Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:35]5[CH2:34][CH2:33][NH:32][CH:31]([C:27]6[O:26][CH:30]=[CH:29][CH:28]=6)[CH2:36]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1coc(C2CNCCN2)c1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CCNC(c5ccco5)C4)c(F)cc3cc2c1=O
Yield: 89.5 %

Procedure:
(RS)-1-Cyclopropyl-3-ethoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 1-cyclopropyl-7,8-difluoro-3-ethoxycarbonyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.05 g) and (RS)-2-(2-furyl)piperazine (0.6 g). (RS)-1-Cyclopropyl-3-ethoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.3 g) is obtained in the form of a yellow solid, m.p. 182° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[H-].[Na+].Cl[S:21]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=1)(=[O:23])=[O:22].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:21]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=1)(=[O:22])=[O:23]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2nccs2)cc1F
Temperature: 25 °C
Yield: 102.2 %

Procedure:
To an ice cooled solution of N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 9.0 g, 35.9 mmol, 1 eq) in THF (80 ml) was added 60% sodium hydride (2.15 g, 53.9 mmol, 1.5 eq) portionwise. The mixture was stirred for 30 minutes before the addition of methyl 4-(chlorosulfonyl)-2-fluorobenzoate (Preparation 13, 9.06 g, 35.9 mmol, 1 eq) then stirred for a further hour at room temperature. The reaction mixture was added to water (20 ml) and the THF evaporated in vacuo. The residue was diluted with water (200 ml), extracted into DCM (3×200 ml), dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound as an orange solid (17.1 g, 36.7 mmol).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:18])=[O:3].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>C(O)C>[O:3]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:18])[CH:1]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1ccc(OCc2ccccc2)cc1O
Reaction time: 0.17 h
Yield: 166.8 %

Procedure:
17.63 g (72.6 mmoles) of 2-hydroxy-4-benzyloxyacetophenone, 17.60 g (165.8 mmoles) of benzaldehyde and 35.20 g of 50% strength sodium hydroxide solution in 200 ml of ethanol were stirred for 3 days, during which crystals precipitated. The crystal sludge was acidified with 100 ml of 5N hydrochloric acid and was stirred for 10 minutes. The mixture was filtered with suction to give 40.0 g of moist crystals. The crude product was recrystallized from 800 ml of ethanol.
Reaction SMILES: N(C(C1C=C(C=CC=1)C(C)=C)(C)C)=C=O.OCCCCCCOC([C:26]1[C:27](=[O:41])[O:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[C:31](N(CC)CC)[CH:30]=2)=O.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(Cl)Cl>[O:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:26][C:27]1=[O:41]
Reactant: CCN(CC)c1ccc2cc(C(=O)OCCCCCCO)c(=O)oc2c1
Agent: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Product: O=c1ccc2ccccc2o1

Procedure:
In this scheme, m-(2-isocyanatoprop-2-yl)-α-methylstyrene (23) and m/p-methylstyrene (24) are polymerised under the action of AIBN as free-radical initiator in toluene at 100° to 110° C. to yield the copolymer (25). The preferred molar proportion x of comonomer (23) is between 0 and 60%. The copolymer (25) obtainable in this manner reacts with 3-(6-hydroxyhexoxycarbonyl)-7-diethylaminocoumarin (26) in the presence of catalytic quantities of dibutyltin dilaurate (DBZD) in refluxing methylene chloride, wherein the copolymer (27) may be obtained with a lateral coumarin luminophore (Et=ethyl).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[N:6][N:5]2[C:11]=1[S:12]([NH2:15])(=[O:14])=[O:13].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[N:6][N:5]2[C:11]=1[S:12]([N:15]=[CH:18][N:19]([CH3:21])[CH3:20])(=[O:14])=[O:13]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12
Solvent: Cc1ccccc1
Product: CN(C)C=NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12
Temperature: 25 °C

Procedure:
2,6-Dichloroimidazo[1,2-b]pyridazin-3-ylsulfonamide (2.00 g, 6.22 mmol) and N,N-Dimethylformamide dimethyl acetal (1.80 ml, 13.5 mmol) were heated under reflux for 4 hours in toluene (20.0 ml). The resulting reaction solution was left to cool to room temperature, and concentrated to dryness under reduced pressure to give the title compound as pale yellow crystals. The yield was 2.36 g (100%).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:16]1[C:17]2[NH:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:14]([C:18]2[CH:23]=[C:22]([C:24](=[O:26])[CH3:25])[CH:21]=[N:20][CH:19]=2)[CH:15]=1
Reactant: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
6-(5-Acetyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (500 mg, 1.4 mmol) is dissolved in 20 mL of 20% TFA in DCM. The mixture is stirred at room temperature for 16 hrs. Then the solvent and the extra reagent are removed and the residue is purified by reversed phase chromatography to give 135 mg of 1-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-ethanone
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:24]=2)=[C:13]([C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]([C:32]([F:35])([F:34])[F:33])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CO>[CH2:3]([N:10]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:24]=2)=[C:13]([CH:25]([OH:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]([C:32]([F:33])([F:35])[F:34])=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=O)c1c(C(F)(F)F)nn(Cc2ccccc2)c1-c1ccc2c(c1)CCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(O)c1c(C(F)(F)F)nn(Cc2ccccc2)c1-c1ccc2c(c1)CCCO2
Reaction time: 2 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, sodium borohydride (6.44 mg, 0.17 mmol) was added portionwise to a solution of ethyl 2-[1-benzyl-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-oxoacetate (49e) (78 mg, 0.17 mmol) in anhydrous methanol (2 mL). After 2 hours stirring, water was added (3 mL). The methanol was removed under reduced pressure, and the aqueous layer was extracted with ethyl acetate (2×5 mL). The organic layer was successively washed with water (3 mL) and brine (3 mL), before being dried over sodium sulfate and concentrated in vacuo to provide the desired alcohol (49f) (70 mg, 0.17 mmol, 89%) which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:36]([O:40][C:41]([NH:43][C@H:44]1[CH2:48][CH2:47][NH:46][CH2:45]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[C:36]([O:40][C:41](=[O:42])[NH:43][C@H:44]1[CH2:48][CH2:47][N:46]([S:23]([C:21]2[CH:20]=[CH:19][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:22]=2)(=[O:25])=[O:24])[CH2:45]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1

Procedure:
Following the same procedure in Example 1, step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (2 g, 5 mmol), N,N-diisopropylethylamine (3.5 mL, 20 mmol) and (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (1.4 g, 7.5 mmol) in (10 mL) methylene chloride. The crude product was purified by MPLC on silica gel using 8-70% EtOAc/hexane. Yield: 2.77 g (100%). 1H NMR (400 MHz, METHANOL-D4) δ 1.35 (s, 9 H) 1.52 (d, J=11.72 Hz, 4 H) 1.58 (s, 9 H) 1.62-1.73 (m, 4 H) 1.75-1.81 (m, 1 H) 1.93-2.00 (m, 1 H) 3.03-3.10 (m, 1 H) 3.24-3.29 (m, 2 H) 3.35-3.47 (m, 3 H) 4.40 (d, J=7.42 Hz, 2 H) 7.71-7.78 (m, 2 H) 8.09 (d, J=1.37 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:16]=[CH:15][C:14]=2[F:26])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CC(C)=O>[C:5]([C:4]1[C:3]([NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:16]=[CH:15][C:14]=2[F:26])=[C:2]([F:1])[CH:9]=[CH:8][C:7]=1[O:10][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])#[N:6]
Reactant: N#Cc1c(O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a solution of 3-fluoro-2-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-6-hydroxy-benzonitrile (360 mg, 1.0 mmol, 1 eq) in acetone was added Cs2CO3 (651.6 mg, 2.0 mmol, 2 eq). The reaction was stirred for 30 min at room temperature then isopropyl 2-bromoacetate (221 mg, 1.2 mmol, 1.2 eq) was added. The reaction was stirred for a further 2 h, then quenched with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 50:1 to 10:1) to give the title compound as a colorless oil (270 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH3:7][N:8]=[C:9]=[O:10].O>CN(C=O)C>[CH3:7][NH:8][C:9](=[O:10])[NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1
Reactant: CN=C=O
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Nc1nnn[nH]1
Temperature: 100 °C
Yield: 89.8 %

Procedure:
5-Aminotetrazole (5.5 g, 0.065 mole) was dissolved in 75 ml of DMF. On the addition of methylisocyanate (5 g) the temperature began to slowly rise to 40° C. with the formation of a white solid. The solution was heated for 90 minutes at 100° C. and on cooling, poured into cold water. The resulting white solid was filtered, water washed and dried to give 8.3 g of product which softened at 264°-267° C. but was not melted completely at 305° C.
Reaction SMILES: [F:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>[Cu](Cl)Cl.C(Cl)Cl>[F:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH:3]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=CC(F)c1ccccc1
Agent: Cl[Cu]Cl
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/C(F)c1ccccc1
Temperature: 23 °C
Reaction time: 0.03 h
Yield: 30.1 %

Procedure:
To a 500 mL RBF containing 2-fluoro-2-phenylacetaldehyde (320.00 mg, 2316.5 μmol) was added DCM (10 mL) and the mixture was allowed to stir at 23° C. for 2 min. At this time, (R)-2-methylpropane-2-sulfinamide (364.99 mg, 3011.5 μmol) was added in one portion to the mixture followed by copper(II) chloride (856.51 mg, 6370.4 μmol) at 5:30 μm. The reaction was allowed to stir overnight and then filtered through a plug of celite over silica gel. The solvent was removed and the crude residue was purified on a silica gel column (15 to 35% EtOAc in hexanes) to give the product (168 mg, 30%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1)[CH:10]([CH3:12])[CH3:11].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>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].O1CCCC1.O.CO>[CH2:9]([N:13]1[CH:17]=[C:16]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:15]=[N:14]1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)Cn1cc(-c2ccc(N)cc2)cn1
Temperature: 85 °C

Procedure:
A suspension of 4-bromoaniline (406 mg, 2.362 mmol), 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (650 mg, 2.60 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (57.9 mg, 0.071 mmol) and sodium carbonate (526 mg, 4.96 mmol) in a 6:2:1 mixture of tetrahydrofuran/water/methanol (12 ml) in a microwave vial was subjected to three vacuum/nitrogen purge cycles. The vial was sealed and heated in an oil bath at 85° C. overnight. The mixture was dissolved in a mixture of ethyl acetate (45 ml) and water (20 ml), and the separated aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (20 ml), dried with magnesium sulfate, filtered and concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.CN1C(=O)CCC1.[CH2:21]([Mg]Cl)[CH:22]([CH3:24])[CH3:23]>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:5]=1
Reactant: CC(C)C[Mg]Cl
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(CC(C)C)nc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (1.66 g, 8.23 mmol) in dry THF (50 mL), NMP (1.1 mL, 11.5 mmol) is added. The mixture is cooled to −74° C. before a 2 M solution of isobutylmagnesium chloride (7 mL, 14.0 mmol) in THF is added. Stirring is continued at −75° C. for 1 h, before the mixture is warmed to 0° C. The reaction is quenched by carefully adding water. The mixture is diluted with EA, washed with water followed by brine, dried over MgSO4, filtered and concentrated to give crude 2-isobutyl-6-methoxy-isonicotinic acid methyl ester (1.20 g) as an oil; LC-MS: tR=1.37 min; [M+1]+=224.12.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([OH:8])[CH3:7])[CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[CH:15]=[C:14]([O:8][CH:6]([CH:3]2[CH2:5][CH2:4]2)[CH3:7])[N:13]=[CH:12][N:11]=1
Reactant: CC(O)C1CC1
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(Oc1cc(Cl)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.19 g of 1-cyclopropylethanol in tetrahydrofuran was added dropwise at room temperature. After stirring at room temperature for 10 minutes, 0.5 ml of a solution containing 0.3 g of 4,6-dichloropyrimidine in tetrahydrofuran was added dropwise at 0° C., followed by stirring at the same temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product of 4-chloro-6-(1-cyclopropylethoxy)pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[C:18]([CH2:23][NH2:24])=[N:19][CH:20]=[CH:21][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:24][CH2:23][C:18]2[C:17]([CH3:16])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1CN
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 4-formylpiperidine-1-carboxylic acid tert-butyl ester (Bioorg. Med. Chem. Lett. 2002, 12, 1785-1790), C-(3-methylpyridin-2-yl)-methylamine and NaBH(OAc)3 in CH2Cl2 gave 4-{[(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:18][CH3:17])=[O:10])[CH2:6]1
Reactant: Cc1cccc(Cl)c1OC1CN(C(=O)Cl)C1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2c(C)cccc2Cl)C1
Reaction time: 72 h
Yield: 146.6 %

Procedure:
A stirred solution of 3.9 g (0.015 mole) of 3-(2-chloro-6-methylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 3.5 mL (0.045 mole) of 40% aqueous monomethylamine. After stirring for 72 h the reaction mixture was diluted with 200 mL of water and the precipitated solid collected by filtration to give 5.6 g of wet white product. The crude product was recrystallized (after drying) from benzene/ligroin, yielding 2.9 g (75.9%) of white crystalline product, mp 119°-121° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 6.4 %

Procedure:
To a solution of (R)-tert-butyl 2-((S)-(2-aminoethoxy)(3-chlorophenyl)methyl)morpholine-4-carboxylate (1.62 g, 4.38 mmol) and DMAP (280 mg) in dry CH2Cl2 (15 mL), Et3N (1.33 g, 13.14 mmol) was added. The resulting mixture was cooled to 0-5° C. in an ice-water bath and a solution of methyl chloroformate (2.06 g, 21.9 mmol) in dry CH2Cl2 (5 mL) was added dropwise. The reaction mixture was stirred for 1-2 h at 0-5° C. Tlc showed the starting material had disappeared. Water (30 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with 10% aq citric acid (2×10 mL) and brine, dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford the desired product (120 mg, 6%). 1H NMR (MeOD) 1.45 (s, 9H), 2.80-2.92 (m, 2H), 3.0 (m, 1H), 3.60 (s, 3H), 4.15 (m, 2H), 4.25 (d, 1H), 7.20-7.35 (m, 4H).
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[C:8]([N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:15]3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:4][CH2:3][CH2:2]1.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[CH2:34][C:35](O)=[O:36]>>[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([N:14]3[CH2:19][CH2:18][N:17]([C:35](=[O:36])[CH2:34][C:29]4[N:30]=[CH:31][CH:32]=[CH:33][N:28]=4)[C@@H:16]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[CH2:15]3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)Cc1ncccn1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccc(F)cc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3ncccn3)[C@@H](Cc3ccc(F)cc3)C2)cc1OC1CCC1
Yield: 81 %

Procedure:
Prepared by the method outlined for Example 189 using (S)-1-(3-cyclobutoxy-4-methoxyphenyl)-3-(4-fluorobenzyl)piperazine and 2-(pyrimidin-2-yl)acetic acid as starting materials. Product was obtained as a colorless solid (81%). LC/MS 3.59 min, [M+1]+ 491.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[O:25][C:26]4([CH2:30][CH2:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N+:14]([O-:49])=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=4)[O:25][C:26]4([CH2:30][CH2:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)c1c2c(c3c([n+]1[O-])CC(C)(C)C[C@@H]3O[Si](C)(C)C(C)(C)C)C1(CCCC1)O[C@@H]2c1ccc(C(F)(F)F)cc1
Reaction time: 18 h

Procedure:
280 mg (3′R,9′S)-9′-(tert-butyldimethylsilyloxy)-4′-isopropyl-7′,7′-dimethyl-3′-(4-(trifluoromethyl)phenyl)-6′,7′,8′,9′-tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinoline] are dissolved in 5 ml chloroform and treated with 80 mg of meta-chloroperbenzoic acid (MCPBA) (<77%). The mixture is stirred for 18 hours and then partitioned between dichloromethane and a solution of sodium sulfite in water (5%). The organic phase is washed with saturated aqueous sodium bicarbonate and dried with sodium sulphate. After evaporation of the solvents the residue is chromatographed on silica gel (hexane/ethylacetate 4:1).
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[CH3:31][O:32]C1C=CC=CC=1C=O>>[CH3:31][O:32][C:29]1[CH:30]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccccc1C=O
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: COc1ccccc1CNCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 2-methoxybenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 422 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (1H, br. s.) 10.27 (1H, s) 8.04 (1H, t, J=5.56 Hz) 7.99 (1H, d, J=5.47 Hz) 7.75 (1H, d, J=5.47 Hz) 7.45 (1H, d, J=5.27 Hz) 7.23-7.32 (2H, m) 7.13-7.21 (1H, m) 6.91 (1H, d, J=8.00 Hz) 6.81-6.87 (1H, m) 6.79 (1H, d, J=5.47 Hz) 6.40 (1H, dd, J=3.51, 1.76 Hz) 3.72 (3H, s) 3.67 (2H, s) 3.34 (2H, q, J=6.31 Hz) 2.65 (2H, t, J=6.35 Hz)