Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[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[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl.[NH2:27][CH2:28][C:29](N)=[O:30]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:27][CH2:28][CH:29]=[O:30])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NCC(N)=O
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC=O)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and glycinamide hydrochloride.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.P(=O)(O)(O)O.N([O-])=O.[Na+].[BrH:23]>O>[Br:23][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: Br
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(Br)sc2c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Into a 150 mL beaker, 2-amino-6-nitrobenzothiazole (5.1089 g, 25.39 mmol, 1 eq) was mixed vigorously with phosphoric acid, 85 wt. % (22.6 mL, 13 eq) at 50° C. The solution was then cooled to −20° C., using an acetone/dry ice bath. To this, a solution of NaNO2 (1.943 g, 28.16 mmol, 1.1 eq) in water (5.0 mL), also cooled to −20° C., was added slowly over the course of 15 min. After 1 h, the resulting suspension was poured over a solution of CuBr (4.593 g, 32.02 mmol, 1.3 eq) in 48% HBr (25.3 mL) at rt and was stirred. Additional HBr (≈35 mL) aided in transfer. After 1 h, the mixture was heated at 40° C. for 2 h. After 2 h, the heat was turned off and the reaction continued to stir at rt for 16 h. The crude mixture was diluted with water to a final volume of 200 mL and was extracted with DCM (3×). The organics were dried over anhydrousmg2SO4, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto silica gel, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with DCM/Hex 1:1→2:1→neat DCM]. Fractions containing product were combined, concentrated in vacuo, and re-chromatographed to give the title compound as an orange solid. 1H NMR (400 MHz, CDCl3): δ=8.11 (d, J=9.2 Hz, 1H), 8.38 (dd, J=9.2, 2.4 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H). MS (ES+): m/z 258.95/260.96 (100/96) [MH+]. HPLC: tR=3.43 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH:1]([Si:3]([CH:8]=[CH2:9])([CH:6]=[CH2:7])[CH:4]=[CH2:5])=[CH2:2].[C:10]1([PH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:17]1([P:16]([CH2:2][CH2:1][Si:3]([CH2:8][CH2:9][P:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH2:6][CH2:7][P:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:4][CH2:5][P:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C[Si](C=C)(C=C)C=C
Reactant: c1ccc(Pc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(P(CC[Si](CCP(c2ccccc2)c2ccccc2)(CCP(c2ccccc2)c2ccccc2)CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Yield: 39.2 %

Procedure:
A mixture of 27.2 g (0.2 mole) of tetravinyl silane and 149.5 g (0.804 mole) diphenylphosphine was reacted in a quartz pressure tube at 200° C. with u.v. light initiation until most of the diphenyl phosphine was converted. The hot, molten reaction mixture was added to 720g of hot toluene with stirring. The tetraaduct product precipitated from the solution as a white crystalline solid. The mixture was allowed to coolto ambient temperature and then filtered with suction. After washing with toluene and drying in vacuo, 84 g (47.7%) of crude product was obtained. This was recrystallized from 1200 ml of xylene to obtain 69 g of the pure tetrakis-(diphenylphosphinoethyl) silane of mp. 198°-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[F:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].FC1C=CC=CC=1C=O.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:15]([N:16]([CH3:18])[CH3:17])[C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[F:12]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: C[N+](C)=Cc1ccccc1F
Agent: CNC
Agent: O=Cc1ccccc1F
Agent: [Cl-]
Product: CN(C)C(c1ccccc1F)c1c[nH]c2ccc(Cl)cc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and (2-fluoro-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]2[CH:14]=[N:13][C:12]([S:15][CH3:16])=[C:5]2[S:6][C:7]=1[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1.[Cl-].[Na+].O>[CH3:1][S:2][C:3]1[N:4]2[CH:14]=[N:13][C:12]([S:15][CH3:16])=[C:5]2[S:6][CH:7]=1
Reactant: CSc1ncn2c(SC)c([Si](C)(C)C)sc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncn2c(SC)csc12
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of 1.88 g of 3,7-bis(methylthio)-2-trimethylsilylimidazo[5,1-b]thiazole in 50 ml of THF was ice cooled. A 1 M tetra-n-butylammonium fluoride/THF solution (8.16 ml) was added in an argon atmosphere to the solution. The mixture was stirred at the same temperature for one hr. Brine was added thereto, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 1.30 g of 3,7-bis(methylthio)imidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[NH:45])[NH:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=[CH:29][CH:28]=1>CN(C)C=O>[CH2:38]([O:37][C:35]([NH:34][C:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][N:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[C:7](=[O:13])[C:8]2=[O:12])=[CH:32][CH:31]=1)=[NH:45])=[O:36])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(CCCOc3ccc(C(=N)NC(=O)OCc4ccccc4)cc3)C(=O)C2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.00 g of 1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, and 0.17 g of sodium hydride (60%, oil) was added to the solution, followed by stirring at 50° C. for 30 minutes. Then, the reaction mixture was cooled to room temperature, after which 1.48 g of 1-bromo-3-(4-benzyloxycarbonylamidinophenoxy)propane was added thereto and the resulting mixture was stirred overnight at the same temperature. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=20:1) to obtain 1.76 g of 4-(3-(4-benzyloxycarbonylamidinophenoxy)propyl]-1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine as colorless crystals.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1C=C(C2(O)CCCCC2CCN2CCN(C)CC2)C=CC=1OCC1C=CC=C(C(F)(F)F)C=1.Cl.Cl.[Cl:40][C:41]1[CH:42]=[C:43]([CH:59]([C:67]2([OH:73])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[CH2:60][N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[CH:50]=1>>[ClH:3].[ClH:40].[Cl:40][C:41]1[CH:42]=[C:43]([CH:59]([C:67]2([OH:73])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[CH2:60][N:61]2[CH2:62][CH2:63][N:64]([CH3:4])[CH2:65][CH2:66]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:57])([F:58])[F:56])[CH:50]=1
Reactant: OC1(C(CN2CCNCC2)c2ccc(OCc3cccc(C(F)(F)F)c3)c(Cl)c2)CCCCC1
Reactant: CN1CCN(CCC2CCCCC2(O)c2ccc(OCc3cccc(C(F)(F)F)c3)c(Cl)c2)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(OCc3cccc(C(F)(F)F)c3)c(Cl)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-[1-(3-chloro-4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-2-(4-methylpiperazin-1-ylethyl]cyclohexanol dihydrochloride was prepared from 1-[1-(3-chloro-4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride (See Example 423). MS (ESI) m/z 511; HRMS: calcd for C27H34ClF3N2O2+H+, 511.23336. found (ESI, [M+H]+), 511.231.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH:20]([NH:23][CH2:24][C:25]#[CH:26])([CH3:22])[CH3:21].C([Li])CCC>O>[CH:20]([NH:23][CH2:24][C:25]#[C:26][C:12]1([OH:14])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:22])[CH3:21]
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: C#CCNC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)NCC#CC1(O)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 9.0 g. of fluoren-9-one dissolved in 500 ml. of tetrahydrofuran was added dropwise over one hour to a stirred cold (-80° C.) solution of 500 ml. of tetrahydrofuran containing 9.7 g. of 3-isopropylaminopropyne and 75 ml. of a 1.6 molar tetrahydrofuran solution of n-butyl lithium. After the addition was complete, the reaction mixture was warmed to room temperature and then heated to reflux for sixteen hours. The reaction mixture was next cooled to room temperature and diluted by the dropwise addition of 200 ml. of water. The aqueous mixture was extracted several times with diethyl ether, and the ethereal extracts were combined, and the reaction product was converted to the hydrochloride salt by the addition of 300 ml. of 6N hydrochloric acid to the ethereal solution. The aqueous acid layer containing the reaction product was separated, washed once with fresh diethyl ether, and then made alkaline by the addition of 10 percent sodium hydroxide, which effected liberation of the hydrochloride salt back to the free amine. The free amine was extracted into fresh diethyl ether. The ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure then afforded 2.3 g of 9-(3-isopropylaminopropynyl)-9-hydroxyfluorene. M.P. 214°-215° C.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:28])[C@:6]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)([CH3:15])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C1COCC1>[C:19]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:17][C:16]([C@@:6]([C:5]([OH:28])=[O:4])([CH3:15])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])=[CH:21][CH:20]=1
Reactant: COC(=O)[C@](C)(NC(=O)OC(C)(C)C)c1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@](C)(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
LiOH (1.63 ml, 1M) was added dropwise to a solution of methyl-N-Boc-2-(4-biphenylyl)alaninate (482 mg, 1.36 mmol) in THF (3 ml). The resulting mixture was stirred at rt for 16 h. Solvent was removed under reduced pressure and the residue was taken up in water (10 ml) and washed with EtOAc. The aqueous layer was acidified with HCl (1M) to pH ˜2 and the product was extracted by EtOAc (3×10 ml). The combined extracts were washed with water and brine, dried and concentrated which left 470 mg (90%) as a white solid. MS (ES) m/e 342.4 [M+H]+
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[N:16]1([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][NH2:32])(=[O:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:32]([CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:22]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)(=[O:24])=[O:23])[CH:10]=1
Reactant: NCc1ccccc1S(=O)(=O)N1CCOCC1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1ccccc1S(=O)(=O)N1CCOCC1
Yield: 64.3 %

Procedure:
2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.34 g), 1-[2-(morpholin-4-ylsulfonyl)phenyl]methanamine hydrochloride (2.0 g) and potassium carbonate (1.97 g) were stirred in ethanol (20 ml) at 90° C. for 16 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.82 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:8]=[C:7]2[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:10]([C:12]([OH:14])=O)=[CH:11][C:6]2=[CH:5][CH:4]=1.[NH2:25][C:26]1[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1>>[Cl:32][C:29]1[N:28]=[CH:27][C:26]([NH:25][C:12]([C:10]2[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:7]3=[N:8][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=[C:6]3[CH:11]=2)=[O:14])=[CH:31][CH:30]=1
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)nc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)nc1)c1cc2ccc(C(F)(F)F)nc2n1Cc1cccc(F)c1

Procedure:
According to a method similar to that described in Stage 6.1, by reacting 0.5 g (1.48 mmol) of 6-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, described in Stage 15.2 with 0.288 (2.22 mmol) of 3-amino-6-chloropyridine, we obtain 0.33 g of the expected compound in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([NH:20][NH:21][C:22](=[O:24])[CH3:23])=O)[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]1[O:24][C:22]([CH3:23])=[N:21][N:20]=1)[NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NNC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nnc(-c2cc3c(OCc4ccccc4)cccc3[nH]2)o1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
N′-(4-Benzyloxy-1H-indol-2-ylcarbonyl)acetohydrazide (7.5 g) was dissolved in tetrahydrofuran (250 ml) and triphenylphosphine (9.0 g) and triethylamine (6 ml) were added. The mixture was stirred under ice-cooling. Diisopropyl azodicarboxylate (40% toluene solution) (17.7 g) was added and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.0 g) as yellow crystals.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)CCl.[C:25]([CH:27]=[P:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)#[N:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:14]([O:13][C:11](=[O:12])[NH:10][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:7](=[O:9])[C:27]([C:25]#[N:26])=[P:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)NCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)NCC(NC(=O)OCc1ccccc1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
This intermediate was prepared generally according to the method of Wasserman et al., J. Org. Chem. (1994), vol. 59, 4364. In particular, to a solution of (3-acetylamino-2-benzyloxycarbonylaminopropionic acid (1.40 g, 5.0 mmol, 1 equiv) in CH2Cl2 (50 mL) at 0° C. were added EDC (1.00 g, 5.25 mmol, 1.05 equiv) and DMAP (61 mg, 0.5 mmol, 0.1 equiv). A solution of (cyanomethylene)triphenylphosphorane (prepared as described in Freudenreich et al., J. Am. Chem. Soc. (1984), vol. 106, 3344) (2.50 g, 8.30 mmol, 1.66 equiv) in CH2Cl2 (16 mL) was added to the acid solution dropwise over 20 min. After stirring 2 h at 0° C., the reaction mixture was partitioned between deionized water (30 mL) and CH2Cl2 (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (5% CH3OH in CH2Cl2) to give [1-(acetylaminomethyl)-3-cyano-2-oxo-3-(triphenyl-λ5-phosphanylidene)propyl]-carbamic acid benzyl ester (1.98 g, 70% yield) as a colorless foam. Rf=0.40 (10% CH3OH in CH2Cl2). IR (cm−1) 3312, 2175, 1716, 1437. 1H NMR (CDCl3) δ1.91 (s, 3H), 3.66-3.79 (m, 2H), 5.04-5.06 (m, 1H), 5.10 (s, 2H), 5.94 (br s, 1H), 6.21 (br s, 1H), 7.26-7.70 (m, 21H).
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH3:45])[CH2:3][O:4][C:5](=[O:44])[N:6]=[C:7]([NH2:43])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:29]2[N:33]=[C:32]([O:34][CH2:35]Cl)[N:31]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:30]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])=[CH:10][CH:9]=1.C(=O)([O-])O.[K+].[I-].[Na+].[CH:54]([O:57][C:58](=[O:65])[C:59]([CH3:64])([CH3:63])[C:60]([OH:62])=[O:61])([CH3:56])[CH3:55]>CN(C=O)C>[CH:54]([O:57][C:58](=[O:65])[C:59]([CH3:63])([CH3:64])[C:60]([O:62][CH2:35][O:34][C:32]1[N:31]([C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:30]=[C:29]([C@H:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH2:43])=[N:6][C:5]([O:4][CH2:3][C:2]([CH3:46])([CH3:45])[CH3:1])=[O:44])=[CH:9][CH:10]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])[N:33]=1)=[O:61])([CH3:56])[CH3:55]
Reactant: CC(C)OC(=O)C(C)(C)C(=O)O
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCCl)n(-c3ncccn3)n2)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OC(C)C)n(-c3ncccn3)n2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a mixture of [1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]carbamic acid 2,2-dimethylpropyl ester (Example 2b, 70 mg), potassium hydrogen carbonate (74 mg), and DMF (5 mL), sodium iodide (79 mg) and 2,2-dimethylmalonic acid monoisopropyl ester [CAS No. 7695-26-3] (92 mg) were added, and the resulting mixture was stirred at 45° C. overnight. The reaction mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a racemate of the captioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5](/[CH:9]=C/C(OC)=O)=[C:4]([Cl:15])[CH:3]=1.[O:16]=[O+][O-].CSC>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:16])=[C:4]([Cl:15])[CH:3]=1
Reactant: O=[O+][O-]
Reactant: COC(=O)/C=C/c1c(Cl)cc(Br)cc1Cl
Solvent: CSC
Solvent: ClCCl
Product: O=Cc1c(Cl)cc(Br)cc1Cl

Procedure:
4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL), and a 48% hydrogen bromide aqueous solution (120 mL) was added, followed by stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 ml,) was added dropwise thereto, the mixture was stirred for 30 minutes, and methyl acrylate (200 nit), and water (200 mL) were added, followed by stirring for 1 hour. At room temperature, cuprous oxide (2 g) was added, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved in dichloromethane, an ozone gas was introduced at −70° C., and ozone oxidization was performed. To the reaction solution was added dimethyl sulfide (40 mL), and this was extracted with ethyl acetate to obtain 4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g).
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][NH:12][C:13](=[O:39])[CH2:14][C@@H:15]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:19]2[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:18]=2[N:17]2[C:35]([CH3:38])=[N:36][N:37]=[C:16]12)C(=O)[O-])(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[C:19]3[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:18]=3[N:17]3[C:35]([CH3:38])=[N:36][N:37]=[C:16]3[C@H:15]([CH2:14][C:13]([NH:12][CH2:11][CH2:10][NH:6][CH3:5])=[O:39])[N:21]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCN(CC(C)(C)C)C(=O)[O-])c1nnc(C)n1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Intermediate 16 (189 mg, 0.342 mmol) and trifluoroacetic acid (0.022 mL, 0.285 mmol) were dissolved in DCM (3 mL) and stirred at 25° C. under N2 for 2 h. The solvent was evaporated under vacuum and the residue obtained dissolved in DCM and re-evaporated under vacuum to give a yellow oil which was dried under high vacuum to afford the title compound as a yellow solid (153 mg, 0.270 mmol, 95% yield). LC/MS (M(35Cl)+H)+ 453, (M(37Cl)+H)+ 455; RT 0.74 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(N(CC)CC)C.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([C:20]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a 0C solution of benzotriazole (5.05 g, 42.39 mmol) in CH2Cl2 (100 mL) was added dropwise triethylamine (9.0 ml, 64.57 mmol) followed by cyclopropyl carbonyl chloride (4.2 ml, 46.28 mmol). The mixture was stirred at rt for 1 h and then quenched with a solution of 2N aqueous HCl (75 ml). The organic phase was washed with 2 N HCl (2×75 mL) and water (100 ml), dried with MgSO4 and concentrated in vacuo. The solid residue was washed with hexenes, filtered and dried to yield 1-(cyclopropylcarbonyl)-1H-1,2,3-benzotriazole as a white solid (5.92 g, 75%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][NH:13][CH3:14]>CO>[CH3:12][N:13]([CH3:14])[CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CNC
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CO
Product: CN(C)C1CCC2(CC1)OCCO2

Procedure:
Prepared from 1,4-dioxaspiro[4.5]decan-8-one and dimethylamine. Pale brown oil, Rf : 0.28 (silica gel; methylene chloroide/methanol/concentrated ammonia=9:1:0.1)