Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na:1].[N:2]1([C:11]([CH2:13][C@H:14]([CH2:21][OH:22])[O:15][CH2:16][P:17]([OH:20])([OH:19])=[O:18])=[O:12])[CH:10]=[C:8](C)[C:6](=[O:7])[NH:5][C:3]1=[O:4].N1(C(C[C@H](CO)OCP(OC(C)C)(OC(C)C)=O)=O)C=CC(=O)NC1=O.I[Si](C)(C)C>>[Na:1].[N:2]1([C:11]([CH2:13][C@H:14]([CH2:21][OH:22])[O:15][CH2:16][P:17]([OH:19])([OH:20])=[O:18])=[O:12])[CH:10]=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: Cc1cn(C(=O)C[C@H](CO)OCP(=O)(O)O)c(=O)[nH]c1=O
Agent: CC(C)OP(=O)(CO[C@@H](CO)CC(=O)n1ccc(=O)[nH]c1=O)OC(C)C
Agent: C[Si](C)(C)I
Agent: [Na]
Product: O=C(C[C@H](CO)OCP(=O)(O)O)n1ccc(=O)[nH]c1=O
Yield: 34 %

Procedure:
This compound was prepared as described for 3f, using 21 (154 mg, 0.41 mmol) as a starting material and iodotrimethysilane (0.47 mL, 3.3 mmol). Compound 3g (50 mg, 0.14 mmol) was obtained as a colorless solid, in 34% yield, which was characterized as follows:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2[N:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14].O.[CH2:24]=O.[C:26]([BH3-])#[N:27].[Na+].Cl>CCOC(C)=O>[CH3:24][N:27]([CH3:26])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2[N:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14]
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: COc1ccc(N(C)c2nc(C)nc3ccc(N)cc23)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N(C)c2nc(C)nc3ccc(N(C)C)cc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a mixture of (6-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (16 mg, 0.05 mmol), 2 ml of 37% formaldehyde water solution and sodium cyanoborohydride (6.3 mg, 0.1 mmol) was added 2 N HCl (0.05 ml) at 0° C. The reaction mixture was stirred for 1 h at 0° C., then diluted by EtOAc (10 ml), washed with saturated NaHCO3 aq., brine, dried over Na2SO4, filtered and concentrated by vacuum. The crude product was purified by chromatography on silica gel with acetate, hexane (1:3 to 1:1) as eluent, yielding 11 mg of title compound (68.8%) as yellow solids. 1H NMR (CDCl3): 7.63 (d, J=9.0 Hz, 1H), 7.20-7.12 (m, 3H), 6.91-6.88 (m, 2H), 6.23 (d, J=2.7 Hz, 1H), 3.80 (s, 3H), 3.57 (s, 3H), 2.69 (s, 3H), 2.62 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2([C:12](O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)C(C1C=CC=CC=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].[CH2:47](N1C[C@H]2C(N)CC[C@H]2C1)[C:48]1C=CC=CC=1>>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][C:18]([NH:20][C@@H:21]2[C@H:28]3[C@H:24]([CH2:25][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=4)[CH2:27]3)[CH2:23][CH2:22]2)=[O:19])[CH:10]=[CH:9][CH:8]=[CH:48][CH:47]=1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(CC(c1ccccc1)c1ccccc1)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting 3,3-diphenylpropanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.10 (d, J=7.0, 1H), 7.72 (s, 1H), 7.62 (d, J=7.8, 1H), 7.48 (t, J=7.7, 1H), 7.39 (dd, J=2.6, 7.5, 5H), 7.26 (dt, J=7.6, 15.1, 5H), 7.17 (dd, J=6.2, 13.5, 2H), 4.38-4.27 (m, 1H), 3.54 (d, J=13.4, 1H), 3.38 (d, J=13.4, 1H), 3.15-3.09 (m, 2H), 2.75 (qd, J=3.6, 7.9, 1H), 2.44-2.35 (m, 2H), 2.32 (t, J=8.3, 1H), 2.20 (dd, J=3.3, 8.9, 1H), 2.08 (dd, J=7.8, 9.5, 1H), 1.70 (t, J=7.9, 1H), 1.58-1.46 (m, 2H), 1.18-1.10 (m, 1H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=[O:18])[N:9]2[CH3:19])[C:7](=[O:20])[N:6]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]1=[O:30])(=[O:3])[CH3:2].[CH3:31]I.[H-].[Na+].O>CN(C)C=O>[C:1]([N:4]1[C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:31])[C:10](=[O:18])[N:9]2[CH3:19])[C:7](=[O:20])[N:6]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:5]1=[O:30])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)N1C(=O)N(COCc2ccccc2)C(=O)C12c1ccccc1NC(=O)N2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)N(COCc2ccccc2)C(=O)C12c1ccccc1N(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
3'-Acetyl-1'-benzyloxymethyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'trione (3.06 g) is dissolved in dimethylformamide (20 ml) and thereto is added methyl iodide (1 ml) and further added in portions sodium hydride (60%) (0.3 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added water, and the mixture is extracted with ethyl acetate. The extract is dried and distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent: chloroform) to give 3'-acetyl-1'-benzyloxymethyl-1,3-dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (3 g, yield: 94.5%) as an oily substance.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O)[CH3:14].C[Si](C)(C)[N-:28][Si](C)(C)C.[Li+].B(F)(F)F.CCOCC>O1CCCC1>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:19]([NH2:28])[CH2:6][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH3:14]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CN(C)S(C)(=O)=O
Agent: FB(F)F
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cc(C(N)CS(=O)(=O)N(C)C)ccc1OC

Procedure:
1-(3-Ethoxy-4-methoxyphenyl)-2-(N,N-dimethylaminosulfonyl)ethylamine was prepared by a procedure analogous to that of Example 1 from N,N-dimethyl methanesulfonamide (685 mg, 5.56 mmol) and n-butyllithium (2.5 mL, 2.5 M, 6.3 mmol) in tetrahydrofuran (90 mL), and 3-ethoxy-4-methoxybenzaldehyde (1.0 g, 5.5 mmol), lithium hexamethyldisilazide (4.7 mL, 1.3 M, 6.1 mmol) and boron trifluoride etherate (1.4 mL, 11 mmol) in tetrahydrofuran (5 mL). The product was obtained as a white solid (360 mg, 21% yield): mp, 82.0-83.0° C.; 1H NMR (CDCl3); δ 1.48 (t, J=7.5 Hz, 3H, CH3), 1.91 (br s, 2H, NH2), 2.88 (s, 6H, N(CH3)2), 3.05 (dd, J=3.0, 13.5 Hz, 1H CHH), 3.12 (dd, J=9.2, 13.5 Hz, 1H, CHH), 3.88 (s, 3H, CH3), 4.12 (q, J=7.0 Hz, 2H, CH2), 4.61 (dd, J=2.9, 9.2 Hz, 1H, NCH), 6.83-6.99 (m, 3H, Ar); 13C NMR (CDCl3) δ 14.81, 37.42, 51.02, 56.03, 64.41, 110.74, 111.55, 118.35, 135.97, 148.64, 148.96; Anal Calcd for C13H22NO4S: C, 51.64; H, 7.33; N,9.26. Found: C, 51,41; H,7.11; N, 9.10.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:24]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(C)cc2OC)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-methoxy-4-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (2.3 mg) with purity >90%. LCMS (pos) m/z 371.2.
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@H:45]([C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=4)[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[Cl:53][C:49]1[CH:48]=[C:47]([C@@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]2[C@@H:25]2[C@@:20]([CH3:54])([CH2:21][CH2:22]3)[C@@:19]3([CH3:55])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH3:46])[CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((S)-1-(3-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (12 g, 14.66 mmol) in dichloromethane (130 mL) was added TFA (80 mL, 14.66 mmol). The reaction mixture was stirred at rt for 2 hr and diluted with DCM, washed with water twice. And the organic layer was concentrated, diluted with MeCN/H2O (1:5, 36 mL) and freeze-dried under high vacuo to give the title compound (9.9 g, 12.89 mmol, 88%). This material was combined with several batches made under similar conditions and freeze dried together for characterization (31 g, 41 mmol) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.38-7.13 (m, 4H), 6.97 (d, J=15.6 Hz, 1H), 5.82-5.59 (m, 2H), 5.26-5.06 (m, 1H), 4.50 (dd, J=5.3, 11.0 Hz, 1H), 3.29-3.09 (m, 1H), 2.81-2.48 (m, 3H), 2.37-2.00 (m, 3H), 2.00-0.68 (m, 47H).
Reaction SMILES: [N+:1](C1C=CC(C=O)=CC=1)([O-])=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-])=O.[H][H]>>[NH2:12][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:1]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Product: NCc1cccc(N)c1
Yield: 95.5 %

Procedure:
Reaction was carried out in the same manner as in Example 1 except that p-nitrobenzaldehyde was replaced by m-nitrobenzaldehyde Reaction was complete in 115 minutes, during which hydrogen (32 Nl) was absorbed. Post-treatment as in Example 1 was successively carried out to obtain M-aminobenzylamine having a purity of 99.91% (46.7 g, yield 95.5%, b.p. 131°-132° C./6 mm Hg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][CH:3]1[CH2:4][CH2:5]2
Reactant: CS(=O)(=O)Cl
Reactant: CN1C2CCC1CC(O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 2.799999952316284 °C
Reaction time: 0.25 h

Procedure:
Tropine (500 g, 3.54 mol) and triethylamine (590 mL, 430 g, 4.25 mol) were mixed in dichloromethane (10 L) and cooled to <−5° C. under a stream of nitrogen. A solution of methane sulphonyl chloride (329 mL, 487 g, 4.25 mol) in dichloromethane (2 L) was added over 4.33 h between −10.4 and −4.9° C. The mixture was stirred for 15 min, the cooling bath removed, and potassium carbonate solution (2.5 L, GB98596-043)) and deionised water (1.25 L) were added. The additions took 4 min and caused an exotherm raising the temperature to 2.8° C. The mixture was warmed to 15 to 20° C., filtered and the phases allowed to separate. The aqueous phase was extracted further with dichloromethane (2.5 L). The combined organic phases were heated to distil off dichloromethane at atmospheric pressure; 10 L were collected over 1.75 h reaching a base temp. of 42.8° C. and vapour temperature of 42° C. Hexane (7.5 L) was added and after allowing the mixture to cool (overnight) the mixture was filtered and the filtrate returned to a clean flask. The solution was reheated to distil at atmospheric pressure; 7.5 L were collected up to base and vapour temperatures of 60.5 and 62° C. respectively. The mixture was cooled to 0 to 5° C., stirred for 1 h, the product filtered off and washed with hexane (1.5 L). The product was dried under vacuum in a dessicator. Crystallisation from ethyl acetate/hexane or dichloromethane/hexane gave crystalline title compound which was then used in Step 3.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.[C:45]([O-:48])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:10]1([C:16]2[CH:15]=[CH:14][C:13]([C:12]3[C:6]4[CH2:5][C:4]5[S:3][C:2]([C:37]6[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=6)=[CH:9][C:8]=5[C:7]=4[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[N:11]=3)=[CH:18][CH:17]=2)[CH2:21][CH2:45][O:48][CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)cc2)c2c1-c1cc(-c3ccc(N)nc3)sc1C2
Temperature: 100 °C
Yield: 74 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.2 g, 2.3 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (0.75 g, 3.4 mmol), Na2CO3 (2 M, 5.4 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give the corresponding intermediate 5-[6-(4-Morpholin-4-yl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine as brown solid in 74% yield.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:12]=[N:13][C:14]([CH2:17]Br)=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][S:20]([O-:22])=[O:21].[Na+].O>CN(C)C=O>[C:1]1([S:7]([O:10][C:11]2[CH:12]=[N:13][C:14]([CH2:17][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)[O-]
Reactant: O=S(=O)(Oc1ccc(CBr)nc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Cc1ccc(OS(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a solution of 6-(bromomethyl)pyridin-3-yl benzenesulfonate (30 g) in N,N-dimethylformamide (200 mL) was added sodium methylsulfinate (11.2 g), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (30 g, yield 100%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:7])[NH:5][N:6]=1.[H-].[Na+].S(OC)(O[CH3:23])(=O)=O>CS(C)=O>[CH3:23][N:5]1[C:4](=[O:7])[N:3]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[C:2]([CH3:1])=[N:6]1
Reactant: Cc1n[nH]c(=O)n1-c1ccc([N+](=O)[O-])cc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nn(C)c(=O)n1-c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 13.5 parts of 2,4-dihydro-5-methyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one in 100 parts of dimethyl sulfoxide are added 2 parts of sodium hydride dispersion 78% and the whole is stirred till foaming has ceased. Then there are added dropwise 8.1 parts of dimethyl sulfate. Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted three times with trichioromethane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 6.3 parts of 2,4-dihydro-2,5-dimethyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one; mp. 153.2° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][N:7]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-bromo-7-azaindole (67, 1.5 g, 7.6 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60% in mineral oil, 0.27 g, 11.0 mmol) and triisopropylsilyl chloride (2.6 mL, 12.0 mmol), under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give the compound (68, 1.6 g, 59%). MS(ESI) [M+H+]+=352.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.[O:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1>C(OCC)C.C1COCC1>[OH:19][C:20]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24][CH2:25]1
Reactant: Brc1cccnc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
A solution of 3-bromopyridine (9.09 mL, 94.31 mmol) in diethyl ether (50 mL) was added dropwise to a stirred solution of 1.6M n-butyl lithium in hexane (58.9 mL, 94.31 mmol) in diethyl ether (500 mL) cooled to −78° C., over a period of 15 minutes under nitrogen. The resulting suspension was stirred at −78° C. for 1 hour. A solution of benzyl 4-oxopiperidine-1-carboxylate (20 g, 85.74 mmol) in diethyl ether (50 mL) and THF (50 mL) was added dropwise over 15 minutes. The reaction mixture was stirred at −78° C. for 1 hour, warmed to 0° C. over 2.5 hours and quenched with saturated ammonium chloride solution (500 ml). The mixture was extracted with ethyl acetate (2×500 mL) and the combined extracts were washed with brine (200 mL) then dried over MgSO4 and filtered through a short pad of silica. The silica pad was washed through with ethyl acetate (4×250 mL) and the filtrate was concentrated under vacuum. The residue was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford benzyl 4-hydroxy-4-(pyridin-3-yl)piperidine-1-carboxylate (12.8 g, 48%) as an oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([N:9]1[CH2:22][CH2:21][CH2:20][N:19](P(OCC)(OCC)=O)[CH2:18][CH2:17][N:16](P(OCC)(OCC)=O)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].BrCC1C=CC(CBr)=CC=1>CC#N>[CH2:7]([O:6][P:4]([N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(OCC)N1CCCN(P(=O)(OCC)OCC)CCN(P(=O)(OCC)OCC)CCCNCC1
Agent: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=O)(OCC)N1CCCNCCNCCCNCC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 139.7 %

Procedure:
To a stirred solution of 4,8,11-Tris(diethoxyphosphoryl)-1,4,8,11-tetraazacyclotetradecane (see Bridger, et al., J Med. Chem. (1995) 38:366–378) (6.1 g, 0.01 mol) and K2CO3 (1.89 g, 0.013 mol) in CH3CN (150 ml) was added α,α′-dibromo-p-xylene (13.2 g, 0.05 mol) and the reaction mixture stirred at 70° C. for 1 hour. The solution was cooled to room temperature and the solvent removed under reduced pressure. The residue was partitioned between brine (50 ml) and CH2Cl2 (100 ml). The organic phase was separated, dried (Na2SO4) and concentrated to a minimum volume. The solid was filtered off and the solvent evaporated under reduced pressure to give the crude product as a pale yellow oil. Purification by column chromatography in silica gel (CH2Cl2\CH3OH, 25:1) gave 1-[1-methylene-4-(bromo-methylene)phenylene]-4,8,11-tris(diethoxyphosphoryl-1,4,8,11-tetraazacyclotetra-decane (4.7 g, 59%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.21–1.37 (m, 18H), 1.66–1.74 (m, 2H), 1.82–1.91 (m, 2H), 2.30–2.35 (m, 2H), 2.58–2.63 (m, 2H), 2.99–3.16 (m, 12H), 3.48 (s, 2H), 3.95–4.07 (m, 12H), 4.48 (s, 2H), 7.21–7.35 (4H).
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].C1(C(C2CCCCC2)C([NH:43][C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[C:2]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:24]1[CH2:25][C@@H:26]2[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]2[CH2:23]1)#[N:43]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3cccc(C#N)c3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3-formylbenzonitrile for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.60 (t, J=7.1, 1H), 7.63 (d, J=5.9, 2H), 7.56-7.50 (m, 2H), 7.39-7.30 (m, 3H), 7.29-7.23 (m, J=8.9, 13.2, 2H), 4.32 (dd, J=5.7, 11.2, 1H), 3.53 (d, J=13.6, 0.5H), 3.44 (d, J=13.5, 0.5H), 3.40 (d, J=13.6, 0.5H), 3.28 (d, J=13.6, 0.5H), 3.21 (dd, J=1.3, 10.4, 1H), 2.90 (dd, J=2.8, 9.1, 0.5H), 2.64 (qd, J=6.6, 13.2, 1H), 2.59-2.47 (m, 1H), 2.46-2.37 (m, 1H), 2.37-2.30 (m, 0.5H), 2.26-2.20 (m, 1H), 2.19-2.13 (m, 1H), 2.10 (dt, J=6.2, 12.3, 0.5H), 1.89-1.79 (m, 1H), 1.75 (dt, J=6.1, 20.0, 0.5H), 1.66 (dt, J=7.0, 19.3, 0.5H), 1.47-1.38 (m, 0.5H), 1.38-1.23 (m, 2H), 1.20 (dd, J=3.6, 6.4, 3H), 0.70 (d, J=6.7, 3H); MS (ESI+) m/z 402 (M+H)+.