Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[BH3-][C:4]#N.[Na+].[C:7]1([CH:13]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:14][NH:15][CH:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(O)=O.CO>[C:35]1([CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][N:15]([CH3:4])[CH:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCC(c2ccccc2)c2ccccc2)nc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CC(c1ccccc1)c1ccccc1)C1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.2 %

Procedure:
Add paraformaldehyde (57 mg) and NaBH3CN (46 mg, 0.734 mmol) to a solution of 6-[1-(2,2-Diphenyl-ethylamino)-indan-5-yloxy]-nicotinamide (example 9, 110 mg, 0.245 mmol) in 5% AcOH/MeOH (3 ml) and stir at ambient temperature for two days. Concentrate the reaction mixture and partition remaining residue between EtOAc and 1M aq. K2CO3. Separate layers and wash organic with 1M aq. K2CO3 and brine before dying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/45% EtOAc/DCM) to obtain 74 mg of the title compound as a white solid. Mass spectrum (ion spray): m/z=464 (M+1); 1HNMR (CDCl3): 8.54 (s, 1H), 8.15 (d, 1H), 7.30-7.15 (m, 10H), 6.95-6.81 (m, 4H), 5.81 (br. s, 2H), 4.39 (t, 1H), 4.20 (t, 1H), 3.02 (d, 2H), 2.94-2.75 (m, 2H), 2.27 (s, 3H), 2.06 (m, 2H).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:4]=2[N:3]=1.[Br:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][C@H:32]2[CH3:37])=[N:27][CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][N:34]([C:2]3[NH:3][C:4]4[C:10]([C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=5)=[CH:9][C:8]([C:20]([F:23])([F:22])[F:21])=[CH:7][C:5]=4[N:6]=3)[CH2:33][C@H:32]2[CH3:37])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[C@@H]1CNCCN1c1ncccc1Br
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Product: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(-c4cc(F)c(F)c(F)c4)c3[nH]2)CCN1c1ncccc1Br

Procedure:
The benzoimidazole from step (b) above (105 mg, 0.3 mmol) reacted with (2R)-1-(3-bromopyridin-2-yl)-2-methylpiperazine (77 mg, 0.3 mmol, Example 43a) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 570 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([NH2:20])[C:10]=2[C:11]2[CH:16]=[C:15](S(C)=O)[N:14]=[CH:13][N:12]=2)[CH:7]=1.[NH:21]1[CH2:29][CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22]1>CN1C(=O)CCC1>[NH2:20][C:9]1[C:10]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:21]3[CH2:29][CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22]3)[CH:16]=2)=[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]2[N:8]=1
Reactant: Cc1cnc2c(-c3cc(S(C)=O)ncn3)c(N)nn2c1
Reactant: NC(=O)C1CCCNC1
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(-c3cc(N4CCCC(C(N)=O)C4)ncn3)c(N)nn2c1
Temperature: 200 °C

Procedure:
6-methyl-3-(6-(methylsulfinyl)pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine (60 mg, 0.21 mmol) was dissolved in NMP with nipecotamide (100 mg, 0.78 mmol)and heated to 200° C. in a microwave for 20 min. The reaction mixture was purified by RP HPLC (C18, CH3CN/H2O 0.1% TFA) and the pure fractions were poured into ethyl acetate/0.5 N NaOH. The organic phase was dried over sodium sulfate and concentrated to a yellow solid which was dissolved in 1N HCl in MeOH and concentrated to the HCl salt as a yellow solid, 20 mg, 0.052 mmol, 26%. LC/MS MH+353.4
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:21]>CN(C)C1C=CN=CC=1>[C:7]([CH2:6][C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=2)=[CH:3][CH:4]=1)#[N:8]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: N#CCc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: N#CCc1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Yield: 66.7 %

Procedure:
In the same manner as that described in Example 2(1), a reaction was carried out using commercially available 4-aminobenzyl cyanide (329 mg, 2.5 mmol), N,N-diisopropylethylamine (0.91 ml, 5.2 mmol), 4-formylbenzoyl chloride (350 mg, 2.1 mmol) and 4-(dimethylamino)pyridine (a catalytic amount) and the reaction mixture was treated according to a similar procedure to that described in Example 2(1) to afford 4′-(cyanomethyl)-4-formylbenzanilide (370 mg, yield 67%) as a pale yellow solid which was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give pale yellow powdery crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=O)[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[F:27][C:28]([F:36])([F:35])[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([NH:34][C:31]2[S:32][CH:33]=[C:29]([C:28]([F:36])([F:35])[F:27])[N:30]=2)=[O:26])[CH:21]=[CH:20][S:19]3)[CH2:2][CH2:3]1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 (200 mg, 0.539 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (100 mg, 0.593 mmol) in the presence of EDCI hydrochloride (206 mg, 1.079 mmol) and DMAP (99 mg, 0.809 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 72 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.24-0.26 (m, 2H), 0.47-0.49 (m, 2H), 1.15-1.18 (m, 1H), 3.75 (d, J=6.9 Hz, 2H), 3.79 (s, 3H), 6.96-6.99 (m, 1H), 7.09 (t, J=7.8 Hz, 1H), 7.30-7.33 (m, 1H), 7.40-7.42 (m, 1H), 7.46 (d, J=15.6 Hz, 1H), 7.87 (d, J=15.6 Hz, 1H), 8.03 (s, 1H), 8.06 (d, J=4.2 Hz, 1H), 12.94 (s, 1H); ESI-MS (m/z) 521.34 (MH)+.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O>O.C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[N:2][OH:3])[CH2:10][CH3:9])=[CH:14][CH:15]=1
Reactant: NO
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(=NO)c1ccc(OC)cc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of hydroxylamine hydrochloride (3.33 grams, 48 mmol) and sodium acetate (4.92 grams, 60 mmol) in 20 milliliters of water was added to a stirred solution of 4-methoxypropiophenone (5.26 grams, 30.0 mmol) in a mixture of water (30 milliliters) and ethanol (30 milliliters), a further 20 milliliters of ethanol was added to get a homogenous solution, which was stirred overnight. The resulting slurry was filtered, the filtrate was partially concentrated, to remove the ethanol and a white solid precipitated. The slurry was filtered and the solid was washed with water, and dried in vacuo (25° C., <1 mm) to afford 5.26 grams (98%) of product as a white solid: 1H NMR (CDCl3) δ7.64-7.42 (m , 2H), 7.04-6.81(m, 2H), 3.82(s, 3H), 2.81(q , J=7.6 Hz), 2H), 1.17(t , J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:29])=[C:5]([SH:30])[CH:4]=1)#[N:2].CC1(C)C2C=CC=CC=2I([C:41]([F:44])([F:43])[F:42])O1>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:29])=[C:5]([S:30][C:41]([F:44])([F:43])[F:42])[CH:4]=1)#[N:2]
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2SC(F)(F)F)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Under argon, (4S)-4-(4-cyano-2-sulfanylphenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (45 mg, purity 50%, 53 μmol) was dissolved in dichloromethane (1 ml). At −78° C., 3,3-dimethyl-1-(trifluoromethyl)-1,3-dihydro-1λ3,2-benziodoxole (26 mg, 79 μmol; 1.5 eq.) was added, and the mixture was stirred for 2 h. The reaction solution was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Kromasil C18 column, 20×50 mm; mobile phase: acetonitrile/water+0.1% TFA). After lyophilization, the title compound was obtained as a solid (11.4 mg, 44% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:5][C:6]1[O:10]C=[N:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12].Cl>CO>[CH3:14][O:13][C:11](=[O:12])[CH:7]([NH2:8])[C:6](=[O:10])[CH2:5][C:4]1[CH:15]=[CH:16][C:17]([F:18])=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)c1ncoc1Cc1ccc(F)c(F)c1
Agent: Cl
Solvent: CO
Product: COC(=O)C(N)C(=O)Cc1ccc(F)c(F)c1
Temperature: 80 °C
Yield: 104.6 %

Procedure:
To 5-(3,4-difluorobenzyl)-4-methoxycarbonyloxazole (0.100 g, 0.393 mmol) in methanol (5 mL) was added 2 mL of 6N HCl, and the solution heated at 80° C. for 2 hours. The reaction mixture was concentrated to yield 0.100 g (88%) of a solid which was used as such for the subsequent step.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH:10]([C:12]1[S:16][N:15]=[C:14]([C:17]([Cl:20])([Cl:19])[Cl:18])[N:13]=1)[NH2:11].Cl.C(O)C>O>[Cl:20][C:17]([Cl:18])([Cl:19])[C:14]1[N:13]=[C:12]([NH:10][N:11]=[CH:1][C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])[S:16][N:15]=1
Reactant: O=Cc1ccccc1O
Reactant: NNc1nc(C(Cl)(Cl)Cl)ns1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1ccccc1C=NNc1nc(C(Cl)(Cl)Cl)ns1
Yield: 83 %

Procedure:
A mixture of 1.3 g (0.01 mole) salicylaldehyde, 2.4 g (0.01 mole) 5-hydrazino-3-trichloromethyl-1,2,4-thiadiazole, 1 ml hydrochloric acid (conc.), and 100 ml ethanol was heated 5 hours on a steam bath. Water was added and the solution cooled in a freezer several days. The resulting solid was removed by filtration to give 2.8 g (83% yield) (mp. 204°-205° C.).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[C:19]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:36])=O>C(Cl)Cl>[Cl:36][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[C:19]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CN(c1ncccc1CNc1nc(Nc2ccc(CO)cc2)ncc1C(F)(F)F)S(C)(=O)=O
Solvent: ClCCl
Product: CN(c1ncccc1CNc1nc(Nc2ccc(CCl)cc2)ncc1C(F)(F)F)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A suspension of 6 (800 mg, 1.66 mmol) in DCM (5 mL) was cooled to 0° C. and treated with a solution of thionyl chloride (0.266 ml, 3.65 mmol) in DCM (2.0 mL). The reaction mixture was allowed to warm to 25° C. and stirred at 25° C. for 20 hours. The reaction mixture was then treated with DCM and washed with water (2×). The aqueous layer was collected and washed with DCM. The combined organic layers were then dried over MgSO4, filtered and concentrated to provide 7 as a white solid. Yield: 668 mg, 80%. 1H NMR (500 MHz, d6-DMSO) δ: 6.68 (s, 1H), 8.45 (d, 1H), 8.28 (s, 1H), 7.64 (m, 2H), 7.42 (m, 3H), 7.14 (d, 2H), 4.82 (d, 2H), 4.66 (s, 2H), 3.17 (s, 3H), 3.15 (s, 3H). FAK IC50: 0.00155 μM (Table 1, Example 348)
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1)#[N:2].[NH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:9])=[C:5]([CH3:12])[CH:4]=1)#[N:2]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: Cc1cc(C#N)ccc1C(=O)O
Product: Cc1cc(C#N)ccc1C(=O)N1CCCCc2ccccc21

Procedure:
The carboxylic acid from Example D (0.96 g, 5.95 mmol) was reacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.80 g, 5.44 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 0.59 g (38%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][C:19]2[S:22][C:23]([NH:25][C:26](=[O:28])[CH3:27])=[N:24][C:18]=2[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[S:22]1[C:19]2[CH2:20][CH2:21][NH:15][CH2:16][CH2:17][C:18]=2[N:24]=[C:23]1[NH:25][C:26](=[O:28])[CH3:27]
Reactant: CC(=O)Nc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(s1)CCNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
35 ml trifluoroacetic acid was added to 2.4 g 2-acetylamino-4,5,7,8-tetrahydro-thiazolo[4,5-d]-azepine-6-carboxylic acid tert-butyl ester in 80 mL chloroform. The reaction was stirred 3 h at RT and concentrated. The residue was dissolved in 75 mL chloroform and basified with 2.5 M potassiumcarbonate solution. The chloroform layer was separated and concentrated to give 1.3 g of the desired product., (M+H)+=212
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1>CC1C=CC=CC=1C.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[NH:9][C:5]3[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=3[N:10]=2)=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ti+4]
Agent: CC[O-]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2[nH]1
Yield: 15 %

Procedure:
To a solution of 4,5-difluoro-benzene-1,2-diamine (2.0 g, 6.94 mmol; CAS Reg. No. 76179-40-3) in o-xylene (25 ml) was added 4-chloro-2-nitro-benzoic acid (2.78 g, 6.94 mmol; CAS Reg. No. 6280-88-2) and titanium tetraethoxide (2.9 ml, 6.94 mmol) at 25° C., and the reaction mixture was allowed to stir at reflux temperature for 14 h. After the completion of reaction, solvents were evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (18-20% ethyl acetate/n-hexane) to afford the desired compound as a yellow powder (15%). MS (Turbo Spray): m/z=310.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1.FC(F)(F)S(OC1[C:37]2[CH:38]=[CH:39][C:40]([C:48]#[C:49][C:50]3[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=3)=[CH:41][C:42]=2C(C)(C)CC=1)(=O)=O>>[CH3:29][C:2]1([CH3:1])[C:38]2[CH:39]=[C:40]([C:48]#[C:49][C:50]3[CH:51]=[CH:52][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:59][CH:60]=3)[CH:41]=[CH:42][C:37]=2[C:5]([C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C(C)(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71), 300 mg (0.63 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (colorless oil) using 84 mg (0.94 mmol) of cuprous cyanide, 40 mg (0.94 mmol) of lithium chloride and 120 mg (1.1 ml, 1.88 mmol) of tert-butyllithium (1.7M solution in pentane).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C(C#N)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O
Yield: 82.6 %

Procedure:
Analogously to the preparation of Example 27, (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol) and ethanesulfonyl chloride (36 mg, 282 μmol) were reacted with one another for 3 h. This gave the title compound as a colorless solid (99 mg, 83% of theory).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.Cl.[CH2:12]([N:19]1[CH2:24][CH2:23][CH2:22][C:21](=O)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].C(O)(C)C>>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]=[C:21]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: C1=C(c2c[nH]c3ccccc23)CN(Cc2ccccc2)CC1
Temperature: 80 °C

Procedure:
A mixture of indole (29, 17 mmol) and 1-benzyl-piperidin-3-one hydrochloride hydrate (7.7 g, 34 mmol) and 2N KOH/isopropanol is heated at 80° C. for 14 hours, cooled to room temperature, poured over ice/water and extracted with ethyl acetate. The extracts are combined, washed with water, dried over Na2SO4 and concentrated in vacuo to afford the title product, identified by HPLC and mass spectral analyses.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[CH:32]1[CH2:34][O:33]1>>[OH:33][C@@H:32]([CH:24]1[CH2:25][C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23]1)[CH2:34][N:8]1[CH2:12][CH2:11][C@H:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1
Reactant: c1ccc2c(c1)CC(C1CO1)C2
Reactant: O=S(=O)(c1ccc(O)cc1)[C@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)[C@H]1CCN(C[C@@H](O)C2Cc3ccccc3C2)C1

Procedure:
The title compound, MS: m/e=388.3 (M+H+) was prepared from (S)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid and (RS)-2-indan-2-yl-oxirane.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([NH2:28])[C:20]=2[N:19]=[C:18]1[CH2:29][O:30][CH2:31][CH3:32]>>[NH2:28][C:21]1[C:20]2[N:19]=[C:18]([CH2:29][O:30][CH2:31][CH3:32])[N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:25]=2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)N[C@@H]1C[C@H]1c1ccccc1

Procedure:
Using the method of Examples 94-105, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 437.2674.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[C:21]([O:35][CH:36]4[CH2:39][CH2:38][CH2:37]4)=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][CH3:33])=[O:31])[C@@H:25]([CH3:34])[CH2:24][CH2:23]4)[N:19]=2)([OH:14])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:40]I.O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[C:21]([O:35][CH:36]4[CH2:37][CH2:38][CH2:39]4)=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][CH3:33])=[O:31])[C@@H:25]([CH3:34])[CH2:24][CH2:23]4)[N:19]=2)([O:14][CH3:40])[CH2:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CI
Reactant: COC(=O)N1c2ccc(-c3csc(C4(O)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N1c2ccc(-c3csc(C4(OC)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.012 g, 0.30 mmol) was added to a solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.100 g, 0.19 mmol) in N,N-dimethylformamide (2 mL), and the resulting mixture was stirred for 30 min at room temperature. Methyl iodide (0.014 mL, 0.23 mmol) was added, and the resulting mixture s stirred overnight at room temperature. The reaction mixture was poured into 10 mL of water, extracted with 3×10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC with ethyl acetate/petroleum ether (13). This resulted in 70 mg (68%) of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-methoxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate as colorless oil. MS (ESI, pos. ion) m/z 544 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: Cc1ccc(B(O)O)c(C)c1
Product: Cc1ccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2,4-dimethylbenzeneboronic acid (CAS RN 55499-44-0). Colorless solid (52%). MS (ESI): m/z=453.4 [M+H]+.