Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@@H:22](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:23]([OH:34])([CH2:31][CH2:32][OH:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])[C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].F[B-](F)(F)F.[CH3:57][O+](C)C.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@@H:22](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:23]([OH:34])([CH2:31][CH2:32][O:33][CH3:57])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[O:21])[C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Reactant: C[O+](C)C
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.4 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-dimethylcarbamoyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (15.0 mg, 21.5 μmol) was dissolved in dichloromethane (0.5 mL), and trimethyloxonium tetrafluoroborate (6.7 mg, 45.1 μmol) and 2,6-di-tert-butyl-4-methylpyridine (9.3 mg, 45.1 μmol) were added at 0° C. The mixture was stirred at room temperature for 5 hours. The reaction mixture was purified by preparative HPLC to obtain the title compound (3.5 mg, 22% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH2:27]([NH2:29])[CH3:28].[BH4-].[Na+].[OH-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:11][CH:12]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][NH:29][CH2:27][CH3:28])[CH:18]=2)[N:6]=1
Reactant: CCN
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNCc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Yield: 83 %

Procedure:
A small vial (2 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (68 mg, 189 μmol) and THF (0.5 ml). To this was added a 2M solution of ethylamine in THF (100 μl). After stirring overnight methanol (1 ml) and sodium borohydride (11 mg) was added, then after another hour 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 61 mg (83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.1 Hz, 3H) 2.38-2.44 (m, 2H, partially obscured by solvent) 2.93 (s, 3H) 3.56 (s, 2H) 6.61 (br. s., 2H) 6.66 (br. s., 1H) 7.05 (d, J=8.8 Hz, 2H) 7.12 (t, J=74.18 Hz, 1H) 7.14-7.28 (m, 3H) 7.33-7.39 (m, 1H) 7.42 (d, J=8.8 Hz, 2H); MS (APPI) m/z 389 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>CCO.O>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH:8]=[N:12][OH:13])=[N:6][CH:7]=1
Reactant: NO
Reactant: Cc1cc(C=O)ncc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C=NO)ncc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of the compound obtained in Step B (3.1 g) in EtOH (47.5 ml) and water (23 ml) were added hydroxylamine hydrochloride (1.4 g) and sodium acetate (1.9 g). The reaction was stirred for 15 min at room temperature. The white solid was filtered off and the solution concentrated in vacuo to afford the crude title product (2.2 g, white solid), which was used directly for the next step. LCMS (Method F) 2.09 min, M+H 564/566.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][SiH3])=[CH:9][CH:8]=1)=[CH2:2].C1(=O)OC(=O)C=C1.C(OCCOC1C=CC(CO[SiH3])=CC=1)=C.[OH-].[Na+]>O>[CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[CH:11][CH:12]=1)=[CH2:2]
Reactant: C=COCCOc1ccc(CO[SiH3])cc1
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=COCCOc1ccc(CO)cc1
Temperature: 75 °C

Procedure:
Aqueous Dissolution of 2-(4-SilyloxymethylPhenoxy)-Ethyl Vinyl Ether/Maleic Anhydride Copolymer--A slurry was made with 20 g of 2-(4-silyloxymethyl-phenoxy)ethyl vinyl ether/maleic arthydride copolymer in 498 g of distilled water. To this was added 108 g of a 20% aqueous NaOH solution. The slurry was heated to 75° C. for 48 hours. The reaction was then cooled to room temperature to give a 3.37% concentrated solution of 2-(4-hydroxymethyl-phenoxy)-ethyl vinyl ether/maleic diacid at pH 12.7.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH2:12][CH2:13][C:14]1([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>O.C(OCC)(=O)C>[O:4]=[C:3]1[NH:12][CH2:13][C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[O:27][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroacetyl chloride (4.88 mL) was added dropwise to a vigorously stirred mixture at 0° C. of potassium carbonate (17.43 g) in water (78 mL) and tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (10.4 g) in ethyl acetate (92 mL). After 30 minutes at 0° C. the mixture was extracted with ethyl acetate and the organic layer dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in THF (200 mL) and added dropwise over 3 hours to a stirred solution under nitrogen and heated at reflux of potassium tert-butoxide (1M in tert-butanol, 75 mL) and THF (250 mL). The mixture was cooled to room temperature and allowed to stir for 18 hours. Most of the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine, the aqueous layer was re-extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by trituration with a mixture of ether (30 mL) and isohexane (20 mL) to afford the subtitled product. Yield 8.20 g.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[CH:16][C:15]=2[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]#[N:37]>CC(C)=O>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:35][C:36]#[N:37])=[CH:25][CH:26]=3)=[CH:16][C:15]=2[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(9-benzyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenol (0.421 g, 1.191 mmol) was reacted with K2CO3 (0.198 g, 1.429 mmol) and bromoacetonitrile (0.171 g, 1.429 mmol) in acetone to give the product (0.369 g, 0.940 mmol, 79%) as a white solid, mp 149-153° C. 1H NMR (DMSO-d6) δ 1.79-1.86 (m, 4H), 2.63-2.72 (m, 4H), 5.19 (s, 2H), 5.34 (s, 2H), 7.04 (d, J=7.5 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 7.22 (t, J=7.2 Hz, 1H), 7.27-7.30 (m, 3H), 7.41 (d, J=8.6 Hz, 1H), 7.62 (s, 1H), 7.65 (d, J=8.6 Hz, 2H); [ESI(+)], m/z 393 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: O=C1COC1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (639 mg, 2.00 mmol, Eq: 1.00) and oxetan-3-one (288 mg, 4.00 mmol, Eq: 2.0) in THF (10 ml) was added acetic acid (360 mg, 343 μl, 5.99 mmol, Eq: 3.0). The reaction mixture stirred under N2, at 55° C. for 1 h. Then sodium triacetoxyborohydride (847 mg, 4.00 mmol, Eq: 2.0) was added and the mixture was stirred at 65° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM and saturated NaHCO3. The layers were separated and the organic layer was washed with water. The organic layer was then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 40% (60:10:1 DCM:MeOH:NH4OH)/DCM) gradient) to give 6-chloro-2-methyl-4-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-2H-pyridazin-3-one (453 mg, 60%). LC/MS-ESI observed [M+H]+ 376. 1H NMR in CDCl3 is consistent with desired product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:25]1[CH2:30][CH:29]=[C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:27][CH2:26]1>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][N:25]1[CH2:26][CH:27]=[C:28]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[CH2:29][CH2:30]1)[CH2:22][CH2:21]2
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4ccccc34)CC1)CC2
Temperature: 80 °C
Yield: 67.8 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.348 g, 1.00 mmol) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.793 g, 4.00 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) followed by recrystallization from ethanol provided 0.254 g (68%, 40% ee) of 3-(1-{[(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a yellow crystalline powder. [α]D25=−28.22 (c 9.92 in chloroform, 40% ee); Rf=0.34 (silica, ethyl acetate:hexanes 4:1); mp 190-194° C. dec; Anal. Calcd. for C24H26N2O2.0.1 H2O: C, 76.61; H, 7.02; N, 7.44. Found: C, 76.42; H, 6.99 N, 7.43.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14]>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:20][CH:19]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCCCC(=O)c2ccc(F)cc2)cc1
Yield: 100 %

Procedure:
The title compound (58.0 g, 100%) was prepared from 4-thiocresol and 4-chloro-4'-fluorobutyrophenone as described in Example 2 as an oil; IR(neat): C=O @ 1700 cm-1 ; NMR(DMSO-d6, TMS): δ 1.8-1.95(m,2H, CH2), 2.26(s,3H,ArCH3), 2.98(t,2H,CH2 --CO), 3.16(t,2H,S--CH2), 7.1-8.1(m,8H, aromatic); mass spectrum m/e 288.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:35][C:36]([F:45])([F:44])[C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH3:13][C:11]([CH3:12])([CH3:14])[C:10]([NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][O:1][C:40]2[CH:41]=[CH:42][C:37]([C:36]([F:45])([F:44])[F:35])=[CH:38][CH:39]=2)[N:8]=1)=[O:15]
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
N-(6-Hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.625 g), triphenylphophine (0.786 g) and 4-trifluoromethyl-phenol (0.486 g) in toluene was treated at RT under an argon atmosphere with diisopropyl azodicarboxylate (0.67 g). The mixture was stirred for 2 h, partitioned between ice water and AcOEt, the layers were separated, the aqueous layer twice extracted with AcOEt. The combined organic layers were washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 100 to 85%) to give 2,2-dimethyl-N-[6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-yl]-propionamide (0.98 g) as a yellow oil. MS (ESI): 353.2 (MH+).
Reaction SMILES: [OH-].[Na+].O.[CH2:4]1[C@@H:9]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]2[CH2:7][CH2:6][N:5]1[CH2:23][CH2:24][O:25][CH2:26][C:27]([O:29]CC)=[O:28].Cl>C(O)C>[CH2:4]1[C@@H:9]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]2[CH2:7][CH2:6][N:5]1[CH2:23][CH2:24][O:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COCCN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
65 ml of a 10% w/v aqueous solution of sodium hydroxide and 200 ml of water were added to a solution of 44.85 g of ethyl (S)-2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)ethoxyacetate (prepared as described in Example 58) in 450 ml of ethanol, and the mixture was stirred at room temperature for 2 hours. At the end of this time, it was adjusted to a pH value of 4 by the addition of concentrated hydrochloric acid and concentrated by evaporation under reduced pressure. The crystals which precipitated were collected by filtration and recrystallized from water to give 39.20 g (yield 90%) of the title compound as the monohydrate, melting at 105°-108° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]([CH3:16])([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:17][CH3:18].N1C2C(=CC=CC=2)C=CC=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:10]=[C:9](/[CH:11]=[CH:12]\[C:13]([CH3:16])([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC(C)(C)O)nc21
Agent: [Pd]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CCn1c(-c2cccc(F)c2)nc2c(N)nc(/C=C\C(C)(C)O)nc21

Procedure:
To a solution of 200 mg of 4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-butyn-2-ol in 20 ml of methanol were added 5 μl of quinoline and 20 mg of 10% palladium/barium carbonate and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 minutes. The palladium/barium carbonate was filtered off and the filtrate was concentrated and then the resulting residue was subjected to a silica gel column chromatography (15 g of silica gel; dichloromethane-dichloromethane/methanol=60:1-40:1) to give (Z)-4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-buten-2-ol. This was dissolved in methanol and five drops of 5N hydrochloric acid were added thereto followed by concentrating. Ethyl acetate and ether were added to the resulting residue and the crystals were collected by filtration and washed with ether to give 851 mg of the product. The yield was 26%.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2].CC(O)=[O:34]>>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][C:24](=[O:34])[C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC(=O)[C@]12C
Temperature: 50 °C
Yield: 50 %

Procedure:
CrO3 (17.0 g, 170 mmol) was added to a solution of compound 1.8a (17 g, 39.5 mmol) in AcOH (270 mL). The resulting mixture was heated at 50° C. for 24-36 h. Upon complete disappearance of the starting material by TLC, the solvent was evaporated under vacuum and the crude material was dissolved in ethyl acetate (400 mL) and water (200 mL). The two phases were separated and the organic layer was washed twice with water (2×100 mL) and then once with saturated brine solution (100 mL). The organic phase was dried over anhydrous Na2SO4 (40 g) and filtered. The filtrate was concentrated under vacuum and the resulting solid was purified by column chromatography [49 mm (W)×600 mm (L), 60-120 mesh silica, 120 g], eluting with ethyl acetate/hexane (1:5) [10 mL fractions, 3 mL/min elution, monitored by TLC and detected with UV light (254 nm) lamp]. The product-containing fractions were combined and concentrated under vacuum to afford compound 1.9a (8.8 g, 50% yield) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.OO.[O-]Cl.[Na+]>O.CO>[CH2:2]1[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:8][N:9]=[N:1]1
Reactant: NCC1(CN)CCCC1
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Solvent: O
Product: C1CCC2(C1)CN=NC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
C-(1-Aminomethyl-cyclopentyl)-methylamine (4.87 g) was taken up in a mixture of H2O (40 mL) and MeOH (10 mL), and cooled in an ice bath. Simultaneously, H2O2 (23.9 mL of a 30% solution, 6 equiv.) and NaClO (54.3 mL of a 10% solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred for 2 h. at room temperature. Extraction with DCM, drying over Na2SO4 and evaporation under reduced pressure yielded 3.74 g of a clear, light-yellow liquid containing 90% of the anticipated product and 10% of the diamine starting material. This material was used in subsequent steps without further purification. 1H NMR (400 MHz, CDCl3) δ 1.48-1.57 (m, 4H), 1.62-1.69 (m, 4H), 4.26 (s, 4H).
Reaction SMILES: [CH2:1]([N:6]([CH3:12])[C:7](=O)[N:8]([CH3:10])[CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:6]([CH3:12])[C:7]([N:8]([CH3:10])[CH3:9])=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CCCCCN(C)C(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-pentyl-1,1,3-trimethylurea (7.5 g) in benzene (80 ml) with 4-(2-aminophenyl)morpholine (6.46 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.06 ml) for 45 hours at 70° C. gave 1-pentyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine (b.p. 98° C. at 1.5 mm Hg).
Reaction SMILES: C1C2C(=CC=CC=2)C=C1.CCC(C[O:16][C:17](C(N(CC[NH+](C)C)C)=O)([C:24]1[CH:29]=CC=CC=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC.[Cl-].[BrH:40].OO>ClCCl.O>[Br:40][C@@H:24]1[CH2:29][C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:17]1[OH:16]
Reactant: Br
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: C1=Cc2ccccc2C1
Agent: OO
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O[C@@H]1c2ccccc2C[C@H]1Br
Reaction time: 8 h
Yield: 83.9 %

Procedure:
237 ml of water, 173.9 g of indene (92 wt %; 1.38 mol), 2.8 g of Triton X-100 and 262.0 g of hydrogen bromide (47 wt %; 1.52 mol, 1.1 mol/mol indene) were put into a 1000-ml 3-mouthed flask, and emulsified by stirring together with a magnetic stirrer. The emulsion was stirred at 60° C. as 147.2 g of hydrogen peroxide (35 wt %; 1.52 mol, 1.1 mol/mol indene) was added dropwise over 4 hours and 20 minutes. After stirring for 2 hours at the same temperature, stirring was continued at room temperature overnight. 200 ml of dichloromethane was added to the reaction mixture, and after stirring at room temperature for 1 hour it was filtered at decreased pressure. The wet crystals were dried, to obtain 246.1 g of pale yellow crystals of trans-2-bromoindan-1-ol (yield 83.9%; GC purity 97.0%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH2:17])[CH:5]=1.[F:19][C:20]([F:25])([CH3:24])[C:21](O)=[O:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH:17][C:21](=[O:22])[C:20]([F:25])([F:19])[CH3:24])[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Reactant: CC(F)(F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)c1cc(NC(=O)C(C)(F)F)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 65.2 %

Procedure:
3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (0.7 g, 2.89 mmol, from Preparation 2), 2,2-difluoropropionic acid (0.370 g, 2.89 mmol), EDCI (4.34 mmol), and HOBt (4.34 mmol) and NMM (14.45 mmol) were added to 25 mL of acetonitrile. The reaction mixture was stirred at room temperature for 21 hours, after which the acetonitrile was removed under reduced pressure. The residue was partitioned between water and EtOAc, and the combined organic layers were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc/hexanes 35:1) to give 0.630 g of 3-(2,2-difluoro-propionylamino)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester as a white solid, MS (M+H)=335.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9]CC)=O.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([NH:13][NH2:14])=[O:9]
Reactant: NN
Reactant: CCOC(=O)c1cn[nH]c1C
Solvent: O
Solvent: CCO
Product: Cc1[nH]ncc1C(=O)NN
Temperature: 120 °C

Procedure:
In a 25 mL sealed tube, ethyl 5-methyl-1H-pyrazole-4-carboxylate (0.25 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (1 mL, 5 eq.) was introduced dropwise at RT and the reaction mixture was heated at 120° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 5-methyl-1H-pyrazole-4-carbohydrazide (0.24 g) which was used without further purification in the following step.