Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[CH2:7][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:10][C:11]=1[NH:12][C:13]([O:15]C1C=CC=CC=1)=O)=[O:5])C.[CH2:29]([NH2:32])[C:30]#[CH:31].C1CCN2C(=NCCC2)CC1.NC(N)=O.[OH-].[Na+].Cl>C1COCC1>[C:25]([O:24][C:22]([N:8]1[CH2:9][CH2:10][C:11]2[NH:12][C:13](=[O:15])[N:32]([CH2:29][C:30]#[CH:31])[C:4](=[O:5])[C:6]=2[CH2:7]1)=[O:23])([CH3:26])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C1=C(NC(=O)Oc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Reactant: C#CCN
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C#CCn1c(=O)[nH]c2c(c1=O)CN(C(=O)OC(C)(C)C)CC2

Procedure:
Ethyl-4-phenoxycarbonylamino-1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate (5.0 g) was dissolved in THF (50 ml), and propargylamine (1.32 ml) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (0.2 ml) were added and the resultant mixture was stirred at room temperature for 2 hours. After production of an intermediate (urea) was confirmed by TLC, a 5 N aqueous sodium hydroxide solution (5 ml) was added and the resultant mixture was further stirred at room temperature for 2 hours. To the reaction solution, 6 N hydrochloric acid was added to neutralize and the resultant mixture was then concentrated. To the residue, water was added and the mixture was extracted with ethyl acetate. After the organic layer was washed with a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated under reduced pressure. A precipitate was obtained by filtration. The titled compound (3.78 g) was obtained as a white powder.
Reaction SMILES: C1(C(NC2C(C(N)=[O:15])=CN=C(SC)N=2)(C)C)CC1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH:30]1([C:33]([NH:36][C:37]2[C:42]([C:43]([NH2:45])=[O:44])=[CH:41][N:40]=[C:39]([S:46]([CH3:48])=[O:47])[N:38]=2)([CH3:35])[CH3:34])[CH2:32][CH2:31]1>C1COCC1>[CH:30]1([C:33]([NH:36][C:37]2[C:42]([C:43]([NH2:45])=[O:44])=[CH:41][N:40]=[C:39]([S:46]([CH3:48])(=[O:15])=[O:47])[N:38]=2)([CH3:35])[CH3:34])[CH2:32][CH2:31]1
Reactant: CSc1ncc(C(N)=O)c(NC(C)(C)C2CC2)n1
Reactant: CS(=O)c1ncc(C(N)=O)c(NC(C)(C)C2CC2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(Nc1nc(S(C)(=O)=O)ncc1C(N)=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of 4-((2-cyclopropylpropan-2-yl)amino)-2-(methylthio)pyrimidine-5-carboxamide (390 mg, 1.46 mmol) in THF (6 mL) was added mCPBA (447 mg, 2.2 mmol) portion-wise. The reaction mixture was stirred for 0.5 h at 0° C. The mixture was concentrated under vacuum and purified by silica gel column chromatography (2.5%-10% DCM in methanol) to give a mixture of 4-((2-cyclopropylpropan-2-yl)amino)-2-(methylsulfinyl)pyrimidine-5-carboxamide and 4-((2-cyclopropylpropan-2-yl)amino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (382 mg, 1.32 mmol, 90% yield). MS (ESI) m/z 299.1 [M+H]+ and 283.1 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40]3[S:41][C:42]4[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=4[N:44]=3)=[CH:35][CH:34]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:38]=[CH:37][C:36]([NH:39][C:40]4[S:41][C:42]5[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=5[N:44]=4)=[CH:35][CH:34]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4s3)cc2)OC1(C)C
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6s5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-1,3-benzothiazol-2-amine was prepared from cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzothiazol-2-amine (0.100 g, 0.283 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as an off-white powder (0.035 g, 28%): 1H NMR (DMSO-d6, 400 MHz) δ 10.71 (s, 1H), 8.23 (s, 1H), 7.98 (d, 2H), 7.84 (d, 1H), 7.65 (d, 3H), 7.35 (t, 1H), 7.19 (t, 1H), 4.80 (m, 1H), 3.50 (m, 1H), 2.67-2.09 (m, 15H), 1.71-1.57 (m, 4H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.47 min., 100%; m/z 540 (MH+).
Reaction SMILES: [C:1](C1C=C(C(=O)CSCC)C=C(C(C)(C)C)C=1O)(C)(C)C.[C:22]([C:26]1[CH:27]=[C:28]([C:37](=[O:43])[CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:27]=[C:28]([C:37](=[O:43])[CH2:38][S:39]([CH2:42][CH3:1])(=[O:41])=[O:40])[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:23])([CH3:24])[CH3:25]
Reactant: CCSCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(C(=O)CS(C)(=O)=O)cc(C(C)(C)C)c1O
Product: CCS(=O)(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
This material is prepared from impure 1-(3,5-di-t-butyl-4-hydroxyphenyl)-2-(ethylsulfanyl)ethanone (following the method of 1-(3,5,-di-t-butyl-4-hydroxyphenyl)-2-(methylsulfonyl)ethanone). Crystallization (of the crude product) from EtOAc/hexanes followed by a second crystallization then a flash chromatography with EtOAc followed by a third crystallization with refrigeration gives white crystals, mp=119.5°-120.5° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][O:22][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>FC(F)(F)C(O)=O.O>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][OH:22])[O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CO[C@@H](COCc1ccccc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOP(=O)(CO[C@H](CO)COCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of diethyl (S)-[2-benzyloxy-1-(t-butyldiphenylsilyloxymethyl)ethoxy]methylphosphonate (3.09 g, 5.4 mmol) in trifluoroacetic acid/water 2:1 (12 ml) was stirred at ambient temperature for 1 hour. The solution obtained was extracted with hexane (2×10 ml) and the aqueous containing phase evaporated to dryness. The residue obtained was treated with ethanolic ammonia (5 ml) for 5 minutes at ambient temperature, the solvent evaporated and the residue chromatographed on silica gel using dichloromethane/methanol 95:5 as eluant. The title compound was obtained as a colourless oil (1.35 g, 75%). IR: νmax (film) 3380, 3060, 3030, 2980, 2910, 2860, 1495, 1480, 1450, 1390, 1370, 1250, 1160, 1100, 1075, 975, 910, 890, 820, 780, 740, 700 cm-1. 1H NMR: δH [(CD3)2SO]1.21, 1.22 (2×3H, 2×t, J=7 Hz, (OCH2CH3)2, 3.4-3.65 (5H, m, CH2, CH,CH2), 3.94 (2H, d, J=8.5 Hz, OCH2P), 3.97-4.1 (4H, m, (OCH2CH3)2), 4.5 (2H, s, CH2Ph), 4.67 (1H, t, J=5.5 Hz, D2O exchangeable OH), 7.20-7.40 (5H, m, Ph). Found: C, 53.20; H, 7.72%. C15H25O6P 0.33 H2O requires: C, 53.25; H, 7.64%. m/z: observed 332.1383. C15H25O6P requires 332.1387. [α]D25 (CHCl3) +16.7° (c=1.06).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@H:11]([CH3:15])[C:12]([NH2:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1N=C(Cl)N=C(Cl)N=1.O>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]([C:12]#[N:14])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](C#N)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a solution of benzyl[(1R)-2-amino-1-methyl-2-oxoethyl]carbamate (10 g, 45 mmol) in 50 mL of N,N-dimethylformamide was added 2,4,6-trichloro-1,3,5-triazine (4.15 g, 22.5 mmol). After 2 h, 100 mL of water was added and the mixture was filtered. The solids were washed with 100 mL aqueous sodium bicarbonate (2×) and dried under vacuum to give pure benzyl[(1R)-1-cyanoethyl]carbamate (7.2 g). MS 205.2 ((M+1).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=1)[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:11]2[C@@H:7]3[C@@H:6]([CH2:10][CH2:9][CH2:8]3)[C:4]([OH:3])=[C:13]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=4[S:16](=[O:30])(=[O:29])[N:15]=3)[C:12]2=[O:31])=[N:34][CH:35]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cn1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccc(F)cn3)C1=O)N2
Temperature: 60 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A solution of cis-2-{(5-fluoro-pyridin-2-ylmethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentane-carboxylic acid ethyl ester (0.085 g, 0.146 mmol) in ethanol (2 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (0.218 mL) and stirred for 2 h at 60° C. Glacial acetic acid (0.200 mL) was added, the solvents were removed in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-{3-[1-(5-fluoro-pyridin-2-ylmethyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.052 g, 0.097 mmol, 66.5%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.47-1.69 (3H, m), 1.96-2.14 (3H, m), 3.06 (3H, s), 3.95-4.01 (1H, m), 4.61 (1H, bs), 4.96 (1H, d, J=16.5 Hz), 7.46-7.52 (2H, m), 7.56-7.58 (2H, m), 7.67-7.72 (1H, m), 8.51 (1H, d, J=3.5 Hz), 10.18 (1H, s). LC-MS (ESI) calcd for C22H22FN5O6S2 535.10, found 536.4 [M+H+].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:25][CH2:24]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: Cc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Yield: 87 %

Procedure:
Method 1 was followed using 4-fluoro-3-nitrotoluene (1.0 eq), 4-(N-Boc-amino) piperidine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 1-(4-methyl-2-nitro phenyl)piperidin-4-ylcarbamate (87%). LCMS (m/z): 336.1 (MH+); LC Rt=3.32 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Se](=O)=[O:16]>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:16])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ncccc2Cl)cc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ncccc2Cl)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
{circle around (1)} 100 g (0.49 mol) of 3-chloro-2-para-tolylpyridine was dissolved in 1 L of 1,4-dioxane in a reactor. 163.4 g (1.47 mol) of selenium dioxide was added, and the mixture was refluxed for 4˜6 hours. The reaction solution was cooled to 25° C., and floating matter was filtered off with celite. A 10% sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure, yielding 4-(3-chloropyridin-2-yl)benzaldehyde as represented below in a 85% yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].[OH:27][CH2:28][CH2:29][C:30](O)=[O:31]>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][NH:25][C:28](=[O:27])[CH2:29][CH2:30][OH:31])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(O)CCO
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCN)cc3)no2)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNC(=O)CCO)cc3)no2)cc1C
Yield: 5 %

Procedure:
The title compound (3 mg) is prepared in analogy to Example 163 by coupling 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethylamine (50 mg, 135 μmol) with 3-hydroxypropionic acid (18 mg, 202 μmol); LC-MS: tR=0.71 min; [M+1]+=442.76.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[N:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[C:10]([C:18]#[N:19])[C:11](=[O:17])[NH:12]2.[OH-:20].[NH4+]>C(O)(=O)C>[CH3:6][C:7]1[N:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[C:10]([C:18]([NH2:19])=[O:20])[C:11](=[O:17])[NH:12]2
Reactant: Cc1nccc2[nH]c(=O)c(C#N)cc12
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)c(C(N)=O)cc12
Reaction time: 8 h

Procedure:
To 200 ml of concentrated sulfuric acid chilled in an ice bath was added with stirring 37 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile and the reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was then poured on ice (1 liter beaker, half filled), the resulting mixture cooled in an ice bath and then neutralized by adding aqueous ammonium hydroxide, followed by addition of acetic acid to make the mixture slightly acidic. The separated solid was collected, washed with water, air-dried, then recrystallized from a large volume of dimethylformamide (1.2 l.) and dried at 95° C. to yield 28.4 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxamide, m.p. >320° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-])=O)=[CH:13][C:12]=1[OH:21])[CH2:8]2>CCO>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([NH2:18])=[CH:13][C:12]=1[OH:21])[CH2:9]2
Reactant: Cc1cc(C2C3CC4CC(C3)CC2C4)c(O)cc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1cc(C2C3CC4CC(C3)CC2C4)c(O)cc1N
Reaction time: 8 h

Procedure:
To a solution of 2-admantyl-4-methyl-5-nitrophenol (231 mg, 1.6 mmol) in EtOH (2 mL) was added Pd- 5% wt on carbon (10 mg). The mixture was stirred under H2 (1 atm) overnight and then filtered through Celite. The filtrate was evaporated to dryness to provide 2-admantyl-4-methyl-5-aminophenol (C-12), which was used without further purification. HPLC ret. time 2.52 min, 10-99% CH3CN, 5 min run; ESI-MS 258.3 m/z (MH+).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.C([O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=1)=[O:35])(C)(C)C>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:39]3[CH:40]=[CH:41][C:36]([C:34]([OH:35])=[O:33])=[CH:37][CH:38]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: O=C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1

Procedure:
Compound 58a was prepared from compound 3a and 4-(tert-butoxycarbonyl)phenylboronic acid pinacol ester using the methods described in Example 57, Step A.
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:13])=[CH:7]/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11]>[Pd]>[CH3:14][CH:2]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:7][CH2:8][CH2:9][C:10]([CH3:12])=[O:11])[CH3:13])[CH3:1]
Reactant: CC(=O)/C=C/C=C(\C)CCC=C(C)C
Agent: [Pd]
Product: CC(=O)CCCC(C)CCCC(C)C

Procedure:
Using the apparatus and procedure described in Example 1 but employing a 0.5% (wt./wt.) Pd on Al2O3 catalyst (DEGUSSA, E257H/D) pseudoionone was hydrogenated to produce hexahydropseudoionone. The process parameters were as stated below:
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[N:15]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH2:14][CH2:13][N:12]([C:20]2[C:21]([Cl:36])=[C:22]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:23]=[C:24]([C:26]#[N:27])[CH:25]=2)[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[Cl:36][C:21]1[C:20]([N:12]2[CH2:13][CH2:14][N:15]([CH:16]3[CH2:19][O:18][CH2:17]3)[CH:10]([CH2:9][OH:8])[CH2:11]2)=[CH:25][C:24]([C:26]#[N:27])=[CH:23][C:22]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(CO[Si](C)(C)C(C)(C)C)C2)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(CO)C2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
(+/−) Tert-butyl (3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)carbamate (551 mg, 1.026 mmol) was taken up in THF (5 mL) and TBAF (1.539 mL, 1.539 mmol) was added dropwise. The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and washed with water, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-100% 20% (2N NH3/MeOH)/DCM). (+/−) Tert-butyl (2-chloro-5-cyano-3-(3-(hydroxymethyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (416 mg) was obtained as an orange glass.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[N:31]=[C:30]([CH3:32])[N:29]([CH3:33])[C:17]2=[N:18][C:19]=1[N:20]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].CI.[C:47](OCC)(=O)C>CN(C=O)C>[F:42][C:2]([F:41])([F:1])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[N:31]=[C:30]([CH3:32])[N:29]([CH3:33])[C:17]2=[N:18][C:19]=1[N:20]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:8]1[N:12]=[N:11][N:10]([CH3:47])[N:9]=1
Reactant: CCOC(C)=O
Reactant: Cc1nc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)nc2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c(N(CC3CC3)CC3CC3)nc2n1C
Reaction time: 0.25 h
Yield: 4.4 %

Procedure:
To a solution of (6-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-bis-cyclopropylmethyl-amine (0.220 g, 3.7 mmol.) in DMF (8 mL) was added 60% sodium hydride (0.017 g, 0.741 mmol.) at 0° C. and the resulting reaction mixture was stirred at the same temperature for 15 min. and then methyl iodide (0.046 mL, 0.0741 mmol.) was added and continued to stir for 30 min. The crude product was extracted with ethyl acetate (250 mL), washed with water (250 mL×2) and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography using 230-400 mesh silica gel eluting with 1:1 hexane: ethyl acetate yielded 0.010 gm (yield: 4.4%) of pure colorless gummy compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[CH:14]=O)[CH2:3][CH2:2]1.[C:16]([O:20][C:21](=[O:44])[NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:43])[C:30]2[CH:35]=[C:34]([N+:36]([O-])=O)[C:33]([NH:39][CH3:40])=[C:32]([O:41][CH3:42])[CH:31]=2)[CH2:24]1)([CH3:19])([CH3:18])[CH3:17].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.C(Cl)Cl>[C:16]([O:20][C:21](=[O:44])[NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([C:30]2[CH:31]=[C:32]([O:41][CH3:42])[C:33]3[N:39]([CH3:40])[C:14]([C:6]4[N:5]([CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:9]5=[N:10][CH:11]=[CH:12][CH:13]=[C:8]5[CH:7]=4)=[N:36][C:34]=3[CH:35]=2)=[O:43])[CH2:24]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1cc2cccnc2n1CC1CC1
Reactant: CNc1c(OC)cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A solution of 1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.743 g, 3.71 mmol) in ethanol (60 mL) was added to a round bottom flask containing (R)-tert-butyl(1-(3-methoxy-4-(methylamino)-5-nitrobenzoyl)piperidin-3-yl)carbamate (1.529 g, 3.74 mmol) and the resulting solution stirred at room temperature. A solution of sodium dithionite (1.375 g, 6.71 mmol) in water (30 mL) was added portionwise to the reaction mixture. The reaction mixture was heated to 100° C. and stirred under nitrogen for 4 hours. The reaction mixture was concentrated under vacuum then diluted with DCM (150 ml) and water (150 ml). The organic layer was collected and the aqueous layer washed with DCM (3×100 ml). Organic layers were collected, dried with Na2SO4, filtered through a hydrophobic frit and concentrated under vacuum to yield 2 g of crude product as yellow solid. This was dissolved in a minimum volume of DCM and purified using Biotage SP4 on a 50 g SNAP silica cartridge. The column was eluted with a gradient of 70-100% ethyl acetate in DCM for 10CV. Appropriate fractions were collected and concentrated under vacuum to yield the title compound as a yellow solid (1.55 g).
Reaction SMILES: [CH3:1][O:2][C@:3]12[CH2:17][C@@H:16]([CH2:18][OH:19])[CH2:15][N:14]([CH3:20])[C@@H:13]1[CH2:12][C:11]1[C:21]3[C:8]([N:9]([CH3:22])[CH:10]=1)=[CH:7][CH:6]=[CH:5][C:4]2=3.C(N(CC)CC)C.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>C(Cl)Cl>[S:30]([O:19][CH2:18][C@@H:16]1[CH2:17][C@@:3]2([O:2][CH3:1])[C@@H:13]([CH2:12][C:11]3[C:21]4[C:8](=[CH:7][CH:6]=[CH:5][C:4]2=4)[N:9]([CH3:22])[CH:10]=3)[N:14]([CH3:20])[CH2:15]1)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]
Reactant: CO[C@]12C[C@@H](CO)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@]12C[C@@H](COS(=O)(=O)c3ccc(C)cc3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Yield: 72.7 %

Procedure:
A mixture of 10 g of 10-methoxy-1,6-dimethylergoline-8β-methanol, 12.4 ml of triethylamine, and 12.6 g of tosyl chloride in 200 ml of methylene chloride is refluxed 5 hr. The solution is washed first with 10% Na2CO3 and then with water, the solvent is evaporated in vacuo, and the residue is crystallized from methanol to give 11 g of 10-methoxy-1,6-dimethylergoline-8β-methanol tosylate; m.p. 169° C.