Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-fluoro-phenylboronic acid to give [1-(4-fluoro-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 305(MH+).
Reaction SMILES: [OH-:1].[Na+].C([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)([OH:16])[CH2:12][CH2:11]1)C1C=CC=CC=1>C(O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:13]2([OH:16])[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]2)=[CH:20][CH:21]=1)(=[O:1])[NH2:26]
Reactant: [OH-]
Reactant: N#Cc1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(OCC2(O)CCNCC2)cc1

Procedure:
4N sodium hydroxide (6.8 mL) was added to an ethanol solution (30 mL) of the compound (2.2 g) obtained in Step 3 of Example 4 and the mixture was heated under reflux for four and half hours. The solvent was removed under reduced pressure and to the residue was added water (30 mL), and the precipitate was collected by filtration.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)C=C.[CH3:12][CH2:13][CH2:14]CCC>>[CH2:14]([C:10]1[CH:9]=[C:8]([F:11])[CH:7]=[CH:6][C:5]=1[OH:4])[CH:13]=[CH2:12]
Reactant: C=CCOc1ccc(F)cc1
Reactant: CCCCCC
Product: C=CCc1cc(F)ccc1O

Procedure:
381.8 parts of oily 4-allyloxy-fluorobenzene are heated in an oil-bath for 8 hours at a temperature of about 245° -250° C. After cooling, the reaction mixture is poured onto 1200 parts of hexane. The mixture is extracted three times with sodium hydroxide solution 20% (total volume of sodium hydroxide: 2000 parts). The aqueous layer is washed with petroleum ether, acidified with 1300 parts of concentrated hydrochloric acid solution and extracted with ether. The extract is dried over calcium chloride, filtered and evaporated. The oily residue is distilled in vacuo, yielding 313.6 parts of 2-allyl-4-fluorophenol; bp 143° C at 48 mm. pressure; nD20 : 1.5225; d2020 : 1.1130.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([S:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([S:15]([CH3:16])=[O:27])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1SC)CCN(C(C)=O)CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1cc2c(cc1S(C)=O)CCN(C(C)=O)CC2

Procedure:
Following the general procedure of Example 4, 3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H3-benzazepine is reacted with one equivalent of 3-chloroperbenzoic acid to give 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Following the procedure of Example 4, 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with 3N hydrochloric acid to give 8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. This methoxy compound is treated with pyridine hydrochloride to give 8-hydroxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: CN1CCOCC1.Cl.Cl.[CH3:10][N:11]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:15]2=[CH:16][CH:17]=[C:18]([C:19]([F:22])([F:21])[F:20])[N:14]2[CH2:13][CH2:12]1.[OH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=1[O:39][CH3:40].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:26]2[CH2:27][CH2:28][C:23]3([N:11]([CH3:10])[CH2:12][CH2:13][N:14]4[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:16]=[C:15]34)[CH2:24][CH2:25]2)=[O:35])=[CH:32][C:31]=1[O:39][CH3:40]
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCNCC2
Reactant: COc1cc(C(=O)O)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N2CCC3(CC2)c2ccc(C(F)(F)F)n2CCN3C)ccc1O
Temperature: 60 °C
Yield: 56.4 %

Procedure:
4-Methyl morpholine (1.59 mL, 14.4 mmol) was added to a mixture of 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]dihydrochloride (1.00 g, 2.89 mmol), 4-hydroxy-3-methoxy-benzoic acid (486 mg, 2.89 mmol), EDCI (831 mg, 4.33 mmol), HOBt (585 mg, 4.33 mmol) and DMF (10 mL) at room temperature. The mixture was heated at 60° C. overnight before it was cooled to room temperature and partitioned between ethyl acetate and 1N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (0-100% ethyl acetate/hexanes) to give (4-hydroxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone (690 mg, 58%). ESI-MS m/z calc. 423.2, found 424.1 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, CD3CN) δ 7.04 (d, J=1.8 Hz, 1H), 6.94 (dd, J=8.1, 1.9 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.82 (s, 1H), 6.62-6.56 (m, 1H), 6.05 (d, J =3.9 Hz, 1H), 4.35 (s, 1H), 4.00 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.64 (s, 2H), 3.36 (t, J=6.0 Hz, 2H), 3.29 (s, 1H), 2.36 (s, 3H), 2.16-2.04 (m, 2H), 1.81 (dd, J=17.1, 7.3 Hz, 2H).26-7.21 (m, 2H), 7.14 (t, J=8.1 Hz, 1H), 2.78 (d, J=1.4 Hz, 2H), 1.24 (d, J=0.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:38])[CH2:36][CH3:37]
Reactant: CCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 19 h
Yield: 52 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Propionyl chloride (0.22 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 19 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.116 g, 52%). 1H NMR (Acetone d6, 400 MHz) δ 8.23 (d, J=9 Hz, 2 H), 8.00 (d, J=9 Hz, 2 H), 7.53 (d, J=9 Hz, 1 H), 7.02 (d, J=9 Hz, 1 H), 5.73 (d, J=9 Hz, 1 H), 5.69-5.64 (m, 1 H), 5.48 (dd, J=5 and 8 Hz, 1H), 2.37 (s, 3 H), 2.34 (q, J=7 Hz, 1 H), 1.47 (d, J=6 Hz, 3 H) and 1.02 (t, J=8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[NH:37][NH2:38]>O1CCCC1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:38][NH:37][C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 111.4 %

Procedure:
To a solution of the carboxylic acid (6b, 371 mg, 1.34 mmol) of Example 9 or 16 in tetrahydrofuran (7 mL) were added triethylamine (0.227 mL) and isobutyl chloroformate (218 μl) under ice-cooling, followed by stirring at 0° C. for 15 minutes. To the reaction solution was added t-butyl carbazate (245 mg) at 0° C., followed by stirring at room temperature for 1.5 hours, and then concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1) to afford 583 mg of the title compound (yield 98%).
Reaction SMILES: O=C1C2[C:5](=CC=CC=2)[C:4](=O)[N:3]1[O:12][CH2:13][C:14]1[N:15]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]3[N:24]=[N:25][N:26]=[C:18]3[C:17]=2[N:27]=1.O.NN.[CH2:40](O)C>>[CH3:23][C:20]1[N:19]2[N:24]=[N:25][N:26]=[C:18]2[C:17]2[N:27]=[C:14]([CH2:13][O:12][N:3]=[C:4]([CH3:5])[CH3:40])[N:15]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][S:33]([CH3:36])(=[O:34])=[O:35])[C:16]=2[C:21]=1[CH3:22]
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNS(C)(=O)=O)c12
Reactant: CCO
Agent: NN
Solvent: O
Product: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A mixture of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]methanesulfonamide (205 mg, 0.40 mmol), hydrazine hydrate (0.4 mL), and ethanol (4 mL) was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was partitioned between 1 M aqueous HCl (20 mL) and dichloromethane (10 mL). The aqueous phase was washed with dichloromethane (3×8 mL), then was adjusted to pH 12 with 1 M aqueous sodium hydroxide and was concentrated under reduced pressure. To the residue was added acetone (10 mL) and methanol (10 mL), and the reaction mixture was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (20 mL) and saturated aqueous sodium carbonate (20 mL). The aqueous phase was extracted with dichloromethane (3×10 mL). The organic layers were combined, washed with saturated aqueous sodium carbonate (3×10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 20-40% CMA in chloroform, where CMA is 80:18:2 chloroform/methanol/concentrated ammonium hydroxide) to yield 91 mg of N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}methanesulfonamide as a white foam.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](=O)[CH2:20][C:21](OCC)=[O:22])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]2[CH:20]=[C:21]([OH:22])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:16][CH:17]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Product: N#Cc1ccnc(-n2nc(Cc3ccc(Cl)cc3)cc2O)c1
Yield: 32 %

Procedure:
The title compound was prepared in 32% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 4-(4-chlorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].S([O:12][CH3:13])(OC)(=O)=O.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17](O)=[O:18].O>C(OCC)(=O)C>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([O:12][CH3:13])=[O:18]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(C)cccc1C
Reaction time: 1 h

Procedure:
K2CO3 (10.1 mmol, 1.5 equiv.) and dimethyl sulfate (7.4 mmol, 1.1 equiv.) were added at 25° C. to a solution of 2,6-dimethylbenzoic acid (6.7 mmol, 1 equiv.), and the mixture was stirred for 1 h. The solvent was reduced under reduced pressure, the residue was taken up in ethyl acetate (100 ml), and water (20 ml) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with sat. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The crude product was used in the next stage without being purified further. Yield: quantitative
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1>CS(C)=O>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[O:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnccn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a slurry of sodium hydride (about 60% oil suspension, 114 mg) in dimethyl sulfoxide (5 ml) was added dropwise tert-butyl 4-hydroxy-1-piperidinecarboxylate (576 mg). Considerable foaming occurred and the solution turned pale orange. To this solution was added chloropyrazine (377 mg) and the mixture was stirred at room temperature for 12 hours. The resulting mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was triturated with a mixture of ethyl acetate and n-hexane to give the title compound (472 mg) as white crystals.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2([C:41]([F:44])([F:43])[F:42])[O:32][N:31]=[C:30]([C:33]3[S:34][C:35]([C:39]#[CH:40])=[C:36]([CH3:38])[CH:37]=3)[CH2:29]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1>CN(C=O)C.[Cu]I>[CH2:1]([N:8]1[CH:40]=[C:39]([C:35]2[S:34][C:33]([C:30]3[CH2:29][C:28]([C:23]4[CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[CH:22]=4)([C:41]([F:44])([F:43])[F:42])[O:32][N:31]=3)=[CH:37][C:36]=2[CH3:38])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1-c1cn(Cc2ccccc2)nn1
Reaction time: 16 h
Yield: 25.6 %

Procedure:
CuI (47 mg) is added to a solution of benzylazide (33 mg), DIPEA (1.05 ml) and 5-(3,5-dichloro-phenyl)-3-(5-ethynyl-4-methyl-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazole (100 mg) in DMF (2.0 ml). After 16 hours at room temperature, the reaction is quenched with a saturated aqueous solution of NaHCO3 and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 1-benzyl-4-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-1H-[1,2,3]triazole (34 mg) as a yellowish foam. MS (HPLC/MS): 537 (MH+). Retention time: 5.04 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([OH:28])[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1c(C)cccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1c(C)cccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg), ethyl 6-methylsalicylate (360 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight and was further stirred at 140° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (168 mg, yield 91%).
Reaction SMILES: [Br:1]C(Cl)(Cl)C(Cl)(Cl)Br.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=O)=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]([Br:1])[CH:26]2[CH2:28][CH2:27]2)=[CH:19][N:18]=1
Reactant: O=C(Nc1ccc(F)nc1)C1CC1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(N=C(Br)C2CC2)cn1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 1,2-dibromotetrachloroethane (7.23 g, 0.022 mol) in 1,2-dichloroethane (50 ml) and triethylamine (4.49 g, 0.044 mol) was added to a stirred suspension of N-(2-fluoro-5-pyridyl)-cyclopropane carboxamide (2.0 g, 0.011 mol) - see Example 2 stage 1 and triphenylphosphine (5.83 g, 0.022 mol) in 1,2-dichloroethane (25 ml) at -10° C. under nitrogen at such a rate so that the temperature did not rise above -10° C. After complete addition (11/4 hours) the reaction mixture was allowed to warm up to room temperature and any triphenyl phosphine oxide was removed by filtration. Further quantities of triphenylphosphine oxide were removed by trituration of the residue with hexane. The filtrate was evaporated to give N-(2-fluoro-5-pyridyl)-cyclopropylmethanimidoyl bromide (2.54 g, 95%) as a yellow crystalline solid which was used in the next stage without further purification or characterisation.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[O:9])[N:4]=[C:3]1[C:24]([O:26]CC)=[O:25].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:9])[N:4]=[C:3]1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1nc(NC(=O)OCCSc2ccc(C(F)(F)F)cc2)cn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(NC(=O)OCCSc2ccc(C(F)(F)F)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
Ethyl 1-methyl-4-[2-(4-trifluoromethyl-phenylsulfanyl)-ethoxycarbonylamino]-1H-imidazole-2-carboxylate (0.69 g, 1.65 mmol) prepared in the capping step was dissolved in THF/H2O (27.40 ml/13.70 ml), 1N LiOH (4.57 ml) was added thereto, and the mixture was stirred at room temperature. After 15 hours have passed, the reaction solution was acidified to pH 2.0 by 1N HCl and then extracted with EA and water. The organic layer was washed with aqueous NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was recrystallized from EA and n-hexane to give 1-methyl-4-[2-(4-trifluoromethyl-phenylsulfanyl)-ethoxycarbonylamino]-1H-imidazole-2-carboxylic acid (0.52 g, 80.94%) of a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)=O.[ClH:13]>C1(C)C=CC=CC=1>[Cl:13][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: Cl
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)o1
Reaction time: 0.17 h

Procedure:
5-Chloromethyl furfural was prepared by reaction of fructose with concentrated hydrochloric acid in toluene in a well-stirred two-phase system. The reaction was conducted at 85° C. for 10 minutes. The product was recovered by decanting the organic layer and removing toluene under vacuum.
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9]1)=[C:17]1[C:19]([CH3:22])=[CH:20][S:21][C:16]1=[CH:15][CH:14]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:25]([N:12]1[C:13]2[C:18](=[C:17]3[C:19]([CH3:22])=[CH:20][S:21][C:16]3=[CH:15][CH:14]=2)[C:10]2[CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:24][CH2:23][C:11]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CN(Cc1ccccc1)CC4
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1csc2ccc3c(c4c(n3Cc3ccccc3)CCN(Cc3ccccc3)C4)c12

Procedure:
The compound is formed analogously to that described in Example 28, from 3.3 g of 9-benzyl-1-methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole and 2 ml of benzyl bromide in 50 ml of hexamethylphosphoric acid triamide in the presence of NaH. Melting point: 206° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([C:25]1[C:26]([Cl:35])=[N:27][C:28]3[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>C(#N)C>[Cl:35][C:26]1[C:25]([C:13]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O)ccc21

Procedure:
A solution of tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate 1-7 (2.50 g, 4.91 mmol, 1 equiv) and triethylamine trihydrofluoride (3.60 mL, 22.1 mmol, 4.50 equiv) in acetonitrile (100 mL) was stirred at 23° C. for 20 hours. The reaction mixture was concentrated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to tert-butyl 2-(2-chloro-3-quinolinyl)-5-hydroxy-1H-indole-1-carboxylate (1-8) as a tan colored foam. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H, J= 9.0 Hz), 8.17 (s, 1H), 8.07 (d, 1H, J=8.4 Hz), 7.86 (d, 1H, J=8.1 Hz), 7.77 (br t, 1H, J=8.4 Hz), 7.61 (br t, 1H, J=8.1 Hz), 7.03 (d, 1H, J=2.6 Hz), 6.93 (dd, 1H, J=8.8, 2.6 Hz), 6.55 (s, 1H), 1.26 (s, 9H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:23][CH2:24][C:25]#[N:26])[CH2:19][CH2:20][C:21]#[N:22])=[CH:13][CH:12]=1)[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:5]([CH2:4][CH2:3][CH2:1][NH2:2])[CH2:6][CH2:7][CH2:8][NH2:9])=[CH:16][CH:15]=1)[CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: N#CCCN(CCC#N)Cc1ccc(CN(CCC#N)CCC#N)cc1
Reactant: [H][H]
Solvent: C1COCCO1
Product: NCCCN(CCCN)Cc1ccc(CN(CCCN)CCCN)cc1
Yield: 96 %

Procedure:
6.97 g of 1,4-bis(N,N-bis(2-cyanoethyl)aminomethyl)benzene, 0.70 g of Raney Co and 100 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 180° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 7.00 g of the title compound.