Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>CN(C=O)C>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:32]1[C:27]([CH3:26])=[N:28][CH:29]=[CH:30][CH:31]=1)[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: Cc1ncccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: Cc1ncccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-methylpyridine-3-boronic acid (CAS RN 899436-71-6) and using DMF as solvent for the reaction. Yellow sticky liquid (11%). MS (ESI): m/z=439.8 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[O:6][NH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[C:24]4[C:25]([C:29]([O:31]C)=[O:30])=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[C:21]3[CH2:33][CH2:34][CH3:35])=[CH:15][CH:14]=2)=[N:3]1.[OH-].[Na+].Cl>>[O:1]=[C:2]1[O:6][NH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[C:24]4[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[C:21]3[CH2:33][CH2:34][CH3:35])=[CH:15][CH:14]=2)=[N:3]1
Reactant: CCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A mixture of methyl 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-propylbenzimidazole-7-carboxylate (703 mg) in 0.3N-NaOH (12 ml) was stirred at 60° C. for one hour, and then adjusted to pH 3 with 0.1N-HCl. Resulting precipitates were extracted with a mixture of chloroform-ethanol (10:1; 150 ml). The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol to give the title compound as colorless prisms (550 mg, 90%), m.p. 169°-171° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[C:8]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:22]([O:26][C:27]([N:29]([CH:42]([CH3:44])[CH3:43])[CH2:30][C@H:31]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:17]([NH:16][C:15]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:32](=[O:33])[C@@H:31]([C:35]3[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=3)[CH2:30][N:29]([CH:42]([CH3:44])[CH3:43])[C:27](=[O:28])[O:26][C:22]([CH3:25])([CH3:23])[CH3:24])[CH2:3][CH2:2]2)[NH:13][CH:14]=1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)Nc1c[nH]c2nccc(N3CCNCC3)c12
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Nc1c[nH]c2nccc(N3CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 47 %

Procedure:
N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)butyramide (0.050 g, 0.174 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0625 g, 0.183 mmol, see Example H), HOBT-H2O (0.0373 g, 0.244 mmol), and EDCI (0.0434 g, 0.226 mmol) were placed in DCM (5 mL) at room temperature. DIEA (d 0.742; 0.152 mL, 0.870 mmol) was then added, and the reaction was stirred at room temperature for 5 hours. The reaction was then poured into saturated Na2CO3 and extracted into DCM. The organic fractions were combined, dried, filtered and concentrated to give a crude residue that was purified by column chromatography (500:10-500:20 DCM:MeOH) to give (S)-tert-butyl 3-(4-(3-butyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.050 g, 47.0% yield).
Reaction SMILES: [Na].C(O)C.[Br:5][C:6]1[CH:7]=[C:8]([N:12]2[CH:16]=[N:15][C:14]([OH:17])=[N:13]2)[CH:9]=[CH:10][CH:11]=1.Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[Br:5][C:6]1[CH:7]=[C:8]([N:12]2[CH:16]=[N:15][C:14]([O:17][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:25])=[N:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: Oc1ncn(-c2cccc(Br)c2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(Br)c2)n1
Yield: 77.4 %

Procedure:
The process was carried out as described in Example 3, starting with 2.8 g of sodium, 50 ml of ethanol, 75 ml of dimethylsulfoxide, 29 g of 1-(3-bromophenyl)-3-hydroxy-1,2,4-1H-triazole and 21.9 g of ethyl 2-bromopropionate. The yield was 31.8 g of the desired product, m.p. 83°-85°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.[H-].[Na+].Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:21][CH:22]=1>CN(C=O)C.CCCCCCC>[CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[S:21][CH:22]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(O)c1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cccc(OCc2csc(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(3-Hydroxy-phenyl)-acrylic acid methyl ester (85 mg, 0.48 mmol) was dissolved in dry DMF (1.5 ml) and NaH (14 mg, 0.60 mmol) was added as a suspension in heptane (0.5 ml). The mixture was stirred at room temperature for 10 min. 4-Chloromethyl-2-phenyl-thiazole (100 mg, 0.48 mmol) was added portion-wise and the solution left stirring for 4 h. The reaction mixture was quenched with H2O (2 ml) and extracted with EtOAc (3×1 ml). The combined organic layers were washed with H2O (3×1 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [H-].[Na+].SCCCS.Br[CH2:9][CH2:10][P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12]>CCCCCC>[CH:10]([P:11](=[O:12])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH2:9]
Reactant: CCOP(=O)(CCBr)OCC
Agent: SCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: C=CP(=O)(OCC)OCC
Temperature: 0 °C
Yield: 90 %

Procedure:
A sample of 60% NaH in mineral oil (95 mmol) was placed in a 2-neck round bottom flask and charged with dry hexane (20 mL). This solution was allowed to stir for ten minutes, after which the hexane-mineral oil layer was completely removed. The flask was then charged with dry tetrahydrofuran (100 mL), followed by dropwise addition of HS(CH2)3SH (46 mmol) with constant stirring. The resulting solution was cooled at 0° C. and BrCH2CH2P(O)(OC2H5)2 (95 mmol) was added dropwise with constant stirring over a period of 30 minutes. Excess NaH was quenched by addition of 50 mL of deionized water. The solution was extracted from ethyl acetate (3×50 mL) and washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. Upon filtering, the solvent was removed in vacuo to afford compound 5 in 90% yield along with a trace amount of diethyl vinylphosphonate. The compounds were separated on a silica gel column (20 cm; 60 mesh) using 90:10 ethyl acetate to hexane solvent mixture. Removal of the solvent in vacuo, afforded compound 5 as a viscous, yellow-green oil with an overall yield of 88%. High resolution FAB/MS Anal. Calcd. for C15H34O6P2S2 : 436.1272; Found: [M+H+ ], m/z=437.1350. 1H NMR (CDCl3): δ1.34 (t, 3JHH =9.0 Hz, 12H, OCH2CH3), 1.87 (qn, 2H, CH2CH2CH2), 2.03 (m, 4H, PCH2CH2), 2.65 (t, 3JHH =9.0 Hz, 4H, CH2CH2CH2), 2.74 (m, 4H, PCH2CH2), 4.11 (m, 8H, OCH2CH3). 13C NMR (CHCl3): δ16.3 (d, 3JPC =4.5 Hz, OCH2CH3), 24.8 (d, 2JPC =3.0 Hz, PCH2CH2), 26.6 (d, 1JPC =136.6 Hz, PCH2CH2), 28.5 (s, CH2CH2CH2), 30.5 (s, CH2CH2CH2), 61.6(d, 2JPC =6.0 Hz, OCH2CH3). 31P MNR (CDCl3): δ29.1 (s).
Reaction SMILES: [OH:1][CH:2]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2)[C:3]([O:5][CH3:6])=[O:4].[O:17]=C(C12CC3CC(CC(C3)C1)C2)C(OC)=O>>[OH:17][C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([C:2](=[O:1])[C:3]([O:5][CH3:6])=[O:4])([CH2:14]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)C(O)C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)C(=O)C12CC3CC(CC(C3)C1)C2
Product: COC(=O)C(=O)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
As shown in Scheme II, in this method, adamantyl bromide (Formula A) is alkylated via zinc chloride catalysis to produce α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B). α-Hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B) is then esterified using acetyl chloride in methanol to produce α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula C). α-Hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula C) is then converted to α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula D) by Swern oxidation. α-Oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula D) is then hydroxylated to form 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula 1a), which is then hydrolyzed to form 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula 1).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:23](=[O:31])[C@@H:22]3[CH2:32][CH2:33][C@H:34]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[F-].[K+].C(OCC)(=O)C>CO>[Si:43]([O:42][C@H:34]([C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1)[CH2:33][CH2:32][C@@H:22]1[C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)=[CH:16][CH:17]=2)[N:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]1=[O:31])([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)cc2)c1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(-c2cccc(O)c2)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
(3R,4S)-4-(3′-{[tert-Butyl(dimethyl)silyl]oxy}biphenyl-4-yl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (0.60 g, 0.86 mmol) was stirred at room temperature in dry methanol (20 mL) under a nitrogen atmosphere. Potassium fluoride (0.10 g, 1.72 mmol) was added and the reaction mixture was stirred 1.5 h at room temperature. The solution was poured into ethyl acetate and washed successively with water (2×), 10% aqueous sodium bicarbonate, water and brine. The organic solution was dried over sodium sulfate, filtered, concentrated and purified by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 50%) to afford (3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one (0.46 g, 92%) as a white foam; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.2, Hz, 2H,) 7.37 (d, J=8.2 Hz, 2H), 6.9-7.4 (m, 12H), 6.8 (m, 1H), 4.9 (br s, 1H), 4.67 (t, J=6.0 Hz, 1H), 4.63 (d, J=2.5 Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.0 (m, 4H), 0.87 (s, 9H), 0.02 (s, 3H), −0.16 (s, 3H).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccccc1F
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: Fc1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-fluorobenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-fluorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: N#Cc1cnc(Br)s1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C#N)s3)CC2)c(Cl)c1Cl

Procedure:
To a solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1; 0.330 g, 1.058 mmol) in NMP (2 ml) was added TEA (0.150 ml, 1.058 mmol) followed by the addition of 2-bromo-1,3-thiazole-5-carbonitrile (prepared according to F. Campagna et al. Tet. Lett, 1977, 21, 1815-1816) (0.200 g, 1.058 mmol) at room temperature. Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 20 minutes. The crude mixture was diluted with EtOAc and washed with water several times. The extracts were combined dried over magnesium sulfate and concentrated to give the desired product. (0.450 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:5][C:6]=1[CH3:7].[Cl:19]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:19][CH2:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)C1CCN(c2nc(C)c(C)s2)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(c2nc(CCl)c(C)s2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
To a mixture of ethyl 1-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine-4-carboxylate (6.51 g), acetonitrile (100 mL) was added N-chlorosuccinimide (3.24 g) at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give ethyl 1-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperidine-4-carboxylate as colorless crystals (1.93 g, yield 26%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 76-77° C.
Reaction SMILES: [CH2:1]([P:8](CC(C(OCC1C=CC=CC=1)=O)CCC(OCC1C=CC=CC=1)=O)(=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.[Pd]>[CH2:1]([PH:8](=[O:9])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: O=[PH](O)Cc1ccccc1

Procedure:
Benzyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid(0.5 g, 1.0 mmol) in 20 mL of water containing 120 mg of 10% Pd/C was hydrogenated on a Parr hydrogenator at 40 psi for 6 hours. Filtration through a Celite pad followed by evaporation on high vacuum gave 0.17 g (57%) of 2-[(benzylhydroxyphosphinyl)methyl]pentanedioic acid(4,R=CH2Ph) as a white solid. 1H NMR (D2O): 7.1 ppm(m,5H), 2.9 ppm(d,2H), 2.4 ppm(m,1H), 2.1 ppm(t,2H), 1.8 ppm(m,1H), 1.6 ppm(m,3H) Elemental Analysis, Calculated C13H17O6P: C52.00H5.71: Found: C51.48H5.70
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:21])([F:20])[C:13]1([C:16](OC)=[O:17])[CH2:15][CH2:14]1>ClCCl>[F:11][C:12]([F:21])([F:20])[C:13]1([CH2:16][OH:17])[CH2:15][CH2:14]1
Reactant: COC(=O)C1(C(F)(F)F)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCC1(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 26.7 ml (26.7 mmol) of diisobutylaluminum hydride (1M in dichloromethane) were slowly added dropwise to a solution of 1.89 g (10.7 mmol) of methyl 1-(trifluoromethyl)cyclopropanecarboxylate in 10 ml of dichloromethane. The mixture was then stirred at 0° C. for another 2 h and the reaction was subsequently terminated by addition of 10 ml of methanol. The reaction mixture was diluted with 30 ml of aqueous 20% strength sodium potassium tartrate solution and 30 ml of aqueous buffer solution (pH 7) and stirred vigorously at room temperature overnight. The phases were separated and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product corresponded to the title compound. Yield: 0.96 g (64% of theory)
Reaction SMILES: [CH2:1]=[CH:2][C:3]([N:5]1[CH2:10][C@H:9]([N:11]2[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:20][CH:21]=3)[C:13]3=[C:29]([NH2:33])[N:30]=[CH:31][N:32]=[C:12]23)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:34]([O:37][CH2:38][O:39][C:40](ON1C(=O)CCC1=O)=[O:41])(=[O:36])[CH3:35].C(N(CC)CC)C>CN(C)C(=O)C>[C:34]([O:37][CH2:38][O:39][C:40](=[O:41])[NH:33][C:29]1[N:30]=[CH:31][N:32]=[C:12]2[N:11]([C@@H:9]3[CH2:8][CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH:2]=[CH2:1])[CH2:10]3)[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:20][CH:21]=3)[C:13]=12)(=[O:36])[CH3:35]
Reactant: CC(=O)OCOC(=O)ON1C(=O)CCC1=O
Reactant: C=CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: C=CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(NC(=O)OCOC(C)=O)ncnc32)C1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Alternatively, a mixture of ibrutinib (25 mg, 1.0 eq), (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (1.5 eq), and triethylamine (3.0 eq) in N,N-dimethylacetamide (DMA) (1.0 mL) was stirred at 20° C. overnight. The reaction was then purified by reverse-phase (C-18) liquid chromatography using water and acetonitrile as eluents to yield compound (1).
Reaction SMILES: O[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:26]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1)=[N+:27]=[N-:28]
Reactant: OCc1ccc2nc[nH]c2c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1ccc2nc[nH]c2c1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) suspension of 5-(hydroxymethyl)-benzimidazole (920 mg, 6.2 mmol) in THF (12 mL) was added sequentially DPPA (1.46 mL, 6.8 mmol) and DBU (1.11 mL, 7.4 mmol). The resulting solution was heated to reflux for 5 h, cooled to RT, and concentrated in vacuo. The residue was partitioned between sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. Silica gel chromatography (15% MeOH—CHCl3), afforded the title compound as a brown solid:
Reaction SMILES: O.O.[OH-].[Li+].C[O:6][C:7](=[O:21])[CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1>CO>[C:11]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][C:7]([OH:21])=[O:6])[CH:10]=1
Reactant: COC(=O)Cc1cccc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cccc(-c2ccccc2)c1

Procedure:
Water (39 mL), followed by lithium hydroxide monohydrate (4.2 g, 101.5 mmol) were added to a solution of biphenyl-3-yl acetic acid methyl ester (11.43 g, 50.57 mmol) in methanol (265 mL). The mixture was stirred at ambient temperature for 2h then the organics were removed under reduced pressure. The mixture was acidified with dilute hydrochloric acid (1M, 80 mL), extracted with chloroform (2×100 mL), dried (MgSO4) and evaporated under reduced pressure to afford biphenyl-3-yl acetic acid as a white solid, yield 10.6 g, (99%), analytical HPLC Rt=16.565 min, HPLC-MS (single main UV peak with Rt=7.91 min, 213.1 [M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][CH:18]2[OH:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)(Cl)(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc([N+](=O)[O-])c2c1CCCC2O
Agent: O=[Cr](=O)(Cl)Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCCOc1ccc([N+](=O)[O-])c2c1CCCC2=O
Yield: 76.4 %

Procedure:
5-[3′-(t-Butoxycarbonylamino)propyloxy]-1-hydroxy-8-nitro-1,2,3,4-tetrahydronaphthalene (2.46 g) is dissolved in dry methylene chloride (110 ml), and thereto are added molecular sieves 3A (6.73 g) and pyridinium dichlorochromate (1.5 equivalent), and the mixture is refluxed. After the reaction is completed, the mixture is diluted with ether, and the insoluble materials are removed by filtration through a pad of Celite. The filtrate is concentrated, and the residue is purified by silica gel column chromatography to give the title compound (1.87 g) as a colorless powder.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]2[CH2:28][CH:27]3[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:21])[C:3]1=[O:31].[C:32]1([CH3:41])[CH:37]=[CH:36][CH:35]=[C:34]([N:38]=[C:39]=[O:40])[CH:33]=1>ClCCl>[CH:24]12[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30]1)[CH2:28][N:22]([C:20]([CH2:19][N:4]1[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:8][CH:2]([NH:1][C:39]([NH:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([CH3:41])[CH:33]=3)=[O:40])[C:3]1=[O:31])=[O:21])[CH2:23]2
Reactant: NC1N=C(C2CCCCC2)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NC2N=C(C3CCCCC3)c3ccccc3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.19 g) in dichloromethane (10 ml) was added m-tolyl isocyanate (0.064 g) at room temperature. The mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo. The residue was subjected by column chromatography on silica gel with chloroform and a mixture of chloroform and ethyl acetate (5:1) to give N-[(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-cyclohexyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea (0.075 g) as a white amorphous mass.