Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]([CH3:19])[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH:20]([CH3:38])[C@H:21]([C:34]([O:36][CH3:37])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C.CC(C)N=C=NC(C)C.CCOCC>[C:1]([N:11]([CH3:19])[C@H:12]([C:16]([N:20]([CH3:38])[C@H:21]([C:34]([O:36][CH3:37])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)OC
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 3.25 g of Z-N-Me-Val-OH, 2.2 g of N-Me-Tyr(3-tBu)-OMe and 1.88 g of HOBT in DMF (30 ml), DIC (1.9 ml) was added under cooling with ice and the mixture was stirred at room temperature for 23 hours. Water was added to the reaction mixture and extraction was effected with ether. The extract was washed with saturated brine and the organic layer was dried with sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 100:10:1) to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-OMe in the amount of 1.96 g (47%).
Reaction SMILES: [CH:1]12[CH2:29][CH2:28][CH:4]([N:5]([C:7]3[N:12]=[C:11]([C:13]4[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=4)[N:10]=[C:9]4[N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:21]=[CH:22][C:8]=34)[CH2:6]1)[CH2:3][O:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.[N:44]([C:47]1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3CC4CCC3CO4)N=2)=CC=1)=[C:45]=[O:46]>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH:1]12[CH2:29][CH2:28][CH:4]([N:5]([C:7]3[N:12]=[C:11]([C:13]4[CH:14]=[CH:15][C:16]([NH:17][C:45]([NH:44][CH3:47])=[O:46])=[CH:18][CH:19]=4)[N:10]=[C:9]4[N:20]([CH2:23][C:24]([F:26])([F:27])[F:25])[N:21]=[CH:22][C:8]=34)[CH2:6]1)[CH2:3][O:2]2
Reactant: O=C=Nc1ccc(-c2nc(N3CC4CCC3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: Nc1ccc(-c2nc(N3CC4CCC3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC3CO4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
A solution of 4-(4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (50 mg, 0.12 mmol) in dichloromethane (2.5 mL) was treated triethylamine (160 μL), followed by triphosgene (27 mg, 0.09 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1.2 mL)—was added to the 5-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.2]octane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 1-(4-(4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea. MS (ES+): 462.3 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C@@H:7]([CH2:16][S:17]C(=O)C)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[OH-].[Na+]>CO>[SH:17][CH2:16][C@@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:6]([NH:5][C@H:4]([C:3]([OH:26])=[O:2])[CH2:22][CH2:23][S:24][CH3:25])=[O:21]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@@H](CSC(C)=O)Cc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)[C@@H](CS)Cc1ccccc1C)C(=O)O
Reaction time: 2 h

Procedure:
To N-[2(S)-acetylthiomethyl-3-(2-methylphenyl)propionyl]-(S)-methionine methyl ester (0.60 g, 1.5 mmol) in degassed MeOH (15 ml) add 1.0N NaOH (degassed) (5.0 ml). After 2 hr., concentrate in vacuo to 5 ml., add 5.0 ml 1.0N HCl, and separate the gum. Dissolve this in EtOAc, dry and concentrate to obtain the title compound, m.p. 116°-117°, [α]D26 =+13.0° (EtOH).
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:46]=[CH:45][C:14]([C:15]([C:17]2[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=3)[S:20][C:21]=2[C:22]2[N:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=2)=[O:16])=[CH:13][CH:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:16])([CH:3]2[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[C:17]2[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=3)[S:20][C:21]=2[C:22]2[N:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[N:23]=2)=[CH:45][CH:46]=1
Reactant: CN1CCC(Cl)CC1
Reactant: CC(=O)Nc1cc(-c2cc(C(=O)c3ccc(Cl)cc3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2cc(C(O)(c3ccc(Cl)cc3)C3CCN(C)CC3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Temperature: 45 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
A 25 mL round bottom flask charged with magnesium turnings (23.0 mg, 0.947 mmol) was flame-dried. To the flask was added tetrahydrofuran (1.00 mL) and a drop of 1,2-dibromoethane. The mixture was heated to 45° C. for 10 min and cooled to rt. To the mixture was added 4-chloro-N-methylpiperidine (126 mg, 0.947 mmol). The reaction was stirred at 35° C. under an atmosphere of nitrogen for 12 hrs. The mixture turned cloudy, and magnesium turnings eventually disappeared, as the reaction progressed. To a solution of N-{4-[4-(4-chlorobenzoyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide (113 mg, 0.204 mmol) in tetrahydrofuran (1.00 mL) was added the pre-prepared Grignard reagent solution dropwise at 0° C. In 3 hrs, the reaction was warmed to rt. In another 3 hrs, the reaction was quenched with water and distributed between NaHCO3(aq) saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was dried and concentrated. Purification on a silica gel column (gradient elution, 1-20% MeOH) provided N-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamide as a yellow solid (59.0 mg, 44.3% yield). LCMS: (AA) ES+ 653, 655; NMR (400 MHz, CDCl3) δ 8.77-8.66 (s, 1H), 8.60-8.49 (s, 1H), 8.31-8.23 (d, J=5.3 Hz, 1H), 8.15-8.08 (m, 2H), 7.66-7.60 (s, 1H), 7.34-7.23 (m, 3H), 7.17-7.08 (d, J=8.7 Hz, 2H), 5.45-5.38 (s, 2H), 3.63-3.51 (m, 2H), 3.49-3.44 (s, 3H), 3.02-2.90 (d, J=10.8 Hz, 1H), 2.90-2.78 (d, J=11.2 Hz, 1H), 2.28-2.20 (m, 4H), 2.20-2.09 (m, 1H), 2.07-1.95 (m, 1H), 1.96-1.78 (m, 2H), 1.76-1.58 (qd, J=12.7, 3.8 Hz, 1H), 1.16-1.07 (d, J=12.5 Hz, 1H), 0.99-0.85 (m, 2H), 0.02-1-0.04 (s, 9H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]([CH3:44])=[CH2:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=C(CC)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([CH3:44])[CH3:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)c1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Agent: CCc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Yield: 91 %

Procedure:
Prepared in 91% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-(prop-1-en-2-yl)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 700.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C=CC=CC=1>C(Cl)Cl>[C:14]([O:13][C:11](=[O:12])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:23][CH:22]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.6 %

Procedure:
4-chlorobenzeneboronic acid (2.05 eq, 2.05 g), N-boc tyramine (1 eq, 6.55 mmol, 1.60 g), cooper(II)-acetate (1.01 eq, 1.20 g) and pyridine (5 eq, 2.64 ml) were dissolved in 70 ml of dry DCM. In the solution were added 4 Å molecular sieves (3 g) and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was then filtered over a celite pad, it was diluted with 150 ml of diethyl ether and was subsequently washed with 150 ml of 0.5 N HCl water solution, 150 ml of water and 150 ml of brine. The organic phase was dried, the solvent was evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 50 g normal phase silica SNAP column and cyclohexane/EtOAc solvent system (gradient 5-30% of EtOAc in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was {2-[4-(4-chloro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.7 g, yield=68.14%, purity=94%). MS: [M−H]−=346.13 1H NMR (300 MHz; CDCl3) δ/ppm 1.42 (s, 9H), 2.75 (t, J=7.0 Hz, 2H), 3.35 (m, 2H), 6.87-6.95 (m, 4H), 7.14 (d, J=8.45 Hz, 2H), 7.22-7.28 (m, 2H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH:31][C:32]1[CH:36]=[C:35]([CH2:37][CH2:38][C:39](O)=[O:40])[O:34][N:33]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:31][C:32]1[CH:36]=[C:35]([CH2:37][CH2:38][C:39]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[O:40])[O:34][N:33]=1
Reactant: O=C(O)CCc1cc(O)no1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C2CCN(C(=O)CCc3cc(O)no3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Yield: 25 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (46.8 mg, 0.112 mmol), 3-(3-hydroxy-isoxazol-5-yl)-propionic acid (17.7 mg, 0.112 mmol), triethylamine (47 uL, 0.337 mmol) and BOP (47.6 mg, 0.112 mmol) in 1 mL DMF were reacted as above. The crude product was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[3-(3-hydroxy-isoxazol-5-yl)-propionyl]-piperidin-4-yl}-phenyl)-amide as a white solid (15.5 mg, 25%). ES-MS calcd for C28H25F3N4O5 (m/e) 554.53, obsd 555 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH:7]1C(Cl)=CC=C(Cl)C=1.[NH2:15][C:16]1[C:21]([NH:22]C)=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH3:7][N:15]1[C:2](=[O:3])[C:1](=[O:5])[NH:22][C:21]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNc1cccnc1N
Reactant: Clc1ccc(Cl)cc1
Product: Cn1c(=O)c(=O)[nH]c2cccnc21
Reaction time: 1 h

Procedure:
To a mixture of 8 ml. of oxalyl chloride in 150 ml. dichlorobenzene at 60° C. was added lowly 7.5 g. of 2-amino-3-methylaminopyridine. After completion of addition, the temperature of the reaction mixture was allowed to rise to 130° C. It was stirred at this temperature for 1 hour, filtered hot, and the solid washed with ether, m.p. 168°-174° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:22]1[C:30]2[C:25](=[CH:26][N:27]=[C:28]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:29]=2)[N:24](COCC[Si](C)(C)C)[N:23]=1>Cl.O>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:28]2[CH:29]=[C:30]3[C:22]([N:3]4[CH2:4][CH2:5][C:6]5([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]5)[C:2]4=[O:1])=[N:23][NH:24][C:25]3=[CH:26][N:27]=2)[CH:32]=1
Reactant: C[Si](C)(C)CCOCn1nc(N2CCC3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c2cc(-c3cccnc3)ncc21
Agent: Cl
Solvent: O
Product: O=C1N(c2n[nH]c3cnc(-c4cccnc4)cc23)CCC12CCNCC2
Yield: 26.6 %

Procedure:
A solution of benzyl 1-oxo-2-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (0.140 g, 0.229 mmol) in 2.00 M of Hydrogen chloride in Water (16.2 mL) was stirred at 100° C. for 18 h. The reaction was concentrated then submitted for rHPLC to give 295 (21.2 mg, 26.5% yield). ESI MS m/z=349.2 (M+1). 1H NMR (400 MHz, DMSO) δ 9.19 (d, J=1.8 Hz, 1H), 9.07 (s, 1H), 8.67 (s, 1H), 8.57 (d, J=4.6 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.51 (dd, J=7.9, 4.7 Hz, 1H), 3.97 (t, J=7.0 Hz, 2H), 2.92 (d, J=12.6 Hz, 2H), 2.63 (dd, J=21.4, 9.3 Hz, 2H), 2.20 (t, J=7.0 Hz, 2H), 1.74 (td, J=12.5, 4.1 Hz, 2H), 1.48 (d, J=13.0 Hz, 2H)
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[N:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:14][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:3][NH:2][CH3:1])=[N:6]1
Reactant: CNC(=O)c1nn(C)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1nn(C)c2ccccc12
Temperature: 25 °C
Yield: 104 %

Procedure:
To a solution of N,1-dimethyl-1H-indazole-3-carboxamide (3.42 g, 18 mmole) in dry THF (90 mL) was added a solution of LiAlH4 in THF (1.0 M, 36 mL, 36 mmole) slowly at RT. After 2 hr the mixture was heated to a gentle reflux. After 4 hr the mixture was cooled to RT and quenched by dropwise addition of 2.0 M NaOH until a white solid had formed. The mixture was dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (3.28 g, 100%) as an oil which was sufficiently pure for use in the next step: MS (ES) m/e 176 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=O)=[CH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:5]2
Reactant: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Brc1ccc2[nH]c(CN3CCCC3)cc2c1
Temperature: 0 °C

Procedure:
To a suspension of (5-bromo-1H-indol-2-yl)-pyrrolidin-1-yl-methanone (0.53 g, 1.8 mmol) in THF (50 mL) at 0° C. was slowly added lithium aluminum hydride (0.20 g, 5.4 mmol). The mixture was stirred under nitrogen at 0° C. for a while and the cooling bath was allowed to warm to room temperature. The mixture was then stirred at room temperature for 17 hours. The reaction was quenched by careful, successive, dropwise addition of water (0.2 mL), 15% NaOH aqueous solution (0.2 mL), and water (0.6 mL). The solid was filtered and washed with MeOH and CH2Cl2. The filtrate was concentrated to dryness, and dried under vacuum, to give 5-bromo-2-pyrrolidin-1-ylmethyl-1H-indole as a white solid. Yield: 0.45 g (90%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([O:9][CH2:10][CH3:11])[C:6]=1[C:7]#[N:8].[OH-].[Na+].CN(C)[CH:16]=[O:17]>P(Cl)(Cl)(Cl)=O>[NH2:1][C:2]1[S:3][C:4]([CH:16]=[O:17])=[C:5]([O:9][CH2:10][CH3:11])[C:6]=1[C:7]#[N:8]
Reactant: CCOc1csc(N)c1C#N
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1c(C=O)sc(N)c1C#N
Reaction time: 4 h

Procedure:
168 parts of 2-amino-3-cyano-4-ethoxythiophene (Example 1) are dissolved in 500 parts of dimethylformamide, and 200 parts of phosphoryl trichloride are added dropwise to the stirred solution. The reaction is exothermic, and the rate of dropwise addition is adjusted so that the temperature of the reaction mixture does not exceed 50° C. Stirring is continued for 4 hours at 50° C., 50 parts of ice are added, and the mixture is stirred until a clear solution has formed. This solution is run into 2000 parts of 12.5% strength sodium hydroxide solution and the temperature is kept at 20°-30° C. Stirring is continued for 8 hours at room temperature, after which the product is filtered off under suction, washed with water and dried. 185 parts of 2-amino-3-cyano-4-ethoxy-5-formylthiophene are obtained. A sample recrystallized from pentanol melts at 245°-246° C. and has the following analytical values:
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:13]1=[O:34])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:13]1=[O:34]
Reactant: O=C(N[C@H]1CCCN(P(=O)(Nc2ccccc2)Nc2ccccc2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CCCN(P(=O)(Nc2ccccc2)Nc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Palladium black (20 mg) was added to a solution of (3S)-3-benzyloxycarbonylamino-1-bis(phenylamino)phosphinyl-2-piperidone (200.2 mg, 0.4184 mmol) in methanol (4 mL), and the resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O>[CH2:19]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([O:13][CH3:14])([O:2][CH3:1])[C:4]1=[O:12])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: COC1(OC)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C(OC)(OC)c2ccccc21
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of 3.86 g of 3,3-dimethoxyindolin-2-one in 30 ml of N,N-dimethylformamide was added dropwise to a suspension of 1.2 g of sodium hydride (60%) in 40 ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After the mixture was stirred at that temperature for 30 minutes, 2.60 ml of allyl bromide was added thereto. The resulting mixture was stirred for 1 hour and then concentrated. Chloroform was added to the residue, and the mixture was washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform/hexane=1/1) to give 4.19 g (90%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[NH2:1][C:2]1[C:3]([C:9]([N:12]2[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: C1CNC1
Reactant: Cc1ccc(N)c(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1ccc(N)c(C(=O)N2CCC2)n1
Temperature: 70 °C
Yield: 65.5 %

Procedure:
To a stirred mixture of 3-amino-6-methylpicolinic acid (525 mg, 2.17 mmol) and azetidine (124 mg, 146 μl, 2.17 mmol) at r.t. in THF (15 ml) under an argon atmosphere were added HATU (1.65 g, 4.35 mmol) and 4-methylmorpholine (719 μl, 6.52 mmol). The mixture was heated to 70° C. overnight, then cooled to r.t. and concentrated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient to give the title compound (272 mg, 65%) as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:27]=[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCCCCCCC(=N)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: CCCCCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Reaction time: 1.25 h

Procedure:
To a solution of 0.59 g (2.84 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 6 mL of toluene, 0.503 g (3.1 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 5 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxynonanimidamide (compound of example 47; 1.0 g, 3.8 mmol) diluted with 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[CH3:11][O-:12].[Na+].C(OCC)C.Cl>CO>[CH3:11][O:12][C:7](=[O:9])[CH2:8][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)CC(C)(C)CC(=O)O
Temperature: 0 °C
Yield: 67.5 %

Procedure:
Combine 3,3-dimethylglutaric anhydride (1.00 g, 7.03 mmol) and sodium methoxide (2.5 mL, 14.1 mmol, 30 wt % in methanol) in methanol (20 mL) and heat at reflux for 3 h. Cool the reaction to room temperature and pour into ice water (100 mL). Add diethyl ether (25 mL) and adjust the pH of the mixture to pH=2 with 2 N HCl (10 mL) and separate the layers. Extract the aqueous layer with diethyl ether (25 mL) and combine the organic layers, dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford 3,3-dimethylpentanedioic acid monomethyl ester as a colorless oil (0.827 g, 68%): 1H NMR (CDCl3, 300 MHz) δ 1.14 (s, 6H), 2.46 (s, 2H), 2.48 (s, 2H), 3.67 (s, 3H), 10.9 (br s, 1H); APCI MS (Negative mode) m/z 173 [C8H14O4−H]−.