Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)=[O:10]
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Step 1): A mixture of 5-dimethylamino-2-nitrobenzoic acid [J. Med. Chem., 24, 742 (1981)](9.0 g, 40 mmol), 4-aminomethyl-1-diphenylmethylpiperidine (12.0 g, 40 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimido hydrochloride (WSC) (8.0 g, 40 mmol) and 4-dimethylaminopyridine (DMAP) (5 g, 40 mmol) in dichloromethane (400 ml) was stirred at 0° C. for 1 hour, then at room temperature for 3 days. The reaction mixture was washed with 1N HCl, then water. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (5% methanol in dichloromethane) to give 5-dimethylamino-2-nitro-N-[(1-diphenylmethyl-piperidin-4-yl)methyl]benzamide (47%) as yellow solid: mp 200° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Product: CN1CCN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
5-Amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-methylpiperazine were reacted and worked up in the same way as in Example 1 to give 5-amino-1-cyclopropyl-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 216°-218° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(N(CC)CC)C.[S:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CN(C)C=O>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:28]3[CH2:29][CH2:30][S:26][CH2:27]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: C1CSCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSC3)nc21
Yield: 50.2 %

Procedure:
A solution of 1.0 g (3.7 mmol) of 7-chloro-1,4-dihydro-1-ethyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.8 g (8.0 mmol) of triethylamine, 1.1 g (12.0 mmol) of 97% thiazolidine in 30 ml of N,N-dimethylformamide was stirred at room temperature for 18 hours. The solvent was removed at reduced pressure and the residue dissolved in water using 1.0N sodium hydroxide to adjust to pH 12.0. The solution was filtered to remove a trace of insoluble material and the filtrate was acidified to pH=3.0 with 6.0N hydrochloric acid. The precipitate was removed by filtration, washed with water and the wet filter cake recrystallized from ethanol clarifying with charcoal to give 0.6 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(3-thiazolidinyl)-1,8-naphthyridine-3-carboxylic acid; mp 288°-289° C.
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:13][C:14]1[N:15]=[C:16]([C:25](OC)=[O:26])[S:17][C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>O1CCCC1>[CH3:13][C:14]1[N:15]=[C:16]([C:25]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:26])[S:17][C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1nc(C)c(-c2ccncc2)s1
Reactant: Nc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2ccccc2)sc1-c1ccncc1
Reaction time: 1 h
Yield: 33.3 %

Procedure:
n-Butyllithium (14-17% in hexane, 1.2ml) was added to dropwise a stirred solution of aniline (0.12 ml) in dry tetrahydrofuran (3 ml) at room temperature under nitrogen atmosphere. Then, methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (200 mg) was added to a stirred solution at room temperature under nitrogen atmosphere, and the mixture was stirred in the same condition for 1 hour. The resulting precipitates were collected by filtration, and the precipitates were washed with water, and air-dried. The precipitate was recrystallized from benzenepetroleum ether to give 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxanilide (80 mg, yield 33.3%) as colorless plates.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]5[N:25]([S:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)(=[O:30])=[O:29])[CH:26]=[CH:27][C:20]=45)[CH:15]=[C:14]([NH2:37])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:47][CH2:48][C:49]1[S:50][CH:51]=[C:52]([C:54](Cl)=[O:55])[N:53]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:47][CH2:48][C:49]1[S:50][CH:51]=[C:52]([C:54]([NH:37][C:14]2[CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]4[N:25]([S:28]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)(=[O:29])=[O:30])[CH:26]=[CH:27][C:20]=34)[CH:17]=[C:18]3[C:13]=2[CH:12]=[N:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[O:55])[N:53]=1
Reactant: O=C(Cl)c1csc(CCl)n1
Reactant: Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 12.9 %

Procedure:
1-(Phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-indazol-4-amine (663 mg, 1.252 mmol) in chloroform (10 mL) was stirred at 0° C. DIPEA (0.437 mL, 2.504 mmol) was added into the reaction mixture, followed by 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (300 mg, 1.530 mmol) in chloroform (10 mL). The reaction mixture was stirred at 0° C. for 15 mins. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (400 mg, 1.252 mmol) was added and the reaction was monitored by LCMS. When no further conversion was apparent, a further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (1.6 g, 1.252 mmol) was added and the reaction mixture was stirred for 18 h. The solution was treated with DCM (25 mL) and saturated aqueous sodium bicarbonate (25 mL) and stirred for 10 mins. The organic layer was separated, washed with aqueous sodium chloride (25 mL) and then passed through a hydrophobic frit. The residual solvent volume was reduced and the mixture was purified by silica column chromatography (Flashmaster II, 100 g cartridge) using a gradient of 0-100% ethylacetate/cyclohexane over 60 min to afford the title compound as a white solid (111 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH2:23][C:24](O)=O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O1CCCC1.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH:10][CH2:24][CH2:23][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH:2]=1
Reactant: NCCCc1cccnc1
Reactant: COc1ccc(CCCC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CCCCNCCCc2cccnc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 3-(3-pyridyl)propylamine (517.8 mg, 1.679 mmoles), 4-(3,4-dimethoxyphenyl)butanoic acid (376.5 mg, 1 equiv.) and N-hydroxysuccinimide (193.2 mg, 1.1 equiv.) in methylene chloride (15 mL) at 0° C. was treated with EDC hydrochloride (353.1 mg, 1.1 equiv.). The mixture was allowed to warm to room temperature after 10 minutes. Stirring was continued for 16 hours and then the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was re-extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and evaporated to give a colorless oil. This crude amide was dissolved in dry tetrahydrofuran (5 mL) under argon. The solution was cooled to 0° C. and then treated with 1 M borane-tetrahydrofuran complex (7.0 mL, 4 equiv.). The mixture was heated at reflux for 16 hours and then cooled to room temperature. Dry methanol (10 mL) was added carefully to the stirred mixture to avoid foaming. The resulting solution was evaporated under reduced pressure and the residue dissolved in dry methanol (20 mL). The mixture was heated at reflux for 4 hours and then evaporated. The crude amine was carried on without purification.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>C1COCC1>[C:13]1([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24]([CH3:1])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCN(CCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To 2.64 mL (18.9 mmol) of diisopropylamine in 30 mL of dry THF at -78° was added 6.9 mL (17.3 mmol) of 2.5M n-butyllithium in hexanes. The mixture was allowed to warm to room temperature and then was cooled once again to -78°. To the stirred solution was added 4.11 g (15.7 mmol) of 1-(2-phenylethyl)-4-carboethoxypiperidine in 25 mL of dry THF. The mixture was allowed to warm to -40° and 0.98 mL (15.7 mmol) of iodomethane was added to the reaction mixture. The mixture was stirred at -40° for 15 minutes and then allowed to stir at room temperature for 3 hours. The mixture was evaporated to dryness and the residue was dissolved in water. The aqueous solution was extracted with methylene chloride and the extracts were dried and evaporated to give 3.70 g of 1-(2-phenylethyl)-4-methyl-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.15-7.21 (m, 5H); 4.11-4.20 (q, 4H); 2.71-2.94 (m, 4H): 2.52-2.61 (m, 2H): 2.11-2.24 (m, 4H); 1.47-1.59 (m, 2H); 1.21-1.30 (t, 3H); 1.20 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C1C(N)=CC2[C:19]([O:21]C3(C4C=CC(O)=CC=4OC4C=C(O)C=CC3=4)C=2C=1)=[O:20].CCN=C=NCCCN(C)C.Cl.[OH-].[Na+]>>[NH2:2][C@H:3]([C:19]([OH:21])=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: Nc1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Reactant: NCCc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HA (1 g, 2.5 mmol) was dissolved in 100 ml of distilled water, forming an initial solution. Tyramine hydrochloride (162 mg, 0.93 mmol) and 5-aminofluorescein (81 mg, 0.23 mmol in 1.62 ml DMSO) were added to this solution. EDC.HCl (479 mg, 2.5 mmol) and NHS (290 mg, 2.5 mmol) were then added and the pH of the mixture was maintained at 4.7 with 0.1 M NaOH. The solution was stirred overnight at room temperature and then brought to pH 7.0. The solution was next filtered with grade 1 Whatman™ cellulose filter paper to remove unconjugated aminofluorescein that had precipitated. The filtrate was collected into dialysis tubes of molecular cut-off 3500 Da. Then the dialysis and lyophilization procedures described in Example I-A were carried out. The degree of substitution of tyramine was calculated from 1H NMR and the degree of aminofluorescein conjugated was estimated by comparing the absorbance value at 490 nm of 1 mg/ml fluorescence-conjugated HA-Tyr solution to a set of aminofluorescein standards. The degrees of substitution of tyramine and aminofluorescein were 4 and 0.4, respectively.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])=[CH:17][CH:16]=1>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])=[CH:19][C:20]=1[N+:1]([O-:4])=[O:2]
Reactant: BrCCCCc1ccc(CCCCBr)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(CCCCBr)ccc1CCCCBr
Reaction time: 0.17 h

Procedure:
To 1 ml of 60% nitric acid was added 1 ml of 97% sulfuric acid under ice-cooling, and the mixture was stirred for 10 minutes. After adding 0.42 g of 1,4-bis(4-bromobutyl)benzene, the whole was stirred at a room temperature for an hour. The reaction mixture was poured onto ice, and extracted with total 60 ml of chloroform. The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated under a reduced pressure to remove the solvent. The residue was applied to a silica gel column and eluted with chloroform/hexane (1:1). From the first fraction, 0.43 g of the title compound was obtained as a pale yellow liquid.
Reaction SMILES: C([O-])(=O)C([O-])=O.[CH3:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[N+](CC)(CCC)CCC.[CH3:26][C:27]1C([N+]([O-])=O)=CC=C[C:28]=1[N+:36](CC)([CH2:40][CH2:41]C)[CH2:37][CH2:38][CH3:39].[OH-].[Na+]>C(OCC)(=O)C>[CH3:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:41][CH2:40][N:36]([CH2:37][CH2:38][CH3:39])[CH2:28][CH2:27][CH3:26]
Reactant: CCC[N+](CC)(CCC)c1cccc([N+](=O)[O-])c1C
Agent: O=C([O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCN(CCC)CCc1cccc([N+](=O)[O-])c1C

Procedure:
2- Methyl-3-nitro-N,N-di-n-propyl phenyl ethyl ammonium oxalate (34 g) is added to solution of Sodium hydroxide (680 ml, 1.4%) and stir until the clear solution is obtained. Further, ethyl acetate (170 ml) is added and organic layer separated out, washed with brine solution and dried over Sodium sulphate (20 gm). Ethyl acetate is distilled out under vacuum at 50-60° C. to get residue of 2-Methyl-3-nitro-N,N-di-n-propyl phenyl ethyl amine as a free base.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH2:20][N:21]([CH3:23])[CH3:22])[CH3:8])=[CH:4][CH:3]=1.C([OH:30])(C)(C)C.[OH-].[K+]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:30])=[CH:14][C:13]=2[CH2:20][N:21]([CH3:22])[CH3:23])[CH3:8])=[CH:24][CH:25]=1
Reactant: CC(C)(C)O
Reactant: CN(C)Cc1cc(C#N)ccc1OCCN(C)Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CN(C)Cc1cc(C(N)=O)ccc1OCCN(C)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-{2-[N-(4-chlorobenzyl)-N-methylamino]ethoxy}-3-(dimethylaminomethyl)benzonitrile (5.0 g), tert-butanol (50 ml) and powdered potassium hydroxide (10.0 g) was boiled under reflux for 1 hour. The mixture was cooled to ambient temperature and poured into saturated brine (100 ml). The mixture was extracted with dichloromethane to give an oil which solidified slowly on drying under vacuum. The solid obtained was recrystallised from propan-2-ol to give 4-{2-[N-(4-chlorobenzyl)-N-methylamino]ethoxy}-3-(dimethylaminomethyl)benzamide, m.p. 123°-124° C.
Reaction SMILES: [Cl:1][CH:2]([C:9]#[N:10])[CH2:3][S:4][CH2:5][C:6]([NH2:8])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>Cl>[Cl:1][CH:2]([C:9]#[N:10])[CH2:3][S:4][CH2:5][C:6]#[N:8]
Reactant: N#CC(Cl)CSCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: N#CCSCC(Cl)C#N
Reaction time: 8 h

Procedure:
To the mixture obtained from Example 1, tosyl chloride (42 g) was added in portions with cooling. The resultant mixture was stirred for 5.5 hours, and then stood overnight. The solution was then poured into 4M hydrochloric acid (300 ml), stirred for 30 minutes, and then extracted with dichloromethane (×4). The combined extracts were washed with saturated brine, dried (magnesium sulphate) and evaporated to obtain the title compound as a dark red oil (30.95 g) 'H n.m.r. δ (CDCl3) 3.35(2H, d, J=7Hz, CH2CH), 3.55(2H,s,CH2CN), 4.77 (1H,t, J=7Hz, CH2CH).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[C:16]([CH:23]=[CH2:24])[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([O:22][CH3:31])=[O:21])[CH:17]=[C:16]([CH:23]=[CH2:24])[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2]
Reactant: C=Cc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: C=Cc1cc(C(=O)OC)nc(-c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 50-mL vial with a screw-top septum 2-(4-(4-cyano-3-(trifluoromethyl) phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylic acid (340 mg, 0.83 mmol) was dissolved in DMF (5 mL) and treated with potassium carbonate (343.6 mg, 2.49 mmol) and iodomethane (0.5 mL). The mixture was stirred at room temperature for three hours, diluted with 100 mL water, and extracted with 2×50 mL diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide methyl 2-(4-(4-cyano-3-(trifluoromethyl) phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylate. The residue was used in the next step without purification. LC/MS: m/z=426 [M+H]+.
Reaction SMILES: C1COCC1.Cl[CH2:7][C:8]([Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14])=[CH:9][CH2:10]Cl>[Zn].CCCCC>[CH3:14][O:13][Si:12]([O:15][CH3:16])([O:17][CH3:18])[C:8]([CH:9]=[CH2:10])=[CH2:7]
Reactant: CO[Si](OC)(OC)C(=CCCl)CCl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=CC(=C)[Si](OC)(OC)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
Four grams (41×1.5 mmols) of Zn powder and 15 ml of THF were added, under agitation, to 10 g (41 mmols) of the 1,4-dichloro-2-(trimethoxy)silyl-2-butene obtained by the above procedure. The mixed solution was heated and refluxed for 1 hour and then cooled down to room temperature, followed by adding 30 ml of dried pentane. The resulting ZnCl2 was removed by filtration and the solvent was distilled off under reduced pressure, followed by vacuum distillation to obtain 5.0 g of 2-(trimethoxy) silyl-1,3-butadiene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1.[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH2:25])([CH3:19])([CH3:18])[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH:25][S:12]([C:4]1[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:14])=[O:13])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=S(=O)(Cl)c1cc(Br)cc2cnccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(Br)cc2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A slurry of 7-bromo-isoquinoline-5-sulfonyl chloride (16.3 g, 35.5 mmol) in CH2Cl2 (200 mL) is added in small portions to a stirred solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (6 mL, 37.9 mmol) and pyridine (2.79 mL, 34.5 mmol) in CH2Cl2 (100 mL) at 0° C. under nitrogen. The resultant mixture is allowed to stir at ambient temperature overnight. The mixture is diluted with another 100 mL CH2Cl2, washed with saturated aqueous NaHCO3 (150 mL) solution, dried, filtered and concentrated. The dark oil is subject to column chromatography (Biotage 75 short; eluted with 10-20% CH3CN/CH2Cl2+0.2% NEt3) to give the title compound as a white solid. ESIMS: m/z 430 [(M+H)+, 79Br], 432 [(M+H)+, 81Br].
Reaction SMILES: CC(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[C:20]3[CH:21]=[CH:22][C:23]4[NH:27][C:26](=[O:28])[CH2:25][C:24]=4[C:19]=3[O:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+].C(Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl.CN(C=O)C>[C:43]1([CH2:6][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]3[C:20]4[CH:21]=[CH:22][C:23]5[NH:27][C:26](=[O:28])[CH2:25][C:24]=5[C:19]=4[O:18][N:17]=3)[CH2:10][CH2:9]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2noc3c4c(ccc23)NC(=O)C4)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2c(ccc3c(CCC4CCN(Cc5ccccc5)CC4)noc23)N1
Yield: 44 %

Procedure:
The procedure described in Example 12f was followed with the piperidine obtained in step e (0.042 g, 0.109 mmol) and TFA (1.5 mL) in CH2Cl2 (6 mL), Na2CO3 (0.058 g, 0.545 mmol) and benzyl bromide (0.016 mL, 0,131 mmol) in DMF (6 mL). After purification by chromatography (1-10% MeOH-CH2Cl2), the title compound (0.018 g, 44%) was obtained as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].N[CH2:15][CH:16]1[CH2:20][CH:19]([O:21][CH3:22])[O:18][CH:17]1[O:23][CH3:24]>C(Cl)Cl>[CH3:24][O:23][CH:17]1[CH:16]([CH2:15][NH:13][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH2:20][CH:19]([O:21][CH3:22])[O:18]1
Reactant: NC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: COC1CC(CN)C(OC)O1
Solvent: ClCCl
Product: COC1CC(CNC(=O)Nc2ccc([N+](=O)[O-])cc2)C(OC)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
25.1 g (0.15 mol) of 4-nitrophenylurea were dissolved in 150 ml of methylene chloride. The solution was filtered and then 27.0 g (0.17 mol) of 3-aminomethyl-2,5-dimethoxytetrahydrofuran dissolved in 150 ml of methylene chloride were added dropwise at 0° C. The mixture was stirred at room temperature for 1 h and the resulting precipitate was filtered off with suction. 45 g (91%) of the product were obtained. Melting point 172°-174° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1.[CH:10]1([Mg]Br)[CH2:12][CH2:11]1>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH:10]2[CH2:12][CH2:11]2)[OH:9])[CH:5]=[N:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1cncc(Br)c1
Solvent: C1CCOC1
Product: OC(c1cncc(Br)c1)C1CC1
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromo-5-pyridinecarboxaldehyde (651 mg, 3.50 mmol) in THF (20 ml) at −78° C. was added cyclopropylmagnesium bromide (0.5M in THF, 7.49 ml, 3.74 mmol). After 10 minutes, additional cyclopropylmagnesium bromide (0.5M THF, 3.0 mL, 1.5 mmol) was added. After stirring for an additional five minutes the reaction was quenched with saturated aqueous ammonium chloride. The resulting mixture was diluted with dichloromethane and water and the layers were separated. The aqueous layer was extracted two additional times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 7%) to afford (5-bromo-pyridin-3-yl)-cyclopropyl-methanol; MS (ES+) m/z 228.2 (M+H)+.