Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Br[CH2:14][CH2:15][OH:16]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
4-nitrobenzenethiol (10 g) was dissolved in methanol (100 ml), 3N sodium hydroxide (32.2 ml) was added to the mixture, and 2-bromoethanol (9.7 g) was added dropwise to the mixture. The mixture was stirred for 1 hour at room temperature, the solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane/ethyl acetate, to give 2-[(4-nitrophenyl)sulfanyl]ethanol (10.6 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36].O>CN(C)C(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1)=[O:36]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)CCl)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (948 mg, 2.14 mmol) produced in Example D25(iii) in N,N-dimethylacetamide (20 mL) was added chloroacetyl chloride (425 μL, 5.34 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water (60 mL), and the mixture was extracted with ethyl acetate (30 mL, 15 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→30/70), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (778 mg, 71%) as a white solid.
Reaction SMILES: O.[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C@H:28]([CH2:47][O:48]CC1C=CC(OC)=CC=1)[O:29][C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:25])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C@H:28]([CH2:47][OH:48])[O:29][C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:25])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCCCCC(=O)O[C@@H](COCc1ccc(OC)cc1)COC(=O)CCCCCCCCCCCNC(=O)OCc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)O[C@@H](CO)COC(=O)CCCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of CH2Cl2 (50 mL) and H2O (5 mL) under air was added the diacylglycerol [7] (3.12 g, 4.00 mmol). DDQ (1.81 g, 8.00 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 solution (20 mL), brine (20 mL) and dried over MgSO4. Flash chromatography eluting with 40-50% EtOAc in hexane gave the alcohol [8] (2.40 g, 3.62 mmol, 91%) as an off white solid: (Found: C, 70.7; H, 10.1; N, 2.1. C39H67O7N requires C, 70.7; H, 10.2; N, 2.1%); m.p. 56-58° C. [α]D20=−3.2 (c 1.02 in CHCl3); Rf=0.20 (30% EtOAc/hexane); γmax(CHCl3)/cm−1 3450, 2924, 2854, 1724, 1602, 1517, 1465, 1413, 1372, 1251, 1164; δH (400 MHz; CDCl3) 7.34-7.25 (5 H, m, Bn), 5.10-5.05 (3 H, m, CH2CHCH2, OCH2C6H5), 4.81 (1 H, bs, NH), 4.31 (1 H, dd, J 11.9, 4.4, CH2CHCH2), 4.20 (1 H, dd, J 11.9, 5.8, CH2CHCH2), 3.71 (2 H, d, J 5.8, CH2CHCH2), 3.16 (2 H, q, J 6.6, CH2NH), 2.32 (2 H, t, J 7.5, OCOCH2), 2.30 (2 H, t, J 7.8, OCOCH2), 1.63-1.59 (4 H, m, OCOCH2CH2, CH2CH2NH), 1.58-1.45 (2 H, m, CH2CH2CH2NH), 1.25 (36 H, bs, COC15H31, C11H22NH), 0.87 (3 H, t, J 6.6, CH2CH3); δC (63.5 MHz; CDCl3) 173.7, 173.4 (OCO), 156.4 (NHCO), 136.7, 128.5, 128.0, 112.6 (4×Bn), 72.1 (CH), 66.6, 62.1, 61.4 (3×CH2), 41.1 (NHCH2), 34.3, 34.1, 31.9, 30.0, 29.7, 29.6, 29.5, 29.3, 29.2, 29.1, 26.7, 24.9, 22.7 (12×CH2), 14.1 (CH3); m/z (CI) [Found (M+Na)+ 684.4828. C39H67O7NNa requires M, 684.4816].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncc(CO)cn1
Product: Cc1ncc(CCl)cn1

Procedure:
A solution of (2-methylpyrimidin-5-yl)methanol (95 mg, 0.77 mmol) in thionyl chloride (1 mL) was stirred at room temperature for 1 h. The mixture was concentrated to dryness and used without purification. LCMS MH+ 143.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[O:41]=[S:37]1(=[O:40])[CH2:36][CH2:35][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:39][CH2:38]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S1(=O)CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCS(=O)(=O)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide. MS (ESI): mass calcd. for C20H19FN4O4S2, 462.08; m/z found, 463.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.62-8.60 (m, 1H), 8.16-8.14 (m, 1H), 8.13-8.12 (m, 1H), 8.05 (t, J=8.1 Hz, 1H), 7.69-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.39-7.36 (m, 1H), 7.25-7.21 (m, 2H), 4.81 (s, 2H), 3.36-3.30 (m, 4H), 3.02-2.98 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.Cl>O.CS(C)=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccc(Cl)cc3)cc2)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
To 12 ml of dimethylsulfoxide is dissolved 1.12 g of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione, and 480 mg of 50% sodium hydride in oil is added to the solution. The mixture is stirred at room temperature for 15 minutes, to which is added 0.81 g of 4-chlorobenzyl chloride. The whole mixture is stirred at 50° C. for 4 hours. Water is added to the mixture and the mixture is acidified with 2 N-hydrochloric acid. The mixture is subjected to extraction with ether. The extract is washed with water and dried. Ether is distilled off to give an oily substance. The oily substance is subjected to column chromatography on 30 g silica gel, elution being carried out with cyclohexane-ethyl acetate (2:1). By the above procedure there was obtained 425 mg of 5-[4-(4-chlorobenzyloxy)benzyl]thiazolidine-2,4-dione.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[OH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[OH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:21][CH2:20]1
Reactant: OCCOCCN1CCNCC1
Reactant: O=Cc1ccc2c(n1)COC2=O
Product: O=C1OCc2nc(CN3CCN(CCOCCO)CC3)ccc21
Yield: 27.1 %

Procedure:
In a process similar to that described in Preparation 8, 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (150 mg, 0.92 mmol) and 1-[2-(2-hydroxyethoxy)ethyl]-piperazine (181 μL, 1.01 mmol) are reacted to provide the title compound as yellow oil (80 mg, 27%).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[CH:14]=[C:15]([CH3:18])[CH:16]=O)C.C[O-].[Na+].O>CO>[CH3:18][C:15]1[CH:14]=[N:9][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:10][CH:16]=1
Reactant: CCOC=C(C)C=O
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cnc(-c2ccccc2)nc1
Reaction time: 0.5 h

Procedure:
To a solution of benzamidine hydrochloride (500 mg, 3.19 mmol) and 3-ethoxy-2-methylacrylaldehyde (400 mg, 3.51 mmol) in Methanol (10 mL) was added a NaOMe-solution (30 percent in methanol) dropwise under stirring over 30 minutes. After stirring for 4 hours water (20 mL) was added and mixture was stirred for further 30 minutes at room temperature. After filtration the obtained precipitate was washed with water and dried. White solid. Yield: 220 mg, 41%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.34 (s, 3H), 7.44-7.54 (m, 3H), 8.37-8.45 (m, 2H), 8.64 (d, J=0.6 Hz, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=15.7, 128.1, 128.5, 128.8, 130.6, 137.9, 157.6, 162.7; (ESI): m/z=170.97 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:12][C:13]2[C:18]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:20]=3)=[CH:17][C:16]([C@H:45]([N:47]3[CH2:52][CH2:51][N:50]([S:53]([CH3:56])(=[O:55])=[O:54])[CH2:49][CH2:48]3)[CH3:46])=[CH:15][N:14]=2)[CH:7]=[N:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[CH:1]([C:4]1[CH:5]=[C:6]([NH:12][C:13]2[C:18]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=3)=[CH:17][C:16]([C@H:45]([N:47]3[CH2:52][CH2:51][N:50]([S:53]([CH3:56])(=[O:55])=[O:54])[CH2:49][CH2:48]3)[CH3:46])=[CH:15][N:14]=2)[CH:7]=[N:8][C:9]=1[O:10][CH3:11])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(C(C)C)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cc1C(C)C
Temperature: 80 °C
Yield: 31.5 %

Procedure:
A dark red solution of (R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.097 g, 0.124 mmol) and trifluoromethanesulfonic acid (0.055 mL, 0.620 mmol) in 1 mL TFA was sealed and heated to 80° C. for 30 min. The reaction was cooled with ice, then quenched with 10N NaOH until basic, and partitioned between water and DCM. The aqueous layer was extracted with DCM 2 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This material was dissolved in DMSO (plus a few drops TFA) and purified by RPHPLC, 10-80% ACN/H2O (plus 0.1% TFA); product-containing fractions were concentrated to dryness, then treated with sat'd aq. NaHCO3 and DCM. The aq. layer was extracted 3×DCM and combined organics dried over sodium sulfate, filtered, and concentrated in vacuo to give (R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine as a yellow solid (0.021 g, 0.039 mmol, 31% yield). m/z (ESI, +ve ion) 542 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.58 (br. s., 1H), 8.69 (br. s., 1H), 8.17-8.34 (m, 2H), 7.92 (br. s., 1H), 5.38 (br. s., 2H), 3.97 (s, 3H), 3.47-3.62 (m, 1H), 3.11-3.31 (m, 5H), 2.77 (br. s., 3H), 2.49-2.68 (m, 7H), 1.44 (d, J=6.1 Hz, 3H), 1.27 (d, J=6.8Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:7]=2[CH:24]=1.[CH2:27]=[O:28]>C1(C)C(C)=CC=CC=1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:27][OH:28])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:7]=2[CH:24]=1
Reactant: Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2
Reactant: C=O
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 8-trifluoromethyl-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine in xylene is heated with excess paraformaldehyde in a sealed, glass-lined vessel at 155°-160° C. to give 8-trifluoromethyl-1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:1]1([C:4]([NH:6][C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:29]=4)=[O:21])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 18.2 %

Procedure:
To a solution of 3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzooxazol-6-yl}oxy)benzoic acid (221 mg, 653 μmol) produced in Example B1(vi) in pyridine (5 mL) were added 3-(trifluoromethyl)aniline (298 mg, 1.85 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (328 mg, 1.71 mmol) and N,N-dimethylpyridine-4-amine (21.6 mmol, 177 μmol), and the mixture was stirred at room temperature for 14 hr. The mixture was concentrated under reduced pressure, and the obtained residue was dissolved in methanol (1 mL) and ethyl acetate (50 mL). This solution was washed with 0.1N hydrochloric acid (50 mL), saturated aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/98→80/20), and triturated with diisopropyl ether to give the title compound (57.3 mg, 18%) as a pale-brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:27])[NH:18][CH:19]([C:24](=O)[NH2:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:28])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:27])[NH:18][CH:19]([C:24]#[N:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(NC(=O)C1CCCCC1NC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a 0° C. solution of the amide of step 3 (13.2 g, 33.9 mmol) in 150 mL of anhydrous pyridine was added trifluoroacetic anhydride (5.50 mL, 38.9 mmol) dropwise slowly over a 3 min period. The reaction mixture was stirred for 15 min and then poured into a slurry of ice and 1N HCl solution. The mixture was extracted with 500 mL of ethyl acetate, and washed with three 400 mL portions of 1N HCl, 400 mL of water, dried over sodium sulfate, filtered and concentrated to give a crude solid. Recrystallization from ethyl acetate/hexanes gave 11.3 g of [2-(1-Cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester as a white solid. Yield: 90%, MS: 394 (M+Na+), mp=103.6-106.5° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:33]=[C:32]5[C:28]([C:29](=[O:36])[N:30]([CH3:35])[N:31]5[CH3:34])=[CH:27][CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:33]=[C:32]5[C:28]([C:29](=[O:36])[N:30]([CH3:35])[N:31]5[CH3:34])=[CH:27][CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(=O)n(C)n(C)c5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(=O)n(C)n(C)c5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,2-dimethyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (9.4 mg, 0.014 mmol) in THF (0.5 mL) and methanol (0.5 mL) was added 1N NaOH solution (0.5 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O4S: 627.2; found: 627.2. 1H NMR (400 MHz, CD3OD) δ 8.75 (d, J=5.2 Hz, 1H), 8.49 (s, 1H), 8.06 (s, 1H), 7.96 (dd, J=5.2, 1.2 Hz, 1H), 7.90 (s, 1H), 7.85 (q, J=8.4 Hz, 2H), 7.70-7.67 (m, 1H), 7.61-7.56 (m, 3H), 5.27 (s, 1H), 3.51 (s, 3H), 3.47 (s, 3H), 2.62 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36][OH:37])[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:26]CC5C=CC=CC=5)[CH:14]=[CH:15][C:16]=4[O:18]CC4C=CC=CC=4)[C:11](=[O:34])[C:10]=1[C:9]=23.[NH2:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][NH2:44].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[NH2:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][NH:44][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36][OH:37])[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([OH:26])[CH:14]=[CH:15][C:16]=4[OH:18])[C:11](=[O:34])[C:10]=1[C:9]=23
Reactant: NCCNCCN
Reactant: O=C1c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2-c2nn(CCO)c3ccc(Cl)c1c23
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: NCCNCCNc1ccc2c3c(nn2CCO)-c2c(O)ccc(O)c2C(=O)c13
Yield: 78 %

Procedure:
A mixture of 5.1 g (10 mmol) of 5-chloro-2-(2-hydroxyethyl)-7,10-bis(phenylmethoxy)anthra[1,9-cd]-pyrazol-6(2H)-one, 10 g (100 mmol) of diethylenetriamine, 1.4 g (10 mmol) of anhydrous potassium carbonate, and 60 ml of pyridine is heated at reflux for 28 hours. The mixture is cooled, the solids are collected by filtration then washed sequentially with water and 2-propanol to give 3.1 g of the product; mp 185°-190° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[Br:19][C:15]1[C:14]([CH3:18])=[C:10]([C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12]
Reactant: [Br-]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A solution of Example 104A (10 g, 40 mmol) and tetrabutylammonium tribromide (19.2 g, 40 mmol) in DMF (250 mL) was treated slowly with water (250 mL). The resulting suspension was stirred for 18 hours and partitioned between water (1.2 L) and ethyl acetate (500 mL). The organic layer was washed with water (2×1 L), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in dichloromethane (900 mL), washed with water (5×1 L) and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (11.7 g). MS (ESI(−)) m/e 328, 330 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.60 (br s, 1H), 9.68 (s, 1H), 7.63 (d, 1H), 7.39 (d, 1H), 2.37 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[OH:24])[N:15]=1.Cl>O.O1CCOCC1>[OH:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:25])=[O:5])[S:12][CH:13]=1
Reactant: COC(=O)CCCCc1nc(-c2ccc(OC)cc2O)cs1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2csc(CCCCC(=O)O)n2)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Add a solution of LiOH.H2O (1.76 g, 41.9 mmol) in water (25 mL) to a rapidly stirred solution of 5-[4-(2-hydroxy-4-methoxy-phenyl)-thiazol-2-yl]-pentanoic acid methyl ester (2.69 g, 8.4 mmol) in dioxane (50 mL), stir at room temperature. After 1 hour, acidify to pH 1 with 5N HCl solution and cool under N2 in a refrigerator. Filter out solids and rinse with ice cold water. Dry solids in a vacuum oven overnight to afford the title compound (2.50 g, 96%). MS (IS) 308 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@H:10]2[C@@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@@H:13]3[C@H:12]([CH2:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH:37]([O-])([O-])OCC>C(O)(=O)C>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[CH:37][N:9]2[C@H:10]1[C@@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@@H:13]2[C@H:12]([CH2:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]2=[O:34])[CH2:11]1
Reactant: CN(CCCN1C(=O)c2ccccc2C1=O)C[C@@H]1C[C@@H](Nc2ncnc(Cl)c2N)[C@@H]2OC(C)(C)O[C@H]12
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)O
Product: CN(CCCN1C(=O)c2ccccc2C1=O)C[C@@H]1C[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 130 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A solution of 2-(3-((((3aR,4S,6R,6aS)-6-((5-amino-6-chloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)propyl)isoindoline-1,3-dione (180 mg, 0.35 mmol) in ethyl orthoformate (5.8 mL, 35 mmol) was treated with acetic acid (4 drops) and heated at 130° C. for 7 hours. The reaction was cooled to room temperature and stirring was continued overnight. The reaction was concentrated and purified by flash chromatography (7N NH3 in MeOH/DMC 4:96) to yield 2-(3-((((3aR,4S,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)propyl)isoindoline-1,3-dione (165 mg, 90%) as a thick light brown syrup. MS (ESI+) for C26H29ClN6O4 m/z 525.4 [M+H]+.