Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC([O-])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[CH2:8]1[CH2:9][CH2:10][N:5]2[C:10](=[N:5][CH2:6][CH2:7][CH2:8]2)[CH2:6][CH2:7]1
Reactant: c1ccncc1
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Product: C1CCC2=NCCCN2CC1

Procedure:
Compounds of Formula (I) wherein R1 is -SO2NHCO2R22 may be prepared by reacting an appropriate chloroformate with the sulfonamide (39) in pyridine or in the presence of DBU in THF to afford the desired compound (41), as outlined in Scheme 12. ##STR54##
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31]C=CC=4C)=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42]>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:42][CH2:41][C:40]4[CH:43]=[CH:44][CH:45]=[C:38]([CH3:37])[CH:39]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:3]=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1cccc(CN)c1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1cccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)c1

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3-methylbenzylamine, m.p. 130-132° C. MS [(+)ESI, m/z]: 538 [M+H]+ Anal. Calcd for C36H33N3O2: C, 80.12; H, 6.16; N, 7.79. Found: C, 80.01; H, 6.33; N, 7.61.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: COCCNC1CCCc2c(ccc(N)c2OC)C1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COCCNC1CCCc2c(ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c2OC)C1

Procedure:
The title compound was prepared from 1-methoxy-N(6)-(2-methoxyethyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2,6-diamine (200 mg, 0.8 mmol) and (1S,2S,3R,4R)-3-(2,5-dichloropyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (290 mg, 0.76 mmol) in an analogous manner to Example 946 to afford a tan solid (30 mg, 8%). Mp: 98-99° C. LCMS (m/e) 527 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.20 (m, 1H), 7.92 (s, 1H), 7.43 (s, 1H), 7.00 (d, J=8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 6.40 (m, 1H), 6.35 (m, 1H), 5.70 (br s, 1H), 5.56 (br s, 1H), 4.37 (m, 1H), 3.73 (s, 3H), 3.52 (m, 2H), 3.37 (s, 3H), 3.10 (m, 2H), 2.96-2.82 (m, 5H), 2.62 (m, 2H), 2.51 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 2.10 (m, 1H), 1.96 (m, 1H), 1.77 (m, 2H), 1.64 (d, J=8 Hz, 1H), 1.50 (m, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]C1.[CH3:11][OH:12].[CH3:13][O-:14].[Ba+2].C[O-]>C1C=CC=CC=1>[OH:1][C:6]1[CH:7]=[C:8]([CH:11]2[O:14][C:13]3[CH:9]=[CH:10][CH:5]=[CH:6][C:7]=3[CH2:8][O:12]2)[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: CO
Reactant: C[O-]
Reactant: c1ccc2c(c1)OCCO2
Agent: [Ba+2]
Solvent: c1ccccc1
Product: COc1ccc(C2OCc3ccccc3O2)cc1O

Procedure:
A 30-g. portion of the benzodioxan compound prepared in Example 1C was dissolved in 300 ml. of warm benzene, diluted with 600 ml. of methanol containing 70 mmol. of barium methoxide, and then stored 18 hours at 5° C. After adding 10 g. of ammonium acetate, volatiles were evaporated and the residue was extracted with two 500-ml. portions of chloroform. The chloroform was washed once with 500 ml. of water, the water was reextracted with 500 ml. of chloroform, and the combined chloroform extracts were washed once with 300 ml. of water. Evaporation and crystallization from diethyl ether-n-hexane gave the neutral form of the novel sweet compound (23 g., 95%), m.p. 105°-106° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36]([CH:38]1[O:40][CH2:39]1)Br.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:36][CH:38]1[CH2:39][O:40]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 443) (87 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution, and potassium carbonate (93 mg) and epibromohydrin (0.06 ml) were added to the solution. The mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (97 mg, yield 99%).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]2[C:6]([C:9]3[CH:16]=[CH:15]C(C#N)=[CH:11][CH:10]=3)=[CH:7][N:8]=[C:2]12.S(=O)(=O)(O)O.[C:22]([OH:25])(=[O:24])[CH3:23]>>[S:1]1[CH2:5][CH2:4][N:3]2[C:6]([C:9]3[CH:16]=[CH:15][C:23]([C:22]([OH:25])=[O:24])=[CH:11][CH:10]=3)=[CH:7][N:8]=[C:2]12
Reactant: CC(=O)O
Reactant: N#Cc1ccc(-c2cnc3n2CCS3)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(-c2cnc3n2CCS3)cc1
Temperature: 100 °C

Procedure:
2.00 g (8.80 mmol) of contaminated 4-(2,3-dihydroimidazo[2,1-b]thiazol-5-yl)benzonitrile is placed in 60 mL of 50% acetic acid solution at 0° C. and slowly combined with 30 mL of concentrated sulfuric acid with stirring and cooling in the ice bath. The reaction mixture is heated to 100° C. for 17 hours and then poured into 500 mL of ice water. The precipitated product formed is filtered off. The mother liquor is combined with sodium chloride and extracted with 300 mL of ethyl acetate, washed with saturated sodium chloride solution, dried with magnesium sulfate, and the solvent is distilled off. The residue remaining is combined with the above precipitate. Yield: 1.25 g (40% over 2 steps); Rf value: 0.55 (silica gel; ethyl acetate/ethanol=9:1); C12H10N2O2S (246.29); mass spectrum: (M+H)+=247
Reaction SMILES: Cl.[CH3:2][NH2:3].[F:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](O)=[O:9]>>[F:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8]([NH:3][CH3:2])=[O:9]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(F)c(F)c1
Yield: 75 %

Procedure:
Using methanamine hydrochloride and 3,4-difluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (d, J=4.55 Hz, 3 H) 7.55 (dt, J=10.61, 8.34 Hz, 1 H) 7.72 (dddd, J=8.59, 4.55, 2.15, 1.39 Hz, 1 H) 7.86 (ddd, J=11.68, 7.89, 2.15 Hz, 1 H) 8.48-8.59 (m, 1 H). ESI-MS: m/z 172.1 (M+H)+. mp=142.7-145.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27].O>C(O)CCC.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[C:11](=[N:26][NH2:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1C(=O)c1ccccc1OCc1ccccc1
Reactant: NN
Solvent: C1CCOC1
Solvent: CCCCO
Solvent: O
Product: COc1ccccc1C(=NN)c1ccccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A stirred suspension 2-benzyloxy-2′-methoxybenzophenone (13) (7.98 g, 0.025 mol) in hydrazine monohydrate (16 mL, 0.328 mol) and 1-butanol (25 mL) was heated to reflux overnight. After cooling to room temperature, the reaction mixture was poured into water saturated with salt and diluted with tetrahydrofuran. The organic phase which forms was separated, washed with water, saturated salt, and evaporated to dryness by rotary evaporation followed by application of high vacuum and mild heating. The resulting oil, 2-benzyloxy-2′-methoxybenzophenone hydrazone (14), which sometimes solidifies, still contains n-butanol and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]([CH3:12])[CH3:11])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].C([O:15][C:16]([NH:18][CH2:19][C@@H:20]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]2[O:32][CH2:33][O:34][C:27]=12)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=O)C.[CH3:35]CCCCCC=CCCC>O1CCOCC1>[CH2:33]1[O:32][C:28]2[C:27](=[C:26]([C@@H:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:19][NH:18][C:16]([NH:1][C:2]3[C:3]([N:10]([CH3:11])[CH3:12])=[N:4][CH:5]=[N:6][C:7]=3[O:8][CH2:9][CH3:35])=[O:15])[CH:31]=[CH:30][CH:29]=2)[O:34]1
Reactant: COc1ncnc(N(C)C)c1N
Reactant: CCCCC[C@@H](CNC(=O)OCC)c1cccc2c1OCO2
Reactant: CCCC=CCCCCCC
Solvent: C1COCCO1
Product: CCCCC[C@@H](CNC(=O)Nc1c(OCC)ncnc1N(C)C)c1cccc2c1OCO2
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 0.66 g of 5-amino-4-dimethylamino-6-methoxypyrimidine, 1.28 g of N-ethoxycarbonyl-(R)-2-(2, 3-methylenedioxyphenyl) heptylamine, 0.55 g of 1, 8-diazabicyclo [5, 4, 0] undec-7-ene and 10 ml of dioxane was stirred at 100° C. for 16 hours and the solvent evaporated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate-n-hexane (2:1-3:1), and the product was dissolved in ether. The solution was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate and the solvent evaporated. The residue was triturated with n-hexane to give 0.63 g of the titled compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NCCc3c[nH]c4ccccc34)n2)cc1
Yield: 81 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and Tryptamine (18 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (44 mg, 81% yield.) MS/ES+: m/z=474.
Reaction SMILES: OC1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=CC=1.[CH3:18]C(=C)C.[Si]([O-])([O-])([O-])[O-].[Al+3].[Si]([O-])([O-])([O-])[O-].[Si]([O-])([O-])([O-])[O-].[Al+3].[Al+3].[Al+3]>>[OH:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:8]([CH3:9])([CH3:10])[CH2:5][C:6]2([CH3:7])[CH3:18]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=C(C)C
Agent: [Al+3]
Agent: [O-][Si]([O-])([O-])[O-]
Product: CC1(C)CC(C)(C)c2cc(O)ccc21

Procedure:
114 g (0.5 mol) of 2,2-bis-(4-hydroxyphenyl)-propane, 90 g (1.6 mol) of isobutylene and 25 g of an aluminum silicate are stirred in an autoclave for 6 hours at around 300° C. under the naturally prevailing pressure. The catalyst is then filtered of while still hot. 41.8 g (44% of the theoretical) of 5-hydroxy-1,1,3,3-tetramethyl indane are isolated by fractional distillation in vacuo from the 170.9 g of reaction mixture.
Reaction SMILES: [C:1]([C:4]#[CH:5])([CH3:3])=[CH2:2].C([Li])CCC.[CH:11]([CH:13]=[CH2:14])=[O:12].[NH4+].[Cl-]>CCCCCC.O1CCCC1>[CH3:2][C:1](=[CH2:3])[C:4]#[C:5][CH:11]([OH:12])[CH:13]=[CH2:14]
Reactant: C=CC=O
Reactant: C#CC(=C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(O)C#CC(=C)C
Temperature: 25 °C

Procedure:
10 g Isopropenylacetylene are taken up in abs. tetrahydrofuran and under an inert gas 94.5 ml of 1.6M solution of n-butyllithium in hexane added dropwise at -20°. The mixture is then cooled to -78° and 8.5 g of acrolein added dropwise. The reaction mixture is warmed to room temperature, poured into saturated aqueous NH4Cl and repeatedly extracted with ether. The organic phase is washed, dried and concentrated in vacuum. An oil is obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>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.COCCOC>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][CH:33]([N:36]2[CH:40]=[C:39]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([CH2:11][C:12]5[CH:13]=[C:14]6[C:19](=[CH:20][C:21]=5[F:22])[N:18]=[CH:17][CH:16]=[CH:15]6)=[CH:9][N:10]=4)[N:7]=3)[CH:38]=[N:37]2)[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 90 °C

Procedure:
A microwave tube was charged with 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 180.2, 500 mg, 1.599 mmol), 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (prepared as described in published patent application WO 2007/066185 p. 9 & 10; 905 mg, 2.398 mmol), Pd(PPh3)2Cl2 (56 mg), 2 M K2CO3 (2.158 mL) and DME (5 mL) and was heated at 90° C. for 2 h under stirring. The RM was extracted with EtOAc and aqueous NaHCO3. The organic layer was dried and concentrated in vacuo. The reside was dried under vacuum (12 mbar) for 3 days to afford the title compound (tR 4.5 min (conditions 3), MH+=528)
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][Mg]Br)[CH:14]=[CH:15][CH:16]=1.COC1C=C(CCBr)C=CC=1.[Mg]>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:8])[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(CC[Mg]Br)c1
Reactant: O=Cc1ccccc1
Agent: COc1cccc(CCBr)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(CCC(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzaldehyde (920 μl, 9 mmol) in dry THF (20 mL) was added slowly a solution of 2-(3-methoxyphenyl) ethylmagnesium bromide prepared from 2-(3-methoxyphenyl) ethyl bromide (2.1 g. 9.77 mmol) and magnesium (300 mg, 12 mmol). The mixture was stirred at room temperature for ½ hour then quenched with saturated NH4Cl. The mixture was then extracted into EtOAc, washed with H2O, dried (Na2SO4), filtered and concentrated in vacuo, then purified by silica gel chromatography (30% EtOAc/Hexane) to provide the desired product as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].Br[CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O>[Si:24]([O:23][CH2:22][CH2:21][N:9]1[CH2:10][CH2:11][N:7]([C:5]2[S:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([CH3:1])[CH:6]=2)[C:8]1=[O:12])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCN(CCO[Si](C)(C)C(C)(C)C)C2=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a stirred suspension of ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate (0.85 g, 3.33 mmol) in anhydrous N,N-dimethylformamide (8 mL) under nitrogen atmosphere was added in one portion sodium hydride (60% in mineral oil, 0.16 g, 4.00 mmol). The resulting reaction mixture was stirred at ambient temperature for 1 h, and then (2-bromoethoxy)(tert-butyl)dimethylsilane (0.86 mL, 4.01 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 h, and then partitioned between ethyl acetate (100 mL), water (35 mL) and brine (35 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-30% ethyl acetate in hexanes to afford the title compound as a colorless solid in 79% yield (1.09 g): 1H NMR (300 MHz, CDCl3) δ 6.13 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.85-3.69 (m, 6H), 3.41 (t, J=5.2 Hz, 2H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H): MS (ES+) m/z 413.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:16][C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1.[O-]C1C=CC=CC=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.O>[CH3:24][C:19]1[CH:20]=[C:21]([CH3:23])[N:22]=[C:17]([NH:16][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[N:18]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Cc1cc(C)nc(N)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cn(-c2ccc(Nc3nc(C)cc(C)n3)cc2C#N)cn1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile (200 mg, 0.76 mmol), 2-amino-4,6-dimethyl-pyrimidine (141 mg, 1.14 mmol), sodium phenoxide (266 mg, 2.29 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (21 mg, 0.02 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene=xanthphos (26 mg, 0.04 mmol) in 5 mL of dioxane was heated to 80° C. under argon for 2 hours. The mixture was diluted with water, extracted with ethyl acetate and the product purified by by chromatography on silica gel using dichloromethane/methanol 9:1 v/v as an eluent. The title compound was obtained as a colorless solid (144 mg, 62%). MS ISP (m/e): 305.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): 8 (ppm)=10.08 (s, 1H), 8.44 (s, 1H), 8.15 (d, 1H), 7.89 (s, 1H), 7.55 (d, 1H), 7.25 (s, 1H), 6.76 (s, 1H), 2.36 (s, 6H), 2.18 (s, 3H).
Reaction SMILES: C1(C)C=C[C:4]([S:7](O)(=O)=O)=[CH:3][CH:2]=1.[CH2:12]1CCCCC1.[CH2:18]([OH:23])[CH2:19][CH:20]([OH:22])[CH3:21].CCCC=S>O>[CH3:21][CH:20]1[CH2:19][CH2:18][O:23][CH:2]([CH2:3][CH2:4][S:7][CH3:12])[O:22]1
Reactant: C1CCCCC1
Reactant: CC(O)CCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCCC=S
Solvent: O
Product: CSCCC1OCCC(C)O1

Procedure:
Into a 100 ml reaction flask equipped with spin bar, reflux condenser, heating mantle and hot plate with magnetic stirring apparatus is placed 0.2 grams para-toluenesulfonic acid, 5 ml cyclohexane and 4.5 grams of 1,3-butanediol. Slowly added to the reaction mass over a period of 30 minutes is 3-methylthiopropionaldehyde (5.2 grams; 0.05 moles). The reaction mass is then heated to reflux and refluxed for a period of 9 hours. During the refluxing process, water of reaction is removed from the reaction mass. At the end of the 9 hour refluxing period, the reaction mass is then cooled and transferred to a separatory funnel and washed with one 50 ml portion of saturated sodium chloride solution and then dried over anhydrous sodium sulfate, filtered and distilled on a Microvigreux column yielding the following fractions:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12](/[CH:17]=[CH:18]/[C:19]#[N:20])[CH:13]=[CH:14][C:15]=1[Cl:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.C1COCC1>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:17][CH2:18][C:19]#[N:20])=[CH:11][C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(/C=C/C#N)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2E)-3-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-chlorophenyl]acrylonitrile from the previous step (1 eq.) in toluene (0.01 M) was added at 80° C. benzenesulfonyl hydrazide (3×1 eq.) over 3 h. The reaction mixture was diluted with EtOAc and washed sequentially with water, sat. aq. NaHCO3 and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded a yellow oil. The residue was taken up in THF (0.1 M) and added tetrabutylammonium fluoride (1.0 M THF solution, 1.1 eq.). The resulting reaction mixture was stirred at RT for 2 h. After quenching the reaction with sat. aq. NH4Cl, the mixture was extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[N:5]=[CH:6][CH:7]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.Cl.FC(F)(F)C1C=CC=C[C:32]=1[O:33]C1CCNCC1>>[CH3:8][N:4]1[C:3](=[O:9])[C:2]([NH:1][C:32]([N:18]2[CH2:17][CH2:16][CH:15]([O:14][C:13]3[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=[C:11]([F:10])[CH:12]=3)[CH2:20][CH2:19]2)=[O:33])=[CH:7][CH:6]=[N:5]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Fc1cc(OC2CCNCC2)cc(C(F)(F)F)c1
Reactant: Cn1nccc(N)c1=O
Agent: Cl
Product: Cn1nccc(NC(=O)N2CCC(Oc3cc(F)cc(C(F)(F)F)c3)CC2)c1=O
Yield: 42 %

Procedure:
Compound 67 is prepared from intermediate 4c and from 4-(3-fluoro-5-trifluoromethyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 42%).