Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O-].[Na+].Cl.[CH:6]1([NH:11][C:12]([NH2:14])=[NH:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])[C:24]([C:25](=O)[C:26]#[CH:27])=[C:20]2[CH:19]=[CH:18][CH:17]=1>C(O)C>[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])[C:24]([C:25]3[CH:26]=[CH:27][N:14]=[C:12]([NH:11][CH:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[N:13]=3)=[C:20]2[CH:19]=[CH:18][CH:17]=1
Reactant: C#CC(=O)c1c(-c2occc2C)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccoc1-c1nn2c(Cl)cccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Sodium ethylate solution (21% T, 0.5 mL, 1.43 mmol) was added to ethanol followed by cyclopentylguanidine hydrochloride (323 mg, 1.98 mmol). The mixture was stirred at room temperature for 30 minutes. 1-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (313 mg, 1.10 mmol) was added to the resultant solution and stirred at room temperature for 15 hours. The reaction mixture was concentrated. Ethyl acetate and water were added to the residue. The phases were separated, the organic phase dried (magnesium sulfate), filtered and concentrated. The residue was recrystallized from ethyl acetate. 4-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (280 mg, 65%) was obtained as a yellow solid. 1H-NMR (CDCl3): δ 8.50 (d, 1H), 8.15 (d, 1H), 7.49 (d, 1H), 7.27 (t, 1H), 7.06 (d, 1H), 6.41 (d, 1H), 6.36 (d, 1H), 5.10 (d, 1H), 4.35 (m, 1H), 2.12 (s, 3H), 2.08 (m, 2H), 1.78–1.53 (m, 6H). MS m/z 394 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:23]([OH:24])[C@@H:22]([CH3:25])[O:21][C@H:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C@@H:10]1[O:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N-:55]=[N+:56]=[N-:57].[Na+]>ClCCl.O.CCOC(C)=O.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[N:55]([C@@:23]1([OH:24])[C@@H:22]([CH3:25])[O:21][C@H:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C@H:10]([O:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])=[O:31])[C@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:56]=[N-:57]
Reactant: COc1ccc(O[C@H]2O[C@H](C)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OC(=O)CCC(C)=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(O[C@H]2O[C@H](C)[C@](O)(N=[N+]=[N-])[C@H](OCc3ccccc3)[C@H]2OC(=O)CCC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Methoxyphenyl 3-O-benzyl-2-O-levulinoyl-α-D-fucopyranoside (6) (971 mg, 2.12 mmol) was azeotroped 2 times with toluene and dissolved in 20 mL of dichloromethane. Pyridine (1.84 g, 1.87 mL, 23.3 mmol) was added and the mixture cooled to 0° C. Triflic anhydride (1.19 g, 0.71 mL, 4.24 mmol) was added and the mixture stirred for 90 min at 0° C. The mixture was quenched by addition of diluted NaHCO3 solution, the phases were separated and the organic layer extracted 3 times with 3% hydrochloric acid, once with water, dried over Na2SO4 and was concentrated. The resulting crude product was azeotroped 3 times with toluene to remove all traces of pyridine and dried for 1 h in vacuo. The yellow product was dissolved in 25 mL of DMF and sodium azide (3.58 g, 55.1 mmol) was added, and the reaction mixture stirred overnight. The mixture was diluted with water and EtOAc, the phases were separated. The organic phase was washed 3 times with brine, dried over Na2SO4 and concentrated. Column chromatography (3:1 hexane/EtOAc) afforded 816 mg (80%, 2 steps) of 7 as a slightly yellow oil: [α]D: +192.6 (c=1.25, CHCl3). IR (thin film, CHCl3): 3015, 2103, 1739, 1713, 1503, 1400, 1359, 1159, 1034 cm−1. 1H NMR (CDCl3, 300 MHz) δ 1.31 (d, J=6.3 Hz, 3H), 2.14 (s, 3H), 2.58 (m, 2H), 2.69 (m, 2H), 3.26 (t, J=9.9 Hz, 1H), 3.77 (s, 3H), 3.83 (m, 1H), 4.08 (m, 1H), 4.84 (d, J=10.8 Hz, 1H), 4.90 (d, J=10.8 Hz, 1H), 4.96 (dd, J=9.9 Hz, J=3.6 Hz, 1H), 5.48 (d, J=3.3 Hz, 1H), 6.83 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.0 Hz, 2H), 7.31-7.42 (m, 5H). 13C NMR (CDCl3, 75 MHz). 18.4, 28.0, 29.8, 37.8, 55.7, 66.8, 67.9, 73.6, 75.4, 76.6, 78.1, 95.7, 114.6, 118.2, 127.8, 127.8, 128.3, 137.8, 150.4, 155.2, 171.9, 205.7. MALDI-HRMS: m/z [M+Na]+ calcd 506.1898, obsd 506.1889.
Reaction SMILES: [F:1][C:2]1([F:23])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH2:20])=[O:14])=[CH:11][C:5]=2[O:4][C:3]1([F:22])[F:21].NC1C=CC2OC(F)(F)C(F)(F)OC=2C=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][N:46]=2)[C:41]([CH:48]=O)=[CH:40]1>>[F:23][C:2]1([F:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][CH2:48][C:41]3[C:42]4[C:47](=[N:46][CH:45]=[CH:44][CH:43]=4)[NH:39][CH:40]=3)=[O:14])=[CH:11][C:5]=2[O:4][C:3]1([F:22])[F:21]
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: Nc1ccsc1C(=O)Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Agent: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Product: O=C(Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2)c1sccc1NCc1c[nH]c2ncccc12

Procedure:
EXAMPLE 10 was prepared according to the procedure described in EXAMPLE 5 using N-(2,2,3,3-tetrafluorobenzodioxan-6-yl) 3-aminothiophene-2-carboxamide (prepared as described in example 1 part 1, using 6-amino-2,2,3,3-tetrafluorobenzodioxan instead of 4-trifluoromethoxyaniline) and 7-azaindole-3-carboxaldehyde (EXAMPLE 8, part 1) instead of 2-(N-methylcarbamoyl)pyridine-4-carboxaldehyde. MS (ES+): 479 [MH+]
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[H-].[Na+].Br[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[F:38].O>CN(C)C=O.C(OCC)(=O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][N:7]([C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1)[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:31]=[CH:30][C:29]=1[F:38]
Reactant: FC(F)(F)c1cc(CNc2ncc(Br)cn2)cc(C(F)(F)F)c1
Reactant: Fc1ccc(C(F)(F)F)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.25 h
Yield: 99 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (8.55 g) is dissolved in N,N-dimethylformamide (20 ml), and thereto is added sodium hydride (60%) (855 mg) under ice-cooling, and the mixture is stirred for 15 minutes. To the reaction solution are added 2-bromomethyl-1-fluoro-4-trifluoromethyl-benzene (5 g), and the mixture is stirred at room temperature overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (11.1 g). MS (m/z): 576/578 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[NH:3]1.N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[C:25]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=2)[CH2:10][CH2:11][C:2]1([CH3:18])[CH3:1])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C(C)c1ccc2c(c1)CCC(C)(C)N2
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)C(C)c1ccc2c(c1)CCC(C)(C)N2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
3.0 g of methyl 2-(1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 11) were added to 30 ml of pyridine, and 2.6 g of benzoyl chloride was further added to the solution. The mixture was stirred at room temperature for 15 hours, followed by addition of ice-water and extraction with ether. The ethereal solution was washed with 10% hydrochloric acid, water and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Ether was distilled off to give 3.9 g of methyl 2-(1-benzoyl-1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 17).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[N:13]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])[N:14]=[CH:15][C:16]=1[CH:17]1[CH2:19][CH2:18]1)=O)C>C1COCC1>[CH:17]1([C:16]2[CH:15]=[N:14][N:13]([C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[C:12]=2[CH2:10][OH:9])[CH2:19][CH2:18]1
Reactant: CCOC(=O)c1c(C2CC2)cnn1-c1c(Cl)cccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1c(C2CC2)cnn1-c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a 0° C. mixture of LAH powder in THF (20 mL) is added a solution of 4-cyclopropyl-2-(2,6-dichloro-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester (2.4 mmol, 0.8 g) in THF (10 mL). The reaction is stirred for 2 h at 0° C. The reaction is quenched with a sequence of water (0.26 mL), 5N NaOH (0.26 mL) and water (0.78 mL). The reaction mixture is stirred for 1 h at 0° C. The reaction mixture is filtered and the filtrate is adsorbed onto silica gel and purified using a gradient of 30-50% EtOAc/Hexanes to yield the title compound (0.36 g, 53%). LC-ES/MS m/e 283.0 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[N:17]=[C:16]([C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=3[CH2:37][OH:38])[CH:14]=2)[N:9]=1.CO>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][N:2]([CH3:6])[C:3](=[O:4])[O:38][CH2:37][C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH2:7])[N:17]=[C:16]2[C:18]([N:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28]1)=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
20 μl of dimethylcarbamoyl chloride are added to a solution of 100 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 5 ml of dimethylformamide (DMF), and the mixture is heated at 80° C. for 18 h. After 18 h, 10 ml of methanol are added, the mixture is evaporated to dryness in vacuo and purified by normal-phase chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][C:14]([C:16]1[C:20]2[N:21]=[CH:22][N:23]=[C:24]([S:25][CH3:26])[C:19]=2[S:18][CH:17]=1)=[O:15].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][C:14]([C:16]1[C:20]2[N:21]=[CH:22][N:23]=[C:24]([S:25]([CH3:26])=[O:35])[C:19]=2[S:18][CH:17]=1)=[O:15]
Reactant: CCOC(=O)c1ccc(C)c(NC(=O)c2csc3c(SC)ncnc23)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C)c(NC(=O)c2csc3c(S(C)=O)ncnc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-methyl-3-(4-(methylthio)thieno[3,2-d]pyrimidine-7-carboxamido)benzoate (500 mg, 1.29 mmol) was dissolved in DCM (6 mL) and m-CPBA (290 mg, 1.67 mmol) was added thereto at 0° C. The reaction mixture was stirred at room temperature for 2 hours, diluted with DCM (30 mL) and washed with sat. NaHCO3 solution. The organic layer was dried with anhydrous MgSO4, filtered with Celite and concentrated to obtain the title compound without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH3:17])=[CH:11][C:10]=2[N+:18]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.Cl[Sn]Cl.C([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOC(C)=O.O.C(Cl)Cl.CCCCCC>[NH2:18][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH3:17])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC=Cc1ccc(OCc2ccccc2)c(N)c1
Yield: 32.3 %

Procedure:
A solution of 1-[4-phenylmethoxy-3-nitrophenyl]propene (12.74 g, 47.3 mmol) and SnCl2.2H2O (53.4 g, 237 mmol) in 200 mL of EtOAc was refluxed for one hour. After cooling, 100 mL of hexane and then a solution of 41 g of K2CO3 (297 mmol) in 35 mL H2O were added with vigorous stirring, whereupon 300 mL of CH2Cl2 and 100 g Na2SO4 were added prior to filtration through Celite. After concentration, the residue was chromatographed twice on silica gel eluting with 7% to 17% Et2O/hexane to obtain 3.66 g of 1-[3-amino-4-phenylmethoxyphenyl]propene as a 98:2 mixture of trans to cis isomers. The title compound was prepared from 1-[3-amino-4-phenylmethoxyphenyl]propene following the procedure described in part 4 of step F of Example 1, except that the crude product was chromatographed on silica gel eluting with 50% EtOAc/hexane and then recrystallized from EtOAc/hexane to obtain 3.11 g.
Reaction SMILES: [OH:1][CH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl.CO>[OH:1][CH:2]1[C:6]2=[N+:7]([O-:30])[CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=1
Reactant: O=C1c2cccnc2C(O)N1c1cnn(CC(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc[n+]([O-])c2C(O)N1c1cnn(CC(F)(F)F)c1
Reaction time: 24 h
Yield: 54.3 %

Procedure:
As shown in step 18-i of Scheme 18, to 7-hydroxy-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 2055, 4.35 g, 14.6 mmol) in CHCl3 (80 mL) and MeOH (40 mL) was added mCPBA (5.39 g, 21.9 mmol). After stirring for 24 hours, additional mCPBA (1.26 g, 7.30 mmol) was added. After stirring an additional 16 hours, the resulting precipitate was collected by filtration and washed with DCM (10 mL) and Et2O (20 mL) to give 7-hydroxy-5-oxo-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine 1-oxide (Compound 2059, 2.49 g) as a white solid: ESMS (M+H) 315.25; 1H NMR (DMSO-d6, 300 MHz) δ 8.44 (d, J=6 Hz, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.65 (m, 2H), 7.43 (d, J=9 Hz, 1H), 6.41 (d, J=9 Hz, 1H), 5.20 (q, J=9 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:10]1(=[O:14])[CH2:13][CH2:12][CH2:11]1.O>C1COCC1>[Cl:9][C:3]1[C:2]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: O=C1CCC1
Reactant: Cc1ccc(Br)c(Cl)n1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCC2)c(Cl)n1
Temperature: -15 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A suspension of molecular sieves (4 Å) and 3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5, 5 g, 24.2 mmol) in THF (50 mL) was cooled to −15° C. 1.3 M isopropyl magnesium chloride lithium chloride complex solution in THF (19.6 mL, 25.4 mmol) was added within 30 min. Stirring was continued for 1 h at −15° C. Cyclobutanone (1.87 g, 2.00 mL, 26.6 mmol) was slowly added. Stirring was continued for 2 h at −15° C. and for further 2 h at 0° C. Water (2.5 mL) was added, the mixture was concentrated in vacuo, and poured onto sat. aqueous NH4Cl solution. The mixture was extracted with EtOAc (2×100 mL). The combined extracts were washed with ice water (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 140 g, heptane/EtOAc 0-40% in 120 min.) to give the title compound (3.33 g, 70%) as white solid, MS (ESI): m/e=198.1 [MH+].
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:32]3[C:23](=[CH:24][C:25]4[O:30][CH2:29][CH2:28][O:27][C:26]=4[CH:31]=3)[O:22][CH2:21]2)[C:13]1=[O:33])C1C=CC=CC=1.C(OC1C=CC(CN2C3C(=CC=CC=3)C3(COC4C=C5C(=CC3=4)CCO5)C2=O)=CC=1)C1C=CC=CC=1>>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:32]3[C:23](=[CH:24][C:25]4[O:30][CH2:29][CH2:28][O:27][C:26]=4[CH:31]=3)[O:22][CH2:21]2)[C:13]1=[O:33]
Reactant: O=C1N(CCCOCc2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C1N(Cc2ccc(OCc3ccccc3)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(CCCO)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in Example 17 and making non-critical variations using 1′-[3-(benzyloxy)propyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-[4-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(3-hydroxypropyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (83%): mp 157-158° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.33-7.27 (m, 1H), 7.18-7.15 (m, 1H), 7.08-7.03 (m, 1H), 6.95-6.92 (m, 1H), 6.48 (s, 1H), 6.19 (s 1H), 4.73 (ABq, 2H), 4.19-4.08 (m, 4H), 3.02-3.80 (m, 2H), 3.61-3.55 (m, 2H), 2.98 (d, J=6.0 Hz, 1H), 1.98-1.85 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.8, 155.3, 144.6, 141.9, 138.3, 132.4, 128.9, 124.1, 123.6, 120.6, 111.4, 108.5, 99.4, 80.0, 64.5, 63.9, 58.3, 58.1, 36.4, 29.8; MS (ES+) m/z 353.8 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:22])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH2:19][O:20][CH3:21])[CH:7]=[CH:8][CH:9]=1.N1C=CN=C1.[C:28]([Si:32]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)Cl)([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[Si:32]([O:1][CH2:2][CH2:3][C:4]1[C:5](=[O:22])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH2:19][O:20][CH3:21])[CH:7]=[CH:8][CH:9]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
20 g (65 mmol) of the compound from Example 30A are dissolved in 75 ml of anhydrous N,N-dimethylformamide, and, with ice-cooling, first 5.3 g (78 mmol) of imidazole and then, a little at a time over a period of 3 min, 19 g (72 mmol) of tert-butyldiphenylchlorosilane are added. Cooling is removed, and the mixture is stirred at room temperature for a further 19 h. The reaction solution is diluted with ethyl acetate and washed three times with water and twice with saturated sodium chloride solution. The mixture is then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. tert-Butyl methyl ether is added to the residue, and the resulting crystals are filtered off and dried under reduced pressure. This gives 39 g (90% of theory) of the desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:24][CH3:25])=[C:10]([C:19](OCC)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CO.[BH4-].[Li+].O>O1CCCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:24][CH3:25])=[C:10]([CH2:19][OH:20])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (60.43 g, 174 mmol, 1 equivalent, e.g. which can optionally be as prepared in Intermediate 4) in dry tetrahydrofuran (300 ml) was added dry methanol (28.3 ml, 22.3 g, 698 mmol, 4 equivalents), followed by slow addition of lithium borohydride (LiBH4, 2 M solution in tetrahydrofuran, 262 ml, 523 mmol, 3 equivalents) over 30 minutes. The mixture was heated as the lithium borohydride was added, reaching reflux after about 20 minutes. Further aliquots of methanol (14.1 ml, 2 equivalents, each time) were added after 1 hour and again after 1.5 hours, and the heating was continued for a further 30 minutes (for 2 hours total). The reaction mixture was cooled (ice/water bath) and was carefully treated with methanol (100 ml, non-dried) followed by cautious addition of water (200 ml) which resulted in cloudiness and then a precipitate. Addition of more water (800 ml) produced a more homogenous suspension which was stirred for 1 hour and which was then extracted with dichloromethane (about 1.5 L total volume). The organic extracts were combined, were washed with water and then brine, and were dried and evaporated to give the title compound as a white solid (49.84 g). LCMS m/z 305 [MH+]; TRET=1.79 and 1.83 min (double peak).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[O:6][CH3:7]>[NH4+].[OH-]>[NH2:12][C:11]1[N:2]=[CH:3][CH:4]=[C:5]([O:6][CH3:7])[C:8]=1[C:9]#[N:10]
Reactant: COC(C=CN(C)C)=C(C#N)C#N
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccnc(N)c1C#N
Yield: 74.2 %

Procedure:
A mixture of D2 (16 g, 90.39 mmol) in NH4OH (100 ml, 30% in water) was heated at reflux for 3 h. After cooling in an ice bath a yellow solid precipitated. The solid was filtered off, washed with cold isopropanol and dried in vacuo to yield compound D3 (10 g, 76%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:22]=1)[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:22]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cccc(C(O)c2cccc(-c3ccccn3)c2)c1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)c1cccc(C(=O)c2cccc(-c3ccccn3)c2)c1OCc1ccccc1

Procedure:
A solution of crude 3 (10.25 mmol) in dichloromethane (160 mL) was treated with manganese dioxide (14 g, 15 equiv.) and this suspension was stirred under reflux for 6 hr. The reaction mixture was filtered through Celite and the filter cake was washed with ethyl acetate. The solvent was removed on a rotary evaporator and the crude product was purified by chromatography on silica (110 g) with 5% ethyl acetate in heptane (5 L) to produce 4 (2.75 g, 64% over 2 steps).