Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]=[N+:11]=[N-:12])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]=[N+:11]=[N-:12])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Reaction time: 16 h

Procedure:
To a solution of (2S,4S)-4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.8 g, 28.8 mmol) in methylene chloride (30 mL) was added a mixture of trifluoroacetic acid and methylene chloride (1:5, 20 mL) and the reaction mixture was stirred at room temp. for 16 h. The reaction mixture was concentrated under reduced pressure to give (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid methyl ester trifluoroacetate salt (9.6 g, crude) as a light brown oil. The compound was used in the next step without further purification. MS calcd. for C6H11N4O2 [(M+H)+] 171.0, obsd. 171.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][OH:25]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][NH:22][CH2:23][CH2:24][OH:25])[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: NCCO
Product: Cn1c(-c2cncc(CNCCO)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and 2-amino-ethanol are processed according to the method described in Example 170 to give 6-chloro-2-{5-[(2-hydroxy-ethylamino)-methyl]-pyridin-3-yl}-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.65-2.72 (m, 2H), 3.49-3.55 (m, 2H), 3.79 (s, 3H), 3.92-3.98 (m, 2H), 4.61 (br. s., 1H), 7.37 (dd, J=8.3, 1.8 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 8.10-8.13 (m, 1H), 8.75-8.79 (m, 2H). HRMS (ESI) m/z 341.1175 [(M+H)+ Calcd for C19H18ClN4O: 341.1169].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30]Cl>>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Reactant: CN(C)CCCCl
Product: CN(C)CCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
When 3-(4-hydroxyphenylsulfonyl)-2-phenylbenzofuran is reacted with 3-dimethylaminopropyl chloride by the procedure described in Example 1, 3-[4-(3-dimethylaminopropoxy)phenylsulfonyl]-2-phenylbenzofuran is obtained.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[C:13]#[CH:14]>C(O)C>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:13]([C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:14][N:3]=[N:2]2)=[CH:11][CH:10]=1)#[N:9]
Reactant: C#CC(=O)OCC
Reactant: N#Cc1ccc(N=[N+]=[N-])cc1
Solvent: CCO
Product: CCOC(=O)c1cnnn1-c1ccc(C#N)cc1
Yield: 7.3 %

Procedure:
A solution of 4-azidobenzonitrile (5.3 g, 36.77 mmol, 1.00 equiv) and ethyl prop-2-ynoate (10.82 g, 110.30 mmol, 3.00 equiv) in ethanol (160 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 650 mg (7%) of ethyl 1-(4-cyanophenyl)-1H-1,2,3-triazole-5-carboxylate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.54 (s, 1H), 8.11 (d, J=8.0 Hz, 2H), 7.90 (d, J=8.0 Hz, 2H), 4.27-4.22 (m, 2H), 1.20 (t, J=6.8 Hz, 3H) ppm. LCMS (method C, ESI): RT=0.87 min, m/z=243.1 [M+H]+ and 2.4 g (26%) of ethyl 1-(4-cyanophenyl)-1H-1,2,3-triazole-4-carboxylate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1H), 8.24 (d, J=8.8 Hz, 2H), 8.13 (d, J=8.8 Hz, 2H), 4.41-4.36 (m, 2H), 1.36 (t, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.71 min, m/z=243.1 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2.[ClH:13].[CH3:14][S:15]([NH:18][C:19]1[CH:20]=[CH:21][C:22]2[O:32][C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:25][C:24](=[O:33])[C:23]=2[CH:34]=1)(=[O:17])=[O:16].C(=O)(O)[O-].[Na+]>C(O)C>[ClH:13].[N:11]1[O:10][N:9]=[C:8]2[CH:12]=[C:4]([CH2:3][CH2:2][N:29]3[CH2:30][CH2:31][C:26]4([CH2:25][C:24](=[O:33])[C:23]5[CH:34]=[C:19]([NH:18][S:15]([CH3:14])(=[O:16])=[O:17])[CH:20]=[CH:21][C:22]=5[O:32]4)[CH2:27][CH2:28]3)[CH:5]=[CH:6][C:7]=12
Reactant: BrCCc1ccc2nonc2c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc4nonc4c3)CC1)O2
Yield: 41.2 %

Procedure:
A suspension of 5-(2-bromoethyl)benzofurazan (0.39 g, 1.72 mmol), 3,4-dihydro-6-methanesulfonamidospiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one hydrochloride (0.24 g, 0.69 mmol) and sodium bicarbonate (0.21 g, 2.55 mmol) in ethanol (13.2 ml) was heated at reflux temperature for 24 hr. Solvent evaporation and chromatography (silica gel, chloroform-methanol-ammonium hydroxide, 97/3/0.3) gave an oil; conversion to the hydrochloride gave the hydrochloride (0.14 g, 41%); mp>250° C. Anal. Calcd for C22H24N4O3 ·HCl C, 53.59; H, 5.12, N, 11.37. Found: C, 53.55; H, 5.15; N, 11.12.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:17][CH2:18][CH3:19])[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)=[O:8])(=[NH:3])[NH2:2].[H][H]>CO.[Pd]>[C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:17][CH2:18][CH3:19])[CH:11]=[C:12]([NH2:14])[CH:13]=1)=[O:8])(=[NH:2])[NH2:3]
Reactant: [H][H]
Reactant: CCCn1cc([N+](=O)[O-])cc1C(=O)NCCC(=N)N
Agent: [Pd]
Solvent: CO
Product: CCCn1cc(N)cc1C(=O)NCCC(=N)N
Reaction time: 0.5 h

Procedure:
To a solution of 4-nitro-1-propyl-1H-pyrrole-2-carboxylic acid (2-carbamimidoyl-ethyl)-amide (52 mg, 0.2 mmol) in 15 ml of MeOH was added 20 mg of 5% Pd/C under argon. The reaction mixture was flashed with hydrogen and shaken under hydrogen at 30 psi for 30 min. The catalyst was removed by filtration through celite and washed with methanol. The filtrate was evaporated to dryness to give 4-amino-1-propyl-1H-pyrrole-2-carboxylic acid (2-carbamimidoyl-ethyl)-amide 34. This product was immediately used in next step reaction.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][CH2:11]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:18]([CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:1](=[O:3])[CH3:2])[CH2:11][CH2:12]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CCN(CCOc2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NCC1CCN(CCOc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (8.72 g) was added with stirring to a mixture of 4-aminomethyl-1-(2-phenoxyethyl)piperidine (20.0 g) in pyridine (85 ml) containing 4-dimethylaminopyridine (catalytic amount) with cooling to maintain ambient temperature. The mixture was stirred overnight at ambient temperature and then evaporated to dryness. Water was removed by adding toluene and removing the toluene by distillation. The residue was dissolved in water (100 ml) and 2M hydrochloric acid (50 ml). The solution was washed with dichloromethane, basified with concentrated sodium hydroxide solution and extracted with dichloromethane to give N-[1-(2-phenoxyethyl)piperid-4-ylmethyl]acetamide as an oil which solidified on standing, m.p. 79°-80° C.
Reaction SMILES: O[C:2]1[C:11]2C(=C(C(F)(F)F)C=CC=2)N=C(C(O)CC)[C:3]=1C(NC1SC=CN=1)=O.[C:28]([OH:41])(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[C:28]([O:41][CH2:3][CH2:2][CH3:11])(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reactant: CCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCC(=O)OCCC

Procedure:
Using the procedure of Example 5, 5 g of 4-hydroxy-2-(1-hydroxypropyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide and 2.8 g of lauric acid were reacted to obtain 6 g of 1-[4-hydroxy-3-(2-thiazolylamino)-carbonyl]-8-(trifluoromethyl)-2-quinolinyl]-propyl dodecanoate melting at 158° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10](Cl)[N:5]2[N:4]=1.C(O)(C)C.[CH2:22]([CH2:24][NH2:25])[OH:23]>O>[CH3:1][N:2]([C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10]([NH:25][CH2:24][CH2:22][OH:23])[N:5]2[N:4]=1)[CH3:17]
Reactant: NCCO
Reactant: CN(C)c1nc2nc3c(c(Cl)n2n1)SCCC3
Solvent: O
Solvent: CC(C)O
Product: CN(C)c1nc2nc3c(c(NCCO)n2n1)SCCC3

Procedure:
A mixture of 1.35 g (0,005 mole) of 2-dimethylamino-5-chloro-7,8-dihydro-9H-thiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine, 5 ml of isopropanol and 0.61 g (0.01 mole) of ethanolamine is boiled for half an hour under stirring. 10 ml of water are added to the warm solution. The mixture is cooled, then the separated product is filtered and washed with water and cold isopropanol.
Reaction SMILES: [I:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[I:1][C:2]1[CH:7]=[N:6][N:5]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)[C:4](=[O:8])[CH:3]=1
Reactant: C1=COCCC1
Reactant: O=c1cc(I)cn[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: O=c1cc(I)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.9 %

Procedure:
A mixture of 5-iodo-2H-pyridazin-3-one (8.640 g, 38.92 mmol) in tetrahydrofuran (150 mL) was treated with para-toluenesulfonic acid (1.49 g, 7.86 mmol) and 3,4-dihydro-2H-pyran (8.98 mL, 98.18 mmol). The reaction was stirred at 25° C. for 2 d. After this time, the reaction was filtered. The filtrate was treated with para-toluenesulfonic acid (6 g) and 3,4-dihydro-2H-pyran (9 mL), and the reaction stirred at 25° C. for 6 h. The reaction was concentrated in vacuo, taken up in ethyl acetate (400 mL), washed with a saturated aqueous sodium bicarbonate solution (400 mL), and a saturated aqueous sodium chloride solution. The aqueous layer was extracted with ethyl acetate (300 mL) and was washed with a saturated aqueous sodium chloride solution. The combined organics were dried over sodium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 400 g, 0% to 50% ethyl acetate/hexanes) afforded 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (2.73 g, 23%) as a clear light brown, viscous oil. The material contained an impurity. However, it was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:22]=[CH:21][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc4ccccc4c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and naphthalene-2-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-naphthalen-2-yl-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 381(MH+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CO>[Pd](Cl)Cl.C1(C)C=CC=CC=1>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[C:19]([C:20]#[N:21])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
2M Sodium carbonate solution (200 ml) was added to a stirred mixture of 4-methylphenylboronic acid (30 g), 2-bromobenzonitrile (36.4 g), palladium (II) chloride (0.4 g), methanol (200 ml) and toluene (200 ml) at 5° C. The temperature rose to approximately 20° C. and a solid precipitated. The reaction mixture was then heated at reflux for 2 hours. The reaction mixture was allowed to cool and water (100 ml) was added, followed by diatomaceous earth (5 g). The mixture was stirred for 15 minutes, then filtered through diatomaceous earth. The organic phase of the filtrate was separated and washed with 2M sodium carbonate solution and then water. The organic phase was then filtered and the filtrate evaporated. The resultant solid was recrystallised from petroleum ether (b.p. 110°-120° C.) to give 4'-methylbiphenyl-2-carbonitrile (33 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: C#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethynylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (44.0 mg, 0.079 mmol) in DCM (6 ml) was added TFA (2.0 mL) and the reaction mixture was stirred at rt for one hour. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethynylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (23 mg, 0.042 mmol, 54% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.72 (s, 1H), 7.53 (s, 1H), 7.29-7.40 (m, 2H), 7.25 (s, 1H), 7.20 (s, 1H), 4.63 (s, 2H), 3.74 (s, 1H). LC-MS (ES+) m/z 429.00, [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:12][CH2:13][O:14][CH3:15])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:18][CH3:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[N:6]([CH2:12][CH2:13][O:14][CH3:15])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:18][CH3:19])=[N:22][CH:23]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C(=O)CCCc2c1ccc(N)c2OC
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2OC)CCCC(=O)N3CCOC)ncc1Cl

Procedure:
Analogous to procedure Example 101b, 7-Amino-6-methoxy-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (50 mg, 0.190 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (55 mg, 0.185 mmol) were converted to the desired product 12× (26 mg, 27%), purified by ISCO chromatography. 1H-NMR (CDCl3) δ 11.09 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.14 (s, 1H), 7.50 (m, 2H), 7.42 (s, 1H), 712 (t, J=7.5 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.21 (br s, 1H), 3.80 (s, 3H), 3.54 (br m, 2H), 3.28 (s, 3H), 3.05 (d, J=5.0 Hz, 3H), 2.32 (br m, 2H), 1.0-2.5 (low, broad m's, 6H); LC/MS (ESI-pos) m/z 525.37 (M+H). M.P.=205-207° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][OH:20])[N:10]=2)=[CH:4][CH:3]=1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(CO)cccc3n2)o1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CNc2ccc3c(COc4ccccc4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-methanol (180 mg, 672 mmol) was dissolved in 12 mL tetrahydrofurane. Phenol (70 mg, 0.745 mmol) and triphenylphosphine (200 mg, 0.763 mmol) were added at room temperature. Diisopropyl azodicarboxylate (159 mg, 0.787 mmol) was slowly added at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of 50 mL 2N sodium carbonate. The mixture was extracted three times with dichloromethane (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a light brown oil (90 mg, 39%), MS: m/e=345.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.CN.[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][NH:35][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:30])[F:31])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:16]
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCOC
Yield: 44.7 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (46.0 mg) was prepared by following General Procedure F starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 467; and 1H NMR (DMSO-d6, 400 MHz): δ 8.39 (1H, br. s), 8.07 (1H, br. s), 7.92 (1H, br. s), 7.74-7.72 (1H, br. m), 7.51-7.49 (1H, m), 7.37-7.35 (1H, m), 4.35 (4H, br. s), 3.73-3.72 (2H, br. t), 3.24 (3H, s), 2.82-2.80 (3H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1>C(#N)C>[F:33][C:32]([F:34])([F:35])[C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:12]2[CH2:11][CH2:10][C:9](=[CH:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:16][CH:15]=3)[CH2:14][CH2:13]2)=[CH:26][CH:27]=1)([OH:40])[C:36]([F:37])([F:39])[F:38]
Reactant: O=[N+]([O-])c1ccc(C=C2CCNCC2)cc1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C=C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 5 h
Yield: 64.6 %

Procedure:
To a stirred mixture of 4-(4-nitrobenzylidene)piperidine (23.83 mmol, 5.2 g) and potassium carbonate (31.0 mmol, 4.28 g) in acetonitrile was added a solution of 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (23.83 mmol, 8.03 g) in acetonitrile. The reaction was stirred for 5 hours then was concentrated under reduced pressure. Dichloromethane was added and the reaction was filtered. The filtrate was chromatographed on silica (eluting with a gradient of dichloromethane to dichloromethane/ethyl acetate) to give the title compound (7.3 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C@@H:17]([CH2:31][CH3:32])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.O[C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][CH:35]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH:38]([C:37]1[CH:40]=[CH:41][C:34]([O:27][C:26](=[O:28])[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:16])[CH2:31][CH3:32])=[CH:30][CH:29]=2)=[CH:35][CH:36]=1)=[O:39]
Reactant: CC[C@H](C)CCCOc1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)CCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
3.7 g of N,N'-dicyclohexylcarbodiimide were added portionwise at 0° C. while stirring to a solution of 3.4 g of (S)-p-(4-methylhexyloxy)benzoic acid, 1.76 g of p-hydroxybenzaldehyde and 0.15 g of 4-(dimethylamino)-pyridine in 100 ml of dichloromethane. The mixture was stirred at 0° C. for a further 1 hour and at room temperature for 2 hours, then filtered and the filtrate was washed with 2N sodium carbonate solution and then with water, dried over sodium sulphate and concentrated. Chromatography of the residue on 120 g of silica gel with hexane/ethyl acetate (vol. 9:1) gave 4.2 g of pure (S)-p-(4-methylhexyloxy)benzoic acid p-formylphenyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[CH:11]=1.CI.[Mg].[C:15](=[O:17])=[O:16]>CCOCC>[CH3:10][C:9]1[C:5]2[CH:4]=[CH:3][C:2]([C:15]([OH:17])=[O:16])=[CH:11][C:6]=2[S:7][CH:8]=1
Reactant: Cc1csc2cc(Br)ccc12
Reactant: O=C=O
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: Cc1csc2cc(C(=O)O)ccc12
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-3-methylbenzo[b]thiophene (16.8 g) and methyl iodide (23.8 g) was added dropwise to a stirred mixture of dry ether (150 ml) and magnesium (11.06 g) at such a rate that gentle reflux was maintained. When the addition was complete, the mixture was heated under reflux with stirring for 30 minutes, then cooled and poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated, 2N hydrochloric acid (100 ml) was added and the mixture was shaken. The ether layer was separated and the aqueous layer was extracted with ether. The ether solutions were combined, dried (Na2SO4) and evaporated to give a solid which was crystallized from ethyl acetate to give 3-methylbenzo[b]thiophene-6-carboxylic acid (7.71 g), m.p. 230°-232° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[F:12][CH:13]([F:23])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=1.N>>[F:12][CH:13]([F:23])[O:14][C:15]1[CH:16]=[C:17]([C:21]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: C#Cc1cccc(OC(F)F)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cccc(OC(F)F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and 1-(difluoromethoxy)-3-ethynylbenzene (Fluorochemicals, 84 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 6.95 (s, 1H), 7.31 (dd, J=8.3, 2.0 Hz, 1H), 7.47 (s, 1H), 7.59 (t, J=8.1 Hz, 1H), 7.70 (t, J=2.1 Hz, 1H), 7.77-7.83 (m, 1H), 8.18 (ddd, J=9.3, 2.8, 1.8 Hz, 1H), 8.61 (d, J=2.8 Hz, 1H), 8.98 (t, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 307 (M+H)+.