Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH3:2].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[N:14]=[CH:15][CH:16]=[C:17]2[C:21]([CH2:22][N:23]([CH3:25])[CH3:24])=[C:20]([CH3:26])[N:19]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[C:18]=12>C(O)C>[I-:1].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[N:14]=[CH:15][CH:16]=[C:17]2[C:21]([CH2:22][N+:23]([CH3:2])([CH3:24])[CH3:25])=[C:20]([CH3:26])[N:19]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[C:18]=12
Reactant: Cc1c(CN(C)C)c2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Reactant: CI
Solvent: CCO
Product: Cc1c(C[N+](C)(C)C)c2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
The compound prepared in Example 619 was treated with a saturated sodium bicarbonate solution to obtain [7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-dimethylamine. Iodomethane (40 μl, 0.64 mmol) was added to a solution of [7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-dimethylamine (136 mg, 0.32 mmol) in ethanol (2 ml). The reaction mixture was stirred overnight at room temperature. The resulting precipitate was filtered and then dried to give the titled compound as a white solid (Yield 82%).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+].I[CH2:30][CH:31]([OH:34])[CH2:32][OH:33].O>CN(C)P(N(C)C)(N(C)C)=O.CCOCC>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCC(O)CI
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 7.34 g of 4-(n-hexadecylamino)benzoic acid, 4.80 g of 25% aqueous sodium hydroxide, and 12.6 g of 3-iodo-1,2-propanediol in 50 ml of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate, m.p. 112° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)([OH:13])[CH2:9]1)C1C=CC=CC=1.IC.N1CCOCC1>CN(C)C=O>[Cl:21][C:16]1[CH:15]=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][N:8]([CH3:1])[CH2:9]2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: OC1(c2cc(F)cc(Cl)c2)CCN(Cc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1COCCN1
Product: CN1CCC(O)(c2cc(F)cc(Cl)c2)C1

Procedure:
Preparation according to Example 34: (+)-1-benzyl-3-(3-chloro-5-fluorophenyl)-pyrrolidin-3-ol (0.1 g, 0.33 mmol) and iodomethane (1 mL, 15.9 mmol), dimethyl formamid (2 mL), morpholine (2 mL). Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1). Yield: 0.05 g. [α]D=+21° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 114-115° C.; MS m/z (relative intensity, 70 eV) 229 (M+, 7), 129 (9), 109 (7), 58 (30), 57 (bp).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:15]([C:17]1[N:21]2[CH:22]=[C:23]([C:26]([O:28]C(C)(C)C)=[O:27])[CH:24]=[CH:25][C:20]2=[CH:19][N:18]=1)=[O:16])=[O:11]>ClCCl.CC(C)=O>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:15]([C:17]1[N:21]2[CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=[CH:25][C:20]2=[CH:19][N:18]=1)=[O:16])=[O:11]
Reactant: COC(=O)c1cc(C(=O)c2ncc3ccc(C(=O)OC(C)(C)C)cn23)ccc1[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)c2ncc3ccc(C(=O)O)cn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
2.13 ml (28.68 mmol) of trifluoroacetic acid are added to 610 mg (1.43 mmol) of tert-butyl 3-[3-(methoxycarbonyl)-4-nitrobenzoyl]imidazo[1,5-a]pyridine-6-carboxylate in 2 ml of dichloromethane and the mixture is stirred at ambient temperature for 5 hours. The reaction medium is concentrated under reduced pressure and then the residue obtained is taken up in acetone. The precipitate formed is filtered off, washed with acetone and dried. 450 mg of a yellow powder are obtained. Melting point: 290° C.; 1H NMR (d6-DMSO): 3.90 (3H, s), 7.78 (1H, d), 8.04 (1H, s), 8.12 (1H, d), 8.26 (1H, d), 8.68 (1H, d), 8.75 (1H, s), 10.26 (1H, s)
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[N:27]([CH2:28][CH2:29][O:30][C:31]4[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][C:32]=43)[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]>C(Cl)Cl>[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[C:32]4[CH:35]=[C:36]([S:39]([N:6]5[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]5)(=[O:41])=[O:40])[CH:37]=[CH:38][C:31]=4[O:30][CH2:29][CH2:28][N:27]3[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]
Reactant: CN(C)C1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCC(N(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl-piperidin-4-yl-amine (45 mg, 0.35 mmol) and NEt3 (83 μL, 0.59 mmol) in DCM (15 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (93 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 1 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-16% MeOH in EtOAc) then freeze-dried from MeCN/H2O affording 131 (29 mg, 52%) as a white solid. LCMS: RT 2.83 min [M+H]+ 486.3. 1H NMR (DMSO, 400 MHz): δ 8.79 (1H, d, J=2.42 Hz), 8.00 (1H, s), 7.93 (1H, d, J=0.62 Hz), 7.63 (1H, dd, J=10.74, 2.40 Hz), 7.26 (1H, d, J=8.62 Hz), 5.72-5.71 (1H, m), 4.61-4.60 (4H, m), 3.60-3.57 (2H, m), 2.40-2.39 (2H, m), 2.15-2.05 (1H, m), 2.10 (6H, s), 1.77-1.73 (2H, m), 1.49 (6H, d, J=6.62 Hz), 1.46-1.37 (2H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][CH:9]([O:20][C:21](=[O:31])[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[CH3:23])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.O>[Cl:32][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][CH:9]([O:20][C:21](=[O:31])[CH:22]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:28][CH:29]=1)[CH3:23])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)C(C)c2ccc(N)cc2)cc1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)C(C)c2ccc(NS(C)(=O)=O)cc2)cc1OC
Temperature: 0 °C
Yield: 36.1 %

Procedure:
Compound 16 (26 mg, 0.05 mmoles) is dissolved in dry CH2Cl2 (10 mL) under nitrogen atmosphere. The solution is cooled to 0° C. and triethylamine (0.009 mL, 0.066 mmoles) and methanesulphonyl chloride (0.0052 mL, 0.06 mmoles) are added. The mixture is then allowed to react at room temperature for 17 hours. The reaction mixture is then diluted with water (15 mL) and extracted with AcOEt (2×30 mL). The organic phase is dried over Na2SO4 and the solvent is evaporated. The crude is purified by preparative HPLC to yield 10 mg of the title compound as a mixture of diastereoisomers.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]([CH3:18])[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.CCO.O>[C:3]([O:7][C:8]([N:10]([CH3:18])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)CCN(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
To a mixture of sodium hydroxide (112 g, 2.8 mol) in THF (1200 mL) and EtOH (1800 mL) was added ethyl 3-(tert-butoxycarbonyl(methyl)amino)propanoate (300 g, 1.4 mol). The resulting mixture was stirred for 3 h. The mixture was diluted with water (1000 mL) and evaporated to remove volatiles. The water phase was washed with CH2Cl2 (800 mL×3). The inorganic layer was cooled in an ice bath and acidified with 1 N HCl until the pH was adjusted to 1-2. CH2Cl2 (1000 mL×4) was quickly added to extract the product acid. The organic phase was dried over anhydrous Na2SO4 and concentrated to give 3-(tert-butoxycarbonyl(methyl)amino)propanoic acid (208 g, 73.2%) as oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N:26]2[CH2:31][CH2:30][N:29]([C@@H:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:33])[CH2:28][CH2:27]2)[C:17]1=[O:40])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[S:52](Cl)(=[O:54])=[O:53]>ClCCl>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:5]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[N:26]3[CH2:31][CH2:30][N:29]([C@@H:32]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH3:33])[CH2:28][CH2:27]3)[C:17]2=[O:40])[CH2:4][CH2:3][CH2:2][NH:1][S:52]([C:48]2[S:47][CH:51]=[CH:50][CH:49]=2)(=[O:54])=[O:53])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccc(C(CCCN)N2C(=O)c3cccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(C(CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.6 %

Procedure:
A 10-mL round bottom flask was charge with Compound 66 (20.0 mg, 0.04 mmol), potassium carbonate (8.0 mg, 0.06 mmol), and dichloromethane (0.5 mL). Thiophene-2-sulfonyl chloride (8.0 mg, 0.04 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and purified via flash chromatography (230-400 mesh silica gel 60, gradient 100:0-95:5 CH2Cl2:methanol) to give 9.8 mg of Compound 68 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.71-7.74 (m, 1 H), 7.51-7.61 (m, 3 H), 7.29-7.38 (m, 6 H), 7.02-7.18 (m, 3 H), 6.73-6.80 (m, 1 H), 5.10-5.17 (m, 1 H), 4.50-4.57 (m, 1 H), 3.86 (s, 3H), 3.83 (s, 3 H), 3.31-3.39 (m, 4 H), 3.06-3.11 (m, 4 H), 2.65-2.74 (m, 2 H), 2.45-2.55 (m, 1 H), 2.20-2.31 (m, 1 H), 1.58-1.63 (m, 2 H), and 1.49 (d, J=6.8 Hz, 3 H); MS (ES+) 689 (M+1).
Reaction SMILES: [ClH:1].CC(C)CCC[NH:7][C:8]([C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13](C(C)CN3CCCC3)[C:12]=2[CH:11]=1)=S.C(O)(=[O:35])C>O>[ClH:1].[CH:11]1[C:12]2[NH:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:20][C:21]=2[CH:22]=[CH:23][C:10]=1[C:8]([NH2:7])=[O:35]
Reactant: CC(=O)O
Reactant: CC(C)CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Agent: Cl
Solvent: O
Product: NC(=O)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of N-(4-methylpentyl)-l0-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide hydrochloride (1.2 g) and mercuric acetate (0.88 g) in acetic acid (20.5 cc) is stirred for 16 hours at a temperature in the region of 20° C. The orange suspension obtained is diluted with distilled water (50 cc), filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with distilled water (50 cc) and ethyl acetate (100 cc). The mixture is alkalinized to pH 13 with sodium hydroxide (d=1.33). The organic phase is separated and then washed successively with distilled water (2×25 cc) and saturated aqueous sodium chloride solution (25 cc). The organic phase is then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oily yellow residue (0.82 g) is dissolved in ethyl acetate (10 cc) and treated, with stirring, with a 3.3N solution (0.55 cc) of hydrochloric acid in isopropyl ether. After 1 hour with stirring at a temperature in the region of 5° C., the solid formed is drained, washed with ethyl ether (3×10 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(4-Metylpentyl)-l0-[(2RS)-1-1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.6 g) is thereby obtained in the form of a very pale yellow solid, m.p. 218° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2.[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>ClCCl>[Si:17]([O:12][CH:9]1[CH2:10][C:11]2[C:2]([NH2:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7][CH2:8]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc2c1CC(O)CC2
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N)c2C1

Procedure:
A mixture of Example 1F (2.33 g, 14.3 mmol), tert-butylchlorodimethylsilane (2.6 g, 17.2 mmol) and imidazole (2.9 g, 42.3 mmol) in dichloromethane (40 mL) were stirred at ambient temperature overnight. The mixture was then washed several times with water and once with brine. The organic layer was separated and dried over anhydrous sodium sulfate. Filtration and concentration afforded the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.09 (s, 6H), 0.88 (s, 9H), 1.63 (m, 1H), 1.82 (m, 1H), 2.24 (m, 1H), 2.75 (m, 3H), 4.11 (m, 1H), 4.7 (br s, 2H), 6.28 (d, J=7.4 Hz, 1H), 6.42 (d, J=7.8 Hz, 1H), 6.77 (dd, J=7.8, 7.4 Hz, 1H). MS (ESI) m/z 278 (M+H)+.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:27][C:28]1[CH:29]=[C:30]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)O)[CH:31]=[CH:32][C:33]=1[F:34].C(N(CC)CC)C>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:35]([C:30]1[CH:31]=[CH:32][C:33]([F:34])=[C:28]([F:27])[CH:29]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:11])[CH2:3]2
Reactant: O=C(O)C1CN2CCC1CC2
Reactant: OC(c1ccccc1)c1ccc(F)c(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OC(c1ccccc1)c1ccc(F)c(F)c1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (80 mg, 0.42 mmol), EDC (120 mg, 0.62 mmol), and HOBT (96 mg, 0.62 mmol) were dissolved in dry THF (3 ml). (3,4-Difluorophenyl)(phenyl)methanol (101 mg, 0.46 mmol) was dissolved in dry THF (2 ml) and then added to the reaction mixture. Triethylamine (203 μl, 1.46 mmol) was finally added, and the resulting reaction was stirred at room temperature overnight. The volatiles were evaporated, and the crude was taken up with EtOAc and washed with water and then with sat. NaHCO3. The organic phase was dried over sodium sulfate, filtered, and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (3,4-difluorophenyl)(phenyl)-methyl quinuclidine-3-carboxylate (65 mg, mixture of diastereoisomers).
Reaction SMILES: [C:1]([N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]1([CH3:14])[CH3:13])(=[O:3])[CH3:2].[C:15]([Cl:18])([Cl:17])=[O:16]>C(C(C)=O)C>[ClH:17].[C:1]([N:4]1[C:5]([CH3:14])([CH3:13])[CH2:6][CH:7]([O:12][C:15]([Cl:18])=[O:16])[CH2:8][C:9]1([CH3:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)N1C(C)(C)CC(O)CC1(C)C
Solvent: CCC(C)=O
Product: CC(=O)N1C(C)(C)CC(OC(=O)Cl)CC1(C)C
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
A solution of 19.9 grams (0.1 mol) of 1-acetyl-2,2,6,6-tetramethyl-4-hydroxypiperidine in 150 ml of dry methyl ethyl ketone is added dropwise at 0° C. over a 30-minute period to a solution of 28 ml (approximately 0.4 mol) of phosgene in 150 ml of methyl ethyl ketone. The reaction mixture is stirred at 0° C. for one hour, then at 20° C. for eighteen hours. Excess dissolved phosgene is flushed out into an absorption trap with a stream of nitrogen. The solid precipitate is removed by filtration, washed twice with methyl ethyl ketone and dried with suction to yield 13.7 grams (52% yield) of the title compound which melts at 113°-114° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[C@@H:13]([NH2:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([N:24]2[CH2:30][C:29]([F:32])([F:31])[C:28](=[O:33])[N:27]([CH3:34])[C:26]3[CH:35]=[N:36][C:37]([NH:39][C:40]4[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][C:41]=4[O:49][CH3:50])=[N:38][C:25]2=3)[CH2:23][CH2:22][CH2:21][CH2:20]1.F[P-](F)(F)(F)(F)F.[CH3:58]N(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH3:58])[CH:13]([NH:18][C:44](=[O:45])[C:43]2[CH:47]=[CH:48][C:40]([NH:39][C:37]3[N:36]=[CH:35][C:26]4[N:27]([CH3:34])[C:28](=[O:33])[C:29]([F:31])([F:32])[CH2:30][N:24]([CH:19]5[CH2:20][CH2:21][CH2:22][CH2:23]5)[C:25]=4[N:38]=3)=[C:41]([O:49][CH3:50])[CH:42]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CN(C(=O)OCc3ccccc3)CCC2OC)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A mixture of 0.078 g (0.30 mmole) of (rac)-(3S,4S)-3-amino-4-hydroxy-piperidine-1-carboxylic acid benzyl ester, 0.113 g (0.25 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.1138 g (0.30 mmole) 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate, 0.0776 g (0.60 mmole) of diisopropylethylamine and 2 mL of dimethylformamide was stirred at room temperature for 1 hour. The mixture was poured into 50 mL of water and extracted three times with 25 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated aqueous ammonium chloride solution, once with 25 mL of saturated aqueous sodium bicarbonate solution, once with 25 mL of brine and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (96:4) to give 0.088 g of rac-(3S,4S)-3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-4-methoxy-piperidine-1-carboxylic acid benzyl ester (I-58) as a foam. Tritruration of the foam with diethyl ether gave a white solid.
Reaction SMILES: C(O[CH2:9][C@@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:11]1=O)C1C=CC=CC=1.P(O)(O)O.O.[CH:29](O)(C)C>[Ir](Cl)(Cl)(Cl)Cl>[CH2:16]([O:15][CH2:14][C:13]1[CH:10]=[CH:9][CH:29]=[CH:11][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)O
Reactant: O=C1C[C@H](COCc2ccccc2)[C@H]1COCc1ccccc1
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: OP(O)O
Solvent: O
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
A mixture of (2S-trans)-2,3-bis[(benzyloxy)methyl]cyclobutanone (0.25 g., 0.806 mmole), iridium tetrachloride (0.016 g., 0.0483 mmole), phosphorous acid (0.397 g., 4.84 mmole) and water (0.3 ml.) in isopropanol (3 ml.) was refluxed overnight. The solvent was evaporated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 10% hydrochloric acid, brine, and 5% sodium bicarbonate. The organic layer was dried (magnesium sulfate) and the solvent was evaporated to give [1S-(1α,2β,3β)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzyl ether; TLC (40% ethyl acetate/hexane) Rf =0.51.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](O)=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>C1C=CC=CC=1>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([Cl:20])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(-c2ccccc2)cc1
Yield: 100.8 %

Procedure:
A suspension of 4-biphenyl acetic acid (8.48 g, 40 mmole) in dry benzene was cooled and stirred in an ice bath and oxalyl chloride (5.0 ml, 57.5 mmole) was added, followed dropwise by a solution of dry dimethylformamide (0.5 ml) in dry benzene. After the vigorous gas evolution subsided, the resulting solution was stirred at room temperature for 30 minutes. It was then evaporated and dried in vacuo (oil pump ~30) to afford 4-biphenylacetyl chloride as a solid (9.3 g, ~100%). This was used for reaction without further characterization. The above acid chloride was dissolved in CH2C12 (400 ml), stirred in an ice bath and a solution of sodium azide (3.9 g, 60 mmole) and (n-Bu)4N+H-SO4 (1.0 g) in water (120 ml) was added. (Ref. J. R. Pfister and W. E. Wyman, Synthesis, 38 (1983). The mixture was then stirred vigorously in the ice bath. After 45 minutes, the CH2Cl2 layer was separated, washed with water and brine, dried (MgSO4 anhydrous) and evaporated in vacuo (at ~25° ; CAUTION: DO NOT HEAT) to afford the title compound as a solid (8.5 g, 90.4%). The IR spectrum (Nujol) showed a weak peak at 2273 cm-1 (N=C=O) and a very strong peak at 2140 cm-1 (N3). It showed only one spot on tlc (silica gel, EtOAc-hexane, 1:1) and was used in the next step without further characterization.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#N)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.Cl.[OH2:28]>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: O
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Diisobutyl-aluminum hydride (86 mL of a 1 M solution in methylene chloride, 86 mmol) was added under nitrogen dropwise over 1 h to a solution of 4′-methoxy-1,1′-biphenyl-4-carbonitrile (15.0 g, 71.7 mmol), prepared in the previous step, in 500 mL of methylene chloride at ice bath temperature. After the addition the ice bath was removed and the reaction was stirred at room temperature for 1 h. By TLC starting material remained. The reaction was cooled to ice bath temperature and an additional 60 mL (60 mmol) of the diisobutylaluminum hydride was added dropwise over 1 h. After the addition the reaction was stirred at room temperature for 16 h. At room temperature 2 N HCl was added slowly until the reaction was acidic. Additional water and methylene chloride were added and the mixture filtered. The organic layer was then separated and the aqueous layer extracted multiple times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give 4′-methoxy-1,1′-biphenyl-4-carbaldehyde (12.5 g, 82%) as a pale yellow solid, MS (EI) m/z 212. Elemental Analysis for C14H12O2. Calc'd: C, 79.23; H, 5.70; N, 0.00. Found: C, 77.92; H, 5.87; N, 0.00