid ethyl ester (9.00 g, 35.0 mmol), lithium hydroxide (13.5 g, 563 mmol), tetrahydrofuran (190 mL) and water (143 mL) was stirred at 25° C. for 64 h. The material was concentrated to remove most of the THF, taken up in 350 mL of water and washed with EtOAc (3×50 mL); acidified with 3.7% HCl to pH<1 and the precipitate extracted with 3×100 mL of EtOAc. The combined EtOAc extracts were washed with 50 mL of water, 50 mL of brine, dried (Na2SO4) and concentrated to give the titled compound, 2-phenylethynyl-thiazole-5-carboxylic acid (7.79 g; 97%), as a yellow powder, which was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.69-7.60 (m, 2H), 7.51-7.38 (m, 3H). LC/MS (Method 1), RT=0.57 min. Calculated [M+H]+=230; Observed [M+H]+=230.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[CH:12][N:13]=2)[CH2:6][CH2:7]1)(=[O:24])[CH3:23]
Reactant: OC1CCN(c2ncc(-c3ccc(Cl)cc3Cl)cn2)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCN(c2ncc(-c3ccc(Cl)cc3Cl)cn2)CC1

Procedure:
6 g of 2-(4-hydroxypiperidino)-5-(2,4-dichlorophenyl)pyrimidine (Example 5) and 60 ml of acetic anhydride are heated under reflux for 4 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH:12]1(N=C=NC2CCCCC2)CCCCC1>CO>[CH3:12][O:7][C:6](=[O:8])[C:5]1[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=1)[OH:11]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: COC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-methylsalicylic acid (75 g, 0.49 mmol) in MeOH (500 mL) at 0° C. was treated with dicyclohexylcarbodiimide (101 g, 0.49 mmol) and the mixture was stirred at room temperature for 2 h. The precipitated dicyclohexylurea was removed by filtration and the filtrate was concentrated in vacuo. The crude residue was purified by distillation (110° C. bath temp, 0.5 mm Hg) to afford 4-methylsalicylic acid methyl ester
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]([S:15]([OH:18])(=[O:17])=[O:16])[CH2:11][C:12]([OH:14])=[O:13])=[O:7])(C)(C)C.Cl.O1CCOCC1.C1(=O)[O:31][C:29](=[O:30])[CH:28]=[CH:27]1>CC(N(C)C)=O>[C:12]([CH2:11][CH:10]([S:15]([OH:18])(=[O:16])=[O:17])[CH2:9][NH:8][C:6](=[O:7])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30])([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NCC(CC(=O)O)S(=O)(=O)O
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: O=C(O)/C=C\C(=O)NCC(CC(=O)O)S(=O)(=O)O
Reaction time: 8 h
Yield: 82.8 %

Procedure:
4-(Tert-butoxycarbonylamino)-3-sulfobutanoic acid (321 mg, 1.13 mmol) was stirred in the mixture of HCl (conc)/Dioxane (1:4, 15 ml) for 30 min, evaporated and coevaporated with EtOH/Toluene (1:1, 4×20 ml) to dryness. To the dryness material was added maleic anhydride (121 mg, 1.23 mmol) and DMA (20 ml) and the mixture was stirred overnight, evaporated and run through C-18 column eluted with water and crystallized with EtOH/Hexane to afford 263 mg (83%) of the title compound. ESI MS 279.8 (M−H). The NMR data are the same through the route with 4-azido-3-sulfobutanoic acid.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:9]([O:11][C:12]([N:14]=[C:15]=[O:16])=[O:13])[CH3:10]>C(N(CC)CC)C.C(Cl)Cl>[CH2:1]([O:3][P:4]([C:15]([NH:14][C:12](=[O:13])[O:11][CH2:9][CH3:10])=[O:16])([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC(=O)P(=O)(OCC)OCC

Procedure:
To a solution of 11.0 parts of diethylphosphite in 175 parts of methylene chloride and 4 drops of triethyl amine was added 10.0 parts of ethoxycarbonyl isocyanate. The solution was refluxed for 3 hours. Removing the solvent under reduced pressure left 18.5 parts of colorless oil which partially crystallized. The crystals were washed with cyclohexane to give 7.3 parts of ethyl N-(diethylphosphonocarbonyl)carbamate, m.p. 75° -64° , The proton nmr spectrum was consistent with this structure (δNH = 10.0 ppm)
Reaction SMILES: [CH2:1]([C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]#[N:17])[CH2:5]1)[CH:2]=C.[O:18]=[O+][O-]>ClCCl>[O:18]=[CH:2][CH2:1][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]#[N:17])[CH2:5]1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H]1C[C@H](CC#N)OC2(CCCCC2)O1
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OC2(CCCCC2)O1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-4-(2-propenyl)-1,5-dioxa-spiro[5.5]undecane-2-acetonitrile 4.26 g (19.42 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 5.6 g (21.36 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 4.04 g of pure (±)-cis-4-(2-oxo-ethyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CCO>[OH:31][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[NH2:8][CH2:9][C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)CN(Cc1ccccc1)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C(F)(F)CN
Reaction time: 8 h
Yield: 94 %

Procedure:
In a round bottom flask, Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (1.72 g, 5.2 mmol) was solubilized in EtOH (25 mL) and TFA added (0.4 mL, 5.5 mmol). Under an atmosphere of nitrogen Pd(OH)2/C (170 mg of 20% Pd by wt. wet) was added. The reaction mixture was repeatedly purged with nitrogen and then left under hydrogen overnight. At this point the reaction was deemed complete by LCMS, filtered through a pad of Celite, the pad washed with EtOH and the filtrate concentrated without heating to yield a foggy syrup which starts to crystallize upon standing (1.31 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (t, J=7.20 Hz, 3 H) 3.72 (t, J=16.17 Hz, 2 H) 4.34 (q, J=7.24 Hz, 2 H). [M+H] calc'd for C5H9F2NO2, 154; found 154.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[Br:18][C:19]1[C:24]([CH:25]=[CH:26][C:27](O)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:20]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1C(=O)CCC1>C1COCC1>[Br:18][C:19]1[C:24]([CH:25]=[CH:26][C:27]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:20]=1
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)c(Br)n1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)nc2Br)cc(F)c1NS(C)(=O)=O
Yield: 55.9 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (41.2 mg, 0.148 mmol) was reacted with 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-acrylic acid (1.0 eq, 42 mg), DMTMM (1.0 eq, 41 mg) and NMP (1.2 eq, 20 μl) in THF to give the title compound (42 mg, 55.8%) after purification by column chromatography (Hex/EtOAc=3/2).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[Cl:14][C:15]1[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:21]([C:20]2[CH:19]=[N:18][CH:17]=[CH:16][C:15]=2[Cl:14])=[O:22])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=C(O)c1cnccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CNc1ncc(C(F)(F)F)cc1NC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
A mixture of 524 mg of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 500 mg of 4-chloronicotinic acid, 790 mg of EDCI hydrochloride, 37 mg of HOBt and 4 ml of pyridine was stirred at room temperature for 4 hours. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 828 mg of 4-chloropyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-chloropyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9]2)=[N:3][CH:2]=1.[H][H]>[Pd].CO>[N:8]1([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCN(Cc2ccncn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1cc(CN2CCNCC2)ncn1

Procedure:
To 0.01 g (0.09 mmol) of 10% palladium on carbon was added a solution of 0.14 g (0.45 mmol) of the title compound from Step A in 5 mL anhydrous methanol. The resulting suspension was subjected to hydrogen at atmospheric pressure while stirring. After 4 h the mixture was filtered through a pad of Celite. The pad was washed with methanol (25 mL) and the combined filtrates were concentrated in vacuo to afford the title compound as a pale yellow residue without further purification. LC/MS: m/z (ES) 179.1 (MH)+.
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: ClSCl
Reactant: CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(SCl)C(=O)OC(C)(C)C
Temperature: 5 °C
Yield: 103.1 %

Procedure:
To a solution of 62 g (0.6 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to 0° C. under a nitrogen atmosphere was added a solution made up of 50.9 g (0.4 mole) of t-butyl N-methylcarbamate, 44.5 g (0.44 mole) of triethylamine and 100 ml of methylene chloride. The temperature was maintained at -2° to 5° C. during the addition. After stirring for one additional hour at 5° C., the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. Solid was removed by extracting the product with hexane. After filtration the hexane solution was concentrated to give 81.5 g of t-butyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[F:33][C:31]1[CH:30]=[C:22]([O:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:21]=[C:20]([F:19])[C:32]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: Fc1cc(F)cc(OC2CCOCC2)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(OC3CCOCC3)cc2F)OC1(C)C
Yield: 33 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 equiv.), butyllithium (1.3 equiv.) and 4-(3,5-difluorophenoxy)tetrahydro-2H-pyran (1.0 equiv.) to give 2-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 33% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.21-1.34 (m, 12H), 1.78 (dtd, J=12.72, 8.31, 8.31, 3.91 Hz, 2H), 1.93-2.09 (m, 2H), 3.59 (ddd, J=11.64, 8.31, 3.13 Hz, 2H), 3.89-4.01 (m, 2H), 4.48 (tt, J=7.78, 3.77 Hz, 1H), 6.40 (d, J=9.39 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:39])[N:24]=[C:23](C2C=CC=CC=2Cl)[C:22]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:21]=2[N:20]([CH3:37])[C:19]1=[O:38])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:39])[N:24]=[CH:23][C:22]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:21]=3[N:20]([CH3:37])[C:19]2=[O:38])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(C)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=Cc2cc(Cl)ccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-F), the title compound was prepared as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:60][C:61]([F:65])([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][C:61]([F:65])([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)(F)F)C4CC4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
To a solution of [9-chloro-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (82 mg, 0.21 mmol) and tributyl phosphine (0.10 mL, 0.41 mmol) in tetrahydrofuran (0.84 mL) was added 1,1′-(azodicarbonyl) dipiperidine (104 mg, 0.41 mmol), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2,2,2,-trifluoroethanol (0.15 mL, 2.06 mmol), and the mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled at room temperature and concentrated in vacuo. The residue was diluted with diethyl ether. The residual solid was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40% ethyl acetate/n-hexane mixture. The desired fractions were concentrated in vacuo. The residual oil was crystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (35.8 mg, 0.075 mmol, 36%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].C(Cl)CCl.O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:10]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:3]=[C:2]([C:11]([O:13][N:19]2[C:23](=[O:24])[CH2:22][CH2:21][C:20]2=[O:25])=[O:12])[N:1]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: O=C1CCC(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-quinoline carboxylic acid (1.2 eq.) in DMF at 0° C. was treated with EDC (1.4 eq.). The mixture was stirred at 0° C. for 1 to 2 h and then N-hydroxysuccinimide (1.0 eq.) was added. After stirring at RT for more than 3 h, the reaction mixture was poured into 60% sat. NaHCO3 and the product filtered: 1H NMR (CDCl3, 300 MHz, ppm) 8.35 (d, 1H), 8.27 (d, 1H), 8.19 (d, 1H), 7.87 (d, 1H), 7.80 (m, 1H), 7.68 (m, 1H), 2.91 (s, 4H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:39]3[CH:40]=[CH:41][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:37][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 41 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 4-methylsulfonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (41%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[N:10]=[C:9]([C:11]2[CH:25]=[CH:24][C:14]3[N:15]([CH3:23])[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:8][S:7][C:6]1=[O:26].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.C1COCC1>C(N(CC)CC)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[N:10]=[C:9]([C:11]3[CH:25]=[CH:24][C:14]4[N:15]([CH3:23])[C:16]([C:18]5[O:19][CH:20]=[CH:21][CH:22]=5)=[N:17][C:13]=4[CH:12]=3)[CH2:8][S:7][C:6]2=[O:26])=[O:36])=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cn1c(-c2ccco2)nc2cc(C3=NN(CCCN)C(=O)SC3)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(-c2ccco2)nc2cc(C3=NN(CCCNC(=O)Nc4ccc(Cl)cc4)C(=O)SC3)ccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
120 mg (0.30 mM) of 3-(3-aminopropyl)-5-[2-(2-furyl)-1-methyl-1H-benzimidazol-5-yl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 50.1 mg (0.33 mM) of 1-chloro-4-isocyanatobenzene are added to 2 ml of THF and 164.33 μl (1.33 mM) of triethylamine. The mixture is stirred at room temperature for 20 hours. The solid is filtered off and washed with water and then with isopropanol to give, after drying, 106 mg of N-(4-chlorophenyl)-N′-{3-[5-[2-(2-furyl)-1-methyl-1H-benzimidazol-5-yl]-2-oxo-2H-1,3,4-thiadiazin-3(6H)-yl]propyl}urea.
Reaction SMILES: C(O[CH2:4][CH2:5][C:6]#[N:7])C.C(O)C.[NH:11]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[NH2:12].OCC[N+](C)(C)C>CO>[NH2:7][C:6]1[CH2:5][CH2:4][N:11]([C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[N:12]=1
Reactant: NNc1nc2ccccc2s1
Reactant: CCOCCC#N
Agent: C[N+](C)(C)CCO
Solvent: CO
Solvent: CCO
Product: NC1=NN(c2nc3ccccc3s2)CC1

Procedure:
A mixture of 5.0 g. of β-ethoxypropionitrile, 100 ml. of absolute ethanol, 8.25 g. of 2-hydrazinobenzothiazole and 2.5 g. of 50% w/v choline in methanol is refluxed on a steam bath for 16 hours, then the solvent is removed in vacuo. Water is added and the solid is collected by filtration. The solid is recrystalized twice from ethanol to give 5.75 g. of the product of the Example as grey prisms, m.p. 231.5°-235° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][N:6]1[C:5]([O:30][CH3:31])=[N:4][C:3]2[C:7]1=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=2[NH2:1]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3C(=O)c4ccccc4C3=O)c2n1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The product from step (vi) (1 g) was dissolved in ethanol (10 ml) and hydrazine monohydrate (1 ml) was added and stirred at ambient temperature for 10 h. The resultant was concentrated under reduced pressure and the residue suspended in DCM (10 ml) and stirred for 1 h. The suspension was filtered, washed with DCM. The solution was washed with water and dried. The solution was concentrated under reduced pressure to give the subtitled compound. Yield 700 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:30][CH2:29]1.N1C=CC=CC=1>>[CH2:25]([O:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:34]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)(=[O:36])=[O:35])=[CH:7][C:6]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1)[CH3:26]
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Reactant: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: c1ccncc1
Product: CCOc1ccc(NS(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
120 mg (0.34 mmol) of the compound from example 42A are reacted with 319 mg (1.36 mmol) of 4-methyl-1-piperazinesulfonyl chloride in 8 ml (98.9 mmol) of pyridine overnight.