Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4]([O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[C:23]1[CH3:38]>>[CH:1]([S:4]([O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[C:23]2[CH3:38])=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCN
Reactant: CC(C)S(=O)(=O)Oc1ccc(OCC2CO2)cc1
Product: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCNCC(O)COc1ccc(OS(=O)(=O)C(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-(4-isopropylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24]>>[F:21][C:4]1[CH:3]=[C:2]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:31]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-Methylsulfonyl benzene boronic acid. MS (M+H) 431.1
Reaction SMILES: CS(O[CH2:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])(=O)=O.[C-:16]#[N:17].[Na+]>CS(C)=O.O>[CH3:8][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:15])[CH2:6][C:16]#[N:17]
Reactant: CC(C)(COS(C)(=O)=O)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(CC#N)c1ccccc1
Temperature: 110 °C
Yield: 57.3 %

Procedure:
2-Methyl-2-phenylpropyl methanesulfonate (52) (12 g, 52.6 mmol) was stirred in dimethyl sulfoxide (106 ml), sodium cyanide (10.3 g, 210 mmol, Eq: 4) was added and the reaction mixture was heated to 110° C. for 20 hours. The reaction mixture was cooled, diluted with water, extracted three times with ether, washed with ether, water, and brine, and dried over magnesium sulfate. The solvent was removed on a rotary evaporator. Chromatography was conducted (2% to 15% over 20 min on a 40 g silica gel column) to give 3-methyl-3-phenylbutanenitrile (53) as a clear oil (4.8 g, 57%).
Reaction SMILES: FC1C(F)=C(F)C(F)=C2C=1[NH:4]C(=O)C(=O)N2.[N+:17]([C:20]1[C:29]([Br:30])=[C:28]([Br:31])[CH:27]=[C:26]2[C:21]=1[NH:22][C:23](=[O:33])[C:24](=[O:32])[NH:25]2)([O-:19])=[O:18].[OH-].[K+].NOS(O)(=O)=O>O>[NH2:4][N:25]1[C:26]2[C:21](=[C:20]([N+:17]([O-:19])=[O:18])[C:29]([Br:30])=[C:28]([Br:31])[CH:27]=2)[NH:22][C:23](=[O:33])[C:24]1=[O:32]
Reactant: O=c1[nH]c2cc(Br)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Reactant: O=c1[nH]c2c(F)c(F)c(F)c(F)c2[nH]c1=O
Agent: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Br)c(Br)cc21
Reaction time: 0.08 h
Yield: 64 %

Procedure:
The procedure of Shin, S. C. and Lee. Y. Y., Taehan Hwahakhoe Chi 27 (5): 382-4 (1983) was adapted. To a stirred red solution of 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (120 mg, 0.33 mMol) and 3N KOH (2 mL) in distilled water (5 mL) at 65° C. was dropwise added a colorless solution of NH2OSO3H (56 mg, 0.50 mMol) in distilled water (0.5 mL) with stirring, whereupon a yellow precipitate came out after 5 mins. The mixture was stirred at 65° C. for 1 h and allowed to stand at room temperature overnight, then the precipitate was collected by filtration at 50° C., washed with distilled water (2 mL), then air dried at 50° C. overnight, affording 80 mg (64%) of crude 1-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (free base Na+ by NMR, D2O), as a yellow amorphous solid (80% desired 1-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione with 20% starting material by NMR). (It is not known if the reaction actually gave the 1-amino or 4-amino isomer.) A 80 mg sample of crude 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (0.211 mMol) was dissolved into distilled water (10 mL) at 50° C., then acidified with AcOH to pH=5. After the insoluble material was removed by filtration, it was heated at 60°-70° C. until a clear solution was obtained, then slowly cooled, and a yellow precipitate came out. The precipitate was crystallized from hot EtOH, collected by filtration, and washed with cold ethanol (2 mL), then dried in the air at 60° C. for 4 h, affording 57 mg (45.6%) of pure 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (free base H). NH2OSO3H (40 mg, 0.35 mMol) was added to the mother liquid, and allowed to react at 65°-70° C. for 30 min to give a second crop of pure 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (26 mg, 21%), using the same procedure as above. The total yield is 66%. Mp was measured: the color of 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione changed to dark yellow at 301° C.; the decomposition of 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione is obvious at 310° C. and it melted to a black liquid at 320°-1° C. IR (KBr, cm-1): 3414; 3211; 1745; 1728; 1682; 1631; 1546. NMR (1H, DMSO-d6): δ 5.832 (s, 2H); 8.047 (s, 1H); 12.565 (s, 1H). HRMS: calcd for C8H4N4O4Br2 (M+)m/z: 377.8613; found: 377.8583.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][Br:37])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(-c2ccc(F)c(F)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(-c2ccc(CBr)cc2)cc1F
Temperature: 0 °C

Procedure:
Next, to a solution comprising 25 g of the previously obtained 4-(3,4-difluorophenyl)benzyl alcohol, 40 g of triphenylphosphine and 80 ml of dichloromethane was added dropwise a solution comprising 64 g of carbon tetrabromide and 35 ml of dichloromethane under stirring at 0° C. After completion of the dropwise addition, the mixture was stirred at the same conditions for one hour, and then raised to room temperature and stirred for one hour to react the materials. After completion of the reaction, the reaction mixture was extracted with hexane, washed with a saturated NaCl aqua, dried and the solvent was removed under reduced pressure, and the residue was purified by recrystallization to obtain 20 g of 4-(3,4-difluorophenyl)benzyl bromide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=[O:24])[O:16]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:15](=[O:16])[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]1=[O:24])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CN(CCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C

Procedure:
2 g (9.9 mmol) of tert-butyl(4-aminobutyl)methylcarbamate and 1.46 g (9.9 mmol; 1 equivalent) of 2-benzofuran-1,3-dione are solubilized in 50 ml of toluene and the reaction mixture is maintained under reflux for 24 hours in a Dean-Stark. The solvent is evaporated off under reduced pressure and the expected product is purified on a silica column (eluent: dichloromethane/methanol: 90/10).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])=O.[NH2:13][S:14]([C:17]1[CH:18]=[C:19]([C:23](=[S:25])[NH2:24])[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]>>[CH2:11]([C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:24]=[C:23]([C:19]2[CH:18]=[C:17]([S:14]([NH2:13])(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=2)[S:25][CH:2]=1)[CH3:12]
Reactant: NC(=S)c1cccc(S(N)(=O)=O)c1
Reactant: CCc1ccncc1C(=O)CBr
Product: CCc1ccncc1-c1csc(-c2cccc(S(N)(=O)=O)c2)n1
Yield: 38.1 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-ethylpyridin-3-yl)ethanone hydrobromate (161 mg) and 3-(aminosulfonyl)benzenecarbothioamide (110 mg), the title compound (67 mg) was obtained as colorless powder crystals.
Reaction SMILES: CC(C)(C)C#C.C([Li])CCC.BrCCCCCCBr.[CH3:20][C:21]([CH3:31])([CH3:30])[C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1.[Na]>CN(C=O)C.CS(C)=O.C1COCC1>[CH3:20][C:21]([CH3:30])([CH3:31])[C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: CCCCCCC#CC(C)(C)C
Reactant: c1c[nH]cn1
Agent: BrCCCCCCBr
Agent: C#CC(C)(C)C
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)C#CCCCCCCn1ccnc1
Temperature: -78 °C

Procedure:
Add 5 ml. freshly distilled THF and 413 mg. 3,3-dimethyl-1-butyne to a dry reaction flask, cool to -78° C. then add 2.01 ml. n-butyl lithium (2.5M in hexane), stir about 30 minutes at -78° C., transfer into 3 ml. THF and 4.9 gm. 1,6-dibromo hexane at 0° C., stir 6 hours and add 2 ml. dry DMSO to form a precipitate. Wash with water, in methylene chloride. Elute through a short bed of silica with hexane to remove polar material giving a mixture of 1,6-dibromo hexane and 1 bromo-(9,9-dimethyl-dec-7-yne. (b) Stir overnight at room temperature 4.73 gm. of the mixture prepared in step (a), 5 ml. DMF and 2.1 gm. sodium imidazole, in a reaction flask. Add methylene chloride, wash with water, then brine and dry over sodium sulfate. Elute on a coarse silica column with methylene chloride, then 2% methanol/methylene chloride. Combine fractions containing product and chromatograph on a coarse silica column with 25% ethylacetate/methylene chloride, then 35% ethylacetate/ methylene chloride to isolate the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][C:9]2[C:10]([N:15]([CH3:22])[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.CC(C)([O-:32])C.[K+]>CS(C)=O.CC(O)(C)C>[CH3:22][N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[C:9]([CH2:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[OH:32])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN(c1cccnc1)c1ncccc1CC(c1cccnc1)c1cccnc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: CN(c1cccnc1)c1ncccc1CC(O)(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of 3-(2,2-dipyridin-3-ylethyl)-N-methyl-N-pyridin-3-ylpyridin-2-amine (34 mg) in 1.2 mL of DMSO:t-BuOH (80:20) was added potassium tert-butoxide (21 mg). The reaction was stirred under an oxygen balloon at room temperature for 2 h, then quenched by adding 2 drops of water. Purification by reverse phase HPLC gave 26 mg of 2-{2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}-1,1-dipyridin-3-ylethanol as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.54 (d, J=1.9 Hz, 2H), 8.47 (dd, J=4.6, 1.7 Hz, 2H), 8.35 (dd, J=4.6, 1.7 Hz, 1H), 8.21 (dd, J=4.6, 1.2 Hz, 1H), 8.05 (d, J=2.7 Hz, 1H), 7.59-7.57 (m, 2H), 7.24-7.15 (m, 4H), 7.08-7.05 (m, 1H), 6.99-6.95 (m, 1H), 4.57 (s, 1H), 3.55 (s, 2H), 3.21 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)=[CH:4][CH:3]=1.Br[C:22]1[CH:36]=[CH:35][C:25]([CH2:26][N:27]2[CH2:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28]2)=[CH:24][C:23]=1[F:37]>>[F:37][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][C:22]=1[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:18][C:11]=2[CH:12]=1)[CH2:26][N:27]1[CH2:28][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:30]1
Reactant: Cc1ccc(Cc2ccc3oc(B(O)O)cc3c2)cc1
Reactant: COC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccc(C)cc5)ccc4o3)c(F)c2)C1

Procedure:
In a similar manner as described in general procedure D, 5-(4-methylbenzyl)-benzofuran-2-ylboronic acid (150 mg, 0.56 mmol) was reacted with methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (155 mg, 0.51 mmol) to give methyl 1-(3-fluoro-4-(5-(4-methylbenzyl)benzofuran-2-yl)benzyl)azetidine-3-carboxylate as white solid: MS (ESI) m/z: Calculated: 443.51; Observed: 444.0 (M++1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@H:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1.[O:31]=[C:32]([O-:43])[C@@H:33]([C@H:35]([C@@H:37]([C@@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[OH:36])[OH:34].C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@@]6(C)C[C@@H](O)CC[C@]6(C)[C@H]5CC(=O)[C@]4(C)[C@H]3[C@@H]2C)CC1.O=C([O-])[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1.C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@@]6(C)C[C@@H](O)CC[C@]6(C)[C@H]5CC(=O)[C@]4(C)[C@H]3[C@@H]2C)CC1>>[CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH:18]=[C:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1.[O:31]=[C:32]([O-:43])[C@@H:33]([C@H:35]([C@@H:37]([C@@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[OH:36])[OH:34]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@]5(C)C[C@@H](O)CC[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Agent: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Tigogenin gluconate and Hecogenin gluconate were similarly prepared by replacing diosgenin by tigogenin and hecogenin, respectively, in the above preparation.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][C:25]([NH:27][NH2:28])=O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:24][C:25]1[NH:13][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][N:4]=2)=[N:28][N:27]=1
Reactant: N#Cc1ncc2cccnc2c1O
Reactant: COc1ccc(CC(=O)NN)cc1OC
Product: COc1ccc(Cc2nnc(-c3ncc4cccnc4c3O)[nH]2)cc1OC

Procedure:
The title compound was prepared in a similar manner to that described in example 1 from of 8-hydroxy-1,6-naphthyridine-7-carbonitrile (50 mg, 0.29 mmol) and 2-(3,4-dimethoxyphenyl)acetic hydrazide (315 mg, 1.5 mmol) as a yellow solid (36 mg, 34%). 1H NMR (CDCl3): δ 9.19 (m, 1 H), 8.93 (s, 1 H), 8.32 (d, J=8.4 Hz, 1 H), 7.63 (m, 1 H), 6.98-6.95 (m, 2 H), 6.82 (d, J=8.0 Hz, 1 H), 4.19 (s, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H); MS m/z 364 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]Cl)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]>CN(C)C=O>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCN(CCCl)CC1
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCn2c3ccccc3c(=O)c3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 4.5 g of 9-acridanone, 1.1 g of sodium hydride and 100 ml of dimethylformamide is stirred for 0.5 hour, then treated with 5.2 g of 2-(4-acetyl-1-piperazinyl)-ethyl chloride hydrochloride, stirred at 70° for 15 hours and evaporated. The residue is treated with water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated. By crystallization from ethanol there is obtained 10-[2-(4-acetyl-1-piperazinyl)ethyl]-9-acridanone of melting point 241°-243°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[C@H:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[C:30]([CH3:38])[CH:29]=3)=[CH:22][CH:21]=2)=[O:18])[C@@H:15]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10]1>C(Cl)Cl>[CH3:8][N:9]1[C@H:16]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[C:30]([CH3:38])[CH:29]=3)=[CH:24][CH:25]=2)=[O:18])[C@@H:15]([C:39]([OH:41])=[O:40])[CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10]1
Reactant: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)OC(C)(C)C)CC4(CC4)CN3C)cc2)c2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)O)CC4(CC4)CN3C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 149.6 %

Procedure:
TFA (1.0 mL) was added to a solution of tert-butyl (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (105.0 mg) in CH2Cl2 (1.0 mL) and the mixture was stirred at room temperature for 5 h. The solvent was removed to provide (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylic acid (140 mg) as an TFA salt. ESI (M+H)+ 460.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[NH:13]1[C:17]2[CH:18]=[CH:19][S:20][C:16]=2[C:15]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=3)=[N:14]1.CO>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:30]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:15]1[C:16]3[S:20][CH:19]=[CH:18][C:17]=3[NH:13][N:14]=1)=[CH:29]2)([OH:33])[CH2:31][CH3:32]
Reactant: Brc1ccccn1
Reactant: CCC(=O)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1)c1ccccn1
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
To a solution of 2-bromopyridine (224 mg, 1.42 mmol) in anhydrous tetrahydrofuran (2 mL) is added n-BuLi (1.6 M in hexane, 0.95 mL, 1.52 mmol) at −78° C. under nitrogen. After stirring for 20 minutes, to it is added a solution of 142-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl)-propan-1-one (140 mg, 0.473 mmol, Example 28) in anhydrous tetrahydrofuran (4 mL) drop wise. After 30 minutes, the cooling bath is removed and continued stirring at ambient temp for 30 minutes. The reaction is quenched by the addition of saturated ammonium chloride (4 mL) followed by water (4 mL). The reaction mixture is extracted with ethyl acetate (120 mL). Ethyl acetate phase is washed with water, brine and dried over sodium sulfate. Purification by chromatography (10 g silica gel cartridge, 30-60% ethyl acetate gradient in heptane) afforded product. It is then dissolved with minimum amount of methanol and triturated with water to give 1-pyridin-2-yl-1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-propan-1-ol (171 mg, 31%, Example 31) as a beige solid; 1H NMR [(CD3)2SO)]: δ 13.195 (1H, s), 11.417 (1H, s), 8.472 (1H, d), 7.742-7.661 (4H, m) 7.259-7.166 (4H, m), 6.59 (1H, s), 5.697 (1H, s, OH), 2.361 (2H, m), 0.785 (3H, t); LC/MS: 375 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:12]S([O-])(=O)=O)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH:10]([CH3:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N+:18]=[N-:19]
Reactant: CC(CNC(=O)OC(C)(C)C)CS(=O)(=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CNC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 85 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)propan-2-ylmethanesulfonate (10.0 g, 39.5 mmol) in DMF (100 mL) at RT was added NaN3 (7.7 g, 118.5 mmol). The reaction mixture was stirred at 85° C. for 24 h, cooled to RT, diluted with cold water (300 mL) and extracted with diethyl ether (3×300 mL). The combined organic layers were washed with saturated NaHCO3 (2×200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-azidopropylcarbamate (7.0 g, 88.6%) as a light yellow oil. 1HNMR (CDCl3): δ3.6 (m, 1H, CH), 3.25 (m, 1H, CH2), 2.9 (m, 1H, CH2), 1.49 (s, 9H, CH3), 1.2 (d, 3H, CH3).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=2)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[CH:14][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: COC(=O)c1ccc(-c2ccsc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (4-thien-3-yl)benzoate (552 g, 1.60 mmol) in THF (5 mL) at 0° C. was added 1.0 M lithium aluminum hydride in diethyl ether (1.60 mL, 1.60 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 3 hours, cooled to 0° C., and quenched by dropwise addition of water (0.10 mL), 4 N aq. NaOH (0.10 mL), and water (0.30 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The title compound was obtained as an oil and was used without furthur purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].N#N.C([O-])(O)=O.[Na+]>ClCCCl>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][NH:18][C:17]2[C:11]3[N:10]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]=3[CH:14]=[CH:15][CH:16]=2)[CH:23]=1
Reactant: Nc1cccc2[nH]c(-c3cccc(C(F)(F)F)c3)nc12
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N#N
Agent: O=C([O-])O
Solvent: ClCCCl
Product: FC(F)(F)c1cccc(-c2nc3c(NCc4cccnc4)cccc3[nH]2)c1
Yield: 46 %

Procedure:
A mixture containing 2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-4-amine (13; 120 mg, 0.43 mmol), nicotinaldehyde (16; 51 mg, 0.47 mmol) and NaBH(OAc)3 (143 mg, 0.67 mmol) in 1,2-dichloroethane (10 mL) was stirred at room temperature for 12 h under an inert atmosphere of N2. Saturated aqueous NaHCO3 (10 mL) was added and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (gradient elution, petroleum ether:ethyl acetate=1:1 to 1:3) to afford N-(pyridin-3-ylmethyl)-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-4-amine (Compound) (70 mg, 0.198 mmol, 46%) as a pale yellow solid. MS (ESI) calcd for C20H15F3N4: 368.12; found: 369 [M+H].