Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(O[C:15]([N:17](C)[C@@H:18]([CH3:49])[C:19]([NH:21][C:22]3[CH:48]=[CH:47][C:25]([CH2:26][C@@H:27]4[CH2:31][CH2:30][C@H:29]([C@H:32]([OH:39])[C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[N:28]4[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:24][CH:23]=3)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C1COCC1.ClCCl>[OH:39][C@H:32]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C@H:29]1[CH2:30][CH2:31][C@@H:27]([CH2:26][C:25]2[CH:47]=[CH:48][C:22]([NH:21][C:19](=[O:20])[C@@H:18]([NH:17][CH3:15])[CH3:49])=[CH:23][CH:24]=2)[N:28]1[C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41]
Reactant: C[C@@H](C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3cccnc3)N2C(=O)OC(C)(C)C)cc1)N(C)C(=O)OC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CN[C@@H](C)C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 0.410 g (0.593 mmol) of tert-butyl(2S,5R)-2-[4-({(2S)-2-[[(9H-fluoren-9-yloxy)carbonyl](methyl)amino]propanoyl}amino)benzyl]-5-[(R)-hydroxy(pyridin-3-yl)methyl]pyrrolidine-1-carboxylate from step A in 3 mL of anhydrous THF was 0.152 g (1.78 mmol) of piperidine. The resulting mixture was stirred at ambient temperature for 24 h and then was diluted with 25 mL of dichloromethane. The mixture was washed with water then dried over magnesium sulfate. The mixture was filtered and evaporated to dryness in vacuo to afford the crude title compound which was used without further purification. LC-MS: m/z (ES) 469 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[CH2:11][CH2:12][C:13]#[CH:14].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:10](=[O:15])[CH2:11][CH2:12][C:13]#[CH:14])[C:17](=[O:16])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: C#CCCC(=O)Nc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1F
Yield: 99.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 34(B), from N-(2,4-difluorophenyl)pent-4-ynamide (630 mg, 3.01 mmol) and (BOC)2O (789 mg, 3.61 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, 100% DCM as eluent) to afford 924 mg of tert-butyl 2,4-difluorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield: 99%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].Cl[CH2:12]Cl.[N+](=C)=[N-]>CCOCC>[CH3:12][O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10]
Reactant: ClCCl
Reactant: C#CCN1CC[C@H](O)C1=O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: C#CCN1CC[C@H](OC)C1=O

Procedure:
A mixture of 2.0 g of (S)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 70 g of silica gel and 200 ml of dichloromethane was cooled in an ice bath. A 300 ml solution of diazomethane in ether was added portion-wise. The reaction was filtered, washed with methanol and concentrated in vacuo. The residue was purified by chromatography (silica gel), giving 700 mg of (S)-3-methoxy-1-(2-propynyl)-2-pyrrolidinone, [α]D26 =-71° (dichloromethane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]=[CH:6][C@@H:7]([CH3:29])[C@@H:8]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:11][OH:12])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[CH:5]=[CH:6][C@@H:7]([CH3:29])[C@@H:8]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15])[CH:11]=[O:12])[CH3:2]
Reactant: CCOC(=O)C=C[C@@H](C)[C@H](C[C@@H](CO)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)C=C[C@@H](C)[C@H](C[C@@H](C=O)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h

Procedure:
The alcohol 59 (3.86 g, 8.34 mmol) in CH2Cl2 (20 mL) was treated with Dess-Martin periodinane (5.3 g, 12.5 mmol). After 1 h, the mixture was quenched with saturated NaHCO3 (50 mL). The aqueous layer was extracted with ethyl ether (20 mL×2) and the combined extracts were dried over anhydrous MgSO4. Filtration and concentration followed by short flash column chromatography (hexane/EtOAc 4:1) to remove the residue from Dess-Martin reagent provided the aldehyde as a colorless oil: 1H NMR (300 MHz, CDCl3) 9.53 (s, 1H), 7.02 dd, J=15.9, 6.6 Hz, 1H), 5.77 (dd, J=15.9, 1.4 Hz, 1H), 4.15 (dq, J=1.0, 7.2 Hz, 2H), 4.07 (ddd, J=6.4, 4.8, 1.4 Hz, 1H), 3.84 (ddd, J=8.6, 6. 8, 4.4 Hz, 1H), 2.52 (m, 1H), 1.66 (m, 2H), 1.25 (t, J=7.1 Hz, 3H), 0.99 (d, J=6.9 Hz, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H), 0.03 (s, 6H).
Reaction SMILES: [CH2:1]([C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[S:10]1C=CC=C1CC(O)=O.[CH3:19][CH2:20][O:21]CC>>[C:20]([S:10][CH2:9][CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:21])[CH3:19]
Reactant: C=C(CC)C(=O)OCC
Reactant: CCOCC
Reactant: O=C(O)Cc1cccs1
Product: CCOC(=O)C(CC)CSC(C)=O
Temperature: 65 °C
Reaction time: 36 h

Procedure:
Ethyl 2-ethyl-2-propenoate (Arch. Pharm., 313, 846 (1980)) (5 g, 39 mmol) was diluted with 5.6 mL (78 mmol) of thiolacetic acid and stirred at 65° C. for 36 hours. The mixture was then diluted with Et2O, washed with H2O and the organic phase was dried with Na2SO4. Evaporation to dryness yielded the title material as an orange oil which was used as such for the next step.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1.[C:39](O)(=[O:41])[CH3:40].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:39]([NH:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)O
Reactant: N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
(1R*,2R*,5S*,6R*)-6-Amino-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 108; 475 mg, 0.89 mmol), glacial acetic acid (0.076 ml, 1.34 mmol), triethylamine (0.14 ml, 0.98 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (257 mg, 1.34 mmol) and 4-dimethylaminopyridine (2 crystals) were combined in dichloromethane (4 ml) and stirred overnight at room temperature. The reaction mixture was washed with water and extracted with dichloromethane (×3). The organics were dried (MgSO4), and concentrated in vacuo to give the title compound as a yellow oil (384 mg, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Reactant: Fc1ccc(CBr)cc1
Product: N#Cc1ccc(N(Cc2ccc(F)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-fluorobenzyl bromide
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[CH:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C>N1C=CC=CC=1>[C:1]([OH:7])(=[O:6])/[CH:2]=[CH:3]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC=O
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: CCCCCC/C=C/C(=O)O
Temperature: 0 °C
Reaction time: 60 h
Yield: 64 %

Procedure:
Malonic acid (342 g, 3.3 mole) is dissolved in 555 ml of dry pyridine (slightly exothermic). The mixture is cooled in ice water and n-heptaldehyde (342 g, 3.0 mole) is added with stirring. After the addition is complete, the ice bath is removed and the mixture allowed to stand at room temperature for 60 hours, and then heated on a steam bath for 8 hours. The reaction mixture is poured onto an equal volume of water. The organic layer is separated, washed with 900 ml 25% HCl, taken up in benzene, washed with water and dried. Distillation under vacuum gave trans-2-nonenoic acid, b.p. 123°C/2 mm, 297 g, 64% yield.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([OH:27])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([O:27][C:2]2[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:17]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1O
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C#N)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2CCC(=O)O)c(C#N)c1

Procedure:
The title compound was prepared by the method of example 3 step viii) using the product from step iii) and the product from example 35 step ii).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:3]=1[CH:4]=[N:5][NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].Cl>CN1C(=O)CCC1.O>[I:20][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][CH:18]=1)[N:6]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[N:5]=[CH:4]2
Reactant: O=C(O)c1ccc(NN=Cc2cc(I)ccc2F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Yield: 94.1 %

Procedure:
4-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (141d, 3.42 g, 8.9 mmol) and potassium tert-butoxide (2.29 g, 20.5 mmol) was stirred under argon atmosphere in NMP (45 mL) at 150° C. for 15 min. The mixture was then cooled, diluted with water and acidified with aqueous HCl (1.7 M). The precipitate that formed was collected by filtration and dried in vacuo to give crude 4-(5-iodo-1H-indazol-1-yl)benzoic acid (3.05 g, 94%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]#[C:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)=[CH:7][N:6]=1)=[O:4].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]#[C:13][CH2:14][OH:15])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(C#CCO[Si](C)(C)C(C)(C)C)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1ncc(C#CCO)cc1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-amino-5-[3-(tert-butyl-dimethyl-silanyloxy)-prop-1-ynyl)-pyridine-2-carboxylic acid methyl ester (711 mg, 2.22 mmol) in DCM (6 ml) was added 10.2 ml TFA (133 mmol) at 0° C. and the mixture was stirred at room temperature for 17 h. To the mixture was added toluene (18 ml) and the solvents were evaporated. The residue was dissolved in EtOAc (66 ml) and washed with aq. 1M Na2CO3 solution, the aq. Phase was extracted back with EtOAc. The combined organic layers were washed with half-saturated aq. sodium chloride, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (DCM to DCM/MeOH 94:6) to provide the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:17][C:18](O)=[O:19])[S:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CO>C1COCC1>[Cl:14][C:13]1[CH:12]=[C:11]([Cl:15])[CH:10]=[C:9]([Cl:16])[C:8]=1[S:5]([N:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:17][CH2:18][OH:19])(=[O:7])=[O:6]
Reactant: O=C(O)CN(C1CC1)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(c1c(Cl)cc(Cl)cc1Cl)N(CCO)C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 2 M soln. of borane-dimethylsulfide complex in THF (4.96 ml, 9.92 mmol) was added to a soln. of [cyclopropyl-(2,4,6-trichlorobenzenesulfonyl)-amino]-acetic acid (1.77 g, 4.96 mmol) in anhydrous THF (30 ml) and the mixture was stirred for 1 h, while cooling with ice. The reaction mixture was stirred at RT for approx. 18 h, MeOH (2 ml) was then cautiously added and the mixture was concentrated i. vac. MeOH was repeatedly added to the residue and the mixture concentrated i. vac. 5% strength NaHCO3 soln. was added to the crude product, the mixture was extracted with EtOAc and the organic phase was dried with Na2SO4 and concentrated i. vac. Yield: 1.02 g (60%)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1COCC1>[C:1]([C:4]1[CH:5]=[N:6][N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(=[S:32])[NH2:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ncc(C(N)=S)c1-c1ccc(F)cc1
Yield: 69.4 %

Procedure:
A solution of the mixture (711 mg, 2.33 mmol) obtained in step 5 and Lawesson's reagent (754 mg, 1.86 mmol) in THF (10 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was treated with ethyl acetate and diethyl ether to give a mixture (415 mg, 55%) of tert-butyl 4-carbamothioyl-5-(4-fluorophenyl)-1H-pyrazole-1-carboxylate and tert-butyl 4-carbamothioyl-3-(4-fluorophenyl)-1H-pyrazole-1-carboxylate as a yellow powder.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[Cl:16][C:17]1[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>C1COCC1>[Cl:16][C:17]1[S:21][C:20]([S:22]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]([CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:6]2=[O:14])(=[O:24])=[O:23])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CN(C)CCn1c(=O)[nH]c2ccccc21
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCn1c(=O)n(S(=O)(=O)c2ccc(Cl)s2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-[2-(dimethylamino)ethyl]-1,3-dihydrobenzimidazol-2-one (20 mg, 0.1 mmol) in THF at room temperature is treated with (5-chlorothien-2-yl)sulfonyl chloride (26 mg, 0.12 mmol) followed by diisopropylethylamine (25 uL, 0.2 mmol) and dimethylaminopyridine (5 mg), stirred at room temperature for 16 hours and concentrated in vacuo. The resultant residue is dissolved in a mixture of dimethylsulfoxide, methanol and water and purified by Gilson1 preparative HPLC to give the title product, 16 mg, [M+H] 386, retention time (RT) 2.83 minutes. 1Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1>O1CCCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[NH2:12])=[CH:16][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(Cc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (89 mg, 4.61 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (500 mg, 3.08 mmol; Aldrich) was added in portions. After 5 minutes the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 1-(bromomethyl)-4-fluorobenzene (0.416 mL, 3.38 mmol; Aldrich) was added dropwise. After 30 minutes the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL), extracted with dichloromethane (2×10 mL) and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 218 (M+H−NH3)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[CH:17](O)=[O:18].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[F:15][C:9]1[CH:10]=[CH:11][C:12]([NH:14][CH:17]=[O:18])=[CH:13][C:8]=1[NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N)ccc1F
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(NC=O)ccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl(5-amino-2-fluorophenyl)carbamate (10.0 g, 44.2 mmol) in tetrahydrofuran (60 mL) was added a mixture of formic acid (8.34 mL, 221 mmol) and acetic anhydride (5.01 mL, 53.0 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (10 mL), filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure to give tert-butyl [2-fluoro-5-(formylamino)phenyl]carbamate as a brown oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1(C(=CC=CC=1)O)O.C(=O)([O-])[O-].[K+].[K+]>>[C:3]1([CH3:12])[C:4]([S:7]([Cl:10])(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1S(=O)(=O)Cl
Yield: 42.6 %

Procedure:
p-Toluenesulfonyl chloride (2.88 g, 15.08 mmol) was added in two portions, 30 minutes apart, to a stirring solution of pyrocatechol (1.49 g, 13.53 mmol) and potassium carbonate (2.05 g, 14.85 mmol). The solution was heated to reflux for 4 hours. The cooled solution was evaporated under reduced pressure, and the residue was taken up in ethyl acetate (100 cm3) and water (100 cm3). The aqueous layer was extracted with ethyl acetate (2×100 cm3), and the combined extracts were washed with brine (2×200 cm3), dried (MgSO4), and evaporated under reduced pressure. The residue was triturated with diethyl ether (2×20 cm3), and the precipitate was removed by filtration to give unreacted toluenesulfonyl chloride (1.10 g). The filtrate was evaporated under reduced pressure. The yellow crystals were recrystallized from ethyl acetate and heptane to give mono protected pyrocatechol, (1.65 g, 53%) as clear crystalline squares, mp 80-84° C.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:2][CH3:1])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Reactant: CN
Solvent: CCO
Product: CNCCCOc1ccc(OCc2ccccc2)cc1
Yield: 71 %

Procedure:
To 150 ml of ethanol containing methylamine (16 g) was added 1-benzyloxy-4-(3-bromopropyloxy)benzene (14 g). The solution was heated for 12 hours at 100° under nitrogen at 1000 psi. The solvent was evaporated in vacuo and the residue treated with 20% sodium hydroxide to ~pH10. The oil was extracted with ethyl acetate and converted in its hydrochloride salt in the usual manner to give 8.4 g (70%) of 1-benzyloxy-4-(3-methylaminopropoxy)benzene as its hydrochloride salt, mp 202°-204.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:9][O:8][C:5]1[N:4]=[CH:3][C:2]([NH:1][C:18](=[O:19])[CH2:17][Cl:16])=[CH:7][CH:6]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)CCl)cn1
Reaction time: 0.25 h

Procedure:
A solution of 3-amino-6-methoxypyridine (25.0 grams) in absolute ether (160 ml) was charged into a glass reaction flask equipped with a mechanical stirrer, dropping funnel and thermometer. The solution was cooled to a temperature of about 0° C and pyridine (18.1 ml) was added thereto. A solution of chloroacetyl chloride (17.0 ml) in ether (40 ml) was then slowly added to the flask with stirring over a period of about 15 minutes resulting in the formation of a precipitate. The temperature of the reaction mixture was kept between about 0° to 5° C during the addition of the chloroacetyl chloride. After completion of the addition stirring was continued for a period of about 30 minutes. The solid precipitate which had formed was then recovered by filtration and was washed with aqueous sodium bicarbonate and then with water. The washed product was then dried to yield the desired product N-(6-methoxy-3-pyridyl)-α-chloroacetamide as a white solid having a melting point of 117° to 118° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>O>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1cccc(O)c1
Solvent: O
Product: O=C(Nc1cccc(O)c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 3-aminophenol (Aldrich) according to the method described in Example 2. Melting Point: 158-160° C. (water)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:37])[N:7]3[CH2:14][C:13]4([CH2:19][CH2:18][N:17](C(OCC5C6C=CC=CC=6C6C5=CC=CC=6)=O)[CH2:16][CH2:15]4)[CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.N1CCCCC1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:37])[N:7]3[CH2:14][C:13]4([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC2(CC1)Cc1nc3cc(Br)ccc3c(=O)n1C2
Solvent: C1CCNCC1
Solvent: O
Solvent: ClCCl
Product: O=c1c2ccc(Br)cc2nc2n1CC1(CCNCC1)C2

Procedure:
A solution of (9H-fluoren-9-yl)methyl 6′-bromo-9′-oxo-3′,9′-dihydro-1′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]quinazoline]-1-carboxylate (0.6 g, 1.1 mmol, 1 equiv) and piperidine (4 mL) in DCM (50 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.