Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)=[O:19])[CH3:16].[O:30]([C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClC(Cl)C>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:24]=[CH:25][C:26]([NH:29][CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[C:37]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:38]=2)=[CH:27][CH:28]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.40 mmol) was added to a solution of (−)-(trans)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (III-1a) (0.116 g, 0.56 mmol) and 3-phenoxybenzaldehyde (1.15 g, 0.56 mmol) in 5 mL of dichloroethane. The mixture was stirred at room temperature for one hour and then partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by chromatography (silica gel, hexane:ethyl acetate) to give (−)-(trans)-ethyl-2-[4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl]cyclopropanecarboxylate (III-2a) (0.167 g, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 3H), 7.11 (t, J=7.32 Hz, 2H), 7.02 (m, 1H), 6.99 (d, J=8.60 Hz, 2H), 6.92 (d, J=8.42 Hz, 2H), 6.89 (m, 1H), 6.54 (d, J=8.60 Hz, 2H), 4.19 (s, 2H), 4.17 (q, J=7.14 Hz, 2H), 4.03 (br s, 1H), 2.44 (m, 1H), 1.78 (m, 1H), 1.52 (m, 1H), 1.28 (t, J=7.14 Hz, 3H), 1.25 (m, 1H). ES-MS m/z 388 (MH+). Aqueous sodium hydroxide (1.0 mL of a 25% solution) was added to a solution of III-2a (0.167 g, 0.43 mmol) in 4 mL of methanol and the mixture was heated at reflux for 8 hours. The volatile solvents were removed under vacuum, water was added, and the pH was adjusted to 5 with saturated aqueous sodium bisulfate. The mixture was extracted with dichloromethane, the organic phase was dried over sodium sulfate and concentrated to give 0.192 g of the title compound (III-3a) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.34 (t, J=8.42 Hz, 2H), 7.29 (t, J=7.87 Hz, 1H), 7.10 (m, 2H), 6.98 (s, 1H), 6.93 (d, J=7.68 Hz, 2H), 6.81 (d, J=8.42 Hz, 1H), 6.75 (d, J=8.23 Hz, 2H), 6.42 (d, J=8.42 Hz, 2H), 6.08 (m, 1H), 4.20 (m, 2H), 2.02 (m, 1H), 1.44 (m, 1H), 1.15 (m, 1H), 0.91 (m, 1H). ES-MS m/z 360 (MH+). [α]25,D=−187° (dichloromethane, c=4). Product was determined to be >99% ee by chiral SFC according to Method 1.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([C:36]([OH:38])=O)=[C:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:30]=2)=[CH:22][CH:21]=1.[C:39]([O:43][C:44]([N:46]1[CH2:49][CH:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:52]=2[O:58][CH3:59])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].CN1CCOCC1>C1COCC1>[C:39]([O:43][C:44]([N:46]1[CH2:47][CH:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH:57][C:36]([C:28]3[S:27][C:26]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=4)=[N:30][C:29]=3[CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:38])=[CH:53][C:52]=2[O:58][CH3:59])[CH2:49]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O
Reactant: COc1cc(N)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)Nc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)c(OC)c1
Temperature: 5 °C
Yield: 89.8 %

Procedure:
Mix 1-propanephosphonic acid cyclic anhydride (50% in EtOAc) (528.7 g, 831.3 mmol) and THF (1110 mL) and chill to 5° C. Add 2-(4-chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carboxylic acid (185.0 g, 593.43 mmol) followed by 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (192.2 g, 914.4 mmol). Charge N-methylmorpholine (99 mL, 1247 mmol) dropwise over 15 min and remove the ice bath immediately after the addition. Heat the reaction to 65° C. for 16 h and quench with water (555 mL). Dilute with EtOAc (1110 mL) and partition the layers. Wash with saturated sodium bicarbonate (555 mL) and with brine (555 mL). Distill the organic solvent until <5% THF remains and then back-add with ethyl acetate as needed to a total of 740 mL solvent at the end of the distillation. Add heptane (230 mL) at 75° C. and seed with authentic product at 55° C. Allow to cool to room temperature, filter, and rinse twice with heptane-EtOAc (2×100 mL, 1:1). Dry in a vacuum oven at 40° C. to obtain 313.5 g (90%) of the title compound as an orange-brown solid. ES/MS m/z (35Cl) 586 [M−1]−.
Reaction SMILES: CSC1C=CC(C2N([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)N=C(C(F)F)C=2)=CC=1.ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl.O>[C:17]1([S:20]([NH2:23])(=[O:22])=[O:21])[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4-[5-(4-[Methylthio]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (0.5 g, 1.27 mmol) was dissolved in methylene chloride (30 mL) and cooled to 0° C. To this solution was added m-chloroperoxybenzoic acid (MCPBA) (60%, 0.77 g, 2.7 mmol) and the solution was allowed to warm to room temperature while stirring for 18 hours. A solution of Na2S2O5 (2 g) in H2O (25 mL) was added to the reaction mixture and the solution stirred vigorously for 0.5 hour. The layers were separated and the organic layer was washed with saturated NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4 and concentrated to yield 4-[5-4-[methylsulfonyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide as a white solid, 0.22 g, 40%, mp=209°-210° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1C(=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[Si:7]([CH3:17])([CH3:16])[CH2:6]1.C[Si]1(C)C2C=CC=CC=2[S:22](=[O:30])(=[O:29])NC1.C([Li])CCC.ClCCCBr>O1CCCC1>[CH3:16][Si:7]1([CH3:17])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:22](=[O:30])(=[O:29])[N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[CH2:6]1
Reactant: C[Si]1(C)CNS(=O)(=O)c2ccccc21
Reactant: C[Si]1(C)CN(CCCCl)C(=O)c2ccccc21
Agent: ClCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si]1(C)CN(CCCCl)S(=O)(=O)c2ccccc21

Procedure:
4,4-Dimethyl-2-(3-chloropropyl)-3H-1,2,4-benzothiazasiline 1,1-dioxide may be obtained in a manner similar to that described in Example 4 for the preparation of 3-(3-chloropropyl)-1,1-dimethyl-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline, but using 3.2 g of 4,4-dimethyl-3H-1,2,4-benzothiazasiline 1,1-dioxide, 10.5 cm3 of n-butyllithium, 5.3 g of 1-chloro-3-bromopropane and 50 cm3 of tetrahydrofuran. After purification by flash chromatography on a silica column under a nitrogen stream at moderate pressure (0.5-1.5 bar) with a dichloromethane-cyclohexane mixture (50--50 by volume) as eluent, 1.95 g of 4,4-dimethyl-2-(3-chloropropyl) 3H-1,2,4-benzothiazasiline 1,1-dioxide are obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=[O:5])[CH3:2].[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+]([O-])=O)[C:16]=1[C:17]#[N:18])([O-:14])=[O:13]>>[C:17]([C:16]1[C:15]([N+:12]([O-:14])=[O:13])=[CH:22][CH:21]=[CH:20][C:19]=1[O:9][CH2:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])([CH3:10])[CH3:11])#[N:18]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCNC(=O)NC(C)(C)CO
Product: CCNC(=O)NC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 65 %

Procedure:
Prepared as in Example 215c from 1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)urea (Example 230d) and 2,6-dinitrobenzonitrile in 65% yield. MS 307 (MH+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14](OC)=[O:15])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1cnoc1-c1ccc(Cl)s1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of methyl 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionate (3.10 g) in tetrahydrofuran (80 ml) was gently added diisobutylaluminum hydride (1.5 M toluene solution, 17 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propan-1-ol (2.02 g, yield 73%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 1.41 (1H, br t, J=5 Hz), 1.8–2.0 (2H, m), 2.73 (2H, t, J=8 Hz), 3.73 (2H, td, J=6, 5 Hz), 6.98 (1H, d, J=4 Hz), 7.29 (1H, d, J=4 Hz), 8.17 (1H, s).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH:9]=[CH:10][C:11](=[CH:12][CH:13]=[CH:14][C:15](OC)=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[CH:12][CH:13]=[CH:14][CH2:15][OH:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C=CC=C1C=CCCc2ccccc21
Solvent: CCOC(C)=O
Product: OCC=CC=C1CCCCc2ccccc21

Procedure:
By the method of Preparation 2, except to quench into saturated NH4Cl and extract into ethyl acetate, methyl 4-(8,9-dihydrobenzocyclohepten-5-ylidene)-2-butenoate (7.7 g., 0.032 mol) was reduced to yield present title product which was recrystallized from isopropyl ether (3.8 g, 56%, mp: 108°-109° C.). 1H-NMR (CDCl3) delta: 7.61 (d, 7Hz, 1H); 7.25-7.02 (m, 3H); 5.51-5.79 (m, 2H); 4.02 d, 4Hz, 2H); 2.39-3.01 (m, 6H); 1.80-2.01 (m, 4H). Anal Calcd. for C15H20O2 : C, 7.55; H, 8.68. Found: C, 77.72; H, 8.69.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH3:20])[C:18]([C:21]34[CH2:28][CH2:27][C:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH2:25][CH2:26]3)[CH2:23][CH2:22]4)=[N:17][N:16]=2)=[C:11]([O:34][CH3:35])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:35][O:34][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[N:19]([CH3:20])[C:18]([C:21]23[CH2:26][CH2:25][C:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH2:27][CH2:28]2)[CH2:23][CH2:22]3)=[N:17][N:16]=1
Reactant: CCCCCC12CCC(c3nnc(-c4ccc(OCc5ccccc5)cc4OC)n3C)(CC1)CC2
Agent: [Pd]
Solvent: CO
Product: CCCCCC12CCC(c3nnc(-c4ccc(O)cc4OC)n3C)(CC1)CC2

Procedure:
A solution of 3-[4-(benzyloxy)-2-methoxyphenyl]-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (1-E) (272 mg, 0.572 mmol) in MeOH (8 mL) was hydrogenated for 19 h with 10% Pd/C catalyst (27 mg) at room temperature and atmospheric pressure. The catalyst was filtered and washed with MeOH. The MeOH was removed in vacuo to afford 3-methoxy-4-[4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]phenol (1-F). MS: m/z 384 (M+1); 1H NMR (500 MHz, DMSO-d6): δ 9.94 (s 1H), 7.09 (d, 1H, J=8.3), 6.53 (d, 1H, J=1.6 Hz), 6.46 (dd, 1H, J=2.2, 8.2 Hz), 3.72 (s, 3H), 3.40 (s, 3H), 1.95 (m, 6H), 1.44 (m, 6H), 1.07-1.33 (m, 8H), 0.86 (t, 3H, J=7.2).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([C:26]2[C:27]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:23]=[CH:22][N:21]=1>C(O)CCC.O1CCOCC1>[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH:18][C:20]3[N:25]=[C:24]([C:26]4[C:27]([C:32]5[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=5)=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:23]=[CH:22][N:21]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: Cc1ccc(-c2nn(C)cc2-c2ccnc(Cl)n2)cc1
Reactant: CN1CCC(COc2cccc(N)c2)CC1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: Cc1ccc(-c2nn(C)cc2-c2ccnc(Nc3cccc(OCC4CCN(C)CC4)c3)n2)cc1

Procedure:
3-(1-Methyl-piperidin-4-ylmethoxy)-phenylamine dihydrochloride (206 mg, 0.7 mmol) is suspended in 1.5 mL n-butanol and 1.5 mL dioxane. 2-Chloro-4-(1-methyl-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidine (100 mg, 0.35 mmol) is added and the mixture heated under reflux for 15 h. The yellow suspension is evaporated to dryness and the residue portioned between 8 mL 20% potassium carbonate solution and 10 mL dichloromethane. The organic phase is dried with sodium sulfate and evaporated. The crude product is purified by flash-chromatography on Silica Gel using dichloromethane/methanol 100:1.25→100:5 and then dichloromethane/methanol/conc. ammonia 100:5:0.25→100:10:0.25. The title compound is obtained as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5](N(OC)C)=[O:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[Cl:24].[Li]CCCC.[NH4+].[Cl-]>C1COCC1>[Cl:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[CH2:15][C:5]([C:4]1[CH:11]=[CH:12][N:13]=[C:2]([Cl:1])[CH:3]=1)=[O:6]
Reactant: COc1ccc(CBr)c(Cl)c1
Reactant: CON(C)C(=O)c1ccnc(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccnc(Cl)c2)c(Cl)c1
Temperature: -72 °C
Reaction time: 0.25 h

Procedure:
2-Chloro-N-methoxy-N-methyl-isonicotinamide (24.6 g, 0.127 mol) and 1-bromomethyl-2-chloro-4-methoxy-benzene [CAS Reg. No. 54788-17-9] (34.7 g, 0.147 mol) were dissolved in THF (720 ml), cooled down to −72° C. and treated over a period of 1.3 h with 1.6 M n-BuLi in hexanes (157 ml, 0.251 mol) without exceeding −70° C. The reaction mixture was stirred at −72° C. for 15 min, warmed up to −20° C. (duration: 35 min) and treated with saturated aqueous NH4Cl (400 ml). After 5 min, the reaction mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous NH4Cl, dried over MgSO4, filtered off and concentrated in vacuo to yield an orange oil (46.5 g). The residue was purified by flash chromatography (600 g silica gel, ethyl acetate/heptane 1:1) to give the title compound as orange viscous oil (17.1 g). MS (m/e, neg. ion)=294.2 [M−H+].
Reaction SMILES: C([O:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[Cl:14])C=C.C[N+]1([O-])CC[O:20]CC1.[CH3:24][C:25]([CH3:27])=[O:26]>O.[Os](=O)(=O)(=O)=O>[NH2:15][C:8]1[N:7]=[C:6]2[C:11]([N:12]=[CH:13][N:5]2[O:4][CH2:24][CH:25]([OH:26])[CH2:27][OH:20])=[C:10]([Cl:14])[N:9]=1
Reactant: C=CCOn1cnc2c(Cl)nc(N)nc21
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Nc1nc(Cl)c2ncn(OCC(O)CO)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
A solution of 9-allyloxy-2-amino-6-chloropurine (374 mg, 1.66 mmol) and osmium tetroxide (catalytic) in acetone (10 ml) and water (10 ml) was treated with 4-methylmorpholine N-oxide (290 mg, 2.49 mmol) and stirred under nitrogen at 25° C. for 16 hours. The reaction was evaporated to dryness under reduced pressure and the residue chromatographed on silica gel (eluted with acetone) affording the title compound (325 mg, 76%), m.p. 173°-5° C. UV: λmax (MeOH) 224 (ε 26,400), 310 (ε 7,600) nm. IR: υmax (KBr) 3500, 3410, 3330, 3200, 3100, 1645, 1630, 1615, 1560, 1520, 1470 cm-1. 1H NMR: δH [(CD3)2SO] 3.42 (2H, m, CH2OH), 3.78 (1H, m, CHOH), 4.20 (1H, dd, J=10.7, 7.3 Hz, CH2ON), 4.41 ( 1H, dd, J=10.7, 3.2 Hz, CH2ON), 4.74 (1H, t, J=5.7 Hz, OH), 5.14 (1H, d, J=5.2 Hz), 7.13 (2H, br.s, NH2), 8.36 (1H, s, H-8). Found: C, 36.41; H. 3.91, N, 25.91%, M+ 259.0462. C8H10ClN5O3.0.3H2O requires C, 36.18; H, 4.04; N, 26.35%, M+ 259.0469.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=2[O:4]1.[CH:19](OCC)=[O:20]>O1CCCC1>[CH:19]([CH:13]([CH2:12][C:7]1[CH:8]=[CH:9][C:10]2[O:11][CH2:3][O:4][C:5]=2[CH:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:20]
Reactant: CCOC(=O)CCc1ccc2c(c1)OCO2
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)Cc1ccc2c(c1)OCO2
Reaction time: 0.25 h

Procedure:
First, 42.4 g of 60% NaH was suspended in 500 ml of tetrahydrofuran (THF). 84.5 g (purity: 93.7% by weight) of ethyl 3-(3,4-methylenedioxyphenyl)-propionate was dissolved in 100 ml of THF and added dropwise to the suspension solution prepared above at room temperature. After the resultant suspension solution was raised in temperature to 40° C. and stirred for 15 minutes, 131 g of ethyl formate was added dropwise for 2.5 hours to the suspension solution and stirred for a further 3 hours.
Reaction SMILES: [CH3:1][S:2]([C:5]([CH3:33])([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[C:6]([NH:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)=[O:7])(=[O:4])=[O:3].FC(F)(F)S(O[C:40]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH:41]=1)(=O)=O.[C:49](=O)([O-])[O-].[Na+].[Na+].O>C(OCC)(=O)C.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.O1CCOCC1>[C:40]1([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][C:5]([CH3:33])([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]([NH:8][O:9][CH:10]([O:11][CH3:49])[CH2:15][CH2:14][CH2:13][CH3:12])=[O:7])=[CH:23][CH:22]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH:41]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(CCC(C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)OC1(C)C
Reactant: O=S(=O)(OC1=CCCCCC1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCC(OC)ONC(=O)C(C)(CCc1ccc(C2=CCCCCC2)cc1)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To flask containing 2-methanesulfonyl-2-methyl-N-(tetrahydro-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butyramide which may be prepared by the method described in Preparation 3 (800 mg, 01.66 mmol) was added cyclohept-1-en-1-yl trifluoromethanesulfonate (812 mg, 3.32 mmol), sodium carbonate (528 mg, 4.99 mmol), water (500 uL) and 1,4-dioxane (4 mL). To this mixture was added pd tetrakis (288 mg, 0.249 mmol) and the mixture was heated to 50° C. with stirring overnight. The mixture was diluted with ethyl acetate and washed with water 2×. The phases were separated, silica gel was added to the organic extracts and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford 4-(4-cyclohept-1-en-1-ylphenyl)-N-[(1-methoxypentyl)oxy]-2-methyl-2-(methylsulfonyl)butanamide as a solid 205 mg. LCMS: (M+1) 448.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:34]=[CH:33][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH3:32])[CH:25]=2)=[O:23])=[CH:20][CH:19]=1>>[CH2:31]([O:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:1][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:34][CH:33]=1)=[O:23])[CH3:32]
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Reactant: CCOc1cccc(C(=O)c2ccc(Br)cc2)c1
Product: CCOc1cccc(C(=O)c2ccc(Nc3nccc(-c4cnc5ccccn45)n3)cc2)c1
Yield: 48 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo-[1,2-a]pyridin-3-yl)pyrimidine and 4-bromo-3′-ethoxybenzophenone following the general method of Example 2. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 98:2, as the eluent affording 0.11 g (48% yield) of the title compound as a yellow solid: mp 197.3-197.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1 H), 10.17 (d, J=6.8 Hz, 1 H), 8.68 (s, 1 H), 8.53 (d, J=5.4 Hz, 1 H), 8.00 (d, J=8.5 Hz, 2 H), 7.82-7.79 (m, 3 H), 7.55-7.51 (m, 2 H), 7.47 (t, J=8.2 Hz, 1 H), 7.28 (d, J=7.5 Hz, 1 H), 7.23-7.17 (m, 3 H), 4.10 (q, J=6.8 Hz, 2 H), 1.36 (t, J=6.9 Hz, 3 H); 13C NMR (400 MHz, DMSO-d6) δ 194.4, 159.4, 158.7, 157.6, 157.4, 148.4, 145.4, 139.7, 139.4, 131.6, 129.9, 129.8, 129.8, 127.5, 22.0, 121.3, 118.6, 118.2, 117.8, 114.8, 114.2, 108.6, 63.6, 15.0; MS (ESP) m/z 436 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Li+].[Cl-].[CH2:14]([O:16][C:17](=[O:23])[C:18](OCC)=[O:19])[CH3:15]>C1COCC1>[O:19]=[C:18]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[C:17]([O:16][CH2:14][CH3:15])=[O:23]
Reactant: Ic1ccc2ncccc2c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc2ncccc2c1
Temperature: -20 °C
Yield: 70 %

Procedure:
Under inert atmosphere 255 g 6-iodoquinoline (1 mol) is dissolved in THF and cooled to −20° C. and 808 g IpMgCl.LiCl (1.1 moles) is added. This cold solution is added to a solution of 438 g diethyloxalate (3 moles) in 1800 mL THF at low temperature (−78° C.). The reaction mixture is heated to 0° C. and is quenched with a saturated ammonium acetate solution (0.8 L/mole). Ethyl oxo(quinolin-6-yl)acetate is extracted with ethyl acetate (1 L) from this mixture. After chromatography (silica, heptanes/ethyl acetate) ethyl oxo(quinolin-6-yl)acetate was obtained in 70% yield.
Reaction SMILES: [N:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH:18]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:2]1[N:1]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[CH:18][C:9]3=[C:10]2[C:5](=[CH:6][CH:7]=[CH:8]3)[CH2:4][CH2:3]1
Reactant: O=CNc1ccccc1N1CCCc2ccccc21
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: C1=Nc2ccccc2N2CCCc3cccc1c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a stirred solution of 32.8 g of N-[2-(1,2,3,4-tetrahydro-1-quinolinyl)phenyl]formamide in 500 ml of dry toluene was added 99.6 g of phosphorus oxychloride. The initial solution was heated under nitrogen for 5 hours at 75° and thereafter stirred at room temperature overnight. The solvent and excess phosphorus oxychloride were removed at aspirator pressure with mild heating. The residue was washed twice with ether and twice with hexane to remove traces of phosphorus oxychloride. The residue was triturated and heated with 25 ml of ethanol. The ethanol was removed on a rotary evaporator and the resulting material was treated with 1 liter of ethyl acetate and 50 ml of dilute sodium hydroxide solution. The two phases were stirred vigorously until the residue was dissolved (except for some interfacial material). The dark aqueous layer was separated and back-extracted with 250 ml of ethyl acetate. The combined organic extracts were filtered, washed four times with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to leave 25.2 g. A part of this material (20 g) was purified further by chromatography on 500 g of silica gel (column packed in dichloromethane) using dichloromethane as eluant. The appropriate fractions were combined and concentrated to afford 9.1 g of crystalline product. This material was recrystallized from a small volume of toluene to provide 4.9 g, m.p. 118°-120° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4Cl)c3)csc12
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1ccccc1Cl

Procedure:
3-[3-(2-Chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 3-[3-(2-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 11 supra) and ethanolamine (Aldrich) following the procedure described in Example 16 as a light-yellow solid.