Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[O:17])[CH:12]=3)[C:7]=2[C:6]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:26]2)=[CH:5][CH:4]=1)#[N:2].[OH-:42].[K+].OO.O>CS(C)=O>[C:1]([C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[O:17])[CH:12]=3)[C:7]=2[C:6]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:26]2)=[CH:5][CH:4]=1)(=[O:42])[NH2:2]
Reactant: [OH-]
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C#N)ccc(N4CCC[C@@H](NC(=O)OCc5ccccc5)C4)c23)CC1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(N4CCC[C@@H](NC(=O)OCc5ccccc5)C4)c23)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.9 %

Procedure:
Step 5 A solution of (R)-benzyl 1-(1-cyano-7-(4-methylpiperazine-1-carbonyl)-9H-carbazol-4-yl)piperidin-3-ylcarbamate (108 mg, 0.196 mmol) in DMSO (2 mL) was treated with 22% aqueous potassium hydroxide (0.208 mL, 0.981 mmol), and then dropwise with a solution of 30% aqueous hydrogen peroxide (0.200 mL, 1.961 mmol). The mixture was stirred at rt for 2.5 h. Water was added, the resulting suspension was stirred at rt for 15 min, and the solid was collected by filtration, washed with water and dried to afford (R)-benzyl 1-(1-carbamoyl-7-(4-methylpiperazine-1-carbonyl)-9H-carbazol-4-yl)piperidin-3-ylcarbamate as an off-white solid (89 mg, 80%). 1H NMR (400 MHz, methanol-d4) δ 8.17 (d, J=8.13 Hz, 1H) 7.81 (d, J=8.35 Hz, 1H) 7.66 (s, 1H) 7.30 (d, J=7.91 Hz, 1H) 7.09-7.26 (m, 5 H) 6.82 (d, J=8.35 Hz, 1H) 4.90-5.03 (m, 2H) 3.87-3.99 (m, 1H) 3.57-3.68 (m, 1 H) 3.27-3.54 (m, 5H) 3.06-3.19 (m, 4H) 2.69-2.82 (m, 1H) 2.47-2.65 (m, 1H) 1.98-2.11 (m, 1H) 1.83-1.97 (m, 2H) 1.32-1.53 (m, 1H). Mass spectrum m/z 569.3 (M+H)+.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH2:46]O)=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:51]>ClCCl.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.CN(C)C1C=CN=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH2:46][Cl:51])=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(CO)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(CCl)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
623 mg of the alcohol of Step F were dissolved in 8 ml of dichloromethane with 834 ml of tosyl chloride, and over 20 minutes, a solution of 534 mg of 4-dimethylamino-pyridine and 5 ml of dichloromethane was added. After stirring for one hour, 2.2 ml of N hydrochloric acid were added with stirring, and after decanting, the organic phase was dried and distilled under reduced pressure. The residue was chromatographed over silica and eluted with dichloromethane-ethyl acetate (9-1) to obtain 245 mg of 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-3-chloromethyl-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate crystallizing from ether.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]=O)=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[N:26]1([CH2:24][CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([C:14]3[CH:13]=[N:12][C:11]4[N:10]([N:9]=[CH:8][C:7]=4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:15]=3)=[CH:21][CH:20]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=CCCc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: c1ccc(-c2cnn3cc(-c4ccc(CCCN5CCOCC5)cc4)cnc23)cc1

Procedure:
A solution of 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]propanal (2-5, 150 mg, 0.458 mmol, 1 equiv), morpholine (0.048 mL, 0.55 mmol, 1.2 equiv), acetic acid (0.026 mL, 0.55 mmol, 1.0 equiv), and sodium triacetoxyboro-hydride (116 mg, 0.547 mmol, 1.20 equiv) in dichloroethane (8 mL) was stirred in the presence of 4 angstrom molecular sieves for 15 minutes. The reaction mixture was partitioned between saturated sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (50% hexane in chloroform saturated with ammonia gas, grading to 100% chloroform saturated with ammonia gas) to give 6-[4-(3-morpholin-4-ylpropyl)phenyl]-3-phenylpyrazolo[1,5-a]pyrimidine (2-6) as a yellow solid (mp=147-149° C.). 1H NMR (400 MHz, CDCl3) δ8.82 (s, 2H), 8.45 (s, 1H), 8.06 (br d, 2H, J=7.8 Hz), 7.53 (d, 2H, J=8.2 Hz), 7.47 (t, 2H, J=7.8 Hz), 7.35 (d, 2H, J=8.2 Hz), 7.29 (t, 1H, J=7.8 Hz), 3.73 (m, 4H), 2.73 (t, 2H, J=7.5 Hz), 2.46 (m, 4H), 2.40 (t, 2H, J=7.2 Hz), 1.87 (pentet, 2H, J=7.7 Hz).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[CH3:10][C:11]1[C:12]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1>>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:21]2[CH2:22][CH2:23][N:18]([C:12]3[C:11]([CH3:10])=[CH:16][C:15]([CH3:17])=[CH:14][N:13]=3)[CH2:19][CH2:20]2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3csc(Br)c3)CC2)c(C)c1
Yield: 76.2 %

Procedure:
Using 5-bromothiophene-3-carboxylic acid (500 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (462 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (700 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CCO>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2CO)CC1
Temperature: 25 °C
Yield: 65 %

Procedure:
The reaction mixture of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbaldehyde (23.00 mg; 0.05 mmol; 1.0 eq.) and sodium borohydride (7.8 mg; 0.21 mmol; 4.0 eq.) in EtOH (2.00 ml) was stirred at room temperature over weekend. The reaction mixture was workup and purified by reverse phase chromatography (Yamazen, acetonitrile/0.1% NH4OH in water). The pure fractions were lyophilized to afford the title compound in 65% yield. LC-MS: (M+1=451, obsd.=451).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]1.BrCCCN1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:21]=[C:20]1[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17](=[O:26])[N:1]1[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: N#CC1CCN(CCCN)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 46.2 %

Procedure:
A suspension of 3-pyrrolidinecarbonitrile (302) (Swidinsky, J., et al., J. Pharm. Sci. 1967, 56, 192-196) (4.5 g, 15.6 mmol), N-(3-bromopropyl)phthalimide (3.48 g, 13.0 mmol), and K2CO3 (2.16 g, 15.6 mmol) in DMF (20 mL) was stirred at 100° C. for 1.5 h. The solution was cooled, the solvent evaporated and the residue partitioned between water (50 mL) and EtOAc (50 mL). The organic fraction was extracted with 1 M HCl (2×50 mL) and the acidic fraction washed with Et2O (2×20 mL). The acidic fraction was made basic with dilute aqueous NH3 solution and the alkaline solution was extracted with DCM (3×25 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give phthalimide 303 (1.70 g, 46%) as a colourless oil: 1H NMR δ 7.82-7.87 (m, 2H, Harom), 7.69-7.74 (m, 2H, Harom), 3.75-3.79 (m, 2H, CH2), 2.87-2.93 (m, 2H, CH2N), 2.52-2.60 (m, 5H, CH2, CH2N, CH), 2.06-2.15 (m, 1H, CH2), 1.96-2.04 (m, 1H, CH2), 1.87 (p, J=7.0 Hz, 2H, CH2); 13C NMR δ 168.4 (2), 133.9 (2), 132.2 (2), 123.1 (2), 122.1, 57.2, 52.6 (2), 36.3, 29.1, 27.2, 26.1; HRMS (FAB+) calcd for C16H17N3O2 (M+) m/z 283.1321, found 283.1318.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][N:15]3C(OC(C)(C)C)=O)=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+]>Cl>[C@H:13]12[CH2:18][C@H:16]([NH:15][CH2:14]1)[CH2:17][N:12]2[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
1,1-Dimethylethyl (1S,4S)-5-[[4-(methoxycarbonyl)phenyl]methyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (44.1 g, 127.3 mmol) was slurried in HCl (2 M in water, 0.6 L). The solid went into solution over 2 hours, and the solution was stirred for another 16 hours. The reaction was cooled to −5 C. and saturated K2CO3 was added slowly enough to keep the temperature below 0 C. to prevent ester hydrolysis. Once the pH was 11, the solution was extracted with CH2Cl2 until no product was observed in the water layer by TLC (3×). The combined organic fractions were concentrated under vacuum to obtain pure methyl 4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (30.3 g, 97%) as the freebase; 1H NMR (CD3OD) δ 7.98 (d, 2H), 7.49 (d, 2H), 4.00 (sbr, 1H), 3.90 (s, 3H), 3.88 (d, 1H), 3.80 (d, 1H), 3.57 (sbr, 1H), 3.39 (ddbr, 1H), 3.03 (ddbr, 1H), 2.88 (ddbr, 1H), 2.72 (ddbr, 1H), 2.09 (dbr, 1H), 1.75 (dbr, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[H-].[Na+].Br.Br[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[N:7]=1
Reactant: Nc1ncc2sc(=O)[nH]c2n1
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc2sc(=O)n(Cc3cccnc3)c2n1
Temperature: 30 °C

Procedure:
5-Amino-3H-thiazolo[4,5-d]pyrimidin-2-one (107 mg, 0.64 mmol) was dissolved in DMF (4 mL) at ambient temperature. Sodium hydride (30 mg, 1.32 mmol) was added and the mixture was heated to 30° C. Stirring was continued for 0.5 h before 3-bromomethyl-pyridine hydrobromide (179 mg, 0.71 mmol) was added. The mixture was then heated to 75° C. and allowed to stir for 4 h. Upon completion, the reaction was allowed to cool to room temperature, then concentrated. Water (12 mL) was added. The resulting mixture was diluted with H2O (12 mL), then extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography (SiO2, 20-50% EtOAc—CH2Cl2) to generate 90 mg (54%) of 54 as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.48 (d, J=3.6, 1H), 8.32 (s, 1H), 7.71 (d, J=8.4, 1H), 7.36 (m, 1H), 6.86 (s, 2H), 5.04 (s, 2H); [M+H]+ 260.1.
Reaction SMILES: C[O:2][C:3](=[O:19])[C@H:4]([N:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:20].O>O1CCOCC1>[ClH:20].[CH3:18][N:11]([C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]([OH:19])=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)[C@@H](c1ccccc1)N(C)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN(c1ccccc1)[C@@H](C(=O)O)c1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
(R)-(Methyl-phenyl-amino)-phenyl-acetic acid methyl ester (I73) (125 mg, 0.49 mmol) is dissolved in dioxane (2 mL). 37% Hydrogen chloride in water (3.00 mL, 36.5 mmol) is added and the mixture is stirred at 70° C. for 18 hours. Then a second portion of 37% hydrogen chloride in water (1.00 mL, 12.2 mmol) is added and the mixture is stirred at 70° C. for additional 36 hours. The mixture is cooled to RT and the white precipitate is filtered and washed with dioxane and Et2O to obtain intermediate I122 as a white solid (97 mg, 71% yield).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(O)(=O)C.[Cl:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30][Cl:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.O>[Cl:25][CH2:26][CH2:27][N:28]([CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][C:9]2[CH:19]=[CH:20][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)=[CH:12][CH:13]=1)[CH2:29][CH2:30][Cl:31]
Reactant: ClCCNCCCl
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(CN(CCCl)CCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
To a solution of 4-(4-methylsulfonylaminophenoxy)benzaldehyde (1.27 g) in dimethylformamide (5 mL)/acetic acid (0.5 mL) was added N,N-bis(2-chloroethyl)amine (856 mg) and the solution was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (31.39 g) was added to the solution, which was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate three times. The extract was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The obtained residue purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give the title compound (790 mg) having the following physical data.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9](=[O:18])[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].CCOCC.[Li+].[OH-].Cl>O.CO>[O:18]=[C:9]([N:6]1[CH2:7][CH2:8][C@H:5]1[C:3]([OH:4])=[O:2])[C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H]1CCN1C(=O)C(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: O=C(C(=O)N1CC[C@H]1C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of (2S)-methyl-1-(1,2-dioxo-2-phenylethyl)azetidine-2-carboxylate from Reference Example 9 (522.5 mg; 2.11 mmol) in a 1:1 mixture of ether:methanol (20.0 mL) was added 1N LiOH in water (3.9 mL) at about 0° C. The mixture was stirred under argon at about 0° C. for about 30 minutes and then at about room temperature overnight. The pH was adjusted to about pH 1 by adding 1N HCl and then the mixture was diluted with water and extracted with dichloromethane. The organic layers were then washed with brine, dried over sodium sulfate and concentrated to give 415.2 mg (67% yield) of the product as a yellow solid. 1H NMR (CDCl3) δ 2.33-2.91 (series of m, 2H); 4.08-4.51 (series of m, 2H); 5.09 and 5.31 (dd, 1H, J=10.3, 6.9, J=10.3, 6.9); 7.40-7.73 (m, 3H); 8.04-8.19 (m, 2H); 8.25-8.80 (br, 1H).
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].[F:12][C:13]([F:28])([S:24](F)(=[O:26])=[O:25])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17]>CCOCC>[F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][O:4][S:24]([C:13]([F:12])([F:28])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])(=[O:26])=[O:25]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OCC(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,2,3,3,3-pentafluoropropanol (3.0 g) was added to a suspension of sodium hydride (1.08 g) in dry ether (50 ml) at 0° C. under an argon atmosphere. Stirred at 0° C. for 15 minutes. Perfluoro-1-butanesulphonyl fluoride (12.08 g) was slowly added. Stirred at reflux for 3 hours, cooled and carefully quenched with H2O. Extracted with ether, twice. The combined extracts were washed with saturated brine dried over MgSO4, filtered and evaporated to give 2,2,3,3,3-pentafluoropropyl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate as an oil. Yield 7.9 g. NMR: (CDCl3) δ 4.9 (m, 2H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl.CO>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@@H:19]([O:22][C:3](=[O:4])[NH2:5])[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OC(N)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A solution of 4.52 g of trichloroacetyl isocyanate in 8 ml of methylene chloride was added to an ice-cooled solution of 3.75 g of (3R)-1-(t-butoxycarbonyl)-3-hydroxypyrrolidine in 40 ml of methylene chloride, and the mixture was stirred for 30 minutes with ice-cooling. After completion of the reaction, the solvent was stripped off from the reaction mixture and the residue was dissolved in 100 ml of methanol. The solution was stirred with 35 g of silica gel for 5 hours at 30° C., and then filtered. The filtrate was concentrated, giving 3.05 g of (3R)-1-(t-butoxycarbonyl)-3-carbamoyloxypyrrolidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([N:12]=[N+]=[N-])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@H](N=[N+]=[N-])c1cccc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: C[C@H](N)c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 61.7 %

Procedure:
To a solution of (S)-1-(3-nitrophenyl)-1-azidoethane (1.55 mmol) in benzene (8 mL) was added water (1.0 mL) and triphenylphosphine (3.18 mmol). The resulting mixture was heated to 80° C. for 19 h. This mixture was cooled, diluted with diethyl ether (50 mL) and washed with 50 mL of 2N aqueous HCl. The aqueous phase was made basic by adding 50 mL of 5N aqueous NaOH then extracted with diethyl ether (3×50 mL). These ether extracts were combined, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified on silica gel in 3%(2M NH3 in MeOH)/CH2Cl2 to yield 78.4 mg of pure title compound and 159 mg of the title compound that is approximately 80% pure by NMR. 1H NMR (500 MHz, CDCl3): δ 8.23 (m, 1H); 8.06 (m, 1H); 7.70 (d, J=8.1 Hz, 1H); 7.48 (t, J=8.1 Hz, 1H); 4.25 (q, J=6.9 Hz, 1H); 1.40 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][OH:24])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:25](Cl)(=[O:29])[C:26]([CH3:28])=[CH2:27]>>[CH2:1]([N:4]([CH2:22][CH2:23][O:24][C:25](=[O:29])[C:26]([CH3:28])=[CH2:27])[C:5]1[CH:6]=[CH:7][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: C=C(C)C(=O)Cl
Product: C=CCN(CCOC(=O)C(=C)C)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
N-allyl-N-(2-hydroxyethyl)-4-(4'-nitrophenylazo)benzenamine (3.26 g, 0.01 mol) is treated with methacryloyl chloride, as discussed in Example 8, to provide N-allyl-N-(2-methacryloyloxyethyl)-4-(4'-nitrophenylazo)benzenamine.
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9])=O.Cl>[OH-].[Na+]>[CH3:16][C:14]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([SH:5])[CH:15]=1
Reactant: COC(=O)c1ccc(C)cc1SC(=O)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)O)c(S)c1
Temperature: 0 °C

Procedure:
A round bottle flask containing a mixture of methyl 2-[(dimethylcarbamoyl)sulfanyl]-4-methylbenzoate (50 g, 197.6 mmol) and an aqueous solution of sodium hydroxide (120 mL, 4 N) was vacuumed and backfilled with nitrogen 3 times. After being refluxed for 2 hours, the resulting mixture was cooled to 0° C. and acidified with an aqueous solution of hydrochloric acid (45 mL, 6 N). The formed precipitate was collected by filtration, and then dissolved in ethyl acetate (500 mL). The solution was dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 4-methyl-2-sulfanylbenzoic acid as a light yellow solid.
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][C:21]([N:25](C)[C:26](=O)OC(C)(C)C)([CH3:24])[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].Cl>ClCCl>[CH3:24][C:21]1([NH:25][CH3:26])[CH2:22][CH2:23][CH:18]([O:17][C:8]2[C:7]3[C:6]4[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=4[S:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH2:19][CH2:20]1
Reactant: CN(C(=O)OC(C)(C)C)C1(C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CNC1(C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 50-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)-N-methylcarbamate (85 mg, 0.18 mmol, 1.00 equiv) in dichloromethane (5 mL) was added hydrochloric acid (6 M, 0.1 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The crude product (70 mg) was purified by preparative HPLC under the following conditions (Waters): column: XBridge Prep C18 OBD column: 5 um, 19*150 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (10% CH3CN up to 30% in 10 min, up to 95% in 2 min, down to 10% in 2 min); flow rate: 20 mL/min; UV detection at 254 & 220 nm. This resulted in 46.9 mg (70%) of 2-[(3R)-12-[[4-methyl-4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide as a white solid. MS: m/z 375 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 8.47 (1H, s), 5.44 (1H, m), 3.84 (1H, m), 3.14 (1H, m), 3.02 (1H, m), 2.79 (1H, m), 2.25-2.35 (5H, m), 2.10 (2H, m), 1.75-1.90 (4H, m), 1.63 (2H, m), 1.19 (3H, s).