Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[NH2:12][CH:13]1[CH2:18][CH:17]2[CH2:19][CH:14]1[CH2:15][CH2:16]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:14]12[CH2:19][CH:17]([CH2:16][CH2:15]1)[CH2:18][CH:13]2[NH:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: NC1CC2CCC1C2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(NC2CC3CCC2C3)nc1

Procedure:
2-Chloro-5-nitropyridine (158 mg, 1 mmol), 2-aminonorbornane hydrochloride (147 mg, 1 mmol), and finely ground potassium carbonate (419 mg, 3 mmol) were heated to 80° C. in 10 mL anhydrous DMF for 3.5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc was filtered, evaporated to dryness to yield 220 mg. ES-MS calcd for C12H15N3O2 (m/e) 233.21, obsd 234.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:13]4[C:14]=3[C:10]([C:11](=[O:25])[NH:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[H-].[Na+].[CH3:29]I>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:13]4[C:14]=3[C:10]([C:11]([O:25][CH3:29])=[N:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CI
Reactant: Cc1noc(C)c1-c1ccc2c(=O)[nH]n3c2c1OCC3c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn2c3c(c(-c4c(C)noc4C)ccc13)OCC2c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one (0.030 g, 0.086 mmol) in N,N-dimethylformamide (0.41 mL) was treated with sodium hydride (6.91 mg, 0.173 mmol) and stirred for 2 h. The reaction mixture was treated with methyl iodide (7.0 μL, 0.112 mmol) and stirred for 1 h. The reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The aqueous solution was extracted with ethyl acetate to give a crude tan solid. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 30 mL/min) gave Example 2 (1.3 mg, 4%, first peak to elute) and Example 3 (2 mg, 6%, second peak to elute) (two separate passes through the preparative LCMS system was needed to isolate both peaks). Example 2: 1H NMR (500 MHz, CDCl3) δ 7.48-7.39 (m, 4H), 7.37-7.30 (m, 2H), 6.97 (d, J=8.0 Hz, 1H), 4.74 (dd, J=11.9, 8.2 Hz, 1H), 4.55 (dd, J=12.0, 3.0 Hz, 1H), 4.34 (dd, J=8.1, 2.8 Hz, 1H), 2.95 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H); LCMS calculated for C21H20N3O3 (M+H)+: m/z=362.1. found: 362.1. Example 3: 1H NMR (500 MHz, CDCl3) δ 7.39-7.30 (m, 3H), 7.27 (d, J=8.3 Hz, 1H), 7.18-7.10 (m, 2H), 6.81 (d, J=8.3 Hz, 1H), 5.37 (dd, J=5.4, 3.4 Hz, 1H), 4.67 (dd, J=11.4, 3.4 Hz, 1H), 4.51 (dd, J=11.5, 5.5 Hz, 1H), 4.04 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H); LCMS calculated for C21H20N3O3 (M+H)+: m/z=362.1. found: 362.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:27])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:27])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=4)=[CH:4][CH:3]=3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC/C=C/c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CC/C=C/c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-5-(3,4-dichloro-phenyl)-pent-4-en-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1.[C:18]1(C)C(S(O)(=O)=O)=CC=C[CH:23]=1>C(O)C>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH2:18][CH3:23])[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1
Reactant: CCN1CCC(O)N(c2nnc(OC)s2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: CCOC1CCN(CC)C(=O)N1c1nnc(OC)s1

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), ethyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-ethoxy-2(1H)-pyrimidinone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.CO.[CH3:29][Si](C=[N+]=[N-])(C)C>C(OCC)(=O)C>[CH3:29][O:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC)c2[nH]1
Temperature: 4 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To an ice-cooled and stirred solution of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.08 g) in ethyl acetate (30 mL)-methanol (8 mL) was added 2M trimethylsilyldiazomethane (diethyl ether solution, 2.8 mL), and the mixture was stirred at 4° C. for 2 h, followed by an addition of 2M trimethylsilyldiazomethane (diethyl ether solution, 2.8 mL). After stirred at 4° C. for 1 h, the reaction mixture was quenched with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium hydrogen carbonate and brine, dried (MgSO4), filtered, and concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (933 mg, 83%) as pale yellow crystals. mp 161-162° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1([CH3:55])[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1>ClCCl>[C:51]([O:50][C:48]([N:45]1[CH2:46][CH2:47][C:42]([NH:41][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])([CH3:55])[CH2:43][CH2:44]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2(C)CCN(C(=O)OC(C)(C)C)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 2 h

Procedure:
To a stirred solution of racemic-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (48.2 mg, 0.103 mmol) in dichloromethane (8 ml) were added N,N-DIISOPROPYLETHYLAMINE (72.7 mg, 98.3 μl, 563 μmol, Eq: 6) and N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (64.2 mg, 0.169 mmol) followed by tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (20.1 mg, 0.0938 mmol, Astatech). The reaction mixture was stirred from 2:00 PM for 2 hrs. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 5% to 70% EtOAc in hexanes) to give rac-4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-4-methyl-piperidine-1-carboxylic acid tert-butyl ester as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 663. found: 663.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Cl:11])=[CH:7][N:6]=1)=O.O.[NH2:13][NH2:14]>CO>[Cl:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([NH:13][NH2:14])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1cnc(Cl)cn1

Procedure:
5-chloro-pyrazine-2-carboxylic acid methyl ester (10.02 g, 58.25 mmol) and hydrazine monohydrate (12.5 mL, 250 mmol) were dissolved in methanol (400 mL) and the reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered and the precipitate collected dried in vacuo to yield the title compound, 5.01 g (50%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][OH:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@H]1[C@H](CO)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C[C@H]1[C@H](CO[Si](C)(C)C(C)(C)C)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1

Procedure:
A solution of (±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(hydroxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (3.6 g, 11.4 mmole), tert-butyldimethylsilyl chloride (3.7 g, 24.5 mmole) and imidazole (2.8 g, 41.2 mmole) in 60 mL of DMF was stirred at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexanes to provide the title compound, as a colorless oil (yield: 3.5 g, 71%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[CH2:25]([O:27][CH2:28][C:29](O)=[O:30])[CH3:26]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:29](=[O:30])[CH2:28][O:27][CH2:25][CH3:26])[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: CCOCC(=O)O
Product: CCOCC(=O)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1

Procedure:
Using a procedure similar to that described in Example 1 except starting with 4-amino-1-[2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine and 2-ethoxyacetic acid, the title compound was obtained as a white glassy solid (68%), mp 112.5°-4.0° C.; MS(CI): 425 (M+H); NMR (300 MHz,DMSO-d6): 1.12(t, 3H, J=7 Hz), 1.49(br m, 2H), 1.61(br m, 2H), 2.26(m, 2H)), 2.45(br m, 2H), 2.93(br m, 2H), 3.45(q, 2H, J=7 Hz), 3.62(br s, 1H), 3.78(s, 2H), 4.34(s, 1H), 6.94(m, 3H), 7.23(m, 4H), 7.48(d, 1H, J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([NH:1][C:2]2[C:3]([C:9](=[O:10])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccccc1Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (3-amino-5-chloro-pyridin-2-yl)-(2-chloro-phenyl)-methanone (26.8 mg, 0.10 mmol) and 3,4-dichloro-benzenesulfonyl chloride (24.5 mg, 0.10 mmol) in anhydrous pyridine (1 mL) were stirred overnight at 60° C. Reaction mixture was concentrated and the residue was treated with 1 M NaOH (5 mL) and THF (5 mL) to hydrolyze bis-sulfonamide. The resultant solution was neutralized to pH 6 and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The was purified by preparative HPLC (20→90% gradient of MeCN-water) and pure product fractions were lyophilized to provide 3,4-dichloro-N-[5-chloro-2-(2-chloro-benzoyl)-pyridin-3-yl]-benzenesulfonamide as a solid. MS m/z: 498.0 (M+Na).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[CH2:13]([NH:20][CH2:21]C(O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH2:21][CH2:3][CH:2]2[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)CNCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1

Procedure:
42.8 g (0.25 mol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 41.3 g (0.25 mol) of N-benzylglycine in 750 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:5]=2[N:6]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])[S:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([OH:19])=[O:18])[C:5]=2[N:6]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: Fc1ccccc1C(Br)c1ccccc1F
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccccc3F)c3ccccc3F)nc1-2
Yield: 58 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]acetate and bis(2-fluorophenyl)methylbromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 58%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([OH:8])=[C:4]2[N:9]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=12.Br[CH2:23][C:24]#[N:25]>>[Br:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:4]=2[C:5](=[O:8])[N:6]([CH2:23][C:24]#[N:25])[CH:7]=1
Reactant: N#CCBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cnc(O)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(CC#N)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 83, Step 1, using 4-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-c]pyri din-7-ol and bromoacetonitrile as the starting materials. LCMS calculated for C16H13BrN3O3S (M+H)+: m/z=406.0, 408.0. found: 405.9, 407.9.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[H-].[Na+].[N:12]([C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:26])=[CH2:25])[CH:19]=1)([CH3:17])[CH3:16])=[C:13]=[O:14]>C1COCC1>[CH2:25]=[C:24]([C:20]1[CH:19]=[C:18]([C:15]([NH:12][C:13](=[O:14])[O:9][C@@H:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)([CH3:17])[CH3:16])[CH:23]=[CH:22][CH:21]=1)[CH3:26]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(C(C)(C)NC(=O)O[C@H]2CN3CCC2CC3)c1
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
To a solution of (R)-quinuclidin-3-ol (194 mg, 1.52 mmol) in THF (5 mL) at room temperature was added NaH [60%, oil] (64 mg, 1.6 mmol). The reaction mixture was stirred for 15 min and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (302 uL, 1.53 mmol) was added dropwise. The reaction was stirred for a period of 30 min and quenched with brine. The solution was extracted with EtOAc and the organic layer was dried over Na2SO4 and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding carbamate (475 mg, 95%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.31 (br s, 3H), 5.33 (s, 1H), 5.17 (s, 1H), 5.08 (s, 1H), 4.77-4.61 (m, 1H), 3.33-2.27 (m, 5H), 2.14 (s, 3H), 2.25-0.75 (m, 6H), 1.68 (br s, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 154.7, 147.2, 143.7, 141.6, 128.5, 124.2, 122.1, 112.8, 70.9, 55.7, 55.5, 47.5, 46.6, 32.2, 31.5, 29.9, 29.6, 25.5, 24.6, 22.9, 22.2, 19.6 ppm. Purity: 100% UPLCMS (210 nm); retention time 0.84 min; (M+1) 329.2. Anal. Calcd. for C20H28N2O2.0.06 (CHCl3): C, 71.59; H, 8.40; N, 8.58. Found: C, 71.51; H, 9.05; N, 8.60.
Reaction SMILES: C([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:54]=[CH:53][C:10]([C:11]([O:26][CH2:27][C@@:28]23[C@@H:34]([O:35]CC4C=CC=CC=4)[C@@H:31]([O:32][CH2:33]2)[C@H:30]([N:43]2[CH:51]=[N:50][C:49]4[C:48](=[O:52])[NH:47][CH:46]=[N:45][C:44]2=4)[O:29]3)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>CO.ClCCl.[Pd]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([O:26][CH2:27][C@@:28]23[C@@H:34]([OH:35])[C@@H:31]([O:32][CH2:33]2)[C@H:30]([N:43]2[CH:51]=[N:50][C:49]4[C:48](=[O:52])[NH:47][CH:46]=[N:45][C:44]2=4)[O:29]3)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]2[CH:53]=[CH:54][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cnc5c(=O)[nH]cnc54)O2)[C@@H]3OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cnc5c(=O)[nH]cnc54)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 224.5 %

Procedure:
Sodium formate (1.2 g) was added to a mixture of compound 24 (1.02 g, 0.52 mmol) and Pd/C (10%, 0.5 g) in methanol (20 mL). The mixture was refluxed for 20 min, cooled to room temperature and diluted with dichloromethane (20 mL). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a white solid material, which was crystallised from 50% ethanol/water to yield 680 mg (77%) of compound 25. δH (DMSO-d6) 8.12, (1H, s 8-H), 8.09 (1H, s, 2-H), 7.43-7.24 (m, 9H, DMT), 6.90 (m, 4H, DMT), 5.97 (1H, s, 1′-H), 4.44 (1H, s, 2′-H), 4.33 (1H, s, 3′-H), 3.97 (1H, d, J 7.5, Bn), 3.91(1H, d, J 7.7), 3.74 (6H, s, DMT), 3.55 (1H, d, J 10.6). δc (DMSO-d6) 158.2, 156.6, 147.3, 146.1, 144.8, 137.1, 135.5, 135.3, 129.8, 127.9, 127.7, 126.8, 124.6, 113.3(DMT, hypoxantine), 87.1, 85.6, 79.3, 71.8, 70.5, 59.9 (ribose), 55.1 (DMT).
Reaction SMILES: [O:1]1[C:5]2([CH2:21][CH2:20][CH2:19][C:7]3([CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH2:8]3)[CH2:6]2)OCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:17][C:15]([CH3:18])([CH3:16])[CH2:14][CH2:13][CH2:12][CH:9]1[CH2:10][CH2:11][C:7]2([CH2:19][CH2:20][CH2:21][C:5](=[O:1])[CH2:6]2)[CH2:8]1
Reactant: CC(C)(O)CCCC1CCC2(CCCC3(C2)OCCO3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(O)CCCC1CCC2(CCCC(=O)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of 5-(1,4-dioxa-dispiro[4.1.4.3]tetradec-9-yl)-2-methyl-pentan-2-ol (18) (420 mg, 1.42 mmol) in acetone (9 mL) was added H2O (catalytic amount) and p-toluenesulfonic acid (catalytic amount). The reaction mixture was stirred at room temperature overnight and then dried over anhydrous MgSO4. The solution was filtered through silica and the filtrate concentrated under reduced pressure. The resulting residue was purified over silica (isooctane/EtOAc, 7:3) to afford 312 mg (86% yield) of the desired ketone isomer as a colorless oil which was characterized as follows:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([SH:13])[CH2:11][SH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:14]([O:16][CH:17](OCC)OCC)[CH3:15].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH:10]1[CH2:11][S:12][CH:17]([O:16][CH2:14][CH3:15])[S:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(S)CS
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC1SCC(CO[Si](C)(C)C(C)(C)C)S1
Reaction time: 6 h
Yield: 94 %

Procedure:
To a solution of 1-t-butyldimethylsilyloxy-2,3-dimercaptopropane (example 47) (32.00 g, 134 mmol) in toluene (400 mL) were added triethylorthoformate (29.0 mL, 174 mmol, 1.3 eq) and pyridinium p-toluenesulfonate (200 mg). The solution was stirred at 120°-130° C. for 6 hr then was quenched at room temperature with a solution of saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane and the organic layer was dried with magnesium sulfate and evaporated under reduced pressure. The crude product was obtained in 94% yield (37.17 g) as a 1:1 mixture and was used without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[OH:20])([CH3:10])[CH3:9]>C(N(CC)CC)C.CN(C1C=CC=CN=1)C>[C:4]([O:20][C:12]1[C:13]([CH:17]([CH3:18])[CH3:19])=[CH:14][CH:15]=[CH:16][C:11]=1[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1OC(=O)CCC(=O)O
Reaction time: 16 h
Yield: 80.2 %

Procedure:
Succinic anhydride (14 g, 140 mmol) and dimethylaminopyridine (0.02 g, 0.16 mmol) were added to a solution of 2,6-diisopropylphenol (20.8 ml, 112 mmol) in triethylamine (50 ml) under nitrogen. After 16 hr at room temperature, solvents were removed under vacuum. The residue was dissolved in water and added to an iced solution of dilute hydrochloric acid. The precipitated product was filtered and recrystallized from ethanol-water to yield 25.0 g (80.2% yield) of 2,6-diisopropylphenyl hydrogen succinate (propofol hemisuccinate), mp 101-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CN3CCOCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide, and morpholine in tetrahydrofuran are reacted to give 8-chloro-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.