Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][C:12]=2[CH3:23])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[N:4]([CH2:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][C:12]=2[CH3:23])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)=[O:1]
Reactant: Cc1ccc(-c2ccccc2)cc1Cn1c(CO)nn(C)c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2)cc1Cn1c(C=O)nn(C)c1=O
Yield: 66.5 %

Procedure:
6.52 g (21.2 mmol) of 5-hydroxymethyl-2-methyl-4-(2-methyl-5-phenylbenzyl-)2,4-dihydro-3H-1,2,4-triazol-3-o ne and 14 g of active manganese dioxide were stirred for 6 hours in nitrogen atmosphere under reflux with heating in 63 ml of chloroform. The reaction solution was filtrated through celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluant:hexane:ethyl acetate=1:1), to obtain 4.32 g (14.1 mmol) of 5-formyl-2-methyl-4-(2-methyl-5-phenylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([C:9]2[N:14]=[C:13]3[N:15]=[CH:16][CH:17]=[C:18]([NH2:19])[C:12]3=[N:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N[C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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].O>[F:21][C:2]([F:1])([F:20])[C:3]1[C:4]([C:9]2[N:14]=[C:13]3[N:15]=[CH:16][CH:17]=[C:18]([NH:19][C:31]4[CH:32]=[CH:33][C:34]([C:35]([F:38])([F:37])[F:36])=[CH:29][N:30]=4)[C:12]3=[N:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ncccc1C(F)(F)F
Reactant: Nc1ccnc2nc(-c3ncccc3C(F)(F)F)cnc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4ncccc4C(F)(F)F)cnc23)nc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a de-gassed mixture of 3-[3-(trifluoromethyl)pyridin-2-yl]pyrido[2,3-b]pyrazin-8-amine (72 mg, 0.25 mmol), cesium carbonate (162 mg, 0.5 mmol), 2-amino-trifluoromethyl pyridine (45 mg, 0.25 mmol) in dioxane (5 mL) under nitrogen, add Pd2dba3 (11 mg) and xantphos (7 mg). Stir the mixture at 100° C. for 3 hours, cool, add water (10 mL) and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum. Purify by chromatography eluting with dichloromethane/methanol/ammonium hydroxide mixture to give the title compound. MS 437 (M+1). 1H NMR δ (CDCl3) 9.42 (1H, s), 9.28 (1H, s), 9.11 (1H, d), 8.95 (1H, d), 8.90 (1H, d), 8.72 (1H, s), 8.25 (1H, d), 7.89 (1H, d), 7.61 (1H,dd), 7.13 (1H, d).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=O)[CH2:21]Cl)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]([NH2:27])=[S:26].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:27][C:25]1[S:26][CH:21]=[C:20]([C:14](=[N:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:24]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)c1csc(N)n1
Yield: 29.2 %

Procedure:
Ethyl 2-(2-benzoyloxyethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 29 g.), thiourea (7.76 g.), sodium acetate (8.37 g.), water (75 ml.) and ethanol (75 ml.) were treated in a similar manner to that of Example A-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-benzoyloxyethoxyimino)acetate (syn isomer, 9 g.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[C:16](=O)[CH:10]([CH2:11][N:12]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([OH:28])[CH2:26][OH:27].CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:18]([N:12]1[CH2:13][CH:14]2[CH2:16][C:10]3([O:27][CH2:26][CH2:25][O:28][CH:11]13)[CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OCCO
Reactant: O=C1C2CN(Cc3ccccc3)CC1CN(Cc1ccccc1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3CN(Cc4ccccc4)C4OCCOC4(C3)C2)cc1

Procedure:
A solution of 3,7-dibenzyl-3,7-diazabicyclo[3.3.1]nonane-9-one (10.0 g; 29.8 mmol; Bionet), ethylene glycol (20 g) and p-TSA (12.5 g; 65.7 mmol) in toluene (200 mL) was refluxed in a Dean-Stark apparatus for 12 h. NaOH (200 mL, 2M) was added and the organic layer separated, dried and concentrated to give the sub-title compound in a quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[N:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1ccccc1-n1cccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3-n3cccn3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-pyrazol-1-yl-benzylamine (111 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-pyrazol-1-yl-benzylamino)-2H-phthalazin-1-one: 46 mg (22.5%): m/z (M+H)=352. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 8.13 (d, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.59 (m, 1H), 7.50 (m, 1H), 7.43 (m, 3H), 7.05 (d, 1H), 6.68 (s, 1H), 6.54 (t, 1H), 4.38 (d, 2H).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>C(Cl)Cl>[C:1]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: c1nc[nH]n1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)n1cncn1
Temperature: 25 °C

Procedure:
Palmitoyl chloride is dissolved in methylene chloride and added dropwise to a solution of 2 equivalents of 1,2,4-triazole in methylene chloride, the mixture is stirred for some hours at room temperature and filtered, and the filtrate is used directly in the reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2.B(F)(F)F.[C:21](O)(=[O:23])[CH3:22]>>[CH2:15]([O:14][C:12]([CH:7]1[CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[C:11]([C:21](=[O:23])[CH3:22])=[CH:10][C:9]=2[O:8]1)=[O:13])[CH3:16]
Reactant: CC(=O)O
Reactant: CCOC(=O)C1CCc2cc(O)ccc2O1
Agent: FB(F)F
Product: CCOC(=O)C1CCc2cc(O)c(C(C)=O)cc2O1
Temperature: 80 °C
Yield: 60 %

Procedure:
Into a solution of 2.23 g of racemic-ethyl 6-hydroxychroman-2-carboxylate in 30 ml of acetic acid was introduced a stream of boron trifluoride gas at 20°-25° C. A cold water bath was used during the introduction of the gas (30-45 minutes) to control the temperature of the exothermic reaction. The cold bath was removed and the reaction mixture was heated at 80° C. for 5 hours; then the reaction mixture was cooled and carefully poured into a mixture of saturated bicarbonate and ice, and the product was extracted with 1:1 tetrahydrofuran-ether. The crude material obtained after evaporation of the solvent was chromatographed on a silica gel column to yield 1.6 g (60%) of racemic-7-acetyl-6-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester as a viscous oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][N:38]([CH3:43])[C:39](=[O:42])[CH:40]=[CH2:41]>CO>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][CH2:41][CH2:40][C:39]([N:38]([CH3:43])[CH3:37])=[O:42])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: C=CC(=O)N(C)C
Solvent: CO
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCCC(=O)N(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 120 h
Yield: 43.5 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (200 mg, 0.39 mmol) was dissolved in stirred methanol (10 ml) and N,N-dimethylacrylamide (40 mg, 0.39 mmol) added. The reaction mixture was stirred for 120 hr at room temperature and then 50° C. for a further 24 hr. More N,N-dimethylacrylamide (9 mg, 0.1 mmol) was added and the reaction mixture was heated at 50° C. for 30 hr. A further portion of N,N-dimethylacrylamide (10 mg, 0.1 mmol) was added and the reaction mixture heated to 50° C. for a further 24 hr. The solvent was then removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (94:4:0.2) increasing in polarity to (93:7:0.3) to give the title compound (100 mg) as a foam. MS: 590 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[O:10][CH2:11][CH:12]([O:14]C1CCCCO1)[CH3:13].C(O[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:3]=1[O:10][CH2:11][CH:12]([OH:14])[CH3:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(COc1c(N)ccc(F)c1F)OC1CCCCO1
Product: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)O)C(=O)OCC
Reaction time: 1.5 h

Procedure:
To the total amount of the product obtained in Example 2 was added 1.24 g of diethyl ethoxymethylenemalonate (XVI, Y=EtO, alkyl=Et, hereinafter abbreviated as EMME). The mixture was heated to 145° to 150° C. with stirring. After 1.5 hours, the system was evacuated to remove formed ethanol, and the mixture was heated a further 30 minutes with stirring under reduced pressure. After cooling, the product was isolated through silica gel column chromatography to yield 1.33 g of the titled compound, which has no tetrahydropyranyl moiety.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)[C@H:14]([N:16]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:17]([C@@H:19]([OH:28])[C@@H:20]([C:25]([OH:27])=[O:26])[CH2:21][C:22]([O-:24])=[O:23])=[O:18])[CH3:15].[Na+].[Na+].O1[C:55]2C=CC=[CH:59][C:54]=2N=C1/C=C/C[C@H](C1C=CC2OCOC=2C=1)[C@H](N(CC1C=CC2C(=CC=CC=2)C=1)C([C@@H](O)[C@@H](C(O)=O)CC([O-])=O)=O)C.C(Br)C=C.O>CN(C)C=O>[CH2:59]([O:26][C:25]([C:20](=[C:19]([C:17](=[O:18])[N:16]([C@H:14]([CH3:15])[C@@H:13]([C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)[CH2:12]/[CH:11]=[CH:10]/[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[OH:28])[CH2:21][C:22]([OH:24])=[O:23])=[O:27])[CH:54]=[CH2:55]
Reactant: C[C@H]([C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)[C@@H](O)[C@H](CC(=O)[O-])C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C=CCBr
Product: C=CCOC(=O)C(CC(=O)O)=C(O)C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Reaction time: 6 h
Yield: 48.1 %

Procedure:
69 mg of disodium (3S,4S)-4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-3-carboxy-4-hydroxybutanoate obtained in Example 67, was dissolved in 3 ml of dimethylformamide, and 19 μl of allyl bromide was added thereto, followed by stirring for 6 hours. Then, 19 μl of allyl bromide was additionally added, followed by further stirring for 15 hours. The reaction solution was poured into water, extracted with ethyl ether and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2). The obtained diallyl ester was treated in the same manner as in Example 69(2) and (3) to obtain 17 mg (yield: 25%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[O-:17][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[Na+].[Na+].O.[OH-].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5](=[O:17])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]=2)(=[O:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C1=CC=C2C(=Cc3ccccc32)C1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a solution of 77.0 g (0.74 mol) of 2-acetylfluorene in 1.1 l of acetic acid are added at 90° C and under intense stirring, 385 g (1.3 mol) of sodium bichromate during a period of 1 hr to 1 hr 15 min. Thereupon, the reaction mixture is allowed to stand under the same conditions for 4 hours, then poured into 4.6 l of water heated to 90° C and kept overnight at room temperature. The precipitate is filtered off, washed with 900 ml of a 2-percent sulfuric acid till a colorless wash solution appears, and with water until the acid reaction disappears. Then the precipitate is treated under intense stirring, with 540 ml of a 5-percent caustic soda solution heated to 90° C, and let cool down to room temperature. The precipitate is filtered off, washed with water and dried in a drying cabinet at 80° C to obtain 62.5 g of crude 2-acetylfluorenone which is then recrystallized from 1.0 l of benzene for the sake of purity. The yield of 2-acetylfluorenone equals 55.5 g (68.0 wt% as calculated for 2-acetylfluorene or 50 wt.% when calculated for fluorene), m.p. 160°-161.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([NH:50][C:51]2[CH:56]=[C:55]([N:57]([CH3:59])[CH3:58])[N:54]=[C:53]([N:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)[N:52]=2)[CH:47]=[CH:48][CH:49]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([NH:50][C:51]2[CH:56]=[C:55]([N:57]([CH3:59])[CH3:58])[N:54]=[C:53]([N:60]3[CH2:65][CH2:64][N:63]([C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:8])[CH2:62][CH2:61]3)[N:52]=2)[CH:47]=[CH:48][CH:49]=1
Reactant: COc1cccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)c1
Reactant: O=C(O)c1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2cc(N(C)C)nc(N3CCN(C(=O)c4cccs4)CC3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A mixture of 2-thiophenecarboxylic acid (15 mg, 0.12 mmol), DIPEA (129 mg, 1.00 mmol) and O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (44 mg, 0.12 mmol) in DMF (5 mL) was stirred at room temperature for 30 minutes. N4-(3-methoxyphenyl)-N6,N6-dimethyl-2-(1-piperazinyl)-4,6-pyrimidinediamine (36 mg, 0.10 mmol) was added to the above mixture and stirred at room temperature for 16 h. The crude product was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). The organic layer washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (25 mg, 57%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[CH3:34]>>[CH3:34][C@@H:29]1[N:28]([CH3:27])[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:30]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C[C@H]1CNCCN1C
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)[C@@H](C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1,2-dimethylpiperazine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (br. s., 3H) 2.36 (s, 3H) 2.60 (s, 3H) 2.90 (br. s., 1H) 3.04 (br. s., 1H) 3.26 (br. s., 2H) 3.41-3.57 (m, 1H) 3.73 (d, J=17.68 Hz, 1H) 4.29 (br. s., 1H) 7.59 (dd, J=8.08, 1.52 Hz, 1H) 7.66 (s, 1H) 7.72 (d, J=8.08 Hz, 1H) 8.03 (dd, J=8.59, 2.02 Hz, 1H) 8.10 (s, 1H) 8.35 (d, J=7.83 Hz, 1H) 8.51 (d, J=1.52 Hz, 1H) 12.09 (br. s., 1H); ESI-MS m/z [M+H]+ 417.3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[N:19][N:20]4[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:14])=[CH:11][N:12]=[C:6]2[CH:5]=1)(=O)[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH2:25]([N:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13]([C:10]3[N:7]4[CH:8]=[CH:9][C:4]([CH:1]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH3:2])=[CH:5][C:6]4=[N:12][CH:11]=3)=[O:14])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(c1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-acetyl-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 146; 10.8 mg, 0.026 mmol) in DCM (0.6 mL) was added morpholine (3 equivalents). The resulting solution was stirred at ambient temperature for two hours, after which sodium triacetoxyborohydride (28 mg, 0.13 mmol, 5 equivalents) was added. The resulting suspension was stirred at ambient temperature for 100 hours. The reaction was quenched with excess saturated aqueous sodium bicarbonate, and the resulting suspension was extracted with EtOAc and DCM. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with MeOH/DCM as eluent to afford 0.3 mg of the desired product as a white solid. MS (ES+APCI) m/z=481 (M+H) detected.
Reaction SMILES: [C:1]12([CH2:11][NH:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>CO.O=[Pt]=O>[C:1]12([CH2:11][NH:12][CH2:13][CH:14]([CH:16]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]3)[OH:15])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: Oc1ccc(C(O)CNCC23CC4CC(CC(C4)C2)C3)cc1
Agent: O=[Pt]=O
Solvent: CO
Product: OC1CCC(C(O)CNCC23CC4CC(CC(C4)C2)C3)CC1
Temperature: 60 °C
Reaction time: 48 h
Yield: 32.5 %

Procedure:
To a solution of 4-(2-((1-adamantylmethyl)amino)-1-hydroxyethyl)phenol (0.3 g, 1 mmol) in MeOH (10 mL) was added PtO2 (60 mg). The mixture was stirred under hydrogen (50 psi) at 60° C. for 2 d. The solvent was removed and purified by preparative TLC to give 4-(2-(1-adamantylmethylamino)-1-hydroxyethyl)cyclohexanol (100 mg, 32%). 1H NMR: (400 MHZ, CDCl3) δ=0.90-1.40 (m, 5H), 1.46 (m, 6H), 1.50-1.65 (m, 6H), 1.66-1.82 (m, 2H), 1.92 (m, 3H), 2.25 (m, 2H), 3.30 (m, 5H), 4.41 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate (48.53 g, 236 mmol) in anhydrous dichloromethane (1 L) was cooled to 0° C. Triethylamine (49.4 mL, 354 mmol)) was added. Methanesulfonyl chloride (20.10 mL, 260 mmol) was added dropwise over a period of 10 minutes. The reaction was allowed to warm to ambient temperature and stir overnight. The reaction was quenched with saturated sodium bicarbonate solution (500 mL). The organic layer was washed with water (3×500 mL) and brine (1×500 mL), dried over sodium sulfate and then concentrated under reduced pressure to provide 66.9 g of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy }ethyl methanesulfonate as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([C:13]2[C:14]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[N:25][NH:26]4)=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>>[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([NH:19][C:14]3[C:13]([C:11]([NH:10][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([O:1][CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:3]=4)=[O:12])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:28]=2)[CH:24]=[N:25]1
Reactant: COc1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1O
Reactant: CN1CCC(O)CC1
Product: COc1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1OC1CCN(C)CC1

Procedure:
The title compound was prepared from N-(3-hydroxy-4-methoxyphenyl)[2-(1H-indazol-6-ylamino)(3-pyridyl)]-carboxamide (Example 36) by a method similar to that described in Example 34 using 4-hydroxy-N-methylpiperidine. MS (ES+): 473 (M+H)+;(ES−):471 (M−H). Calc'd. for C26H28N6O3—472.2.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[S:18][CH2:17][C:16]3[C:15](=[O:19])[CH:14]=[C:13]([C:20]([OH:22])=[O:21])[NH:12][C:11]=3[C:9]=2[CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:24]O>>[CH3:24][O:21][C:20]([C:13]1[NH:12][C:11]2[C:9]3[CH:10]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=[CH:7][C:8]=3[S:18][CH2:17][C:16]=2[C:15](=[O:19])[CH:14]=1)=[O:22]
Reactant: CO
Reactant: CCCCc1ccc2c(c1)-c1[nH]c(C(=O)O)cc(=O)c1CS2
Agent: Cl
Product: CCCCc1ccc2c(c1)-c1[nH]c(C(=O)OC)cc(=O)c1CS2

Procedure:
A solution of 9-butyl-1,4-dihydro-4-oxo-5H-[1]benzothiopyrano-[4,3-b]pyridine-2-carboxylic acid (1.82 g, described in Example 84) in 350 ml of anhydrous methanol saturated with hydrogen chloride is heated at reflux for 17 hours. The solvent is removed by evaporation. Water is added to the residue and the aqueous mixture is extracted with chloroform. The organic extract is dried over magnesium sulfate and evaporated. The residue is subjected to chromatography on silica gel using benzene-ethyl acetate (4:1) as eluant. The eluate is evaporated and the residue is crystallized from ether to give the title compound, m.p. 144°-146° C.