Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:24]1[C:25]([NH:27][CH:28]1[CH:32]([O:33]CC2C=CC=CC=2)[O:31][C:30](=[O:41])[CH2:29]1)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:24]1[C:25]([NH:27][CH:28]([CH:32]=[O:33])[CH2:29][C:30]([OH:41])=[O:31])=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CCCCC1C(=O)NC(C=O)CC(=O)O)C(C)C

Procedure:
To a solution of 100 mg of N—(N-Acetyl-tyrosinyl-valinyl-pipecolyl)-4-amino-5-benzyloxy-2-oxotetrahydrofuran in 10 ml of methanol was added 60 mg of Pd(OH)2 on carbon and the mixture placed under an atmosphere of hydrogen via a balloon. The mixture was filtered through Celite and concentrated providing a white solid. This crude solid was dissolved in 2 ml of methanol and triturated with diethyl ether affording 26 mg of the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[CH:8]=1)=[O:6]>CO>[CH2:19]([O:18][C:16]1[C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:17]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2c(OCc3ccccc3)cc(C(=O)O)cc2O1
Temperature: 60 °C
Yield: 88.2 %

Procedure:
NaOH (23 mL, 69 mmol, 3N aqueous solution) was added to a solution of 4-benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (77a) (7.18 g, 23 mmol) in MeOH (80 mL). The reaction mixture was heated to 60° C. for 3 hr, and concentrated in vacuo. The residue was diluted with H2O (100 mL) and washed with EtOAc (100 mL). The aqueous phase was acidified with 3N aqueous HCl to pH˜2 to form a white precipitate, which was filtered and dried to give a white solid (6.05 g, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1 H) 7.38-7.48 (m, 4 H) 7.33 (t, J=7.07 Hz, 1 H) 7.14 (s, 1 H) 6.88 (s, 1 H) 5.17 (s, 2 H) 2.98 (s, 2 H) 1.42 (s, 6 H); LCMS for C18H18O5 m/z 299.10 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C@H:9]([OH:12])[CH2:10][O:11][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(OC[C@H](O)CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@@H](O)COc1ccc(C#N)cc1
Reaction time: 8 h

Procedure:
57.2 g of (2R)-3-(4 cyanophenoxy)propane-1,2-diol was dissolved in dry pyridine, (300 ml) and treated dropwise with methanesulfonyl chloride, (20.7 ml), at -10° C. The reaction mixture was kept at 5° C. overnight, evaporated at reduced pressure and poured on ice and 2 M hydrochloric acid. The solid precipitate was recrystallized three times from methanol to yield 12.3 g of the title compound, m.p. 119°-121° C., [α]D20 +9.7° (c 1.0, CH3OH).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[CH2:24][CH:25]=[CH2:26])(=O)C.O(C)[Na]>CO>[C@@H:6]1([CH2:24][CH:25]=[CH2:26])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: C=CC[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CO[Na]
Solvent: CO
Product: C=CC[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1-propene (4.15 g, 11.14 mmol) in CH3OH (50 mL) was added NaOCH3 (0.56 mL, 2.2 mmol, 4.0 M in CH3OH). After stirring at rt for 2 hr, the reaction mixture was neutralized using Dowex 50W (acidic form). The resin was filtered off and the filtrate was concentrated to give the title compound. 1H NMR (DMSO-d6) δ 2.09 (m, 1H), 2.49 (m, 1H), 2.88 (t, J=8.9, 1H), 2.98-3.07 (m, 3H), 3.11 (m, 1H), 3.39 (dd, J=11.4, 4.7, 1H), 3.60 (d, J=11.6, 1H), 4.99 (dd, J=10.3, 0.9, 1H), 5.06 (d, J=17.2, 1H), 5.90 (m, 1H).
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH:13]=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[P:15]([O-:32])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:24][P:15]([CH:13]([OH:14])[CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:32])[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: O=CCCc1cccc2ccccc12
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=P(OCc1ccccc1)(OCc1ccccc1)C(O)CCc1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(naphthalen-1-yl)propanal (2.3 g, 12.5 mmol) in DMF (6 mL) under nitrogen is added dibenzyl phosphite (3.3 g, 12.5 mmol), followed by potassium fluoride (0.94 g, 16.2 mmol). After 2 hours, the stirred suspension is diluted with ethyl acetate (60 mL) and washed with water (3×20 mL). The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane (30% to 40% ). Concentration of the pure fractions in vacuo yields [1-hydroxy-3-(naphthalen-1-yl)-propyl]phosphonic acid dibenzyl ester as an oil which solidifies on standing.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][O:18][C@@H:17]([C:21]([N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:30]([O:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])[CH:29]=2)[CH:24]2[CH2:26][CH2:25]2)=[O:22])[CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[ClH:1].[CH2:35]([O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:23]([CH:24]2[CH2:25][CH2:26]2)[C:21]([C@@H:17]2[O:18][CH2:19][CH2:20][NH:15][CH2:16]2)=[O:22])=[CH:29][C:30]=1[O:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)ccc1OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COCCCOc1cc(CN(C(=O)[C@H]2CNCCO2)C2CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4N HCl/dioxane (1 ml) was added under ice cooling to (2R)-2-{[[4-benzyloxy-3-(3-methoxypropoxy)benzyl](cyclopropyl)amino]carbonyl}morpholine-4-carboxylic acid tert-butyl ester (a compound of Reference Example 9, 217 mg) dissolved in chloroform (1 ml), and the mixture is stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. the residue was added water (1 ml) and diethyl ether (2 ml), and then the mixture was slightly stirred. The layer of diethyl ether was removed by decantation and the resulted residue is lyophilized to give (2R)—N-[4-(benzyloxy)-3-(3-methoxypropoxy)benzyl]-N-cyclopropylmorpholin-2-carboxamide hydrochloride (166 mg) as a colorless powder. APCI-MS m/z: 455[M+H]+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C([NH:8][C:9](=[O:36])[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11]1[S:12][C:13]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:14]C=1C(OCC)=O)(=O)C.Cl>C(O)C>[CH3:34][CH:33]([CH3:35])[CH2:32][N:10]1[C:11]2[S:12][C:13]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[CH:14][C:3]=2[C:2](=[O:1])[NH:8][C:9]1=[O:36]
Reactant: CCOC(=O)c1cc(Cc2cccc3ccccc23)sc1N(CC(C)C)C(=O)NC(C)=O
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)Cn1c(=O)[nH]c(=O)c2cc(Cc3cccc4ccccc34)sc21
Reaction time: 3 h
Yield: 65.2 %

Procedure:
Sodium ethoxide (0.036 g) was added to a solution of N′-acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(1-naphthalenylmethyl)-2-thienyl]urea (0.20 g) in ethanol (4 ml). The mixture was stirred for 3 hours then further sodium ethoxide (0.036 g) was added. After a further 3 hours, the mixture was poured into hydrochloric acid (2M, 20 ml) and extracted with ethyl acetate (2×20 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual solid was recrystallised from ethyl acetate/hexane to give the title compound (0.105 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:14][C:11]([CH3:13])([CH3:12])[CH2:10][C:9]2([CH3:16])[CH3:15]
Reactant: CC(C)(O)CC(C)(C)c1cc(Br)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 4-bromo-2-(3-hydroxy-1,1,3-trimethyl-butyl)-phenol (1.1 g, 3.92 mmol) and p-toluene sulfonic acid (0.744 g, 3.92 mmol) in benzene (20 mL) was refluxed overnight. The reaction mixture cooled to ambient temperature, filtered on silica gel and washed with 10% ethyl acetate in hexane. The filtrate and washings were evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as a pale yellow oil (0.84 g, 80%).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])[CH:2]=[CH2:3].Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.CC(CC(OC(C)(C)C)=O)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:7][C:6]([F:9])([F:8])[C:5]([NH:4][CH2:1][CH:2]=[CH:3][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)=[O:10]
Reactant: C=CCNC(=O)C(F)(F)F
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)CC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Product: O=C(NCC=Cc1cccc([N+](=O)[O-])c1)C(F)(F)F
Temperature: 90 °C

Procedure:
Palladium (II) acetate (0.449 g, 0.002 mol) was added to a mixture of N-allyl-2,2,2-trifluoroacetamide (4.2 g, 0.02 mol), 1-bromo-3-nitrobenzene (5.09 g, 0.03 mol) and TBAA. The reaction mixture was flushed with argon and heated under argon at 90° C. for 4 h. The reaction mixture was partitioned between EtOAc and water. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give dark brown viscous liquid. Purification by flash chromatography (5% to 30% EtOAc—hexane gradient) gave 2,2,2-trifluoro-N-(3-(3-nitrophenyl)allyl)acetamide as light yellow solid. Yield (3.5 g, 61%); 1H NMR (400 MHz, DMSO-d6) δ 9.77 (br.s, 1H), 8.27 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 6.71 (d, J=16.0 Hz, 1H), 6.51 (dt, J=5.6, 16.0 Hz, 1H), 4.02 (t, J=5.6 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C(#N)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:2]=2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccn1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
5.00 g (20.49 mmol) 2-Bromo-1-(4-nitrophenyl)-ethanone and 3.86 g (40.98 mmol) 2-aminopyridine are heated to reflux in 50 mL acetonitrile for 3 hours. The mixture is allowed to cool to RT. The solvent is evaporated. The residue is suspended in ethanol and alkalinized with ammonia solution. The precipitate is filtered off, washed with diethyl ether and dried.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])(=[O:11])[CH:9]=[CH2:10].[C:17]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:21])[C:18]([CH3:20])=[CH2:19].[C:30]([OH:35])(=[O:34])[C:31]([CH3:33])=[CH2:32].N(C(C)(C)C(OC)=O)=NC(C)(C)C(OC)=O>C(O)(C)C.C(C(C)=O)C>[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])(=[O:11])[C:9]([CH3:17])=[CH2:10].[C:17]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:21])[C:18]([CH3:20])=[CH2:19].[C:30]([OH:35])(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=CC(=O)OCCOC
Agent: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCc1ccccc1
Solvent: CCC(C)=O
Solvent: CC(C)O
Product: C=C(C)C(=O)OCCOC
Temperature: 87 °C
Reaction time: 1 h

Procedure:
560.0 g of methyl ethyl ketone was placed in a 2 L three-necked flask equipped with a stirrer, a thermometer, and a reflux cooling tube, and heated to a temperature of 87° C. While maintaining the gas inside the reaction vessel in a refluxed state (thereafter, refluxing was continued until the reaction was completed), to this reaction vessel, a mixture including 266.8 g of methyl methacrylate, 63.8 g of methoxyethyl acrylate, 203 g of benzyl methacrylate, 46.4 g of methacrylic acid, and 2.32 g of “V-601” (trade name, manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise at a constant speed so as to complete the addition in two hours. After completing the addition, the resulting mixture was stirred for one hour. Thereafter, a solution of 1.16 g of “V-601” and 6.4 g of methyl ethyl ketone was added thereto, and the mixture thus obtained was stirred for two hours (process (1)). Subsequently, this process (1) was repeated for four times. Then, a solution of 1.16 g of “V-601” and 6.4 g of methyl ethyl ketone was further added, and stirring was continued for 3 hours. After completion of the polymerization reaction, the temperature of the resulting solution was lowered to 65° C. and then, 163.0 g of isopropanol was added thereto and cooled while leaving it standing still. In this way, a resin solution of a copolymer (methyl methacrylate/methoxyethyl methacrylate/benzyl methacrylate/methacrylic acid=46/11/35/8) was obtained. The obtained copolymer had a weight average molecular weight (Mw) of 63,000 and an acid value of 65.1 mgKOH/g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:38])[C:9]=1[CH:10](O)[CH2:11][CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[C:5]#[N:6].CCN(CC)CC.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[CH:17]1[N:16]=[CH:15][N:14]2[CH:10]([C:9]3[C:2]([F:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=3[F:38])[CH2:11][CH2:12][C:13]=12
Reactant: N#Cc1cc(F)c(C(O)CCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c(F)c1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)c(C2CCc3cncn32)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3,5-Difluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]benzonitrile (0.105 g, 0.21 mmol) is dissolved in DMF (5 mL) and cooled down to 0° C. To this is added Et3N (0.043 mL, 0.31 mmol) and methanesulfonyl chloride (0.019 mL, 0.25 mmol). After 2 h, LCMS showed the presence of the intermediate mesylate [MS (ESI) m/z 584.3 (M+H)]. The solution is evaporated to dryness and dissolved in DMF (5 mL), to which is added K2CO3 (0.086 g, 0.62 mmol) and NaI (0.093 g, 0.62 mmol) and the mixture is heated to 90° C. for 0.5 h. The solution is then evaporated, dissolved in MeCN and filtered. The crude residue is purified via flash column chromatography (MeOH/DCM 1:99→MeOH/DCM 1:9) to give 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3,5-difluorobenzonitrile. MS (ESI) m/z 246.2 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.72-2.85 (m, 1 H), 2.93-3.05 (m, 1 H), 3.08-3.21 (m, 2 H), 5.75 (app t, J=7.2 Hz, 1 H), 6.79 (s, 1 H), 7.18-7.41 (m, 3 H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][NH2:33]>>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:14]3[N:15]([C:11]([C:9]4[CH:8]=[CH:7][N:6]=[C:5]([NH:33][CH2:32][C:28]5[S:27][CH:31]=[CH:30][CH:29]=5)[N:10]=4)=[CH:12][N:13]=3)[CH:16]=[CH:17][N:18]=2)[CH2:21][CH2:22]1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: NCc1cccs1
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5cccs5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and thiophen-2-ylmethanamine (182 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford the crude product (115 mg). The crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford {4-[8-(4-methyl-piperazin-1-yl)-imidazo [1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-2-ylmethyl-amine; hydrochloride. (Yield 34 mg, 21.2%). 1H NMR (300 MHz, CD3OD): δ 9.02 (brs, 1H), 8.84 (s, 1H), 8.39 (d, 1H, J=6.3 Hz), 7.69-7.63 (m, 2H), 7.40 (brs, 1H), 7.23 (s, 1H), 7.06-7.03 (m, 1H), 5.62-5.51 (m, 2H), 5.06-4.99 (m, 2H), 3.88-3.75 (m, 4H), 3.48-3.37 (m, 2H), 3.00 (s, 3H). LC-MS: [M+H]+ 407.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Cl.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]Cl>>[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][N:20]1[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:6]2[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]3)/[S:22][C:21]1=[O:23]
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: CN(C)CCCCl
Agent: Cl
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCCN(C)C)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-3-[3-(Dimethylamino)propyl]-5-[(1-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and 3-dimethylamino-1-propyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]=[C:19]1[S:23][C:22](=[O:24])[NH:21][C:20]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:33]([C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[CH:13]=[C:12]2[CH:18]=[C:19]1[S:23][C:22](=[O:24])[NH:21][C:20]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2c[nH]c3ccc(OCc4ccccc4)cc23)S1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(=Cc2cn(S(=O)(=O)c3cccs3)c3ccc(OCc4ccccc4)cc23)S1
Reaction time: 18 h

Procedure:
The product from step A (50 mg) was treated with 1.2 equivalents of NaH in DMF solution with cooling for 1 hr. 2-Thienylsulfonyl chloride (34 mg, 1.3 equivaltents) was added cautiously. After 18 hrs. at ambient temperature and finally at 70° C., the mixture was poured onto ice and the precipitate was filtered. The title compound was filtered and washed with ether. HPLC ‘System 1’ (Ex. 1) showed 80% purity; structure confirmed by mass spec [m\e 497 (M+1)].
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=2[CH:26]([CH3:28])[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:26]([C:18]1[CH:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C(C)C)cc2C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
2-(2,4-diisopropyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (211 mg, 0.54 mmol) is dissolved in EtOH (8 mL), and solid KOH (823 mg, 14 mmol) and water (0.8 mL) are added. The mixture is stirred at RT for 30 min then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with concentrated HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (250) as white solid (188 mg, 95%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:19].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(#N)C>C(O)C>[N:20]1([C:2]2[CH:11]=[CH:10][C:9]3[C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:7]4[C:8]=3[C:3]=2[CH2:4][CH2:5][N:6]4[CH3:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: CN1CCc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Solvent: CC#N
Solvent: CCO
Product: CN1CCc2c(N3CCCC3)ccc3c(=O)c(C(=O)O)cn1c23
Yield: 84 %

Procedure:
15 mg (0.06 mmol) of the compound (191) obtained in Example 64 and 0.1 ml of pyrrolidine were added to 5 ml of acetonitrile, and the solution was heated at reflux for 2 hours. After the solvent was removed by distillation, obtained crystals were dispersed in ethanol and filtered off and washed with ethanol and ether in this order to obtain 15 mg of the subject compound (192) in a 84% yield.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:21])=[CH:14][C:15]([N:18]([CH3:20])[CH3:19])=[N:16][CH:17]=3)[N:7]([CH2:22][CH:23]=[CH2:24])[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.B.[O:31]1CCCC1.O.O.O.O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[N:16][C:15]([N:18]([CH3:19])[CH3:20])=[CH:14][C:13]=3[CH3:21])[N:7]([CH2:22][CH:23]([OH:31])[CH3:24])[C:6]=2[C:5]([CH:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=CCn1c(Nc2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: B
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CC(C)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a solution of N5-[4-chloro-7-(1-ethylpropyl)-1-prop-2-en-1-yl-1H-benzimidazol-2-yl]-N2,N2,4-trimethylpyridine-2,5-diamine (41 mg, 0.100 mmol) in tetrahydrofuran (1.0 mL) was added borane-tetrahydrofuran complex (1.18 M solution in tetrahydrofuran, 0.17 mL, 0.200 mmol) at 0° C. After 2 hr, additional borane-tetrahydrofuran complex (1.13 M solution in tetrahydrofuran, 0.17 mL, 0.200 mmol) was added to the mixture. After 1 hr, additional borane-tetrahydrofuran complex (1.18 M solution in tetrahydrofuran, 0.17 mL, 0.200 mmol) was added to the mixture. After 1 hr, sodium peroxyborate tetrahydrate (154 mg, 1.00 mmol) and water (0.50 mL) was added to the mixture, which was stirred at room temperature for 60 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (23 mg, 0.0535 mmol, 53%) as a colorless solid.