Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH:22]=[O:23])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:24][Mg]Br.CCOCC>O1CCCC1>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]=[C:14]([CH:22]([OH:23])[CH3:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine-4-carbaldehyde (described in Example 1, Step 3) (0.20 g, 0.60 mmol) was dissolved in tetrahydrofuran (6.00 mL) and was cooled to −78° C., then 3.0 M methylmagnesium bromide in ether (0.30 mL, 0.90 mmol) was added. The reaction was stirred at −78° C. for 1 hour at which time LCMS analysis showed that it was mostly done. The reaction was quenched with sat. NH4Cl and was and partitioned between water and EtOAc, the phases were separated and the aqueous phase was washed with additional EtOAc. The combined organic phase was washed with water, then sat. NaCl, dried over MgSO4 and filtered and then the solvent removed in vacuo to leave the crude product. The crude material used in the next reaction without purification. MS: 371 (M+Na+), 349 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:22]12[NH:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][CH2:24][CH2:23]2.N12CCCN=C1CCCCC2>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:27]4[CH2:28][CH:22]5[NH:30][CH2:29][CH:26]4[CH2:25][CH2:24][CH2:23]5)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CC2CNC(C1)CN2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A solution of 0.53 g (2.0 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.44 g (2.2 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 10 ml of pyridine was heated under reflux for 4 hr. The reaction mixture was cooled to room temperature and the solid was filtered and washed with ethanol to yield 0.39 g of the title compound, mp 273°-276° dec.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19](O)=[O:20])[CH2:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22].Cl.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:22].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19]([N:33]3[CH2:34][CH2:35][N:30]([CH2:29][C:28]4[CH:27]=[C:26]([O:25][CH3:24])[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=4)[CH2:31][CH2:32]3)=[O:20])[CH2:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: O=C(O)C1=Cc2ccc(OCc3ccccc3)cc2CC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(=O)C3=Cc4ccc(OCc5ccccc5)cc4CC3)CC2)cc(OC)c1OC
Yield: 74.4 %

Procedure:
Using 7-benzyloxy-1,2-dihydro-3-naphthoic acid (0.4 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.76 g), triethylamine (0.6 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (0.75 ml), an amidation as that described in Example 6 is carried out. The reaction product is purified by silica gel column chromatography (hexane:acetone=1:1-1:2) and converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether to yield 1-(7-benzyloxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.6 g) as colorless crystals, m.p. 196°-199° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([O:17][S:18](=[O:25])(=[O:24])[N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH3:26]N(C=O)C.C(=O)(OC)OC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([O:17][S:18](=[O:24])(=[O:25])[N:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH:14]=[N:15][CH:16]=3)[N:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: CCN(CC)S(=O)(=O)Oc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COC(=O)OC
Product: CCN(CC)S(=O)(=O)Oc1cncc(-c2cc3ccc(Cl)cc3n2C)c1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A flask is charged with diethyl-sulfamic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester (0.175 g, 0.560 mmol) and DMF (5 mL). Dimethyl carbonate (0.116 mL, 1.38 mmol) and potassium carbonate (0.035 g, 0.253 mmol) are added and the reaction is stirred at 150° C. overnight. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (heptane-ethyl acetate, 3:1) to afford diethyl-sulfamic acid 5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester as a yellow solid. MS (ESI) m/z 394.04 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].[BH4-].[Na+].Cl>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][CH2:12][CH2:11][NH2:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: NCCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(NCCN)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3′-Hydroxyacetophenone (1.0 g) and ethylenediamine (1.47 ml) were dissolved in methanol (10 ml), and the solution was stirred at room temperature for 16 hours. The reaction mixture was added with sodium borohydride (277.9 mg), the mixture was stirred at room temperature for 5 hours, and then was added with 1 N hydrochloric acid, and the solvent was evaporated. The resulting residue was added with potassium carbonate and distilled water, and thereby made alkaline, then the mixture was extracted with a 10:1 mixed solvent of chloroform and ethanol, and the organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1 to 5:1:0.1) to obtain the title compound (59.1 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][CH2:13]O)[C:8](=[O:15])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>ClC(Cl)Cl>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][CH2:13][Cl:18])[C:8](=[O:15])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Cl)c2n1CCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cccc(Cl)c2n1CCCCl
Reaction time: 3 h

Procedure:
To a stirred mixture of 5 parts of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one and 75 parts of trichloromethane are added dropwise 8 parts of sulfinyl chloride. Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled and evaporated. The residue is stirred in a small amount of 4-methyl-2-pentanone. The product is filtered off and dried, yielding 4-chloro-3-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Cl[CH:6]([C:12]([C:14]([F:17])([F:16])[F:15])=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].O>CN(C)C=O>[NH2:1][C:2]1[O:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([C:14]([F:15])([F:17])[F:16])[N:4]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc(N)nc1C(F)(F)F
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A mechanically-stirred mixture of 53.2 g (0.885 mol) of urea and 38.6 g (0.177 mol) of ethyl α-chloro-γ,γ,γ-trifluoroacetoacetate was reacted in 50 ml dry dimethylformamide at 100°-110° C. for 71 hours. The reaction mixture was cooled to ambient temperature and the resulting orange slurry was poured into 500 ml of water and then cooled in an ice bath. Suction filtration of the mixture provided a mustard-colored solid material which when dried under an infrared lamp yielded 26.0 g of material. This solid material was slurried in hot chloroform, then cooled in an ice bath to yield 22.1 g of beige plate-like crystal material (m.p. 193-195° C.). A second crystal crop was obtained after concentration of the slurry residue, recrystallization in hot ether and filtration through glass wool. Total yield was 22.4 g of crystal product (m.p.=193°-195° C.) identified in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=4)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[N:18]([CH3:37])[CH:19]=[C:20]([CH2:24][C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[N:27][CH:26]=4)[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: COc1ncc(Cc2cn(C)c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To a solution of 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4(1H)-pyrimidinone (300 mg, 0.561 mmol) and DIPEA (0.294 mL, 1.682 mmol) in DCM (15 mL) was added MeI (0.053 ml, 0.841 mmol). The mixture was stirred at room temperature overnight. Purification via reverse phase flash chromatography then afforded the title compound (100 mg, 32.5% yield). LCMS: rt=3.49 min, [M+H+]=549
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=O)[O:28][C:26](=[O:27])[C:25]2=[CH:31][CH:32]=1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:29](=[O:28])[C:24]5=[CH:23][C:22]([O:21][CH3:20])=[CH:32][CH:31]=[C:25]5[C:26]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)N(CCN1CCC(c3noc4cc(F)ccc34)CC1)C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.63 g. 0.01 mole) and 4-methoxyphthalic anhydride (1.78 g. 0.01 mole) in dichloromethane (100 ml) is stirred at room temperature for 3 hours. The solvent is then removed under reduced pressure and the residual material is purified by flash chromatography. The product is purified further by recrystallization to give N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-methoxyphthalimide.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].O>CC(C)=O>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 33.6 %

Procedure:
5.6 g (0.04 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 was dissolved in 50 ml of acetone, and 4 g of sodium bicarbonate was suspended thereinto. To the suspension was added dropwise 3.7 g of valeryl chloride with stirring. After completion of the dropwise addition, the mixture was further allowed to react at 40° C. for 3 hours. Water was added to the reaction mixture, from which the reaction product was extracted with methylene chloride, followed by the concentration of methylene chloride solution. Thereafter, hexane was added thereto whereby crystals were precipitated. The crystals were collected by filtration and washed with water and benzene to obtain 2.3 g of 5-t-butyl-3-valerylaminopyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][N:19]=[C:20]=[S:21]>ClCCl>[CH3:18][NH:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[S:21]
Reactant: CN=C=S
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Solvent: ClCCl
Product: CNC(=S)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 47.7 %

Procedure:
To a solution of 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole in 3.0 mL dichloromethane were added 6.2 mg (0.0874 mMol) methyl isothiocyanate. The reaction was mixed for 48 hours and to it were then added 0.15 gm (0.0874 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 6.3 mg (48%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:31])=[C:20]([C:22]2[C:23]([C:29]#[N:30])=[CH:24][CH:25]=[C:26]([F:28])[CH:27]=2)[CH:21]=1>>[F:28][C:26]1[CH:27]=[C:22]([C:20]2[CH:21]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:17]=[CH:18][C:19]=2[F:31])[C:23]([C:29]#[N:30])=[CH:24][CH:25]=1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: N#Cc1ccc(F)cc1-c1cc(Br)ccc1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cc(F)ccc4C#N)c3)cnc2c1F
Yield: 43 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 5′-bromo-5,2′-difluorobiphenyl-2-carbonitrile (prepared as described in WO 02/38568) as described in Example 6 to give 5,2′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as a white solid (90 mg, 43%): δH (360 MHz, d6-DMSO) 1.58 (6H, s), 7.21 (1H, m), 7.54-7.65 (2H, m), 7.77 (1H, dd, J 10 and 3), 7.84-7.89 (3H, m), 8.15 (1H, dd, J 9 and 6), 8.49 (1H, d, J 7); m/z (ES+) 408 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:18])[CH2:14][N:15]=[N+:16]=[N-:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:19]([O:18][CH:13]([CH2:12][O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[CH2:14][N:15]=[N+:16]=[N-:17])(=[O:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CN=[N+]=[N-])cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(CN=[N+]=[N-])COS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
3-Azido-2-hydroxypropyl 4-methylbenzenesulfonate 14 (1.83 g, 6.70 mmol) was dissolved in CH2Cl2 (15 mL) and treated with TEA (1.4 mL, 10.00 mmol), a catalytic amount of DMAP and acetic anhydride (0.95 mL, 10.00 mmol) at room temperature. After stirring for 1 hr, silica was added to the reaction mixture, the solvent was evaporated and the residue was purified on silica gel using 50% EtOAc/hexanes as the eluent to afford 2.07 g of 15 (98.8% yield) as a thick, clear, colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 7.79 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 5.02-5.07 (m, 1H), 4.09-4.21 (m, 2H), 3.43-3.53 (m, 2H), 2.46 (s, 3H), 2.05 (s, 3H). Mass Spec (lo-res): Calc'd for C12H15N3O5S: 313.07. found: 314.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])([CH3:23])[CH3:22])[CH:15]=2)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[C:21]([CH3:22])([O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:15]=1)[CH3:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cccc(OC(C)(C)C(=O)OCc3ccccc3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 54 %

Procedure:
3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 125 mL of 20% trifluoroacetic acid/methylene chloride and stirred for 20 minutes. The reaction mixture was evaporated under reduced pressure. The resultant oil was taken up in 400 mL water, made basic with 5N aqueous sodium hydroxide and extracted with ethyl acetate (3×300 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 11.72 g (54% 3 steps) of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester as a pale yellow oil.
Reaction SMILES: Cl.[C:2]([CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][NH:6]1)(=[O:4])[NH2:3].CCN(C(C)C)C(C)C.[C:25](Cl)(=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:2]([CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:25]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:34])(=[O:4])[NH2:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCNC(C(N)=O)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Ethyl 2-carbamoylpiperidine-4-carboxylate hydrochloride (2 g, 7.86 mmol) was slurried in dichloromethane (25 mL) and DIPEA (3.43 mL, 19.65 mmol) was added followed by benzyl carbonochloridate (1.161 mL, 8.25 mmol) dropwise. The reaction was stirred for 1 h then washed with 25 mL of 2 M HCl and water, dried over Na2SO4 and evaporated. The crude product was purified on a 100 g Biotage column with heptane/EtOAc over 4 CV followed by 100% EtOAc over 10 CV. 1-Benzyl 4-ethyl 2-carbamoylpiperidine-1,4-dicarboxylate (1.99 g, 76%) was isolated. 1H NMR (400 MHz, dmso) δ 1.16 (t, 3H), 1.57-1.69 (m, 1H), 1.81-1.92 (m, 1H), 1.95-2.07 (m, 1H), 2.21-2.32 (m, 1H), 2.58-2.67 (m, 1H), 3.29-3.45 (m, 1H), 3.69-3.77 (m, 1H), 3.92-4.06 (m, 2H), 4.34 (t, 1H), 4.99-5.08 (m, 2H), 6.95 (s, 1H), 7.25-7.38 (m, 6H). MS m/z 335 (M+H)+
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.891 g, 5.16 mmol) and thionyl chloride (15 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.0 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.354 g, 3.49 mmol, 88%).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=O)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:23][CH2:24][CH2:25][SH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]2[NH:23][CH2:24][CH2:25][S:26]2)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCCS
Reactant: CCCCCCn1c(=O)c(C=O)c(OC)c2cc(C)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCCCCn1c(=O)c(C2NCCS2)c(OC)c2cc(C)ccc21
Reaction time: 3 h

Procedure:
A solution of 1 -hexyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone (Step (2) of Example 1, 1 g) and 2-aminoethanethiol (0.26 g) in methylene chloride (20 ml) containing p-toluenesulfonic acid (0.1 g) was stirred for 3hrs. The mixture was washed with aqueous sodium bicarbonate, dried, evaporated and then crystallized from ether-hexane to give 1-Hexyl-3-(2-thiazolidinyl)-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 360 (M+); NMR (CDCl3): δ3.17 (m, 2H, CH2S), 3.86 (m, 2H, CH2N), 6.0 (d, 1H, S-CH-N).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[BH4-].[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: O=Cc1cc(O)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc(Cl)c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a mixture of 2-chloro-5-hydroxybenzaldehyde (200 mg, 1.27 mmol, intermediate 28a) and morpholine (280 mg, 3.21 mmol) in methanol (10 mL) was added 2 drops of acetic acid and the mixture was stirred at room temperature for 2 h. To the mixture, sodium borohydride (97 mg, 2.56 mmol) was added and the resulting mixture was stirred at room temperature for 4 h. The mixture was quenched with dilute hydrochloride acid and concentrated to give crude product. This crude material was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (5:1 to 1:1) to give 4-chloro-3-(morpholinomethyl)phenol (150 mg, 51.8% yield) as white solid. LCMS retention time 0.378; LCMS MH+ 228.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1.[I-].[K+].[CH3:17][NH:18][CH3:19]>O1CCCC1>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:4][C:3]([CH2:2][N:18]([CH3:19])[CH3:17])=[N:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: CNC
Reactant: ClCc1nnc(-c2ccc(I)cc2)o1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)Cc1nnc(-c2ccc(I)cc2)o1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
2-Chloromethyl-5-(4-iodophenyl)-[1,3,4]oxadiazole (Intermediate 7) (48 mg, 0.15 mmol) and potassium iodide (25 mg, 0.15 mmol) were dissolved in 2M dimethylamine in tetrahydrofuran (2 ml) and stirred for 18 hours at 20° C. The reaction was evaporated to dryness in vacuo and the product was purified on a 10 g silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetate:cyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol).