Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:9](=[C:10]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:28]C(OC(C)(C)C)=O)[CH2:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[C:15]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:14][N:11]3[N:12]=2)[CH:8]=[CH:7][CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC(=O)NC1(C2C=CC(C3C(C4C=CC=CC=4)=CN4N=C5C(C=CC=C5CO)=C4N=3)=CC=2)CCC1)(C)(C)C>O1CCCC1.Cl.O1CCOCC1>[NH2:28][C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[C:15]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:14][N:11]4[N:12]=[C:13]5[C:9]([CH:8]=[CH:7][CH:6]=[C:5]5[CH2:3][OH:2])=[C:10]4[N:17]=3)=[CH:23][CH:22]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)c1cccc2c1nn1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc21
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(CO)c5nn4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4c5cccc(CO)c5nn4cc3-c3ccccc3)cc2)CCC1
Reaction time: 4 h
Yield: 2.2 %

Procedure:
135.7 mg (0.247 mmol) 2-[4-(tert-Butoxycarbonylaminocyclobutyl)phenyl]-3-phenylpyrimido[1,2-b]indazole-7-carboxylic acid methyl ester, described in example 10, were dissolved in 5 mL tetrahydrofuran. After addition of 18.8 mg (0.5 mmol) lithium aluminium hydride at −78° C., the reaction mixture was stirred was four hours. After addition of another equivalent lithium aluminium hydride stirring was continued for three hours at ° C. Stirring was further continued over night at room temperature. Additional four equivalents lithium aluminium hydride were added and the reaction mixture was stirred for 24 hours at room temperature. 96 mg {1-[4-(7-Hydroxymethyl-3-phenylpyrimido[1,2-b]indazol-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butylester were stirred over night in 6 mL 4M hydrogen chloride in dioxane. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate. After extraction with dichloromethane (trice) the combined organic phases were washed with brine, dried and filtrated. The solvent was evaporated and the residue was purified by HPLC yielding 2.3 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]([OH:22])=O)=[CH:18][C:5]2[CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:8][C:4]=2[CH:3]=1.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[C:27]=1[OH:33])=[O:25]>>[C:24]([C:26]1[C:27]([OH:33])=[C:28]([NH:32][C:20]([C:19]2[C:2]([Cl:1])=[CH:3][C:4]3[O:8][CH:7]([CH2:9][CH2:10][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:6][C:5]=3[CH:18]=2)=[O:22])[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:23]
Reactant: O=C(O)c1cc2c(cc1Cl)OC(CCCc1ccccc1)C2
Reactant: CC(=O)c1cccc(N)c1O
Product: CC(=O)c1cccc(NC(=O)c2cc3c(cc2Cl)OC(CCCc2ccccc2)C3)c1O
Yield: 42 %

Procedure:
Following the process described in example 1 (point K), starting from 6-chloro-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxylic acid and 3-amino-2-hydroxyacetophenone, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with hexane:ethyl acetate, 1:1 (42% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[C:3]=1[CH3:23].[CH3:24][C:25]1([CH3:40])[C:29]2=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=[C:28]2[NH:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:24][C:25]1([CH3:40])[C:29]2=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=[C:28]2[N:27]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][NH:18]4)[C:3]=2[CH3:23])[CH2:26]1
Reactant: Cc1c(-c2cccc3[nH]ccc23)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3[nH]ccc23)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
4-Chloro-5,7-difluoro-2-(1H-indol-4-yl)-3-methylquinoline (42.3 mg, 0.129 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (30 mg, 0.129 mmol), Pd2dba3 (11.8 mg, 0.013 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (12.3 mg, 0.026 mmol), sodium tert-butoxide (37.1 mg, 0.386 mmol), and toluene (1.29 mL) were stirred at 105° C. for 2 h. The reaction mixture was then concentrated and the resulting residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and water, then dried (MgSO4) and concentrated. Purification of the crude product by reverse-phase HPLC (0-70% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-5,7-difluoro-2-(1H-indol-4-yl)-3-methylquinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 8.53 (1H, br. s.), 7.66-7.76 (1H, m), 7.50-7.58 (2H, m), 7.32-7.40 (1H, m), 7.28-7.30 (1H, m), 6.96-7.04 (1H, m), 6.35 (1H, td, J=2.2, 1.2 Hz), 5.80 (1H, t, J=2.1 Hz), 3.88-3.93 (1H, m), 3.75-3.81 (4H, m), 3.72 (1H, dd, J=8.9, 0.5 Hz), 2.99-3.08 (4H, m), 2.15-2.28 (3H, m), 1.52-1.61 (3H, m), 1.43-1.52 (3H, m). Mass Spectrum (ESI) m/e=526.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([O:11]2)[C@H:9]1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([O:11]2)[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2O[C@@H]2[C@H]1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2O[C@@H]2[C@H]1C(=O)O

Procedure:
A solution (1R,2S,5S)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester (2.62 g, 8.21 mmol) in ethyl acetate (32 mL) was hydrogenated under H2 with palladium hydroxide on carbon (1.15 g, 8.21 mmol) for 1 night. The reaction mixture was filtered over a glass fiber filter, quenched with Na2CO3 saturated aqueous solution and was extracted twice with EtOAc. The aqueous layer was acidified with HCl 1N to pH=2 and extracted 4 times with ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated to give the desired material which was used in the next step without further purification. MS (UPLC): 230 [M+H]+, 228 [M−H]−.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[CH3:8][N:9]([CH3:33])[CH:10]([CH2:12][C:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH:18]=C)[CH3:11].O=[O+][O-].CSC>CO>[CH3:8][N:9]([CH3:33])[CH:10]([CH2:12][C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[O:4]
Reactant: C=CCCCC(=O)C(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=[O+][O-]
Solvent: CO
Solvent: CSC
Product: CCCCC(=O)C(CC(C=O)N(C)C)(c1ccccc1)c1ccccc1
Temperature: -20 °C

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 2-dimethylamino-4,4-diphenyl-9-decene-5-one (270 mg) in methanol (5 ml) to adjust the pH to 2.0. The solution was rotary evaporated, and the residue was taken up in methanol. A gentle stream of ozone was passed through the solution at -78° C., until the color turned to sky blue. The reaction was warmed to -20° C., and dimethyl sulfide (3 ml) was added. Rotary evaporation of the solution gave a crude material which was flash-chromatographed over silica gel. Elution with chloroform/methanol (30:1) yielded 80 mg of 2-dimethylamino-4,4-diphenyl-5-oxo-nonanal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:20])[F:21])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(Cl)cc1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 205.4-206.5° C. 1H NMR (acetone-d6 /300 MHz) 7.93 (s, 1H), 7.75 (s, 1H), 7.50 (d, 2H, J=8.9 Hz), 7.19 (d, 2H, J=8.9 Hz), 6.69 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=7.2 Hz). FABLRMS m/z 403 (M-H). ESHRMS m/z 402.9773 (M-H, Calc'd 402.9752). Anal. Calc'd for C17H9Cl2F3O4 : C, 50.40; H, 2.24; Cl, 17.50. Found: C, 50.02; H, 1.98; Cl, 17.79.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]4[CH:37]=[C:38]([Si](C)(C)C)[O:39][C:32]=34)=[CH:26][CH:25]=2)=[N:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([S:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]5[CH:37]=[CH:38][O:39][C:32]=45)=[CH:26][CH:25]=3)=[N:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: C[Si](C)(C)c1cc2nccc(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)c2o1
Reactant: Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nnc(Nc3ccc(Sc4ccnc5ccoc45)cc3)c3ccccc23)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A microwave vial was charged with 3-fluoro-4-methylphenylboronic acid (0.058 g, 0.38 mmol), 4-chloro-N-(4-(2-(trimethylsilyl)furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amine (0.090 g, 0.19 mmol), and sodium carbonate (2.0 M in H2O) (0.38 ml, 0.75 mmol) and dissolved in toluene (1.5 mL) and water (0.2 mL). Pd(Ph3P)4(0.011 g, 0.0094 mmol) was added and the reaction was microwaved at 200° C. for 30 minutes. The reaction was partitioned between water and DCM. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was redissolved in 2 mL THF and TBAF (0.23 ml, 0.23 mmol) was added. The reaction was stirred at RT overnight. The reaction was concentrated and purified via Gilson HPLC (10-90% ACN:H2O). The clean fractions were partitioned between saturated sodium bicarbonate solution and DCM and the aqueous layer was extracted with DCM. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford 4-(3-fluoro-4-methylphenyl)-N-(4-(furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amine as a light yellow solid. MS: M+H+=479.1
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH2:22][CH:23]([OH:26])[CH2:24]O)[CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:26][CH:23]([CH2:22][O:21][C:16]2[CH:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=2[CH3:20])[CH2:24][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(Cl)cc1OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCO
Solvent: c1ccccc1
Product: Cc1ccc(Cl)cc1OCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1

Procedure:
A mixture of 6 parts of 2-bromo-2', 4'-dichloroacetophenone, 6 parts of 3-(4-chloro-o-tolyloxy)-1,2-propanediol, 3 parts of p-toluenesulfonic acid, 80 parts of n-butanol and 180 parts of benzene is stirred and refluxed for 24 hours with water-separator. The solvent is removed in vacuo and the residue is triturated in methanol. The produce is filtered off and crystallized from petroleumether, yielding A + B 2-(bromomethyl)-4-(4-chloro-2-tolyloxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[C:13]([CH:19]=O)[CH:12]=2)[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:19][NH:24][CH3:23])[CH:12]=2)[CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(Oc2cc(Cl)ccc2C#N)cc1C=O
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 67.5 %

Procedure:
4-Chloro-2-(3-formyl-4-methoxy-phenoxy)-benzonitrile (1.00 g, 3.48 mmol), methylamine (2M in methanol, 5.2 ml, 10.4 mmol) and sodium cyanoborohydride (0.24 g, 3.8 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (75 ml) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with water, brine and dried over MgSO4. After filtration, fumaric acid (0.40 g, 3.4 mmol) was added to the filtrate and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(3-methylaminomethyl-phenoxy)-benzonitrile fumarate (892 mg, 61%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.[Cl:8][C:9]1[CH:10]=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[F:15].N12CCN(CC1)CC2>C(#N)C>[Cl:8][C:9]1[CH:10]=[C:11]([S:16]([NH:7][C:3]2[N:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:17])=[O:18])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: Nc1cccnn1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=S(=O)(Nc1cccnn1)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
To a solution of pyridazin-3-amine (5.0 g, 52.63 mmol) in anhydrous acetonitrile (250 mL) was added 3-chloro-4-fluorobenzenesulfonyl chloride (12.05 g, 52.63 mmol) followed by 1,4-diazabicyclo[2,2,2]octane (5.9 g, 52.63 mmol). The reaction was stirred at room temperature for 18 hours. A solid was observed which was collected by filtration and washed with acetonitrile. The filtrate was concentrated in vacuo and the resulting residue purified by silica gel column chromatography (0%-10% methanol in chloroform gradient elution) to afford the title compound (5.3 g, 35%)
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@H:4]1[O:8][C:7](=[O:9])[NH:6][C@@H:5]1[C:10](OC)=[O:11].[Cl-].[NH4+]>C(O)C>[OH:11][CH2:10][C@@H:5]1[C@@H:4]([CH3:3])[O:8][C:7](=[O:9])[NH:6]1
Reactant: COC(=O)[C@H]1NC(=O)O[C@@H]1C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: C[C@H]1OC(=O)N[C@@H]1CO
Reaction time: 3 h

Procedure:
Sodium borohydride (0.55 g, 14.65 mmol) was added to a mixture of (4S,5R)-methyl 5-methyl-2-oxooxazolidine-4-carboxylate (2.12 g, 13.32 mmol) in ethanol (29 mL) at 0° C. The mixture was stirred for 3 hours and then 2 mL of saturated aqueous ammonium chloride was added. The mixture was stirred for 30 minutes and the white solids were filtered through CELITE and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure and dried under vacuum to afford (4R,5R)-4-(hydroxymethyl)-5-methyloxazolidin-2-one. 1H NMR (500 MHz, D2O) δ 4.56-4.37 (m, 1H), 3.60-3.38 (m, 3H), 1.27 (d, J=6.4 Hz, 3H).
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:18][CH2:19][OH:20])[CH2:16][OH:17])=[CH:11][CH:10]=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.COC1C=CC(C=O)=CC=1>O.CC(C)=O.C(O)C.C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:18][CH2:19][O:20][C:16]2=[O:17])=[CH:13][CH:14]=1
Reactant: OCCC(CO)c1ccc(F)cc1
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: O=C1OCC[C@@H]1c1ccc(F)cc1

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. 2-(4-fluorophenyl)-1,4-butanediol (10.0 grams) is dissolved in 150 ml of acetone added to the glycine solution with stirring, followed by the addition of β-NAD+ (Sigma, 0.5 grams). To the resulting solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10,% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (2R)-2-(4-fluorophenyl)butyrolactone as a yellowish solid.
Reaction SMILES: C(Cl)Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[C:13]1([C:16]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])[CH2:15][CH2:14]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:17]2[C:18](=[O:19])[C:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[O:4][C:5]=3[C:13]3([C:16]=2[CH:24]=1)[CH2:15][CH2:14]3
Reactant: COc1ccc(C(=O)O)c(C2(c3cc4ccccc4o3)CC2)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)C1(CC1)c1oc3ccccc3c1C2=O
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 17.3 %

Procedure:
To the DCM solution (10 ml) of 2-(1-benzofuran-2-yl-cyclopropyl)-4-methoxy-benzoic acid (1.0 g, 3.24 mmol), trifluoroacetic acid anhydride (0.45 ml, 3.24 mmol) was added at −78° C., and the mixture was stirred at −78° C. for 10 min, at −50° C. for 10 min, and at −30° C. for 20 min. Thereafter, the mixture was added with water and extracted with DCM. The residues obtained after concentration under reduced pressure were washed with DCM and hexane to obtain the title compound (0.163 g, 70%).
Reaction SMILES: [CH:1]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[CH:2]2[CH:3](O)[CH:4]=[CH:5][CH:6]1O.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH:8]12[CH2:11][CH2:12][CH:1]([CH:10]=[CH:9]1)[C:2]1[C:7]2=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1C=CC(O)C2C3C=CC(CC3)C12
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C1=CC2CCC1c1ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.8 %

Procedure:
To a solution of 27.9 g of tricyclo[6.2.2.02,7]dodeca-4,9-diene-3,6-diol in 165 mL of pyridine were portionwise added 30 mL of POCl3 at 0° C. The reaction was stirred for 3 days at rt before it was quenched by careful addition of ice under cooling. The resulting mixture was extracted with Hept (4×50 mL). The combined organic phases were washed with H2O, 15% HCl solution and again with H2O. The organic phase was dried over MgSO4 and concentrated in vacuo to obtain 10.6 g of the desired compound as yellow oil.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-])=O)=[O:12])([O:3][CH3:4])=[O:2]>CO.[Pd]>[C:1]([C:5]1[S:6][C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20])=[O:12])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)Nc1ccccc1N
Yield: 82.2 %

Procedure:
A slurry of N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(2-nitrophenyl)urea (0.078 g, 0.21 mmol) and 10% Pd/C (0.010 g) in MeOH (15 mL) was stirred under H2 (1 atm.) for 18 h at 20° C. Celite® was added and the slurry was filtered. The resulting solution was concentrated under reduced pressure and the residue was purified by flash chromatography (gradient from 20% EtOAc/hexane to 50% EtOAc/hexane) to afford N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(2-aminophenyl)urea as a foam (0.060 g, 83%): 1H NMR (CDCl3, partial spectrum) δ1.4 (s, 9H), 3.6 (s, 3H), 6.8-7.3 (m, 4H), 7.8 (s, 1H), 9.6 (s, 1H); FAB-LRMS m/z (rel abundance) 348 (M+H, 34%).
Reaction SMILES: FC1C=C(S(C)(=O)=O)C=CC=1OC1N=CN=C2N(C3CCC(C4ON=C(C(C)C)N=4)CC3)N=CC=12.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([N:49]2[C:53]3=[N:54][CH:55]=[N:56][C:57](Cl)=[C:52]3[CH:51]=[N:50]2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].[F:59][C:60]1[CH:61]=[C:62]([OH:70])[CH:63]=[CH:64][C:65]=1[S:66]([CH3:69])(=[O:68])=[O:67]>CN(C)C=O>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([N:49]2[C:53]3=[N:54][CH:55]=[N:56][C:57]([O:70][C:62]4[CH:63]=[CH:64][C:65]([S:66]([CH3:69])(=[O:68])=[O:67])=[C:60]([F:59])[CH:61]=4)=[C:52]3[CH:51]=[N:50]2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CS(=O)(=O)c1ccc(O)cc1F
Agent: CC(C)c1noc(C2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)c(F)c4)ncnc32)CC1
Yield: 43 %

Procedure:
4-[4-(3-Fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared using the procedure described for the preparation of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclo-hexyl]-1H-pyrazolo[3,4-d]pyrimidine (Example 129) by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-fluoro-4-methanesulfonyl-phenol (Intermediate 2) in dimethylformamide. The product was purified by flash chromatography, eluting with 40% ethyl acetate/hexanes to give 4-[4-(3-fluoro-4-methanesulfonyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (75 mg, 43%) as a white solid. Mass spectrum: Observed 491.9.