Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[C:17]([CH3:21])([C:18](O)=[O:19])[CH2:16][N:15]([CH3:22])[C:14](=[O:23])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][NH:29][CH3:30]>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[C:17]([CH3:21])([C:18]([N:29]([CH3:30])[CH3:28])=[O:19])[CH2:16][N:15]([CH3:22])[C:14](=[O:23])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2(C)C(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2(C)C(=O)N(C)C
Reaction time: 96 h

Procedure:
The title compound was prepared from 3-benzyloxy-5,7-dimethyl-2-methoxycarbonyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid using a procedure similar to that described in Example 2, Step 5 except that 2N dimethylamine in THF was used in place of 4-fluorobenzylamine, and the reaction time totaled 4 days. 1H NMR (400 MHz, d6-DMSO) δ 7.47-7.45 (m, 2H), 7.38-7.32 (m, 3H), 5.23 (dd, J=10.8, 16.0 Hz, 2H), 4.16 (d, J=13.6 Hz, 1H), 3.81-3.76 (m, 4H), 3.00 (s, 3H), 2.72 (br s, 6H), 1.78 (s, 3H); ES MS (M+H)=401.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])O)=[C:4]([CH3:19])[CH:3]=1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([CH:8]([Cl:22])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Br)ncc1C(O)c1c(F)ccc(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)ncc1C(Cl)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of (6-bromo-4-methylpyridin-3-yl)(2,3,6-trifluorophenyl)methanol (4.60 g, 13.9 mmol) in methylene chloride (70 ml), thionyl chloride (10.1 ml, 139 mmol) and N,N-dimethylformamide (0.60 ml) were added at 0° C., and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and subsequently water and then saturated aqueous sodium hydrogencarbonate were added thereto at 0° C. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure, to obtain the title compound (4.65 g, 13.3 mmol, 96%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.[C:14]1([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)=[N:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:37][C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:23]4[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:20]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)=[N:21][N:22]=4)=[CH:36][CH:35]=3)=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: Nc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Reactant: COc1cnc2c(Cl)ccnc2c1
Solvent: CN(C)C=O
Product: COc1cnc2c(Nc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2c1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
In a 20 mL sealed tube was dissolved 8-chloro-3-methoxy-1,5-naphthyridine (70 mg, 360 μmol) in DMF (2.00 mL). To this was added N1-(4-phenylphthalazin-1-yl)benzene-1,4-diamine (124 mg, 396 μmol) and the reaction mixture was stirred at 70° C. for 17 h. Upon cooling to RT, the mixture was dissolved in DMF and purified using Gilson reverse phase chromatography. The product fractions were combined, concentrated and the resulting crude was extracted into DCM, washed 1× sodium carbonate, 1×H2O, dried with Na2SO4, filtered through flitted funnel, concentrated to yield N1-(7-methoxy-1,5-naphthyridin-4-yl)-N4-(4-phenylphthalazin-1-yl)benzene-1,4-diamine as light yellow solid. MS [M+H]=471.0; Calc'd 470.5 for C29H22N6O.
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][NH:11][CH2:10][CH2:9]2.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(O)C>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:9]2
Reactant: O=Cc1cccs1
Reactant: Oc1ccc2c(c1)CCNC2
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Oc1ccc2c(c1)CCN(Cc1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of sodium cyanoborohydride is added to a solution of 1.5 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline, 1.2 g of thiophene-2-aldehyde and 1.8 g of toluenesulfonic acid monohydrate in 30 ml of ethanol. The mixture is stirred at room temperature for 8 hours, the solvent is removed in vacuo, and the residue is taken up with water/methylene chloride. The organic phase is again skaken with water, dried and evaporated in a rotary evaporator. The crude oily product is purified by chromatography on silica gel using a mixture of ethyl acetate/methylene chloride in the ratio 1:2. 1.7 g of a colorless oil, which crystallizes on standing (69% of theory), is obtained. Melting point: 110°-112° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:12]3[C:17]([NH:18][C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.N1C2C(=CC=CC=2)C(=O)C1=O.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.Cl>C(OCCO)C.C(OCC)(=O)C.CO>[ClH:1].[CH:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]1[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=1[C:2]([NH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[N:3]2
Reactant: Clc1nc2ccccc2c2[nH]c3ccccc3c12
Reactant: NCCN1CCNCC1
Agent: Cl
Agent: O=C1Nc2ccccc2C1=O
Solvent: CCOC(C)=O
Solvent: CCOCCO
Solvent: CO
Product: c1ccc2c(c1)nc(NCCN1CCNCC1)c1c3ccccc3[nH]c21

Procedure:
A mixture of compound 4a as obtained from the above Synthesis Ex. 1 (1.26 g, 5 mmol) and 1-(2-aminoethyl)piperazine (1.94 g, 15 mmol) in 2-ethoxyethanol (50 mL) was heated at 140-150° C. for 48 hrs (by TLC monitoring). After cooling, the reaction mixture was evaporated in vacuo to give a residue, which was dissolved in ethyl acetate (EA) (50 mL). The EA layer was washed with H2O and brine, and then dried on MgSO4. Concentration of the EA layer gave a residue, which was dissolved in MeOH (10 mL), followed by addition of a solution of 6N HCl at 0° C. The resultant mixture was stirred at room temperature for 8 hrs to result in precipitation, followed by filtration. The precipitate thus collected was washed with MeOH and then dried at 90° C. under reduced pressure for 24 hrs to give N-(11H-indolo[3,2-c]quinolin-6-yl)-2-(piperazin-1-yl)ethanamine hydrochloride, which was purified by flash column chromatography (FCC) (silica gel; MeOH/CH2Cl2=1/10 to 1/3) to give the title compound 5 as an orange color powder (0.51 g, 29% yield).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[C:8](SC)[CH:9]=[CH:10][CH:11]=2)[N:6]=1)([O:3][CH3:4])=[O:2].[CH3:18]SC1C=CC=CC=1N.N1C2C(=CC=CC=2)C=CC=1>>[C:1]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[C:8]([CH3:18])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CSc1ccccc1N
Reactant: COC(=O)c1cc(O)c2cccc(SC)c2n1
Solvent: c1ccc2ncccc2c1
Product: COC(=O)c1cc(O)c2cccc(C)c2n1
Yield: 59 %

Procedure:
Employing the same sequence as employed in the preparation of quinoline F3 but starting with the commercially available o-toluidene (Aldrich Chemical Co.) rather than 2-methylmercaptoaniline (F1) the desired quinoline I1 was obtained (1.24 g, 59% yield over two steps).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:31][CH2:30][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:31][CH2:30][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][C:25]([CH2:28][N:46]6[CH2:50][CH2:49][CH2:48][CH2:47]6)=[CH:24][CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:7][CH:6]=1)=[O:4]
Reactant: C1CCNC1
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)cc5)cc4c3C2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(CN6CCCC6)cc5)cc4c3C2)nc1
Reaction time: 0.17 h
Yield: 176.8 %

Procedure:
To a 0° C. solution of Example 102 (1.0 g, 2.42 mmol) in DCM (50 mL) was added Na(OAc)3BH (1.028 g, 4.8 mmol) and stirred for 10 min. To the reaction mixture was added pyrrolidine (0.861 g, 12.13 mmol) under nitrogen atmosphere and the reaction mixture was continued stirring at room temperature for 4 hr. The progress of the reaction was monitored by TLC and upon completion of the reaction the mixture was partitioned between DCM (100 mL) and water (15 mL) and the organic layer was separated, washed with water (2×10 mL), dried over sodium sulfate filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide methyl-2-{8-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (2 g, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-])=O.C(OCC)(=O)C>[Pd].[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2
Reactant: O=C(Nc1ccc([N+](=O)[O-])c2ccncc12)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)C(F)(F)F)c2cnccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To N-(5-nitroisoquinolin-8-yl)trifluoroacetamide (200 mg) were added ethyl acetate (15 ml) and 5% palladium-carbon (wet, 20 mg) and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hr. Tetrahydrofuran was added to the reaction mixture to dissolve the resultant crystals, and palladium catalyst was removed by celite filtration. The solvent was evaporated from the filtrate to give N-(5-aminoisoquinolin-8-yl)trifluoroacetamide as a crude product. Tetrahydrofuran (12 ml), pyridine (62 μl) and phenyl chloroformate (0.10 ml) were added to the obtained crude product, and the mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with dichloromethane, and washed twice with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was washed with diethyl ether and dried under reduced pressure to give 8-(trifluoroacetylamino)isoquinolin-5-ylcarbamic acid phenyl ester (194 mg).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][C:11]([C:17](=[O:54])[NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:23]=[C:22]3[C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)([NH:14][CH:15]=[O:16])[CH2:10]1)=O)(C)(C)C>C(Cl)Cl>[F:53][C:50]1[CH:51]=[CH:52][C:47]([C:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([NH:18][C:17]([C:11]4([NH:14][CH:15]=[O:16])[CH2:12][CH2:13][NH:9][CH2:10]4)=[O:54])[CH:20]=3)[NH:24][N:23]=2)=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC=O)(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Product: O=CNC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCNC1
Reaction time: 1 h
Yield: 100 %

Procedure:
4M HCl (2 ml) was added to a solution of 3-[3-(4-Fluoro-phenyl)-1Trityl-indazol-5-ylcarbamoyl]-3-formylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (4P) 0.141 (mmol) in MeCl2 (2 ml) at room temperature, then stirred for 1 hour. The solvent was evaporated, hexanes added to residue and supernatant decanted. The residual solid was dried yielding 5P as a white solid (60 mg, 100%) LCMS (MH, 368.2) Retention time=1.91 minutes.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([CH3:13])[CH:7]=1>OS(O)(=O)=O>[F:5][C:6]1[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:9]([NH2:10])=[C:8]([CH3:13])[CH:7]=1
Reactant: Cc1cc(F)ccc1N
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1N
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
Concentrated nitric acid (17 g, 0.18 mol) was added dropwise to a stirred solution of 4-fluoro-2-methylaniline (20 g, 0.16 mol) in cone H2SO4 (300 mL) at −10° C. The mixture was stirred at −10° C. for 10 min., and the reaction mixture was poured into ice water. The resultant solid was collected by filtration and partitioned between EtOAc and aq Na2CO3 solution (pH 8). The organic solution was washed with brine, dried (MgSO4) and concentrated to give 4-fluoro-2-methyl-5-nitroaniline (20 g, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.27 (d, J=6.8 Hz, 1 H), 7.14 (d, J=12.4 Hz, 1 H) 5.37 (s, 2 H), 2.10 (s, 3 H).
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.C[O:18][C:19](=[O:46])[C@H:20]([CH:43]([CH3:45])[CH3:44])[N:21]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]#[N:42])=[CH:31][CH:30]=1)[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].CC1C=CC=CC=1C.[OH-].[Li+]>C(Cl)Cl.O.C1CCCCC1>[CH3:26][CH2:25][CH2:24][CH2:23][C:22]([N:21]([C@H:20]([C:19]([OH:18])=[O:46])[CH:43]([CH3:44])[CH3:45])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]2[NH:42][N:14]=[N:15][N:16]=2)=[CH:33][CH:34]=1)=[O:27]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Temperature: 30 °C
Reaction time: 10 h

Procedure:
To the resultant tributyl tin azide solution in methylene chloride, N-[(2′-cyanobiphenyl-4-yl)-methyl]-N-valeryl-(L)-valine methyl ester (28.3 g) and o-xylene (85 ml) were added and heated to reflux. The reaction mass was maintained at reflux for about 6 hours, 15 minutes and then cooled to about 30° C. 11.7 g of lithium hydroxide in water (198 ml) was added and stirred for about 10 hours at 28-30° C. Reaction completion was confirmed by thin layer chromatography and the organic and aqueous layers were separated. The aqueous layer was washed twice with toluene (2×28.3 ml). To the aqueous layer was added dichloromethane (28.3 ml) and the pH was adjusted to 6.7 using a 20% aqueous acetic acid (32 ml) solution. The aqueous layer was separated and washed with dichloromethane (28.3 ml). The aqueous layer was separated and 113.2 ml of dichloromethane was added. The pH of the reaction mass was adjusted to 5 using acetic acid (8.2 ml). The reaction mixture was stirred for 15 minutes and the organic and aqueous layers were separated. The aqueous layer was again extracted with dichloromethane (113.2 ml). The combined organic layers were washed with water (113.2 ml) and then with a solution of sodium chloride (5.7 g) in water (113.2 ml) followed by a further wash with water (113.2 ml). The organic layer was concentrated at atmospheric pressure and about 90% of the solvent was distilled off at 42° C. To the residual mass cyclohexane (56.6 ml) was added and concentrated under reduced pressure at about 55° C. to obtain a residue. The residue was cooled to 30° C.; 113.2 ml of cyclohexane was added to the residue and stirred for about 55 minutes at 28-30° C. The resultant solid was filtered and washed with cyclohexane (28.3 ml). The obtained solid was dried at about 50° C. for about 6 hours to give 22.3 g of the crude valsartan. (Purity by HPLC 98.75 area-%)
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[C:11]=2[CH:10]=[C:9]1[CH3:21])=O)(C)(C)C.O.[OH-].[Na+]>CO>[CH3:21][C:9]1[NH:8][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[C:11]=2[CH:10]=1
Reactant: Cc1cc2c(CC(=O)O)cccc2n1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(CC(=O)O)cccc2[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a mixture of 1-t-butoxycarbonyl-2-methylindole-4-acetic acid (96.3 g) in methanol (200 ml)-water (100 ml) was added dropwise 5N aqueous solution of sodium hydroxide (200 ml) at room temperature, and the mixture was stirred at 50° C. for 3 hours and then stirred at room temperature for 12 hours. The reaction mixture was extracted with hexane-ether. The aqueous layer was adjusted to acidic condition with hydrochloric acid and then extracted with ethyl acetate. The extraction was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure to give the title compound (53.9 g; crude).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]([CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]([CH3:21])[CH:12]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
10.0 g (61.3 mmol) of 3,4-dichlorophenol, 10.4 g (55.8 mmol) of 4-chloro-2,5-dimethylnitrobenzene and 10.0 g (72.5 mmol) of potassium carbonate are stirred in 200 ml of N,N-dimethylformamide at 100° C. for 6 h, and the mixture is applied to ice, stirred at 0° C. for 15 min and then filtered. The solid is washed with water and hexane and dried under reduced pressure (18.0 g, 98.3% purity, 98.0% yield, log P (pH 2.3)=5.19).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[NH:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][OH:16])[C:2]1[N:4]=[C:5]([N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])[N:7]=[C:8]([N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])[N:1]=1
Reactant: OCCNCCO
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: OCCN(CCO)c1nc(N(CCO)CCO)nc(N(CCO)CCO)n1

Procedure:
It is known that cyanuric chloride will react with diethanolamine to yield hexakis(2-hydroxyethyl)melamine (Jour. Am. Chem. Soc. 73,2984 (1951). ##STR1## wherein R1 is N(CH2CH2OH)2
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4].I[CH3:19].[H-].[Na+]>C1COCC1>[CH3:19][O:1][CH:2]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CI
Reactant: CCOC(=O)C(O)c1cccc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(OC)c1cccc2ncccc12
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of ethyl 2-hydroxy-2-(quinolin-5-yl)acetate (1.5 g, 6.5 mmol) in anhydrous THF in an oven-dried flask under argon was added iodomethane (1.2 mL, 19.2 mmol) and the mixture was cooled over an ice bath. NaH (60% in oil; 0.26 g, 6.5 mmol) was added and the mixture stirred for 1 hour over ice. After removing the ice bath, stirring was continued for an additional 3.25 hours, and more NaH (60%; 0.030 g, 0.75 mmol) was added. The mixture was stirred for 45 minutes then the reaction was quenched with brine and further diluted with water. The aqueous mixture was extracted with EtOAc and the combined organics were washed with water three times, brine once, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (50% EtOAc-hexanes) gave ethyl 2-methoxy-2-(quinolin-5-yl)acetate as a yellow oil (0.9 g, 57% yield).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][N:53]2[CH:57]=[C:56]([C:58]3[C:66]4[C:61](=[N:62][CH:63]=[C:64]([C:67]5[CH:72]=[CH:71][C:70]([CH:73]6[CH2:78][CH2:77][N:76]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:75][CH2:74]6)=[CH:69][CH:68]=5)[CH:65]=4)[N:60](S(C4C=CC(C)=CC=4)(=O)=O)[CH:59]=3)[CH:55]=[N:54]2)[CH:47]=1.[OH-].[Li+]>C1COCC1.CO.O>[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][N:53]2[CH:57]=[C:56]([C:58]3[C:66]4[C:61](=[N:62][CH:63]=[C:64]([C:67]5[CH:68]=[CH:69][C:70]([CH:73]6[CH2:74][CH2:75][N:76]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:77][CH2:78]6)=[CH:71][CH:72]=5)[CH:65]=4)[NH:60][CH:59]=3)[CH:55]=[N:54]2)[CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccnc4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccnc6)c5)c4c3)cc2)CC1

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (150 mg, 0.217 mmol) was hydrolyzed by lithium hydroxide (27 mg, 0.653 mmol) in THF/methanol/water (3/3/3 ml) to yield crude 120 mg (crude) of the titled compound. MS: m/z=532.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](OC)=[O:19])=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:18]([C:15]1[N:16]=[CH:17][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:22])=[CH:13][CH:14]=1)=[O:19]
Reactant: COC(=O)c1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(C=O)nc1)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of methyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylate (4.78 g) in THF (75 mL) was added a toluene solution (1.0 M, 30.8 mL) of diisobutylaluminum hydride at −78° C., and the mixture was stirred at −20° C. for 2 hr under an argon atmosphere. Sodium sulfate decahydrate (22.7 g) was added thereto at −78° C., and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the solvent of the filtrate was evaporated under reduced pressure to give the title compound as a pale-yellow solid (4.30 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C@@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][O:13][CH3:14])=[CH:5][C:4]=1[NH:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1)#[N:2].C([O-])([O-])=[O:31].[K+].[K+].OO>CS(C)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C@@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH2:12][O:13][CH3:14])=[CH:5][C:4]=1[NH:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1)(=[O:31])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: COC[C@@H](CNc1ccc(C#N)c(Nc2cc(C)ns2)c1)NC(=O)OC(C)(C)C
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC[C@@H](CNc1ccc(C(N)=O)c(Nc2cc(C)ns2)c1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
The above mentioned crude oil from step 2 was dissolved in DMSO (2 mL), K2CO3 (500 mg, 3.6 mmol) was added; then H2O2 (50% aq., 2 mL) was added dropwise (gas evolved). The mixture was stirred at 80° C. for 15 min, cooled and was diluted with water, the resulting precipitate was collected by filtration, dried in vacuo to give (R)-tert-butyl 1-(4-carbamoyl-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-methoxypropan-2-ylcarbamate as solid.