Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:18])=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Cl)ccc2c1cnn2Cc1ccccc1
Reaction time: 4 h
Yield: 37.7 %

Procedure:
A solution of 1-benzyl-1H-indazol-4-amine (0.080 g, 0.36 mmol) in DMF (2 mL) was treated with N-chlorosuccinimide (0.053 g, 0.39 mmol) at ambient temperature and stirred for 4 hours. The mixture was diluted with water, extracted with EtOAc, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (10-50% EtOAc in hexanes) to provide 1-benzyl-5-chloro-1H-indazol-4-amine (0.035 g, 38% yield).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH3:26])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:27](O)C.CC[O-].[Na+].CCO>O>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCO
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
Methyl [1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate (Example 85) (0.10 g) was dissolved in, absolute ethanol (10 mL and a catalytic amount of 21% NaOEt/EtOH was added. The reaction was stirred without temperature control for 72 hours, then water (10 mL) was added. The product crystallized, the suspension was cooled to 0° C. and held for 30 minutes. The product was filtered, washed with water (5 mL) and dried to yield 0.071 g (70%) of a white solid: Mass Spectrum: MH+=406. Anal. Calc'd for C18H16N3O4ClS: C, 53.27; H, 3.97; N, 10.3; Cl, 8.74; S, 7.90. Found: C, 53.04; H, 4.00; N, 10.27; Cl, 8.609; S, 7.97.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=O)=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.ClCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([Cl:15])=[O:11])=[CH:4][N:3]=1
Reactant: Cc1nc(Cl)ncc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: ClCl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)ncc1C(=O)Cl
Yield: 61.3 %

Procedure:
A solution of 2-chloro-4-methylpyrimidine-5-carboxylic acid (0.81 g, 4.70 mmol), oxalyl chloride (0.89 g, 7.05 mmol), DMF (2 drops) in CH2 Cl2 (23 mL) was stirred at room temperature under N2 for 4 h. The solution was concentrated and distilled to give the title compound (0.55 g, 61%); b.p. 90°-100° C., 1.3 mm/Hg; 1HNMR (CDCl3) δ d 9.02 (s, 1H), 2.74 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[C:4]=1[CH3:13])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:13][C:4]1[C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=[CH:12][C:3]=1[CH:1]1[CH2:2][O:22]1
Reactant: C=Cc1ccc2c(c1C)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C2CO2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-ethenyl-4-methyl-2-benzofuran-1(3H)-one (1.46 g, 8.38 mmol) was added to DCM (25 mL) at 0° C. then m-CPBA (2.89 g, 16.8 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was washed once each with saturated aqueous Na2S2O3, NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The crude material was purified by MPLC chromatography through 120 g Redi-sep column eluting with 0-80% EtOAc/hexane solvent system to yield 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, CDCl3): 6 ppm 7.77 (d, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 5.30 (s, 2H), 4.12 (s, 1H), 3.27 (t, J=4 Hz, 1H), 2.735 (dd, J=2.2, 5.5 Hz, 1H), 2.43 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](Cl)=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][OH:31])[CH2:26][NH:27][CH3:28])[CH:21]=[CH:22][C:23]=1[Cl:24]>>[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][OH:31])[CH2:26][N:27]([CH3:28])[C:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:15])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CNC[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2ccccc12
Product: CN(C[C@@H](CCO)c1ccc(Cl)c(Cl)c1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12

Procedure:
By the method of Example 3f, 3-nitro-1-naphthoyl chloride was reacted with (S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl-N-methylamine to give N-[(S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-nitro-1-naphthamide. This was reacted by the method of Example 3g to give the title compound: 1H NMR (300 MHz, CDCl3) δ 9.65 (s), 9.44 (s), 9.07-9.02 (m), 8.38-6.04 (m), 4.44-1.18 (m); MS APCI, m/z=445 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1.[CH:30]1(/[CH:33]=[CH:34]/[C:35]#[N:36])[CH2:32][CH2:31]1>>[C:35]([CH2:34][CH:33]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:28])([F:27])[F:29])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1)[CH:30]1[CH2:32][CH2:31]1)#[N:36]
Reactant: N#C/C=C/C1CC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Product: N#CCC(C1CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 89, Step 2 starting from N-{3-[7-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and (2E)-3-cyclopropylacrylonitrile. LCMS (M+H)+: m/z=495.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(OCC)C.C([Mg]Br)C=C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[C:37]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:36]=[CH:35][C:34]=2[C:44]2[O:45][C:46](=[O:54])[C:47]3[CH:53]=[CH:52][N:51]=[CH:50][C:48]=3[N:49]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[C:37]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43]3)[CH:36]=[CH:35][C:34]=2[C:44]([NH:49][C:48]2[CH:50]=[N:51][CH:52]=[CH:53][C:47]=2[C:46]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[O:54])=[O:45])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3cnccc3c(=O)o2)CC1
Agent: C=CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A solution of 2-amino-5-chloropyridine (52 mg, 0.4 mmol) in THF (10 mL) was cooled to 0° C. and treated with a 1 M diethyl ether solution of allylmagnesium bromide (0.4 mL). The mixture was stirred for 5 minutes before adding 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-one (100 mg, 0.2 mmol). The reaction mixture was stirred overnight at ambient temperature then concentrated to dryness under vacuum. The residue was treated with brine (5 mL) and CHCl3 (20 mL). The layers were separated and the organic layer was chromatographed using 1% MeOH in CHCl3 to give 125 mg (0.2 mmol, 99%) of product as a solid.
Reaction SMILES: [C:1]1([CH:7]2[N:12]3[C:13](=[O:19])[NH:14][C:15]4=[CH:16][CH:17]=[CH:18][C:10](=[C:11]34)[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>CC(O)=O>[Br:20][C:18]1[C:10]2[O:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:12]3[C:13](=[O:19])[NH:14][C:15]([C:11]=23)=[CH:16][CH:17]=1
Reactant: O=c1[nH]c2cccc3c2n1C(c1ccccc1)CO3
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccc1)CO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A mixture of 4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (400 mg, 2 mmol) and N-bromosuccinimide (310 mg, 1.7 mmol) in AcOH (10 mL) was stirred at room temperature for 2 h. The reaction mixture was allowed to cool and was concentrated to remove AcOH. The residue was taken up in EtOAc and was washed with water saturated NaHCO3, brine, dried over magnesium sulfate, filtered and concentrated to give crude product. The product was purified by flash column chromatography on a Biotage system eluting with a hexane: EtOAc gradient (0-40%) to give 7-bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as an amber oil (0.30 g, 60%). LCMS calc. for C15H12BrN2O2 (M+H)+: m/z=331.1, 333.1. found: 331.0, 333.0. 1H NMR (300 MHz, CD3OD) δ 7.42-7.23 (m, 3H), 7.23-7.09 (m, 3H), 6.70 (d, J=8.4 Hz, 1H), 5.46 (dd, J=2.6 Hz, 1H), 4.66 (dd, J=11.6, 2.4 Hz, 1H), 4.47 (dd, J=11.6, 3.1 Hz, 1H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.Cl[C:20]([CH3:24])([CH3:23])[C:21]#[CH:22]>O.C1COCC1.[Cu]>[CH3:23][C:20]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])([CH3:24])[C:21]#[CH:22]
Reactant: C#CC(C)(C)Cl
Reactant: COC(=O)c1ccccc1N
Agent: [Cu]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C#CC(C)(C)Nc1ccccc1C(=O)OC
Temperature: 65 °C

Procedure:
To a solution of methyl anthranilate (5.54 g, 36.6 mmol), triethylamine (3.48 g, 34.5 mmol), cuprous chloride (0.21 g, 2.15 mmol), copper powder (0.163 g, 2.56 mmol) in H2O (4 mL) and THF (14 mL) was added 3-chloro-3-methyl-1-butyne (2.21 g, 21.6 mmol). After heating to 65° C. for 4 h the reaction was cooled, diluted with water and extracted using diethyl ether (three times). The combined organic layers were washed with water, dried using MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (5% EtOAc/hexanes-10% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[C:8]2[C:16]1[N:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1.[CH3:35][O:36][CH2:37][CH2:38]Br.O>CN(C)C=O.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:38][CH2:37][O:36][CH3:35])[CH:9]=[C:8]2[C:16]1[N:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1
Reactant: COCCBr
Reactant: COc1cc2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(-c2cc3cccnc3n2S(=O)(=O)c2ccc(C)cc2)c2cc(OC)c(OC)cc21
Reaction time: 16 h

Procedure:
0.01 g of sodium hydride (60%) is added to a solution of 0.1 g of 2-[5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 2.5 ml of anhydrous dimethylformamide, under an inert argon atmosphere at a temperature in the region of 20° C. Agitation is maintained at this temperature for 30 minutes. 0.023 ml of bromoethyl methyl ether is added. The reaction medium is agitated at the same temperature for 16 hours. 3 ml of water and 3 ml of ethyl acetate are added. After separation by settling out, the organic phase is dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a flash-pack chromatography cartridge (silica, dichloromethane as eluent). The fractions containing the product are concentrated under reduced pressure. 0.082 g of 2-[5,6-dimethoxy-1-(2-methoxyethyl)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][CH2:16][CH2:15]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[C:20]([F:21])[CH:19]=3)[CH2:15][CH2:16]2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: Fc1cc2c(cc1F)NCC2
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccnc(Cl)c1)N1CCc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.35 g (2.2 mmol) 2-chloroisonicotinic acid, 0.34 g (2.2 mmol) 5,6-difluoro-2,3-dihydro-1 H-indole, 0.70 mL (5.0 mmol) TEA and 10 mL DMF were mixed with 0.77 g (2.4 mmol) TBTU and stirred for 2 h at RT. The reaction mixture was purified by HPLC. The product fractions were combined and evaporated down.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([CH2:24][CH2:25]Cl)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:24][CH2:25][O:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8](=[O:18])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Reactant: ClCCN1CCCC1
Product: O=c1oc2ccccc2c(OCCN2CCCC2)c1-c1ccccc1
Yield: 46 %

Procedure:
In accordance with Example 1, 10 g. (0.042 mol) of 3-phenyl-4-hydroxy-coumarin are caused to react with 9.3 g. (0.055 mol) of 2-pyrrolidino-1-chlorethane. After evaporation of the methyl isobutyl ketone, the pasty residue is taken up under heat in 150 ml. of a 5% solution of sodium bicarbonate, this being followed by cooling and extraction with chloroform. The substance obtained is dried over Na2SO4 and the chloroform is evaporated under vacuum. A brown oil is obtained. Weight 6.5 g.; yield 46% (theoretical yield 14.1 g.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].F[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[S:19]([OH:21])=[O:20].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[S:19]([OH:21])=[O:20]
Reactant: O=C(O)c1ccc(F)c(S(=O)O)c1
Reactant: Sc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(Sc2ccccc2Br)c(S(=O)O)c1
Temperature: 140 °C

Procedure:
2-Bromobenzenethiol (25 g, 132 mmol) was added to a solution of 4-fluoro-3-sulfino-benzoic acid (13.5 g, 66 mmol) and NaOH pellets (11 g, 264 mmol) in water (30 ml). The yellow mixture was then degassed for 10 minutes and then heated to 140° C. for 48 hours. The reaction was then cooled to 0° C. and acidified to pH 4-5 (pH paper) with concentrated HCl. The precipitate formed was filtered, washed with hexane and was dried in a vacuum dessicator over activated silica overnight (20.69 g, 84%). m/z (LC-MS, ESP), RT=3.67 min, M−−1)=373.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40][CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][N:38]4[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40][CH2:39]4)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[O:7])=[CH:32][CH:33]=1
Reactant: CC(C)C(=O)N[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: CC(C)(O)C1CCNCC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)C(=O)N[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (75 mg, 0.166 mmol) in DCM (5 mL) was added thionyl chloride (0.060 mL, 0.829 mmol) dropwise. The resulting mixture was stirred at 0° C. for 30 minutes. After 30 minutes, the solvent was removed, and the residue was suspended in ACN (5 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in ACN (3 mL), cooled to 0° C., and 2-(piperidin-4-yl)propan-2-ol (95 mg, 0.663 mmol) was added. The reaction was stirred overnight at RT. After 16 hours, the reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH) in DCM to provide (E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a white powder (30 mg, 31.3% yield). MS, m/z (C33H44FN5O3): calcd, 577.3. found, 578.1 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[O:10][CH:11]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:44])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:5][CH:4]=1.[C:59]1(=[O:65])[O:64][C:62](=[O:63])[CH2:61][CH2:60]1>>[CH3:58][O:57][C:54]1[CH:53]=[CH:52][C:51]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:12]2[N:13]([C:18](=[O:44])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:14][CH:15]([O:17][C:59](=[O:65])[CH2:60][CH2:61][C:62]([OH:64])=[O:63])[CH2:16]2)=[CH:56][CH:55]=1
Reactant: CCCCCCCCC=CCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Reactant: O=C1CCC(=O)O1
Product: CCCCCCCCC=CCCCCCCCC(=O)NCCCCCC(=O)N1CC(OC(=O)CCC(=O)O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above described procedure, the amide 102f (2.4 g, 3 mmol) was treated with succinic anhydride and after work-up the amide was isolated as a foam (2.8 g, 99%) and this was used in the next step without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1)[CH2:5][OH:6].[OH-].[K+].[C:16](=O)(OC(Cl)(Cl)Cl)[O:17]C(Cl)(Cl)Cl.[OH-].[Na+]>O.C(OCC)(=O)C.C1COCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:4]2[CH2:5][O:6][C:16](=[O:17])[NH:3]2)=[N:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@H](CO)c1ccc(F)cn1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1N[C@@H](c2ccc(F)cn2)CO1
Yield: 55.8 %

Procedure:
To the solution of (S)-2-amino-2-(5-fluoropyridin-2-yl)ethanol bis-hydrochloride (9.8 g, 43 mmol) in water (200 mL) cooled to 0° C. was added potassium hydroxide (24 g, 430 mmol) followed by THF (200 mL) and the reaction stirred until the temperature reached 0° C. To the reaction was added bis(trichloromethyl) carbonate (13 g, 43 mmol) (in THF, 200 mL) dropwise such that the internal temperature did not exceed 7° C., and the reaction was stirred for 2 hours. The reaction was diluted with ethyl acetate and the aqueous layer made basic with NaOH (1M). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed using a gradient of 50% DCM/EtOAc to EtOAc as eluent to yield (S)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (4.3 g, 24 mmol, 55% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1([CH3:23])[CH2:16][NH:15][CH2:14][CH2:13][N:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:15]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:23])([CH3:10])[CH2:16]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)CNCCN1c1ccccc1
Reactant: Clc1nccc(I)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)CN(c2ccnc(Cl)c2Cl)CCN1c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of D10 (1.083 g, 3.955 mmol), 2,2-dimethyl-1-phenylpiperazine (0.903 g, 4.745 mmol) [C.A.S. 2946-75-0] and DIPEA (1.378 ml, 7.909 mmol) in CH3CN (15 ml) was heated in a sealed tube at 100° C. for 5 days. After cooling, the solvent was concentrated in vacuo. The residue was purified by column chromatography (silica gel; Heptane/EtOAc 100/10 to 80/20 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D55 (0.56 g, 42%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].N12CCCN=C1CCCCC2>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:31](=[O:32])[N:30]([CH3:34])[CH3:29])[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Triethylamine (0.6 g, 5.9 mmol) was added slowly to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and dimethylcarbamoyl chloride (0.3 g, 3.2 mmol) in THF (100 mL). The mixture was stirred at room temperature overnight. Another portion of dimethylcarbamoyl chloride (0.3 g) and 1,8-diazabicyclo[5,4,0]-undec-7-ene (0.6 g) was added and stirred for another day. The mixture was concentrated, and the residue was stirred with 1N HCl (15 mL). The mixture was filtered, and the solid was slurried with hot methanol (10 mL) to give 3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1,1-dimethyl-urea (0.3 g, 46%) as a white solid: mp 169-171° C.; 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H), 2.32-2.64 (m, 2H), 2.80 (s, 6H, 2CH3), 2.85-3.00 (m, 1H), 4.27 (d, J=5.6 Hz, 2H, CH2), 4.40 (d, J=17.3 Hz, 1H), 4.47 (d, J=17.3 Hz, 1H), 5.10-5.17 (dd, J=5.0 and 13.2 Hz, 1H, CH), 6.94 (t, J=5.6 Hz, 1H, NH), 7.44-7.64 (m, 3H, Ar), 11.02 (s, 1H); 13C NMR (DMSO-d6) δ 22.58, 31.18, 35.88, 46.20, 51.55, 121.20, 128.08, 130.38, 131.39, 136.35, 139.77, 158.08, 168.15, 171.00, 172.83; Anal. calcd. for C17H20N4O4: C, 59.29; H, 5.85; N, 16.27. Found: C, 59.05; H, 5.91; N, 15.92.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][N:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[N:26]1>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:29]2[N:25]([CH3:24])[N:26]=[CH:27][CH:28]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: Cn1nccc1-c1ccc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)sc2n1
Yield: 4 %

Procedure:
The titled compound (yield=4%) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 4.20 (s, 3H) 6.86 (d, J=1.26 Hz, 1H) 7.52 (d, J=1.26 Hz, 1H) 7.67 (d, J=8.08 Hz, 2H) 7.92 (d, J=8.59 Hz, 1H) 8.11 (d, J=8.34 Hz, 2H) 8.23 (d, J=8.34 Hz, 1H) 13.03 (s, 1H);); ESI-MS: m/z 394.0 (M+H)+.