Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][Mg]Cl>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:15][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[NH:4][C:3](=[O:10])[CH2:2][CH2:1]2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cl[Mg]Cc1cccc(Cl)c1
Reactant: O=C1CCC2CCC(=O)N12
Product: O=C(CCC1CCC(=O)N1)Cc1cccc(Cl)c1
Yield: 51.5 %

Procedure:
Analogous to the procedure described for Example 1A, Step A, tetrahydro-pyrrolizine-3,5-dione (2 g, 14 mmol) was reacted with 3-chlorobenzylmagnesium chloride (0.25M in Et2O, 62 mL, 15.5 mmol) over 2 h. Purification by medium pressure chromatography eluting with a solvent gradient (2:1 hexanes:EtOAc to EtOAc to 5% MeOH in CH2Cl2) provided 5-[4-(3-chloro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (1.9142 g). 1H NMR (CDCl3) δ7.27 (m, 2H), 7.19 (m, 1H), 7.08 (m, 1H), 6.27 (br, 1H), 3.68 (s, 2H), 3.60 (m, 1H), 2.52 (t, 2H), 2.29 (m, 2H), 2.21 (m, 1H), 1.88-1.60 (m, 3H); MS 266.2 (M+1), 264.2 (M−1).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+]>O>[Br:8][C:6]1[CH:5]=[C:4]([CH3:9])[CH:3]=[C:2]([OH:11])[N:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(N)nc(Br)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)nc(Br)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A solution of 6-amino-2-bromo-4-methylpyridine (45.2 g, 0.24 mol) in water (100 ml) and concentrated sulphuric acid (43 g) at 0° C. was stirred and a solution of sodium nitrite (13.2 g; 0.19 mol) in water (20 ml) was added. After 2 hours, the reaction mixture was warmed to 60° C. and stirred for 1 hour. After cooling, the mixture was extracted with dichloromethane (200 ml). The solvent was removed in vacuo to afford 2-bromo-4-methyl-6-hydroxypyridine (20.2 g; 56%) as colorless crystals. Melting point 152° C. This material was mixed with tribromomethane (100 ml) and phosphoryl bromide (24 g) and heated to reflux for 3 hours. After cooling, the reaction mixture was quenched carefully with an aqueous 50% solution of sodiumhydroxide and the mixture extracted twice each with dichloromethane (100 ml). The solvent was removed in vacuo and the crude product purified by flash silica gel column chromatography using hexane/ethyl acetate (7/3). 2,6-Dibromo-4-methylpyridine (6.9 g; 25%) was obtained. Melting point 77° C. This compound (1.3 g; 5.2 mmol) was then converted using 3-hydroxybenzotrifluoride (1.4 ml; 10.7 mmol) and sodium hydride according to the procedure of Example 1 above to give 2,6-di-(3-trifluoromethylphenoxy)-4-methylpyridine as an oil (1.8 g; 84%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.NC(N)=[S:12].CC(CC)=O>O>[SH:12][C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Cl)nn1
Solvent: CCC(C)=O
Solvent: O
Product: COc1ccc(S)nn1
Yield: 23.4 %

Procedure:
A mixture of 3-chloro-6-methoxy pyridazine (0.69 mol, 100 g), thiourea (1.38 mol, 105 g) and ethyl methyl ketone (1.8 L) was refluxed for 3 hours. The reaction was cooled and the supernatant was poured into water and extracted with 1M sodium hydroxide (4×100 mL). The sodium hydroxide solution was washed with EtOAc (2×50 mL), the aqueous extract was acidified with sufficient conc. HCl to lower the pH to 5 and the resulting yellow solid was collected and air-dried to obtain 3-mercapto-6-methoxy pyridazine (24%, 23 g); mp 198° C.-200° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]([C:12]([OH:14])=[O:13])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:15](O)[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:13][C:12](=[O:14])[C@H:10]([CH3:11])[NH:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CO
Reactant: C[C@H](Nc1cc(F)cc(F)c1)C(=O)O
Product: CC(C)COC(=O)[C@H](C)Nc1cc(F)cc(F)c1

Procedure:
Following General Procedure AH above and using N-(3,5-difluorophenyl)alanine (from Example AC above) and iso-butanol, the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.9 in 3% methanol/methylene chloride) and purification was by preparative plate chromatography (silica gel using 3% methanoumethylene chloride as the eluant).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](OC)=[O:4].C[O-].[Na+].O1CCCC1.[H][H]>C(OCC)C>[CH3:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4]
Reactant: COC(=O)[C@@H](C)Cc1ccccc1
Reactant: [H][H]
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](CO)Cc1ccccc1
Yield: 85.9 %

Procedure:
Methyl (S)-2-methyl-3-phenylpropionate (5 mmol, 78.4% ee), a dichlororuthenium complex 8 (0.05 mmol), sodium methoxide (5 mmol), and tetrahydrofuran (2 mL) were charged into a 100-mL autoclave equipped with a stirrer. Then, the mixture was subjected to hydrogenation at a hydrogen pressure of 5 MPa at 80° C. for 16 hours. The reaction solution was diluted with 20 mL of diethyl ether, and was passed through 8.9 g of silica gel. The silica gel was washed with diethyl ether. The solution thus obtained was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 13.4 g, hexane/ethyl acetate=8/1). Thus, (S)-2-methyl-3-phenylpropanol (645 mg, 18.4% ee) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20]2([CH3:25])OCC[O:21]2)[C:7]1=[O:26])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20](=[O:21])[CH3:25])[C:7]1=[O:26])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)[C@@H](CCC2(C)OCCO2)C[C@H]1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)[C@@H](CCC(C)=O)C[C@H]1Cc1ccccc1

Procedure:
A solution of 12-4 (260 mg, 0.6925 mmol), p-TSA (10 mg) and acetone (20 mL) was heated at reflux for 1 hr. NaHCO3 was added to the cooled reaction mixture and then the mixture was concentrated. The residue was diluted with CHCl3 and then washed with brine, dried (MgSO4), and concentrated to afford 12-5 as an oil.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([CH3:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(C(C)N)ccc1C(C)(C)C#N
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C(C)NC(=O)Cn2cnc3cccc(C#N)c32)ccc1C(C)(C)C#N
Yield: 74.2 %

Procedure:
To a solution of (7-cyano-1H-benzimidazol-1-yl)acetic acid (100 mg, 0.50 mmol) prepared according to scheme 3, 2-{4-[1-aminoethyl]-2-methylphenyl}-2-methylpropanenitrile (101 mg, 0.50 mmol) prepared according to scheme 16 and DMAP (120 mg, 1.00 mmol) stirred in anhydrous DMF (2.0 mL) is added HATU (189 mg, 0.50 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly on a preparative on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (143 mg, 75%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.49 (d, J=7.03 Hz, 3H) 1.75 (s, 6H) 2.61 (s, 3H) 4.99 (q, J=7.03 Hz, 1H) 5.28-5.40 (m, 2H) 7.21-7.29 (m, 2H) 7.33 (d, J=8.20 Hz, 1H) 7.37-7.44 (m, 1H) 7.69 (dd, J=7.42, 0.78 Hz, 1H) 7.98 (dd, J=8.20, 1.17 Hz, 1H) 8.27 (s, 1H) MS [M+H], calcd: 386.2. found: 386.2.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[C:24]([C:32]1[CH:50]=[CH:49][C:35]2[N:36]=[C:37]([C:39]3[C:40]([CH3:48])=[C:41]([C:45]([OH:47])=O)[NH:42][C:43]=3[CH3:44])[NH:38][C:34]=2[CH:33]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][NH:55]C>N1C=CC=CC=1>[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][NH:55][C:45]([C:41]1[NH:42][C:43]([CH3:44])=[C:39]([C:37]2[NH:38][C:34]3[CH:33]=[C:32]([C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:50]=[CH:49][C:35]=3[N:36]=2)[C:40]=1[CH3:48])=[O:47]
Reactant: CNCCN(C)C
Reactant: Cc1[nH]c(C(=O)O)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cc1[nH]c(C(=O)NCCN(C)C)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 60 °C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg, 0.46 mmol) and 1-hydroxybenzotriazole monohydrate (70 mg, 0.46 mmol) were added to a pyridine (2 ml) solution of the 4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrole-2-carboxylic acid (150 mg, 0.42 mmol) obtained in Example 10. N,N,N′-Trimethyl ethylenediamine (43 mg, 0.42 mmol) was added to the resultant solution and heated. The reaction mixture was stirred for 5 hours at 60° C. (internal temperature), and then allowed to cool to room temperature. The solvent was evaporated, and the residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2) to afford N-methyl-N-(2-dimethylaminoethyl-4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrole-2-carboxamide (112 mg, 61%) as a light yellow amorphous.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:6](O)[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.C(OCC)C>P(Cl)(Cl)(Cl)=O>[CH3:20][S:19][C:4]1[N:3]=[C:2]([OH:1])[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=3)[O:17][C:6]=2[N:5]=1
Reactant: CSc1nc(O)c(NC(=O)c2cccc(C)c2)c(O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CSc1nc(O)c2nc(-c3cccc(C)c3)oc2n1
Yield: 38.6 %

Procedure:
21 g of N-(4,6-dihydroxy-2-methylsulfanyl-pyrimidin-5-yl)-3-methyl-benzamide in 100 ml of phosphorus oxychloride were heated to 70° C. for 3 h. After cooling, the mixture was poured into 500 ml of diethyl ether. The precipitate was filtered off and washed with diethyl ether. 7.6 g of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25](=O)[C:26](OC)=[O:27].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]1[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(F)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(F)cc45)C(=O)NC3=O)c21
Temperature: 65 °C
Reaction time: 20 h
Yield: 42.2 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (350 mg, 1.86 mmol) and methyl 2-(5-fluoro-1H-indol-3-yl)oxoacetate (427 mg, 1.93 mmol) in DMF (25 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (6.5 mL, 6.5 mmol) at room temperature under N2. The reaction was heated to 65° C. and stirred for 20 h at this temperature. The reaction mixture was then cooled to room temperature and quenched with 1.0 N hydrochloric acid, extracted with EtOAc (50 mL), washed with H2O (2×30 mL), saturated NaCl (2×30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (282 mg, 42%) as a maroon solid, mp 230° C. dec. 1H NMR (DMSO-d6) δ 11.95 (bs, 1H), 11.18 (bs, 1H), 7.98 (s, 1H), 7.64 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 6.99 (m, 1H), 6.92 (m, 1H), 6.83 (m, 1H), 6.48 (m, 1H), 5.91 (m, 1H), 3.67 (s, 3H). MS (APCI): m/z=360 [C21H14FN3O2+H]+
Reaction SMILES: [Na].[CH3:2][SH:3].CS(O[C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([C:26](=[O:28])[CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C:18](=[CH:19][C:20](=[O:29])[CH:21]=[CH:22]1)[CH2:17][CH2:16]3)(=O)=O>C(O)C>[CH3:2][S:3][C@@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([C:26](=[O:28])[CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C:18](=[CH:19][C:20](=[O:29])[CH:21]=[CH:22]1)[CH2:17][CH2:16]3
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Reactant: CS
Agent: [Na]
Solvent: CCO
Product: CS[C@@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 0 °C

Procedure:
To 6.9 gm. of sodium metal dissolved in 225 ml. of ethanol is added 30 ml. of methylmercaptan followed by 10 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat at reflux for 18 hours. Cool the solution to 0° C., filter solids and crystallize from chloroform/hexane to obtain the title compound; m.p. 180°-183° C.; [α]D26 +101.6° (DMF).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: Fc1cccc(CBr)c1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1cccc(F)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 42.4 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 3-fluoro-benzyl bromide (59 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(3-fluoro-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (64 mg, 42%) as a white solid. APCI-MS (M+H) 315.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[NH:17][C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:27]([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH:27]([CH3:29])[CH3:28])[C:16]2=[O:25])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc2c1n(C(C)C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (360 mg), 2-iodopropane (0.217 mL) and potassium carbonate (180 mg) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 15%-20% AcOEt in hexane) to give the title compound (218 mg) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)cc1
Yield: 91.3 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.9 μL (0.051 mMol) 4-methylbenzoyl chloride, 14.6 mg (91%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[O:11])=[CH:4][C:3]=2[O:2]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1ccc2c(c1)OCO2
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc5c(c4)OCO5)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
Under argon, 4-hydroxyphenyl 3, 4-methylenedioxyphenyl ketone (202 mg) obtained in Example 136 and 4-dimethylaminopyridine (112 mg) were added to xylene (2 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (187 mg) was added, and the admixture was refluxed with heat for 20 hours. The reaction mixture was treated in the same manner as described in Example 124 to obtain 135 mg of the title compound (yield: 38%).
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.S(=O)(=O)(O)[OH:13]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]([NH2:7])=[O:13])=[C:4]([F:11])[CH:3]=1
Reactant: Cc1cc(C#N)c(F)cc1Br
Reactant: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(N)=O)c(F)cc1Br
Temperature: 80 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylbenzonitrile (40 g, 190 mmol) in a mixture of sulfuric acid (98%) and TFA (v/v=4:1, 480 mL) was stirred at 80° C. for 16 h. After the mixture was cooled to room temperature, the resulting mixture was poured into ice-cold water. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give the title compound (41 g, 95% yield) as a white solid. MS (ESI) m/z 232.0 [M+1]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C@H:6]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[Br:22][C:10]1[C:11]([NH2:14])=[N:12][CH:13]=[C:8]([C@@H:6]2[CH2:5][CH2:4][O:3][C@H:2]([CH3:1])[CH2:7]2)[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H]1C[C@H](c2cnc(N)cn2)CCO1
Solvent: CC#N
Product: C[C@@H]1C[C@H](c2cnc(N)c(Br)n2)CCO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
To a solution of 5-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)pyrazin-2-amine (40 mg, 0.207 mmol) in acetonitrile (3 mL) was added NBS (35.0 mg, 0.197 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. After quenched with NaHCO3, the reaction mixture was extracted with EtOAc three times. The organic layers were combined and washed with water, and brine. Dried over Na2SO4, filtered and concentrated to afford 47 mg of 3-bromo-5-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)pyrazin-2-amine, which was used as it was. LCMS (m/z): 274 (MH+), 0.64 min. For 5-((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)pyrazin-2-amine, following the above method, 3-bromo-5-((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)pyrazin-2-amine was obtained. LCMS (m/z): 274 (MH+), 0.65 min. The absolute stereochemistry of the products were assigned arbitrarily.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:22][CH2:21]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:21][CH2:22]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:30]2[CH2:31][CH2:32][CH2:33][O:29]2)[CH:11]=3)=[CH:4][CH:3]=1
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CC2)c2cc(O)ccc12
Reactant: Cc1ccc(S(=O)(=O)OC2CCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(-c2ccc(N)cc2)n(C2CC2)c2cc(OC3CCCO3)ccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
2-(4-aminophenyl)-1-cyclopropyl-6-hydroxyindole-3-carbonitrile (0.29 g, 1.0 mmol), prepared in example 1DD, step A, is mixed with K2CO3 (0.35 g, 2.5 mmol), toluene-4-sulfonic acid tetrahydrofuran-2-yl ester (0.36 g, 1.5 mmol) and acetonitrile (5 mL) and the mixture is stirred at 80° C. overnight. The solvent is removed in vacuum and the residue is treated with DCM and chromatographed (silica gel, DCM/EtOAc, 9/1) to provide 2-(4-aminophenyl)-1-cyclopropyl-6-(tetrahydrofuran-2-yloxy)indole-3-carbonitrile (0.27 g, 75%).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[NH:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]([NH2:13])=[O:12])[CH3:3].[O:14]1[CH2:24][CH:15]1[CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>C(O)CCCC>[C:11]([CH2:10][N:5]1[C:6](=[O:9])[CH2:7][N:8]([CH2:24][CH:15]([OH:14])[CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:4]1[CH:2]([CH3:1])[CH3:3])(=[O:12])[NH2:13]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: CC(C)C1NCC(=O)N1CC(N)=O
Solvent: CCCCCO
Product: CC(C)COC(=O)CC(O)CN1CC(=O)N(CC(N)=O)C1C(C)C
Yield: 49.1 %

Procedure:
A solution of 1.2 g (6.4 mmol) of 2-(1-methylethyl)-5-oxo-1-imidazolidineacetamide and 2 g of 2-methylpropyl 3,4-epoxybutanoate in 40 ml of anhydrous pentanol was stirred at 80° C. for 48 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in 15 ml of 15% HCl, washed with 2×25 ml dichloromethane, basified with sodium carbonate and extracted with 3×35 ml dichloromethane. The organic layer was dried and evaporated to afford 1.08 g of the title compound as a colorless oil (mixture of two diastereoisomers, Rf 0.27 and 0.32 respectively (dichloromethane/methanol 9:1; silica gel plates). Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=300 (M+ --C3H7). IR spectrum (neat): 3400, 3200, 1730 and 1690 cm-1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>>[Cl:10][C:11]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: COC(=O)C(OC)OC
Reactant: NCc1ccc(Cl)cc1Cl
Product: COC(OC)C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 36 h

Procedure:
Into a sealed tube were added methyl dimethoxyacetate (0.78 g, 5.8 mmol) and 2,4-dichlorobenzylamine (1.0 g, 5.8 mmol). This mixture was stirred at 50° C. for 36 h. The completed reaction mixture was transferred to a flask and re-crystallized from heptane yielding the desired product as an off-white solid. MS (ES+): m/z=278.10/280.09/282.08 [MH+]. HPLC: tR=3.03 min (ZQ2, polar—5 min).