Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:20])=O>C(OCC)(=O)C.CN(C=O)C>[Cl:20][C:9]([CH:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10]
Reactant: CCOC(=O)C(CC1CCCCC1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1CCCCC1)C(=O)Cl
Temperature: 0 °C

Procedure:
A solution comprised of 3-cyclohexyl-2-ethoxycarbonylpropionic acid (8.52 g, 37 mmol) in ethyl acetate (80 mL) was cooled to 0° C. was treated sequentially with 2 drops of DMF and oxalyl chloride (3.93 mL) added dropwise over five minutes. The mixture was allowed to warm slowly and after approximately 2 hours concentrated to provide ethyl 2-chlorocarbonyl-3-cyclohexylpropionate.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([S:14]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:7].CN(C=O)C.I[CH2:36][CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:36]([N:17]([S:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])=[O:7])[CH:9]=1)(=[O:15])=[O:16])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1)[CH2:37][CH3:38]
Reactant: CCCI
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(c1ccc(C(=O)OC)cn1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a mixture of 500 mg of methyl 6-{[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}nicotinate and 10 mL of DMF were added 0.300 mL of 1-iodopropane and 400 mg of potassium carbonate, followed by stirring at 80° C. for 5 hours. The reaction mixture was left to stand to cool and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to obtain 200 mg of a methyl 6-{propyl[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}nicotinate as a colorless oily substance. ESI+: 479
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH:10]2[CH:8]([C:9]2([F:13])[F:12])[CH2:7]1)[C:3]([OH:5])=[O:4].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C(Cl)Cl.CO>[NH2:1][CH:2]([CH:6]1[CH2:7][CH:8]2[CH:10]([C:9]2([F:12])[F:13])[CH2:11]1)[C:3]([O:5][CH3:15])=[O:4]
Reactant: NC(C(=O)O)C1CC2C(C1)C2(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(N)C1CC2C(C1)C2(F)F
Temperature: 25 °C
Yield: 84.11 %

Procedure:
To a solution of amino(6,6-difluorobicyclo[3.1.0]hex-3-yl)acetic acid (1.0 g, 5.23 mmol) in CH2Cl2:MeOH (4:1) was added dropwise TMSCHN2 (10.5 mL) over 10 min at 0° C. until a neon yellow color persisted. The reaction mixture was allowed to warm to 25° C. over 19h. The solvent was removed in vacuo to obtain methyl amino(6,6-difluorobicyclo[3.1.0]hex-3-yl)acetate as a light yellow oil (0.9 g, 84.11%). Mass Spectrum (−ESI): 206 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>N1C=CC=CC=1>[C:33]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18](=[O:19])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:9]([CH:30]([CH3:32])[CH3:31])[N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Yield: 10.2 %

Procedure:
Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 7 mg, 0.016 mol) in pyridine (1 ml) was reacted with propionyl chloride (1.4 μl, 0.16 mmol) to yield the title compound (8 mg, 100%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[N+:20]([O-])=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[NH2:20])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(Nc3cnccc3[N+](=O)[O-])ccc21
Solvent: CCO
Product: CC(=O)N1CCc2cc(Nc3cnccc3N)ccc21

Procedure:
A suspension of 1-acetyl-2,3-dihydro-N-(4-nitro-3-pyridinyl)-1H-indole-5-amine, N5 -oxide (13 g) in 250 ml ethanol containing 0.5 g PtO2 was hydrogenated for two days at 60 psi and thereafter filtered through Celite and concentrated to 9 g solid. This solid was purified by HPLC (silica, 20% methanol in ethyl acetate) to give 4 g solid. This was combined with 1 g product obtained from a previous reduction and again purified by HPLC (silica, 20% methanol in ethyl acetate) to give 5 g solid, m.p. 210°-212°. This solid was recrystallized from acetonitrile to give 4 g solid, m.p. 212°-214°.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[C:23](Br)=[C:22]([N+:25]([O-:27])=[O:26])[C:21]([Br:28])=[N:20]3)[CH:13]=2)[N:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(O)CC>[CH2:29]([NH:36][C:23]1[N:19]([CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:4]3[C:5]([NH:4][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([Br:1])=[N:3]3)[CH:13]=2)[N:20]=[C:21]([Br:28])[C:22]=1[N+:25]([O-:27])=[O:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=[N+]([O-])c1c(Br)nn(Cc2cccc(Cn3nc(Br)c([N+](=O)[O-])c3Br)c2)c1Br
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCCO
Product: O=[N+]([O-])c1c(Br)nn(Cc2cccc(Cn3nc(Br)c([N+](=O)[O-])c3NCc3ccccc3)c2)c1NCc1ccccc1

Procedure:
13.9 g of 1,3-bis-(3,5-dibromo-4-nitropyrazol-1-yl-methyl)benzene from step 4.1 are heated together with 6.5 g of benzylamine in 130 ml of n-propanol for 2 hours at 95° C. Subsequently the reaction mixture is cooled and poured into 400 ml water. The precipitate is filtered with suction and recyrstallized from 150 ml of acetonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7]C(O)=O)=[CH:4][CH:3]=1.C1(C=CC(O)=CC=1)O.N12CCCN=C1CCCCC2>CS(C)=O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Oc1ccc(O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: C=Cc1ccc(O)cc1
Temperature: 135 °C

Procedure:
In a 1-liter sulfonating flask equipped with mechanical stirrer, reflux condenser and nitrogen delivery line, 300 ml of dimethyl sulfoxide are added to 150 g (0.91 mol) of 4-hydroxycinnamic acid, 6 g (54 mmol) of hydroquinone and 6 g (39 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture is then heated at 135° C. for 31/2 hours. After cooling, the mixture is poured onto ice and extracted three times with 500 ml of diethyl ether, and the organic phase is washed five times with 100 ml of water, dried over magnesium sulfate and concentrated. The resulting oil is recrystallised twice from n-hexane to yield 69.07 g (0.58 mol, 63% of the theoretical yield) of 4-hydroxystyrene in the form of a white powder (m.p. 68° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[Li]CCCC.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH2:17][CH:18]([OH:20])[CH3:19]
Reactant: FC(F)(F)c1cccc(Cl)c1
Reactant: CC1CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)Cc1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-3-(trifluoromethyl)benzene (1.0 g, 5.5 mmol) in THF (10.0 mL) was added 2.5 M of n-BuLi in hexane (2.2 mL) at −78° C. and stirred for 1 h. Propylene oxide (370 mg, 6.4 mmol) was added to the reaction mixture at −78° C. and slowly warmed to rt. The reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a yellow oil. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to yield the desired product as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ=1.33 (d, J=6.1 Hz, 3H), 1.40 (d, J=6.3 Hz, 1H), 3.08-3.22 (m, 2H), 4.21-4.33 (m, 1H), 7.29-7.34 (m, 1H), 7.58-7.64 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([C:27]([F:30])([F:29])[F:28])([C:23]([F:26])([F:25])[F:24])[OH:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][S:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([S:32][CH3:31])[CH:38]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:21]([C:27]([F:29])([F:30])[F:28])([C:23]([F:25])([F:26])[F:24])[OH:22])=[N:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CSc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)c1
Temperature: 88 °C
Reaction time: 2 h
Yield: 11.2 %

Procedure:
5-(4-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (50.0 mg, 0.10 mmol) prepared in Step 2 of Preparation 22, 3-(methylthio)-phenylboronic acid (25.0 mg, 0.15 mmol), Pd(PPh3)4 (11.5 mg, cat.), ethanol 0.5 mL and a 2N sodium carbonate solution (0.5 mL) were added to 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 6.1 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[Cl:13]N1C(=O)CCC1=O>C(O)(C)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([Cl:13])[C:5]=1[NH2:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(I)ccc1N
Solvent: CC(C)O
Product: COC(=O)c1cc(I)cc(Cl)c1N
Temperature: 80 °C
Yield: 72 %

Procedure:
To a round bottom flask was combined 1.00 g (3.61 mmol) of 2-amino-5-iodo-benzoic acid methyl ester and 18.0 mL isopropyl alcohol. To the solution was added 541 mg (4.05 mmol) of N-chlorosuccinimide and the solution was heated at 80° C. in an oil bath for 2.25 hours. The solution was cooled to room temperature and concentrated. The resulting residue was dissolved in ethyl acetate and an aqueous solution of sodium bisulfite was added. The organic layer was washed three times with water and brine, then dried over sodium sulfate. The organic layer was concentrated to dryness and recrystallized from hexanes to afford 809 mg (2.60 mmol, 72% yield) of 2-amino-3-chloro-5-iodo-benzoic acid methyl ester as tan-orange crystals. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (d, 1H), 7.74 (d, 1H), 6.86 (s, br., 2H), 3.82 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:33])(=[O:32])[N:30](CC[Si](C)(C)C)[C:29](=[O:40])[CH2:28]1)C1C=CC=CC=1.[F:41][C:42]([F:54])([F:53])[C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[S:49]([C:46]2[CH:45]=[CH:44][C:43]([C:42]([F:41])([F:53])[F:54])=[CH:48][CH:47]=2)(=[O:51])=[O:50])[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:40])[CH2:28]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3Cc4ccccc4CN3)cc2OCc2ccccc2)S1(=O)=O
Product: O=C1CN(c2ccc(CCC3Cc4ccccc4CN3S(=O)(=O)c3ccc(C(F)(F)F)cc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-{2-benzyloxy-4-[(E)-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 4-trifluoromethylbenzenesulfonyl chloride analogous to Example 200, steps F, G and H: (M−1)−=546.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:24])[C:5](=[N:10][NH:11][C:12]1[C:22]([F:23])=[CH:21][C:15]2[O:16][C:17]([F:20])([F:19])[O:18][C:14]=2[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:25]OC(OC)N(C)C>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[O:16][C:17]([F:20])([F:19])[O:18][C:14]=3[CH:13]=2)[CH:25]=1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1cc2c(cc1F)OC(F)(F)O2)C(=O)OC
Product: COC(=O)c1nn(-c2cc3c(cc2F)OC(F)(F)O3)cc(OC)c1=O
Yield: 24 %

Procedure:
A mixture of methyl 4-methoxy-3-oxo-2-[(2,2,6-trifluoro-1,3-benzodioxol-5-yl)hydrazono]butanoate (6.31 g, 18.1 mmol) in N,N-dimethylformamide dimethyl acetal (63 mL) was heated to reflux for 2.5 h. The mixture was concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 70/30) and on basic silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (1.53 g, 24% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.79 (3H, s), 3.82 (3H, s), 7.94 (1H, d, J=9.4 Hz), 8.04 (1H, d, J=6.4 Hz), 8.54 (1H, s).
Reaction SMILES: [C:1]1(=[O:5])[O:4][CH2:3][CH2:2]1.C[O-].[Na+].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:5][CH2:1][CH2:2][C:3]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: O=C1CCO1
Agent: C[O-]
Agent: [Na+]
Product: O=C(CCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
β-Propiolactone (5 g, 25 mmol) was added slowly to a stirred solution of sodium methoxide (0.18 g, 3.5 mmol) in benzyl alcohol (45 g, 420 mmol) at 0° C. Stirring was continued for a further 2 hours at 0° C. Then the mixture was warmed to room temperature. After stirred for 7 hours, the reaction mixture was washed with water, dried and distilled to give the title compound. 1H NMR (300 MHz, CDCl3): δ 7.33 (m, 5H), 5.13 (s, 2H), 3.86 (t, J=5.6 Hz, 2H), 2.59 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][NH:19][C:20]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)=[O:21])=[CH:11][CH2:10]1>[Zn].CO.C(O)(=O)C>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][NH:19][C:20]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[O:21])=[CH:11][CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H]1CC(CNC(=O)c2ccc(C(=O)O)cc2)=CC[C@H]1c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
To a solution of Example 15A (35 mg, 0.076 mmol) in mixture of methanol/acetic acid (0.5 mL/0.5 mL), Zn powder (49 mg, 0.76 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (10 mg, 32%). 1H NMR (300 MHz, methanol-d4) δ ppm 8.06-8.16 (m, 2H), 7.88-7.97 (m, 2H), 7.52-7.59 (m, 1H), 7.37-7.49 (m, 2H), 7.10-7.24 (m, 1H), 5.78-5.87 (m, 1H), 3.97-4.06 (m, 2H), 3.83-3.95 (m, 1H), 3.49-3.62 (m, 1H), 2.25-2.61 (m, 4H). MS (ESI) m/z 419 (M+H)+.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH3:8].[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1>>[CH3:8][C:3]1[C:4](=[O:7])[CH2:5][CH2:6][C:2]=1[C:13]1[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1=C(Br)CCC1=O
Product: CC1=C(c2cnn(C)c2)CCC1=O
Yield: 16 %

Procedure:
Synthesized from 3-bromo-2-methylcyclopent-2-enone and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 100% ethyl acetate/hexanes) and further recrystallization yielded the product (21 mg, 16%) as a white solid. 1H NMR (CDCl3, 300 MHz): δ 7.80 (s, 1H), 7.70 (s, 1H), 2.84-2.80 (m, 2H), 2.52-2.48 (m, 2H), 1.95 (t, J=2.1 Hz, 3H). LCMS (ESI): mass calcd for (C10H12N2O) m/z 176.09; measured [M+H]+: m/z 177.09.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]#[N:25])=[CH:21][CH:22]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#CCc1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of (4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (81.6 mg) in acetonitrile (10 mL) were added sodium iodide (73.6 mg) and chloro(trimethyl)silane (0.249 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (73.4 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([NH:8][C:9]2[C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6]1>C(#N)C>[CH:5]1([NH:8][C:9]2[C:14]([C:15]([Cl:3])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1NC1CC1
Solvent: CC#N
Product: O=C(Cl)c1cccnc1NC1CC1

Procedure:
Thionyl chloride (25 ml, 40.8 g, 0.343 mol) was charged in a thin stream to 9.00 g, 0.048 mol, of 2-(cyclopropylamino)-3-pyridine carboxylic acid from Example 2 in acetonitrile. The mixture was heated at reflux temperature for 30 minutes. The mixture was allowed to cool and the thionyl chloride was distilled off at 40° C./23 in. Hg until the pot contents became thick. Toluene (25 ml) was added and distillation of thionyl chloride and toluene at 40° C. was continued until about one-half of the liquid was distilled. The remaining solution was allowed to cool and stirred to promote crystallization. Heptane (25 ml) was added to the mixture with stirring and the mixture filtered under a nitrogen atmosphere to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>C1(C)C=CC=CC=1.ClCCl>[Cl:17][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=c1ccnc(-c2ccc(Cl)cc2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1ccc(-c2nccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
2-(4-chlorophenyl)pyrimidin-4(3H)-one (100 mg, 0.4840 mmol), suspended in toluene (2 ml), was treated with phosphoryl trichloride (443.0 μl, 4.840 mmol) at ambient temperature. The suspension was heated to reflux at which point the reaction became a colorless solution. After 4 hours, the reaction was cooled to ambient temperature and concentrated in vacuo to afford a white solid. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organics were dried with sodium sulfate, filtered, concentrated, and purified on silica gel. Elution with 2-20% ethyl acetate/hexanes provided the title compound (99 mg, 0.4399 mmol, 90.89% yield) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.S(Cl)([Cl:34])=O>ClCCl>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([Cl:34])=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4-(4-phenylquinazolin-2-ylamino)benzoic acid (1.19 g, 3.49 mmol), prepared as described in Example 10, in dichloromethane (50 mL) was added a catalytic amount of dimethylformamide (100 μL) and thionyl chloride (1.50 mL, 20.6 mmol), and the resulting mixture was stirred at rt overnight. The solid was filtered, washed with hexanes, and dried under reduced pressure (high vacuum) to give the product (4-(4-phenylquinazolin-2-ylamino)benzoyl chloride) as a yellow solid (1.21 g, 97%). This material was then added portionwise to a solution of commercially available 3-amino-4-methylbenzyl alcohol (600 mg, 4.37 mmol), and triethylamine (1.0 mL, 7.2 mmol) in dichloromethane (50 mL) that had been cooled to 0° C. in an ice bath. The mixture was allowed to warm to rt overnight, then the solid was collected by filtration, washed with saturated sodium bicarbonate and water and dried under reduced pressure to give N-(5-hydroxymethyl-2-methylphenyl)-4-(4-phenylquinazolin-2-ylamino)benzamide as a pure yellow solid (1.33 g, 86%).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](#[N:10])[CH:8]=[CH2:9]>CO>[CH:1]1([NH:6][CH2:9][CH2:8][C:7]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: C=CC#N
Solvent: CO
Product: N#CCCNC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, cyclopentylamine (5.794 mL, 58.7 mmol) was added dropwise to a solution of acrylonitrile (5.79 mL, 88.1 mmol) in methanol (7 mL). The solution was stirred at room temperature for 30 mins and at reflux for 1 hr, cooled to room temperature, and concentrated under reduced pressure. The desired product as obtained by distillation under vacuum to provide a clear liquid (7.4 g, 91%). 1H NMR (CDCl3, 300 MHz) δ 3.14-3.04 (quint, 1H, J=6.3 Hz), 2.91-2.87 (t, 2H, J=6.9 Hz), 2.53-2.48 (td, 2H, J=0.9, 6.9 Hz), 1.88-1.78 (m, 2H), 1.73-1.49 (m, 4H), 1.36-1.24 (m, 2H), 1.19 (br s, 1H).