Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([CH3:33])[S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29](=[CH2:32])[CH2:30][CH3:31])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[N+](=[CH2:37])=[N-]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([C:29]4([CH2:32][CH3:37])[CH2:31][CH2:30]4)[CH:20]=3)(=[O:18])=[O:17])[CH3:33])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: C=C(CC)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)[C@@H]2CCCc3c2cnn3CC(=O)OCC)c1
Solvent: CCOCC
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(C2(CC)CC2)c1
Yield: 83 %

Procedure:
Starting with ((R)-4-{methyl-[3-(1-methylene-propyl)-5-trifluoromethyl-benzenesulfonyl]-amino}-4,5,6,7-tetra-hydro-indazol-1-yl)-acetic acid ethyl ester and a solution of diazomethane in diethyl ether using the method analogous to the one described above for 2nd step of example 14-1, ((R)-4-{[3-(1-ethyl-cyclopropyl)-5-trifluoromethyl-benzenesulfonyl]-methyl-amino}-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (82 mg, 83%) was obtained as a white solid. MS cald. for C24H30F3N3O4S 513, obsd. (ESI+) [(M+H)+] 514.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][C:24]([F:23])([F:36])[F:35])[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccccc4OC(F)(F)F)c3)cnc2c1F
Yield: 6 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-trifluoromethoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-2′-trifluoromethoxybiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg, 6%): m/z (ES+) 449 [MH+].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:14]1[C:18]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:17][C:16](=[O:27])[NH:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:12]([N:14]1[C:18]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:17][C:16]([O:27][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[N:15]1)[CH3:13]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCn1[nH]c(=O)cc1-c1cccc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCn1nc(Oc2ccc(F)cc2[N+](=O)[O-])cc1-c1cccc(C#N)c1
Temperature: 80 °C
Yield: 40.5 %

Procedure:
1,4-difluoro-2-nitrobenzene (0.63 mL, 5.9 mmol, 2.5 equiv) was added to a mixture of 3-(2-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (500 mg, 2.3 mmol, 1 equiv) and potassium carbonate (970 mg, 7.0 mmol, 3.0 equiv) in dimethyl sulfoxide (5.9 mL). The reaction mixture was heated to 80° C. for 20 minutes, then cooled to 22° C. The crude reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography on silica gel (hexanes, grading to 50% ethyl acetate-hexanes) to afford 3-[1-ethyl-3-(4-fluoro-2-nitrophenoxy)-1H-pyrazol-5-yl]benzonitrile as light-yellow solid (328 mg, 40%). Calcd (M+1)+: 353.1. Found: 353.0.
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[CH3:15].[K+].[Br-]>ClCCl>[OH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12](=[O:17])[CH:13]=[C:14]([CH3:15])[CH3:16]
Reactant: COc1ccsc1C(=O)C=C(C)C
Agent: ClB(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)=CC(=O)c1sccc1O
Temperature: 0 °C

Procedure:
A solution of boron trichloride, (1.0M in dichloromethane, 800 mL, 0.80 mol) was slowly added to a solution of 3-methoxy-2-(3-methyl-1-oxo-2-buten-1-yl) thiophene (52.3 g, 0.27 mol) in dichloromethane (400 mL) at -10° C. to 5° C. The resultant solution was stirred an additional 1.5 h at -5° C. Ice water was added slowly with rapid stirring. The organic layer was separated, dried over sodium sulfate, and eluted through a pad of silica gel. The solvent was evaporated in vacuo and the resultant oil was crystallized from hexanes at -70° C. to give the product, 40.0 g (82%), as a yellow solid: mp 32°-33° C.; IR (KBr): 1641, 1581 and 1541 cm-1 ; MS: m/z 183 (MH+); 1H NMR (CDCl3): δ2.00 (d, J=1.1 Hz, 3H), 2.30 (d, J=1.0 Hz, 3H), 6.25 (m, 1H), 6.75 (d, J=5.3 Hz, 1H), 7.37 (d, J=5.3 Hz, 1H) and 12.14 (s, exchanges with D2O, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10]([CH2:12][C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[O:14])=[O:11])=[CH:2]1.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10]([CH2:12][C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[O:14])=[O:11])=[CH:2]1
Reactant: Cc1cc(NC(=O)CS(=O)c2c[nH]c3ccccc23)no1
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)CS(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc23)no1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
In a 10 mL vial, 2-((1H-indol-3-yl)sulfinyl)-N-(5-methylisoxazol-3-yl)acetamide (50.0 mg, 0.165 mmol) from Step D was dissolved in DMF (5 mL) and cooled to 0° C. Sodium hydride (60% by weight, 13.0 mg, 0.330 mmol) was then added in one portion and the reaction mixture vigorously stirred at 0° C. for 15 minutes. 3-chloro-benzylbromide (21.6 μL, 0.165 mmol) was added in one portion and the reaction mixture was stirred while being allowed to warm to ambient temperature over 3 hours. The reaction mixture was quenched with water (2 mL) and the solution was extracted with ethyl acetate (3×2 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give an oily residue which was purified on a silica gel column (0-50% ethyl acetate:hexanes over 19 min) to yield the title compound (24 mg, 0.056 mmol, 34% yield). LCMS>98% 220 nm, RT=1.26 min, m/z=428 (m+1). 1H NMR (400 MHz, DMSOD6) 11.32 (s, 1H), 8.19 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.38 (s, 1H), 7.21-7.36 (m, 4H), 7.15 (d, J=7.2 Hz, 1H), 6.61 (s, 1H), 5.52 (s, 2H), 4.58 (d, J=13.1 Hz, 1H), 4.14 (d, J=13.1 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([O:12][C@@H:21]2[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)C(c1ccc(F)cc1)N1CCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccc(F)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
2-(4-Fluorophenyl)-2-(piperidin-1-yl)acetic acid hydrochloride (255 mg, 0.93 mmol) was dissolved in dry THF (10 ml) and (R)-quinuclidin-3-ol (355 mg, 2.79 mmol), DCC (384 mg, 1.86 mmol), HOBt (285 mg, 1.86 mmol) were added. The mixture was stirred at room temperature for 16 hours. THF was evaporated and the residue was taken up with EtOAc and washed with sat. NaHCO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=98/2/0.2) to obtain (R)-quinuclidin-3-yl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (126 mg, 39.0% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][CH2:12][CH:13]([OH:36])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH:21]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:13]([OH:36])[CH2:12][NH:11][C:7]34[N:6]=[CH:5][N:4]=[C:3]3[CH:2]=[N:10][CH:9]=[N:8]4)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCC(O)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: CO
Solvent: CCN(CC)CC
Product: OC(CNC12N=CN=CC1=NC=N2)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 6-chloropurine (0.728 g, 4.7 mmol), 1-amino-3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-propanol (1.73 g, 4.77 mmol) and triethylamine (1.36 mL, 9.5 mmol) in MeOH (20 mL) was heated to reflux for 7 days and the solvent was removed in vacuo. The residue was dissolved in CHCl3 and the extracted with aqueous sodium bicarbonate (2×100 mL); the organic phase was dried over sodium sulfate and evaporated to give a solid which was purified by flash chromatography on silica gel with 5% MeOH in CHCl3. The product was a colorless solid which was triturated with ether, 1.5 g (70%), mp 140°-170° C.; IR (KBr) 3000 cm-1 ; 300 MHz 1H NMR (CDCl3); δ: 8.17 (s, 1H), 8.11 (s, 1H), 7.5-7.0 (m, 8H), 4.90 (br s, 1H), 4.34 (s, 1H), 3.87 (br s, 1H), 3.7-2.0 (m, 12H); MS 480 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10]([F:15])[CH2:9]1)#[CH:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:13][CH2:12][C@H:11]1[O:14][C@@H:8]([N:7]2[CH:16]=[C:3]([C:1]#[CH:2])[C:4](=[O:18])[NH:5][C:6]2=[O:17])[CH2:9][C@@H:10]1[F:15])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C#Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: C#Cc1cn([C@H]2C[C@H](F)[C@@H](COC(C)=O)O2)c(=O)[nH]c1=O
Temperature: 0 °C

Procedure:
To a stirred solution of 2',3'-dideoxy-5-ethynyl-3'-fluorouridine (0.106 g 0.4 mmol) in dry pyridine (5 ml) at 0° C. was added acetic anhydride (0.05 ml, 0.48 mmol) and stirring maintained at 0° C. for 1.5 hours. After stirring at room temperature for 24 hours, a further aliquot of acetic anhydride (0.02 ml, 0.2 mmol) was added and the mixture stirred at room temperature for 3 hours. After quenching with methanol (1 ml) the solvent was removed by evaporation under reduced pressure and co-evaporated with portions of ethanol (2×30 ml). The residue was recrystallised from ethanol to give a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19](OC)=[O:20])=[CH:15][CH:14]=2)=[N:3]1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:3]1
Reactant: COC(=O)c1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Yield: 92.7 %

Procedure:
2.0 g (6.48 mmol) of 4,4-dimethyl-2-(4'-methoxycarbonylbiphenyl-2-yl)oxazoline was dissolved in tetrahydrofuran (20 ml). 0.49 g (12.9 mmol) of aluminum lithium hydride was gradually added thereto under cooling with ice, followed by the stirring for 2 hours as such. Water (50 ml) was added thereto to conduct hydrolysis, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.69 g of the title compound (yield 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:27]1([CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[OH:40][C:39]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:11][C:36](=[O:37])[C:35]=1[S:34][CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-methoxyacetophenone (0.797 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 187° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3 H), 3.98 (s, 2 H), 6.62 (s, 1 H), 7.06 (m, 2 H), 7.22 (m, 5 H), 7.73 (m, 2 H), 11.76 (bs, 1 H).
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:10]=1[C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([NH:6][C:3]3[CH:4]=[N:5][S:1][N:2]=3)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1cnsn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3cnsn3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,2,5-thiadiazol-3-amine (28 mg, 0.273 mmol) (Aquila Pharmtech) and perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (Intermediate LLL; 100 mg, 0.182 mmol) were dissolved in THF (1 mL) in a round bottom flask and cooled to 0° C., then lithium bis(trimethylsilyl)amide (1 M in THF, 364 μl, 0.364 mmol) was added and the reaction was stirred for 30 min. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated via rotary evaporation. The residue was purified using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 μm column with a gradient 5-95% acetonitrile and water with 0.1% ammonium hydroxide modifier to yield 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(1,2,5-thiadiazol-3-yl)isoquinoline-6-sulfonamide. m/z (ESI) 467.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]=2[N:10]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(O)(C(F)(F)F)=O>>[CH:23]1([N:12]2[C:11]3[N:10]=[C:9]([C:8]4[CH:7]=[CH:6][N:5]=[CH:4][C:3]=4[CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[N:18]=[CH:17][C:16]=3[N:15]([CH3:19])[C:14](=[O:20])[C@H:13]2[CH2:21][CH3:22])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNS(C)(=O)=O)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 105) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with methane sulfonylchloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 445.2 m/z (M+H)+; 1H-NMR (MeOD, 500 MHz): δ: 8.62 (s, 1H), 8.50 (d, 1H, J=5.0 Hz), 8.05 (s, 1H), 7.82 (d, 1H, J=5.0 Hz), 4.54 (s, 2H), 4.36 (m, 1H), 4.28 (m, 1H), 3.31 (s, 3H), 2.77 (s, 3H), 2.01˜1.58 (m, 10H), 0.78 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3I)[CH:9]=2)[N:3]=1.[F-].[Cs+].[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>CCOC(C)=O>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3[CH:30]=[CH2:31])[CH:9]=2)[N:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc([C@@H]2C[C@H]2c2nc3ccccn3c2I)cc(-n2nc(C)nc2C)n1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: C=Cc1c([C@@H]2C[C@H]2c2cc(-n3nc(C)nc3C)nc(C)n2)nc2ccccn12
Temperature: 80 °C

Procedure:
To Example 8 (0.11 g, 0.23 mmol), cesium fluoride (0.14 g, 0.93 mmol) and bis(tri-t-butylphosphine)palladium(O) (18 mg, 0.04 mmol) under nitrogen was added degassed dioxane (2.3 mL) followed by tributyl(vinyl)stannane (0.30 mg, 0.93 mmol). The reaction was heated at 80° C. for 2 h and, after cooling to room temperature, was diluted with EtOAc (10 mL). The organic layer was washed with saturated aqueous sodium carbonate (2×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give Example 10. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=7.0 Hz, 1H), 7.60 (s, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.21-7.17 (m, 1H), 6.93-6.82 (m, 2H), 5.63 (d, J=18.1 Hz, 1H), 5.43 (d, J=12.1 Hz, 1H), 2.93-2.87 (m, 1H), 2.89 (s, 3H), 2.74-2.70 (m, 1H), 2.67 (s, 3H), 2.39 (s, 3H), 2.00-1.92 (m, 2H) ppm; MS: m/z=372.3 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]1([N:34](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[NH2:34][C:28]1([CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)CCOCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N)CCOCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 4-(aminomethyl)-N,N-dibenzyltetrahydro-2H-pyran-4-amine. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=7.2 Hz, 1 H), 7.87 (d, J=7.6 Hz, 1 H), 7.68 (s, 1 H), 7.64-7.60 (m, 1 H), 7.44 (m, 2 H), 7.29 (dd, J=2.0, 8.4 Hz, 1 H), 6.14 (s, 1 H), 5.16 (s, 2 H), 4.54 (brs, 2 H), 3.86-3.74 (m, 4 H), 3.58 (t, J=4.8 Hz, 2 H), 2.42 (s, 3 H), 2.18 (dd, J=2.4, 4.8 Hz, 2 H), 1.88-1.81 (m, 2 H), 1.57 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[OH:27].[Na+].[CH2:29]([O:31][P:32]([OH:36])[O:33][CH2:34][CH3:35])[CH3:30].Cl>O>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([N:11]=[N:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[OH:27])=[C:2]([P:32](=[O:36])([O:33][CH2:34][CH3:35])[O:31][CH2:29][CH3:30])[CH:7]=1)([O-:10])=[O:9]
Reactant: CCOP(O)OCC
Reactant: O=[N+]([O-])c1ccc(N=Nc2c(O)ccc3cc(S(=O)(=O)[O-])ccc23)c(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOP(=O)(OCC)c1cc([N+](=O)[O-])ccc1N=Nc1c(O)ccc2cc(S(=O)(=O)O)ccc12
Reaction time: 1 h

Procedure:
27 parts of sodium 1-(2'-bromo-4'-nitrophenylazo)-2-hydroxy-6-naphthylsulphonate are stirred with 130 ml of water, and 20 parts of copper sulphate 5-hydrate in 70 parts of water are added. The pH value is adjusted to 7-8 and the mixture is stirred for one hour. Thereafter, 35 parts of phosphorous acid diethyl ester are added dropwise at pH 8. The mixture is subsequently stirred at room temperature for 4 hours and acidified with hydrochloric acid. The precipitate is filtered off, washed and dried and gives 23 parts of diethyl 5-nitro-2-[2'-hydroxy-6'-sulphonaphthylazo]-phenylphosphonate almost free from starting compounds and by-products.
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:13]#[C:14][Si](C)(C)C)[CH:9]=[CH:10][C:11]=1[F:12].C([O-])([O-])=O.[K+].[K+]>CO>[F:19][CH:2]([F:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:13]#[CH:14])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(OCCC(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(F)c(OCCC(F)F)c1
Reaction time: 1.5 h

Procedure:
To a solution of the crude ((3-(3,3-difluoropropoxy)-4-fluorophenyl)ethynyl)trimethylsilane (2.0 g) from the previous step in MeOH (17.5 mL) was added K2CO3 (9.65 g, 69.8 mmol) at room temperature. The reaction mixture was stirred for 1.5 h after which the mixture was filtered. The filter cake was washed with MeOH and the combined filtrate was concentrated over 10 g Celite. Flash chromatography (SiO2, % EtOAc 99% Hexanes to 5:95 EtOAc:Hexanes) provided 700 mg, 76%, of the title compound as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[CH2:29](C(CC)(CC)C([O-])([O-])[O-])[CH3:30].C1(C)C=CC=CC=1>[Pt].C(O)(C)C>[CH3:29][C:30]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: O=C(NCCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1nc2cnc3ccccc3c2n1CCCCCNC(=O)c1ccccc1

Procedure:
A catalytic amount of platinum on carbon was added to a suspension of N1-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide (3.4 g, 9 mmol) in isopropyl alcohol (250 mL). The reaction mixture was placed under a hydrogen atmosphere at 50 psi (3.4×104 pascals) on a Parr apparatus. After 2 hours the reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide crude N1-{5-[(3-aminoquinolin-4-yl)amino]pentyl}benzamide. This material was combined with triethylorthoacetate (1.4 g, 9 mmol) and toluene (200 mL). The reaction mixture was heated overnight on a steam bath with a Vigreux column. The toluene was decanted from the reaction mixture and concentrated under vacuum to provide N1-[5-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]benzamide as an oil.
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15](Cl)=[O:16])([O-:3])=[O:2].[NH3:18].O>CC(C)=O>[N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([NH2:18])=[O:16])([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(=O)Cl
Reactant: N
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(N)=O

Procedure:
3,5-Dinitro-4-chloro-o-toluoyl chloride is treated with two equivalents of ammonia in cold acetone. The mixture is poured into water and the desired product as a precipitated solid collected by filtration.