Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]2[S:33][C:32]3[C:27](=[N:28][CH:29]=[CH:30][C:31]=3Cl)[CH:26]=2)=[O:24])[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]2[S:33][C:32]3[C:27](=[N:28][CH:29]=[CH:30][C:31]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:26]=2)=[O:24])[CH2:15][CH2:14]1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN1CCN(CCCNC(=O)c2cc3nccc(Cl)c3s2)CC1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCCN5CCN(C)CC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide by a procedure analogous to Example 1C. MS: 463 (MH+), HPLC Rf: 3.41 min.; HPLC purity: 99%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.OC[C@H]1CCCN1C(OC(C)(C)C)=O.[F:39][C:40]1[CH:41]=[C:42]([CH:59]=[CH:60][CH:61]=1)[O:43][C:44]1[CH:49]=[CH:48][C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.COCCOC>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:47]3[CH:46]=[CH:45][C:44]([O:43][C:42]4[CH:59]=[CH:60][CH:61]=[C:40]([F:39])[CH:41]=4)=[CH:49][CH:48]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), prepared as described in Example 1 except in the Mitsunobu reaction using (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate instead of (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (254 mg, 0.81 mmol, 1.20 equiv), tetrakis(triphenylphosphane) palladium (47 mg, 0.04 mmol, 0.06 equiv), ethylene glycol dimethyl ether (50 mL), sodium carbonate (180 mg, 1.70 mmol, 2.50 equiv), water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with dichloromethane and the organic layers combined, dried and concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.27 g (79%) of tert-butyl (2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a brown solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:29]O.O>C(Cl)(Cl)Cl.C[Re](=O)(=O)=O.[O-2].[O-2].[Mn+4]>[Si:22]([O:21][CH2:20][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N+:17]([O-:29])=[CH:16][CH:15]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: OO
Reactant: CC(C)(C)[Si](C)(C)OCC(CCCc1ccncc1)CO[Si](C)(C)C(C)(C)C
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCC(CCCc1cc[n+]([O-])cc1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[5-(tert-butyldimethylsilanyloxy)-4-(tert-butyldimethylsilanyloxymethyl)-pentyl]pyridine (0.43 g) prepared in (4) in chloroform (5.0 mL) were added methyltrioxorhenium (VII) (0.0030 g) and aqueous 30% hydrogen peroxide (0.21 mL). The reaction mixture was stirred at RT for 4 hr. An appropriate amount of manganese dioxide (IV) was added to the reaction mixture. The mixture was stirred for 1 hr. Water was added to the mixture and the mixture was extracted with chloroform. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to obtain the crude title compound.
Reaction SMILES: [C:1]1([N:11]2[C:15]([SH:16])=[CH:14][CH:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:24][C:18]([S:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[CH:13][CH:14]=1)([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Sc1ccnn1-c1cccc2ccccc12
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1ccnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(naphthalen-1-yl)-1H-pyrazole-5-thiol (120 mg, 0.53 mmol), ethyl bromoisobutyrate (0.09 mL, 0.58 mmol) and potassium carbonate (81 mg, 0.58 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture, extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% acetone) afforded ethyl 2-methyl-2-(1-(naphthalen-1-yl)-1H-pyrazol-5-ylthio)propanoate as a solid. (124 mg, 69%).
Reaction SMILES: CC1(C)[C@@H]2O[C@@H]2C2C=C(C#N)C=CC=2O1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[C@H:24]([OH:29])[C@@H:23]([N:30]([CH2:37][C:38]([O:40][CH2:41]C)=O)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]=2[CH:43]=1)#[N:17]>>[OH:29][C@@H:24]1[C@@H:23]([N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:37][CH2:38][O:40][CH3:41])[C:22]2[CH:43]=[C:18]([C:16]#[N:17])[CH:19]=[CH:20][C:21]=2[O:26][C:25]1([CH3:28])[CH3:27]
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Agent: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Product: COCCN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O

Procedure:
The title compound was prepared from the title A compound and (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (the title A compound of Example 3) by the procedure described for the title compound of Example 1. The oily residue was purified by flash chromatography on silica gel (ethyl acetate:hexanes/1:6), to give a colorless powder (410 mg, 77%), mp 119°-124° C. [α]D =+54.40 (c=0.43, MeOH). Analysis calculated for C21 H24N2O3 : C, 71.57; H, 6.86; N, 7.95. Found: C, 71.53; H, 6.94; N, 7.73.
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>>[C:26]1(=[O:35])[N:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][C:8]4[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=4[C@@H:6]3[CH2:1]2)[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNC[C@@H]21
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN2c3ccccc3Cc3ccccc3[C@@H]2C1

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bR)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and N-(4-bromobutyl)phthalimide, the title compound was obtained in a quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:22](Cl)(=[O:24])[CH3:23].Cl>C1COCC1.O.C(Cl)Cl>[C:22]([NH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11])(=[O:24])[CH3:23]
Reactant: Cc1cc(C#N)cc(Cl)c1N
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1c(C)cc(C#N)cc1Cl
Reaction time: 8 h
Yield: 34 %

Procedure:
Step G (1). To a stirred solution of 4-amino-3-chloro-5-methylbenzonitrile (0.516 g, 3.1 mmol) in 10 mL of THF at rt was added 6.6 mL of 1.0 M NaHMDS in THF. The resulting reaction mixture was stirred at rt for 30 min., at which time acetyl chloride (3.1 mmol) was added. CH2Cl2 (100 mL) and water (100 mL) were added to the reaction mixture after being stirred overnight, followed by the addition of 5 mL of 1.4 N HCl aqueous solution. Layers were separated and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The extracts were combined and solvents were evaporated in vacuo. The residue was purified by flash chromatography (5-20% EtOAc/DCM) to give 0.220 g of 4-acetamido-3-chloro-5-methylbenzonitrile. 1H NMR (500 MHz, CDCl3) δ 7.57 (s, 1 H), 7.46 (s, 1 H), 7.02 (s, 1 H), 2.31 (s, 3 H), 2.26 (s, 3 H).
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(SSC2C=CC=CC=2)C=CC=CC=1>>[CH:1]1([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Clc1cccc2c1CCN=C2C1CCCCC1
Agent: c1ccc(SSc2ccccc2)cc1
Product: Clc1cccc2c(C3CCCCC3)nccc12

Procedure:
1-Cyclohexyl-5-chloro-3,4-dihydroisoquinoline and diphenyl disulfide were reacted in the same way as in step (c) of Example 13 to afford 1-cyclohexyl-5-chloroisoquinoline as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3].[CH3:12][O-:13].[Na+]>CN(C)C=O>[CH3:8][C:7]([CH:6]=[CH:5][CH2:4][CH:2]([CH3:1])[CH2:3][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])=[CH:9][C:10]([O:13][CH3:12])=[O:11]
Reactant: C[O-]
Reactant: CC(C)CCCC(C)CC=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=C(C)C=CCC(C)CCCC(C)C
Reaction time: 2 h

Procedure:
To a mixture of 1.5 g. of dihydrocitronellal, 2.7 g. of diethyl 3-ethoxycarbonyl-2-methylprop-2-enyl phosphonate and 5 ml. of dimethylformamide, under nitrogen and at 0°, with stirring, is added slowly sodium methoxide (250 mg. sodium and 5 ml. of methanol). After addition is complete, the reaction is left two hours at room temperature and then worked up by extraction with ether/hexane to yield methyl 3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1.C(O)(C(F)(F)F)=O>CS(C)=O>[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:2]3[N:7]=[C:6]4[NH:8][N:9]=[CH:10][C:5]4=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=4)[N:3]=3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: NS(=O)(=O)c1ccc(Nc2nc(Cl)nc3[nH]ncc23)cc1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(Nc2nc(Nc3ccc4[nH]ncc4c3)nc3[nH]ncc23)cc1
Temperature: 120 °C
Yield: 99 %

Procedure:
Compound 4A, 1H-indazol-5-ylamine Compound 5A and TFA (94 ul, 1.1 mmol) were mixed in dry DMSO (1 ml) and heated to 120° C. for 48 hours to provide Compound 12 (99% yield). 1HNMR (CD3OD) δ 8.5 (s, 1H), 8.12 (s, 2H), 7.9 (m, 2H), 7.7 (d, 2H), 7.5 (d, 2H); MS 536 (M+H+).
Reaction SMILES: [OH:1][NH2:2].[OH-].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([C:12]#[C:13][C:14]([O:16]C)=O)[CH:9]=[CH:10][CH:11]=1>O.CO.C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]([C:12]2[O:1][N:2]=[C:14]([OH:16])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C#Cc1cccc(Br)c1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Oc1cc(-c2cccc(Br)c2)on1
Yield: 87 %

Procedure:
Add a solution of hydroxyamine (50% in water, 0.50 mL, 16.3 mmol) in water and NaOH (197 mg, 4.92 mmol) to a solution of methyl 3-(3-bromophenyl)propiolate (980 mg, 4.10 mmol) in a mixture of MeOH and THF (6.0 mL/12.0 mL). Remove the solvents after 2 d. Dissolve the residue in water. Adjust the pH of the aqueous phase to 2 and extract with EtOAc. Dry, filter and concentrate. Purify the residue by flash chromatography eluting with a mixture of EtOAc and hexanes (50:50) to afford the title compound (856 mg, 87%): 1H NMR (d6-DMSO) δ 11.54 (s, 1H), 8.08 (dd, 1H, J=2.0, 1.6 Hz), 7.87 (ddd, 1H, J=8.6, 1.6, 0.8 Hz), 7.75 (ddd, 1H, J=8.2, 2.0, 0.8 Hz), 7.54 (t, 1H, J=7.8 Hz), 6.75 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:41])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[C:33]([O:39][CH3:40])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[C:37]([C:34]1[CH:35]=[CH:36][C:29]2[O:28][C:27]([C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([S:9]([NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:41])=[O:2])(=[O:10])=[O:11])=[CH:13][CH:14]=4)=[CH:23][CH:22]=3)=[O:26])=[C:31]([CH3:32])[C:30]=2[C:33]=1[O:39][CH3:40])#[N:38]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(C#N)c(OC)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C#N)ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.5 %

Procedure:
To 70 mg of (S)-2-{4′-[(5-cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester was added 1.5 mL of THF and 2 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 3 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 42 mg (61% yield) of (S)-2-{4′-[(5-cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.6, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.5, 5.9 Hz, 1 H) 4.2 (s, 3 H) 7.6 (d, J=8.6 Hz, 1 H) 7.8 (m, 7 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.1 Hz, 1 H) 10.7 (s, 1 H).
Reaction SMILES: C(N)(=O)C1C=CC=CC=1.[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16])([O-])=O>CCO>[NH2:10][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16]
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Agent: NC(=O)c1ccccc1
Solvent: CCO
Product: NC(=O)c1ccccc1N

Procedure:
Methyl 5-chloro-2-nitrobenzoate (1) is reacted with an appropriately-substituted phenol (2) and base such as potassium carbonate in a solvent such as NMP to form the corresponding phenoxy-2-nitro-benzoic acid methyl ester (3). Compound (3) is hydrolyzed upon treatment with basic solution such as NaOH in water/MeOH to provide benzoic acid (4). Benzoic acid (4) is treated with thionyl chloride in solvent such as DMF to provide an intermediate acid chloride, which upon treatment with NH4OH in solvent such as THF provides benzamide (5). The nitro-benzamide (5) can be hydrogenated in solvent such as EtOH to provide amino-benzamide (6).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.Cl>C(Cl)Cl>[N:15]1([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(CN2CCCC2)cc1
Yield: 98.2 %

Procedure:
NaB(OAc)3H (32 g, 0.15 mol) was added in portions for 15 min to a mixture of pyrrolidine (9.1 mL, 0.11 mol) and 4-hydroxybenzaldehyde (12.2 g, 0.1 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (20 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with K2CO3 to pH 9 (40 mL) and extracted with chloroform (3×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (17.4 g, 98%) was obtained as white crystals. LCMS-data: (M+H)+ 178.1 and 179.1 (calculated for C11H15NO 177.0). 1H NMR (400Mz)-data (DMSO-d6, J, Hz): 9.19 (br s, 1H, OH); 7.03-7.11 (t, 1H, ArH, J=7.5 Hz); 6.66-6.73 (m, 1H, ArH); 6.34-6.59 (dd, 1H, ArH, J1=1.7 Hz, J2=6.4 Hz); 3.46 (s, 2H, CH2Ar); 2.37-2.43 (m, 4H, CH2CH2CH2CH2); 1.62-1.73 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]1([NH:19][C:20](=O)[CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20]([CH3:21])=[N:10][C:3]=2[CH:4]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Product: COc1ccc2c(c1)nc(C)n2-c1ccccc1

Procedure:
Method A applied to 4-chloro-3-nitroanisol (84 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) yielded the title compound as a pale yellow solid. mp 88-90° C. 1H NMR (DMSO) δ 2.61 (s, 3H), 3.88 (s, 3H), 7.07 (d, J=8.9Hz, 1H), 7.25 (d, J=8.9 Hz, 1H), 7.38 (br s, 1H), 7.65-7.73 (m, 5H); 13C NMR δ 12.5, 55.9, 97.7, 112.6, 114.7, 126.9, 127.8, 130.2, 130.3, 132.8, 133.1, 151.2, 157.6, 157.8. HRMS (FAB): cal. for C15H15N2O [M+H+]: 239.1184; found: 239.1180.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[CH2:20][O:21]/[N:22]=[C:23](/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)\[CH2:24][CH2:25][C:26]([O:28]C)=[O:27].CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[CH2:20][O:21]/[N:22]=[C:23](/[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)\[CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: COC(=O)CC/C(=N\OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CO/N=C(\CCC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of methyl E-4-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (500 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (395 mg, yield 82%) as colorless crystals. m.p. 108-109° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N+:15]([O-])=O.[H][H]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH2:15]
Reactant: [H][H]
Reactant: Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)cc1N

Procedure:
4.8 G. of 1-amino-2-nitro-4-phenoxybenzene is hydrogenated in 100 ml. methanol at 1 atmosphere pressure, in the presence of 1 g. of 5% palladized carbon, until the theoretical uptake of hydrogen has occurred. The catalyst is removed by filtration and the filtrate evaporated to give 1,2-diamino-4-phenoxybenzene.
Reaction SMILES: CN.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@:11]12[CH2:20][O:19][C@@H:18]([CH:21]3[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[O:22]3)[CH2:17][C@H:16]1[CH2:15][S:14][C:13]([NH:28]C(=O)C1C=CC=CC=1)=[N:12]2>C(O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@:11]12[CH2:20][O:19][C@@H:18]([CH:21]3[CH2:25][CH2:24][C:23]([CH3:26])([CH3:27])[O:22]3)[CH2:17][C@H:16]1[CH2:15][S:14][C:13]([NH2:28])=[N:12]2
Reactant: CC1(C)CCC([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)O1
Agent: CN
Solvent: CCO
Product: CC1(C)CCC([C@H]2C[C@H]3CSC(N)=N[C@@]3(c3ccc(F)cc3F)CO2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylamine (8.0 M in ethanol, 500 μL, 4.0 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(5, 5-dimethyltetrahydrofuran-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C78) (30 mg, 0.062 mmol) in ethanol (500 μL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated to an oil and combined with material derived from a reaction run on 0.01 mmol in a similar manner. Purification via silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane) afforded the product as a white solid. By 1H NMR analysis, this product was a single diastereomer. Yield: 19.9 mg, 72%. LCMS m/z 383.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.31-7.37 (m, 1H), 6.93-7.00 (m, 2H), 4.06 (dd, J=10.9, 2.0 Hz, 1H), 3.89 (ap. q, J=6.6 Hz, 1H), 3.69 (d, J=11.3 Hz, 1H), 3.49-3.54 (m, 1H), 2.86-2.91 (m, 2H), 2.66-2.70 (m, 1H), 1.99-2.09 (m, 2H), 1.65-1.78 (m, 4H), 1.26 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N#N.[CH:19]([CH:21]1[CH2:23][O:22]1)=[CH2:20]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C(#N)C.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].C(Cl)(Cl)Cl>[CH2:1]([O:8][N:9]([C@H:21]([CH:19]=[CH2:20])[CH2:23][OH:22])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Reactant: C=CC1CO1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C=C[C@H](CO)N(OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
In a 3 L RBF, a solution of tert-butyl benzyloxycarbamate (Intermediate 153, 86.9 g, 389.22 mmol), N,N(1S,2S)-cyclohexane-1,2-diyl)bis(2-(diphenylphosphino)-1-naphthamide) (18.5 g, 23.39 mmol), Pd2(dba)3-CHCl3 (8.05 g, 7.78 mmol) and TBAB (150.5 g, 466.81 mmol) in acetonitrile (1.8 L) was bubbled with N2 for 30 minutes and the flask was closed with a rubber septum. The solution was then kept in a −20° C. freezer for 2 hrs. 2-vinyloxirane (30 g, 428.02 mmol, 1.10 equiv) was added and the mixture was stirred in the freezer (−20-25° C.) for 3 days. The mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel column eluted with EtOAc/hexane (0-40%) to give the title compound (106 g, 93%) as a pale yellow oil.