Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([OH:27])=O)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH2:39][NH2:40])[CH:36]=[N:37][CH:38]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:34]=[C:35]([CH2:39][NH:40][C:25]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]=2[CH:22]([CH3:24])[CH3:23])=[O:27])[CH:36]=[N:37][CH:38]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Reactant: NCc1cncc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3cncc(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 150 mg, 0.41 mmol) in CH2Cl2 (25 ml) was added EDC (236 mg, 0.82 mmol) and DMAP (75 mg, 0.60 mmol), followed by (5-fluoropyridin-3-yl)methanamine (94 mg, 0.82 mmol). The crude material was purified by chromatography on silica gel (0→80% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:48]2[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reaction time: 18 h
Yield: 49.1 %

Procedure:
To a solution of 6-Chloro-nicotinic acid (3.00 g, 19.0 mmol) in 30 mL dimethylformamide was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (10.9 g, 20.9 mmol), 1-methylpiperazine (2.30 g, 22.1 mmol). and triethylamine (2.18 g, 21.5 mmol). After stirring for 18 hours, this was partitioned between ethyl acetate and water. The ethylacetate layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (elution with 3% methanol/dichloromethane) to yield (6-Chloro-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (2.50 g, 9.33 mmol).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH:6]([CH2:7][CH2:8][CH3:9])[C:5]2[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.[N+:16]([O-])([O-:18])=[O:17].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)(Cl)Cl>[O:15]=[S:2]1(=[O:1])[CH:6]([CH2:7][CH2:8][CH3:9])[C:5]2[C:10]([Cl:14])=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[C:4]=2[NH:3]1
Reactant: CCCC1c2c(Cl)cccc2NS1(=O)=O
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCC1c2c(Cl)ccc([N+](=O)[O-])c2NS1(=O)=O
Reaction time: 24 h
Yield: 17.8 %

Procedure:
1,3-dihydro-2,2-dioxo-4-chloro-3-propyl-2,1 -benzisothiazole (131 mg, 0.54 mmol) was dissolved in chloroform (30 ml) followed by the addition of ammonium nitrate (44 mg, 0.54 mmol) and trifluoroacetic anhydride (397 mg, 214.4 mmol). The mixture is allowed to stir. After 24 hours, the reaction mixture is diluted with chloroform and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (50% Ethyl acetate/Hexane) gave the desired product (28 mg, 20%). EI-MS m/z 289.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:8]=[C:7]([Cl:25])[N:6]=1)=[O:4]>C(O)C.Cl.O1CCOCC1>[ClH:25].[ClH:25].[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:8]=[C:7]([Cl:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)c1cc(NC2CCNCC2)nc(Cl)n1

Procedure:
A solution of 6-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-2-chloro-pyrimidine-4-carboxylic acid methyl ester (3.46 g, 9.34 mmol) in ethanol (50 mL) and 4 M HCl in dioxane (75 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 271.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Oc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccc(O)cc3C[C@@H]21
Yield: 18 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ol following a procedure analogous to that described in Example 1. Yield: 18% of theory; LC (method 1): tR=1.97 min; Mass spectrum (ESI+): m/z=334 [M+H]+.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8]I)=[O:2].[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C=O)C>[CH:1]([NH:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8][N:26]1[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[C:22]1=[O:32])=[O:2]
Reactant: O=CNCC(CCCI)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=CNCC(CCCN1C(=O)c2ccccc2C1=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A mixture of 5-formylamino-1-iodo-4,4-diphenylpentane (7 g) and potassium phthalimide (3.63 g) was stirred in DMF (40 ml) at room temperature for 3 hours. The reaction mixture was poured in ice-water and the syrup which separated out was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was washed with isopropyl ether to provide the title compound (5.2 g) as colorless powder.
Reaction SMILES: C(OP([CH:9]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)/[CH:29]=[C:9](\[CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)P(=O)(OCC)OCC
Reactant: O=Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1cccc(F)c1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 111.5 %

Procedure:
A solution of 4-tert-butyl 1-ethyl 2-(diethoxyphosphoryl)succinate (28.60 g) in tetrahydrofuran (70 ml) was added dropwise to a suspension of 60% oily sodium hydride (3.39 g) in tetrahydrofuran (100 ml) under ice-cooling during 20 minutes, the mixture was stirred at the same temperature for an hour. Next, a solution of 3-fluorobenzaldehyde (10.00 g) in tetrahydrofuran (30 ml) was added thereto and the mixture was stirred at room temperature for 3 hours. Ice-water was added to the reaction mixture under ice-cooling and it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over sodium sulfate and concentrated in vacuo to give 4-tert-butyl 1-ethyl(2E)-2-(3-fluorobenzylidene)succinate (27.7 g) as a crude yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].Cl>C(Cl)Cl>[C:12]([NH:16][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 4.0 g (16 mmol) 2-bromobenzenesulfonyl chloride in 75 mL methylene chloride at 0° C. was added 3.7 mL (35 mmol) tert-butylamine. The mixture was allowed to warm to RT and stir for 1 hour. The mixture was poured into aqueous 5% HCl and extracted three times with ether. The combined organic material was dried over MgSO4, was stripped of solvent in vacuo, then was recrystallized from hexane/acetone to give 3.19 g (70% yield) of the title compound. Rf 0.17 in 10% EtOAc/hexane, visualized by UV;
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:21]([OH:23])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1>[Pd]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:21]([OH:23])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Pd]
Product: O=C(O)[C@H](Cc1c[nH]cn1)NCC(O)C(O)C(O)C(O)CO

Procedure:
The manufacture took place from D-glucose and L-(-)-histidine using palladium/activated carbon (10%) as a catalyst and yielded a product having a melting point of 165° to 170° C. (decomposition).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14](O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]1=[O:21])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>O1CCOCC1.C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14]([Cl:23])[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc[nH]2)c2ccc(Cl)cc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccc[nH]2)c2ccc(Cl)cc21
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A suspension of 4.5 g of 1-acetyl-6-chloro-3-[1-hydroxy-1-(2-pyrrolyl)methylene]-2-indolinone and 3.4 g of phosphorus pentachloride in 50 ml of dioxane and 50 ml of toluene is stirred for 3 hours at 90° C. Then the solvent is distilled off and the residue is purified by chromatography on silica gel (eluant: toluene).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19]>>[CH:18]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]
Reactant: CC(=O)Nc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CC(C)N1CCNCC1
Product: CC(=O)Nc1ccc(-c2ccc(N3CCN(C(C)C)CC3)nn2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-acetylaminophenyl)pyridazine and 1-isopropylpiperazine.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28](I)[S:29][C:22]=12>CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=3)[S:29][C:22]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Clc1ccnc2cc(I)sc12
Solvent: CN(C)C=O
Product: Clc1ccnc2cc(-c3ccncc3)sc12
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Tereakis(triphenylphosphine)palladium (54 mg, 0.05 mmole) was added to a solution of 4-(tributylstannyl)pyridine (0.432 g, 1.17 mmole) and 7-chloro-2-iodothieno[3,2-b]pyridine (0.347 g, 1.17 mmole) in DMF (5 ml). The reaction mixture was stirred at reflux for 3 h, cooled to room temperature. The mixture was filtered, washed with CH2Cl2 and was partitioned between H2O (50 ml) and CH2Cl2 (2×50 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 30-60% EtOAc in hexane to give pale yellow color solid (0.103 g, 36%); 1H NMR (300 MHz, CDCl3) δ8.61 (1H, d, J=5.1 Hz), 7.95 (1H, s), 7.66 (2H, m), 7.44 (2H, m), 7.31 (1H, d, J=5.1 Hz); ESIMS (MH+): 481.10.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[CH:22]=[C:21]([CH:9]([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH2:10][CH2:11][NH:12][CH3:13])[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)NCCOC(CCN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCC(OCCNC(=O)OC)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.9 %

Procedure:
tert-butyl 3-(2-(methoxycarbonyl)aminoethoxy)-3-(3-chlorophenyl)propyl(methyl)carbamate (100 mg) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (8 mL). The reaction mixture was stirred at room temperature for 1 h, then concentrated in vacuo to afford methyl 2-(1-(3-chlorophenyl)-3-(methylamino)propoxy)ethylcarbamate (150 mg, 100%), was used for the next step without purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[ClH:15].[CH3:16]O>>[ClH:15].[ClH:15].[CH3:16][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@@H](CNCc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To 1N HCl/MeOH (50 mL) at 0° C. was added (S)-2-Amino-3-benzylamino-propanoic acid (0.5 g, 2.57 mmol). Reaction was stirred at room temperature overnight. Volatiles were removed to give the product 2-Amino-3-benzylamino-propanoic acid methyl ester dihydrochloride salt as a white solid (0.7 g, 97.5%). MS: m/z=209 M+1.
Reaction SMILES: CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[NH:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:22]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+].Cl.Cl[CH2:38][CH2:39][N:40]([CH3:42])[CH3:41]>O>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=3)[N:22]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45.5 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
In a 22 L 3 neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, drying tube and thermocouple charge DMSO (1385 mL) and 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (206.71 g, 0.5 mol, 1 eq). Heat the resulting suspension to 43-48° C. then add sodium hydroxide powder (50 g, 1.25 mol, 2.5 eq) in one portion. Stir the resulting suspension for 1 hour at 43-48° C. To this suspension add 2-chloro-N,N-dimethylethanamine hydrochloride (90 g, 0.625 mol, 1.25 eq). Stir the resulting suspension for 35-40 minutes. Cool the reaction mixture to 18-23° C. and add cold water (227.4 mL). Once water addition is complete, bring the reaction mixture temperature to 20-25° C., stir for 60-90 minutes and filter the suspension. Wash the solids with a mixture of DMSO (103.4 mL) and water (51.7 mL) two times. Wash the solids with water (2×517 mL) and dry solids on a filter with suction to afford the target compound (219.9 g, 87.5% yield) as a tan solid. 1H NMR (300 MHz, DMSO): 8.04-8.00 (m, 2H), 7.74 (s, 1H), 7.46 (t, J=9.9 Hz, 1H), 4.06-3.99 (m, 4H), 3.03-2.93 (m, 3H), 2.57 (t, J=6.3 Hz, 2H), 2.19 (s, 6H), 1.81-1.77 (m, 2H), 1.70-1.55 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2[CH3:23])[CH3:9])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[B:34](OC(C)C)([O:39]C(C)C)[O:35]C(C)C.[OH-].[Na+]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][N:10]([CH:8]([C:5]2[CH:4]=[C:3]([B:34]([OH:39])[OH:35])[C:2]([F:1])=[N:7][CH:6]=2)[CH3:9])[C@H:11]([CH3:23])[CH2:12]1)=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Yield: 73.4 %

Procedure:
To a 150-mL round-bottomed flask was added (3R)-tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (3.0 g, 9.28 mmol), and tetrahydrofuran (100 mL, 9.28 mmol). The solution was stirred at −78° C. and treated dropwise via syringe with butyllithium solution, 2.5 m in hexanes (4.08 mL, 10.20 mmol) (Aldrich). The solution was stirred at −78° C. for 1 hr and treated in one portion with triisopropyl borate (2.55 mL, 11.13 mmol) (Aldrich). The mixture was stirred at −78° C. for 1 hour. NaOH (1.0N (30 mL) was added and the solution was stirred at room temperature for 30 minutes. The aqueous layer was separated and the organic layer was extracted with additional NaOH (1.0N, 30 mL). The combined aqueous layer was carefully acidified with 5N HCl (12 mL) to a final pH of about 4 to 5. The reaction mixture was extracted with EtOAc (3×100 mL) and the organic extract was dried over sodium sulfate, filtered and concentrated under a vacuum to give 5-(1-((R)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (2.5 g, 6.81 mmol, 73.4% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][NH:6][CH2:7][CH:8]1[O:12][CH2:11][CH2:10][O:9]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][N:6]([CH2:7][CH:8]1[O:12][CH2:11][CH2:10][O:9]1)[C:30](=[O:31])[CH2:29][Cl:28])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOC(CNCC1OCCO1)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CN(CC1OCCO1)C(=O)CCl)OCC

Procedure:
N-(2,2-Diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine (4 grams), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to a temperature of 5° to 10° C and chloroacetyl chloride (1.5 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1.[NH2:57][C@@H:58]1[CH2:63][CH2:62][CH2:61][N:60]([C:64]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[O:65])[CH2:59]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:57][C@@H:58]3[CH2:63][CH2:62][CH2:61][N:60]([C:64]([O:66][CH2:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[O:65])[CH2:59]3)=[O:36])[CH:33]=2)[N:28]([C:38]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (3.1 mmol) was added to a suspension of 3-bromo-1-trityl-1H-indazole-5-carboxylic acid (1 g, 2.07 mmol) in DMF (5 mL) and was stirred at room temperature for 15 minutes. A solution of (R)-benzyl 3-aminopiperidine-1-carboxylate (500 mg, 2.13 mmol) in DMF (5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.72 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:36])[C@@H:12]([NH:28]C(OC(C)(C)C)=O)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:9][C:2]([NH:10][C:11](=[O:36])[C@@H:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)NC(C)(C)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To 2.18 g of (2S)-N-(α,α-dimethylbenzyl)-2-(t-butoxycarbonylamino)-6-benzyloxycarbonylaminohexanamide (prepared as described in Preparation 8) were added 0.47 g of anisole and 10 ml of trifluoroacetic acid, and the solution was stirred for 30 minutes at room temperature. At the end of this time, the excess trifluoroacetic acid was distilled off under reduced pressure. A 5% w/v aqueous solution of sodium bicarbonate was added to the residue, and the mixture was neutralized and then extracted with ethyl acetate. The organic layer was extracted with a 10% w/v aqueous solution of citric acid. The aqueous extract was separated and neutralized with a 5% w/v aqueous solution of sodium bicarbonate and then extracted again with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 1.01 g of the title compound was obtained as an amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH2:25]O)[CH:22]=[C:21]([Cl:27])[C:3]=1[C:4]([N:6]1[C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[C:9]=2[CH:8]=[CH:7]1)=[O:5].P(Br)(Br)[Br:29]>ClCCl>[Br:29][CH2:25][C:23]1[CH:24]=[C:2]([Cl:1])[C:3]([C:4]([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[C:9]=3[CH:8]=[CH:7]2)=[O:5])=[C:21]([Cl:27])[CH:22]=1
Reactant: O=C(Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(CO)cc1Cl)C1CC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: O=C(Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(CBr)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-{1-[2,6-dichloro-4-(hydroxymethyl)benzoyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}cyclopropanecarboxamide (0.37 mmol) in dichloromethane was cooled to 0° C. and was treated dropwise with phosphorous tribromide (0.74 mmol). The reaction mixture was then stirred at room temperature for about 2 hours, diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to get N-{1-[4-(bromomethyl)-2,6-dichlorobenzoyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}cyclopropanecarboxamide as white solid.