Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C[O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH2+:7]1)=O.C(OCC)(=O)C.[OH-].[Na+].[NH3:20]>>[NH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]1[C:4]([NH2:20])=[O:3]
Reactant: COC(=O)[C@H]1CCCC[NH2+]1
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)[C@H]1CCCCN1
Temperature: 60 °C

Procedure:
(2R)-2-(Methoxycarbonyl)piperidinium chloride (2.6 g, 14.5 mmol) was dissolved in ammonia (0.88M, 30 ml). The reaction mixture was heated at 60° C. for 1.5 hr. The mixture was partitioned between ethyl acetate (100 ml) and sodium hydroxide (1N, 100 ml, 100 mmol), the aqueous was washed with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulphate and the solvent evaporated under reduced pressure. Aqueous layer was acidified with hydrochloric acid and evaporated to dryness under reduced pressure. The resultant white solid was triturated with dichloromethane:methanol (9:1), the remaining solid was removed by filtration and the filtrate evaporated under reduced pressure to afford the title compound as a white solid, 1.14 g, (61%).
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](COC)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[CH2:31]=[C:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1>>[CH3:1][O:2][CH2:31][C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1
Reactant: COC[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: COC[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 88 %

Procedure:
The title compound II-ae was prepared in 88% yield from 3,3:17,17-bis(ethylendioxy)-6α-methoxymethylandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.25 (3H, s), 3.24 (2H, m), 2.53-0.75 (21H, m), 1.11 (3H, s), 0.87 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 37.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.029 g (37%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C)C.S(=O)(=O)(O)O>O>[C:1]1([C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CC=C(c1ccccc1)c1ccccc1
Yield: 49.4 %

Procedure:
A mixture of 1,1-diphenyl-1-propanol (64 g, 0.30 mol), isopropanol (300 ml) and a 5 N solution of sulphuric acid (150 ml) was heated at reflux temperature for 18 h. The reaction mixture was cooled, diluted with water (600 ml) and extracted with toluene (3×150 ml). The combined organic phases was dried (Na2SO4) and the solvent was evaporated in vacuo to give a solid residue which was triturated with iso-octane. The solid was collected by filtration to give 28.8 g (49%) of 1,1-diphenyl-1-propene.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Br:10][C:11]1[CH:12]=[N:13][NH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:10][C:11]1[CH:12]=[N:13][N:14]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:15]=1
Reactant: N#Cc1cccc(F)c1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1cccc(-n2cc(Br)cn2)c1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
3-Fluorobenzonitrile (4.4 mL, 40 mmol), 4-bromopyrazole (6 g, 40 mmol) and potassium carbonate (11 g, 80 mmol) were weighed into a flask and flushed with Ar(g). Dry DMF (80 mL) was added and the reaction mixture was stirred at 140° C. for 18 h. The reaction mixture was then cooled to rt and partitioned between EtOAc (200 mL) and brine (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (3×150 mL), the combined organic layers were washed with brine (3×50 mL), dried over Na2SO4, filtered and concentrated to afford a solid. This was recrystallized from EtOAc/hexane to give 3-(4-bromo-1H-pyrazol-1-yl)benzonitrile as a beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: FC(F)(F)CCBr
Reactant: N#Cc1ccc(CC(C#N)C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 27.4 %

Procedure:
Using 1.00 g of (4-cyanobenzyl)malononitrile, 10 ml of N,N-di-methylformamide, 0.36 g of sodium hydride (60% in oil), and 2.37 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.42 g of 2-(4-cyanobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (22)).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1>C1COCC1.ClCCl>[Br:1][CH:42]([C:43]1[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=1)[C:41]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[Cl:34])=[O:50]
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1Cl
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)C(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
29.54 g of phenyltrimethylammonium tribromide are added to a solution of 20.83 g of 1-(2-chlorophenyl)-2-(4-chlorophenyl)ethanone in THF. The homogeneous solution is stirred at room temperature for 1 hour 15 minutes. The reaction medium is filtered and concentrated to dryness. The crude reaction product is taken up in dichloromethane and washed successively with water, with aqueous Na2CO3 solution and then with water. The organic phase is dried over Na2SO4, filtered and concentrated to dryness by distilling off the solvent under reduced pressure. The product is obtained in the form of an oil that crystallizes slowly. The crystals are washed with a minimum amount of ethanol to give the expected product.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O.O>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4](=[CH:3][CH2:2][N:21]2[C:20](=[O:22])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:27])[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=CCBr)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
A solution of 5.775 g (19.900 mM) of tert-butyl 4-(2-bromoethylidene)piperidine-1-carboxylate and 4.05 g (21.9 mM) of potassium phthalimide in 100 ml of N,N-dimethylformamide was stirred at 100° C. for 1 hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over anhydrous magnesium sulfate (MgSO4) and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([N:6]1[C:5]([C:20]2[N:24]([C:25]3[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=3)[N:23]=[CH:22][CH:21]=2)=[C:4]([CH3:3])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]1=[O:19])(=[O:35])[CH3:34]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 1 h

Procedure:
Sodium hydride (12.5 mg of a 60% dispersion in mineral oil, 0.31 mmol) was added to a stirred suspension of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (102 mg, 0.25 mmol) in THF (5.0 mL) under a nitrogen atmosphere. This resulted in degassing and the formation of a yellow solution. Acetyl chloride (0.022 mL, 0.5 mmol) was added and the mixture was stirred for 1 h then left to stand for 16 h. Water (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (2 g Si II SPE eluted with DCM then 10% EtOAc in DCM). Concentration of the appropriate fractions in vacua gave the title compound which was freeze-dried from acetonitrile/water to afford a fluffy white solid (56 mg).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)CCC1CNCCO1
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 59.9 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.64 g, 1.4 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid (0.22 g, 1.4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.45 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Br.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:30]=[C:29]([NH2:31])[CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[N:30]=[C:29]([NH2:31])[CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(CBr)cc1OC
Reactant: Nc1cccc(-c2ccc(C3CCNCC3)cc2)n1
Product: COc1ccc(CN2CCC(c3ccc(-c4cccc(N)n4)cc3)CC2)cc1OC

Procedure:
Prepared from Example 13, using 3,4-dimethoxybenzyl bromide to alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 89%, mp 150-165° C. as the hydrochloride salt.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:22]#[N:23])[CH2:15][CH2:14]1)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([N+:6]([O-:9])=[O:7])=[CH:19][C:20]=2[C:22]#[N:23])[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCc2cccc(C#N)c21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc([N+](=O)[O-])cc(C#N)c21
Temperature: 0 °C
Yield: 66.7 %

Procedure:
To a mixed solution of acetic acid (3.8 ml), concentrated sulfuric acid (4.7 ml) and funing nitric acid (0.8 ml), under cooling with stirring, were added only small portions of N-acetyl-7-cyano-indoline (2.42 g). After stirred at the temperature as such for 7.5 hours, the reaction mixture was poured into ice-water (50 ml). The deposited crystal was collected by filtration, washed with water and acetone, and then dried to give the intended compound 2.6 g (66.7%) as white powder. M.P.: 245°-255° C.
Reaction SMILES: [OH-].[Na+].S([O:8][CH3:9])(OC)(=O)=O.[OH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](O)=[CH:16][CH:17]=2)[CH:12]=1>ClCCl.O>[OH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:8][CH3:9])=[CH:16][CH:17]=2)[CH:12]=1
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2ccc(O)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
Sodium hydroxide (20 ml, 1M) and dimethyl sulfate (15.0 ml, 158 mmol) were added dropwise to a solution of 2,7-dihydroxynaphthalene (6.6 g, 40 mmol) in dichloromethane (100 ml) and water (60 ml). Additional sodium hydroxide (20 ml, 1M) and dimethyl sulfate (15.0 ml, 158 mmol) were added and the resulting mixture was stirred at room temperature for 2 hours. The two phases were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic extracts were washed with 1 M HCl, dried over magnesium sulfate and concentrated under vacuum. The crude material was purified by column chromatography (5:1 heptane/ethyl acetate) to give 2-hydroxy-7-methoxynaphthalene (2.1 g, 30%, 100% AUC HPLC): 1H NMR (300 MHz, CDCl3) δ 7.66-7.70 (m, 2H), 6.94-7.08 (m, 4H), 4.90 (s, 1H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[N:10]#[C:11][NH2:12]>>[C:11]([NH:12][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Cl:1])=[O:8])#[N:10]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: N#CN
Product: N#CNC(=O)c1sccc1Cl

Procedure:
Compounds of this invention with a linker between middle ring and Ar2 may be prepared as illustrated by the exemplary reaction in Scheme 11. Reaction of 3-chloro-thiophene-2-carbonyl chloride with cyanamide produces N-cyano-3-chloro-thiophene-2-carboxylic acid amide, followed by treating with hydroxyamine to give 3-amino-5-(3-chloro-2-thienyl)-1,2,4-oxadiazole. The amine was refluxed with 4-chlorobenzaldehyde in toluene to produce (4-chloro-benzylidene)-[5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-amine.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[CH3:39][NH:40][CH3:41]>>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[CH:11]=[CH:12][C:7]([N:40]([CH3:41])[CH3:39])=[N:8][C:9]=4[CH3:36])[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:34])[F:35])[C:28]([F:29])([F:30])[F:31])=[CH:23][CH:24]=1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CNC
Product: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 70 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A mixture of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (122.3 mg, 0.206 mmol) and dimethylamine (2.0 M tetrahydrofuran solution, 1.0 mL) was stirred at 70° C. for 24 hrs. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (67.3 mg, 0.137 mmol, 67%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][NH:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][N:14]([CH3:17])[C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: Clc1nc(-c2cccnc2)nc2[nH]ccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2c(Cl)nc(-c3cccnc3)nc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a solution of 4-chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.34 mmol, 1.0 eq.) in dry DMF (20 mL) was added Cs2CO3 (221 mg, 0.68 mmol, 2.0 eq.) and iodomethane (54.3 mg, 0.38 mmol, 1.1 eq.) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2.5 h. The reaction mixture was poured into ice water and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 8:1) to give 65 mg of xlvi-a as brown solid (56.7%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([O-:23])([O-])=[O:21].[Na+].[Na+].O>CC#N.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])=[O:21])=[CH:16][CH:15]=2)=[N:3][C:4]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ncc(Br)nc1-c1noc(-c2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)nc1-c1noc(-c2ccccc2)n1
Temperature: 110 °C
Yield: 76 %

Procedure:
5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyrazin-2-amine (200 mg, 0.6287 mmol) 4-carboxyphenylboronic acid (104.3 mg, 0.6287 mmol) and Na2CO3 (133.2 mg, 1.257 mmol) were suspended in MeCN (3.314 mL)/water (3.314 mL) and the mixture de-gassed (×5) and treated with Pd(PPh3)4 (72.65 mg, 0.06287 mmol). The reaction was de-gassed again and heated at 110° C. in the microwave for 30 minutes. The mixture was concentrated to half its original volume and washed with DCM. The aqueous phase was acidified to pH4 (2M HCl) and resulting precipitate collected, washed with water and dried under vacuum (172 mg, 76% Yield). 1H NMR (400.0 MHz, DMSO) d 7.41 (2H, br s), 7.69 (2H, m), 7.76 (1H, m), 7.98 (2H, m), 8.09 (2H, m), 8.29 (2H, m), 8.94 (1H, s); MS (ES+) 360.98
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>O>[CH:1]([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:7])[OH:8])=[O:2]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CO
Solvent: O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
The preparation of N-formyl-L-aspartic anhydride was repeated several times in order to prepare multiple first reaction mixtures. To each of these first reaction mixtures was added 100 ml of one of the alkyl ester or hindered alcohol solvents listed in Table 1 followed by the addition of 44.6 grams (0.27 mole) of L-phenylalanine. The resulting slurries were maintained at room temperature for 5 hours for completion of the in situ coupling process. As the reaction proceeded, the slurries became more and more solidified in each reaction and a quantity of a methanol and water solution (10:1) was added in order to dissolve all the solids therein. 2.0 grams aliquots were analyzed in each reaction mixture by HPLC. The resulting α/β ratios of N-formyl-L-aspartyl-L-phenylalanine formed in each reaction are as follows:
Reaction SMILES: C(O[C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=O)C.Cl.[OH:18][C@H:19]1[CH2:24][CH2:23][C@H](N)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>O>[OH:18][C@H:19]1[CH2:24][CH2:23][C@H:4]([N:6]2[C:7](=[O:16])[C:8]3=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]3[C:10]2=[O:11])[CH2:21][CH2:20]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1

Procedure:
N-Ethoxycarbonylphthalimide (100 g; 0.46 mol) was added to a mixture of trans-4-hydroxycyclohexylamine hydrochloride (69 g; 0.46 mol), potassium carbonate (158 g; 1.15 mol) and water (1 L) at room temperature. After stirring for 3 h the title compound (95 g) was isolated by filtration, washing with water then ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10](=[N:13]O)[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]>C(O)C.O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]1[C:9]2[CH:10]([NH2:13])[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc2c1C(=NO)CO2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cccc2c1C(N)CO2
Reaction time: 18 h
Yield: 95.1 %

Procedure:
A mixture of the above described 4-ethoxy-benzofuran-3-one oxime (4.2 g, 21.7 mmol) in ethanol (200 mL) and tetrahydrofuran (200 mL) with 10% palladium on carbon (4.0 g) was hydrogenated at 23° C. and atmospheric pressure for 18 h. Filtered the catalyst off, washed with ethanol, evaporated the filtrate totally and dried in high vacuum to give the title compound as a light brown solid (3.7 g, 1:1 mixture of product and starting material); MS: m/e=163.3 (M+H+).
Reaction SMILES: [CH:1]([C:4]1([CH2:12][OH:13])[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH:5]1[CH3:11])([CH3:3])[CH3:2].CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH:1]([C:4]12[CH2:9][CH2:8][C:7]([CH3:10])([CH2:6][CH:5]1[CH3:11])[O:13][CH2:12]2)([CH3:3])[CH3:2]
Reactant: CC1=CC(C)C(CO)(C(C)C)CC1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)C12CCC(C)(CC1C)OC2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(1-Isopropyl-2,4-dimethyl-cyclohex-3-enyl)-methanol (165 g, 0.9 mol, obtained as detailed above) was dissolved in toluene with methanesulfonic acid (MSA, 5 g, 0.05 mol). The resulting solution was heated to 70° C. and aged at 70° C. for 2 hours. GC analysis showed the completion of cyclization. The reaction mixture was cooled to room temperature, washed with sodium carbonate solution, and distilled to provide 4-isopropyl-1,5-dimethyl-2-oxa-bicyclo[2.2.2]octane.