Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[N:12]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Brc1cccc(-c2n[nH]c3c2Cc2sccc2-3)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)c2)c2c1-c1ccsc1C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
At 0° C., NaH (60 percent, 0.6 g, 12.0 mmol) was added to a THF solution (15 mL) containing 6-(3-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.1 g, 9.7 mmol). Then SEM-Cl (2.5 mL, 12 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(3-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.0 g, 6.7 mmol) as brown solid in 70% yield.
Reaction SMILES: [O:1]=[S:2]1(=[O:43])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15](C2C=C(C)C=CC=2S([O-])(=O)=O)=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.C[O-:45].[Na+]>CO.O>[O:1]=[S:2]1(=[O:43])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15]([OH:45])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: Cc1ccc(S(=O)(=O)[O-])c(-c2c(C(=O)NCc3ccccc3S(C)(=O)=O)nc(N3CCCCS3(=O)=O)c3cccnc23)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(1,1-dioxido-1,2-thiazinan-2-yl)-7-({[2-(methylsulfonyl)benzyl]amino}carbonyl)-1,6-naphthyridin-8-yl-4-methylbenzenesulfonate (220 mg, 0.34 mmol) was dissolved in methanol (10 mL) and NaOMe (55 mg, 1.02 mmol) was added. The reaction was stirred overnight at room temperature. The crude reaction was diluted with water (10 mL) and extracted with CH2Cl2 (2×10 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oily solid. The material was suspended in methanol and a yellow precipitate fell out of solution. Washing with fresh methanol (2×10 mL) gave the desired product as an off-white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([OH:24])=O.O.[NH2:39][NH2:40]>CS(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([NH:39][NH2:40])=[O:24]
Reactant: NN
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CS(C)=O
Product: NNC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
1,1′-carbonyldiimidazole (21 mg, 0.13 mmol) was added to a solution of 3-(2-chloro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid from above (40 mg, 0.09 mmol) in DMSO (1 mL), and stirred overnight at 60° C. Hydrazine hydrate (13 mg, 0.27 mmol) was added, and the reaction solution was stirred for an additional 4 h at 60° C. The reaction solution was quenched with H2O, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 70% EtOAc in hexanes to afford the desired product (17 mg, 41%). LC-MS (M+H=483, obsd.=438).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17].[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COc1cccc(CCCCCCBr)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCCc2cccc(OC)c2OC)cc1
Yield: 98.4 %

Procedure:
A mixture of 1.00 g (3.3 mmol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene, 0.45 g (3.0 mmol) of 4-hydroxybenzoic acid methyl ester, 0.62 g (4.5 mmol) of potassium carbonate and 0.75 g (4.5 mmol) of potassium iodide in 25 mL of acetone was stirred at reflux for 23 hours. Workup as in Example 16 and purification by HPLC using 15% ethyl acetate-hexane gave 1.10 g (89% yield) of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]benzoic acid methyl ester as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[O:26])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1ccc2ccccc2n1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CCN(Cc1ccc2ccccc2n1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-quinolin-2-ylmethyl-amine
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:40][C:39]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[O:10][C:36](=[O:37])[C:35]=1[S:34][CH2:33][CH2:32][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(O)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(O)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-hydroxyacetophenone (0.688 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (1.84 g, 11.1 mmol), chlorotrimethylsilane (1.41 mL, 11.1 mmol), THF (111 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). 1H NMR (400 MHz, DMSO-d6) δ2.78 (t, 2 H), 2.95 (t, 2 H), 6.62 (s, 1 H), 6.89 (dd, 2 H), 7.21 (m, 5 H), 7.65 (d, 2 H), 10.22 (s, 1 H), 11.05 (bs, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([O:11][C:12]([C:14](=[CH:35][CH:36]=[CH:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=1)[N:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])[CH3:10]>C(#N)C>[CH2:44]([C:41]1[CH:40]=[CH:39][C:38]([C:37]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:15][C:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])=[CH:35][CH:36]=2)=[CH:43][CH:42]=1)[CH3:45]
Reactant: O=Cc1ccccn1
Reactant: CCOC(=O)C(=CC=Cc1ccc(CC)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2ccc(CC)cc2)c(-c2ccccn2)n1

Procedure:
Following General Procedure K, 2-pyridinecarboxaldehyde (41 mg, 0.38 mmol) and 3-ethoxycarbonyl-1,1,1-triphenyl-6-(4-ethylphenyl)-2-aza-1λ5-phosphahexa-1,3,5-triene (Compound 46, 193 mg, 0.38 mmol) in dry acetonitrile (5 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[C:12]#[N:13])(=O)=O)=CC=1.CO.[CH3:31][S-:32].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:31][S:32][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1)[C:12]#[N:13]
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Reactant: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CSC(C#N)c1cccc(C(=O)c2ccccc2)c1
Yield: 80 %

Procedure:
979 mg of O-(p-toluenesulfonyl)-m-benzoylmandelonitrile was dissolved in 2 ml of DMF, and the mixture was stirred in an argon atmosphere under ice cooling. Then, 1.08 ml of a 2.3 M methanol solution of sodium methanethiolate was added dropwise to the solution over 5 minutes, and the mixture was further stirred under ice cooling. An aqueous solution of ammonium chloride (0.2 g/30 ml) was added, and the mixture was extracted with methylene chloride. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was separated by column chromatography (silica gel; methylene chloride) to afford 533 mg (yield 80%) of alpha-(methylthio)(m-benzoylphenyl)acetonitrile as a pale orange oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([NH2:41])[CH:39]=2)[CH:34]=[N:33]1>C1COCC1>[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([NH:41][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])[CH:39]=2)[CH:34]=[N:33]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc3cn[nH]c3c2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 15.8 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 15, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 1H-Indazol-6-ylamine (36 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified over silica (5% MeOH/95% CHCl3) yielding 16% (20 mg, 0.038 mmol) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][SH:46])=[CH:41][CH:40]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]([S:46][CH2:45][C:42]2[CH:43]=[CH:44][C:39]([O:38][CH3:37])=[CH:40][CH:41]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CS)cc1
Reactant: CC(C)(C)OC(=O)C(=CCc1ccccc1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CSC(Cc2ccccc2)C(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)OC(C)(C)C)cc1
Temperature: 75 °C
Yield: 50 %

Procedure:
4-(2-tert-Butoxycarbonyl4-phenyl-but-2-enyl)-piperidine-1-carboxylic acid tert-butyl ester (0.8 g, 1.93 mmol) in DMF (10 mL) was added to a suspension of potassium carbonate (0.20 g, 1.44 mmol) ) and 4-methoxy-α-toluenethiol (0.54 mL, 3.85 mmol) in DMF (10 mL) under nitrogen. The mixture was heated to 75° C. for 24 h and allowed to cool to room temperature. The reaction mixture was then poured into H2O and extracted with ethyl acetate. The organic layers were combined and washed with water. The organic layer was dried, filtered, and concentrated under reduced pressure to give 1.8 g crude material. The crude product was purified by column chromatography (ethyl acetate/hexane, 1:10) to give 4-[2-tert-butoxycarbonyl-3-(4-methoxy-benzylsulfanyl)4-phenyl-butyl]-piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 50%).
Reaction SMILES: Br[C:2]1(Br)[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[O:4][CH2:3]1.[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>CC#N>[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][N:29]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=3)[O:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: CC(C)[Si](Oc1ccc2c(c1)OCC(Br)(Br)C2=O)(C(C)C)C(C)C
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)[Si](Oc1ccc2c(=O)c(N3CCC(O)(c4ccccc4)CC3)coc2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
3,3-Dibromo-7-(triisopropylsilyloxy)-4-chromanone (5.0 g, 10.5 mmol) was dissolved in CH3CN (150 ml) and 4-hydroxy-4-phenylpiperidine (2.2 g, 12.5 mmol) and triethylamine (2.9 ml, 20.8 mmol) were added. The mixture was stirred overnight at ambient temperature, then concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed with water (2×50 ml) and brine, dried over CaSO4, concentrated, and the residue chromatographed on silica gel, using gradient elution with ethyl acetate/hexane to yield title product as a white solid (2.3 g, 54%). A portion was recrystallized from ethanol/ether; mp 163°-163.5° C.; IR (KBr) 3437, 2950, 2870, 1635, 1615, 1600, 1447, 1285, 1247, 1200, 1185, 703, 690. Anal. Calcd. for C29H39NO4Si: C, 70.55; H, 7.96; N, 2.84. Found: C., 70.44; H, 7.76; N, 2.84.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]=[O:27].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([Mg]Br)[CH:33]=[CH:34][CH:35]=1>>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]([C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=1)[OH:27]
Reactant: COc1cccc([Mg]Br)c1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C=O)cc(OC)c21
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C(O)c3cccc(OC)c3)cc(OC)c21

Procedure:
The title compound is prepared from 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde and 3-methoxyphenyl-magnesium bromide as described in examples 35 and 51.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[N:31]=[C:32]=[O:33]>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[NH:31][C:32]([NH:10][C:9]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)=[O:33]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1ccc(N)cc1OC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Nc2c(Cl)cccc2Cl)cc1OC1CCCC1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyaniline (1 g) and triethylamine (0.69 mL) in dry dichloromethane (20 mL) is treated dropwise at 0°-5° C. with a solution of 2,6-dichlorophenyl isocyanate (0.9 g) in dry dichloromethane (10 mL). The resulting mixture is stirred for 30 minutes at this temperature and then for 6 hours at room temperature. The precipitate which forms is collected and stirred with isopropanol (50 mL), with ice cooling. The resulting solid is collected and dried, to give N-(2,6-dichlorophenyl)-N'-(3-cyclopentyloxy-4-methoxyphenyl)urea (1.06 g), m.p. 203°-204° C. [Elemental analysis: C,57.2; H,5.0; N,7.0; Cl,18.2%; calculated: C,57.7; H,5.1; N,7.1; Cl,18.0%].
Reaction SMILES: [S:1]1[C:5]([CH2:6]O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.S(Cl)([Cl:14])=O>>[Cl:14][CH2:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1
Reactant: OCc1cc2ccccc2s1
Reactant: O=S(Cl)Cl
Product: ClCc1cc2ccccc2s1

Procedure:
A solution of benzo[b]thiophen-2-yl-methanol (1 eq.) in thionyl chloride was stirred at 20° C. for 1 h. The crude was concentrated under reduced pressure then partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloromethyl-benzo[b]thiophene, used as such without further purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[N:4]=[C:5]3[CH:10]=[N:9][CH:8]=[CH:7][N:6]3[C:2]=2[C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)=[CH:12][CH:13]=1
Reactant: OB(O)c1ccncc1
Reactant: Fc1ccc(-c2nc3cnccn3c2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2nc3cnccn3c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 27.8 %

Procedure:
To a 25 mL round bottom flask charged with 3-bromo-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (Preparation #5, 0.090 g, 0.31 mmol), 4-pyridineboronic acid (0.045 g, 0.37 mmol), Pd(PPh3)4 (0.018 g, 0.015 mmol) and Cs2CO3 (0.250 g, 0.77 mmol) was added DME (10 mL) followed by water (1 mL). The reaction was allowed to stir at ambient temperature for about 3 minutes followed by submersion into an oil bath which was at about 90° C. After about 16 h, the reaction was concentrated in-vacuo and then purified by RP-HPLC (Table 1, Method d). The pure fractions were combined, concentrated, and lyophilized for about 12 h to give the title compound as a white solid (0.025 g, 23%): LC/MS (Table 1, Method b) Rt=1.54 min; MS m/z: 291.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.I[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.CN1CCOCC1.Cl>O1CCOCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(Nc3ccc(C(=O)O)cc3)ccc21

Procedure:
1.02 g (5 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine, 1.24 g (5 mmol) of 4-iodobenzoic acid, 820 μl (7.5 mmol) of N-methylmorpholine, 360 mg (2.5 mmol) of Cu2O and 15 ml of dioxane were introduced successively into a round-bottomed flask. The entire contents were heated at reflux for 24 hours, the reaction medium poured into 15 ml of 5N hydrochloric acid, the precipitate filtered and the latter washed with water.
Reaction SMILES: [N:1]1([C:6]2[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24].O>CN(C=O)C>[Cl:24][CH2:23][CH2:22][CH2:21][N:10]1[CH:11]=[C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7](=[O:13])[NH:8][C:9]1=[O:12]
Reactant: O=c1[nH]cc(N2CCCC2)c(=O)[nH]1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCl)cc1N1CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-(1-pyrrolidinyl)-2,4(1H,3H)-pyrimidinedione (507 mg, commercially available from Interchim Intermediates) and K2CO3 (386 mg) in dry DMF (10 mL) was stirred for 1 hour at room temperature. 1-Bromo-3-chloropropane (0.28 mL) was added and the mixture was stirred at room temperature for 20 hours. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a silica flash chromatography (eluting with A: dichloromethane, B: dichloromethane/methanol=9/1 at ratio A:B=6:4) to give the title compound as a colourless oil (150 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH:19]1[CH2:21][CH2:20]1)=[O:5])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc2ncc(C#N)c(C3CC3)c2c1

Procedure:
Similar procedure as described in example 46d was used, starting from 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester (example 46c), cyclopropylboronic acid, sodium carbonate and POPd to give 3-cyano-4-cyclopropyl-quinoline-6-carboxylic acid ethyl ester as colorless oil. LC-MS m/e 267 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.[Br:13][C:14]1[CH:21]=[CH:20]C(CO)=[CH:16][CH:15]=1.N1CC=CC1>ClCCl.C(OCC)(=O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:2]([CH2:1][N:3]2[CH2:6][CH:7]=[CH:5][CH2:4]2)=[CH:16][CH:15]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: C1=CCNC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1ccc(CN2CC=CC2)cc1
Reaction time: 1.5 h
Yield: 71.1 %

Procedure:
Triethylamine (0.135 ml, 0.958 mmol) and 60 μl (0.760 mmol) of methanesulphonyl chloride were added to a solution of 70.5 mg (0.377 mmol) of 4-bromobenzylalcohol in dichloromethane (2 ml) under ice cooling, and the mixture was stirred for 1.5 hr. The reaction solution was diluted with 10 ml of ethyl acetate, and the diluted solution was washed with an 8% aqueous sodium hydrogencarbonate solution. The aqueous layer was extracted twice with 3 ml of ethyl acetate. The organic layers were combined, were washed with 25% brine, and were dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under the reduced pressure. The residue was dissolved in 1.8 ml of N,N-dimethylformamide, 87 μl of 2,5-dihydro-1H-pyrrole (70% purity, 0.793 mmol) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was diluted with 10 ml of ethyl acetate, and the diluted solution was washed thrice with 5 ml of water. The aqueous layer was extracted twice with 5 ml of ethyl acetate. The organic layers were combined, were washed with 25% brine, and were dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under the reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform:methanol=18:1) to give 63.8 mg (yield 71%) of the title compound.