Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[NH:15][N:14]=[C:13]([CH3:19])[C:12]=2[N:11]2[CH2:20][CH2:21][N:22]([CH3:25])[C:23](=[O:24])[C:10]=12)C1C=CC=CC=1.[H-].[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:32]Cl.Br>CN(C=O)C.C(O)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:32][N:15]1[C:16](=[O:18])[C:17]2[C:9]([OH:8])=[C:10]3[C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH2:20][N:11]3[C:12]=2[C:13]([CH3:19])=[N:14]1
Reactant: Cc1n[nH]c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1nn(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10-(benzyloxy)-4,8-dimethyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.05 g, 0.15 mmol) in DMF (1 mL) was treated with sodium hydride (5 mg, 0.17 mmol). The resultant mixture was stirred at room temperature for 5 minutes. After bubbling ceased, 3,4-dichlorobenzyl chloride (0.02 mL, 0.16 mmol) was added and the reaction mixture was stirred at room temperature for overnight. The reaction was then treated with 33% HBr solution in acetic acid (2 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was treated with water and the solid precipitated was collected by filtration to provide the titled compound as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:17][N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.O.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>[CH3:17][N:18]1[C:22]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:21][CH:20]=[N:19]1
Reactant: COC(=O)c1cc(Br)cs1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)cs1
Temperature: 75 °C
Yield: 70.1 %

Procedure:
To a solution of methyl 4-bromo-2-thiophenecarboxylate (1.0 g, 4.5 mmol) in dioxane/H2O (5:1, 12 mL) was added K2CO3 (1.86 mg, 13.5 mmol), tetrakistriphenylphosphine Pd(0) (300 mg, 0.25 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.23 g, 5.9 mmol). The reaction mixture was heated to 75° C. in a sealed tube for 2 h. The reaction mixture was concentrated and purified on silica gel (EtOAc/Hex 10-40%) to give the title compound (701 mg, 70%) as a white solid: LC-MS (ES) m/z 223 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1B(O)O>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Product: COc1ccc(OC)c(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)c1

Procedure:
The title compound was prepared from the product of Example 105A and 2,5-dimethoxyphenylboronic acid according to General Method C: LC-MS Method D (ESI+) m/z 372.0 (M+H)+, retention time 1.44 minutes.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][CH:12]([OH:22])[CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH3:9].[CH3:23][S:24][CH2:25][C:26](Cl)=[O:27]>CN(C)C=O>[CH3:23][S:24][CH2:25][C:26](=[O:27])[NH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH:12]([OH:22])[CH2:11][O:10][CH2:8][CH3:9])=[CH:21][CH:20]=1
Reactant: CCOCC(O)COc1ccc(N)cc1
Reactant: CSCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCC(O)COc1ccc(NC(=O)CSC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
Dissolved in 4 ml of dimethylformamide were 2.00 g of triethylamine and 2.11 g of 4-(3-ethoxy-2-hydroxypropoxy)aniline. To the solution was added 1.25 g of methylmercaptoacetyl chloride with ice-cooling and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and the residue was extracted with chloroform. The chloroform layer was washed with water and concentrated. The resulting residue was purified by silica gel column chromatography using a 1:5 ethanol-chloroform mixture, giving 2.85 g of 4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoylmethyl methyl sulfide in 95.3% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH:16]4[CH2:18][CH:13]3[CH2:14][NH:15]4)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH:16]4[CH2:18][CH:13]3[CH2:14][N:15]4[C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:28])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CC4CC3CN4)ccnc2c1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CC2CC1CN2c1ccnc2cc(Cl)ccc12

Procedure:
7-Chloro-4-(2,5-diazanorborn-2-yl)quinoline (110 mg, 0.42 mmol) and 4-fluorophenyl isocyanate (67 μL, 0.59 mmol) are reacted according to method C yielding the title product as a colorless solid after column chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH2:1]([C:5]([CH3:28])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21]C2CCCCO2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([C:5]([CH3:28])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C)(Cc1ccc(OCCOC2CCCCO2)cc1)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCC(C)(Cc1ccc(OCCO)cc1)C(=O)OCC
Yield: 83.1 %

Procedure:
In a similar manner to that described in Reference example 3(f), a reaction was carried out using ethyl 2-butyl-2-methyl-3-[4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl]propionate (4.18 g), which is the product of Reference example 10(c), and p-toluenesulfonic acid monohydrate (2.61 g) and the reaction mixture was treated to afford the desired compound (2.73 g) as a syrup.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([C:13]2[S:17][C:16]([NH:18][C:19]([N:21]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:20])=[N:15][CH:14]=2)=[O:12])[CH:5]=1.C1(N(C2CCCCC2)C(=O)NC2SC=C(C(O)=O)N=2)CCCCC1>>[CH:28]1([N:21]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:19](=[O:20])[NH:18][C:16]2[S:17][C:13]([C:11]([NH:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:34])=[O:2])=[O:12])=[CH:14][N:15]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(=O)c1cccc(NC(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)c1
Agent: O=C(O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Product: O=C(O)c1cccc(NC(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)c1
Yield: 40 %

Procedure:
3-{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-benzoic acid was prepared in 40% yield as described in general procedure F from 3-{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-benzoic acid methyl ester, which in turn was prepared in 21% yield as described in general procedure H using 2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid and methyl-3-amino benzoate.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1cccc(Cl)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.07 g) and 3-chloro-benzenesulfonyl chloride (0.07 g) as a light yellow gum (0.059 g). MS (ESI−): 405.2 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[NH:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.C(#N)C>O>[Br:22][C:16]1[C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:21])=[N:13][NH:14][C:15]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)n[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: COC(=O)c1[nH]nc(OC[C@H](C)NC(=O)OC(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A mixture of methyl 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-1H-pyrazole-5-carboxylate (2.00 g), N-bromosuccinimide (1.43 g) and acetonitrile (50 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white powder (2.20 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:24]=[CH:23][C:22](C)=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:26]C1C=CC2C=C(C(O)=O)SC=2C=1>>[F:26][C:22]1[CH:23]=[CH:24][C:3]2[CH:2]=[C:6]([C:7]([NH:9][C@H:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([OH:13])=[O:12])=[O:8])[S:5][C:4]=2[CH:21]=1
Reactant: O=C(O)c1cc2ccc(F)cc2s1
Reactant: Cc1ccc2c(Cl)c(C(=O)N[C@H](Cc3ccccc3)C(=O)O)sc2c1
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1cc2ccc(F)cc2s1
Yield: 93.1 %

Procedure:
Following the 2a synthetic method, using 8-1-acid (98.10 mg, 0.5 mmol) instead of 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid gave 13a as a colorless oil (159.84 mg, 93.1%). [α]D25: −21.1 (c=0.33, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 8.03 (d, J=8.1 Hz, 1H), 7.98 (s, 1H), 7.90-7.86 (m, 1H), 7.75-7.71 (m, 1H), 7.34-7.13 (m, 6H), 4.95-4.87 (m, 1H), 3.36-3.10 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 172.09, 163.11, 161.49, 159.87, 142.28, 139.46, 137.49, 136.19, 129.22, 128.33, 126.89, 126.63, 126.61, 124.44, 114.09, 108.67, 54.08, 37.01; HRMS (ESI): calcd for: C18H14FNO3S [M−H]−=342.0606, obsd [M−H]−=342.0594.
Reaction SMILES: C([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=2)[C:11]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[C:10]([CH3:27])[NH:9][C:8]=1[CH3:28])=[O:6])(C)C.C(OC(C1C(C2C=CC=C(C#C)C=2)C(C(OCC)=O)=C(C)NC=1C)=O)C>>[C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=2)[C:11]([C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22])=[C:10]([CH3:27])[NH:9][C:8]=1[CH3:28])([OH:6])=[O:4]
Reactant: C#Cc1cccc(C2C(C(=O)OC(C)C)=C(C)NC(C)=C2C(=O)OC(C)C)c1
Agent: C#Cc1cccc(C2C(C(=O)OCC)=C(C)NC(C)=C2C(=O)OCC)c1
Product: C#Cc1cccc(C2C(C(=O)O)=C(C)NC(C)=C2C(=O)OC(C)C)c1
Yield: 20.6 %

Procedure:
The procedure of reaction, treatment and purification of Example 5 were repeated except that 7.6 g (0.02 mol) of 3,5-diisopropoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(3-ethynylphenyl)pyridine obtained in Example was employed instead of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(3-ethynylphenyl)pyridine employed in Example 5 to give 1.4 g of the desired compound (yield: 20%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:25])[CH3:12])=[CH:6][CH:5]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(=S)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 173 %

Procedure:
N-(4-(trifluoromethoxy)phenyl)acetamide (112 g, 0.511 mol) was dissolved in THF (400 ml) and Lawesson's Reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) (100 g, 0.247 mol) was added. The suspension was stirred at rt for 3 days, then filtered, filtrate evaporated and the residue was purified by chromatography (20% EtOAc in hexane) to give 100.5 g (84%) of N-(4-(trifluoromethoxy)phenyl)ethanethioamide.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[C:23]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([O:25]CC)=[O:24]>>[CH:20]1([CH2:19][O:18][C:3]2[C:2]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][C:23]([OH:25])=[O:24])=[CH:31][CH:32]=3)=[CH:17][C:6]([C:7](=[O:8])[NH:9][C@@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[OH:16])=[CH:5][N:4]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Product: O=C(O)CCc1ccc(-c2cc(C(=O)N[C@@H]3CCCC[C@H]3O)cnc2OCC2CC2)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31c, using 5-bromo-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide and 4-(2-carbethoxyethyl)benzene-boronic acid (commercially available) as starting materials to give the product as white solid, MS (ISP): 437.2 (M−H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[H-].[Na+].[CH3:12][N:13]([CH3:35])[S:14]([N:17]1[C:21]2[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=2[N:19]=[C:18]1[C:30](OCC)=[O:31])(=[O:16])=[O:15].[Cl-].[NH4+]>CS(C)=O>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:1][C:30]([C:18]2[N:17]([S:14](=[O:16])(=[O:15])[N:13]([CH3:35])[CH3:12])[C:21]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=3[N:19]=2)=[O:31])[CH:7]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: CCOC(=O)c1nc2cc(OC)c(OC)cc2n1S(=O)(=O)N(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1cc2nc(C(=O)Nc3cc(C)cc(C)n3)n(S(=O)(=O)N(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
In a dry argon atmosphere, 2-amino-4,6-dimethyl pyridine (4.0 g) was dissolved in dry DMSO (30 ml), 60% sodium hydride (1.30 g) was added and stirred at room temperature for 1 hr. A solution of 1-(N,N-dimethylsulfamoyl)-2-ethoxycarbonyl-5,6-dimethoxybenzimidazole (6.56 g) in DMSO (15 ml) was added dropwise while cooling and stirred at room temperature for 2 hrs. The reaction solution was poured into aqueous saturated ammonium chloride solution and extracted with benzene. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel to obtain N-(4,6-dimethyl-2-pyridyl)-1-(N,N-dimethylsulfamoyl)-5,6-dimethoxybenzimidazole-2-carboxamide (5.40 g). This compound was dissolved in THF (250 ml), and then water (70 ml) and conc. hydrochloric acid (7 ml) were added allowed to react overnight at room temperature under agitation. The reaction solution was neutralized with ammonia water, THF was distilled off and the precipitated crystals were filtered off. The crystals obtained was recrystallized from chloroform/methanol to give the title compound (3.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH2:25][CH3:26]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:24][CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 118.1 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (200 mg, 0.81 mmol) and potassium carbonate (214 mg, 2.02 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 30 min. At this time, the reaction was treated with 1-iodopropane (0.12 mL, 1.21 mmol) and heated at 60° C. for 5 h. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (2×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-(6-chloro-1-propyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (277.1 mg) as an orange solid which was used without further purification or characterization.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]=1[O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.[CH3:30][C:31]1[S:35][C:34](B(O)O)=[CH:33][CH:32]=1.CS(C)(=O)=O>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>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:17][CH:16]=1)=[C:2]([C:34]1[S:35][C:31]([CH3:30])=[CH:32][CH:33]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(Br)ccc2c1
Reactant: Cc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CS(C)(=O)=O
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C)s3)ccc2c1
Reaction time: 6 h

Procedure:
To a 3-necked round bottom flask, add 1-(2-(4-(2-bromo-6-methoxynaphthalen-1-yloxy)phenoxy)ethyl)piperidine (25 mg, 75.9 μmol), 5-methylthiophen-2-ylboronic acid (20 mg, 140.86 μmol), tetrakis(triphenylphosphine)palladium (20 mg, 17.3 μmol), and dimethyl sulfone (DMSO) (2 mL). Purge the reaction vessel with nitrogen five times. Heat the mixture was at 100° C. for 6 hours, followed by 80° C. for 40 hours.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:11]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)cc(Cl)c3c2CC1
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3cc(Cl)cc(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 90 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol) was added to a solution of tert-butyl 8,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.30 g, 0.84 mmol) in DMF (5 mL). After 25 min, β-bromophenetole was added (0.23 mL). The reaction was quenched with saturated aqueous NH4Cl after 18 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (9:1) to give 0.36 g (90%) of a white solid: mp 131.5-133.0° C.; 1H NMR (300 MHz, CDCl3) δ 7.04 (d, J=1.7 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 6.77 (m, 2H), 4.41 (m, 2H), 4.16 (m, 2H), 3.76 (m, 2H), 3.65 (m, 2H), 3.45 (m, 2H), 3.11 (m, 2H), 1.48 (s, 9H); IR (diffuse reflectance) 2974, 2929, 1691, 1600, 1496, 1459, 1413, 1393, 1365, 1348, 1303, 1243, 1170, 1114, 754 cm−1; MS (EI) m/z 474 (M+), 420, 419, 418, 417, 344, 334, 332, 57, 56; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.19; H, 5.99; N, 5.89.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].[C:25](O)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])O.[Na+]>ClCCl>[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
Magnesium sulfate anhydrous (9.62 g, 80 mmol) was suspended at room temperature in dichloromethane (50 mL) and 96% sulfuric acid (1.1 mL, 20 mmol) was added, the mixture was vigorously stirred for 15 min and then 4-hydroxy-3-nitrobenzoic acid (3.7 g, 20.22 mmol) and tert-butanol (9.6 mL, 100 mmol) were added. Stirring was continued for 48 hours. A saturated sodium hydrogen carbonate solution (150 mL) was slowly added and the mixture was diluted with dichloromethane (150 mL). The organic layer was separated and dried (Na2SO4), evaporated to afford tert-butyl 4-hydroxy-3-nitrobenzoate as a yellow solid (4.43 g, 90%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[C:15]([O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:14]=1)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][N:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][CH2:10][CH2:9][NH:7][CH3:6])=[O:30])=[CH:14][C:15]=1[O:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH3:22]
Reactant: CN(C)Cc1ccc(C(=O)NCCN(C)C(=O)OC(C)(C)C)cc1Oc1cccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCNC(=O)c1ccc(CN(C)C)c(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a solution of {2-[4-dimethylaminomethyl-3-(pyridin-3-yloxy)-benzoylamino]-ethyl}-methyl-carbamic acid tert-butylester (250 mg, 0.58 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (1 mL). The reaction was allowed to stir at rt for 16 h and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL), washed with 1 M NaOH (15 mL), dried (Na2SO4), and concentrated under reduced pressure. FCC purification (MeOH/CH2Cl2) provided the desired product (0.13 g, 68%) as a yellow oil. MS (ESI): m/z found, 329.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:29]=[CH:28][C:11]([CH2:12][CH:13]([CH2:17][CH2:18][C:19]2([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]2)[C:14](O)=[O:15])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C1COCC1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:19]1([CH2:18][CH2:17][CH:13]([CH2:14][OH:15])[CH2:12][C:11]2[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:29][CH:28]=2)[CH2:21][CH2:20]1)[CH3:27]
Reactant: CCOC(=O)CC1(CCC(Cc2ccc(C(=O)OC(C)(C)C)cc2)C(=O)O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(CCC(CO)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At −10° C., 25.71 ml (25.71 mmol) of a 1 M borane/THF complex solution are added dropwise to a solution of 5199 mg (12.85 mmol) of 2-[4-(tert-butoxycarbonyl)benzyl]-4-[1-(2-ethoxy-2-oxo-ethyl)cyclopropyl]butanoic acid in 100 ml of THF. After warming to 0° C., the mixture is stirred at this temperature for another two hours and then at room temperature for another hour. After complete conversion, saturated ammonium chloride solution is added, and the reaction mixture is extracted three times with in each case 50 ml of ethyl acetate. The combined organic phases are then dried over sodium sulfate, and the solvent is removed to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). This gives 3412 mg (68% of theory) of a colorless oil.