Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH3:36]>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:28][CH2:35][CH3:36]
Reactant: CCI
Reactant: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(O)c(Cl)cc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc2cc(-c3ccccc3)n(Cc3cccc(C(=O)OC)n3)c2cc1Cl

Procedure:
To a solution of methyl 6-(6-chloro-5-hydroxy-2-phenylindol-1-ylmethyl)pyridine-2-carboxylate (100 mg) in N,N-dimethylformamide (1 mL) were added, potassium carbonate (70.4 mg) and ethyl iodide (0.031 mL) and the mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (83.9 mg).
Reaction SMILES: [H][H].C(O)(=O)C.CS(O)(=O)=O.C(OC([NH:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]=[CH:40][C:41](=[NH:43])[NH2:42])=[CH:35][CH:34]=2)=[O:31])[CH2:26][CH2:25]1)=O)C1C=CC=CC=1>C(OCC)C>[NH2:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([CH:39]=[CH:40][C:41](=[NH:42])[NH2:43])=[CH:37][CH:38]=2)=[O:31])[CH2:26][CH2:25]1
Reactant: [H][H]
Reactant: N=C(N)C=Cc1ccc(OC(=O)[C@H]2CC[C@H](CNC(=O)OCc3ccccc3)CC2)cc1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: N=C(N)C=Cc1ccc(OC(=O)[C@H]2CC[C@H](CN)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 9 ml of a 30% hydrogen bromideacetic acid mixture and 18 ml of glacial acetic acid, was added 2.7 g of 4-(β-amidinoethenyl)phenyl trans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylate methanesulfonate. After stirring the mixture for one hour at room temperature, anhydrous ethyl ether was added to wash out a white solid substance. The solid substance was recrystallized from ethanol to obtain 1.1 g of a white powder of 4-(β-amidinoethenyl)phenyl trans-4-aminomethylcyclohexane carboxylate dihydrobromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[Li][C:15]#[N:16].C(P(=O)(OCC)OCC)#N.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[C:8]2[C:15]#[N:16]
Reactant: COc1cccc2c1CCCC2=O
Reactant: [Li]C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CCC=C2C#N
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 339.9 %

Procedure:
5-Methoxy-1-tetralone (8.80 g) was dissolved in 50 ml of anhydrous THF and cooled to 5° C. under N2 atmosphere. LiCN (0.50g.) was added to the stirred solution, followed by dropwise addition of diethyl cyanophosphonate (9.1 ml) over 10 min. After 45 min at 5° C., the reaction was poured into 200 ml H2O and extracted with EtOAc (3×100 ml). The combined organic extracts were washed with water (3×150 ml), saturated NaCl (150 ml), dried (MgSO4), and evaporated under reduced pressure. The resulting colorless oil was dissolved in benzene (100 ml) and p-toluenesulfonic acid (0.50 g) was added. The reaction was stirred at reflux for 2 hr, cooled to room temperature, and poured into 5% NaHCO3 solution (150 ml). The reaction was extracted with Et2O (2×100 ml) and the combined organic extracts were washed with saturated NaCl solution (150 ml), dried (MgSO4 ), and evaporated under reduced pressure to yield 9.55 g of a white solid. The product was recrystallized from MeOH to yield 7.81 g of the product as white needles.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](Cl)=[O:36])=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:36])[CH2:34][O:33][C:32]2[CH:38]=[CH:39][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)COc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorophenoxyacetyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C1COCC1>CO>[CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: CCOC(=O)C(=Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OCC
Reaction time: 20 h

Procedure:
700 mg (1.5 mmol) of diethyl 2-(3′-{[methyl-(1-phenylmethanoyl)amino]methyl}biphenyl-4-ylmethylene)malonate, 7 ml of THF and 1 ml of methanol are introduced into a three-necked flask under a stream of nitrogen. The reaction medium is degassed, 80 mg of palladium-on-charcoal (5%) are introduced and the mixture is hydrogenated under atmospheric pressure at room temperature for 20 hours. The reaction medium is filtered through Celite and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvents, 450 mg (63%) of the desired product are collected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(F)c1

Procedure:
The title compound was synthesized from methyl 4-(3,4-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.10 g, 0.34 mmol) and lithium hydroxide (0.143 g, 3.4 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 46 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.99-2.16 (m, 1H), 2.45-2.68 (m, 3H), 2.68-2.86 (m, 2H), 3.17-3.29 (m, 1H), 6.30 (s, 1H), 6.97 (ddd, J=6.36, 4.19, 2.05 Hz, 1H), 7.02-7.21 (m, 2H). 19F NMR δ ppm −141.99 (m), −145.62 (m); LCMS-MS (ESI−) 276.0 (M−H); HPLC (UV=98.41%), (ELSD=100%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[N:38]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)[N:37]=[CH:36][CH:35]=1)CCC>>[C:43]([C:42]1[CH:41]=[CH:40][C:39]([N:38]2[C:34]([C:2]3[C:3]([CH3:28])=[C:4]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[N:10]=4)[CH:7]=3)=[CH:35][CH:36]=[N:37]2)=[CH:46][CH:45]=1)#[N:44]
Reactant: Cc1c(Br)cn2cc(NC(=O)C(F)(F)F)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2cc(NC(=O)C(F)(F)F)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from N-[6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-2,2,2-trifluoro-acetamide (Int. 5, 35 mg, 0.075 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 52 mg, 0.113 mmol) using a similar method to that used in Example 1 (Step 4), (6 mg).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:32][CH2:31][O:30][CH2:29][C@H:28]1[CH2:33][C:34](O)=[O:35]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][C@@H:28]5[CH2:29][O:30][CH2:31][CH2:32][O:27]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C[C@@H]1COCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@@H]1COCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (22 mg, 19%), MS (ISP) m/z=457.4 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (R)-(1,4-dioxan-2-yl)-acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([O:13][C:14](=[O:24])[CH2:15][NH:16][C:17]1[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:12].C(OC(=O)CNC1C([N+]([O-])=O)=CC=CN=1)C.C(N(CC)CC)C>O1CCCC1.[Pd]>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][NH:16][C:17]1[C:22]([NH:23][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:12]
Reactant: CCOC(=O)CNc1ncccc1N
Reactant: O=C(Cl)c1cccc(F)c1
Agent: [Pd]
Agent: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1ncccc1NC(=O)c1cccc(F)c1
Yield: 6.6 %

Procedure:
Under a nitrogen atmosphere, 3-fluorobenzoyl chloride (12.9 g, 0.0816 mole) was added dropwise to a stirred and chilled (10°-15° C.) mixture of N-(3-amino-2-pyridinyl)glycine ethyl ester (0.0816 mole) [freshly prepared by the hydrogenation of a solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester in tetrahydrofuran over 5% palladium on carbon at room temperature], triethylamine (8.3 g, 0.0816 mole), anhydrous tetrahydrofuran (200 ml), and powdered molecular sieves. The reaction mixture was stirred at room temperature for 1 hour and was filtered. The filtrate was concentrated in vacuo and the residual solid triturated in isopropyl ether-isopropyl alcohol, giving 24.2 g (94%). Recrystallization of a 2.0-g sample gave 1.72 g of a white powder, mp 134°-135° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[O:33]=[C:34]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36][N:35]1[CH2:44][CH2:45][CH2:46][C:47](O)=[O:48]>ClCCl.CN(C)C1C=CN=CC=1.O>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:47](=[O:48])[CH2:46][CH2:45][CH2:44][N:35]1[C:34](=[O:33])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCn1nnc2ccccc2c1=O
Reactant: O=C1N[C@@H](Cc2ccccc2)CS1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCCn1nnc2ccccc2c1=O)N1C(=O)SC[C@@H]1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of the compound obtained from step c above (2.1 g) in dichloromethane (25 mL) cooled to 0° C., 4-dimethylaminopridine (0.334 g) and triethylamine (5.7 mL) were added. After stirring the reaction mixture for 10 minutes, 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (3.9 g) and 4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (3 g) were added, and the reaction mixture was stirred at room temperature for 14 hours. Dichloromethane and water were added to the reaction mixture. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 25% ethyl acetate in hexane as eluant to afford the title compound (4.4 g). Mass (m/z): 409.16
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([NH:13][C:14](=[O:16])[CH3:15])[CH3:12])=[N:9][CH:10]=1.Br[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][N:26]=[CH:25]2.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][C:20]=2[C:20]2[CH:21]=[CH:22][C:23]([CH2:15][C:14]([NH:13][C@@H:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:17])[F:18])=[CH:10][N:9]=3)[CH3:12])=[O:16])=[CH:24][CH:29]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CC(=O)N[C@H](C)c1ccc(OCC(F)(F)F)cn1
Reactant: Brc1cccc2cncnc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H](NC(=O)Cc1ccc(-c2cccc3cncnc23)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 150 °C
Yield: 75 %

Procedure:
To a suspension of (R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethylamine bis-HCl (0.75 g, 2.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylacetic acid (0.67 g, 2.6 mmol), EDC (0.59 g, 3.1 mmol), and 1-hydroxy-7-azabenzotriazole (0.42 g, 3.1 mmol) in DMF (5 mL) was added diisopropylethylamine (1.8 mL, 10.2 mmol). After stirring for 90 min at room temperature, the reaction mixture was loaded directly onto a silica gel column and purified by normal phase chromatography (20-80% EtOAc/hexanes) to give 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (0.77 g, 65%) as a viscous oil that slowly solidified to a white solid. MS (Electrospray): m/z 465.1 (M+H). To a microwave vial containing 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (50 mg, 0.11 mmol), 8-bromoquinazoline (25 mg, 0.12 mmol), and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) in acetonitrile (1 mL) was added aqueous 1M sodium carbonate (1 mL, 1.0 mmol) and the mixture was heated in a microwave at 150° C. for 10 min. The top organic layer was removed, loaded onto a silica gel column and purified by normal phase chromatography (30-100% EtOAc/hexanes) to give 2-(4-quinazolin-8-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (21 mg, 38%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 9.37 (s, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.96 (m, 2H), 7.75 (m, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.22 (m, 2H), 6.79 (d, J=7.2 Hz, 1H), 5.16 (m, 1H), 4.37 (q, J=8.0 Hz, 2H), 3.68 (s, 2H), 1.44 (d, J=6.8 Hz, 3H); MS (Electrospray): m/z 467.1 (M+H). FLIPR alpha1I IP=19 nM.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[C:8]1([CH3:16])[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.ClC(OCC)=O.P(OCC)(OCC)OCC.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].[OH-].[NH4+]>C(Cl)(Cl)Cl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[CH:16]=[N:5][CH:4]=[CH:3]2
Reactant: Cc1ccc(C=O)cc1
Reactant: COC(CN)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CCOC(=O)Cl
Agent: CCOP(OCC)OCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2cnccc2c1
Temperature: 65 °C
Reaction time: 23 h
Yield: 77.7 %

Procedure:
Aminoacetaldehyde dimethyl acetal (8.83 mL, 81.1 mmol) was added over 1 min to a stirred solution of p-tolualdehyde (9.88 mL, 81.1 mmol) in chloroform (150 mL) at 22° C. An exotherm was noted. The reaction was heated to reflux (65° C.) and half the solvent was removed (azeotropically to remove water). The heat was removed and the yellow solution was cooled to r.t. NMR showed the imine was formed smoothly, however, a trace of aldehyde was observed. The yellow solution was diluted with chloroform to bring the volume back to ˜100 mL, cooled to −3° C. and ethyl chloroformate (7.99 mL, 81.1 mmol) was added dropwise over 5 min followed by triethyl phosphite (17.4 mL, 97.3 mmol) over 10 minutes. The clear yellow solution was then allowed to warm to RT. A reflux condenser added to reaction vessel. After 23 h, titanium tetrachloride (35.6 mL, 324 mmol) was added very slowly (strong exotherm and white fumes observed) and the reaction began to gently reflux (50° C.). Color changed from yellow to dark red to dark brown. Once addition was complete, the dark brown solution was heated to reflux (52° C.) for 10.5 h. After allowing to cool to RT overnight, the dark brown solution was poured onto ice (filled a 2 L beaker with approximately 1 L of ice), the organic layer was separated off, and the aqueous layer was washed with DCM (2×100 mL). The aqueous layer (now orange in color) was poured into a solution of potassium sodium tartrate tetrahydrate (183 g, 648 mmol) in water (300 mL), basified to pH 9 with 28-30% ammonium hydroxide (a white ppt crashed out) and then extracted with DCM (3×200 mL). The organic layer was separated, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to yield 6-methylisoquinoline (9.02 g, 78% yield) as a light tan amorphous solid. Found MS (ESI, pos. ion) m/z: 144.1 [M+H]+
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].O[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)[CH:17]=[CH:16]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH2:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:17]=[CH:16]3)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CCCC[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Yield: 88.3 %

Procedure:
A mixture of trans-4-butyl-cyclohexanol (441 mg, 2.82 mmol), ((R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (572.5 mg, 2.353 mmol) and triphenylphosphine (741 mg, 2.82 mmol) in tetrahydrofuran (20 mL, 0.3 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.556 mL, 2.82 mmol) was added dropwise. The reaction was stirred and refluxed for 3 hours. TLC and LCMS monitoring showed the reaction to be incomplete. The mixture was concentrated and taken up into dichloromethane and subjected to chromatography purification with EtOAc/hexane (10:90 to 80:20) to give product (0.793 g, 88% yield). LCMS 2.35 min (382.93, [M+1], 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].CN(C=O)C.[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Cl.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:25][C:24]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:23]=3[Cl:22])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cc1csc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Reaction time: 16 h
Yield: 84.2 %

Procedure:
To a mixture of ethyl(6-hydroxy-1-benzothiophen-3-yl)acetate (11.0 g) and DMF (200 mL) were added 2,4-dichlorobenzyl chloride (10.9 g) and K2CO3 (9.60 g). The mixture was stirred at 20° for 16 h. The mixture was diluted with EtOAc, and washed successively with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the title compound (15.5 g).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11]>C(O)(=O)C>[NH:6]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])[C:2]([NH2:3])=[O:1]
Reactant: NC(=O)c1cccc(N)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1cccc(C(N)=O)c1
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
Sodium cyanate (1.3 gm, 20 mMole) in 9.0 ml or water was added over a 15 minute period to a solution of 3-aminobenzamide (1.36 gm, 10 mMole) in acetic acid at 35° C. The mixture was stirred for a further 15 minutes during which time a white precipitate formed. This was filtered off, washed with cold water and crystallized from 25% ethanol to give 1.4 gm (78%) of shiny crystals. m.p. >300° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccccc1
Product: O=[N+]([O-])c1cc2c(NCCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36]C)=[O:35])=[O:30])[CH:11]=1)=[O:9].O.[OH-].[Li+]>O1CCCC1.O>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([OH:36])=[O:35])=[O:30])[CH:11]=1)=[O:9]
Reactant: COC(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoate (360 mg, 0.58 mmol, 1.00 equiv) in tetrahydrofuran/water (2:3) (35 mL), and lithium hydroxide hydrate (251.2 mg, 5.98 mmol, 10.25 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of water adjusted to pH 2-3 with hydrogen chloride (2 mol/L). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 325 mg (92%) of 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid as a yellow oil.