Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+]>>[C:1]([NH:4][C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Acetamido-tetralone (15 g) was added in small portions to a cold solution of nitric acid (46 ml) at -30° C. After the addition was complete (2-3 hours), the reaction mixture was stirred at the same temperature for 1 hour, warmed to 0° C. and stirred for 4 hours. The reaction was poured on ice, basified with aqueous sodium hydroxide and extracted with ethyl acetate several times. The organic layer was separated, dried and evaporated. The desired 5-nitro-isomer was separated using flash chromatography (ethyl acetate-methylene chloride) to afford 8.73 g (48%).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)(O)=[O:2].S(Cl)(Cl)=O.[CH3:30][NH:31][CH2:32][CH3:33].N1C=CC=CC=1>ClCCl.O>[CH3:30][N:31]([CH2:32][CH3:33])[C:1]([C:4]1[CH:8]=[N:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[O:2]
Reactant: COc1ccc(-c2c(C(=O)O)cnn2-c2ccc(Cl)cc2)cc1OC
Reactant: CCNC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCN(C)C(=O)c1cnn(-c2ccc(Cl)cc2)c1-c1ccc(OC)c(OC)c1
Temperature: 3 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
The acid prepared in Example 610 (2.6 g) is heated with 75% strength thionyl chloride (50 ml) for 8 hours. The mixture is taken up in dichloromethane and concentrated. The oil obtained (1.4 g) is dissolved in methylene chloride (30 ml) and cooled to about 3° C. A solution of N-methyl-N-ethylamine (0.54 g) and pyridine (0.3 g) in methylene chloride (30 ml) is added, keeping the temperature lower than 5° C. The mixture is stirred for 6 hours 20 minutes at ambient temperature. It is poured into water and extracted with methylene chloride. The mixture is dried over sodium sulphate and concentrated. An orange precipitate (1.2 g; yield=82.2%) is obtained, m.p. 110° C. (compound no. 611).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[H][H]>CCOC(C)=O.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C#CCO)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CCCO)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-(3-hydroxyprop-1-ynyl)benzonitrile (2.0 g, 12.7 mmol) in EtOAc (25 mL), Pd/C (500 mg, 0.47 mmol) was added. A hydrogen balloon was placed over the reaction, and the reaction stirred for approximately four hours. An additional 200 mg (0.19 mmol) of Pd/C was added and the balloon was placed back over the reaction. Upon completion, the reaction mixture was filtered through a pad of celite and concentrated to give 4-(3-hydroxypropyl)benzonitrile which was used without further purifications.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:24]([C:22]3[S:23][C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)=[CH:20][CH:21]=3)=[O:25])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2ccccn2)s1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-(2-pyridyl)thiophene-2-carboxylic acid (Maybridge) according to methods A and C; yield 35 mg, 0.09 mmol (43%): 1H NMR (300 MHz, methanol-d4) δ 2.07-2.29 (m, 5H), 2.48 (s, 2H), 3.49 (d, J=12 Hz, 2H), 3.56 (s, 2H), 3.83 (d, J=13 Hz, 2H), 4.26 (s, 1H), 7.29-7.39 (m, 1H), 7.71 (d, J=4 Hz, 1H), 7.83-7.91 (m, 3H), 8.50-8.56 (m, 1H); MS (DCI/NH3) m/z 340 (M+H)+; Anal. C19H21N3OS.HCl.0.5H2O: C, H, N.
Reaction SMILES: CO[NH:3][CH:4]1[O:28][C:12]2=[CH:13][C:14]([O:16][CH:17]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:18])=[CH:15][C:10]3=[C:11]2[CH:6]([CH2:7][C:8]([CH3:30])([CH3:29])[O:9]3)[CH2:5]1.[OH-].[Na+]>CO.[Ni].[Al]>[NH2:3][CH2:4][CH2:5][CH:6]1[C:11]2[C:12]([OH:28])=[CH:13][C:14]([O:16][CH:17]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH3:18])=[CH:15][C:10]=2[O:9][C:8]([CH3:29])([CH3:30])[CH2:7]1
Reactant: CONC1CC2CC(C)(C)Oc3cc(OC(C)CCCc4ccccc4)cc(c32)O1
Agent: [Ni]
Agent: [Al]
Agent: [Na+]
Solvent: CO
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)OC(C)(C)CC2CCN
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
In a stirred flask, under nitrogen, was placed 17.5 g (0.043 mole) 2-methoxyamino-5,5-dimethyl-8-(5-phenyl-2-pentyloxy)-3,3a,4,5-tetrahydro-2H-pyrano[4,3,2-de]benzopyran in 1800 ml methanol. The mixture was warmed to 40° C. and 1080 ml 1N sodium hydroxide was added in portions over ten minutes. The mixture was heated to 55° C. and 20.4 g Raney Alloy (nickel/aluminum 1:1 by weight) was added in portions over ten minutes (foaming-). The resulting mixture was stirred at 55° C. for one hour, allowed to cool to room temperature and the catalyst removed by filtration. The filtrate was evaporated in vacuo to an oil which was combined with water and 6N hydrochloric acid added to adjust the mixture of pH 6-7. The neutralized mixture was extracted with ethyl acetate, the organic layer backwashed with brine, dried (MgSO4), filtered and the solvent evaporated at reduced pressure to provide 16.4 g crude product as an oil.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH2:7][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC(=O)CC(=O)OCc1ccccc1

Procedure:
2.50 g (19.2 mmol) of methyl 3-oxovalerate, 6.23 g (57.6 mmol) of benzyl alcohol and 234 mg (1.92 mmol) of 4-dimethylaminopyridine were heated under reflux in 30 ml of toluene overnight. Ethyl acetate was added to the reaction solution. After washing with 1 N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: C(C1C=CC(C(C)C)=CC=1N)(C)C.BrC1C(C(C)C)=CC(N)=C(C(C)C)C=1.BrC1C(C(C)C)=CC(N)=C(C(C)C)C=1[N+]([O-])=O.S(=O)=O.[Br:48][C:49]1[C:54]([CH:55]([CH3:57])[CH3:56])=[CH:53][C:52]([S:58]([NH2:61])(=[O:60])=[O:59])=[C:51]([CH:62]([CH3:64])[CH3:63])[C:50]=1[N+:65]([O-])=O>>[NH2:65][C:50]1[C:51]([CH:62]([CH3:64])[CH3:63])=[C:52]([S:58]([NH2:61])(=[O:60])=[O:59])[CH:53]=[C:54]([CH:55]([CH3:57])[CH3:56])[C:49]=1[Br:48]
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)c([N+](=O)[O-])c1Br
Agent: CC(C)c1cc(Br)c(C(C)C)cc1N
Agent: CC(C)c1cc(N)c(C(C)C)c([N+](=O)[O-])c1Br
Agent: CC(C)c1ccc(C(C)C)c(N)c1
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)c(N)c1Br

Procedure:
3-Amino-4-bromo-2,5-diisopropylbenzenesulfonamide is prepared by known general methods (L. F. Fieser and M. Fieser, Reinhold Publishing Corp., N. Y., 3rd ed., 1956, pgs 599-602) from 2,5-diisopropylaniline by acylation to 2,5-diisopropylacetanilide, bromination to 4-bromo-2,5-diisopropylacetanilide, hydrolysis to 4-bromo-2,5-diisopropylaniline, nitration to 4-bromo-2,5-diisopropyl-3-nitroaniline, diazotization in the presence of cuprous chloride and sulfur dioxide to 4-bromo-2,5-diisopropyl-3-nitrobenzenesulfonamide (method of Example 6) and reduction.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][Cl:19])=[CH:13][CH:12]=1.[C:20](Cl)(=O)[CH2:21][CH3:22]>>[Cl:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:3]3[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=3[N:1]=[C:20]2[CH2:21][CH3:22])=[CH:12][CH:13]=1
Reactant: CCC(=O)Cl
Reactant: N#Cc1ccc(N)c(Nc2ccc(CCCl)cc2)c1
Product: CCc1nc2ccc(C#N)cc2n1-c1ccc(CCCl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 Example 1 from 4-amino-3-[4-(2-chloroethyl)anilino]benzonitrile (step 3) and propionyl chloride.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[C:10]([CH2:11][OH:12])[C:6]=2[C:5]([CH3:13])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C.O>C1(C)C=CC=CC=1.C1COCC1>[OH:12][CH2:11][C:10]1[C:6]2[C:5]([CH3:13])=[CH:4][CH:3]=[CH:2][C:7]=2[S:8][CH:9]=1
Reactant: Cc1ccc(Br)c2scc(CO)c12
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2scc(CO)c12
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A solution of 7-bromo-3-hydroxymethyl-4-methyl-benzo[b]thiophene (45.91 g, 179 mmol) in toluene-THF (5/1, 220 ml) was placed in an ice bath, to which a solution of 3.4 M sodium hydrogenated bis(2-methoxyethoxy)aluminum in toluene (215 ml, 731 mmol) was added dropwise over 30 minutes. After the dropwise addition was complete, the reaction mixture was stirred at 70° C. for 3 hours, and it was brought back to room temperature and placed in an ice bath, to which ethyl acetate (300 ml) was slowly added dropwise. After stirring in the ice bath for 5 minutes, water (600 ml) was slowly added dropwise. The internal temperature increased from 17° C. to 35° C. To the reaction mixture, 1 L of water and 500 ml of ethyl acetate were added, and extracted. The aqueous phase was further extracted with 300 ml of ethyl acetate, and the combined organic phase was washed with water (300 ml×6 times). After drying the organic phase on magnesium sulfate, the solvent was evaporated to obtain pale orange crude crystals 3-hydroxymethyl-4-methyl-benzo[b]thiophene (30.80 g, 173 mmol). The yield was 97%.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH2:12][CH3:13])[C:9]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:16][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C[O-].[Na+].CO>[CH2:12]([C:10]1[C:9]2[N:14]=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:16][C:8]=2[C:7]([OH:23])=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[N:11]=1)[CH3:13]
Reactant: CCOC(=O)c1nc(CC)c2nc(-c3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A mixture of 4-ethyl-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (57 mg, 0.17 mmol) and glycine (259 mg, 3.45 mmol) in 0.5 M sodium methoxide/methanol (6.5 mL) was refluxed for 21 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (5 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (50 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.04 (br s, 1H), 9.22 (br s, 1H), 8.17 (m, 2H), 7.64 (m, 3H), 4.05 (d, J=6.2 Hz, 2H), 3.28 (q, J=7.8 Hz, 2H), 1.42 (t, J=7.8 Hz, 3H); MS: (+) m/z 357.97 (M+1), (−) m/z 355.95 (M−1).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[CH3:30])[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[CH3:30])[CH:19]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1cc(Cl)ccc1C1c2c(cc(Br)n2C(C)C)C(=O)N1c1cc(Cl)c(=O)n(C)c1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate N) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a light yellow solid. tR: 7.25 min (HPLC 2); ESI-MS: tR=1.21 min, [M+H]+ 536/538 (LC-MS 1); TLC: Rf=0.20 (EtOAc).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:21]([NH2:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[C:24]1([C:21]([NH:30][C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)([CH3:23])[CH3:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: CC(C)(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(-c3ccnc(NC(C)(C)c4ccccc4)n3)cc2s1

Procedure:
A solution of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.1 g, 0.3 mmol), cumylamine (0.05 mL, 0.4 mmol), cesium carbonate (0.05 g, 0.7 mmol) in N,N-DMF was heated under microwave (CEM) at 180° C. for 20 min. The mixture was diluted with DCM and washed with water, dried over sodium sulfate, and concentrated. The residue was purified by HPLC (5-100% CH3CN in water with 0.05% TFA) to give N-(6-(2-(2-phenylpropan-2-ylamino)pyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 404 (MH+). Calculated exact mass for C22H21N5OS: 403.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O-])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CN1CCOCC1.[BH4-].[Na+].[OH-].[Na+]>COCCOC.O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([CH2:12][OH:13])=[CH:11][C:2]=1[NH2:1]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(CO)cc1N
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
To a solution of 1-methyl 2-aminoterephthalate (10.0 g, 51.2 mmol) and NMM (5.75 mL, 1 equiv) in DME (90 mL) at −15° C. was added dropwise IBCl (6.7 mL, 1 equiv). The mixture was stirred at this temperature for 15 min. The salt was removed by filtration and the solution was cooled down to −15° C. A solution of NaBH4 (3.06 g, 1.5 equiv) in water (30 mL) was added carefully dropwise. At the end of the addition, water (100 mL) was added and the mixture was stirred at r.t. for 15 min. Aq NaOH (2N, 50 mL) was added and the aqueous phase was extracted twice with AcOEt. The organic phase were combined and dried (Na2SO4). The solution was concentrated in vacuo to afford a white solid (8.0 g, 86%) (ES-MS: m/z 182.1 [M+H]+, rt 3.50 min).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:20](=O)[CH2:19][C@@:18]3([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[C:12]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C@@:18]3([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CCCCc2ccccc2)C(=O)C3)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc([C@@]23CCCC[C@@H]2CN(CCCCc2ccccc2)CC3)c1
Yield: 94 %

Procedure:
N-(4-Phenyl-n-butyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline (0.8 g) in anhydrous tetrahydrofuran was treated with 0.8 g of lithium aluminum hydride and refluxed overnight. The reaction mixture was worked up as indicated in Example 2-B to yield 0.7 g of an opaque oil which was evaporatively distilled, bp 80°-90°, and identified as N-(4-phenyl-n-butyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([N:18]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:12]=2)[CH2:8][N:7]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:6]1)[CH:2]=C.[O:40]=[O+][O-].S(C)C>C(Cl)Cl>[C:22]([O:21][C:19]([N:18]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[C:13]1[N:12]=[C:11]([CH2:10][C@@H:9]2[C@H:5]([O:4][CH2:1][CH:2]=[O:40])[CH2:6][N:7]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:8]2)[CH:16]=[C:15]([CH3:17])[CH:14]=1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: C=CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1Cc1cc(C)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: Cc1cc(C[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2OCC=O)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of 5 (100 mg, 0.19 mmol) in CH2Cl2 (10 mL) was cooled to −78° C., to which O3 was charged until the reaction solution turned purple (˜10 min). The O3 flow was stopped, and the reaction was allowed to stir at the same temperature for 30 min. To the resulting solution was added Me2S (150 μL). The reaction mixture was then warmed to room temperature and kept stirring at room temperature for an additional 2 h. The solvent was removed by rotary evaporation and the resulting crude product was purified by flash column chromatography (EtOAc/hexanes, 1:1, Rf=0.2) to yield 6 (87 mg, 87%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 27H), 2.22 (s, 3H), 2.70-2.85 (m, 111), 2.85-2.95 (m, 1H), 3.05-3.15 (m, 1H), 3.16-3.25 (m, 1H), 3.30-3.37 (m, 1H), 3.45-3.70 (m, 2H), 3.85-3.95 (m, 2H), 4.05-4.20 (t, J=10.0 Hz, 1H), 6.90-6.93 (m, 2H), 9.66 (s, −1H); 13C NMR (125 MHz, CDCl3) δ 20.9, 24.7, 27.9, 28.5, 29.7, 34.4, 42.5, 43.2, 48.8, 49.1, 50.3, 51.0, 74.6, 74.9, 79.4, 79.5, 80.4, 83.0, 119.66, 119.73, 122.8, 149.7, 149.8, 151.57, 151.60, 151.8, 154.4, 154.8, 159.87, 158.94, 200.2, 200.6; LC-TOF (M+H+) calcd for C28H44N3O8 550.3128. found 550.3130.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:20]1[C:24](B(O)O)=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2>>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:24]2[O:20][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Reactant: OB(O)c1cc2ccccc2o1
Product: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2cc3ccccc3o2)C1=O
Yield: 23.1 %

Procedure:
200 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-iodo-3(2H)-furanone was coupled with 99 mg of benzo[b]furan-2-boronic acid by following a procedure similar to Step 4 of Example 22 to give 45 mg of 5-{4-(aminosulfonyl)phenyl}-4-(2-benzo[b]furanyl)-2,2-dimethyl-3(2H)-furanone as a solid. mp: 143-145° C. NMR: δ1.60 (s, 6H), 4.92 (br s, 2H), 7.23 (m, 3H), 7.72 (m, 2H), 8.02 (m, 4H), IR (cm−1): 3384, 3245, 1698, 1510, 1253, 1161, 793.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:25])([F:26])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:14]([N:32]3[CH2:33][C:30]([F:34])([F:29])[CH2:31]3)=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: FC1(F)CNC1
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Agent: Cl
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)N2CC(F)(F)C2)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and 3,3-Difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials and isolated (35 mg, 58%); MS (ESI, m/z): 464.6 (M+H+).
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:19][C:20](=[N:51]O)[C:21]1[CH:49]=[CH:48][C:24]([O:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:47])[C@H:37]([NH:39][C:40]([C:42]3[O:43][CH:44]=[CH:45][CH:46]=3)=[O:41])[CH3:38])[CH2:31][CH2:30]2)=[CH:23][C:22]=1[F:50]>CN(C=O)C>[F:50][C:22]1[CH:23]=[C:24]([CH:48]=[CH:49][C:21]=1[C:20]1[N:51]=[C:1]([CH2:2][CH2:3][CH3:4])[O:6][N:19]=1)[O:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:47])[C@H:37]([NH:39][C:40]([C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[O:41])[CH3:38])[CH2:31][CH2:30]1
Reactant: C[C@@H](NC(=O)c1ccco1)C(=O)N1CCCN(CCCOc2ccc(C(N)=NO)c(F)c2)CC1
Reactant: CCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCc1nc(-c2ccc(OCCCN3CCCN(C(=O)[C@@H](C)NC(=O)c4ccco4)CC3)cc2F)no1
Temperature: 115 °C

Procedure:
Butyric acid (0.2 mmol) was treated with 0.5 mL of a 0.46 M solution (0.23 mmol) of 1,1′-carbonyldiimidazole (CDI) in DMF in a 4 mL vial. After mixing for 30 minutes, 0.75 mL of a 0.17 M solution of Example 141F (0.13 mmol) in DMF was added to the vial. The resulting solution was mixed for 4 hours at room temperature. A further 0.5 mL of 0.35 M solution of CDI (0.175 mmol) in DMF was added to the vial. The resulting mixture was heated at 115° C. for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to provide the desired products. 1H NMR (CDCl3) δ1.05 (t, 3H), 1.50 (m, 5H), 1.90 (m, 2H), 2.41 (m, 2H), 2.92 (t, 2H), 3.30-3.70 (m, 4H), 4.10-4.50 (m, 8H), 4.95 (m, 1H), 6.50 (m, 1H), 6.75 (m, 2H), 7.10 (m, 2H), 7.50 (m, 1H), 7.98 (m, 1H);
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:41]([CH3:43])[CH3:42])[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]=3[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)=[CH:19]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:44].C(OCC)C>C(OCC)(=O)C>[ClH:44].[NH2:8][C@@H:9]([CH:41]([CH3:43])[CH3:42])[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]=3[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)=[CH:19]2)[CH2:14]1)=[O:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)[C@H](N)C(=O)OC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 0.5 h

Procedure:
3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate (35 mg, 0.060 mmol) was dissolved in ethyl acetate (2.5 ml). Hydrogen chloride gas was passed through for 5 minutes. The flask was capped and the solution stirred for additional 30 minutes. Diethyl ether was added and precipitate formed. The solid was collected by filtration to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl (2S)-2-amino-3-methylbutanoate hydrochloride. The structure was confirmed by 1H NMR and LC/MS (MH+=486).