Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][C@@H:9]([CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH2:39]>CCO>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][C@@H:9]([CH2:25][NH:39][CH3:38])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CCC(=O)OC(C)(C)C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Solvent: CCO
Product: CNC[C@H](CCC(=O)OC(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 95 %

Procedure:
(S)-tert-butyl 4-((R)-5-tert-butoxy-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (300 mg, 0.55 mmol) was dissolved in 30% MeNH2 in EtOH (60 mL), the solution was heated to 70° C. for 2 h in a pressure sealed vessel. After cooling to rt, the solvent was removed under reduced pressure to give (S)-tert-butyl 4-((R)-5-tert-butoxy-2-((methylamino)methyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate (212 mg, 95%). MS ESI +ve m/z 401 (M+H).
Reaction SMILES: Cl.[Br:2][C:3]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.Cl>[Br:2][C:3]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][N:8]([S:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])(=[O:30])=[O:29])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)CNc2cccc(Br)c2O1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CN(S(=O)(=O)c2ccccc2F)c2cccc(Br)c2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71214.9 %

Procedure:
8-Bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride (518 mg, 2.14 mmol) was dissolved in 5 ml methylene chloride, to which pyridine (253.85 g, 3.21 mmol) was then added. The reaction mix was stirred at room temperature, and 2-fluorobenzenesulfonyl chloride (416.37 mg, 2.14 mmol) was added drop-wise to the reaction mix, after which stirring at room temperature was continued for 2 hours. The reaction mix was then heated to reflux for 1 hour, and cooled to room temperature. The reaction mix was diluted with 5 ml of methylene chloride and 10% aqueous HCl was added. The organic layer was separated, washed with water, then saturated NaHCO3, and dried (Na2SO4). Solvent was removed under reduced pressure, and the residue was purified via flash chromatography (EtOAc in hexane, 5% to 20%) to afford 610 g (71.3%) of 8-bromo-4-(2-fluoro-benzenesulfonyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine as an oil which solidified upon standing. MP: 108.0–110.1° C. MS: (M+H) 401.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:16][C:15]([C:26]#[N:27])=[N:14]1.[F:28][C:29]([F:33])([F:32])[S:30]Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[C:16]([S:30][C:29]([F:33])([F:32])[F:28])[C:15]([C:26]#[N:27])=[N:14]1
Reactant: FC(F)(F)SCl
Reactant: N#Cc1cc(NCc2ccncc2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2ccncc2)c1SC(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
In 10 ml of dichloromethane was suspended 0.5 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-(4-pyridylmethylamino)pyrazole obtained in Example 1 above, and 0.2 g of trifluoromethylsulfenyl chloride in 10 ml of dichloromethane was added thereto dropwise at −20° C. The mixture was taken out of the cooling bath. After stirring for 3 hours, ice-water was added to the mixture to extract. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography to yield 0.4 g of compound No. 1 shown in Table 1 below. The NMR data of the compound were as follows.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH:33]([CH3:35])[CH3:34])=[C:29]([CH:32]=1)[CH:30]=[O:31]>C1COCC1>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH:30]([C:29]3[CH:32]=[C:25]([Br:24])[CH:26]=[CH:27][C:28]=3[CH:33]([CH3:35])[CH3:34])[OH:31])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)N(Cc1ccccc1)CCO2
Reactant: CC(C)c1ccc(Br)cc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1ccc(Br)cc1C(O)c1ccc2c(c1)N(Cc1ccccc1)CCO2
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of 4-Benzyl-6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (1.5 g, 4.93 mmol) in THF (20 mL) was added 1.6 M n-butyl lithium in hexanes (3.0 mL, 74.93 mmol) at −78° C. The reaction was stirred for 30 min. then transferred to a stirred solution of 5-bromo-2-isopropylbenzaldehyde (1.12 g, 4.93 mmol) in THF (15 mL) at −78° C. After stirring for 30 min, the reaction was quenched by the addition of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with water (25 mL) and brine (25 mL), then dried over sodium sulfate, concentrated and purified using neutral alumina column chromatography to give (4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-(5-bromo-2-isopropyl-phenyl)-methanol (1.3 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][N:7]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)[nH]n1
Temperature: 90 °C
Yield: 100.3 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (200 mg, 0.6 mmol) in dioxane (5 mL) was added aqueous sodium hydroxide (2 M, 3.0 mL, 6.0 mmol). After heating at 90° C. for 2 h the solution was cooled to room temperature and neutralized with aqueous hydrogen chloride (2 N). The precipitate was then filtered off and dried to afford the title compound (191 mg, 100%) as a white solid.
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH:30]1([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH:20]3[CH2:21][CH2:22][N:17]([C:15]([C:12]4[CH:13]=[N:14][C:9]([N:2]5[CH2:3][CH2:4][CH2:5][S:1]5(=[O:7])=[O:6])=[CH:10][CH:11]=4)=[O:16])[CH2:18][CH2:19]3)=[CH:25][CH:26]=2)[CH2:31][CH2:32]1
Reactant: O=C(c1ccc(Br)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Reactant: O=S1(=O)CCCN1
Product: O=C(c1ccc(N2CCCS2(=O)=O)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Yield: 60.5 %

Procedure:
Using isothiazolidine 1,1-dioxide (230 mg) and (6-bromopyridin-3-yl)[4-(4-cyclopropylphenoxy)piperidin-1-yl]methanone (635 mg) described in Preparation Example 192 and by the reaction and treatment in the same manner as in Example 1, the title compound (423 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26](O)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]1.Cl.C(N=C=NCCCN(C)C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:29]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]2)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid, thiomorpholine 1,1-dioxide and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a yellow solid (95%).
Reaction SMILES: Cl[Si:2]([Cl:5])([CH3:4])[CH3:3].[CH3:6][C:7]1[CH-:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=[CH:11][CH:10]=2.[Li+]>CCOCC>[Cl:5][Si:2]([CH3:3])([CH3:4])[CH:8]1[C:9]2[C:14](=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[CH3:6]
Reactant: Cc1cc2c(-c3ccccc3)cccc2[cH-]1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li+]
Solvent: CCOCC
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a colorless solution of dichlorodimethylsilane (12.90 g, 100 mmol, 3.00 eq.) in ether (30 ml) at −30° C. was added lithium (2-methyl-4-phenylindenide) (7.07 g, 33.3 mmol, 1.00 equiv.) in portions to give a cloudy yellow mixture. The reaction was allowed to warm to room temperature and stirred for 4 hours, becoming cloudy white with precipitate. The mixture was evaporated under vacuum, leaving a white solid. The solid was extracted with pentane (40 ml), and the extract was filtered to give a light yellow solution and white solid. The solution was evaporated under vacuum, leaving a white solid. Yield 9.85 g (99%). 1H NMR(C6 D6): δ7.59 (d, 2H), 7.44 (m, 1H), 7.36 (m, 3H), 7.22 (m, 2H), 6.86 (d, 1H), 3.42 (d, 1H), 2.11 (d, 3H), 0.27 (s, 3H), −0.03 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([NH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1.[C:25]12[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=1)[NH:30]C(=O)O[C:26]2=[O:27]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:23][C:26](=[O:27])[C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:7]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COC(=O)C(N)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Solvent: c1ccncc1
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)NC(=O)c1ccccc1N
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture of the title G compound, 3-(3-benzyloxy-4-nitro-phenyl)-2-amino-propionic acid methyl ester (597 mg, 1.7 mmol), isatoic anhydride (278 mg, 1.7 mmol) and pyridine (5 mL) is heated with stirring at 80° C. for 7 h and allowed to cool to RT overnight. The mixture is evaporated to dryness, the residue is dissolved in EtOAc and the solution is washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The residue is purified by chromatography (silica gel column, 3×20 cm, on EtOAc-hexane-methanol, 8:12:2) to give 2-(2-amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)-propionic acid methyl ester: 1H-NMR δ 7.815 (d, 1H), 6.294 (s, 1H), 6.825 (d, 1H), 7.384-7.206 (m, 7H), 6.699-6.577 (m, 3H), 5.532 (br s, 2H), 5.093-5.039 (m, 3H), 3.749 s, 3H), 3.403-3.175 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]([N:15]=[C:16]=[O:17])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][N:19]([CH3:21])[NH2:20].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:21])[NH:20][C:16]([NH:15][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[CH3:14])=[O:17]
Reactant: CC(N=C=O)c1cccc(-c2ccccc2)c1
Reactant: CN(C)N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(NC(=O)NN(C)C)c1cccc(-c2ccccc2)c1
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To a solution of 2.29 g of 1-(3-phenylphenyl)ethylisocyanate in 8 ml of toluene was added dropwise 0.78 g (13 mmol) of N,N-dimethylhydrazine with ice-cooling. The mixture was removed from an ice bath and stirred for 1.5 hours. The reaction solution was concentrated, and the residue (2.89 g) was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=2:1and then 1:1 and then 1:2) to obtain 2.29 g (8.08 mmol) of 1,1-dimethyl-4-{1-(3-phenylphenyl)ethyl}semicarbazide as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.S([O:16][CH3:17])(OC)(=O)=O.CC#N.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH3:4])[C:17](=[O:16])[CH:3]=1
Reactant: COc1cnc(Cl)cc1Br
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cn(C)c(=O)cc1Br
Temperature: 25 °C

Procedure:
A solution of 4-bromo-2-chloro-5-methoxypyridine [1020253-15-9] (1 g, 4.5 mmol) in dimethyl sulfate (1.9 mL, 19.5 mmol) was stirred at 120° C. for 16 h in a sealed tube. After cooling to rt, CH3CN and a saturated aqueous NaHCO3 solution were added and the mixture was stirred at rt over the weekend. CH2Cl2 was added and the phases were separated. The organic layer was dried (Na2SO4), filtered and concentrated to give the title compound as a white powder. ESI-MS: tR=0.57 min; [M+H]+ 218/220 (LC-MS 1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Brc1ccc2ccccc2c1
Product: COc1ccc(-c2ccc3ccccc3c2)cc1

Procedure:
The title compound was prepared by reacting 2-bromonaphthalene (3.04 g, 14.7 mmol) with 4-methoxyphenylmagnesium bromide according to method used to prepared intermediate 10 to yield 2.89 g (89%) of a white solid: mp 114° C.; 1H NMR (CDCl3): δ 3.86 (3H, s), 7.01 (2H, d, J=9.06 Hz), 7.43-7.50 (2H, m), 7.65 (2H, d, J=8.73 Hz), 7.71 (1H, dd, J=1.84 Hz, J=8.56 Hz), 7.83-7.89 (3H, m), 7.98 (1H, d, J=0.67 Hz); MS (EI) m/z 234 (M)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:9]=2)[CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:3]=1.[Br:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1>>[Br:28][C:29]1[N:30]=[CH:31][N:32]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[C:10]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[CH:9]=3)[CH:5]=[C:4]([C:24]([F:27])([F:25])[F:26])[N:3]=2)[CH:33]=1
Reactant: Brc1c[nH]cn1
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Product: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example A.39) (0.85 g, 2.0 mmol) and commercially available 4-bromo-imidazole (0.44 g, 3.0 mmol) according to the general procedure IVa. Obtained as a light yellow solid (0.83 g, 78%). MS (ISP) 535.0 [(M+H)+]; mp 159° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2O.[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:13][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)(=[O:12])[CH3:11]
Reactant: OC1CC2CCN1CC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CN2CCC1CC2

Procedure:
The thus obtained (+) quinuclidinol was esterified with acetic anhydride to yield in a quantitative manner the desired novel (+) 3-acetoxy quinuclidine. The hydrochloride was obtained from a solution of hydrogen chloride in anhydrous ether, M.P. = 175° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:21])[C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)(C(C)(C)C)(C)C>C(O)C.Cl.O>[Cl:20][C:15]1[N:14]=[C:13]([N:12]([CH3:21])[CH2:11][CH2:10][CH2:9][OH:8])[C:18]([F:19])=[CH:17][N:16]=1
Reactant: CN(CCCO[Si](C)(C)C(C)(C)C)c1nc(Cl)ncc1F
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(CCCO)c1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
A mixture of N-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-fluoro-N-methyl-4-pyrimidinamine (Example 82, 2.22 g, 6.65 mmol) in ethanol/HCl/water (95:1:4, 50 mL) was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was passed through a plug of silica gel to give the title compound (1.13 g, 77%) as a viscous yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, 1H), 3.59 (t, 2H), 3.43 (t, 2H), 3.24 (d, 3H), 1.74-1.71 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[C:12]3=2)[C:7]1=[O:23].[H-].[Na+].[CH3:30]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]3[CH2:19][CH2:18][N:17]([CH3:30])[C:16](=[O:20])[C:12]3=2)[C:7]1=[O:23]
Reactant: O=C1NCCn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 9-(3-chloro-4-fluorobenzyl)-7-hydroxy-3,4,10,11-tetrahydro-2-H-pyrazino[2,1-a]-2,6-naphthyridine-1,6,8(9H)-trione (53 mg, 0.14 mmol; Example 5), and sodium hydride (12.3 mg; 60% dispersion in oil) in DMF (2 mL) was stirred at 0° C. for 20 minutes. To the resultant solution, methyl iodide (96 mg, 0.68 mmol) was added and the reaction mixture was heated at 40° C. for four hours. The reaction mixture was quenched with methanol and concentrated under vacuum. The residue was purified by reverse phase high pressure liquid chromatography. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].Cl>CCOC(C)=O.C(#N)C>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:18])=[CH:6][CH:7]=2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1ccc(CBr)cc1
Reactant: COC(=O)Cc1ccc(CCNS(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCc1ccc(CN(CCc2ccc(CC(=O)O)cc2)S(C)(=O)=O)cc1

Procedure:
A mixture of [4-[2-methanesulfonylamino-ethyl]-phenyl]-acetic acid methyl ester (38 mg, 0.14 mmol), 1-bromomethyl-4-butylbenzene (35 mg, 0.15 mmol), K2CO3 (25 mg, 0.182 mmol) and acetonitrile was heated at reflux for 1 h. Aqueous HCl (2 mL, 1N) and EtOAc (30 mL) were added to the reaction. The organic solution was dried with MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.28-7.05 (m, 8H), 4.37 (s, 2H), 3.65 (s, 3H), 3.58 (s, 2H), 3.26 (t, 2H), 2.77 (t, 2H), 2.69 (s, 3H), 2.60 (t, 2H), 1.59 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12](Br)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][S:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: OB(O)c1ccccc1
Reactant: CSCc1cc(Br)c2ncccc2c1
Product: CSCc1cc(-c2ccccc2)c2ncccc2c1

Procedure:
6-(methylthiomethyl)-8-bromoquinoline and benzene boronic acid can be combined to form 6-(methylthiomethyl)-8-phenylquinoline, and
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][CH:17]2[C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23]O>>[CH3:23][O:21][C:20]([CH:17]1[C:18]2[C:14](=[CH:13][CH:12]=[C:11]([C:3](=[O:10])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)[CH2:15][CH2:16]1)=[O:22]
Reactant: O=C(c1ccccc1)c1ccc2c(c1)C(C(=O)O)CC2
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCc2ccc(C(=O)c3ccccc3)cc21

Procedure:
Analogously to the description in Example 2, 13 g of 6-benzoyl-indane-1-carboxylic acid methyl ester and 75 ml of 2 N sodium hydroxide solution in 500 ml of methanol give 6-benzoyl-indane-1-carboxylic acid of boiling point 200° C./0.04 mm Hg as a yellowish, viscous oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:50])[C@@H:20]([NH:28][C:29](=[O:49])[C@H:30]([C:42]([S:45]([CH3:48])(=[O:47])=[O:46])([CH3:44])[CH3:43])[NH:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][C:60](O)=[O:61]>>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([O:50][C:60](=[O:61])[CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][O:52][CH3:51])[C@@H:20]([NH:28][C:29](=[O:49])[C@H:30]([C:42]([S:45]([CH3:48])(=[O:46])=[O:47])([CH3:44])[CH3:43])[NH:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOCCOCC(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cccc(C#N)c1)C(C)(C)S(C)(=O)=O
Product: COCCOCCOCC(=O)O[C@H](CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cccc(C#N)c1)C(C)(C)S(C)(=O)=O

Procedure:
Example 160, [M+H]+ 868.5, was prepared in a manner analogous to Example 147 starting from N-tert-butyl-2-[3(S)-[[N-(3-cyanobenzoyl)-3-(methanesulfonyl)-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-3(S)-isoquinolinecarboxamide (Example 39) and 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (Aldrich 40,7000-3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8](Cl)(=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:20])=[O:26])([OH:7])=[O:6]
Reactant: NCCCC(=O)O
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Product: O=C(O)CCCNC(=O)c1ccccc1SSc1ccccc1C(=O)NCCCC(=O)O
Yield: 49.9 %

Procedure:
Following the procedure in Preparation 30, 16 g (0.15 mol) of 4-amino-butanoic acid was reacted with 10.8 g (0.03 mol) of 2,2'-dithiobisbenzoyl chloride to afford 7.14 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4](Cl)[N:3]=1.[OH-].[Na+]>[Zn].C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: c1ccccc1
Product: Clc1cnc(Cl)c(Cl)c1
Reaction time: 7 h

Procedure:
To a 5-liter 3-neck flask fitted with a reflux condenser, a heater, thermometer and a stirrer were added 216.9 grams (1.0 mole) of 2,3,5,6-tetrachloropyridine, 500 milliliters of benzene, 1.0 liter of 8N sodium hydroxide and 130.7 grams (2.0 gram atoms) of zinc dust. The pH of the mixture was 14-15 and the mixture was heated and refluxed, with stirring, for 7 hours. After completion of the reaction, the reaction mixture was cooled and filtered. The filter cake was washed with benzene and the benzene wash was combined with the filtrate. Gas-liquid chromatography of the mixture indicated a 2,3,5-trichloropyridine content of about 131.35 grams (72 percent of theoretical).