Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[C@@H:18]([CH3:21])[CH2:19][OH:20]>>[OH:20][CH2:19][C@H:18]([N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:21]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: C[C@H](Cl)CO
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)CO

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and (2S)-2-chloro-1-propanol: MS (ES) m/z 283 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:10]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][N:12]=2)[CH2:9][CH2:8][N:7]([C:25](OC(C)(C)C)=O)[CH2:6]1)=[O:4].Cl.[CH2:33]([C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)C(Cl)=[N:42][N:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH2:51](N(CC)CC)C>C(OCC)C.C(Cl)Cl>[CH2:24]([O:23][C:21]([C:14]1[C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]([N:10]2[CH2:9][CH2:8][N:7]([C:25]3[C:48]4[C:49](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:40]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:41][N:42]=3)[CH2:6][C@H:5]2[C:3]([O:2][CH3:1])=[O:4])=[N:12][CH:13]=1)=[O:22])[CH3:51]
Reactant: CCN(CC)CC
Reactant: Clc1nnc(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)OC)nc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)C[C@H]2C(=O)OC)nc1C(F)(F)F
Reaction time: 2.5 h
Yield: 8 %

Procedure:
To a methylene chloride (0.02M) solution of (S)-4-(5-Methoxycarbonyl-4-trifluoromethyl-pyrimidin-2-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl-ester (69 mg, 0.153 mmol), is added 1N HCl (2 mmol), 2M in diethyl ether. Stir reaction mixture at room temperature for 18 h. Concentrate and dilute with dioxane (0.1 M), followed by addition of 1-benzyl-4-chloro-phthalazine (0.153 mmol) and triethylamine (0.459 mmol). Microwave reaction mixture for 30 min at 150° C. MS shows some starting material still present. Microwave for an additional 2.5 h at 150° C. Concentrate reaction mixture and purify by column chromatography 0-75% ethyl acetate/heptane gradient to afford the title compound. (8% yield)
Reaction SMILES: ClC1C(F)=CC=C(Cl)C=1[C@H](OC1C(N)=NC=C(B2OC(C)(C)C(C)(C)O2)C=1)C.[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][N:39]([CH:41]3[CH2:46][CH2:45][N:44](C(=O)CO)[CH2:43][CH2:42]3)[CH:40]=2)=[CH:32][C:31]=1[O:51][C@@H:52]([C:54]1[C:59]([Cl:60])=[CH:58][CH:57]=[C:56]([F:61])[C:55]=1[Cl:62])[CH3:53]>>[Cl:62][C:55]1[C:56]([F:61])=[CH:57][CH:58]=[C:59]([Cl:60])[C:54]=1[C@H:52]([O:51][C:31]1[C:30]([NH2:29])=[N:35][CH:34]=[C:33]([C:36]2[CH:37]=[N:38][N:39]([CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH:40]=2)[CH:32]=1)[CH3:53]
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)CO)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: C[C@@H](Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to procedure 62 using 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine and 4-(4-bromo-pyrazol-1-yl)-1-cyclopentyl-piperidine (prepared according to general procedure 11 using bromocyclopentane as alkylation reagent). 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.31 (m, 1H), 7.07 (m, 1H), 6.88 (s, 1H), 6.08 (m, 1H), 4.64 (m, 1H), 2.04 (m, 2H), 1.98 (m, 2H), 1.86 (d, J 8 Hz, 3H), 1.73 (m, 2H); LCMS: 435 [M+1]; c-Met Ki: 0.02 μM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O-:20][C:21]#[N:22].[Na+]>C(O)(=O)C.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[CH:18][N:17]([C:21]([NH2:22])=[O:20])[N:16]=3)=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Sc2ccc(-c3cc[nH]n3)cc2)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)n1ccc(-c2ccc(Sc3ccc(F)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A solution of 3-[4-(4-fluorophenylthio)phenyl]-1H-pyrazole (85 mg, 0.31 mmol) in 1.5 mL glacial acetic acid was treated with a solution of sodium cyanate (31 mg, 0.47 mmol) in 0.5 mL of water. The resulting white suspension was stirred at room temperature overnight. The suspension was then diluted with 10 mL of EtOAc, resulting in a yellow solution which was washed with water and sat. NaHCO3 solution, dried over Na2SO4 and evaporated. The residue was trituated with 3 mL of 25% EtOAc/hexane. The white solid that formed was collected by filtration and dried to give 65 mg (66%) of the title compound, mp 150-155° C. (TLC Rf=0.22 (25% EtOAc/hexane)). 1H NMR (300 MHz, CDCl3): δ8.27 (d, J=2.1 Hz, 1H, pyrazole H), 7.77 (d, J=7.5 Hz, 2H, PhH), 7.48-7.06 (m, 6H, PhH), 6.71 (d, J=2.1 Hz, 1H, pyrazole H), 5.31 (br s, 2H, NH2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]([NH2:45])[CH:36]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:45][C:37]2[CH:36]=[N:35][C:44]3[C:39]([CH:38]=2)=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Nc1cnc2ccccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(Cl)nc1

Procedure:
A solution of 6-chloro-nicotinic acid (2.95 g, 18.7 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospate (HBTU) (7.09 g, 18.7 mmol), quinolin-3-ylamine (2.7 g, 18.7 mmol), and N,N-diisopropylethylamine (8.2 mL, 46.7 mmol) in acetonitrile was heated at reflux. The resultant mixture was cooled, and the crystalline product was collected by filtration, to give a colorless solid, 3.1 g (58%). MS: m/z 284 (MH+). 1H NMR (DMSO-d6): 7.61 (t, 1 H), 7.70 (d of t, 1 H), 7.77, (d, 1 H), 8.00 (d, 2 H), 8.43 (d of d, 1 H), 8.85 (d, 1 H), 9.05 (d, 1 H), 9.14 (d, 1 H) and 10.95 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH3:22])[C:19]([C:23](OC)=[O:24])=[C:18]([NH:27][C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=O.[CH3:38][O:39][C:40]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:41]=1[CH2:48][NH2:49].C([BH3-])#N.[Na+]>O1CCOCC1.CO>[CH3:38][O:39][C:40]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:41]=1[CH2:48][N:49]1[C:23](=[O:24])[C:19]2[C:18]([NH:27][C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[N:17][C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[N:21][C:20]=2[CH2:22]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: O=[Se]=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(CN2Cc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
A mixture of methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate (500 mg, 1.065 mmol) and selenium dioxide (236 mg, 2.130 mmol) in dioxane (10 mL) was heated at 100° C. for 24 h. The solution was subsequently cooled and filtered. The filtrate was concentrated under reduced pressure and dried to give a brown foam (534 mg; dihydroxyl form was observed via mass spectroscopy), which was used directly in the next step without further purification. A mixture of the unpurified intermediate (534 mg, 1.065 mmol) and (2,4-dimethoxyphenyl)methanamine (0.160 mL, 1.065 mmol) in MeOH (10 mL) was stirred at RT for 10 min, after which sodium cyanoborohydride (100 mg, 1.597 mmol) was added, and the reaction mixture was stirred at RT for 20 h. The reaction mixture was warmed to 50° C. and stirred for an additional 2 h to complete the reaction. The mixture was cooled to RT and the solid filtered and washed with MeOH to give the title compound as a pinkish solid (237 mg, 37%). [M+H] calc'd for C33H42N6O5, 603; found, 603.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3].Br[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Reactant: Cc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=CCn1ccnc1-c1sc(-c2ccnc(C)c2)cc1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Yield: 70.9 %

Procedure:
To a solution of 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole (300 mg, 0.48 mmol) and 4-bromo-2-picoline (68.9 mg, 0.40 mmol) in DMF (10.0 mL) was added bis(triphenylphosphine)palladium dichloride (14.1 mg, 0.02 mmol) under atmosphere of Argon then the mixture was heated at 90° C. for 1 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column chromatography (SiO2, elution with 3-5% MeOH in DCM) to give 121 mg of product (67%). LC/MS (AA) ES+ 428. 1H NMR (400 MHz, d6 DMSO) δ: 8.48 (d, J=4.8 Hz, 1H), 7.93 (s, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.60 (br s, 1H), 7.50-7.53 (m, 1H), 7.41 (dd, J=2.1, 8.4 Hz, 1H), 7.18-7.21 (m, 2H), 7.03 (d, J=1.1 Hz, 1H), 5.53-5.64 (m, 1H), 5.04 (dd, J=1.3, 10.3 Hz, 1H), 4.82 (dd, J=1.3, 17.1 Hz, 1H), 4.26-4.31 (m, 2H), 2.51 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[NH2:17][CH2:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:17][CH2:18][C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCc1ccco1
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccco3)c3ccccc3nc21
Yield: 34.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 0.0043 mol), DMSO (3 mL) and 2-aminomethylfuran (0.8 mL, 0.009 mol) was heated at 90° for 3 hours. The reaction mixture was then partitioned between CH2Cl2 (50 mL) and water (50 mL). The aqueous layer was separated and then extracted with CH2Cl2 (25 mL) and then the CH2Cl2 layers were combined, washed with water dried over Na2SO4 and reduced to a volume of about 3-5 mL. The solution was passed through a silica gel column eluting with ethyl acetate to afford the product which was recrystallized from ether/CH2Cl2 to afford 430 mg of 1-ethyl-N-(2-furanylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 156°-158° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.C1(O)C=CC=CC=1.Cl>N1C=CC=CC=1.C(Cl)Cl>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:11](=[O:13])[O:9][C:3]=2[CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(F)cc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: O=c1[nH]c2ccc(F)cc2o1
Temperature: 60 °C

Procedure:
2-amino-5-fluorophenol [4.0 grams (g) (0.03 moles) (M)] was dissolved in 40.0 ml pyridine. The mixture was cooled with an ice bath while triphosgene [3.5 g (0.03 M)] was added. The mixture was heated to 60° C. for 3.0 hours. Thin layer chromatography showed that some of the starting phenol was still present. The mixture was then cooled; triphosgene [0.35 g 0.003 M)] was added and heated to reflux for 4.0 hours. The mixture was cooled, methylene chloride and 10% hydrogen chloride solution was added and stirred to room temperature.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Cl:40]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:40][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([NH:11][C:12]1[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: COc1nccnc1NS(=O)(=O)c1cccc(F)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1nccnc1NS(=O)(=O)c1cccc(F)c1Cl
Yield: 29 %

Procedure:
Prepared as for Example 130, 3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide (Example 131a) (0.283 g), lithium di-iso-propylamide (prepared from di-iso-propylamine (0.30 g) and n-butyl lithium (0.96 mL of a 2.5M solution in hexanes)) and hexachloroethane (0.994 g) in anhydrous tetrahydrofuran (20 mL) afforded the titled compound (0.092 g) as a white solid after re-crystallisation from tert-butyl methylether.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:12]1(=[O:14])[C:9]2=[C:10]3[C:5](=[CH:6][CH:7]=[CH:8]2)[CH:4]=[CH:3][CH:2]=[C:1]3[CH2:11]1
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1Cc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
1-Naphthylacetic acid (100 g, 530 mmol) was dissolved in dichloromethane (15 ml). Thionyl chloride (158 g, 1.32 mol) was added under ice-cooling and the mixture was heated under reflux for 1 hr. The solvent was evaporated and 1,2-dichloroethane (500 ml) was added to the obtained residue for dissolution. Aluminum chloride (150 g, 1.12 mol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water, and the mixture was extracted with dichloromethane. The extract was washed with water and saturated brine, dried over magnesium sulfate and concentrated to give acenaphthen-1-one (80 g) as yellow crystals.
Reaction SMILES: CO[C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.[CH2:21]1COC[CH2:22]1>>[CH2:21]([C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1)[CH3:22]
Reactant: C1CCOC1
Reactant: COc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Product: CCc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of 355 mg (1.17 mmol) 2-(2-methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 4 ml THF were added at <10° C. drop-wise over 20 min 2.35 ml (4.7 mmol) 2-Methylmagnesium chloride solution in THF. The resulting brown solution was stirred at ambient temperature for 1 h, then quenched with saturated aqueous NH4Cl solution (cooling with ice bath) and extracted three times with tert-butyl methyl ether. The combined organic phases were washed three times with brine, dried over Na2SO4, filtered and evaporated. 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole was obtained as yellow oil: MS (ISP): 286.1 ((M+H)+).
Reaction SMILES: [C:1]([NH:9][C:10]1[N:14]([C@@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]2)[C:13]2[CH:25]=[C:26]([CH2:29]O)[CH:27]=[CH:28][C:12]=2[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:35][C:36]1([CH3:44])[CH2:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[NH:37]1>C(Cl)Cl>[C:1]([NH:9][C:10]1[N:14]([C@@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:20]2)[C:13]2[CH:25]=[C:26]([CH2:29][N:37]3[C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][CH2:41][C:36]3([CH3:44])[CH3:35])[CH:27]=[CH:28][C:12]=2[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccccc3)nc3ccc(CO)cc32)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccccc3)nc3ccc(CN4C(C)(C)CCCC4(C)C)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
cis-Methyl 4-(2-benzamido-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.05 g, 0.123 mmol) was suspended in DCM (1.2 mL) and cooled to 0° C. under nitrogen atmosphere. To this mixture was added thionyl chloride (0.292 g, 2.454 mmol), and the mixture was stirred for 30 minutes. The resulting mixture was concentrated under reduced pressure and dried under high vacuum. The residue was suspended in 2 mL of DMSO and cooled in an ice bath under nitrogen atmosphere. To this mixture was added 2,2,6,6-tetramethylpiperidine (0.173 g, 1.227 mmol) dropwise, and the reaction was stirred in an ice bath for 30 minutes and at RT for another 30 minutes. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL). The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The residual yellow oil was triturated with 10% water/MeOH to afford cis-methyl 4-(2-benzamido-6-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (20 mg, 30.8% yield). MS m/z=531.2 [M+H]. Calc'd for C32H42N4O3: 530.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 12H) 1.54-1.73 (m, 6H) 1.73-1.99 (m, 4H) 2.25-2.41 (m, 2H) 2.46-2.54 (m, 2H) 2.84-3.02 (m, 1H) 3.81 (s, 3H) 3.93 (s, 2H) 4.73-5.08 (m, 1H) 7.25 (d, J=8.31 Hz, 1H) 7.39-7.62 (m, 4H) 7.74 (s, 1H) 8.23-8.35 (m, 2H) 12.76 (s, 1H).
Reaction SMILES: [CH2:1]([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:2][CH3:3].[OH-].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:7][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[O:19])=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCS(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCS(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Yield: 64.1 %

Procedure:
Procedure A was followed with 1-propanesulfonamide (5.0 g, 40.6 mmole), in acetone (40 ml), and 1.0N sodium hydroxide (40.6 ml). After ten minutes of stirring, 4-chlorophenyl isocyanate (6.2 g, 40.6 mmole) dissolved in about 40 ml of acetone was added over a five minute period. The mixture was allowed to stir for about two hours and filtered. The filtered solid was washed with water which dissolved most of it. 1N HCl (40 ml) was added to the combined filtrates and the resulting precipitate was filtered off and dried at about 65° C. under vacuum to provide 7.2 g of product.
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:27][C:28]1([CH3:35])[C:32]([CH3:34])([CH3:33])[O:31][BH:30][O:29]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Cl-].[NH4+]>O1CCOCC1>[CH:14]1([C:3]2[C:4]3[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:5]=3[NH:6][C:2]=2[B:30]2[O:31][C:32]([CH3:34])([CH3:33])[C:28]([CH3:35])([CH3:27])[O:29]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Reactant: CC1(C)OBOC1(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2[nH]c(B3OC(C)(C)C(C)(C)O3)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (2.00 g, 5.84 mmol) in 1,4-dioxane (20 ml) was added triethylamine (3.20 ml, 22.9 mmol). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (2.50 ml, 17.2 mmol) was added dropwise under an argon stream and the mixture was stirred at room temperature for 30 min. To the mixture were added 2-(dicyclohexylphosphino)biphenyl (245 mg, 0.699 mmol) and palladium acetate(II) (39.0 mg, 0.173 mmol) under an argon stream, and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. A mixed solvent of hexane-ethyl acetate (10:1) was added to the obtained residue and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give methyl 6-cyclohexyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.66 g, yield 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.O>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH:12]=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1cccc(-c2cc3c(C=O)c[nH]c3cc2Cl)c1
Yield: 52.5 %

Procedure:
To a solution of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (300 mg, 2 mmol) in dioxane/DMF=1/1 (4 mL) was added (3-methoxyphenyl)boronic acid (463 mg, 1.8 mmol), potassium carbonate (828 mg, 6 mmol) in water (1 mL), and Pd (dppf)Cl2 (50 mg) in a microwave vial. The sealed vial was irradiated in the microwave on a Biotage Smith Synthesizer at 110° C. for 30 min, TLC (petroleum ether/ethyl acetate=1:1) showed the reaction was complete. The solvent was removed in vacuo and the mixture was partitioned between ethyl acetate and water. The combined organics were dried over sodium sulfate, concentrated in vacuo, and purified by combi-flash to give the title compound (270 mg, 47%) as a yellow solid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][CH2:23][CH:24]([OH:39])[CH2:25][N:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>CC(C)CC(=O)C>[ClH:22].[CH:28]1[C:27]2[N:26]([CH2:25][CH:24]([OH:39])[CH2:23][N:12]3[CH2:11][CH2:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)([OH:15])[CH2:14][CH2:13]3)[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(C2(O)CCNCC2)cc1
Reactant: OC(CCl)Cn1c2ccccc2c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1ccc(C2(O)CCN(CC(O)Cn3c4ccccc4c4ccccc43)CC2)cc1
Product: Cl
Yield: 52.2 %

Procedure:
4-(4-Methoxyphenyl)piperidin-4-ol (0.50 g, 0.0024 mol) was dissolved in 4-methyl-pentan-2-one (35 mL), K2CO3 (1.33 g, 0.0096 mol) and 9-(3-chloro-2-hydroxy-1-propyl)carbazole (0.42 g, 0.0016 mol) were added, and the resulting mixture was stirred at reflux temperature overnight. The reaction mixture was filtered and the solvent was removed in vacuo. The residual oil was purified on a silica gel column (Eluent: CH2Cl2 /ethanol/25% NH4OH (aq) (92.75:7:0.25)). The product was acidified with 2M HCl(g) in diethyl ether, to give the title compound 0.39 g (51%). M.p. decomposes at 125° C.