Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[CH2:21][O:20]1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:18][C:19]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC1(c2cnccn2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cnccn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a stirred solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido(4,3-b)indole (350 mg, 1.75 mmol) in DMF (4 mL) was added sodium hydride (210 mg, 5.25 mmol) followed by dropwise addition of 2-(2-methyl oxiranyl)pyrazine (310 mg, 2.275 mmol) at 10° C. and the reaction mixture was further stirred at RT for 16 h. After completion, the reaction mixture was poured into ice cooled water, extracted with EtOAc (3×75 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated yielding crude product, which was re-crystallized in ether and hexane to yield a yellow solid product (350 mg). 1H NMR (DMSO, Oxalate salt) d (ppm): 8.65 (s, 1H), 8.55 (s, 1H), 8.50 (d, 1H), 7.10 (s, 1H), 6.90 (d, 1H), 6.78 (d, 1H), 4.30 (m, 4H), 3.20 (m, 2H), 3.0 (m, 2H), 2.90 (s, 3H), 2.30 (s, 3H), 1.50 (s, 3H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([CH3:23])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si](C(C)(C)C)(C)C)[CH2:36]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[C:21]([O:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)([CH3:23])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([OH:42])[CH2:36]2)=[CH:10]1
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccc(F)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1C=CC2=C[C@@H](O)C[C@H](OC(=O)C(C)(C)Oc3ccc(F)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O)CC(=O)O1
Yield: 76.1 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.08 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[2-(4-fluorophenoxy)-2-methylpropionyloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 175, above] and 20.8 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 565 mg of the title compound as white crystals, melting at between 142° and 145° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[CH:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.O>ClCCl>[CH:39]1([C:45]([O:31][C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]4[CH2:12][CH2:11][N:10]([C:6]5[C:3]6[CH:4]=[CH:5][S:1][C:2]=6[CH:9]=[CH:8][CH:7]=5)[CH2:15][CH2:14]4)=[CH:22][CH:23]=3)[N:28]=2)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2n1)C1CCCCC1

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added triethylamine (0.64 ml), with stirring under ice-cooling, cyclohexanecarbonyl chloride (0.49 ml) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=4:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl cyclohexanecarboxylate (1.08 g).
Reaction SMILES: [NH2:1][C:2]1[NH:18][C:5]2=[CH:6][C:7]3[C:8]([CH3:17])([CH3:16])[C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[CH2:13]([N:10]1[C:11]2[CH:12]=[C:4]3[N:3]=[C:2]([NH:1][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:18][C:5]3=[CH:6][C:7]=2[C:8]([CH3:17])([CH3:16])[C:9]1=[O:15])[CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Solvent: O
Solvent: c1ccncc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Yield: 67.9 %

Procedure:
A solution of D3 (500 mg) and benzoyl chloride (0.6 ml; 5.12 mmol) in pyridine (15 ml) is stirred at RT for 20 h. After completion, water is added and the aqueous layer is extracted with EtOAc. The combined organic layer is washed with hydrochloric acid (1 N), saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with CH2Cl2/MeOH (30:1) afford the title compound (484 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>CCOCC>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:29](=[O:30])[NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: O=C=Nc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(Nc1ccccc1Cl)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol) in dry ether (10 ml) was added to a stirred suspension of sodium hydride (0.024 g., 1 mmol) in dry ether (15 ml) at −10° C. during 10 min. The reaction mixture was stirred for 20 min. Then 2-chlorophenyl isocyanate (0.184 g:, 1.2 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2 hours during which the temperature was allowed to rise to room temperature (35° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (20:80) as eluant to give 2i; yield: 0.25 g. (63.7%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:11]=[C:10](I)[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].O.C(O[CH2:39][CH3:40])(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:11]=[C:10]([C:40]3[CH:39]=[CH:8][C:9]4[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:3]=3)[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc3ccccc3c1)=CCC2c1ccccc1
Yield: 67 %

Procedure:
240 mg of tetrakis(triphenylphosphine)palladium and then a solution of 0.69 g of 2-naphthylboronic acid, isolated in the trimer anhydride form, in 20 cm3 of methanol were added to a solution of 2 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate in 40 cm3 of toluene. 45 cm3 of a 2N aqueous sodium carbonate solution were added dropwise and the reaction mixture is brought to reflux for four hours. After cooling, 80 cm3 of water and 60 cm3 of ethyl acetate were added. The organic phase was separated by settling, washing with water to neutrality and dried over magnesium sulphate. After concentrating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume). 1.33 g (67%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-(2-naphthyl)-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were thus obtained in the form of a white foam, the characteristic of which was as follows:
Reaction SMILES: [NH:1]1CCO[CH2:3][CH2:2]1.[SH:7][C:8]1[NH:9][C:10](=[O:19])[CH:11]=[C:12]([CH2:16][CH2:17][CH3:18])[C:13]=1[C:14]#[N:15].BrCC#N.BrCC(N)=O>>[C:2]([CH2:3][S:7][C:8]1[NH:9][C:10](=[O:19])[CH:11]=[C:12]([CH2:16][CH2:17][CH3:18])[C:13]=1[C:14]#[N:15])#[N:1]
Reactant: CCCc1cc(=O)[nH]c(S)c1C#N
Reactant: C1COCCN1
Agent: N#CCBr
Agent: NC(=O)CBr
Product: CCCc1cc(=O)[nH]c(SCC#N)c1C#N

Procedure:
The morpholine salt of 2-mercapto-6-oxo-4-propyl-1,6-dihydro-pyridine-3-carbonitrile (see above) was reacted with 2-bromoacetonitrile as described above for 2-bromoacetamide to provide 2-cyanomethylsulfanyl-6-oxo-4-propyl-1,6-dihydro-pyridine-3-carbonitrile. This nitrile (19.02 g, 81.53 mmol) and N-phenyltrifluoromethanesulfonimide (29.59 g, 82.00 mmol) were dissolved in 100 mL of dry dioxane. Diisopropylethylamine (19.3 mL, 135 mmol) was added and the mixture was stirred at room temperature under argon for 4 h. The solvent was concentrated. The residue was dissolved in EtOAc and ether and the resulting solution was filtered through a pad of silica gel which was washed with ether. The filtrate was concentrated and the resulting yellow solid was collected by filtration and dried under vacuum to provide trifluoro-methanesulfonic acid 5-cyano-6-cyanomethylsulfanyl-4-propyl-pyridin-2-yl ester (18.45 g, 62%).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][N:13]2[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[C:9]([C:25]2[O:26][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]3)=[CH:28][N:29]=2)[CH:8]=1.CC1(C)C(C)(C)OB([C:48]2[CH:56]=[CH:55][CH:54]=[C:53]3[C:49]=2[CH:50]=[CH:51][NH:52]3)O1>O.C(O)(C)C>[NH:52]1[C:53]2[C:49](=[C:48]([C:7]3[CH:15]=[C:14]4[C:10]([CH:11]=[N:12][N:13]4[S:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)(=[O:17])=[O:18])=[C:9]([C:25]4[O:26][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][N:34]([CH:37]([CH3:38])[CH3:39])[CH2:33][CH2:32]5)=[CH:28][N:29]=4)[CH:8]=3)[CH:56]=[CH:55][CH:54]=2)[CH:50]=[CH:51]1
Reactant: CC(C)N1CCN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)N1CCN(Cc2cnc(-c3cc(-c4cccc5[nH]ccc45)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of sodium bicarbonate (228.0 g) in water (2.7 L) was added to a suspension of 6-Chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (271.2 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (263.2 g, available from Apollo Scientific Limited) in isopropanol (2.7 L) stirred under nitrogen at ambient temperature. After degassing, via evacuation and flushing with nitrogen, 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (29.83 g) was added. The mixture was degassed again and was then heated to 90±3° C. and held at this temperature for 2 hours. The mixture was cooled to 20±5° C. over 25 minutes and aged at this temperature overnight. The resultant suspension was filtered, washed with water (1.35 L) and then slurried with toluene (4×1.35 L). The solid was dried under vacuum at 50° C. to give the title compound as grey solid (302.7 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[CH:4][CH:3]=1.[C:13]([C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[C:23](=[O:28])[N:22]([C:29]1[C:37]3[CH2:36][O:35]B(O)[C:33]=3[CH:32]=[CH:31][CH:30]=1)[N:21]=[CH:20]2)([CH3:16])([CH3:15])[CH3:14].N1C=CC=CC=1.[NH4+].[Cl-]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCCl>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([N:22]4[N:21]=[CH:20][C:19]5[C:24](=[C:25]([F:27])[CH:26]=[C:17]([C:13]([CH3:14])([CH3:15])[CH3:16])[CH:18]=5)[C:23]4=[O:28])[C:37]=3[CH2:36][OH:35])[CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Reactant: N#Cc1c[nH]c2nc(Br)ccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(Br)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 48 h
Yield: 10.3 %

Procedure:
In a 25 mL round-bottomed flask, 6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (75.0 mg, 338 μmol, Eq: 1.19), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (100 mg, 284 μmol, Eq: 1.00) and copper acetate (52.2 mg) were combined with 1,2-dichloroethane (3.00 ml) to give a blue suspension. Pyridine (44.9 mg, 45.9 μl, 568 μmol, Eq: 2) was added. The reaction mixture was heated to 45° C. and stirred for 2 d. Mixture was poured into 20 mL sat NH4Cl and extracted with EtOAc (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 25% to 45% EtOAc in hexanes) to give 6-bromo-1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (16 mg, 10.3%).
Reaction SMILES: [C:1]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[CH2:27][SH:28])([O:3][CH2:4][CH3:5])=[O:2].[CH2:29]=[O:30]>CO>[C:1]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[CH2:27][S:28][CH2:29][OH:30])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C=O
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Solvent: CO
Product: CCOC(=O)C1=C(C)NC(CSCO)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 3,5-dicarboethoxy-6-methyl-2-mercaptomethyl-4-(m-nitrophenyl)-1,4-dihydropyridine in MeOH (25 ml) is added with a 37% formaldehyde aqueous solution (6 ml, 79 mmol.). The obtained solution is refluxed for 1.5 hours. The solvent is evaporated under reduced pressure and the residue is dissolved in ethyl acetate (50 ml). The organic phase is washed (3×60 ml), separated, dried on Na2SD4, filtered and the solvent is evaporated under reduced pressure; the oily residue is crystallized from isopropyl ether, obtaining 3 g of 3,5-dicarboethoxy-4-(m-nitro-phenyl)-6-methyl-2-(hydroxymethylthiomethyl)-1,4-dihydropyridine, m.p. 113°-114° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[N:10]([CH3:12])[CH3:11].[C:17]([O-])(=[O:19])C.[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[C:14]([Cl:16])[C:15]=1[CH:17]=[O:19]
Reactant: CN(C)c1cc(Cl)cc(Cl)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)c1cc(Cl)c(C=O)c(Cl)c1
Temperature: 100 °C

Procedure:
Phosphoryl chloride (0.56 cm3, 6.1 mmol) was added dropwise to cooled N,N-dimethyl formamide (4 cm3) under nitrogen. 3,5-dichloro-N,N-dimethylaniline (1.16 g, 6.1 mmol) was then added to the solution which was then heated under nitrogen at 100° C. for 3 h. The solution was cooled, poured onto ice (6 g) and the mixture adjusted to pH 6 by addition of a saturated solution of sodium acetate. The suspended solid was collected and recrystallised from ethyl acetate-petroleum spirit 60°-80° C. mixture giving pale yellow needles of 2,6-dichloro-4-dimethylaminobenzaldehyde (0.8 g) mp 169°-71° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[CH:20]1([C:26]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1C=CC=CC=1>[CH2:35]([O:34][C:32]([C:26]1([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH:4]=[C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH2:30][CH2:31]1)=[O:33])[CH3:36]
Reactant: BrCCC=C1c2ccccc2C=Cc2ccccc21
Reactant: CCOC(=O)C1(C2CCCCC2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1(C2CCCCC2)CCN(CCC=C2c3ccccc3C=Cc3ccccc32)CC1
Yield: 39 %

Procedure:
A mixture of 5-(3-bromopropylidene)-5H-dibenzo[a,d]cycloheptene (4.45 g, 14.2 mmol), ethyl 4-cyclohexyl-4-piperidinecarboxylate (3.4 g, 14.2 mmol, prepared similarly as described in Brit. 1 124 661 (1967)), potassium carbonate (2.1 g, 15.2 mmol) and N,N-dimethylformamide (10 ml) was heated at 120° C. for 5 h. Benzene (50 ml) and water (50 ml) were added and the phases were separated. The organic phase was dried and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel (50 g) using mixtures of benzene and chloroform as eluents to give 2.6 g (39%) of 1-(3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-cyclohexyl4-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[CH3:16][O:17][C:18](=[O:22])[CH2:19][C:20]#[N:21].C[O-].[Na+]>CO>[NH2:21][C:20]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=2)[C:19]=1[C:18]([O:17][CH3:16])=[O:22]
Reactant: COC(=O)CC#N
Reactant: ON=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccc(OC(F)(F)F)cc2)noc1N
Yield: 81.9 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-4-(trifluoromethoxy)benzimidoylchloride (8.00 g, 33.39 mmol), methylcyanoacetate (4.31 g, 43.41 mmol) and sodium methoxide (3.61 g, 66.78 mmol), a white solid required compound (8.27 g, 27.35 mmol, 82%) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:12])[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:7]2=[O:17].[C:18]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:18])[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:7]2=[O:17]
Reactant: O=C([O-])[O-]
Reactant: COCCn1c(=S)[nH]c2c(I)cccc2c1=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COCCn1c(SC)nc2c(I)cccc2c1=O
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
A sealable flask was charged with 2-amino-3-iodobenzoic acid (5.02 g, 19.09 mmol) and 2-methoxyethyl isothiocyanate (3.35 g, 28.6 mmol) in tBuOH (30 mL) followed by TEA (3.98 mL, 28.6 mmol). The flask was sealed and heated in an oil bath at 100° C. for 4 h with a blast shield. The reaction mixture was cooled to RT and the off white solid was filtered, rinsed with 2×25 mL of ether and dried to give 8-iodo-3-(2-methoxyethyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (6.21 g, 17.15 mmol, 90% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (1H, s), 8.26 (1H, dd, J=7.6, 1.2 Hz), 8.00 (1H, dd, J=7.9, 1.3 Hz), 7.17 (1H, t, J=7.7 Hz), 4.60 (2H, t, J=6.5 Hz), 3.65 (2H, t, J=6.6 Hz), 3.31 (3H, s). m/z (ESI, +ve) 362.8 (M+H)+. To a 500-mL round-bottomed flask was added sequentially 8-iodo-3-(2-methoxyethyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (6.01 g, 16.59 mmol), THF (75 mL K2CO3 (5.73 g, 41.5 mmol), and MeI (2.06 mL, 33.2 mmol). The reaction mixture was heated in an oil bath at 65° C. for 6 h. The mixture was concentrated to half of its volume, poured into ice/water (100 mL) and stirred for 10 min. The suspension was filtered and the solid was washed with cold water (20 mL) and cold ether (20 mL). The off-white solid was dried to give 8-iodo-3-(2-methoxyethyl)-2-(methylthio)quinazolin-4(3H)-one (715a; 4.91 g). The filtrate was extracted with 50 mL of EtOAc. The EtOAc layer was concentrated and the brown solid was stirred in 5 mL of ether and 5 mL of hexanes. The solid was filtered and dried to give 8-iodo-3-(2-methoxyethyl)-2-(methylthio)quinazolin-4(3H)-one (715a; 1.1 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (1H, dd, J=7.6, 1.4 Hz), 8.09 (1H, dd, J=7.9, 1.3 Hz), 7.22 (1H, t, J=7.7 Hz), 4.25 (2H, t, J=6.2 Hz), 3.65 (2H, t, J=6.2 Hz), 3.30 (3H, s), 2.75 (3H, s). m/z (ESI, +ve) 376.7 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][N:19]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]([OH:29])=[N:20]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:29][C:21]1[CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:19]([CH2:18][CH2:17][NH:16][C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:15])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(O)nn1CCNC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
Benzyl bromide (0.13 mL, 1.1 mmol) was added to a stirred suspension of ethyl 1-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-hydroxy-1H-pyrazole-5-carboxylate (0.3 g, 1 mmol) and Cs2CO3 (0.65 g, 2 mmol) in ACN (5 mL). The mixture was stirred at room temperature for 16 hours and the solvents were evaporated in vacuo. The crude product was diluted with water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield ethyl 3-(benzyloxy)-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1H-pyrazole-5-carboxylate (0.29 g, 73% yield) as a colourless oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:21]([CH:22]2[CH2:24][CH2:23]2)[C:20]2[C:25]([Br:30])=[C:26]([F:29])[CH:27]=[CH:28][C:19]=2[N:18]=1)[CH3:16])(C)(C)C>C(Cl)Cl.CO>[Br:30][C:25]1[C:20]2[N:21]([CH:22]3[CH2:23][CH2:24]3)[C:17]([C@@H:15]([NH2:14])[CH3:16])=[N:18][C:19]=2[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(Br)c2n1C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: C[C@H](N)c1nc2ccc(F)c(Br)c2n1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
TFA (1 mL) was added to a solution of [(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (133 mg, 0.33 mmol) in DCM (3 mL). After stirring at RT for 2 h, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil (87 mg, 87%). LCMS (Method C): RT 1.99 min [M+H]+ 298.10
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH2:21][CH2:20][O:19][CH3:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: COCCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2-methoxyethanol. White solid. MS (m/e): 237.9 ([M+H-Me2C═CH2]+, 100%)