Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=1>>[ClH:1].[F:38][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=1[F:37])[CH2:30][O:18][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][C:4]3[CH:19]=[C:20]([OH:24])[C:21]([CH3:23])=[CH:22][C:3]=3[F:2])=[N:7][CH:8]=[N:9]2)=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: Fc1ccc(CBr)cc1F
Agent: Cl
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccc(F)c(F)c1
Yield: 31.4 %

Procedure:
Using an analogous procedure to that described in Example 36, 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (224 mg, 0.6 mmol), (prepared as described for the starting material in Example 22), was treated with 4-bromomethyl-1,2-difluorobenzene (149 mg, 0.72 mmol) to give 7-(3,4-difluorobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (90 mg, 31%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][C@H:26]([OH:29])[CH2:27][OH:28]>>[OH:29][C@@H:26]([CH2:27][OH:28])[CH2:25][N:24]([CH3:23])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNC[C@H](O)CO
Product: CN(C[C@@H](O)CO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-3-(methylamino)propane-1,2-diol(1.2 equiv) to give 181 (14.9 mg, M+1 401.1)
Reaction SMILES: [C:1]([C:6]1[CH:14]=[CH:13][C:12]2[N:11]3[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:10]3=[CH:9][C:8]=2[CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:22]([O:21][C:19]([N:17]1[CH2:16][CH2:15][N:11]2[C:12]3[CH:13]=[CH:14][C:6]([C:1](=[N:31][CH2:30][C:29]4[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:28]=4[O:27][CH3:26])[CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=3[CH:9]=[C:10]2[CH2:18]1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCCC(=O)c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 8-butyryl-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.0 g, 2.9 mmol) in CH2Cl2 (20 mL), cooled to 0° C., was added 2,4-dimethoxybenzyl amine (0.5 mL, 3.2 mmol) and Et3N (1.2 mL, 9 mmol). To this mixture was added a solution of TiCl4 (1.8 mL, 1M, 1.8 mmol) in CH2Cl2 dropwise via an addition funnel. Upon completion of addition, the reaction was stirred at room temperature for 6 h before it was quenched with a saturated solution of NaHCO3. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, filtered, and concentrated to give a crude product that was used immediately without further purification.
Reaction SMILES: [O-]CC.[Na+].Cl[CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([O:36][CH3:37])=[CH:34][N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:10].C(Cl)Cl.CO>C(O)C>[N:11]1([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:35]([O:36][CH3:37])=[CH:34][N:33]=[CH:32][N:31]=3)[CH2:26][CH2:25]2)[CH2:6][CH2:7][CH2:8][C:9]1=[O:10]
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(NC(=O)CCCCl)cc23)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(N4CCCC4=O)cc23)CC1
Temperature: 78 °C
Yield: 36.2 %

Procedure:
To a mixture of 1-[3-[5-amino-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (2.3g, 6.3 mmol), and sodium carbonate (0.67 g, 6.3 mmol) in 25 mL of acetone, cooled to 0° C., was added dropwise 4-chlorobutyryl chloride (0.89 g, 6.3 mmol). Additional acetone (10 mL) was added and the suspension was stirred for 19 h at 23° C. The insoluble material was separated by filtration and the acetone was removed in vacuo. The crude material was dissolved in EtOAc, and the solution was washed with water, dried (brine, MgSO4), filtered, and concentrated in vacuo to give crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.98 g, 4.2 mmol, 67%) as a gum. Sodium ethoxide (0.67 mL, 2.1 mmol, 21% in ethanol) was added dropwise to a solution of crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.0 g, 2.1 mmol) in ethanol (5 mL). After the addition, the reaction mixture was heated at 78° C. for 90 min and then cooled to room temperature. The insoluble solid was separated and the filtrate was concentrated in vacuo. Silica gel column chromatography (95:5:0.5 CH2Cl2 -MeOH-30% NH4OH) afforded 1-[3-[5-[2-pyrrolidinone-1-yl]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (0.33 g, 0.76 mmol, 36%). The free base (0.25 g, 0.58 mmol) was dissolved in a minimum volume of acetonitrile. A concentrated solution of oxalic acid (0.052 g, 0.58 mmol) in CH3CN was added with stirring. The precipitate was separated by filtration, washed sparingly with CH3CN, and dried at 70° C. in vacuo overnight to give the title compound (0.17 g, 56%): mp 100°-101° C. Anal. Calcd for C24H30N6O2.1.0 C2H2O4.1.15 H2O: C, 57.26; H, 6.34; N, 15.41. Found: C, 56.90; H, 5.96; N, 15.51.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11]Br)=[CH:6][CH:5]=1.[N:15]1([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[S:26])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>C(O)C>[O:18]1[CH2:17][CH2:16][N:15]([CH2:21][CH2:22][CH2:23][N:24]([C:25]2[S:26][CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:14])=[CH:5][CH:6]=3)[N:27]=2)[C:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)=[O:43])[CH2:20][CH2:19]1
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: O=C(Cl)c1cccs1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)c1ccc(-c2csc(N(CCCN3CCOCC3)C(=O)c3cccs3)n2)cc1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A mixture of 4-(2-bromo-acetyl)-benzoic acid methyl ester (77 mg, 0.3 mmol) and (3-morpholin-4-yl-propyl)-thiourea (61 mg, 0.3 mmol) in dry ethanol (3 mL) was heated at reflux for 10 min, cooled to room temperature, and concentrated in vacuo. The resulting residue was suspended in dichloromethane (3 mL) followed by the addition of N,N-diisopropylethylamine (105 μL, 0.6 mmol) and thiophene-2-carbonyl chloride (34 μL, 0.32 mmol). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (1.5 mL) and subjected to HPLC purification (Method Y). The resulting free amine was dissolved in MeOH (1 mL) and 1M HCl/ether (50 mL) was added. The precipitate was filtered and dried in vacuo to provide the title compound (52 mg) as an off-white solid as the hydrochloride salt. LC/MS (ESI) m/z 472.3 [M+H]. HPLC retention time (Method A)=2.80 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.N1C=CC=CC=1.O>O1CCCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([NH:15][S:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[CH:17]=3)[NH:21][N:20]=2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc2[nH]nc(-c3ccc(Cl)cc3)c2c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccc(Cl)cc3)c2c1
Yield: 92.6 %

Procedure:
N-[3-(4-Chlorophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained in the following way: a solution of 0.515 g 2-methylsulfonylbenzenesulfonyl chloride in 3 ml of tetrahydrofuran is added dropwise to a solution, cooled to 0° C., of 0.45 g of 5-amino-3-(4-chlorophenyl)-1H-indazole, of 15 ml of tetrahydrofuran and of 0.165 ml of pyridine. After reacting for 30 minutes at a temperature in the region of 0° C. and 2 hours at a temperature in the region of 20° C., 50 ml of distilled water are added to the reaction medium. The medium is extracted with 30 ml of ethyl acetate. The organic phase is then washed with 3 times 20 ml of distilled water and the aqueous phase is extracted again with 30 ml of ethyl acetate. The organic phases are pooled, dried over magnesium sulfate, filtered and concentrated to dryness by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/ethyl acetate (99/1 by volume) mixture as eluent. 0.79 g of N-[3-(4-chlorophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide is thus obtained in the form of a white powder melting at 242° C. (analysis C20H16ClN3O4S2.0.65CH3OH % calculated C, 52.01; H, 3.49; Cl, 7.67; N, 9.10; O, 13.85; S, 13.88. % found C, 52.02; H, 3.78; Cl, 7.91; N, 9.21; S, 13.45).
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:5]2=[C:6]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24](Cl)=[O:25].CO>ClCCl>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[N:7]=[CH:8][CH:9]=2)[NH:16][C:2]=1[CH3:1])=[O:25]
Reactant: Cc1cc2ccnc(NC(=O)C3CC3)c2[nH]1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: Cc1[nH]c2c(NC(=O)C3CC3)nccc2c1C(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
N-(2-Methyl-1H-pyrrolo[2,3-c]pyridin-7yl)cyclopropanecarboxamide (100 mg, 0.46 mmol) was added to a stirred suspension of aluminium chloride (620 mg, 4.65 mmol) in dry dichloromethane (5 mL) and the mixture was stirred at room temperature for about 1 hour under argon atmosphere. This was followed by drop wise addition of a solution of 2,6-dichlorobenzoyl chloride (194 mg, 0.93 mmol) in dichloromethane and stirring overnight at room temperature. After completion, methanol (10 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The residual mass was diluted with water and extracted with ethyl acetate. The combined organic layer was neutralized using aq. sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-[3-(2,6-dichlorobenzoyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (70 mg, 39%).
Reaction SMILES: [C:1]([NH:4][C:5]([CH3:12])([CH:9]([CH3:11])[CH3:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(OC(Cl)=O)C.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1.[Na]>C(N(CC)CC)C.C(OCC)C.CN(C)C=O>[C:1]([NH:4][C:5]([CH3:12])([CH:9]([CH3:11])[CH3:10])[C:6]([NH:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:27])=[O:28])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)(C(=O)O)C(C)C
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CCOC(=O)Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 116.7 %

Procedure:
2-Acetamido-2,3-dimethylbutyric acid (1.5 g) is dissolved in a solution of triethylamine (2.7 g) in diethyl ether (50 mL) and cooled to 0° C.; ethylchloroformate (1.1 g) is added dropwise and the mixture is stirred at 0° to room temperature over one hour. The mixture is filtered, and the filtrate is concentrated in vacuo to afford the oily mixed anhydride (1.5 g). This material is mixed with 3 g of p-toluenesulfonamide, sodium salt, in 25 mL dimethylformamide, and the resulting mixture is heated at 80° C. for 16 hours. The reaction is cooled, concentrated in vacuo, and the residue is partitioned between methylene chloride and saturated, aqueous sodium bicarbonate. Acidification of the aqueous layer with conc. HCl to pH 1, extraction with CH2Cl2, drying, and stripping the organic phase affords the title product (3.3 g).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:9][CH2:10][OH:11]>C1COCC1>[OH:11][CH2:10][CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: OCCI
Reactant: C1CNCCNC1
Solvent: C1CCOC1
Product: OCCN1CCCNCC1

Procedure:
A 2.329 g portion of homopiperazine dissolved in 10 ml of THF was mixed with 830 mg of iodoethyl alcohol to carry out 24 hours of reaction at room temperature. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was purified by Sephadex LH-20 (Pharmacia) (chloroform:methanol=1:1) and Diaion HP-20 (Mitsubishi Chemicals) to obtain 305 mg of 1-(2-hydroxyethyl)homo-piperazine. Next, Under cooling with ice, 150 mg of 1-(2-hydroxyethyl)homopiperazine and 159 mg of 2-chlorobenzoxazole were added to 3 ml of DMF, and the reaction was carried out for 17 hours at the same temperature and then for 24 hours at room temperature. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was dissolved in 100 ml of ethyl acetate, washed with sodium hydrogencarbonate aqueous solution (pH 8) and water in that order, dehydrated with sodium sulfate and then concentrated under a reduced pressure. Thereafter, the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=30:1) to obtain 72 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Cl:12])=[CH:7][C:6]=1Br.CCCCCC.C([Li])CCC.[C:25]([C:27]1[C:32]([O:33][Si](C)(C)C)=[CH:31][CH:30]=[CH:29][N:28]=1)#N.C([O:40]CC)C>>[Cl:12][C:8]1[C:9]([F:11])=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[C:6]([CH:7]=1)[C:25]([C:27]1[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][N:28]=1)=[O:40]
Reactant: COCOc1cc(F)c(Cl)cc1Br
Reactant: C[Si](C)(C)Oc1cccnc1C#N
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COCOc1cc(F)c(Cl)cc1C(=O)c1ncccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-4-chloro-5-fluorophenol methoxymethylether (17.65 g) in diethyl ether (400 ml) was cooled to -78° C. To the solution was added dropwise, under argon atmosphere, 1.6M n-butyllithium hexane solution (45 ml). The mixture was stirred for one hour under the same conditions, followed by dropwise addition of 2-cyano-3-trimethylsilyloxypyridine (13.18 g) at -78° C. The cooling bath was then removed, and the reaction mixture was stirred overnight while raising the temperature to room temperature. The reaction was suspended by the addition of methanol (50 ml). Then the solvent was distilled off. To the residue were added methanol (300 ml) and conc. hydrochloric acid (7 ml). The mixture was stirred for 2 hours at room temperature. The reaction mixture was neutralized with an aqueous solution of potassium carbonate, which was subjected to extraction with ethyl acetate. The extract solution was dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (elution with ethyl acetate/hexane) to afford 2-(5-chloro-4-fluoro-2-methoxymethoxybenzoyl)-3-hydroxypyridine (9.18 g) (Compound F-1). Physico-chemical properties and spectrum data are shown in Table 22 and Table 23.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][CH:23]=O)=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][Cl:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.S(C)C.CO.Cl>C1COCC1>[Cl:1][C:2]1[C:3]([NH:22][CH3:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][Cl:20])=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1
Reactant: CCc1nc2cc(NC=O)c(Cl)cc2n1-c1ccc(CCCl)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: CCc1nc2cc(NC)c(Cl)cc2n1-c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of (6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylformamide, step 1, 112 mg, 0.3 mmol) in THF (15 ml) was added Me2S B3 (0.07 ml, 0.77 mmol) under nitrogen at room temperature. The mixture was refluxed for 1 h. Then the mixture was cooled to room temperature and was added methanol (3 ml) and 2N aqueous HCl (12 ml). The mixture was stirred at 70° C. for 30 min. The volatile component was removed under reduced pressure, and the residue was dissolved with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous NaHCO3 (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1:4) to afford 93 mg (87%) of the title compound as white solids.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[C:19]1([N:25]=[C:26]=[S:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[C:19]1([NH:25][C:26](=[S:27])[NH:2][N:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NN1Cc2ccccc2C1
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: S=C(Nc1ccccc1)NN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 1.7 g (0.01 mole) of N-amino dihydroisoindole hydrochloride in 10 ml of dimethyl formamide was added 1 ml of triethylamine followed by 1.35 g (0.01 mole) of phenylisothiocyanate. The reaction mixture was allowed to stir at room temperature overnight. Water (25 ml) was added, the mixture stirred for 1 hr., and filtered. After drying there was obtained 2.6 g of the desired product, mp: 192°-193° dec. The IR and NMR were consistent with the proposed structure.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=O)=[CH:31][CH:30]=1.[CH:39]1[C:47]2[C:46]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:45]=3[O:44][C:43]=2[CH:42]=[CH:41][C:40]=1[NH2:54]>>[CH:39]1[C:47]2[C:46]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:45]=3[O:44][C:43]=2[CH:42]=[CH:41][C:40]=1[NH:54][C:36](=[O:38])[CH2:35][C:32]1[CH:31]=[CH:30][N:29]=[CH:34][CH:33]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: O=C(Cc1ccncc1)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 44.9 %

Procedure:
Following the procedure of Example 30, triethylamine (0.40 mL, 2.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.33 g, 1.7 mmol), N-hydroxybenzotriazole (0.23 g, 1.7 mmol), 4-pyridylacetic acid(0.24 g, 1.4 mmol), and 6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-2-pyridin-4-ylacetamide (0.18 g). MS (ESI) m/z 335 ([M+H]+); MS (ESI) m/z 333 ([M−H]−).
Reaction SMILES: [CH2:1]([C:3]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[CH3:2].Br[C:32]1[N:36]=[C:35]([C:37]2[CH:38]=[CH:39][C:40]([CH2:45][CH:46]([CH3:48])[CH3:47])=[C:41]([CH:44]=2)[C:42]#[N:43])[S:34][N:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[C:42]([C:41]1[CH:44]=[C:37]([C:35]2[S:34][N:33]=[C:32]([C:8]3[C:3]([CH2:1][CH3:2])=[C:4]([CH:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:22][CH2:23]4)[CH:5]=[CH:6][CH:7]=3)[N:36]=2)[CH:38]=[CH:39][C:40]=1[CH2:45][CH:46]([CH3:48])[CH3:47])#[N:43]
Reactant: CC(C)Cc1ccc(-c2nc(Br)ns2)cc1C#N
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(-c2nsc(-c3ccc(CC(C)C)c(C#N)c3)n2)cccc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Yield: 99.2 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-piperidinecarboxylate (70 mg, 0.169 mmol), 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-(2-methylpropyl)benzonitrile (D60) (81 mg, 0.253 mmol) and Pd(Ph3P)4 (19.47 mg, 0.017 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (1 mL) was added tripotassium phosphate (107 mg, 0.506 mmol). This solution was stirred in MW irradiation at 120° C. for 20 Min. The solution was dried directly with silica gel and purified on column chromatography to afford 1,1-dimethylethyl 4-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)-1-piperidinecarboxylate (D124) (89 mg). MS (ES): C31H38N4O2S requires 530.3. found 531.3 (M+H+).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
2.4 g of 50% sodium hydride in oil is added at 0° C. and under an inert atmosphere to 10 g of para-iodo-phenol in 150 ml of dimethylformamide, the mixture is maintained under agitation for 30 minutes and 5.9 ml of benzyl bromide is added. After agitation for 30 minutes while allowing the reaction medium to return to ambient temperature, the reaction medium is poured onto ice and a precipitation of the product is observed. After drying, 14.7 g of expected product is obtained.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:11][C:12]1[N:16]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:15]([C:22]([O:24][CH3:25])=[O:23])=[C:14]([CH:26]=[O:27])[N:13]=1.C(O)(=O)C>CO.C(Cl)Cl>[Br:11][C:12]1[N:16]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:15]([C:22]([O:24][CH3:25])=[O:23])=[C:14]([CH:26]([OH:27])[CH2:4][N+:1]([O-:3])=[O:2])[N:13]=1
Reactant: COC(=O)c1c(C=O)nc(Br)n1CC=C(C)C
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(C(O)C[N+](=O)[O-])nc(Br)n1CC=C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
35 ml nitromethane are added to 1.14 g caesium carbonate in 15 ml of methanol at ambient temperature. Then the mixture is combined with a solution of 3.50 g methyl 2-bromo-3-(3-methyl-2-buten-1-yl)-5-formyl-3H-imidazole-4-carboxylate in 20 ml of methanol and 5 ml methylene chloride and stirred for 15 minutes at ambient temperature. Then 0.5 ml acetic acid are added and the solution is evaporated down in vacuo. The flask residue is combined with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down.