Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)[CH3:2].[CH2:10]([N:12](CC)CC)[CH3:11].[N+:17]([C:20]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=2[Cl:43])=[CH:28][C:21]=1[O:22][CH:23]([CH3:27])[C:24](Cl)=[O:25])([O-:19])=[O:18]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[CH2:1]([N:3]([CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)[C:24](=[O:25])[CH:23]([O:22][C:21]1[CH:28]=[C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=2[Cl:43])[CH:30]=[CH:31][C:20]=1[N+:17]([O-:19])=[O:18])[CH3:27])[CH3:2].[CH2:10]([NH:12][C:24](=[O:25])[C:23]([CH2:4][CH:5]1[O:6][CH2:7][CH2:8][O:9]1)([O:22][C:21]1[CH:28]=[C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=2[Cl:43])[CH:30]=[CH:31][C:20]=1[N+:17]([O-:19])=[O:18])[CH3:27])[CH3:11]
Reactant: CCN(CC)CC
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: CCNCC1OCCO1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC1OCCO1)C(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CCNC(=O)C(C)(CC1OCCO1)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-Ethyl-N-(1,3-dioxolan-2-ylmethyl)amine (1.31 grams; 0.01 mole), toluene (40 ml) and triethylamine (3 ml) were charged into a glass reaction vessel equipped with a magnetic stirrer, thermometer and addition funnel. A solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (4.2 grams; 0.01 mole) in toluene (30 ml) was added dropwise, with stirring at room temperature. A slight exotherm was observed. After the addition was completed stirring was continued for a period of about 1.5 hours. After this time the reaction mixture was transferred into a separatory funnel and was washed twice with water (60 ml), with dilute aqueous sodium bicarbonate (60 ml; 5% conc.) and again with water (60 ml). The washed organic phase was dried by passing it through phase separation paper and was thereafter stripped of solvent leaving a viscous oil as the residue. This residue was subjected to chromatography using a clay column (150 ml) and mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. Nine fractions were collected. Fractions six and seven were combined and stripped of solvents to yield the desired product N-ethyl-(1,3-dioxolan-2-yl-methyl)-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide as an amber gum.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:19]([C:21]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][C:24](O)=[O:25])#[N:20].Cl.[O:40]([CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[O:25]=[C:24]([N:50]1[CH2:51][CH2:52][CH:47]([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:48][CH2:49]1)[CH2:23][CH2:22][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:19]#[N:20]
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: N#CC(CCC(=O)O)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(CCC(=O)N1CCC(Oc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
1-Hydroxybenzotriazole hydrate (5.67 g, 42 mmol) and triethylamine (14.88 mL, 107 mmol) were added to 4-cyano-4,4-diphenylbutanoic acid (WO97/24325) (10.39 g, 39 mmol) and 4-phenoxy-piperidine hydrochloride (6.32 g, 36 mmol) in N,N-dimethylformamide (150 mL). The mixture was stirred for 10 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.20 g, 42 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with water (100 mL) and brine (30 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether, filtered off, washed through with diethyl ether and purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 75:25 to 50:50, to afford the title compound as a white solid (14.4 g) in a 95% yield.
Reaction SMILES: CN1CCNCC1.[Li]CCCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=2[CH:15]=[CH:14]1.CN(C)CCN(C)C.[CH2:32]([Sn:36](Cl)([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>CCCCCC.C1COCC1>[CH2:41]([Sn:36]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:37][CH2:38][CH2:39][CH3:40])[C:14]1[O:13][C:17]2[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=2[CH:15]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=Cc1ccc2occc2c1
Agent: CN(C)CCN(C)C
Agent: CN1CCNCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cc(C=O)ccc2o1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 33.8 %

Procedure:
To a solution of N-methylpiperazine (0.75 g, 7.5 mmol) in hexane (15 mL) at 0° C. under nitrogen was added dropwise a solution of n-BuLi (3 mL, 7.43 mmol, 2.5M/hexanes), and the reaction mixture was stirred at 0° C. for 40 min. 1-Benzofuran-5-carbaldehyde (1.0 g, 6.8 mmol) was added dropwise to the reaction mixture at 0° C. and the resulting mixture was stirred at 0° C. for 15 min. After addition of tetramethylethylenediamine (TMEDA) (1.7 g, 14.96 mmol), a solution of n-BuLi (6.0 mL, 14.86 mmol, 2.5M/hexanes) was added dropwise to the reaction mixture at 0° C. and the reaction mixture was allowed to warm up to room temperature and stirred for a total of 18 h. After the reaction mixture was cooled to 0° C. and THF (30 mL) was added, the reaction mixture was cooled to −50° C., tributyltin chloride (4.87 g, 14.96 mmol) was added dropwise, and the reaction mixture was stirred at −50° C. for 15 min. and at room temperature for 5-6 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted into diethyl ether. The organic layer was dried over sodium sulfate and concentrated and the crude product was purified by column chromatography (ethyl acetate/hexane, 2%) to give 1.0 g (34%) of 2-(tributylstannyl)-1-benzofuran-5-carbaldehyde as a yellow oil.
Reaction SMILES: I[C:2]1[C:10]2[N:9]3[CH:11]=[N:12][N:13]=[C:8]3[CH:7]=[N:6][C:5]=2[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[CH3:22][OH:23].CN([CH:27]=[O:28])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][Si:18]([CH3:21])([CH3:20])[CH2:17][CH2:16][O:15][CH2:14][N:4]1[C:5]2[N:6]=[CH:7][C:8]3[N:9]([CH:11]=[N:12][N:13]=3)[C:10]=2[C:2]([C:22]([O:28][CH3:27])=[O:23])=[CH:3]1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c1ncc1nncn12
Reactant: CO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c2ncc3nncn3c12
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 74 %

Procedure:
To a solution of 8-iodo-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.050 g, 0.12 mmol, prepared using KK from Preparation #GGG.1.1 and NaH), TEA (0.034 mL, 0.24 mmol), MeOH (0.25 mL, 6.2 mmol), and DMF (0.6 mL) purged with nitrogen was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0098 g, 0.012 mmol). The mixture was purged with CO and a balloon of CO was attached to the reaction vessel. The mixture was warmed to about 100° C. After about 4.5 h, the solution was allowed to cool to ambient temperature. Water (5 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 25-75% EtOAc/heptane over 30 min to afford methyl 6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carboxylate (0.0311 g, 74%): LC/MS (Table 1, Method n) Rt=0.74 min; MS m/z: 348 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C1COCC1.[C-]#[Si+].[C:19]([Cu])#[N:20]>O.CN1C(=O)CCC1>[Cl:11][C:4]1[N:3]=[C:2]([C:19]#[N:20])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [C-]#[Si+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 180 °C

Procedure:
2,6-dichloro-3-nitro-pyridine (2.5 g, 12.9 mmol) is taken up in a solvent mixture of THF and NMP (5:1, 13 mL), combined with two spatula tips of silicon carbide and CuCN (2.3 g, 26.0 mmol) and heated to 180° C. in the microwave reactor for 45 min. Then the solid obtained is suspended in H2O, extracted with ethyl acetate, washed with NaCl-sln., the organic phase is dried on MgSO4, the solvent is eliminated in vacuo and 6-chloro-3-nitro-pyridine-2-carbonitrile (HPLC-MS: tRet.=1.01 min, MS(M+H)+=182, method LCMSBAS1) is obtained.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1)#[C:25][CH3:26]>>[F:14][C:10]1([F:13])[CH2:9][CH2:8][C:7]2([C:15]3([N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]3)[C:22]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]4[CH:30]=[N:31][CH:32]=[C:27]([C:24]#[C:25][CH3:26])[CH:28]=4)[CH:23]=3)[CH2:6]2)[CH2:12][CH2:11]1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Reactant: CC#Cc1cncc(B(O)O)c1
Product: CC#Cc1cncc(-c2ccc3c(c2)C2(N=C(C)C(N)=N2)C2(CCC(F)(F)CC2)C3)c1
Yield: 23.9 %

Procedure:
The title compound (26 mg, 24% yield) was prepared as described for Example 28c starting from 6′-bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 27, 100 mg, 0.26 mmol) and 5-(prop-1-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 50.5 mg, 0.31 mmol). 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.22-1.30 (m, 1 H), 1.51 (br. s., 2 H), 1.71 (br. s., 1 H), 1.78-1.97 (m, 4 H), 2.09 (s, 3 H), 2.19 (s, 3 H), 3.06 (d, 1 H), 3.15 (d, 1 H), 6.61 (s, 2 H), 6.85 (d, 1 H), 7.41 (d, 1 H), 7.56 (dd, 1 H), 7.91 (t, 1 H), 8.51 (d, 1 H), 8.67 (d, 1 H). MS (APCI+) m/z 419.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH2:8][N:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[C:15]([Cl:24])[CH:14]=1)[CH2:10][CH:11]=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:34][O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][NH:27][CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:25])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:23])[F:22])=[C:15]([Cl:24])[CH:14]=1
Reactant: COC(=O)CCCN
Reactant: CC(C)(C)OC(=O)CCN(CC=O)c1ccc(OC(F)(F)F)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COC(=O)CCCNCCN(CCC(=O)OC(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.50 g (1.3 mmol) of 3-[(3-chloro-4-trifluoromethoxy-phenyl)-(2-oxo-ethyl)-amino]-propionic acid tert-butyl ester in 6 ml dichloromethane was added dropewise to a cooled (0° C., pH ca. 5) suspension of 0.22 g (1.4 mmol) methyl 4-aminobutyrate hydrochloride, 0.18 ml (1.3 mmol) triethylamine, 0.15 ml (2.6 mmol) acetic acid and 0.32 g (1.5 mmol) sodium triacetoxyborohydride in 4 ml of dichloromethane and stirred 30 min at 0° C. The reaction was extracted with aqueous saturated NaHCO3/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3 and dried over Na2SO4 to yield after evaporation of the solvent 0.61 g (83%) of the titled compound as yellow oil. MS: 483.19 (MH+, Cl).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11]([Cl:18])[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.C(OC([NH:30][C@H:31]([C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)[CH3:32])=O)(C)(C)C>C(#N)C>[ClH:18].[NH2:30][C@H:31]([C@@H:33]1[CH2:37][CH2:36][N:35]([C:11]2[C:12]([F:17])=[CH:13][N:14]3[C:9]([C:10]=2[CH3:19])=[C:8]([CH:20]2[CH2:21][CH2:22]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:34]1)[CH3:32]
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCNC1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Solvent: CC#N
Product: Cc1c(N2CC[C@@H]([C@H](C)N)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Product: Cl

Procedure:
A sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in anhydrous acetonitrile, reacted with (3R,1S)-3-(1-(t-butoxycarbonylamino)ethyl)pyrrolidine (prepared as described by Schroeder et al., J. Heterocyclic Chem., 29: 1481-1498 (1992)), and carried forward as described in Example 253k-l to give the title product. mp 250°-255° C. (dec.). MS 374 (M+H)+ ; 1H NMR (D6 -DMSO) δ: 0.59 (m, 2H), 1.00 (m, 2H), 1.29 (d, 3H, J=6 Hz), 1.77 (m, 1H), 2.13 (m, 1H), 2.29 (m, 1H), 2.41 (m, 1H), 2.64 (s, 3H), 3.57 (s, 1H), 3.76 (m, 3H), 3.94 (m, 1H), 7.91 (s, 1H), 8.17 (brs, 3H), 9.07 (d, 1H, J=l 1 Hz), 13.83 (brs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22]([OH:24])=O.Cl.[OH:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22]([N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][CH:35]=[CH:36][C:27]=2[OH:26])[CH2:32]1)=[O:24]
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Reactant: Oc1cccc2c1CCNC2
Agent: Cl
Product: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)N3CCc4c(O)cccc4C3)c2cc1OC
Yield: 27.4 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 113 (27.4% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.64 and 2.89 (2t, 2H), 3.47-4.09 (m, 8H), 4.42 and 4.94 (2s, 2H), 6.29-6.78 (m, 2H), 6.85-7.12 (m, 2H), 7.36-7.42 (m, 1H), 7.50-7.65 (m, 2H), 8.12-8.21 (m, 1H), 8.29-8.35 (m, 1H), 9.48 and 9.54 (2s, 1H); MS (ESI) m/z 460 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:20]([S:22][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:9]([CH2:18][OH:19])[CH2:10]1)(=[O:23])[CH3:21]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)S[C@H]1C[C@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
(2R,4R)-1-t-Butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (i.e., a substrate) and potassium thioacetate (KSAc) are dissolved in dimethylformamide (DMF), and the mixture is stirred. The conditions for this reaction are shown in Table 1, Step A-5. The reaction mixture is diluted with ethyl acetate, and ice water is added. The organic layer is taken, successively washed with aqueous sodium hydroxide, hydrochloric acid, water and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2R,4S)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol. NMR δ(CDCl3) ppm: 1.47(s, 9H), 2.05(t, 2H), 2.34(s, 3H), 3.0 to 3.3(m, 1H), 3.40(dd, J=11.6 Hz, J=5.2 Hz, 1H), 3.5 to 3.9(m, 3H), 3.9 to 4.2(m, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:20][CH2:19][CH2:18][C:7]2=[N:8][C:9]3[CH:10]=[CH:11][C:12]([OH:17])=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[Br:21]Br>C(O)(=O)C.O>[C:1]([N:4]1[CH2:20][CH2:19][CH2:18][C:7]2=[N:8][C:9]3[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([Br:21])[C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCc2nc3ccc(O)cc3c(C)c2C1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCCc2nc3ccc(O)c(Br)c3c(C)c2C1

Procedure:
2.5 gm (9.3 millimols) of 2-acetyl-9-hydroxy-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline were dissolved in 60 ml of glacial acetic acid and 12 ml of water, and the solution was brominated at room temperature with a solution of 1.48 gm (9.3 millimols) of bromine in 10 ml of glacial acetic acid. After distilling off the solvent, the residue was dissolved in water, and the solution was adjusted to a pH-value of 7.5 with 2 N sodium hydroxide, whereupon the reaction product crystallized out.
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.[C:15]1(N2CCOCC2)[CH2:19][CH2:18][CH2:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[O:14]1[C:16]2[CH2:17][CH2:18][CH2:19][C:15]=2[C:2]([C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]2)=[N:13]1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: COC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@H]1CC[C@H](c2noc3c2CCC3)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-methyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (0.900 g, 4.10 mmol) and 4-cyclopentenylmorpholine (1.23 ml, 8.19 mmol) in dichloromethane (21 ml) was added triethylamine (0.714 ml, 5.12 mmol) at 0-5° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 h. The solvent was evaporated. The residue was redissolved in 6 M aqueous hydrogen chloride solution (20.5 ml) and stirred at reflux for 4 h. After cooling to room temperature the reaction mixture was poured on ice, basified with 2 M aqueous sodium hydroxide solution (80 ml) and washed with two 50-ml portions of ethyl acetate. The combined organic layers were extracted with two 50-ml portions of 1 M aqueous sodium hydroxide solution. The combined aqueous layers were acidified to pH 2-3 by addition of concentrated hydrochloric acid and extracted with three 100-ml portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated in tert-butyl methyl ether (50 ml). The precipitate was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography with n-heptane/ethyl acetate as eluent to give the title compound (0.060 g, 6%) as off-white solid. MS m/e: 234 ([M−H]−)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2([O:15][CH3:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([OH:8])[CH:7]=1.I[CH2:18][C:19]#[N:20]>>[C:19]([CH2:18][O:8][C:6]1[CH:5]=[C:4]([C:9]2([O:15][CH3:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=[C:2]([OH:1])[CH:7]=1)#[N:20]
Reactant: N#CCI
Reactant: COC1(c2cc(O)cc(O)c2)CCOCC1
Product: COC1(c2cc(O)cc(OCC#N)c2)CCOCC1
Yield: 27 %

Procedure:
4-(3,5-Dihydroxyphenyl)-4-methoxytetrahydropyran was reacted with one equivalent of iodoacetonitrile using the procedure described in Example 1 to give 4-(3-cyanomethoxy-5-hydroxyphenyl)-4methoxytetrahydropyran (27%) as an oil.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:21](=[O:22])[C:20]2[C:23]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:24]=3[S:25][C:19]=2[N:18]=[C:17]1[CH3:31]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:21](=[O:22])[C:20]4[C:23]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:24]=5[S:25][C:19]=4[N:18]=[C:17]3[CH3:31])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc2sc3c(c2c(=O)n1N)CCCCC3
Product: Cc1nc2sc3c(c2c(=O)n1NC(=O)CC12CC4CC(CC(C4)C1)C2)CCCCC3

Procedure:
1-Adamantaneacetyl chloride and 3-amino-2-methyl-3,5,6,7,8,9-hexahydro-4H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.49-1.76 (m, 15 H) 1.78-1.89 (m, 2 H) 1.91-2.00 (m, 3 H) 2.08 (d, J=15.0 Hz, 1 H) 2.16 (d, J=15.0 Hz, 1 H) 2.34 (s, 3 H) 2.84 (s, 2 H) 3.11-3.29 (m, 3 H) 10.76 (s, 1 H); MS (ESI+) m/z 426 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([NH:16][NH2:17])=O)=O)(C)(C)C.[O:18]=[C:19]1[NH:24][C:23]2[CH:25]=[C:26]([C:29](N)=[NH:30])[CH:27]=[CH:28][C:22]=2[O:21][CH2:20]1.C(O)(=O)C>CN(C=O)C>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[NH:16][N:17]=[C:29]([C:26]2[CH:27]=[CH:28][C:22]3[O:21][CH2:20][C:19](=[O:18])[NH:24][C:23]=3[CH:25]=2)[N:30]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)NN
Reactant: N=C(N)c1ccc2c(c1)NC(=O)CO2
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1COc2ccc(-c3n[nH]c(C4CCCCN4)n3)cc2N1
Temperature: 120 °C

Procedure:
1.5 mmol of 2-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 3 ml DMF. 1 eq of 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamidine and 90 ul acetic acid were added and the reaction mixture heated to 120° C. overnight. The solvent was evaporated and the crude extracted from ethylacetate/water. The resulting oil was taken up in 15 ml DCM and treated with 3 ml TFA. The reaction mixture was reduced to dryness.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C@H:15]([NH:21]C(OCC(Cl)(Cl)Cl)=O)[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:30]([OH:32])=[O:31])[CH2:3]1.[C:33](O)(=O)C>[Zn]>[NH2:21][C@@H:15]1[CH2:14][C@@:12]2([CH3:13])[C@@H:8]([CH2:9][CH2:10][C@@H:11]2[C:30]([O:32][CH3:33])=[O:31])[C@H:7]2[C@H:16]1[C@:17]1([CH3:20])[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@H:2]([OH:1])[CH2:19][CH2:18]1
Reactant: CC(=O)O
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]2(C)[C@@H](C(=O)O)CC[C@@H]12
Agent: [Zn]
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](N)C[C@]12C

Procedure:
A solution of the product of Preparation 3 (2.4 g) in glacial acetic acid (25 ml) was stirred with zinc (2.5 g) for 4 hours. The zinc was removed by filtration and washed with water (50 ml) and ether (50 ml). The filtrate and washings were brought to pH 10 with 0.88 NH3 solution and extracted with ether (×4). The extract was washed with water, dried and evaporated to leave a solid (1.65 g). A portion was crystallised from ether to give the title compound, m.p. 113°-116°, [α]D +38°
Reaction SMILES: [Mg].C1COCC1.[C:7]([O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18](Br)[CH2:19][CH2:20]Br)(=[O:9])[CH3:8].Cl>C1(C)C=CC=CC=1.O>[C:7]([O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18]1[CH2:20][CH2:19]1)(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1c(C)cccc1C(Br)CCBr
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1c(C)cccc1C1CC1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A 300 ml four-necked round-bottomed flask was equipped with a magnetic stirrer bar, a thermometer, a reflux condenser and a drying tube. Magnesium (1.50 g, 61.7 mmol), toluene (15 ml) and anhydrous THF (15 ml) were added to the flask under a nitrogen atmosphere. The mixture was heated in an oil bath of 75° C. for 15 minutes (temperature of the mixture was 62-64° C.). Subsequently, the mixture was heated in an oil bath of 75° C. and a solution of 2-(1,3-dibromopropyl)-6-methylphenyl acetate (17.9 g, purity: 67%, 34.3 mmol) in toluene (60 ml) was added thereto over 30 minutes. The temperature of the mixture was raised to 89° C. After the mixture was stirred in an oil bath of 75° C. for 5.5 hours, the mixture was cooled and 6M hydrochloric acid (20.5 ml, 123 mmol) was added dropwise thereto over 15 minutes such that the temperature of the reaction mixture did not exceed 45° C. After the mixture was stirred at room temperature for 1 hour, it was diluted with water (20 ml) and it was stirred for 10 minutes. The solution was separated and the organic layer was successively washed with a saturated aqueous NaHCO3 solution (50 ml) and water (50 ml) and concentrated to obtain 11.1 g (purity: 45.2%, 26.4 mmol) of 2-cyclopropyl-6-methylphenyl acetate as a brown gum.