Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Br:8].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Br:8])[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1Br
Yield: 85 %

Procedure:
3-Fluoro-4-bromotoluene (ex. Fluorochem) (24.9 g) in tetrachloromethane was reacted with N-bromosuccinimide (23.5 g) in the presence of benzoyl peroxide and light to give 3-fluoro-4-bromobenzyl bromide (30 g). The bromide was treated with sodium and diethyl malonate as in example 6, subsequent acid hydrolysis afforded 3-(3-fluoro-4-bromophenyl) propanoic acid (10 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[OH:34])[CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[C:20]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.N1CCCN2CCCCCC=12.[C:65]([O:68][CH2:69][CH2:70][CH2:71][S:72]([NH2:75])(=[O:74])=[O:73])(=[O:67])[CH3:66]>CN(C)C=O>[C:65]([O:68][CH2:69][CH2:70][CH2:71][S:72]([NH:75][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:32][C@@H:33]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[OH:34])=[CH:17][CH:16]=2)=[CH:19][C:20]=1[O:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[O:26])(=[O:73])=[O:74])(=[O:67])[CH3:66]
Reactant: CC(C)COc1cc(-c2ccc(NCCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Reactant: CC(=O)OCCCS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(NCCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1OCC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.4 %

Procedure:
To a solution of 4′-[[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-3-isobutoxy-4-biphenylcarboxylic acid (60.0 mg) in N,N-dimethylformamide (0.450 ml) was added 1,1′-carbonylbis-1H-imidazole (18.3 mg) and the mixture was stirred at room temperature for 1.5 hours under nitrogen atmosphere. To the mixture were added 2,3,4,6,7,8,9,10-octahydropyrimido-[1,2-a]azepine (0.0185 ml) and a solution of 3-(aminosulfonyl)propyl acetate (22.4 mg) in N,N-dimethylformamide (0.300 ml) and the mixture was stirred at room temperature for 2 days. The reaction mixture was warmed to 120° C. and stirred at the same temperature for 2 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation gave the crude product which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3 to 1/1) to give 3-[[[[4′-[[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-3-isobutoxy-4-biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (34.1 mg) as a yellow paste.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([C@@H:13]1[NH:17][C:16](=[O:18])[CH2:15][C@@:14]1([OH:20])[CH3:19])[CH3:12].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:4]1[CH:3]=[C:2]([N:17]2[C:16](=[O:18])[CH2:15][C@@:14]([OH:20])([CH3:19])[C@@H:13]2[CH2:11][CH3:12])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CC[C@@H]1NC(=O)C[C@]1(C)O
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C[C@]1(C)O

Procedure:
Using 4-bromo-2-chlorobenzonitrile (459 mg), (4S,5S)-5-ethyl-4-hydroxy-4-methylpyrrolidin-2-one (350 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (180 mg), tris(dibenzylideneacetone)dipalladium(0) (93 mg) and cesium carbonate (929 mg), and in the same manner as in Example 62, the title compound was obtained as colorless crystals (yield: 318 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[O:31])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: CN(C)CCN
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with N1,N1-dimethylethane-1,2-diamine, HATU and DIPEA in THF to give 334 as a colorless solid after reverse phase HPLC. MS: (ESI+) 555.2
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:2].C1COCC1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>C(Cl)Cl>[OH:2][CH:1]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(O)c2ccccc2)c2ccccn2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (0.400 mg, 1.63 mmol) in 30 mL 1:1 THF:CH2Cl2 at −20° C. was added phenylmagnesium bromide (0.979 mL, 1.96 mmol, 2.0 M in THF) dropwise. The reaction was allowed to warm to rt. After 30 minutes, saturated aqueous ammonium chloride was added, and the mixture was filtered and concentrated to provide crude ethyl 1-[hydroxy(phenyl)methyl]-4-oxo-4H-quinolizine-3-carboxylate as a yellow solid. To a solution of the resultant residue (115 mg, 0.356 mmol) in 4 mL 1:2:1 DMSO:MeOH:H2O was added sodium hydroxide (0.100 g, 2.50 mmoL). The reaction was heated to 60° C. for 1 h, cooled to rt, and subjected to purification via reverse phase HPLC to yield the title compound that gave a mass ion (ES+) of 296.2 for M+H+.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[C:8]([C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[N+:22]=[N-:23])=[CH:18][C:17]=1[CH3:26])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(C1C=CC(C)=CC=1CN=[N+]=[N-])(=O)C1C=CC=CC=1>C(O)C>[NH2:3][C:2]1[N:21]([CH2:20][C:19]2[CH:24]=[CH:25][C:16]([C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:17]([CH3:26])[CH:18]=2)[N:22]=[N:23][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: Cc1cc(CN=[N+]=[N-])ccc1C(=O)c1ccccc1
Reactant: N#CCC(N)=O
Agent: Cc1ccc(C(=O)c2ccccc2)c(CN=[N+]=[N-])c1
Agent: [Na]
Solvent: CCO
Product: Cc1cc(Cn2nnc(C(N)=O)c2N)ccc1C(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 31 %

Procedure:
A stirred solution of sodium (104 mg, 4.50 mmol) in absolute ethanol at 60° C. was treated with 2-cyanoacetamide (378 mg, 4.50 mmol), kept 5 min, and treated with a solution of 942 mg of a 4:1 mixture of 4-benzoyl-3-methyl-benzyl azide and 2-benzoyl-5-methylbenzyl azide in absolute ethanol (6 ml). The mixture was refluxed 1 hour, cooled to 0° , and filtered. The solid was washed twice with water, acidified with acetic acid, and dried. The ethanol filtrate was acidified with acetic acid and evaporated to dryness at 40° C. under vacuum. The residue from the filtrate was combined with the above solid and chromatographed on a column of silica gel (125 g) eluted in 17 ml fractions with 19:1 (v/v) dichloromethane-methanol. Fractions 19-25 were combined and evaporated to dryness, and the residue was triturated with diethyl ether (3×10 ml). The remaining solid was dried 18 hours at ambient temperature under vacuum to provide 330 mg (31%) 5-amino-1-(4-benzoyl-3-methylbenzyl)-1,2,3-triazole4-carboxamide, m.p. 181°-182° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:12]#[N:13].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH2:8][C:12]#[N:13])[CH:7]=1
Reactant: N#Cc1ncc(CCl)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cnc(C#N)c(Cl)c1
Temperature: 130 °C

Procedure:
To a solution of 3-chloro-5-(chloromethyl)picolinonitrile (from the previous step) in DMSO (0.2 M) was added sodium cyanide (1.25 eq). The reaction mixture was heated at 130° C. under microwave irradiation. The reaction mixture taken up in water and EtOAc, and extracted with EtOAc. Organic phases were dried over anhydrous Na2SO4, and concentrated. Flash chromatography (silica gel, 20-50% EtOAc in hexanes) of the crude afforded 3-chloro-5-(cyanomethyl)picolinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:39][CH2:38][C:37]4[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:42])[F:43])=[CH:41][CH:40]=4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(trifluoromethyl)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=604.92 (M+H+); retention time=1.01 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([C:17](=[O:25])[NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[C:27]([O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2([C:17](=[O:25])[NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16][CH2:15][N:14]([C:36](=[O:37])[C@@H:35]([NH:34][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])[CH2:39][C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)[CH2:13][CH2:12]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: COC(=O)c1ccc(CC2(C(=O)NC3CCCCC3)CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)[C@H](Cc3cccs3)NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-cyclohexylcarbamoyl-piperidin-4-ylmethyl)-benzoic acid methyl ester (3.32 mmol; 1.19 g) in DMF (50 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (3.32 mmol; 0.90 g), N,N-diisopropyl-N-ethylamine (6.64 mmol; 1.18 mL) and HBTU (4.32 mmol; 1.64 g), and the resulting mixture was stirred at room temperature overnight. Ethyl acetate (150 mL) was added, and the resulting solution was washed with a 1H hydrochloric acid solution (2×50 mL), and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated. The residue was purified via flash column chromatography (eluent gradient: 0 to 10% methanol in dichloromethane) and the desired fractions were combined and evaporated to yield 4-[1-(2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl)-4-cyclohexylcarbamoyl-piperidin-4-ylmethyl]-benzoic acid methyl ester. MS (ESI) m/z 612.13 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:38]([N:40]1[CH2:45][CH2:44][N:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1)[CH3:39]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:50][CH2:51][CH:46]([N:43]4[CH2:44][CH2:45][N:40]([CH2:38][CH3:39])[CH2:41][CH2:42]4)[CH2:47][CH2:48]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCN1CCN(C2CCNCC2)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCN(CC)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-ethyl-4-piperidin-4-yl-piperazine (Matrix) to give the title compound. HR-MS (ES, m/z) calculated for C40H53Cl2N6O2 [(M+H)+] 719.3602, observed 719.3606.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@@H:24]([OH:25])[C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CCOC(=O)c1ccc([C@H](O)c2c(C(C)C)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and ethyl 4-iodobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:22](=[O:23])[C:11]3=[CH:12][NH:13][C:14]([CH3:21])=[C:15]([CH2:16][CH2:17][CH2:18][C:19]#[N:20])[C:10]3=[N:9]2)=[CH:4][CH:3]=1.CO[CH:26](OC)[CH2:27][NH2:28]>CS(C)=O.[Cu]Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:22](=[O:23])[C:11]3=[CH:12][NH:13][C:14]([CH3:21])=[C:15]([CH2:16][CH2:17][CH2:18][C:19]4[NH:28][CH:27]=[CH:26][N:20]=4)[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1CCCC#N
Reactant: COC(CN)OC
Agent: Cl[Cu]
Solvent: CS(C)=O
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1CCCc1ncc[nH]1
Temperature: 100 °C
Yield: 8.2 %

Procedure:
To a solution of the product of Example 107 (0.131 g, 0.4 mmol) and aminoacetaldehyde dimethylacetal (43 μl, 0.4 mmol) in DMSO (1 ml) was added copper(I) chloride (0.04 g, 0.4 mmol) and the mixture heated at 100° C. for 120 hours. The solvent was removed in vacuo and the residue suspended in formic acid (10 ml) and heated at 70° C. for 18 hours. The reaction was filtered and the solvent evaporated from the filtrate in vacuo. The crude product was purified by flash chromatography (silica gel, 6-10% MeOH/CH2Cl2) to give the title compound as a yellow solid (0.012 g, 8.1%). 1H NMR (360 MHz, CD3OD) δ8.34 (1H, s), 8.02 (2H, d, J 8.7 Hz), 7.42 (2H, d, J8.7 Hz), 7.11 (2H, br s), 2.99 (2H, br s), 2.80 (2H, br s), 2.40 (3H, s), 2.05 (2H, br s); MS (ES+) m/z 368/370 [MH]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([C:30](=[N:32]O)[NH2:31])[CH:29]=1.CCN(C(C)C)C(C)C>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([C:30]2[N:31]=[C:11]([C:10]3[CH:14]=[CH:15][C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[C:8]([CH3:7])[CH:9]=3)[O:13][N:32]=2)[CH:29]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCOCC3)c(C)c2)n1

Procedure:
Oxalyl chloride (138 μL; 1.63 mmol; 3 eq.), Intermediate 35 (120 mg; 0.54 mmol; 1 eq.), Intermediate 23 (100 mg; 0.54 mmol, 1 eq.) and DIEA (280 μL; 1.63 mmol; 3 eq.) were reacted according to general procedure 2. Purification by precipitation from DCM/c-hexane afforded the title compound as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>C(O)C>[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:34][CH:33]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Oc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (25.0 mg, 0.0464 mM), then 4-hydroxy-benzaldehyde (6.2 mg, 0.051 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (19.2 mg, yield: quantitative).
Reaction SMILES: [CH3:1][S:2](NC1C=CC=CC=1N1CCN(C(OC(C)(C)C)=O)CC1)(=[O:4])=[O:3].[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]1[CH2:47][CH2:46][N:45]([C:48](=[O:78])[C@H:49]([NH:58][C:59]([C@@H:61]2[CH2:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH2:63][N:62]2[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])=[O:60])[CH2:50][C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)[CH2:44][CH2:43]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CS(Cl)(=O)=O.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)CCl>[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][N:35]([S:2]([CH3:1])(=[O:4])=[O:3])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]1[CH2:43][CH2:44][N:45]([C:48](=[O:78])[C@H:49]([NH:58][C:59]([C@@H:61]2[CH2:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH2:63][N:62]2[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])=[O:60])[CH2:50][C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)[CH2:46][CH2:47]1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCN(c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1)S(C)(=O)=O

Procedure:
tert-Butyl 3-[N-((1R)-2-{4-[2-({2-[(tert-butoxy)carbonylamino]ethyl}(methylsulfonyl)amino)phenyl]piperazinyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)-carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared according to the procedure for Preparation III using tert-butyl 3-[N-((1R)-2-{4-[2-({2-[(tert-butoxy) carbonylamino]ethyl}amino)phenyl]piperazinyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step 1) (370 mg, 0.45 mmol), methanesulfonyl chloride (41 μl, 0.530 mmol), pyridine (40 μl, 0.495 mmol), DMAP (cat.), and ClCH2CH2Cl (15 mL). The crude material was purified by flash chromatography, (SiO2, 1:1 hexane:EtOAc) to afford the desired material (155 mg). MS (ESI, pos. ion) m/z: 839 (M+H), (ESI, neg. ion) m/z: 837 (M−H). Calc'd for C42H55ClN6O8S: 839.44.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([NH:28][OH:29])=[O:27])=[CH:24][CH:25]=1)=[O:15])[CH3:3].C(O)(C)C.O.O.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>O>[CH3:3][N:2]([CH2:4][C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([NH:28][OH:29])=[O:27])=[CH:24][CH:25]=1)=[O:15])[CH3:1].[S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=1)([O-:45])(=[O:44])=[O:43]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CN(C)Cc1c(C(=O)NCCOc2ccc(C(=O)NO)cc2)oc2ccccc12
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 75 °C

Procedure:
1.66 kg of abexinostat (free base) are placed in 9.48 kg of a mixture of isopropanol/water (50/50 weight/weight) at ambient temperature. para-Toluenesulphonic acid monohydrate (0.83 kg) in 2.36 kg of water is added at ambient temperature. The mixture is then heated at 75° C. for 30 minutes before being cooled to 0° C. When crystallisation is complete, the suspension is filtered at 20° C. After drying, crystalline form I of abexinostat tosylate is obtained in a yield of about 85% and with a purity greater than 99%. The solid was characterised by the X-ray powder diffraction diagram, Raman spectrum and NMR spectrum as set out in Examples 3-5 and 6 hereinbelow.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[N:29][CH:28]=1.C(Cl)CCl.C(N(CC)CC)C.FC(F)(F)C(O)=O>CN(C=O)C.COCCOC>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)=[O:34])=[CH:7][CH:6]=1)(=[O:9])=[O:10]
Reactant: O=C(O)c1cncnc1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1)c1cncnc1
Reaction time: 16 h

Procedure:
To a solution of the compound of Step 2 (0.1 g, 0.244 mmol), pyrimidin-5-carboxylic acid (0.03 g, 0.244 mmol) HOAT (0.033 g, 0.244 mmol) and EDC (0.047 g, 0.244 mmol) in DMF (1 mL) at room temperature was added triethylamine (0.068 mL, 0.489 mmol). After 18 hr pyrimidin-5-carboxylic acid (0.03 g, 0.244 mmol) HOAT (0.033 g, 0.244 mmol), EDC (0.047 g, 0.244 mmol) and triethylamine (0.068 mL, 0.489 mmol) were added. The reaction mixture was stirred for a further 16 hr, diluted with DME (2 mL), treated with trifluoroacetic acid, and purified directly by reverse phase HPLC waters Prepak C-18 column eluting with 5-95% CH3CN: water containing 0.1% TPA. The pure fractions were combined and lyophilized to afford the title compound. C23H16Cl2N4O4S MH+ requires 515.0342 found 515.0349. Proton NMR (400 MHz, CDCl3) δ 6.53 (d, J=8.8 Hz, 1H), 6.62 (d, J=8.2 Hz), 7.00-7.10 (m, 3H), 7.14 (t, J=7.8 Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.64(d, J=8.6 Hz, 2H), 7.70-7.80 (m, 3H), 8.03(s, 1H), 9.28 (s, 2H), 9.43 (s, 1H).