Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[C:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:11]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[CH2:16][NH+:15]([CH2:23][CH2:24][NH+:25]([CH3:27])[CH3:26])[CH2:14][CH2:13][N:12]3[C:28]=2[CH:29]=1)(O)=[O:4].[N:36]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C>[CH:30]1([C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:3]([NH:45][S:42]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)(=[O:44])=[O:43])=[O:4])=[CH:29][C:28]=3[N:12]3[CH2:13][CH2:14][N:15]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:11]=23)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NS(=O)(=O)N1CCOCC1
Reactant: C[NH+](C)CC[NH+]1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N4CCOCC4)cc32)-c2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To 11-carboxy-14-cyclohexyl-6-[2-(dimethylammonio)ethyl]-5,6,7,8-tetrahydroindolo-[2,1-a][2,5]benzodiazocin-6-ium dichloride (1 eq) (prepared from the product described in Example 20, Step 5, by iterative freeze drying in the presence of aqueous HCl) in DCM (0.06 M) was added morpholine-4-sulfonamide (1.5 eq), EDCI (1.5 eq) and DMAP (1.5 eq). The solution was stirred at RT overnight. The solvent was evaporated in vacuo and the crude was purified by automated RP-MS-HPLC (stationary phase: column Waters SYMMETRY prep. C18, 7 μm, 19×300 mm. Mobile phase: MeCN/H2O buffered with 0.1 TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (31%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][C:35](=[O:44])[C:36]3[N:37]([N:39]=[C:40]([CH2:42][OH:43])[CH:41]=3)[CH:38]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>ClCCl.CN(C=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:34][C:35](=[O:44])[C:36]3[N:37]([N:39]=[C:40]([CH:42]=[O:43])[CH:41]=3)[CH:38]=2)=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(-c2cn3nc(CO)cc3c(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cn3nc(C=O)cc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
599 mg (1.41 mmol) Dess-Martin periodinane is added to a solution of 140 mg (0.471 mmol) 6-(4-tert-butyl-phenyl)-2-hydroxymethyl-5H-pyrazolo[1,5-a]pyrazin-4-one in 5 ml dichloromethane and 1 ml DMF. The reaction mixture is stirred at ambient temperature for 18 hours. The reaction mixture is filtered and the filtrate is washed with saturated sodium thiosulfate solution and with saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulfate and evaporated. The residue is triturated with tert-butylmethylether, the solid is filtered off and dried under vacuum to give 6-(4-tert-butyl-phenyl)-4-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrazine-2-carbaldehyde as light yellow crystals; HPLC/MS: 1.93 (C), [M+H] 296.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:20])([CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1)[CH3:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:21][CH2:22][C:23](Cl)=[O:24]>CCOC(C)=O>[C:1]([O:7][C:8]([CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:23](=[O:24])[CH2:22][Cl:21])([CH3:20])[CH3:9])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)C(=O)OC(C)(C)C1NCCc2ccccc21
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OC(C)(C)C1c2ccccc2CCN1C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-methyl-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl pivalate (2.79 g) was dissolved in a 1:4 mixed solvent (30 mL) of EtOAc-saturated aqueous sodium bicarbonate. A solution of chloroacetyl chloride (0.9 mL) in EtOAc (6 mL) was added dropwise to the reaction liquid under ice-cooling, followed by stirring at room temperature for 2 hours and extraction with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 1-[2 (chloroacetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-methylethyl pivalate (3.01 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[N:23]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=5[Cl:38])[N:24]=[N:25][C:26]=4[C:27]([F:30])([F:29])[F:28])=[CH:16][C:15]=3[CH3:39])=[CH:10][C:7]=2[S:8][CH:9]=1)=[O:4].C1COCC1.[Li+].[OH-].Cl>O.CO>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[N:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[CH:13][C:6]4[C:5]([C:3]([OH:4])=[O:2])=[CH:9][S:8][C:7]=4[CH:10]=3)=[C:15]([CH3:39])[CH:16]=2)=[C:26]([C:27]([F:30])([F:29])[F:28])[N:25]=[N:24]1
Reactant: COC(=O)c1csc2cc(-c3ccc(OCc4c(C(F)(F)F)nnn4-c4c(Cl)cccc4Cl)cc3C)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2c(C(F)(F)F)nnn2-c2c(Cl)cccc2Cl)ccc1-c1ccc2c(C(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To a solution of 6-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophene-3-carboxylic acid methyl ester (0.14 g, 0.23 mmol) in a 1:1:1 mixture of THF, methanol, water (3 mL) is added LiOH (0.10 g, 2.36 mmol). The reaction is stirred for 18 h at room temperature. The reaction is adjusted to pH 3 with 1N HCl and extracted with EtOAc to yield the title compound (0.09 g, 66%). LC-ES/MS m/e 576.0 (M−1).
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6](O)[C:3]=1[C:4]#[N:5].P(Cl)(Cl)([Cl:14])=O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:14][C:6]1[C:3]([C:4]#[N:5])=[C:2]([OH:1])[N:9]=[C:8]([CH3:10])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c(C#N)c(O)n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: Cc1cc(Cl)c(C#N)c(O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.5 %

Procedure:
To a solution of 2,4-dihydroxy-6-methylnicotinonitrile (1.5 g, 10 mmol) in acetonitrile (50 mL) was added benzyltriethylammonium chloride (9.1 g, 40 mmol) and phosphorus oxychloride (6.13 g, 40 mmol). The resulting mixture was stirred for 4 hours at room temperature. The solvent was removed by rotary evaporation. To the residue was added dichloromethane (100 mL) and water (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give crude product which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1) to afford 4-chloro-2-hydroxy-6-methylnicotinonitrile (800 mg, 48%) as a brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH2:10])=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].P(Cl)(Cl)(Cl)=O>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]#[N:10]
Reactant: NC(=O)C=Cc1cccs1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC=Cc1cccs1
Reaction time: 1 h

Procedure:
β-(Thien-2-yl) acrylamide (5.2 g.) was mixed with sodium metabisulphite (12.9 g.) and heated with phosphoryl chloride (2.4 ml.) on a steam bath. After 1 hr., more phosphoryl chloride (10 ml.) was added and the mixture heated for a further 3.5 hrs. The mixture was cooled in an ice-bath and iced water cautiously added. The mixture was extracted into chloroform and the chloroform layer was washed with saturated sodium hydrogen carbonate solution, dried over sodium sulphate, and evaporated in vacuo to a brown oil. Distillation gave β-(thien-2 -yl) acrylonitrile, 1.50 g. (33%), b.p. 82- 86° /0.5 mm., λmax. (EtOH) 306 nm, (ε 18600).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1>>[CH3:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[CH:24]([C:23]3[CH:18]=[CH:19][C:20]4[O:28][CH2:27][O:26][C:21]=4[CH:22]=3)[NH:5][CH:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:6][C:7]2=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(C)cc12
Product: COC(=O)C1Cc2c([nH]c3ccc(C)cc23)C(c2ccc3c(c2)OCO3)N1

Procedure:
The cis and trans isomers of the title compound were prepared using the method described in Intermediate 1 but starting from racemic 5-methyl-tryptophan methyl ester and piperonal.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].N1C=CC=CC=1.[C:11](Cl)(=[O:15])[O:12][CH2:13][CH3:14].Cl>CCCCCC.C1COCC1>[C:11](=[O:15])([O:12][CH2:13][CH3:14])[O:4][CH2:1][CH:2]=[CH2:3]
Reactant: CCOC(=O)Cl
Reactant: C=CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOC(=O)OCC
Reaction time: 2 h
Yield: 81 %

Procedure:
A reactor equipped with a stirrer, thermometer and reflux condenser was charged with 469 g of allyl alcohol, 693 g of pyridine, and 1,200 g of THF. With stirring, 797 g of ethyl chlorocarbonate was added dropwise to the mixture while the internal temperature was controlled at −5° C. After the completion of dropwise addition, the reaction solution was aged at room temperature for 2 hours to complete the reaction. The reaction solution was neutralized with aqueous hydrochloric acid. This was combined with 1,000 ml of hexane and washed with water, whereupon the hexane layer was separated and dried over anhydrous sodium sulfate. The solution was precision distilled, collecting a fraction having a boiling point of 149-150° C. Allyl ethyl carbonate, 769 g, was obtained in a yield of 81%. It had a purity of 99.5% as analyzed by gas chromatography. On analysis by 1H-NMR in heavy chloroform, peaks appeared at 1.28 ppm (3H, t), 4.14 ppm (2H, q), 4.57 ppm (2H, d), 5.3 ppm (2H, m), and 5.9 ppm (1H, m). Also on analysis by 13C-NMR in heavy acetone, signals were observed at 14.4, 64.2, 68.4, 118.2, 133.2, and 155.5 ppm. On IR analysis, a strong signal of carbonyl radical was observed at 1748 cm−1. With these data, the product was identified to be allyl ethyl carbonate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.[CH3:11][C:12]1[CH:18]=[C:17]([C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([CH3:25])=[CH:15][C:13]=1[NH2:14]>C(Cl)Cl>[CH3:6][N:7]([CH3:10])[CH:8]=[N:14][C:13]1[CH:15]=[C:16]([CH3:25])[C:17]([C:19]#[C:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:18][C:12]=1[CH3:11]
Reactant: CN(C)C=O
Reactant: Cc1cc(C#CC(C)(C)C)c(C)cc1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(N=CN(C)C)c(C)cc1C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
Phosphorus oxychloride (182 mg) was added to a mixture of 5 ml of dichloromethane and 145 mg of N,N-dimethylformamide at 25° C. After the mixture was stirred at 25° C. for 1 hour, 1 ml of a methylene chloride solution containing 200 mg of the 2,5-dimethyl-4-(3,3-dimethyl-1-butynyl)aniline (Compound 4-25) produced in Production Example 2 was added dropwise thereto. The mixture was stirred at 25° C. for 2.5 hours, and the reaction solution was then poured into ice water. The pH was adjusted to 11 with an aqueous 1 N potassium hydroxide solution, and extraction was performed 3 times with dichloromethane. The organic layer was collected, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), thereby obtaining 30 mg of N,N-dimethyl-N′-[2,5-dimethyl-4-(3,3-dimethyl-1-butynyl)phenyl]formamidine (Compound 52).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][C:17]([Br:20])=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][C:17]([Br:20])=[CH:18][CH:19]=1)=[O:14]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc(Br)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1ccc(Br)s1
Yield: 73.3 %

Procedure:
Ethyl difluoroacetate (2.43 g, 19.6 mmol) was placed in a 100 mL round bottom flask, and dissolved in ether (15 mL). To the stirred solution was added 25 weight % sodium methoxide (4.23 g, 19.5 mmol) loll owed by 2-acetyl-5-bromothiophene (3.59 g, 17.5 mmol). After two hours a precipitate formed and THF (15 mL) was added to allow stirring to continue. The reaction was stirred at room temperature 6.2 hours, then treated with 3N HCl (20 mL). The organic layer was collected and washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil which was crystallized from methylene chloride/isooctane to give yellow needles (3.63 g, mp 83.5°-85°C., 73%). 1H NMR (CDCl3) 300 MHz 14.60 (br s, 1H), 7.53 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 7.19 (m, 1H), 6.32 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -127.00 (d); M+282.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:15]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]1[C:17]([O:19][CH3:20])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[OH:15][CH:16]([C:21]([O:1][CH2:2][CH2:3][NH:4][C:5]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:14])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: O=C(NCCO)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)C(O)C(OCCNC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.8 g (50 mmol) of benzyl (2-hydroxyethyl)carbamate and 12.7 g (50 mmol) of methyl 2,3-epoxy-3,3-diphenylpropionate were dissolved in 80 ml of methylene chloride and, with ice-cooling, 0.95 g (5 mmol) of p-toluenesulfonic acid was added. The reaction mixture was stirred at room temperature for 24 hours and then diluted with methylene chloride and extracted with 2M aqueous sodium hydroxide solution, the organic phase was separated off and dried over sodium sulfate and the solvent was distilled off. The residue (22.2 g of an oil) was directly reacted further.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH3:38])[C:28]=1[N:29]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[N:30]1)[O:5][CH:6]([C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[O:15])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].O.O1CCCC1.O.[OH-].[Li+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH3:38])[C:28]=1[N:29]1[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=[N:30]1)[O:5][CH:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:24][CH:25]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a flask containing ethyl 3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoate (117 mg, 0.22 mmol) was added water (0.55 mL), tetrahydrofuran (0.55 mL), and methanol (0.55 mL). Lithium hydroxide monohydrate (508 mg, 12.1 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was concentrated and acidified to pH=3 with citric acid (10%). A white precipitate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (+/−)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (90 mg, 81%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 7.88 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J=8.4 Hz, 2H), 6.80 (t, J=5.9 Hz, 1H), 6.56 (s, 2H), 5.16 (dd, J=7.8, 5.1 Hz, 1H), 3.71 (q, J=5.9 Hz, 2H), 2.69 (t, J=5.8 Hz, 2H), 2.04-1.91 (m, 1H), 1.88 (s, 6H), 1.86-1.67 (m, 1H), 1.63-1.31 (m, 2H), 0.96 (t, J=7.3 Hz, 3H). MS (M+1): 504.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.O.[CH2:12]([NH2:15])[CH2:13][NH2:14]>>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([NH:14][CH2:13][CH2:12][NH2:15])=[N:3]1
Reactant: Clc1nsc2ccccc12
Reactant: NCCN
Solvent: O
Product: NCCNc1nsc2ccccc12
Temperature: 80 °C

Procedure:
Ethylenediamine (45 mL) was heated to 80° C. A room temperature solution of 3-chlorobenzo[d]isothiazole (12 g, 70.7 mmol) in ethylenediamine (5 mL) was added to the heated ethylenediamine dropwise. The resulting solution was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature and water (75 mL) was added. The aqueous mixture was extracted with ethyl acetate twice and the ethyl acetate layers were separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine as a light yellow solid (8 g).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[CH:5]1[C:10](=[O:11])[O:9][C:7](=[O:8])[CH:6]=1.C1(N)CCCCC1.[OH2:19]>>[CH2:1]=[CH:2][CH:3]=[CH2:4].[C:7]([OH:19])(=[O:8])/[CH:6]=[CH:5]\[C:10]([OH:9])=[O:11]
Reactant: O=C1C=CC(=O)O1
Reactant: O
Agent: C=CC=C
Solvent: NC1CCCCC1
Product: O=C(O)/C=C\C(=O)O
Reaction time: 1 h

Procedure:
of the same butadiene-maleic anhydride copolymer as in Example 11, 40g. of cyclohexylamine and 500 ml. of water were fed in a separable 1 liter flask equipped with a stirrer and a reflux condenser. A reaction was carried out for 1 hour at 100° C. under a nitrogen gas atmosphere to give a transparent, viscous, aqueous butadiene-maleic acid copolymer cyclohexylamine salt solution. To this aqueous solution was added over a period of 10 minutes a separately prepared aqueous solution of 56g. of magnesium acetate tetrahydrate in 100 ml. of water. After completion of the addition, heating was applied up to near 100° C. while a violent stirring was applied to the interior pf the flask, resulting in that there were deposited many solids in the form of small lumps. The solids were separated from the liquid phase by means of hot filtration and collected in a flask. Cooling of the flask in an ice-water bath resulted in that after 5 minutes the solids therein were completely converted into an aqueous solution. To the aqueous solution thus obtained there were repeatedly applied such heating and cooling operations. At every repetition the aqueous solution on heating was converted into a rubber-like matter and on cooling reverted to its original liquid phase.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25]Cl)[CH:12]=3)=[CH:10][C:3]=12.[I-:37].[Na+]>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][I:37])[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCl)c2cc1OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Yield: 110.4 %

Procedure:
A suspension of 0.760 g of 4-chloro-2-[1-(2-chloroethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.315 g of sodium iodide in 70 ml of 2-butanone is brought to reflux for approximately 24 hours. The reaction mixture is evaporated to dryness under reduced pressure (13 kPa), taken up with 50 ml of water, and extracted with three times 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). 0.98 g of 4-chloro-2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a yellow oil, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][C:25](=[O:28])[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[BH4-].[Na+]>C1COCC1>[F:29][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCC(O)C3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (30 mg, 0.07 mmol, 1.00 eq) in dry THF (3 mL) was added NaBH4 (5.34 mg, 0.14 mmol, 2.00 eq) at 0° C. and left to stir at RT for 1 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford crude product which was purified using preparative HPLC to afford the title compound as (10.00 mg, 0.02 mmol, 32.9%) off-white gum. 1H NMR (400 MHz, DMSO-d6): δ 8.26-8.39 (bs, 1H), 7.98-8.20 (m, 1H), 7.53-7.72 (m, 2H), 6.53-6.71 (m, 1H), 4.42 (d, J=5.52 Hz, 1H), 3.70 (d, J=3.83 Hz, 1H), 3.48-3.51 (m, 2H), 2.08-2.37 (m, 6H), 1.69-2.05 (m, 8H), 1.26-1.49 (m, 2H). m/z: 423 [M+H]+
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.C1(Br)CC1.[Mg].[NH2:11][C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:26]=[C:25]([C:36](N(OC)C)=[O:37])[CH:24]=2)=[CH:19][CH:18]=1)=[O:13]>C1COCC1>[CH:1]1([C:36]([C:25]2[CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][NH:14][C:12]([NH2:11])=[O:13])=[CH:18][CH:19]=3)[N:27]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[N:26]=2)=[O:37])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: COc1ccc(-n2nc(C(=O)N(C)OC)cc2-c2ccc(CCNC(N)=O)cc2)cc1
Agent: BrC1CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(=O)C3CC3)cc2-c2ccc(CCNC(N)=O)cc2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of cyclopropylmagnesium bromide, which was prepared from cyclopropyl bromide (257 ml) and magnesium (57 mg) in THF (1 ml) as usual method, was added a solution of 5-(4-{2-[(aminocarbonyl)-amino]ethyl}phenyl)-N-methoxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-carboxamide (90 mg) in THF (3 ml) dropwise at ambient temperature. The mixture was stirred at 50° C. for 5 hours. The reaction mixture was cooled to ambient temperature and was quenched by adding saturated aqueous ammonium chloride solution. The mixture was extracted with AcOEt. The organic layer was washed with 1M HCl, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by MeOH/CHC3 10%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give N-(2-{4-[3-(cyclopropylcarbonyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}ethyl)urea (23 mg) as a powder.