Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(N2CCNCC2)=O)CC=CC1.Cl[C:15]1[N:24]=[C:23](N)[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1>>[CH3:27][O:26][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:28][CH3:29])[N:16]=[CH:15][N:24]=[CH:23]2
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: O=C(C1CC=CC1)N1CCNCC1
Product: COc1cc2cncnc2cc1OC

Procedure:
N-(3-cyclopentenylcarbonyl)piperazine (2.7 g., 0.015 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (3.6 g., 0.015 mole) are reacted according to the procedure of Example 127(a). The crude product crystallized from methanol affords analytically pure 4-amino-2-4-(3-cyclopentenylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 215.5°-217.5° C. (corr.).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[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])[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([I:32])C(=O)C1>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:32])=[C:9]([CH3:11])[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])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Cc1c(I)c2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the solution of (S)-tert-butyl 2-((4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carboxylate (1.0 g, 2.86 mmol, 1.0 eq) in DMF (20 mL), NIS (0.675 g, 3.00 mmol, 1.05 eq) was added at 0° C. The resulted mixture was stirred and warmed to RT for 12 h. Solvent was removed and purified by column chromatography to afford (S)-tert-butyl 2-((4-chloro-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carboxylate as white solid (1.0 g, 77% in yield) which was converted to the title compound as described in Example 30 above. LCMS m/z 519.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:15][CH:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH:12]1[CH2:24][CH:25]=[CH2:26])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:24]([CH:12]1[CH2:13][CH:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][N:11]1[C:9](=[O:10])[CH:8]([NH2:7])[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)[CH:25]=[CH2:26]
Reactant: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(N)Cc1ccc(F)cc1

Procedure:
[2-(2-Allyl-4-benzyloxy-pyrrolidin-1-yl)-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 53, (0.67 g, 1.4 mmol) is dissolved in methylene chloride (21 mL), and trifluoroacetic acid (9 mL) is added. The reaction mixture is stirred for 1 hourr and then concentrated in vacuo. MeOH (40 mL) is added and the solvent is removed in vacuo to afford the desired product in approximately quanitative yield as a viscous oil which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH2:38][CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:36][CH2:37][CH2:38][CH3:39])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Reactant: CCCCBr
Product: CCCCOc1cc2c(cc1OC)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with butyl bromide
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[BH4-].[Na+]>CO>[S:1]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]([OH:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: CC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)O)cccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a stirred solution of 1-(1-tosyl-1H-indol-4-yl)ethanone (500 mg, 1.4 mmol, CASRN 112970-73-7) in dry MeOH (5 mL) at 0° C. was added NaBH4 (80 mg, 2.1 mmol) and the mixture was stirred at RT overnight. The mixture was concentrated in vacuo and the residue was diluted with EtOAc, washed sequentially with water and brine. The organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography to afford 420 mg (95%) of 1-(1-tosyl-1H-indol-4-yl)ethanol (282) as white semi-solid: 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=8.4 Hz, 2H), 7.81-7.76 (m, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.31-7.23 (m, 2H), 6.98 (d, J=3.6 Hz, 1H), 5.23 (d, J=4 Hz, 1H), 5.04-5.01 (m, 1H), 2.30 (s, 3H), 1.33 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(N(CC)CC)C>[CH2:19]([O:18][C:16](=[O:17])[NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCC[Si](OCC)(OCC)OCC
Temperature: -10 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
3-Aminopropyltriethoxysilane (442 g.), light petroleum (b.p. 30°-40°, 1600 ml) and anhydrous triethylamine (255 g.) were placed under dry nitrogen in a three-necked flask equipped with a stirrer and dropping funnel. The mixture was cooled to -10° C. and a solution of redistilled ethyl chloroformate (217 g.) in light petroleum (b.p. 30°-40° C., 600 ml) was added dropwise over 2 h. The mixture was allowed to warm to ambient temperature and left overnight. The mixture was then rapidly filtered and the solid washed with light petroleum (2 × 300 ml). The combined filtrate was then concentrated and fractionally distilled to give ethyl-N-(3-triethoxysilylpropyl)carbamate (517 g.), b.p. 125°-135° C./0.09 mm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1B1OC(C)(C)C(C)(C)O1)[NH2:27]>>[NH2:27][C:26]1[CH:28]=[CH:29][C:30]([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[C:5]3[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:24]([F:23])[CH:25]=1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Product: CCOC(=O)N1Cc2nc(-c3ccc(N)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 45 %

Procedure:
Method as described for example 47 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The residue was purified by prep. HPLC at high pH, yielding the title compound (55 mg, 0.14 mmol, 45%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22](O)[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[C@@H:13]([Cl:28])[CH2:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2].CS(Cl)(=O)=O.O>N1C(C)=CC(C)=CC=1C.CN(C=O)C>[C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[C@@H:13]([Cl:28])[CH2:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: CS(=O)(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
A solution of 14.0 g of 21-acetoxy-6α-chloro-11β-hydroxy-16α-methyl-1,4-pregnadiene-3,20-dione in 29 ml of collidine and 90 ml of DMF is combined with 11 ml of methanesulfonic acid chloride containing 3% sulfur dioxide and agitated at room temperature. After 15 minutes, 15 ml of water is added under ice cooling. The thus-obtained precipitate is filtered off, washed with water, and dried in the open air. The crude product is chromatographed on silica gel. With 33-61% ethyl acetate-hexane, 12.1 g of 21-acetoxy-6α-chloro-16α-methyl-1,4,9(11)-pregnatriene-3,20-dione is obtained. A sample, recrystallized from ethyl acetate-hexane, melts at 181° C. [α]D25 =+22° (chloroform).
Reaction SMILES: [ClH:1].[CH2:2]([C:9]1[N:10]=[C:11]([NH2:14])[NH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[N:15]([CH2:18][C:19]([CH3:27])=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N+:16]=[N-:17]>>[ClH:1].[CH3:27][C:19](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][N:15]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:9]2[N:10]=[C:11]([NH2:14])[NH:12][CH:13]=2)[N:17]=[N:16]1
Reactant: C#CCCCCCc1c[nH]c(N)n1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCCCc2c[nH]c(N)n2)nn1
Yield: 58.9 %

Procedure:
4-Hept-6-ynyl-1H-imidazol-2-ylamine hydrochloride (0.060 g, 0.281 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.058 g, 0.336 mmol) following the general procedure for click reactions outlined above to produce 4-{5-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-pentyl}-1H-imidazol-2-ylamine hydrochloride (0.064 g, 65%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.23 (s, 1H), δ 6.93-6.83 (m, 5H), δ 6.38 (s, 1H), δ 6.08 (s, 1H), δ 4.93 (s, 2H), δ 2.51 (t, 2H), δ 2.09 (t, 2H), δ 1.43 (s, 3H), δ 1.41 (m, 2H), δ 1.25 (m, 2H), δ 1.05 (m, 2H) ppm; 13C (75 MHz, CD3OD) δ 147.7, 144.8, 136.3, 132.8, 129.8, 128.9, 128.6, 128.5, 128.2, 127.6, 127.5, 127.0, 108.5, 61.3, 28.0, 27.6, 27.5, 24.0, 22.9, 14.7 ppm; HRMS (ESI) calcd for C20H27N6 (M+) 351.2291, found 351.2291.
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].[C:26](Cl)(=[O:28])[CH3:27]>ClCCl.N1C=CC=CC=1>[Cl:25][C:8]1[CH:9]=[C:10]([F:24])[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])=[CH:12][C:7]=1[N:6]([S:3]([CH2:2][Cl:1])(=[O:5])=[O:4])[C:26](=[O:28])[CH3:27]
Reactant: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(c1cc(N2C(=O)[C@H]3C[C@H](F)CN3C2=O)c(F)cc1Cl)S(=O)(=O)CCl

Procedure:
To a solution of the title compound of Example 1, Step H (4.14 g, 10 mmol) in anhydrous dichloromethane (200 mL) and pyridine (5 mL) was added a solution of acetyl chloride (0.863 g, 11 mmol) in dichloromethane (10 mL) dropwise at room temperature. After completion of the reaction (monitored by tlc), the organic phase was washed with water (50 mL) and diluted with HCl (5%, 50 mL). The organic layer was separated, dried (MgSO4), and the solvent was removed in vacuo to give the title compound of Step A, a compound of this invention, as a white solid (4.3 g, 94%) melting at 198-200° C. 1H NMR (CDCl3) δ 7.56 (m, 2H), 5.52 (m, 1H), 5.40 (dd, 1H), 4.84 (d, 1H), 4.62 (dd, 1H), 4.08 (m, 1H), 3.62 (m, 1H), 2.68 (m, 1H), 2.05 (s, 3H), 1.98 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)=[CH:30][CH:29]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=CC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 92.6 %

Procedure:
0.14 g of 10% w/w palladium-on-charcoal and 1.569 g of ethyl 3-{1-[2-bis(4-fluorophenyl)methoxyethyl]-4-piperidyl}acrylate (prepared as described in Example 1) were added to 30 ml of ethanol, and the mixture was stirred in an atmosphere of hydrogen at room temperature for 30 minutes. At the end of this time, the catalyst was removed by filtration, and the filtrate was freed from the solvent by distillation under reduced pressure, to afford 1.46 g (93% yield) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([I:15])=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19]CC)=O)=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([I:15])=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:19])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2ccc(I)cc2c1=O
Product: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Yield: 88.7 %

Procedure:
A slurry of 1.11 g of ethyl 1-(tert-butyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate from Preparation No. 9 in 2.0 g of 4-chlorobenzylamine is heated under argon at 160° C. for 18 hours, then cooled to room temperature and triturated with 1N HCl. The solid is filtered, washed well with water, and dried under vacuum. Flash chromatography using 20% ethyl acetate in dichloromethane provides 1.22 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: Clc1ccc2[nH]ccc2c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccc2c(c1Cl)CCN2
Yield: 90 %

Procedure:
4,5-Dichloroindole (D31) was reduced in the usual way with sodium cyanoborohydride in glacial acetic acid to give the title compound (D32) (1.22 g, 90%)
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH:9]1[NH:30]C(=O)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.[ClH:41].C(OCC)C>[Cl-].[Na+].O>[ClH:41].[NH2:30][CH:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10]1
Reactant: CCOC(=O)NC1Cc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N)C3)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To ethyl 1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate (33 mg, 0.066 mmol; see example 195) was added 2N potassium hydroxide in ethanol (4 mL, 8.00 mmol) and stirred at 90° C. for 1 h. 50% brine was added and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried, filtered and evaporated to obtain a clear oil m=27.3 mg. Added 2N hydrochloric acid/diethyl ether and stirred at room temperature for 2 h, filtered, washed with diethyl ether and dried to obtain the desired product as a white solid. m=8.6 mg (28%)
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:23]=2)[CH:18]=[CH:17]1>>[S:15]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:21]1[CH:20]=[C:19]2[CH:18]=[CH:17][NH:16][C:24]2=[N:23][CH:22]=1
Reactant: Brc1cc2c(s1)-c1ccccc1OCC2
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: c1ccc2c(c1)OCCc1cc(-c3cnc4[nH]ccc4c3)sc1-2

Procedure:
2-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine from Example 73 was reacted with 7-azaindole-5-boronic acid pinacol ester using standard Suzuki coupling procedure. Purification on prep HPLC gave 136. 1H NMR (400 MHz, CDCl3): 3.30 (2H, t), 4.40 (2H, t), 6.56-6.58 (1H, m), 7.05-7.07 (2H, m), 7.15-7.18 (2H, m), 7.36 (1H, t), 7.75 (1H, d), 8.16 (1H, d), 8.63 (1H, d). MS: (ESI+) 318
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8](O)=[O:9].B>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9]
Reactant: O=C(O)CCc1ccco1
Agent: B
Solvent: C1CCOC1
Product: OCCCc1ccco1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
To 3-(furan-2-yl)propanoic acid (1.4 g, 10 mmol) in THF (50 mL) was added dropwise borane (1M) (20 mL, 20 mmol). The mixture was stirred at rt for 12 hrs, quenched with MeOH, and the mixture was concentrated. The resulting residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 1.0 g (79%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.87-1.94 (m, 2H) 2.74 (t, J=7.32 Hz, 2H) 3.69 (t, J=6.10 Hz, 2H) 6.28 (dd, J=3.05, 1.83 Hz, 1H) 7.30 (d, J=0.92 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3]O.[H][H]>COCCOCCOCCOCCOC>[CH3:5][C:2]1([CH3:6])[CH2:3][NH:1][C:2]([CH3:6])([CH3:3])[CH2:5][NH:1]1
Reactant: [H][H]
Reactant: CC(C)(N)CO
Agent: COCCOCCOCCOCCOC
Product: CC1(C)CNC(C)(C)CN1
Yield: 62 %

Procedure:
In this example, 139 cc of a Ni-Fe-Cu-Mn catalyst (1/8" diameter) were charged to an 0.815" ID tubular upward flow reactor. A liquid feed containing 2-amino-2-methyl-1-propanol and tetraglyme (a tetraethylene glycol dimethyl ether solvent) (1/1.18 by weight) was pumped through the catalyst bed at a rate of 0.12 lb/hr at 240° C. Hydrogen was also passed through the reactor at a rate of about 6 L/hr. The pressure was maintained at 800 psig. The products were collected. GLC analysis showed that a 62% yield of 2,2,5,5-tetramethylpiperazine and a 14% yield of 3,3,6,6-tetramethyl-2-piperazinone were obtained with a 90% conversion of 2-amino-2-methyl-1-propanol. The resulting reaction mixture was fractionally distilled at atmospheric pressure under nitrogen. Both products were further recrystallized from ether.
Reaction SMILES: [F:1][C:2]([C:5]1[S:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:6]=1[C:18](OCC)=[O:19])([F:4])[CH3:3].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:1][C:2]([C:5]1[S:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:6]=1[CH2:18][OH:19])([F:4])[CH3:3]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1C(C)(F)F
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2nsc(C(C)(F)F)c2CO)cc1
Temperature: -78 °C

Procedure:
Into a 50-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazole-4-carboxylate (191 mg, 0.59 mmol, 1.00 equiv), toluene (3 mL). This was followed by the addition of DIBAL-H(25% in toluene) (1.67 g, 5.00 equiv) dropwise with stirring at −78° C. The resulting solution was stirred for 2 h at 30° C. The reaction progress was monitored by LCMS. The reaction mixture was cooled to 0° C. with a water/ice bath, then quenched by the addition of 10 mL of water and 10 mL NH4Cl. The resulting solution was extracted with 4×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by TLC-plate. This resulted in 32 mg (19%) of [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methanol as a orange solid. Mass spectrum (ESI, m/z): Calcd. For C14H15F2NOS, 284.1 (M+H). found 284.1.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C(=O)([O-])O.[Na+].[CH:28]1(CBr)[CH2:31][CH2:30][CH2:29]1>CN1C(=O)CCC1>[CH2:28]1[CH2:31][CH:30]([CH2:1][N:2]2[C@@H:12]3[CH2:13][C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[C:16]5[O:21][C@H:6]6[C:7]([CH2:9][CH2:10][C@:11]3([OH:22])[C@:5]6([C:15]=45)[CH2:4][CH2:3]2)=[O:8])[CH2:29]1
Reactant: BrCC1CCC1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CCC2)[C@H]1O5
Yield: 66.1 %

Procedure:
A slurry of noroxymorphone (Example 5, 220 mg; 0.766 mmol), sodium hydrogen carbonate (77 mg; 0.92 mmol), cyclobutylmethyl bromide (160 mg; 1.07 mmol) and NMP (1 mL) was stirred under a nitrogen atmosphere at 90° C. for 19 h. Then the reaction mixture was cooled and quenched with water (10 mL). After adjusting the pH to 9, the product was extracted with DCM (3×5 mL). The combined organic layers were washed with water, brine and dried over MgSO4. Column chromatography afforded 180 mg (66%) of nalbuphone as a white solid; mp 170-172° C. (acetone), [lit. 173-174° C. (chloroform)]xxii; Rf 0.64 (ethyl acetate+20% methanol); [α]20D=−180.44 (c=1.0, MeOH); IR(CHCl3) v 3561, 3454, 2966, 2931, 2830, 1720, 1616, 1457, 1318, 1142, 1057, 944 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.74 (d, J=8.0 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 5.64 (bs, 1H, OH), 4.72 (s, 1H), 3.11 (d, J=18.4 Hz, 1H), 3.04 (ddd, J=14.4, 14.4, 3.6 Hz, 1H), 2.92 (d, J=4.9 Hz, 1H), 2.57 (m, 5H), 2.42 (ddd, J=12.4, 12.4, 4.4 Hz, 1H), 2.33 (d, J=14.4 Hz, 1H), 2.20 (ddd, J=12.0, 12.0, 2.2 Hz, 1H), 2.11 (m, 2H), 1.95 (m, 1H), 1.90 (m, 2H), 1.87 (m, 2H), 1.66 (ddd, J=13.6, 13.6, 2.2 Hz, 1H), 1.56 (d, J=12.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 209.68, 143.45, 138.69, 129.02, 124.34, 119.87, 117.71, 90.58, 70.31, 62.74, 60.48, 50.93, 43.74, 36.18, 33.73, 31.32, 30.69, 27.00, 26.79, 22.96, 18.76; MS (FAB+) m/z (%): 41 (27), 69 (9), 98 (5), 300 (88), 355 (38), 356 (100); HRMS calcd for C21H26NO4 356.1856. found 356.18552.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2B(O)O)[CH:21]=[CH:20][N:19]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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:14]([NH:13][C:11]([C:8]1[C:6]2=[N:7][C:2]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]=3[CH:18]=[N:19][CH:20]=[CH:21]4)=[CH:3][N:4]=[C:5]2[NH:10][CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: OB(O)c1cccc2ccncc12
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3cccc4ccncc34)nc12
Temperature: 90 °C
Yield: 65.3 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.1 g, 0.337 mmol), isoquinolin-8-ylboronic acid (64 mg, 0.37 mmol), Pd2 dba3 (77 mg, 0.067 mmol), X-Phos (64 mg, 0.135 mmol) and Na2CO3 (107 mg, 1.01 mmol) in dioxane (20 mL) and water (5 mL) was heated to 90° C. for 16 hours under N2 atmosphere. Reaction mixture was concentrated and the residue was purified by preparative-TLC (methanol:dichloromethane=1:10) to afford N-tert-butyl-2-(isoquinolin-8-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (76 mg, 66%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 11.77 (s, 1H), 9.95 (s, 1H), 8.89 (s, 1H), 8.69 (d, 1H, J=5.7 Hz), 8.45 (s, 1H), 8.41 (s, 1H), 8.01-7.84 (m, 4H), 1.46 (s, 9H). LCMS: (M+H)+=346.