Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[C:19]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)([C:28]#[N:29])[CH:18]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:17]3)=[O:15])=[N:9]2)[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:19]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([C:28]#[N:29])[CH:18]([CH2:37][C:38]([CH3:39])([CH3:40])[CH3:41])[NH:17]2)=[O:15])=[N:9]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(C[C@@H](O)CO)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (81 mg, 0.133 mmol), pyridinium p-toluene sulfonic acid (5 mg, 0.0198 mmol) and methanol (4 mL) was microwaved at 120° C. for 5 min. Solvent evaporated and purified by reverse phase chromatography (20-95% of ACN/water) to rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (26.5 mg, 35%) as an off-white powder. HRMS (ES+) m/z Calcd for C29H33Cl2N5O3S+H [(M+H)+]: 570.2033. found: 570.2032.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][NH2:21].OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:21]([CH2:20][CH2:19][CH2:18][OH:17])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCCO
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, is reacted with 3-hydroxypropylamine under substantially similar conditions to those described under Example 9 for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one as white crystals, m.p. 111°-113° C.; νmax (nujol) 1630, 3150, 3350 cm-1, δ(d6DMSO) 1.8 (m, 2H), 2.4 (s, 3H, 3.35 (t, 2H), 4.33 (t, 2H), 7.3 (d, 1H), 8.2 (d, 1H).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[NH:28][C:29]3[C:34]([C:35]=2CCNCCCCC2C=CC(NS(C)(=O)=O)=CC=2)=CC(C(N2CCOCC2)=O)=CC=3)[CH:23]=[C:24]([CH3:26])[CH:25]=1>COCCO>[CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[NH:17][C:27]([C:22]1[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[CH:23]=1)=[C:35]2[CH2:34][CH2:29][NH2:28])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Reactant: CCCCn1ccnc1Cc1ccc(NN)cc1
Solvent: COCCO
Product: CCCCn1ccnc1Cc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Yield: 8.7 %

Procedure:
A solution of 350 mg (1.43 mmol) of (4-(1-butyl-1H-imidazol-2-ylmethyl)phenyl]hydrazine and 362 mg (1.72 mmol) of 3-chloropropyl 3,5-dimethylphenyl ketone (EXAMPLE 4) in 3 mL of 2-methoxyethanol was stirred at reflux under nitrogen for 3 hours. The solution was then cooled and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (elution with 95:5 CH2Cl2-MeOH followed by 95:5:0.5 CH2Cl2-MeOH-concd. NH4OH) gave 50 mg (9%) of material that was satisfactory for use in the next step.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Cl[C:61]1[N:68]=[CH:67][CH:66]=[CH:65][C:62]=1[C:63]#[N:64].CC1(C)C(C)(C)OB([C:77]2[CH:82]=[CH:81][C:80]([OH:83])=[CH:79][CH:78]=2)O1>>[OH:83][C:80]1[CH:81]=[CH:82][C:77]([C:61]2[N:68]=[CH:67][CH:66]=[CH:65][C:62]=2[C:63]#[N:64])=[CH:78][CH:79]=1
Reactant: N#Cc1cccnc1Cl
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: N#Cc1cccnc1-c1ccc(O)cc1

Procedure:
Compound 56A was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with 2-chloronicotinonitrile and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: ESI (+)/LC/MS: 197 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:14]=[N:15][C:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH3:20])[C:18]=2[CH3:19])[CH2:9][CH2:8]1)=O)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:48]>C(#N)C>[CH2:21]([C:16]1[N:15]=[N:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:5]3[NH:2][C:1]([Cl:48])=[CH:3][N:4]=3)[CH2:8][CH2:9]2)=[C:18]([CH3:19])[C:17]=1[CH3:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)NCC#N)CC2)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(c3ncc(Cl)[nH]3)CC2)c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid cyanomethyl-amide (20 mg, 0.055 mmol) and triphenyl phosphine in acetonitrile (1 mL) at 25° C. is added carbon tetrachloride (42 mg, 0.28 mmol). After being stirred at 50° C. for 3 h, the mixture is concentrated, and diluted with CH2Cl2 (10 mL) and washed with sodium hydroxide (2 mL, 1N), and H2O (2 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 3-benzyl-6-[4-(5-chloro-1H-imidazol-2-yl)-piperidin-1-yl]-4,5-dimethyl-pyridazine (11.8 mg, 56%).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][CH3:4].[Na].[O:8]1[CH:10]([CH2:11][CH3:12])[CH2:9]1.S(=O)(=O)(O)O>>[OH:5][CH:2]([CH2:3][CH3:4])[CH2:1][O:6][CH2:9][CH:10]([OH:8])[CH2:11][CH3:12]
Reactant: CCC1CO1
Reactant: CCC(O)CO
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CCC(O)COCC(O)CC
Temperature: 100 °C

Procedure:
A 500 ml, three neck, round bottom flask equipped with magnetic stirrer, internal thermometer, addition funnel, condenser, argon supply, and heating mantle, is flushed with argon. Then 1,2-butanediol (about 270 g, about 3 moles, Aldrich) is added and sodium metal (about 1.2 g, about 0.05 moles, Aldrich) is added and the sodium is allowed to dissolve. Then the reaction mixture is heated to about 100° C. and epoxybutane (about 71 g. about 1 mole, Aldrich) is added dropwise with stirring. Heating is continued until the reflux of epoxybutane has ceased and heating is continued for an additional hour to drive the conversion to completion. The reaction mixture is neutralized with sulfuric acid, the salts are removed by filtration, and the liquid is fractionally distilled under vacuum to recover the excess butanediol. The desired ether is obtained as a residue. Optionally, it is purified by further vacuum distillation.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](O)=[N:8][C:7]([CH3:12])=[N:6][C:5]=2[C:4]([CH3:13])=[N:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>P(Cl)(Cl)(Cl)=O>[Cl:15][C:9]1[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:13])[C:5]=2[N:6]=[C:7]([CH3:12])[N:8]=1
Reactant: Cc1nc(O)c2c(n1)c(C)nn2C
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c2c(n1)c(C)nn2C
Yield: 89.7 %

Procedure:
A mixture of 30.5 g (0.17 mol) of 1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol and 37 g (0.18 mol) of phosphorus pentachloride in 350 ml of phosphorus oxychloride is stirred under reflux for seven hours and the resulting solution is evaporated in vacuo. The solid residue is redissolved in 300 ml of methylenedichloride and stirred with 200 ml of a saturated aqueous solution of sodium bicarbonate. The organic layer is dried over MgSO4 and evaporated in vacuo to give 30 g (98%) of 7-chloro-1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine, mp 91°-93° C. from ethyl acetate-pet ether.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]([NH2:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:30]1[CH:35]([NH2:36])[CH2:34][CH2:33][CH:32]([NH2:37])[CH2:31]1>O>[NH2:36][C@H:35]1[CH2:30][CH2:31][C@H:32]([NH:37][C:2]2[CH:3]=[C:4]([N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5]3[N:6]([C:8]([C:11]([NH2:13])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:33][CH2:34]1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(N)=O)cnc23)cc1
Reactant: NC1CCC(N)CC1
Solvent: O
Product: COc1ccc(CN(c2ccccc2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(N)=O)cnc23)cc1
Temperature: 160 °C

Procedure:
To a vial containing crude 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide 35 mgs from 1a was added trans-1,4-cyclohexyldiamine (250 mgs, mmol). The resulting mixture was heated to 160° C. for 4 h. The mixture was cooled to room temperature and diluted with water causing a precipitate to form. The precipitate was collected, washed with water and dried to give crude 6-((trans)-4-aminocyclohexylamino)-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide.
Reaction SMILES: C1COCC1.[O:6]=[C:7]1[N:19]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([NH:28][C@H:29]([CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=4[CH:37]=3)[C:30]([O:32]CC)=[O:31])=[O:27])[CH2:22][CH2:21]2)[C:10]2[CH:11]=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[NH:8]1.O.[OH-].[Li+]>O>[O:6]=[C:7]1[N:19]([CH:20]2[CH2:21][CH2:22][N:23]([C:26]([NH:28][C@H:29]([CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=4[CH:37]=3)[C:30]([OH:32])=[O:31])=[O:27])[CH2:24][CH2:25]2)[C:10]2[CH:11]=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[NH:8]1
Reactant: CCOC(=O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(n2c(=O)[nH]c3c4ccccc4ncc32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(n2c(=O)[nH]c3c4ccccc4ncc32)CC1
Reaction time: 8 h

Procedure:
A mixture of 15 mL THF and 1.65 g (3.0 mmol) ethyl (R)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate was combined with a solution of 0.40 g (6.3 mmol) lithium hydroxide hydrate in 5 mL water and stirred overnight. The reaction mixture was evaporated down under reduced pressure, the residue was taken up in water and acidified by the addition of 1 M HCl. The precipitate was suction filtered and dried.
Reaction SMILES: [CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]2=[O:14])[C:3](=O)[CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]1[C@@H:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C@H:12]2[OH:14])[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2CN2C(=O)CCC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@@H]1c2ccccc2CN2CCC[C@@H]12

Procedure:
A solution of 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-3,10-dione in THF (20 mL) was added to a suspension of LAH (7.95 mmol, 302 mg) in THF (10 mL). The mixture was refluxed for 16 hours and then quenched by the addition of H2O (0.3 ML), NaOH (15%, 0.3 mL) and additional H2O (0.9 mL). The precipitate was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with CH2Cl2/MeOH/NH4OH (150/8/1) to give cis-1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-10-ol as an off-white solid (178 mg): mp 131-133° C. (lit (Rigo, B.; Kolocouris, N. J. Heterocyclic. Chem. 1983, 20, 893) mp 135-136° C.); 1H NMR (300 MHz) δ 7.52 (br d, J=7.2 Hz, 1 H), 7.16-7.25 (m, 2 H), 7.02 (br d, J=6.9 Hz, 1 H), 4.46 (d, J=8.4 Hz, 1 H), 3.97 (d, J=14.7 Hz, 1 H), 3.38 (d, J=14.7 Hz, 1 H), 3.18 (td, J=8.4, 2.4 Hz, 1 H), 2.56 (br s, OH), 1.60-2.32 (m, 6 H); 13C NMR (75 MHz) δ 138.53, 134.70, 127.01, 126.71, 126.46, 125.91, 73.59, 67.50, 55.45, 54.67, 29.12, 21.55; MS (FAB), m/e 190 (100, M+H), 172 (30), 119 (15); HRMS (FAB) m/e calcd for (C12H15NO+H) 190.1232, found 190.1228.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:7]2[C:12]([C:13](=[O:28])[C:14]=1[CH2:15][NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21](N(C)C)=[CH:20][CH:19]=1)=[CH:11][CH:10]=[C:9]([O:29][CH3:30])[CH:8]=2)=[O:4].NCC1C(=O)C2C(=CC(OC)=CC=2)N(C2C=CC=CC=2)C=1C(OC)=O.[Cl:62]C1C=CC(C(Cl)=O)=CC=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:7]2[C:12]([C:13](=[O:28])[C:14]=1[CH2:15][NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([Cl:62])=[CH:20][CH:19]=1)=[CH:11][CH:10]=[C:9]([O:29][CH3:30])[CH:8]=2)=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1c(CNC(=O)c2ccc(N(C)C)cc2)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Agent: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Product: COC(=O)c1c(CNC(=O)c2ccc(Cl)cc2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
3-[(4-Dimethylamino-benzoylamino)-methyl]-7-methoxy-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester as prepared starting from intermediate K and 4-chloro-benzoyl chloride. MS calcd. for C26H21ClN2O5 [(M+H)+] 477.1, obsd. 477.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[C:44]([F:54])=[CH:45][C:46]([F:53])=[C:47]([S:49](Cl)(=[O:51])=[O:50])[CH:48]=1>C(#N)C>[F:53][C:46]1[CH:45]=[C:44]([F:54])[C:43]([Cl:42])=[CH:48][C:47]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cc(Cl)c(F)cc3F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 28.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0283 g, 0.0613 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-chloro-2,4-difluorobenzenesulfonyl chloride (0.0482 g, 0.195 mmol) to obtain 4-(2,4-difluoro-5-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0117 g, yield 28%).
Reaction SMILES: [C:1]1(OB=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:16]([O:23][C:24]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[C:33](Cl)[CH:32]=[CH:31][C:30]=1[C:36]#[N:37])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl.COCCOC.O>[CH2:16]([O:23][C:24]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[C:33]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:32]=[CH:31][C:30]=1[C:36]#[N:37])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(Cl)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Reactant: O=BOc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Water (0.74 mL), phenylboranic acid (0.12 g), sodium carbonate (0.21 g), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (3.0 mg) were added to an ethylene glycol dimethyl ether (3.0 mL) suspension of the obtained 2-(benzyloxy)-N-(5-chloro-2-cyanophenyl)-5-(piperidin-1-yl)benzamide, followed by heating to reflux under a nitrogen atmosphere for 1 hour. After cooling the reaction mixture to room temperature, phenylboranic acid (0.12 g), sodium carbonate (0.21 g), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (3.0 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 40 minutes. The reaction mixture was cooled to room temperature, and then chloroform and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 90-50% hexane/ethyl acetate] to obtain 0.32 g of 2-(benzyloxy)-N-(4-cyanobiphenyl-3-yl)-5-(piperidin-1-yl)benzamide as a yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[CH:53][C:52]=1[SH:61].C([O-])([O-])=O.[K+].[K+]>O.C(#N)C.C(Cl)Cl>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:28][CH2:29]5)=[N:22][CH:23]=4)=[C:3]([CH2:2][S:61][C:52]4[CH:53]=[CH:54][C:55]5[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=5)[N:51]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Reactant: Sc1ccc2ccccc2n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CSc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Compound 21a (152 mg, 0.307 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (2 mL) and DIEA (107 mL, 0.615 mmol) were added. The solution was cooled to 0° C. and MsCl (35.8 mL, 0.461 mmol) was added dropwise via microsyringe. The reaction was stirred at 0° C. for 15 min and then the solvent was removed under reduced pressure. The crude material was placed in a 50 mL round bottom flask equipped with a stir bar and then 2-quinolinethiol (56.2 mg, 0.338 mmol) and K2CO3 (63.7 mg, 0.461 mmol) were added. Dry ACN (10 mL) was added and then the reaction was stirred at rt for 20 h. The reaction was diluted with water (20 mL) and extracted with DCM (3×30 mL). The combined organic extracts were washed with brine (20 mL) and then dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-60% ACN/DCM to afford compound 22a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.54 (d, J=2.2 Hz, 1H), 7.96 (d, J=5.6 Hz, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.87 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.56-7.66 (m, 1H), 7.38-7.47 (m, 1H), 7.26 (d, J=6.1 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.03 (d, J=5.6 Hz, 1H), 4.85 (s, 2H), 3.89-3.98 (m, 4H), 3.81-3.89 (m, 4H), 3.56 (d, J=5.4 Hz, 8H), 1.49 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H38N8O3S: 639.3 (M+H). Found: 639.4.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5](=[O:8])[CH2:6][SH:7].[Cl:9][CH2:10][CH2:11][N:12]([CH2:36][CH2:37][Cl:38])[P:13]([N:29]([CH2:33][CH2:34][Cl:35])[CH2:30][CH2:31][Cl:32])(=[O:28])[O:14][CH2:15][CH2:16]OS(C1C=CC(Br)=CC=1)(=O)=O>CO.C1(C)C=CC=CC=1>[CH3:3][NH:4][C:5](=[O:8])[CH2:6][S:7][CH2:16][CH2:15][O:14][P:13]([N:29]([CH2:33][CH2:34][Cl:35])[CH2:30][CH2:31][Cl:32])([N:12]([CH2:11][CH2:10][Cl:9])[CH2:36][CH2:37][Cl:38])=[O:28]
Reactant: CNC(=O)CS
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CNC(=O)CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl
Reaction time: 0.5 h

Procedure:
To a solution of crushed sodium hydroxide pellets, 2.28 g (57 mmol), in 20 mL anhydrous methanol cooled in an ice bath was added N-methyl-2-mercaptoacetamide, 3 g (28.5 mmol), slowly, followed by the addition of 20 mL anhydrous toluene and 2-(4-bromobenzenesulfonyloxy)ethyl tetrakis(2-chloroethyl)-phosphorodiamidate, 34.4 mL of 0.83 M solution in toluene (28.5), while maintaining the temperature at 5° C. or less. After stirring for about 30 min, the reaction mixture became a white slurry. It was stirred at 5° C. to room temperature overnight. LC-MS analysis indicated all the starting material, N-methyl-2-mercaptoacetamide, was consumed and the desired product was formed as a major product. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between diisopropyl acetate and brine. The aqueous phase was further extracted with diisopropyl acetate three times, and the combined organic phases were dried (MgSO4) and evaporated to give the crude product, which was purified by column chromatography on a silica column using hexane/acetate and acetate/methanol as eluting solvents to afford N-methyl-2-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]acetamide as a light yellow oil, 12 g (88% yield). 1H NMR (DMSO): δ 7.90 (bs, 1H) 4.05 (m, 2H), 3.71 (m, 8H), 3.33 (m, 8H), 3.12 (s, 2H), 2.87 (m, 2H), 2.59 (d, 3H, J=4.7 Hz), 2.76 (m, 1H). Mass spectrum (LC-MS): m/z 496 [C13H26Cl4N3O3PS+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([C:10]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[O:11])[C:6]=2[CH:19]=1.[Mg].[Cl-].[NH4+]>CO.BrCCBr>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH:7]([C:10]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[O:11])[C:6]=2[CH:19]=1
Reactant: CCCN(CCC)C(=O)c1csc2ccc(N)cc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: CO
Product: CCCN(CCC)C(=O)C1CSc2ccc(N)cc21
Reaction time: 4 h

Procedure:
30 g of 5-amino-N,N-dipropyl-3-benzothiophencarboxamide were dissolved in 250 ml of dry methanol. 15 g of magnesium turnings were added (eventually activated by addition of a few drops of 1,2-dibromoethane). The mixture was stirred at 30°-35° C. for 4 hours with periodically cooling to keep the temperature down. 2 l of a saturated ammonium chloride solution were added and the product extracted with ethyl acetate. The organic phase was separated, washed with water, dried (MgSO4) and the solvent evaporated. Isopropyl ether was added, and by cooling the title compound precipitated and was filtered off. Yield: 20 g. M.P. 100° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][N:4]=[C:3]1[N+:8]([O-:10])=[O:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>C(O)C>[CH3:1][N:2]1[C:6]([CH:7]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][N:4]=[C:3]1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cnc([N+](=O)[O-])n1C
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: Cn1c(C=Cc2ccccc2)cnc1[N+](=O)[O-]
Yield: 16 %

Procedure:
A mixture of 7.2 g. of 1,5-dimethyl-2-nitroimidazole, 41.2 ml. of benzaldehyde and 7.9 g. of potassium tert-butoxide in 300 ml. of ethanol is refluxed for 35 minutes under nitrogen. The residue, which is obtained by evaporation of the reaction mixture under vacuum, is extracted with ethyl ether and filtered. The ethyl ether solution after concentration yields an oily residue which is chromatographed through 300 g. of silica gel by eluting with chloroform. After evaporation of the solvent under vacuum at 40° C., an oily residue is obtained which crystallizes on standing. After washing with a small amount of methyl ethyl ketone, 1.9 g. (16%) of a product which melts at 170°-180° C. is obtained.