Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CCC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CCC(=O)N1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 28.9 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 265c (200 mg, 0.53 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (834 mg, 2.10 mmol), Pd(dppf)Cl2 (19 mg, 0.0263 mmol), K3PO4 (223 mg, 1.052 mmol), sodium acetate (86 mg, 1.052 mmol), acetonitrile (10 mL), and water (5 drops). After three cycles of vacuum/argon flush, the reaction mixture was heated at 100° C. for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 265d (100 mg, 29%) as yellow oil. MS-ESI: [M+H]+ 653.3
Reaction SMILES: C(O)C(N)(CO)CO.[O:9]=[CH:10][C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])[OH:12].C(O)C(N)(CO)CO.C(=O)([O-])[O-]>>[CH2:19]([OH:20])[C@H:17]([C@H:15]([C@@H:13]([C@@H:11]([CH2:10][OH:9])[OH:12])[OH:14])[OH:16])[OH:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
NAC and THAM were granulated separately with an aqueous solution of gum arabic and dextrose. The granulate was dried, mixed with flavour, saccharin and mannitol and pressed into tablets. A similar composition was prepared by replacing THAM with THAM carbonate (807 mg, corresponding to 534 mg of THAM).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[N:8](C(OC(C)(C)C)=O)[C:9](=[O:16])[C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:16])[C:10]3([CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(CCOCC2)c2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2cc(Br)ccc2C12CCOCC2
Reaction time: 5 h
Yield: 103.1 %

Procedure:
A mixture of tert-butyl 6-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-carboxylate (preparation 6b, 4.20 g, 11.0 mmol) and a 5M solution of hydrogen chloride in 1,4-dioxane (25 mL) was stirred at room temperature. After 5 hours, the mixture was concentrated in vacuo to give the title compound (3.20 g, 98%) as a pale pink solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:31][NH2:32]>CO>[O:22]1[C:18]2[CH:17]=[CH:16][C:15]([C:12]([CH2:13][CH3:14])=[C:11]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:32][CH3:31])=[CH:6][CH:7]=3)=[CH:23][C:19]=2[CH2:20][CH2:21]1
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2c(c1)CCO2
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2c(c1)CCO2
Temperature: 85 °C

Procedure:
To a stirred solution of 4-(1-(4-(2-chloroethoxy)phenyl)-2-(2,3-dihydrobenzofuran-5-yl)but-1-enyl)phenol (500 mg, 1.0 eq) in 20 mL MeOH, 10 mL CH3NH2 (aq) was added and heated at 85° C. for 24 h. The solvent was removed in vacuo, water was added to the residue and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.10 & 7.01 (d, J=8.8 Hz, 2H), 6.92 (s, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.82 & 6.74 (d, J=8.8 Hz, 2H), 6.79 & 6.75 (d, J=8.8 Hz, 2H), 6.57 (d, J=8.4 Hz, 1H), 6.51 & 6.45 (d, J=8.8 Hz, 2H), 4.51 (t, J=8.4 Hz, 2H), 4.10 & 3.96 (t, J=4.8 Hz, 2H), 3.09 (t, J=8.8 Hz, 2H), 3.01 & 2.93 (t, J=4.8 Hz, 2H), 2.54 & 2.50 (s, 3H), 2.39-2.46 (m, 2H), 0.90-0.94 (m, 3H); m/z=416 [M+1]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31].C(=O)([O-])N.O.NN>C(Cl)Cl.CO>[NH2:9][CH2:8][C@@H:3]1[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]1[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: C=CCOC(=O)Cl
Agent: NC(=O)[O-]
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CN
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (5 g, 19.4 mmol) in CH2Cl2 at 0° C. was added DIPEA (3.8 mL), followed by allyl chloroformate (2.6 mL). The reaction was allowed to warm to rt overnight. After 16 h, the reaction was concentrated to remove the CH2Cl2, and then re-suspended in EtOAc and washed with 1 M HCl (2×), brine (2×), dried (MgSO4) and concentrated to give the crude carbamate which was used without further purification. A mixture of the crude carbamate and hydrazine hydrate (2 g, 39 mmol) in MeOH (100 mL) was heated at 60° C. for 2 h. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with 2 N NaOH (2×), brine, and then dried (Na2SO4). The solvent was removed in vacuo to obtain the title compound which was used without further purification. ESI-MS (m/z): 213 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>[Cl-].[Cl-].[Zn+2]>[OH:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:9])[CH:4]=[CH:5][C:6]=1[C:10](=[O:12])[CH3:11]
Reactant: Cc1c(O)cccc1O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)c1ccc(O)c(C)c1O
Temperature: 105 °C

Procedure:
A mixture of 2-methyl-benzene-1,3-diol, acetic anhydride and ZnCl2 was heated at 150-60° C. for 3.5 h, and processed as reported in the literature. (Pearson. D. E. et. al., Synthesis, 533, 1972 and the references cited therein). The crude was purified using flash chromatography (silica gel, 0-5% CH3CN in chloroform) to obtain the title compound. Yield, 73%; mp, 65-66° C. (EtOAc-PE 60-80° C.); MS (CI): 195 (M++29), 169 (M++1); analysis: C9H10O3 requires C, 65.05; H, 6.07. found C, 65.44; H, 6.62%.
Reaction SMILES: Br[C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[CH:4][C:5]2[O:24][CH2:23][C:8]3=[N:9][N:10]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:11](=[O:14])[CH:12]([CH3:13])[N:7]3[C:6]=2[CH:25]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH3:13][CH:12]1[C:11](=[O:14])[N:10]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:9]=[C:8]2[CH2:23][O:24][C:5]3[CH:4]=[C:3]([C:26]([F:29])([F:28])[F:27])[C:2]([C:40]4[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[CH2:38][CH:39]=4)=[CH:25][C:6]=3[N:7]12
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A mixture of 9-bromo-1-methyl-8-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (Example #53, Step E, 0.08 g, 0.162 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.10 g, 0.324 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloride dichloromethane complex (0.026 g, 0.032 mmol) and K2CO3 (0.045 g, 0.324 mmol) in dioxane (1.2 mL) and water (0.2 mL) was heated at reflux for 6 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 40% EtOAc in petroleum ether) to give tert-butyl 4-(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.07 g, 73%) as a pale-white solid. 1H NMR (methanol-d4, 400 MHz): δ 7.28 (s, 1H), 7.10 (s, 1H), 5.64 (s, 1H), 5.11 (q, J=10.4 Hz, 2H), 4.97 (q, J=6.8 Hz, 1H), 4.69 (d, J=13.2 Hz, 2H), 4.04 (s, 2H), 3.70 (m, 4H), 2.39 (s, 2H), 1.51 (s, 9H), 1.47 (d, J=6.8 Hz, 3H), 0.96 (t, J=8.4 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[OH-:32].[Na+].OO.Cl>O.CC(OC)(C)C.CCCCCCC.C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][OH:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: Cl
Agent: OO
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: OCC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.1 %

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (131.0 g, 0.448 mol) and THF (500 mL) at ambient temperature. Add a 0.5M THF solution of 9-borabicyclo[3.3.1] nonane (9-BBN) (985.5 mL, 0.493 mol) over 20 minutes, keeping the pot temperature below 25° C. Stir the resulting mixture at ambient temperature for 16-18 hours. Cool the solution to 0-5° C. and quench with 3N NaOH (164.3 mL, 0.493 mol) over 5-10 minutes. Stir at 0-5° C. for 10-15 minutes and remove cooling bath. Add a 30% aqueous solution of hydrogen peroxide (160.2 mL, 1.57 mol) over 1 hour, maintaining a pot temperature of 30-35° C. Stir the resulting mixture for 1 hour and dilute with water (1.31 L) and MTBE (1.31 L). Layer separate and re-extract the aqueous layer with MTBE (655 mL). Combine organics and wash with water (2×655 mL) and brine (2×655 mL). Dry the MTBE solution over sodium sulfate, filter and concentrate in vacuo to afford 169.1 g of crude oil (theory=139.1 g). Treat the crude with 5N HCl (358 mL, 1.79 moles) and stir 5 minutes. Add water (250 mL) and stir 15-20 minutes. Add heptane (1.31 L) and stir 5 minutes. Layer separate and re-extract the aqueous layer with MTBE (655 mL). Discard these organic extracts and add 5N NaOH (403 mL, 2.02 moles) to the aqueous portion. Stir 5 minutes then dilute with MTBE (1.31 L) and layer separate. Re-extract the aqueous layer with MTBE (655 mL). Combine the MTBE extracts and wash with water (655 mL), then dry over sodium sulfate, filter and concentrate in vacuo to afford 137.8 g (99.0%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 1.87 (m, 1H), 2.03 (m, 1H), 2.33 (m, 2H), 2.43 (m, 1H), 2.50 (d, 1H), 2.66 (d, 1H), 2.83 (m, 1H), 2.93 (m, 1H), 3.39 (d, 1H), 3.50 (m, 1H), 3.74 (m, 1H), 3.88 (m, 1H), 4.18 (d, 1H), 4.80 (bs, 1H), 7.26 (m,2H), 7.32 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].CI.[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][O:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([C:10](=[O:12])[CH3:11])=[C:2]([CH3:1])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(C)c(O)cc1C
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)c(C(C)=O)cc1C
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of 1-(2,5-dimethyl-4-hydroxy-phenyl)-ethanone 14.6 g, methyl iodide 16.6 g, potassium carbonate 26.8 g and acetone 200 ml was stirred with heating under reflux for eight hours. The reaction mixture was cooled to room temperature and was filtered, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(4-methoxy-2,5-dimethyl-phenyl)-ethanone 15.1 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:21])=[CH:17][N:16]=1
Reactant: NCc1ccccn1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCc2ccccn2)cn1
Yield: 74 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using 2-(aminomethyl)pyridine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:95:5, 191 mg, 74%) which was obtained as a white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](Cl)=[N:7][CH:8]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=2)=[N:7][CH:8]=1
Reactant: OCc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 100 °C
Yield: 100.1 %

Procedure:
To a solution of 5-trifluoromethyl-2-chloro-pyridine (150.0 g, 0.826 mol) in DMF (1.9 L) was added 3-hydroxy-phenyl-methanol (112.5 g, 0.906 mol) and of potassium carbonate (171.0 g, 1.237 mol). The solids were washed into the flask with 100 mL of DMF. The stirred mixture was heated to 95-105° C. for 5 h. It was cooled to ambient temperature and then poured into 5 L of stirred ice-water. The mixture was extracted with ether:hexane (2:1, 1.5 L, 1.0 L). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to dryness to give the product (222.5 g, 100%).
Reaction SMILES: C(OC([NH:11][C:12]([C@H:14]1[C@@H:17]([C:18]([NH2:20])=[O:19])[CH2:16][NH:15]1)=[O:13])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH:15]1[CH2:16][C@H:17]([C:18]([NH2:20])=[O:19])[C@@H:14]1[C:12]([NH2:11])=[O:13]
Reactant: NC(=O)[C@H]1CN[C@H]1C(=O)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H]1CN[C@H]1C(N)=O

Procedure:
A solution of cis-N-(Benzyloxycarbonyl) azetidine 2,3-dicarboxylic acid and, e.g., ammonia are reacted with [(CH3)2N]3PCl2 to form the cis-N(benzyloxycarbonyl)azetidine-2,3-dicarboxamide (XI), as set forth by Appel et al., Chem. Ber. 116, 2037-2040 (1983). XI, 10% Pd/C and methanol are hydrogenated in a Parr shaker under 3 atm of hydrogen, for 4 hours. The catalyst is filtered off and thoroughly washed. The solution is evaporated to dryness and dried in vacuo to arrive at cis-azetidine-2,3-dicarboxamide.
Reaction SMILES: C([O:3][C:4]([CH:6]([C:14](OCC)=[O:15])[CH:7]([CH2:9][CH2:10][CH2:11][CH2:12]C)C)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S(=O)(=O)(O)O>[Na].C(OCC)C>[CH2:7]([CH:6]([CH2:14][OH:15])[CH2:4][OH:3])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(C)C(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CO)CO

Procedure:
A solution of compound from Example 1 (59.2 g, 257 mmol) in sodium-dried diethyl ether (50 cm3) was added dropwise to a mixture of lithium aluminum hydride (19.5 g, 514 mmol) in dry diehtyl ether (450 cm3) with vigorous stirring and heated under gentle reflux. During this period, four 50 cm3 portions of dry diethyl ether were added. After further heating (1 h), water (75 cm3) was carefully added to decompose excess lithium aluminum hydride, followed by sulphuric acid (20%, 350 cm3). The aqueous layer was extracted with diethyl ether (2×100 cm3), the combined ethereal layers washed with water (2×100 cm3) and dried (MgSO4). The solvent was removed in vacuo to give the product as a colourless oil.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[N:13][CH:14]=2)[N:7]=[N:6][N:5]=1>O.C1COCC1>[CH3:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[N:13][CH:14]=2)[N:7]=[N:6][N:5]=1
Reactant: CCOC(=O)Cc1ccc(-n2nnnc2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnnn1-c1ccc(CC(=O)O)nc1
Temperature: 25 °C

Procedure:
Lithium hydroxide (161 mg, 3.84 mmol) dissolved in water (3 mL) was added to ethyl 2-(5-(5-methyl-1H-tetrazol-1-yl)pyridin-2-yl)acetate (776 mg, 3.14 mmol) in THF (10 ml) and stirred at room temperature. The reaction was followed by TLC. Evaporated off the organics without heating and cooled in ice bath then acidified with 1N HCL (3.84 ml, pH ˜3). Extracted with EtOAc/THF (2×), washed with brine (1×), dried over Na2SO4, filtered and concentrated to yield 2-(5-(5-methyl-1H-tetrazol-1-yl)pyridin-2-yl)acetic acid: 1H-NMR (500 MHz, CD3OD) δ ppm 8.79 (d, J=2.4 Hz, 1H), 8.098 (dd, J=8.0, 2.5 Hz, 1H), 7.710 (d, J=8.3 Hz, 1H), 3.978 (s, 2H), 2.649 (s, 3H)
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O1CCCC1.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[C:10](=[O:12])[CH3:11])=[CH:23][CH:24]=1
Reactant: CC(=O)N(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccc(N)cc1)Cc1ccc(N)cc1
Temperature: 80 °C
Yield: 110.6 %

Procedure:
A mixture of the product from Example 68A (250 mg, 0.759 mmol), iron powder (424 mg, 7.59 mmol), and ammonium chloride (203 mg, 3.80 mmol) in ethanol (1 mL), tetrahydrofuran (1 mL) and water (0.250 mL) was heated at 80° C. for 18 hours. The mixture was allowed to cool to rt, filtered, rinsed with methanol, and concentrated in vacuo. The residue was partitioned between EtOAc and H2O, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (226 mg, 90%). MS (ESI) m/z 269.9 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:31])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)c1ccccn1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccccn1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and pyridine-2-carboxylic acid to yield (3aR,4S,7aR)-4-(pyridine-2-carbonyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester eliminated ion); RT=3.433 min; HPLC Method III
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][N:8]([C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=3)[CH2:9][CH:2]12.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][O:32][C:33]2[CH:34]=[C:35]([NH2:38])[NH:36][N:37]=2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][N:8]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:38][C:35]4[NH:36][N:37]=[C:33]([O:32][CH2:31][C:25]5[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:23]([O:22][CH3:21])[CH:24]=5)[CH:34]=4)=[O:16])=[CH:18][CH:19]=3)[CH2:9][CH:2]12
Reactant: COC(=O)c1ccc(N2CC3CCCNC3C2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CC5CCCNC5C4)cc3)[nH]n2)cc(OC)c1
Yield: 30.5 %

Procedure:
4-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide was prepared following the procedure as for Example 115, but starting from methyl 4-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)benzoate (0.221 g, 0.85 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine HCl (0.243 g, 0.85 mmol) and 2M trimethylaluminium in toluene (1.06 ml, 2.13 mmol). The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.124 g, 30.5%) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)=[CH:32][CH:31]=1)[CH2:3][C@H:4]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:16]([O:15][C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C@@H:4]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:3][C@@H:2]([NH:1][C:47](=[O:48])[C@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[NH:45][C:43]([O:42][CH3:41])=[O:44])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)=[CH:34][CH:35]=1)=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](N)Cc1ccc(-c2nccs2)cc1)O[Si](C)(C)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2nccs2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution containing the product from Example 146A (0.053 g) in tetrahydrofuran (0.70 mL) were added the product from Example 1F (0.015 g, 0.079 mmol), DEPBT (0.033 g, 0.110 mmol), and N,N-diisopropylethylamine (0.065 mL, 0.373 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with chloroform and ending with 80 % ethyl acetate in chloroform to give the product (0.042 g).