Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:29]5[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccc(C(C)(C)C)cc5)cn4)CC3)nc2)cc1
Yield: 45.1 %

Procedure:
Following the procedure of Example 1, crude crystals were obtained from the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol) synthesized in Reference Example 1 and 4-t-butylphenylboronic acid (226.0 mg, 1.20 mmol). The crude crystals were recrystallized from chloroform-hexane to yield the title compound as colorless needles (melting point: 268.0-270.0° C.) (117.0 mg, yield: 42%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11](Cl)[C:10]=2Cl)=[C:4]([CH2:18][O:19][CH3:20])[N:3]=1.[Cl:21]C1C=C(CC#N)C=CC=1Cl>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:10]=[CH:11][C:12]([Cl:21])=[C:13]([Cl:15])[CH:14]=2)=[C:4]([CH2:18][O:19][CH3:20])[N:3]=1
Reactant: COCc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Product: COCc1nc(N)nc(N)c1-c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared in an analogous manner to the compound of Example 2 from 3,4-dichlorophenylacetonitrile (Aldrich), mp. 204°-206° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].CO.Cl>C[O-].[Na+].O>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4]
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 79.4 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) and 5-amino-valeric acid (597 mg, 5.1 mmol) in 0.5 N NaOMe in MeOH solution (6.8 mL, 3.4 mmol) was heated to reflux overnight. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl solution to pH=3-4. Precipitate was collected and rinsed with water. It was dried in vacuo to provide the title compound (102 mg, 0.27 mmol) in 80% yield. LC-MS ESI−: 379.07 (M−1)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[I:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>[N+](C)([O-])=O.C(OCC)C>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[I:23])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Reactant: O=C(Cl)c1ccccc1I
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccccc3I)ccc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
250 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1benzopyran were dissolved in 10 ml of nitromethane and cooled in an ice-bath under a nitrogen atmosphere. 280 mg of finely powdered aluminum chloride were added followed, after 5 minutes, by 700 mg of 2-iodobenzoyl chloride. After stirring at 0° C. for 30 minutes and at room temperature for 1 hour the mixture was diluted with diethyl ether and washed with sodium hydroxide solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to give 230 mg of 3,4-dihydro-2,2-dimethyl-6-(2-iodobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[OH:3].[ClH:6].[CH2:7]([O:9]CC)[CH3:8]>C(O)C>[ClH:6].[CH2:7]([O:9][C:1](=[NH:5])[CH:2]([OH:3])[CH3:4])[CH3:8]
Reactant: CCOCC
Reactant: CC(O)C#N
Agent: Cl
Solvent: CCO
Product: CCOC(=N)C(C)O
Reaction time: 60 h

Procedure:
A solution of lactonitrile (378 g, 5.32 mol) in ethyl ether (1.46 L) and ethanol (0.34 L) was saturated with hydrogen chloride gas at 0-5° C. for 0.5 h and kept at 5° C. for 60 h. The resulting precipitate was filtered off and washed twice with ethyl ether to give the title compound of Preparation Twelve, Step A as a solid, 815 g (99%). mp: 165-168° C.; 1H NMR (CD3OD, 250 MHz) δ 1.45-1.53 (c, 6H), 4.40-4.61 (c, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:32])[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25]>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:32])[C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:28][CH2:27]1)=[O:25]
Reactant: COCCN(C)C(=O)N1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: COCCN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 and piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide using General Procedure B-3 yielded 4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:19]4[CH:23]=[CH:22][N:21]=[C:20]4[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:18][CH2:17]1
Reactant: c1cc(-c2ncc[nH]2)ccn1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccncc3)nc2N1C1CC1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate O instead of Intermediate C and with 4-(1H-imidazol-2-yl)pyridine instead of 2-phenyl-1H-imidazole. LCMS: 376.1 m/z (M+H)+; ret. Time: 3.90 min (Analytical Method C).
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[S:14]([C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)(=[O:16])=[O:15])[CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:13]([S:14]([C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)(=[O:15])=[O:16])[C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:31])=[O:5])=[CH:29][CH:28]=1
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(C(=O)OC(C)(C)C)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(C(=O)O)c2)n1
Reaction time: 3 h
Yield: 16.9 %

Procedure:
A solution of 3-[(4-chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoic acid tert-butyl ester (1.33 g, 0.02 mol) in a mixture of trifluoroacetic acid/dichloromethane (20 ml, 1:1 v/v) was stirred for 3 hrs. The reaction mixture was concentrated to dryness in vacuo to afford the title compound as a white solid (1.37 g). HPLC retention time 2.75 min. Mass spectrum (ES+) m/z 405.9 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>ClCCl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH:12]([S:14](=[O:16])(=[O:15])[NH:28][CH:25]1[CH2:26][CH2:27][N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24]1)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CNC(=O)OCc1ccccc1)S(=O)(=O)Cl
Reactant: CC(C)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(NS(=O)(=O)C(C)CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
245 mg (0.84 mmol) of crude (2-chlorosulfonyl-propyl)-carbamic acid benzyl ester in 3 ml dichloromethane were added dropwise to a solution of 143 mg (1.2 equiv.) 1-isopropyl-piperidin-4-ylamine and 214 μl DIPEA in 3 ml dichloromethane. After 2 h stirring at room temperature the reaction mixture was washed with 5 ml of a saturated NaHCO3-solution. The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure to give crude [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-propyl]-carbamic acid benzyl ester as yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[O:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1.O>[O:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A degassed solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Inter-mediate 1; 74 mg, 0.2 mmol) in dioxane (4 mL) and a degassed solution of potassium carbonate (83 mg) in water (0.4 mL) were added to a reaction vial containing (2-phenoxy)phenylboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.; 128 mg, 0.6 mmol). The solution was degassed and bis(tri-cyclohexylphos-phine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) was added. The mixture was heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica, and washed with dioxane (1 mL) and dimethylacetamide (1 mL). 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl (0.8 mL) was added. The solvent was evaporated and the residue was triurated with 50% aqueous methanol to give 3-(2′-phenoxy-biphenyl-4-yloxymethyl)-benzoic acid. Mass spectrum MH+=397.
Reaction SMILES: C(O)(=[O:3])C.[CH2:5]([N:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.BrBr.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[OH:3][CH:18]1[N:12]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13](=[O:14])[NH:15][C:16]1=[O:17]
Reactant: CC(=O)O
Reactant: O=C1CN(Cc2ccccc2)C(=O)N1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NC(=O)N(Cc2ccccc2)C1O

Procedure:
In a solvent mixture of 250 ml of acetic acid and 40 ml of ethyl acetate was dispersed 190 g of 1-benzylhydantoin and the mixture was refluxed under heating with stirring. To the mixture was added dropwise 164 g of bromine over a period of one hour, and the mixture was refluxed under heating for 30 minutes. The solvent was distilled off under a reduced pressure and the residue was allowed to stand for cooling. To the residue were added dropwise an aqueous sodium bicarbonate solution prepared by dissolving 53 g of sodium bicarbonate in 400 ml of water and then 200 ml of water. The reaction vessel was cooled with water and the crystals thus-deposited were collected by filtration, washed with water and dried to obtain 182 g of 5-hydroxy-1-benzylhydantoin as colorless crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][O:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[N:11][C:12]=3[NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:17]([CH3:29])[CH:16]=3)[NH:7][N:6]=2)[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCCl)c23)ccc1OCc1ccccn1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1ccccn1
Yield: 28 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylpiperazine to give the title compound in 28% yield; NMR Spectrum: 2.11 (s, 3H), 2.24 (s, 7H), 2.51 (hidden by DMSO, 4H), 2.77 (t, 2H), 4.41 (t, 2H), 5.21 (s, 2H), 6.99 (d, 1H), 7.35 (t, 1H), 7.44 (s+d, 2H), 7.54 (d, 1H), 7.84 (t, 1H), 8.21 (s, 1H), 8.24 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 475 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.C([N-]C(C)C)(C)C.[Li+].[I:28]I>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([I:28])=[CH:10][C:3]=12
Reactant: II
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(I)cc2c(Br)ccnc21
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a −78° C. solution of Example 135A (250 mg, 0.741 mmol) in 10 mL tetrahydrofuran was added lithium diisopropylamide (2.0M solution in tetrahydrofuran, 0.556 mL, 1.112 mmol) slowly over the course of 5 minutes. The resulting solution was stirred at the same temperature for 30 minutes after which iodine (376 mg, 1.483 mmol) in 5 mL of tetrahydrofuran was slowly added over 10 minutes. The reaction was stirred at −78° C. for 2.5 hours, and was quenched by addition of 1M aqueous sodium thiosulfate solution. The mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound. MS (ESI+) m/z 462 (M+1).
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH2:28][NH:27][CH2:26][CH2:25]5)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH2:28][N:27]([CH3:34])[CH2:26][CH2:25]5)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: N#CCC(C1CC1)n1cc(-c2nc(-c3ccc4c(c3)CCNC4)cc3nccn23)cn1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCc2cc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CC5)c4)n3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To 3-cyclopropyl-3-(4-(7-(1,2,3,4-tetrahydroisoquinolin-6-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 52; 10 mg, 0.024 mmol) in DCM/MeOH (1 mL/1 mL) was added formaldehyde (49 mg, 0.49 mmol) and sodium triacetoxyborohydride (16 mg, 0.073 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (5.0 mg, 48% yield). MS (apci) m/z=424.3 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](#[N:18])[CH:16]=[CH2:17]>ClCCl.[H-].[Na+]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:17][CH2:16][C:15]#[N:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: C=CC#N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCCOC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Sodium hydride [50% w/w in mineral oil] (2.0 g) was added to a slurry of 1-benzyl-4-piperidinol (400 g) and acrylonitrile (530 g) at 0° C. over 1 hour. The reaction mixture was warmed slowly to room temperature and stirred for 18 hours after which time the acrylonitrile was removed under reduced pressure and the residue taken up in isopropanol (1 L). The resulting yellow precipitate was filtered off. The filtrate was evaporated under reduced pressure to afford an orange oil which was dissolved in dichloromethane and washed with water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by distillation to afford 2-[(1-benzyl-4-piperidyl)oxy]ethyl cyanide (308 g), b.p. 150-160° C. @ 0.2 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[NH:19][CH:20]=[CH:21]3)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.8 %

Procedure:
A slurry of dichlorobis(triphenylphosphine)palladium(II) (119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00 g, 2.79 mmol). The reaction slurry was stirred at 25° C. for 10 min and then treated with a mixture of 5-indolylboronic acid (670 mg, 4.19 mmol) in water (5 mL) and a 2M aqueous sodium carbonate solution (2.8 mL, 5.58 mmol). The resulting reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to 25° C. and then filtered to remove the catalyst. The filtrate was partitioned between water (50 mL) and methylene chloride (50 mL), and the layers were separated. The aqueous layer was further extracted with methylene chloride (50 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid methyl ester (347 mg, 36%) as a light brown oil: EI-HRMS m/e calcd for C23H25NO2 (M+) 347.1885, found 347.1887.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][C@H:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[C:30](OCC)(=[O:32])C.CCCCCC>C(Cl)(Cl)Cl>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C@@H:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]([CH3:29])=[C:2]([O:32][CH3:30])[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: CCOC(C)=O
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: COc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Yield: 98 %

Procedure:
Using (−)-N-((3R)-7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 51, the title compound was synthesized in the same manner as in Example 36. Yield: 98%. Melting point: 150-151° C. (ethyl acetate -hexane). [α]D20=+55.9° (c=0.50, chloroform).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH:16]([Si:19]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])Cl)([CH3:18])[CH3:17]>CN(C=O)C>[CH3:13][O:12][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([Si:19]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:16]([CH3:18])[CH3:17])[CH:2]=[CH:3]2)=[O:11]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 1 g of methyl indole-5-carboxylate (5.7 mmol) in 10 mL of dry DMF 273 mg of NaH (mineral oil dispersion 50-60%, 5.7 mmol) were added and the mixture cooled to 0° C. Triisopropylchlorosilane (1.06 g, 5.7 mmol) were added drop wise and after 1 hour LC-MS showed complete conversion of the starting material to the title product. The mixture was diluted with 30 mL of DCM and washed with saturated Na2CO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified with SiO2 column eluting with n-hexane. The title compound was obtained (500 mg, yield 26%)
Reaction SMILES: [CH:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH2:17])[CH:9]=2)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>ClCCl>[CH:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH:17][C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27])[CH:9]=2)([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)n1c2c(c3cc(N)ccc31)CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1c2c(c3cc(NC(=O)Oc4ccccc4)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
The N-isopropyl-6-amino-1,2,3,4-tetrahydrocarbazole (9.84 g) and 5.05 g of triethylamine were dissolved in 100 mL of dichloromethane, and added dropwise with 7.85 g of phenyl chloroformate. The reaction mixture was stirred at room temperature for 3 hours, then washed with 10% aqueous citric acid and then with saturated aqueous sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=8/2) and recrystallized from a mixture of hexane and ethyl acetate, to obtain 2.27 g of N-isopropyl-6-phenoxycarbonylamino-1,2,3,4-tetrahydrocarbazole.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:15][C:10]=3[N:9]=[C:8]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:16]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:14]1[CH:13]=[CH:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:9][C:10]=2[CH:15]=1
Reactant: COC(=O)CCCCCBr
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
150 mg of N-(1,2-diphenyl-1H-benzimidazol-5-yl)-4-fluorobenzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 12 mg of sodium hydride and stirred for 30 minutes at 20° C. 98 mg of 6-bromohexanoic acid methyl ester was added, allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.