Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.CCOC(C)=O>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A slurry of 10% Pd/C (500 mg) in DMF (5 mL) was added to a solution of tert-butyl 5-nitro-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (I8) (1.40, 4.59 mmol) in DMF (45 mL) and the resulting mixture was stirred under a hydrogen atmosphere for 16 hours at room temperature. EtOAc (100 mL) was added and the resulting suspension was filtered through a Celite pad, washing with EtOAc (150 mL). The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. and then 0-20% MeOH in EtOAc) to give the title compound I9 as a yellow oil (1.18 g, 93%); 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J=2.4, 1.0 Hz, 1H), 7.00-6.87 (m, 2H), 4.22 (brs, 2H), 3.59 (brs, 2H), 2.85-2.67 (m, 3H), 1.86 (m, 2H), 1.72-1.59 (m, 2H), 1.46 (s, 9H). LCMS-A: rt 4.416 min; m/z 278 [M+H]+.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([O:8][S:2]([NH2:5])(=[O:3])=[O:4])[CH:10]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OS(N)(=O)=O)c1

Procedure:
Following the procedure of Example 78, a reaction of 8.8 ml (0.10 mole) chlorosulfonyl isocyanate and 15.2 g (0.10 mole) of methyl 3-hydroxybenzoate in 200 ml of toluene was heated at reflux for 7.5 hr and worked up to obtain 10.53 g, mp 145°-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[CH3:14][CH2:15][O:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]([O:16][CH2:15][CH3:14])=[O:18])=[CH:24][CH:23]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(OC)cc2)cc1
Reaction time: 19 h

Procedure:
To a solution of 10 g. of p-methoxycinnamoyl chloride in 200 ml. of dichloromethane is slowly added a solution of 0.24 g. of benzocaine and 7.1 ml. of triethylamine in 200 ml. of dichloromethane. The mixture is stirred for 19 hours, then the organic layer is washed with 200 ml. of 10% hydrochloric acid followed by 200 ml. of brine, dried over magnesium sulfate, and condensed to a solid. This solid is crystallized from 100 ml. of ethanol, giving 10.6 g. of the desired product as yellow crystals, m.p. 163°-165.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][CH2:21][CH2:22][O:23][C:24]1[N:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][CH:29]=1>>[CH:30]([OH:32])=[O:31].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[N:25][C:24]([O:23][CH2:22][CH2:21][F:20])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: O=C(O)c1cnc(OCCF)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCCF)cn3)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) and 5-(2-fluoro-ethoxy) -pyrazine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as an off-white amorphous material. MS (ISP): m/z=442.3 [M+H]+.
Reaction SMILES: ClCCl.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([Cl:18])=[C:11]([CH2:13][NH:14]C(=O)C)[CH:12]=1)(=[O:6])[CH3:5].S(=O)(=O)(O)O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:14][CH2:13][C:11]1[CH:12]=[C:7]([C:4](=[O:6])[CH3:5])[CH:8]=[CH:9][C:10]=1[Cl:18]
Reactant: CC(=O)NCc1cc(C(C)=O)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)c1ccc(Cl)c(CN)c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To 199.8 kg of a dichloromethane solution of N-[(5-acetyl-2-chlorophenyl)methyl]acetamide obtained in Example 3-(B), 90 kg of water and 46 kg (0.45 kmoles) of 98% sulfuric acid were added. Dichloromethane was distilled off under normal pressure over 1.5 hours until the inner temperature reaches 100° C., followed by aging for 6 hours. After the completion of the reaction, the reaction solution was cooled to 50° C. over 20 minutes and 90 kg of water and 105 kg of toluene were added. After cooling, 212 kg of an aqueous 25% sodium hydroxide solution was added dropwise at 15 to 25° C. over 2.5 hours. After heating to 40° C. over 30 minutes, the organic layer was partitioned to obtain a toluene solution of 1-[3-(aminomethyl)-4-chlorophenyl]ethan-1-one.
Reaction SMILES: [Si:1]([N:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][CH:10]=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][O:17][SiH:18]([O:21][CH3:22])[O:19][CH3:20]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[Si:1]([N:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][Si:18]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:16])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CO[SiH](OC)OC
Reactant: C=CCN(CCCC)[Si](C)(C)C(C)(C)C
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CCCCN(CCC[Si](OC)(OC)OC)[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 22.8 g (0.1 mol) of N-t-butyldimethylsilyl-N-butyl-N-allylamine and 0.07 g of a toluene solution of platinum/1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (Pt concentration 3 wt %) and heated at 50° C. Once the internal temperature became steady, 12.2 g (0.1 mol) of trimethoxysilane was added dropwise over 1 hour. Stirring was continued at the temperature for a further 1 hour. The reaction solution was distilled, collecting 27.3 g of a fraction having a boiling point of 128-129° C./0.4 kPa.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14]>O>[OH:14][CH2:13][CH2:12][CH2:11][NH:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NCCCO
Solvent: O
Product: N#Cc1ccc(NCCCO)cc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A mixture of 4-fluorobenzonitrile (12.0 g, 99.1 mmol) and 3-amino-1-propanol (59.6 g, 793 mmol) was stirred at 80° C. under an inert atmosphere for 3 hours before water (150 mL) was added. The mixture was allowed to cool to rt, and was then extracted with diethyl ether. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to yield 17 g (97%) of the title compound as an oil that crystallised upon standing.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N:14][C:15]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:16]([CH3:19])[C:17]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C@H:28]([CH3:32])[C:29](O)=[O:30].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N:14][C:15]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:16]([CH3:19])[C:17]=1[CH3:18])[C:29](=[O:30])[C@H:28]([Cl:27])[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](Cl)C(=O)O
Reactant: Cc1c(NCCNCc2ccccc2)nnc(-c2ccc(F)cc2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(NCCN(Cc2ccccc2)C(=O)[C@@H](C)Cl)nnc(-c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Sequentially treat a solution of N1-benzyl-N2-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)ethane-1,2-diamine (4.90 g, 13.98 mmol) in CH2Cl2 (70 mL) with (R)-(+)-2-chloropropionic acid (1.84 mL, 20.97 mmol), triethylamine (2.92 mL, 20.97 mmol), HOBT (3.21 g, 20.97 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.02 g, 20.97 mmol). Stir the resulting mixture at ambient temperature overnight. Wash the reaction mixture with saturated aqueous NaHCO3. Extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (20% EtOAc in hexanes) to afford the title compound as a yellow foam (4.59 g, 74%). ES/MS m/z 441.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([F:17])[CH2:12][N:11]([C@@H](C1C=CC=CC=1)C)[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([F:17])[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H](c1ccccc1)N1C[C@@]2(F)CCC[C@@]2(NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@]12CCC[C@]1(F)CNC2
Yield: 91.3 %

Procedure:
(1R,5S)-1-(tert-Butoxycarbonylamino)-5-fluoro-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (700 mg, 2.0 mmol) was dissolved in ethanol (30 mL). 10% palladium-carbon (50% wet) (1.01 g) was added, and the mixture was stirred in a hydrogen atmosphere at 50° C. for 15 hours. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=98:2→95:5) to give 446 mg of the title compound as a pale yellow solid.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][C:20](=[O:22])[C:19]([C:23](=O)[CH2:24][CH3:25])=[C:18]([OH:27])[CH2:17]2)=[CH:12][CH:11]=1)=[O:8].[CH2:28]([O:30][NH2:31])[CH3:29]>O>[CH2:28]([O:30][N:31]=[C:23]([C:19]1[C:20](=[O:22])[CH2:21][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7]([O:6][CH3:5])=[O:8])=[CH:11][CH:12]=2)[CH2:17][C:18]=1[OH:27])[CH2:24][CH3:25])[CH3:29]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NC(=O)OC)cc2)CC1=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NC(=O)OC)cc2)CC1=O
Temperature: 40 °C
Reaction time: 15 h
Yield: 58.7 %

Procedure:
Into 30 ml of chloroform was dissolved 1.8 g of 5-[4-(methoxycarbonylamino)phenyl]-2-propionyl-3-hydroxy-2-cyclohexen-1-one and to the solution was added 0.5 g of ethoxyamine. The mixture was agitated for 15 hours at 40° C. and the chloroform containing produced water and a surplus amount of ethoxyamine was distilled off from it under a reduced pressure. And then, the ethyl ether was added in the residue and the crystal sedimented was collected with a filtering step and 1.2 g of desired compound was obtained. It was in the form of colorless crystals having a melting point of 160°-161° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CCN(C)C)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CCN(C)C)cc1
Yield: 55.1 %

Procedure:
Following general procedure D, 1-(6-bromo-4-(4-(2-(dimethylamino)ethyl)phenylamino)quinolin-3-yl)ethanone (76 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (81 mg, 0.28 mmol) to afford the desired product (49 mg, 55%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.30 (s, 1H), 8.19 (dd, J=8.8, 2.0 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.60 (d, J=8.3 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.13 (s, 2H), 3.45-3.37 (m, 2H), 3.29-3.20 (m, 2H), 3.00 (s, 6H), 2.82 (s, 3H); ESI MS m/z 494 [C27H25Cl2N3O2+H]+; HPLC 96.9% (AUC), tR=12.01 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=2)[N:11]=1.[OH-].[Na+].Cl>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3nc4ccccc4o3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of methyl 2-(benzo[d]oxazol-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (100 mg, 0.27 mmol) in tetrahydrofuran (20 mL) and water (2 mL) was added sodium hydroxide (21 mg, 0.53 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (20 mL), adjusted the pH to 6 with hydrochloric acid (3N) and filtered to give 2-(benzo[d]oxazol-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (21.9 mg, 23%).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.CCN(C(C)C)C(C)C>CCO>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[CH2:13][CH2:12][O:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Temperature: 100 °C
Yield: 96.2 %

Procedure:
EtOH (12.00 mL) was added to a microwave vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (2.05 g, 7.02 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 1.489 g, 7.435 mmol) and DIPEA (1.836 g, 14.20 mmol). The vial was sealed and the mixture was heated at 100° C. under microwave irradiation for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a yellow solid (2.46 g, 96%). LCMS calc. for C17H25N4O5 (M+H)+: m/z=365.2. found 365.1.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)[S:4][N:3]=1.[CH2:21]([C:23]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C.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>[CH2:21]([C:23]1[C:30]([C:2]2[N:6]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=3)[S:4][N:3]=2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1c(C=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Temperature: 120 °C
Yield: 93.9 %

Procedure:
To a solution of 3-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazole (D45) (0.93 g), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (0.659 g) and tripotassium phosphate (1.344 g, 6.33 mmol)) in N,N-dimethylformamide (DMF) (6 mL) and water (1.500 mL) stirred under nitrogen was added Pd(Ph3P)4 (0.585 g). The reaction was sealed and heated under microwave at 120° C. for 15 min. After cooling, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (2*8 mL), dried over sodium sulphate, concentrated and purified by column chromatography to afford 2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}benzaldehyde (D47) (1 g) as a brown oil. MS (ES): C21H19F3N2O2S requires 420. found 421.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:26])[N:11]([C@H:21]2[CH2:24][C@@H:23]([OH:25])[CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:26])[N:11]([C@@H:21]3[CH2:22][C@H:23]([O:25][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:24]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:34]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](O)C2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OCC(=O)OCC)C2)c2ncnn12
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
A mixture of 3′-fluoro-4′-{[4-(cis-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.67 g), rhodium(II) acetate (dimer) (0.0066 g) and toluene (10 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl diazoacetate (1.5 g) in toluene (10 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.29 g, 37%).
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl:27][C:28]1[N:33]=[C:32]([Cl:34])[C:31]([CH2:35]I)=[CH:30][N:29]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:26])[CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:35][C:31]1[C:32]([Cl:34])=[N:33][C:28]([Cl:27])=[N:29][CH:30]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of phenylacetic acid methyl ester (1.50 g, 10.0 mmol) (Aldrich) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-phenyl-propionic acid methyl ester as a colorless oil. (Yield 1.00 g, 64.5%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[C:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:14]([N:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(C(C)=O)CC2)cc1
Yield: 102 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (7.7 g), 1-acetylpiperazine (5.0 g) and potassium carbonate (8.1 g) in dimethylformamide (50 ml) was stirred at 80° C. for 5 hr. The reaction mixture was poured into water (250 ml) and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil. The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give the title compound (11.5 g) as a colorless transparent oil.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[NH2:34][C@H:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][C@H:36]1[OH:44].C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:78][C:79]([C:81]1([NH:86][C:87]([CH:89]2[CH2:93][CH:92]([O:94][C:95]3[C:104]4[C:99](=[CH:100][C:101]([O:105][CH3:106])=[CH:102][CH:103]=4)[N:98]=[C:97]([C:107]4[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=4)[CH:96]=3)[CH2:91][N:90]2C(=O)NC(C(=O)NC2C3C(=CC=CC=3)CC2O)C(C)(C)C)=[O:88])[CH2:83][CH:82]1[CH:84]=[CH2:85])=[O:80])C>>[OH:44][C@@H:36]1[CH2:37][C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:35]1[NH:34][C:10]([C@@H:9]([NH:8][C:6]([N:90]1[CH2:91][C@H:92]([O:94][C:95]2[C:104]3[C:99](=[CH:100][C:101]([O:105][CH3:106])=[CH:102][CH:103]=3)[N:98]=[C:97]([C:107]3[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=3)[CH:96]=2)[CH2:93][C@H:89]1[C:87]([NH:86][C@:81]1([C:79]([OH:80])=[O:78])[CH2:83][C@H:82]1[CH:84]=[CH2:85])=[O:88])=[O:7])[CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: O=C([O-])NCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@@H](CC(C)(C)C)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(=O)O
Yield: 30 %

Procedure:
(2S)-tert-butoxycarbonylamino-4,4-dimethylpentanoic acid was attached to the resin as described for the preparation of compound 16 followed by reaction with (1S,2R)-1-amino-2-indanol as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (14.2 mg, 30% yield), Purity by HPLC >95% M+H+776.3.