Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[O:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCCCOc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCOc2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-phenoxyhexyl bromide (1.56 g) were reacted and treated in the same manner as in Example 168 to give 0.78 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-phenoxyhexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:32][C:33]([F:44])([F:43])[C:34]1[N:38]2[CH2:39][CH2:40][NH:41][CH2:42][C:37]2=[N:36][N:35]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:18]([CH3:20])([CH3:21])[C:17]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:41]4[CH2:40][CH2:39][N:38]5[C:34]([C:33]([F:44])([F:32])[F:43])=[N:35][N:36]=[C:37]5[CH2:42]4)[CH:3]=3)[N:9]=2)[NH:14][CH:15]=1)=[O:22]
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCn5c(nnc5C(F)(F)F)C4)c3)nc12
Temperature: 90 °C
Yield: 33.3 %

Procedure:
A mixture of 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.083 g, 0.16 mmol), 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.05 g, 0.24 mmol), Pd(PPh3)4 (0.023 g, 0.02 mmol) and sodium t-butoxide (0.046 g, 0.48 mmol) in toluene (2 mL) were heated under an argon atmosphere in a microwave oven at 90° C. for 1 h. After cooling to room temperature, the reaction mixture was directly purified by flash column chromatography on silica gel with a mixture of 28% aqueous ammonium hydroxide:methanol:DCM (1:10:60) in DCM (20% to 80% gradient over 30 min) to give 25 mg of the desired product as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 8.84 (s, 1H), 8.48 (s, 1H), 8.23 (s, 1H), 7.95 (br s, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 5.74 (s, 2H), 4.80 (s, 2H), 4.37 (t, J=5.3 Hz, 2H), 3.91 (t, J=5.4 Hz, 2H), 3.66 (dd, J=8.2 Hz, 2H), 1.62 (s, 9H), 0 (s, 9H); MS [M+H]+: 600.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)C(=O)C(F)(F)F)#[N:10].C(O)(=O)C>O.CC(C)=O>[OH:28][C:25]1[CH:24]=[CH:23][C:22]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][C:9]#[N:10])=[CH:27][CH:26]=1
Reactant: N#CCCCCN(C(=O)C(F)(F)F)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: N#CCCCCNc1ccc(O)cc1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a solution of 30 g of potassium carbonate dissolved in 90 mL of water and 210 mL of methanol under nitrogen was added the 11.5 g of N-(4-cyanobutyl)-N-(4-hydroxyphenyl)trifluoroacetamide and the reaction was heated at 48°-53° C. for 41/2 hours. The reaction was allowed to stand at room temperature 18 hours and then acidified with 18 mL of acetic acid. Most of the methanol was evaporated and the remaining solution was diluted with a little water and ethyl acetate and made basic with solid potassium bicarbonate. The layers were separated and the aqueous phase was reextracted with ethyl acetate. The ethyl acetate extracts were washed with saturated NaCl solution and dried over anhydrous sodium sulfate. Evaporation of the ethyl acetate solution and trituration in hexane gave a solid which was dissolved in 15 ml of acetone and filtered through a short column of silica gel using acetane-hexane (40:60). The solvent was evaporated and the resulting solid was sublimed at 0.07 mm/125° C. then recrystallized from THF-hexane to yield 2.95 g of 5-[(4-hydroxyphenyl)amino]pentanenitrile, mp 88°-90° C., (22% yield from 4-bromo-N-(4-hydroxyphenyl)butanamide).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2Br)[C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH3:44][S:45]([C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][CH:53]=1)(=[O:47])=[O:46].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[C:52]2[CH:51]=[CH:50][CH:49]=[C:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH:53]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(Cl)ccc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(Cl)ccc4-c4cccc(S(C)(=O)=O)c4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-5-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (660 mg, 0.95 mmol) in dioxane (12 mL) was added (3-(methylsulfonyl)phenyl)boronic acid (285 mg, 1.43 mmol), Pd2(dppf)Cl2 (70 mg, 0.095 mmol) and Na2CO3 (6.0 mL, 2.0 M, aq). The reaction was heated to 90° C. for 2 h, then cooled to RT, concentrated in vacuo. The residue was taken up in CH2Cl2, washed with brine, and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.N1CCCCC1>CO>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:15][C:6]2[S:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[C:2]=2[OH:1])[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C1CSCC1=O
Reactant: O=Cc1cccc(Cl)c1
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)c1csc(Cc2cccc(Cl)c2)c1O
Temperature: 25 °C
Yield: 68.4 %

Procedure:
Methyl 4-oxotetrahydrothiophene-3-carboxylate (18.5 g) and 3-chlorobenzaldehyde (48.5 g) were heated at 100° C. with piperidine (4 ml) for 15 minutes and then allowed to cool to room temperature. The resulting yellow solid was stirred in methanol (300 ml) for 18 hours and collected. The yellow solid was suspended in ethanol (300 m) and dichloromethane (200 ml), para-toluenesulfonic acid(10 g) was added and the suspension was heated at reflux for 48 hours. The reaction mixture was allowed to cool and was then concentrated. The residue was purified by chromatography, eluting with 10:1 isohexane:dichloromethane, to give the sub-title compound (22.32 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:11]([C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH3:17])[CH:12]=1)=[O:6]>CO.CC(C)=O.O.Cl>[CH2:15]([NH:14][C:13]([C:11]1[CH:12]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1)=[O:18])[CH2:16][CH3:17]
Reactant: CCCNC(=O)c1cc(C(=O)OC)cc(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CCCNC(=O)c1cc(C(=O)O)cc(-c2ccccc2)c1
Reaction time: 72 h

Procedure:
A solution of NaOH (44 mg, 1.1 mmol) in 372 μL of MeOH was added to a solution of 68D (284 mg, 0.96 mmol) in 1.8 mL of acetone. The reaction was stirred at room temperature for 16 hrs after which time 10 mg of NaOH and 200 μL of MeOH were added. The reaction was stirred for 72 hrs. The reaction mixture was then concentrated in vacuo and the residue obtained was dissolved in water and a few drops of concentrated HCl were added till pH ˜1. An off-white solid appeared. It was collected by filtration and extensively rinsed with water. The solid was then dried in vacuo (194 mg, 72%). NMR 1H (ppm, CD3OD): 8.43 (t., J4=1.63 Hz, 1H), 8.38 (t., J4=1.73 Hz, 1H), 8.27 (t., J4=1.78 Hz, 1H), 7.71-7.67 (m, 2H), 7.48 (m, 2H), 7.39 (t.t., J3=7.34 Hz, J4=1.36 Hz 1H), 3.39-3.34 (m, 2H), 1.65 (sext., J3=7.18 Hz, 2H), 0.98 (t., J3=7.34 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][O:14][CH2:13]2>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:19]2[CH:12]3[CH2:18][CH2:17][CH:16]2[CH2:15][O:14][CH2:13]3)[CH3:10])=[CH:4][CH:3]=1
Reactant: C1CC2COCC1N2
Reactant: CC(=O)Cc1ccc(Br)cc1
Product: CC(Cc1ccc(Br)cc1)N1C2CCC1COC2
Yield: 28.5 %

Procedure:
The title compound (54 mg, colorless oil) was prepared from 1-(4-bromophenyl)propan-2-one (130 mg) and 3-oxa-8-azabicyclo[3.2.1]octane (100 mg), as in Reference Example P-R5-1.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[CH:19][CH:18]=2)[CH2:8][CH2:7][CH2:6]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[CH:19][CH:18]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CN=[N+]=[N-])c3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CN)c3ccccc32)cc1
Reaction time: 6 h
Yield: 47.2 %

Procedure:
5-Azidomethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.27 g) is suspended in ethanol (50 ml) and the mixture is subjected to catalytic hydrogenation at room temperature under 3 kg/cm2 for 6 hours by using 10% Pd-C (27 mg). The catalyst is removed by filtration with celite and the filtrate is distilled off and the resulting residue is recrystallized from ethanol to give 5-aminomethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.12 g) as colorless needles, m.p. 233°-235° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][Br:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Br)c1CBr
Temperature: 80 °C
Reaction time: 16 h
Yield: 102.8 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1-bromo-2-methyl-3-nitrobenzene (6.86 g, 31.8 mmol) and carbon tetrachloride (40 mL) and heated to 80° C. N-bromo-succinimide (6.96 g, 39.1 mmol) and 2,2′-azobis(2-methylpropionitrile) (522 mg, 3.18 mmol) were added, and the reaction mixture was stirred at 80° C. for 16 h. After this time, the reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with methylene chloride (20 mL). The filtrate was concentrated under reduced pressure to afford crude 114a (9.64 g, 103% crude yield) as a yellow oil, which was used directly in the next step: 1H NMR (500 MHz, CDCl3) δ 7.89-7.86 (m, 2H), 7.35 (t, 1H, J=8.0 Hz), 4.89 (s, 2H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>>[OH:21][C:7]1[C:6]([C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5])=[N:11][CH:10]=[C:9]2[S:12][N:13]=[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=12
Reactant: CCOC(=O)c1ncc2snc(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1ncc2snc(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to Example 1 from 4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine; MS (m/z): 330.09 (M+H+).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[S:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>>[Br:23][C:10]1[C:11]2[C:12]3[CH:22]=[CH:21][S:20][C:13]=3[C:14](=[O:19])[NH:15][C:16]=2[CH:17]=[CH:18][C:9]=1[O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)c3sccc3c2c1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)c3sccc3c2c1Br
Yield: 37.7 %

Procedure:
Following Step 4 from General Procedure A, 8-(tert-butyldimethylsilyloxy)thieno[2,3-c]quinolin-4(5H)-one (740 mg, 2.2 mmol) was reacted with N-bromosuccinimide (480 mg, 2.7 mmol) to afford the desired product (340 mg, 37%) as a brown solid: ESI MS m/z 411 [C17H20BrNO2SSi+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[OH-].[Na+].Br[CH2:12][CH2:13][CH2:14][Cl:15]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][N:6]1[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]1
Reactant: ClCCCBr
Reactant: COC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC1CCN(CCCCl)CC1
Yield: 60.2 %

Procedure:
4-Methoxy-piperidine (1.5 g, 13 mmol), acetone (30 ml, 20 vol), 5M NaOH solution (3.13 ml) and 1-bromo-3-chloropropane (6.14 g, 39 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (1.5 g, 60%) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:29][C:30]([NH2:32])=[O:31]>O1CCCC1.C(OCC)(=O)C>[NH2:32][C:30](=[O:31])[CH2:29][O:27][CH2:26][C:23]1[N:22]=[C:21]([C@H:12]([CH2:11][CH2:10][CH2:9][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[O:25][N:24]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(COCC(N)=O)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 268.6 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (51 mg, 1.28 mmol) in anhydrous tetrahydrofuran (3 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (105 mg, 0.30 mmol) in anhydrous tetrahydrofuran (3 ml) and stirred under a nitrogen atmosphere for 30 minutes. 2-Bromoacetamide (235 mg, 1.70 mmol) was added and the mixture was allowed to warm to room temperature and then heated at 40° C. for 15 hours. The cooled reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (99:1) to pentane:ethyl acetate (0:100) to afford the title compound as a colourless oil (330 mg).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[NH:27][NH2:28])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[NH:27][N:28]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(NC(=O)NN)cc1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: CC(C)(C)c1ccc(NC(=O)NN=c2c(=O)c3ccccc3c2=O)cc1

Procedure:
ninhydrin, 4-(4-tert-butylphenyl)-semicarbazide hydrochloride
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].[I:22]I>CO>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[C:13]([I:22])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(N)c(I)c1
Yield: 46.5 %

Procedure:
To a mixture of (4-amino-benzyl)-carbamic acid tert-butyl ester (4.8 g, 21.6 mmol) and calcium carbonate (2.7 g, 27 mmol) in methanol (60 mL) was added iodine (5.5 g, 21.6 mmol) in portions. The mixture was heated at reflux overnight and then concentrated in vacuo to give a dark brown residue, which was partitioned between ethyl acetate and saturated sodium bisulfite solution. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by chromatography (5%-20% ethyl acetate in hexanes) to give 3.5 g (47%) of the desired product as a brown semi-solid. MS(APCI+): m/z 349.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:19])/[C:5](=[CH:7]\[C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)/N=1.Cl.C([OH:23])C>>[OH:23]/[C:5](=[CH:7]\[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)/[C:4]([O:3][CH2:2][CH3:1])=[O:19]
Reactant: CC1=N/C(=C/c2ccc(-c3ccccc3)o2)C(=O)O1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)/C(O)=C/c1ccc(-c2ccccc2)o1
Yield: 55 %

Procedure:
To an ethanol (10 mL) suspension of (E)-2-methyl-4-((5-phenylfuran-2-yl)methylene)oxazol-5(4H)-one 47 (253 mg, 1.0 mmol) was added 12M HCl (5 mL). The reaction mixture was refluxed for 5 h, then the excess solvent was removed in vacuo. The residue was diluted with ethyl acetate (100 mL), then washed with water (2×30 mL). The organic layer was dried with brine and MgSO4, then concentrated in vacuo. Flash column chromatography on silica gel (n-hexanes:ethyl acetate=10:1) of the residue afforded the desired product 48 in 55% yield (142 mg, yellow solid). 1H NMR (400 MHz, CDCl3): 7.70 (d, J=7.2 Hz, 2H), 7.39 (t, J=7.2 Hz, 2H), 7.27 (t, J=7.2 Hz, 1H), 6.97 (d, J=3.6 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 6.65 (d, J=1.6 Hz, 1H), 6.43 (d, J=1.6 Hz, 1H), 4.37 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[C:10]([NH:12][C:13]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:31]>ClCCl.O1CCOCC1>[ClH:31].[NH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1)[C:10]([NH:12][C:13]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]1)=[O:11]
Reactant: CCOC(=O)C1(NC(=O)C(NC(=O)OC(C)(C)C)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)C(N)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
262 mg (0.61 mmol) of the compound of Example 17A were dissolved in 4 ml of dichloromethane, and 4 ml of a 4N solution of hydrogen chloride in dioxane were added. The solution was stirred at RT for 3 h and then freed from the volatile components on a rotary evaporator. The residue was dried under high vacuum. This gave 223 mg (quant.) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:23][C@H:24]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:23][C@H:24]([C:26]1[CH:27]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O[C@@H]1CC[C@H]2[C@H](C(=O)OC(C)(C)C)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O[C@@H]1CC[C@H]2[C@H](C(=O)O)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 161.1 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 128a; 3.28 g, 5.18 mmol) was dissolved in dichloromethane (30 ml) and trifluoroacetic acid added (8 ml) and the reaction mixture stirred overnight at room temperature. The reaction mixture was concentrated in vacuo then triturated with diethyl ether (×3) to give the title compound as a brown solid (4.82 g).
Reaction SMILES: [CH2:1]([C:5]12[CH2:22][C:21](=[O:23])[C:20]([CH3:24])=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[C:11]([CH3:15])[C:10]([O:16]COC)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.CCOC(C)=O>[CH2:1]([C:5]12[CH2:22][C:21](=[O:23])[C:20]([CH3:24])=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[C:11]([CH3:15])[C:10]([OH:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCc3c(ccc(OCOC)c3C)C1=C(C)C(=O)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC12CCc3c(ccc(O)c3C)C1=C(C)C(=O)C2
Temperature: 80 °C

Procedure:
A solution of 3a-butyl-7-(methoxymethoxy)-1,6-dimethyl-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one (63 mg, 0.19 mmol) in methanol (1.1 mL) was treated with aqueous 2N HCl (0.3 mL), placed under a N2 atmosphere, stirred, and heated in an oil bath at 80° C. for 35 minutes. After cooling, the mixture was diluted with EtOAc (25 mL) and washed with 5% NaHCO3 (10 mL). The organic phase was dried over MgSO4, filtered, and evaporated under vacuum to provide 3a-butyl-7-hydroxy-1,6-dimethyl-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as a solid.
Reaction SMILES: Cl.[CH:2]1([C:8]2([N:18]([CH3:20])[CH3:19])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>>[CH:2]1([C:8]2([N:18]([CH3:20])[CH3:19])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)C1(C2CCCCC2)CCC2(CC1)OCCO2
Agent: Cl
Product: CN(C)C1(C2CCCCC2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6N hydrochloric acid (7 ml) was added to (8-cyclohexyl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethyl-amine (C-5) (1.18 g, 4.41 mmol), and the mixture was stirred overnight at room temperature. When the hydrolysis was complete, the reaction mixture was extracted with ether (2×10 ml), the aqueous solution was rendered alkaline with 5N sodium hydroxide solution, while cooling with ice, the reaction mixture was extracted with dichloromethane (3×20 ml), and the organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product (637 mg) was purified by flash chromatography with CHCl3/MeOH (9:1).