Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([C:19]([CH3:28])([CH3:27])[CH2:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1>CS(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([C:19]([CH3:28])([CH3:27])[CH2:20][C:21]2([C:22]([F:23])([F:24])[F:25])[CH2:2][O:26]2)[C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of trimethylsulfoxonium iodide (343 mg, 1.56 mmol) in 3 mL of anhydrous DMSO was treated with NaH (60% in mineral oil, 66.0 mg, 1.65 mmol) in portions and the mixture was stirred at room temperature for 30 minutes. The mixture was transferred to a solution of 4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one (400 mg, 1.30 mmol) in 1 mL of anhydrous DMSO over 5 minutes and the resulting mixture was stirred overnight. The mixture was quenched with water and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were washed with two 5 mL portions of water, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 380 mg (91% yield) of the title product as a yellow oil. The crude product was sufficiently pure and used without further purification.
Reaction SMILES: C(O)(=[O:3])C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:23]1([S:29][C:30]2[CH:31]([CH3:61])[C@@H:32]3[C@H:49]([C@H:50]([C:56](C)(C)C)CO[SiH](C)C)[C:48](=[O:60])[N:33]3[C:34]=2[C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.C(OCC)(=O)C>[C:23]1([S:29][C:30]2[CH:31]([CH3:61])[C@@H:32]3[C@@H:49]([C@H:50]([OH:3])[CH3:56])[C:48](=[O:60])[N:33]3[C:34]=2[C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)O
Reactant: CC1C(Sc2ccccc2)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@@H](CO[SiH](C)C)C(C)(C)C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1C(Sc2ccccc2)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 μl of acetic acid and 2.1 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran were added to a solution of 298 mg of p-nitrobenzyl (1RS,5S,6S)-2-phenylthio-6-[(1R)-1-t-butyldimethylsilyl-oxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate in 6.4 ml of tetrahydrofuran, kept at 0° to 5° C. with ice-water cooling. The mixture was kept stirred overnight at room temperature, and then for 4 hours in an oil bath at 30° C. The reaction mixture was then diluted with ethyl acetate and washed successively with saturated aqueous sodium chloride solution, 5% aqueous sodium bicarbonate solution, and again saturated aqueous sodium chloride solution. The solvent was distilled off, and the resulting residue was chromatographed on a column of silica gel using a 3/1 mixture of benzene/ethyl acetate as eluent, giving 57 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=2[F:30])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=3[F:30])[CH2:22][CH2:23]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 127 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.43–7.38 (m, 1H), 7.37–7.26 (m, 3H), 6.93–6.83 (m, 2H), 3.96–3.61 (m, 1H), 3.26–3.02 (m, 4H), 2.69–2.59 (m, 1H), 2.51–2.40 (m, 2H), 1.90–1.71 (m, 4H), 1.63–1.47 (m, 4H), 1.18 (d, 6H, J=6.9 Hz), 1.15 (s, 6H); ESMS m/e: 502.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][N:13]=[N:12]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:10][N:11]1[CH:15]=[N:14][N:13]=[N:12]1
Reactant: ClCc1ccccc1
Reactant: O=C(Cn1cnnn1)c1ccc(Cl)cc1Cl
Product: Clc1ccc(C(=Cn2cnnn2)OCc2ccccc2)c(Cl)c1

Procedure:
Analogously to Example 7a,b, after reacting 1-(2,4-dichlorophenyl)-2-tetrazol-1-yl-ethanone with benzyl chloride there was obtained 1-[2-(2,4-dichloro-phenyl)-2-benzyloxy-vinyl]-1H-tetrazole as colourless crystals with m.p. 92° C.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O>[Si:19]([O:3][C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:11][CH2:12][CH3:13])=[O:10])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@@H](O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccccc1

Procedure:
Following a procedure similar to that described in Preparation 23, but using 23.8 g of ethyl (S)-(+)-mandelate, 26.6 g of imidazole, 400 ml of dimethylformamide, 30.1 g of t-butyldimethylsilyl chloride and 100 ml of dimethylformamide, the title compound was obtained as a liquid, boiling at 125.5°/3.0 mmHg (400 Pa). [α]D23 +40.9° (c=1.02, chloroform).
Reaction SMILES: [C:1]1([OH:15])[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:16]Br.O>C(O)(=O)C>[Br:16][C:4]1[C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13][C:14]=2[C:1]([OH:15])=[CH:2][CH:3]=1
Reactant: Oc1cccc2c1Sc1ccccc1S2
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Br)c2c1Sc1ccccc1S2

Procedure:
Thianthren-1-ol (6.5 g, 27.98 mmol) was dissolved in glacial acetic acid (100 ml) and to this solution was added bromine (17.1 μl, 13.99 mmol) in a dropwise fashion over 30 minutes. Water (200 ml) was added to the amber solution and the mixture extracted with EtOAc (3×100 ml). The combined organic extracts were then washed with saturated potassium bicarbonate solution (3×100 ml), dried using MgSO4, filtered and concentrated in vacuo to give the title compound. (7.56 g, 87%). m/z (LC-MS, ESP):, RT=4.92 min, (M++1)=309.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[C:14]([S:24](Cl)(=[O:26])=[O:25])=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=2.Cl>O.O1CCOCC1>[Cl:12][C:13]1[C:14]([S:24]([NH:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:26])=[O:25])=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=2
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2cc1Cl
Reactant: NCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CNS(=O)(=O)c1cc2ccc(Cl)cc2cc1Cl
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a solution of potassium carbonate (11.7 g) and glycine (6.4 g) in water (140 ml) were added 3,6-dichloronaphthalen-2-ylsulfonyl chloride (20.8 g) and dioxane (50 ml) at room temperature, and the mixture was stirred under reflux for 2 hours. After cooling to room temperature, the resultant solution was acidified with 2N hydrochloric acid to a pH in the range of 1 to 2, and extracted with ethyl acetate. The organic layer was washed with water, then with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Ethyl acetate was removed in vacuo to give 19.0 g of the objective compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(O)cn1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(O)c[n+]1[O-]
Reaction time: 1 h
Yield: 96.6 %

Procedure:
5-Hydroxy-2-methylpyridine (25 g) was suspended in chloroform (500 ml) and treated with m-chloroperbenzoic acid (57 g of material described as 57-86% pure). After stirring for 1 hour the solution was dried with MgSO4 and poured onto a silica column. Elution with EtOAc to remove byproducts and then with 20-50% EtOH in EtOAc gave the product (27.7 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31]CCOC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[C:48]1([CH:54]2[CH2:57][CH2:56][N:55]2CC2SC(N3CCC4C(=C(C(=O)/C=C5/SC6C=CC=CC=6N/5COCC[Si](C)(C)C)C=CC=4)C3)=NC=2C(OC)=O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][N:55]3[CH2:56][CH2:57][CH:54]3[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/C=C4/Sc5ccccc5N4COCC[Si](C)(C)C)c3C2)sc1CN1CCC1c1ccccc1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CN3CCC3c3ccccc3)s1)CC2

Procedure:
The title compound was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 71A: 1H NMR (DMSO-d6): δ 12.89 (s, 1H), 8.04 (d, J=7.36 Hz, 1H), 7.80 (d, J=7.98 Hz, 1H), 7.70 (d, J=7.37 Hz, 1H), 7.34-7.54 (m, 9H), 5.47 (br, 1H), 4.70-4.95 (m, 4H), 4.40 (br, s, 1H), 3.88 (br, 1H), 3.76 (d, J=5.83 Hz, 2H), 2.60-2.8 (br, s, 2H). ESI (+)/MS: 582 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:29])[CH:11]([OH:28])[CH:12]([CH3:27])[C:13](=[O:26])[C:14]([CH3:25])([CH3:24])[CH:15]([O:20][CH:21]([CH3:23])[CH3:22])[O:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:37]([O:39][CH2:40][C:41]([Cl:44])([Cl:43])[Cl:42])=[O:38]>C(Cl)Cl>[Cl:42][C:41]([Cl:44])([Cl:43])[CH2:40][O:39][C:37](=[O:38])[O:28][CH:11]([CH:10]([CH3:29])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:12]([CH3:27])[C:13](=[O:26])[C:14]([CH3:24])([CH3:25])[CH:15]([O:20][CH:21]([CH3:22])[CH3:23])[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)OC(OC(C)C)C(C)(C)C(=O)C(C)C(O)C(C)COCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(OC(C)C)C(C)(C)C(=O)C(C)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 7-Benzyloxy-5-hydroxy-1,1-diisopropoxy-2,2,4,6-tetramethyl-heptan-3-one 32 (1.0 g, 2.4 mmol) and pyridine (0.8 mL, 7.3 mmol) in CH2Cl2 (10.0 mL) at 0° C. was added 2,2,2-trichloroethyl chloroformate (668.0 μL, 4.9 mmol) and the mixture was then allowed to warm to rt. After 1 h, the reaction mixture was quenched with brine and then extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 93:7) to give 32a (1.285 g, 92%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 1.03-1.09 (m, 12H), 1.15 (d, J=1.8 Hz, 3H), 1.17 (d, J=1.9 Hz, 3H), 1.19-1.21 (m, 6H), 1.97-2.11 (m, 1H), 3.2 (dd, J=6.2 and 9.0 Hz, 1H), 3.54 (dd, J=4.8 and 9.1 Hz, 1H), 3.57-3.60 (m, 1H), 3.82 (qd, J=3.6 and 5.9 Hz, 2H), 4.47 (s, 2H), 4.57 (s, 1H), 4.72 (d, J=11.9 Hz, 1H), 4.81 (d, J=11.9 Hz, 1H), 5.08 (t, J=6.0 Hz, 1H), 7.29-7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 11.9, 15.0, 18.8, 21.4, 21.7, 22.3, 23.2, 23.4, 35.7, 42.5, 53.4, 53.9, 69.4, 70.9, 71.4, 73.3, 81.3, 94.7, 103.4, 127.5, 127.6, 128.2, 138.2, 154.0, 215.6; IR (film, NaCl, cm−1) 2966, 1760, 1698, 1247; LRMS (ESI) calcd for C27H41O7Cl3Na [M+Na+] 605.2, found 605.2; [α]23D=−20.4 (c=1.0, CHCl3.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([NH2:52])=[N:44][CH:43]=1>>[NH2:52][C:45]1[C:46]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:6]=2)=[CH:43][N:44]=1
Reactant: Nc1ncc(Br)c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)c4ccccc34)nc21

Procedure:
2-(1-((9-Methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.1 g) was reacted with 4-bromoisoquinolin-1-amine via General Procedure G to afford 115 following reverse phase purification. MS (Q1) 517.3 (M)+.—1H NMR (400 MHz, DMSO) δ 9.01 (d, 1H), 8.56 (s, 1H), 8.25 (d, 1H), 7.67 (t, 1H), 7.49 (t, 1H), 7.07 (s, 2H), 4.23 (s, 4H), 4.02 (s, 1H), 3.87-3.66 (m, 10H), 2.89 (d, 3H), 1.99 (t, 2H), 1.66 (d, 2H), 1.35-1.10 (m, 3H), 1.02 (s, 6H).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:24])[CH:20]([CH3:23])[CH2:21][CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH3:24][N:19]([CH:20]([CH3:23])[CH2:21][CH3:22])[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CCC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(C)N(C)c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 8-benzyl-N-methyl-N-(1-methylpropyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (0.64 g) in methanol (20 ml) was added 20% Pd(OH)2/C (0.13 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (20 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (540 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (0.44 g, 82%) as a pale-yellow powder.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:18][CH2:17][C:14]1[CH:15]=[CH:16][C:7]2[CH:6]=[CH:5][C:4]3[N:3]=[C:2]([CH3:1])[NH:11][C:10](=[O:12])[C:9]=3[C:8]=2[CH:13]=1
Reactant: Cc1ccc2ccc3nc(C)[nH]c(=O)c3c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: Cc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1

Procedure:
To a hot solution of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (2.0 g, 8.9 mmol) in benzene (1000 ml) under nitrogen was added N-bromosuccinimide (NBS) (2.0 g, 11 mmol). The solution was stirred at reflux for 1 hour and then concentrated in vacuo to give crude 9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one. The solid was suspended with diethyl N-(4-amino-2-fluorobenzoyl)-L-glutamate (T. R. Jones et al., UK Patent GB 2175 903A, 1986) (6.0 g, 18 mmol) in DMF (20 ml) and stirred under nitrogen at 100° C. for 30 minutes. The reaction mixture was allowed to cool, N-methylmorpholine (1.0 ml, 9.1 mmol) (Aldrich) was added, and the solution concentrated under high vacuum. The residue was purified with silica gel chromatography eluting with methylene chloride:THF (5:1). Fractions containing product were concentrated in vacuo to a thick paste, the solid suspended in a small volume of diethyl ether, filtered under nitrogen, and dried under high vacuum to give diethyl N-(4-(((1,2-dihydro-3-methyl-1oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamate as a white solid (2.3 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, ester CH3), 1.18 (t, J=7 Hz, 3H, ester CH3), 1.87-2.13 (m, 2H, glu CH2), 2.38 (t, J=7 Hz, 2H, ester CH2), 2.43 (s, 3H, C3 --CH3), 4.02 (q, J=7 Hz, 2H, ester CH2), 4.09 (q, J=7 Hz, 2H, ester CH2), 4.34-4.44 (m, 1H, glu CH), 4.57 (d, J=6 Hz, 2H, C9 --CH2), 6.39 (dd, J=15,2 Hz, 1H, Ar), 6.53 (dd, J=9,2 Hz, 1H, Ar), 7.30 (t, J= 6 Hz, 1H, ArNH), 7.44 (dd, J=9,9 Hz, 1H, Ar), 7.60 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8,2 Hz, 1H, Ar), 7.88 (dd, J=7,5 Hz, 1H, glu NH), 8.01 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.53 (s, 1H, N2H). Mass spectrum (CI-CH4): 563 (M+1, 100%). Anal. Calculated for C30H31FN4O6 : C, 64.05; H, 5.55; N, 9.96. Found: C, 64.14; H, 5.59; N, 9.94.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([OH:16])[CH2:15][C@@:9]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:10]([O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39]I.[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([O:16][CH3:39])[CH2:15][C@@:9]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:10]([O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:20]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-ol (Example 43; 22 mg 0.041 mmol), methyl iodide (0.5 ml), sodium hydride (40 mg, 1 mmol) and THF (2 ml) was stirred at room temperature for 24 hours, quenched quenched with saturated aqueous NH4Cl and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by preparative TLC on silica gel (iso-hexane:diethyl ether 30%) to give the title compound (17 mg, 75%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].Br[CH2:16]/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[CH3:22][O:21][C:19](=[O:20])/[CH:18]=[CH:17]/[CH2:16][NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/CBr
Reactant: NCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CNCCc1ccccc1
Reaction time: 4 h

Procedure:
To a stirred solution of phenethylamine (20 mL, 160 mmol) in anhydrous THF (250 mL) was added NaHCO3 (7 g) followed by methyl 4-bromocrotonate (10 mL, 84 mmol). After stirring for 4 h the reaction was concentrated to approximately half the volume and filtered through a pad of silica gel and eluted with 2% MeOH/CHCl3 to wash off the product. The crude product obtained after evaporation of the filtrate was purified by flash chromatography (silica gel, 2% MeOH/CHCl3) to give the title compound as a slightly yellow liquid (16.5 g, 81%). TLC Rf 0.53 (5% MeOH/CHCl3); 1H NMR (CDCl3) δ 1.2 (1H, s), 2.8 (4H, br s), 3.35 (2H, dd), 3.7 (3H, s), 5.95 (1H, dt), 7.0 (1H, dt), 7.25 (5H, br s)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[N:11]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>O.Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Fluoro-4-methoxyaniline (1, R=H, R2=CH3, R3=F) (95 g, 0.67 mol) was added to concentrated hydrochloric acid (250 mL), the suspension was stirred at ambient temperature for 18 hours, then it was cooled to 0° C. and a solution of sodium nitrite (53.7 g, 0.78 mol) in water (200 mL) was added dropwise at 0-5° C. When the addition was complete, the resulting solution was stirred at 0° C. for 1 hour then it was added dropwise at 0-5° C. to a stirred solution of tin (11) chloride dihydrate (638.9 g, 2.83 mol) in concentrated hydrochloric acid (500 mL). The mixture was allowed to warm to ambient temperature then it was stored at 4° C. for 18 hours. The resulting precipitate was collected by filtration, washed with water (400 ml), and ether (1000 mL) and dried in vacuo. The solid hydrochloride salt was basified by addition to 10% aqueous sodium hydroxide solution (800 mL), the free base was extracted into ether (2×400 mL), and the combined extracts were dried (MgSO4) and the solvent removed in vacuo to give (3-fluoro-4methoxyphenyl)hydrazine (2, R1=H, R3=CH2, R3=F) (51.9 g, 50%) as a yellow solid, mp 46-50° C.; 1HNMR (CDCl3/250 MHz): 1.5 (s, 1H, NH—NH2), 3.85 (s, 3H, OCH3), 5.0 (s, 2H, NH—NH2), 6.44 (m, 1H, phenyl 6-H), 6.60 (dd, 1H, phenyl 5-H), 6.79 (t, 1H, phenyl 2-H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Br-].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH2:13][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:13][C:12]2[C:11]([F:10])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Fc1cccc(F)c1C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1Cc1ccc(Br)cn1
Temperature: 25 °C

Procedure:
To a solution of 2,5-dibromopyridine (10 g) in THF was added Tetrakis (2.2 g) and 2,6-difluorobenzylzinc bromide (126 mL, 63 mmol). The reaction was heated to reflux until reaction was complete by TLC. The reaction was cooled to room temperature, filtered through celite, and concentrated in vacuo. The title compound was purified by silica gel (Hexanes/methylene chloride).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[CH:12]=1.[CH3:23][O:24][C:25]1[CH:32]=[C:31]([CH2:33][CH:34]=O)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([BH3-])#N.[Na+]>CO>[CH3:23][O:24][C:25]1[CH:32]=[C:31]([CH2:33][CH2:34][N:7]2[CH2:6][CH2:5][N:4]([CH2:9][CH2:10][C:11]3[CH:20]=[CH:19][C:14]4[C:15](=[O:18])[O:16][CH2:17][C:13]=4[CH:12]=3)[CH:3]([C:2]([F:1])([F:21])[F:22])[CH2:8]2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: COc1cc(CC=O)ccc1C#N
Reactant: O=C1OCc2cc(CCN3CCNCC3C(F)(F)F)ccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)C(C(F)(F)F)C2)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}-2-benzofuran-1(3H)-one (95 mg, 0.27 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (40 mg, 0.23 mmol) in methanol (1.0 mL) at 0° C. was added sodium cyanoborohydride (20 mg, 0.32 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 474.3 [M+1]+. 1H-NMR (500 MHz, CD3OD) δ ppm 7.82 (m, 1H), 7.60 (overlapping m's, 3H), 7.15 (s, 1H), 7.02 (m, 1H), 5.38 (s, 2H), 3.98 (s, 3H), 3.90 (m, 1H), 3.58 (m, 2H), 3.51 (m, 2H), 3.43 (m, 2H), 3.20 (m, 4H), 3.12 (m, 2H), 3.08 (m, 2H). (0.65 μM)