Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]=[C:9]=[O:10])=[CH:3][CH:2]=1.[F:11][C:12]1[C:13](=[O:19])[NH:14][C:15](=[O:18])[NH:16][CH:17]=1>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([N:16]2[CH:17]=[C:12]([F:11])[C:13](=[O:19])[NH:14][C:15]2=[O:18])=[O:10])=[CH:3][CH:2]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C=NCc1ccncc1
Product: O=C(NCc1ccncc1)n1cc(F)c(=O)[nH]c1=O
Reaction time: 4 h

Procedure:
To the above solution of 4-pyridylmethyl isocyanate was added 5-fluorouracil (2.60 g.) at 80° C. and stirred for 4 hours at the same temperature. The resultant mixture was evaporated in vacuo. The residue was washed with diethyl ether (3 times) and crystallized. The crystals were filtered and washed with a small amount of ethanol. To the washed crystals a small amount of pyridine was added, and the mixture was warmed to be dissolved and cooled to be recrystallized. The crystals were washed successively with ethyl acetate and diethyl ether to give 1-[N-(4-pyridylmethyl)carbamoyl]-5-fluorouracil (1.75 g.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])([C:14]([F:18])([F:17])[CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].S(=O)(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])([C:14]([F:18])([F:17])[CH2:15][O:16][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCc2ccccc2)(C(F)(F)CO)C1
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCc2ccccc2)(C(F)(F)COS(C)(=O)=O)C1
Reaction time: 0.83 h

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (13.6 g) and triethylamine (11.4 ml) in chloroform (136 ml) cooled to 0° C. was added methanesulfonyl chloride (7.8 ml), and the mixture was stirred for 50 minutes. To the mixture was added 5% aqueous potassium bisulfate solution, and the mixture was extracted with ethyl acetate. The separated organic layer was sequentially washed with 4M aqueous sodium hydroxide solution twice and saturated aqueous sodium chloride solution once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the titled compound (17.1 g).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][CH:2]1[N:7]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A mixture of (±)-tert-butyl 3-methylpiperazine-1-carboxylate (1.5 g), 1-fluoro-4-nitrobenzene (1.06 g) and potassium carbonate (2.07 g) in dimethyl sulfoxide (15 ml) was stirred at 120° C. for 15 hours. The reaction mixture was cooled to room temperature and poured into water (30 ml). The mixture was extracted with ethyl acetate three times. The combined organic layers were washed successively with water (twice) and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 2:1) to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][NH:15][C:14](=O)[C:13]=3[CH:20]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[Cl:24][C:14]1[C:13]2[CH:20]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:4][CH:5]=3)[CH:10]=[CH:11][C:12]=2[O:18][CH2:17][CH2:16][N:15]=1
Reactant: O=C1NCCOc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)C(Cl)=NCCO3)cc1

Procedure:
A solution of 7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (3.6 g, 11.7 mmol) and phosphorous pentachloride (2.56 g, 12.3 mmol) in toluene (80 mL) was refluxed for 2 hours. The reaction mixture was concentrated to yield 5-chloro-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine and used in subsequent steps without further purification.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:26][C:22]1[O:23][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:24])[F:25])=[CH:18][CH:17]=2)=[CH:20][N:21]=1
Reactant: FC(F)(F)c1ccc(-c2cnco2)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
LiHMDS (1.06 M in THF, 28.59 mL, 30.3 mmol) was added to a solution of 5-(4-(trifluoromethyl)phenyl)oxazole 30 (5.38 g, 25.25 mmol) in THF (100 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of hexachloroethane (8.96 g, 37.87 mmol) in THF (10 mL) was added at −78° C., and the mixture was stirred at −78° C. for 2 h and allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by adding EtOAC: H2O (50 mL: 15 mL), and then extracted with Ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. The product was purified by column chromatography (Acetone/hexane as an eluent) to provide 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (6.05 g, 97% yield) as white solid. MS (ES) m/z 248 (M+H+).
Reaction SMILES: N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][C:23]1([CH3:38])[C@@H:25](/[CH:26]=[C:27](/Br)\[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[C@H:24]1[C:35]([OH:37])=[O:36].[C:39]([C@@H:41](O)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:43]=1)#[N:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:22][C:23]1([CH3:38])[C@@H:25](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[C@H:24]1[C:35]([O:37][C@H:41]([C:39]#[N:40])[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:43]=1)=[O:36]
Reactant: CCCOC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOC(=O)/C=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
0.9 ml of pyridine and 2 g of dicyclohexylcarbodiimide were added to a solution of 2.6 g of the product of Step A in 40 ml of methylene chloride and the mixture was stirred for 10 minutes. 2 g of (S)α-cyano-3-phenoxy-benzyl alcohol were added to the mixture which was stirred for 10 minutes after which 25 mg of 4-dimethylamino-pyridine were added thereto. The mixture was stirred for 90 minutes and was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 95-5 cyclohexane-ethyl acetate mixture to obtain 0.743 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-propoxycarbonyl-ethenyl]-cyclopropane-1-carboxylate and 3.64 g of a mixture. The latter was dissolved in 4 volumes of hot isopropyl ether and the mixture was stirred at 20° C. and was then vacuum filtered to obtain another 2.32 g of the desired ester melting at 68° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)[C:28](O)=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:28](=[O:29])[C:27]2[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=[C:25]([C:24]([F:39])([F:23])[F:38])[CH:26]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NCCS(C)(=O)=O
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Yield: 10 %

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 17 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). A second chromatography (preparative HPLC (Phenomenex Gemini® column), gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2)) gave the desired product as an off-white foam (10%). MS (ESI): m/z=566.10 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[CH:10][C:9]2=[O:24])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:32][C:33](OC(C)=O)=[O:34].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:33]([O:24][C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[CH:10]=1)(=[O:34])[CH3:32]
Reactant: O=c1cc(-c2cccc(C(F)(F)F)c2)[nH]c2c([N+](=O)[O-])cccc12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12

Procedure:
A solution of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinolin-4(1H)-one 37 (707 mg, 2.11 mmol), triethylamine (1 mL), and Ac2O (0.7 mL) in CH2Cl2 (10 mL) was stirred at room temperature for 16 h. Sat. aq NaHCO3 (10 mL) was added, and the reaction extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated to give 38.
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]([NH2:14])[CH3:13].[CH:15]([C:18]([CH3:25])([CH:22]([CH3:24])[CH3:23])[C:19](Cl)=[O:20])([CH3:17])[CH3:16]>O1CCCC1>[CH:15]([C:18]([CH3:25])([CH:22]([CH3:24])[CH3:23])[C:19]([NH:14][CH:12]([C:8]1[O:7][CH:11]=[CH:10][CH:9]=1)[CH3:13])=[O:20])([CH3:17])[CH3:16]
Reactant: CC(N)c1ccco1
Reactant: CC(C)C(C)(C(=O)Cl)C(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(NC(=O)C(C)(C(C)C)C(C)C)c1ccco1
Reaction time: 8 h
Yield: 45.5 %

Procedure:
In a 25 mL round bottom flask, fitted with magnetic stirrer, 15 mL of tetrahydrofuran, 2.1 mmol (1.5 eq.) of pyridine and 1.54 mmol (1.1 eq.) of 1-(furan-2-yl)ethanamine were added. 1.4 mmol of 2-isopropyl-2,3-dimethylbutanoyl chloride (prepared by hydrolysis of 2-isopropyl-N,2,3-trimethylbutanamide, WS-23 with NaNO2 in H2SO4 and subsequent acid chloride formation with SOCl2) were added and the mixture was stirred at room to temperature for 16 hours, overnight. The reaction mixture was extracted with MTBE and HCl (1N in water). The organic layer was washed with NaOH (1N in water) and brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography, obtaining 160 mg of a beige solid, mp 57-60° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].C(O)(=O)C.[NH2:18][N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[N:22][N:21]=[C:20]1[S:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[N:18][N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[N:22][N:21]=[C:20]1[S:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: Cc1nnc(SCc2ccccc2F)n(N)c1=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(C=Nn2c(SCc3ccccc3F)nnc(C)c2=O)ccc1OC
Temperature: 65 °C

Procedure:
0.054 g of 3-ethoxy-4-methoxybenzaldehyde and 0.017 ml of acetic acid were added to a solution of 0.080 g of 4-amino-3-(2-fluorobenzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one in 4 ml of ethanol, and the mixture was stirred at 65° C. The resultant precipitate was filtered off with suction, giving 4-[(3-ethoxy-4-methoxybenzylidene)amino]-3-(2-fluorobenzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH2:13])[CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[ClH:15].[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH:13][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: Clc1ccncc1
Reactant: Nn1ccc2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(ccn2Nc2ccncc2)c1
Yield: 51.5 %

Procedure:
A solution of 5-nitro-1H-indol-1-amine (4.5 g) and 4-chloropyridine hydrochloride (4.5 g) in 175 ml of isopropanol was stirred at reflux for two hours, another equivalent of 4-chloropyridine hydrochloride was added and the mixture was refluxed for two additional hours. The reaction mixture was then cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to 9 g of dark oil. This oil was purified by flash chromatography (silica, ethyl acetate) to give 3.8 g of light brown solid, m.p. 183°-184° C. This material was converted to the hydrochloride salt and recrystallized twice from methanol/ether to give 3.5 g of orange needles, m.p. 300°-302° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:13].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:21]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:23]([N:22]([CH2:36][CH3:37])[CH2:20][CH3:21])=[O:35])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:3]1=[O:13]
Reactant: NC1(c2ccccc2)C(=O)Nc2cc(Cl)c(Cl)cc21
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3)c3cc(Cl)c(Cl)cc32)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.293 g of 3-amino-5,6-dichloro-1,3-dihydro-3-phenylindol-2-one and 0.290 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a DCM/AcOEt mixture (85/15; v/v) as the eluent gives the expected product after crystallization from a DCM/iso ether mixture. m=0.26 g. M.p.=119°-121° C.
Reaction SMILES: [CH:1]([O:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].[Cl-].[Li+].Cl.[O:29]1CCO[CH2:31][CH2:30]1>>[C:30]([C:14]1[CH:13]=[C:12]([CH2:11][CH:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:17]=[CH:16][CH:15]=1)(=[O:29])[CH3:31]
Reactant: CCOC(=O)C(Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)OC(C)C
Reactant: C1COCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Product: CCOC(=O)C(Cc1cccc(C(C)=O)c1)OC(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2.037 g of Ethyl 2-isopropoxy-3-(3-[(trifluoromethyl)sulfonyl]oxyphenyl)-propanoate, 2.5 g of ethyl [1-(1,1,1-tributylstannyl)vinyl]ether, 500 mg of lithium chloride and 186 mg of dichlorobis(triphenylphosphine) palladium were dissolved in 15 ml of dioxane, and the mixture was stirred at 90° C. overnight under nitrogen atmosphere. The solution was cooled in ice bath, added with 1N-hydrochloric acid, and extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography, to give 1.041 g of the title compound in the 6:1 hexane-ethyl acetate fraction.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].C[C:25]([N:27](C)C)=O>>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[O:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[C:25]#[N:27])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:7]=[CH:6]2
Reactant: CC(=O)N(C)C
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C#N)cc21
Temperature: 150 °C
Yield: 95 %

Procedure:
6-Bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole (31.2 g, 82 mmol) and Cu(I)CN (13.9 g, 156 mmol) were dissolved in DMA and degassed with nitrogen under vacuum. The reaction mixture was heated to 150° C. for 16 hours. The mixture was cooled to room temperature and diluted with ethyl acetate before washing twice with 7M NH4OH. The organics were washed with brine and degassed with nitrogen before being dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed eluting with 10% ethyl acetate in hexanes to afford 25.1 g of product (95% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8]C)=O.Cl.[C:12](=[NH:17])([NH2:16])[CH2:13][CH2:14][CH3:15].C[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:16]=[C:12]([CH2:13][CH2:14][CH3:15])[NH:17][C:6](=[O:8])[CH:5]=1
Reactant: CCCC(=N)N
Reactant: COCC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1nc(COC)cc(=O)[nH]1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of methyl 4-methoxy-3-oxobutanoate (15.0 g), butanimidamide hydrochloride (15 g) and sodium methoxide (28% in methanol, 51 mL) in methanol (150 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (17 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C12CCCC2
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)NCC21CCCC1
Temperature: 20 °C
Reaction time: 0.2 h
Yield: 88 %

Procedure:
A solution of borane-dimethyl sulfide complex in THF (2 M, 3.75 mL) was added to 6′ chloro-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one under nitrogen and the resulting solution stirred at 20° C. for 0.2 h then at reflux for 1 h. The mixture was cooled then MeOH (3 mL) was added slowly (caution,) and reflux resumed for 1 h. Excess solvent was evaporated in vacuo and chromatography of the residue (SiO2; gradient elution with 0-40% Et2O in petrol) gave the title compound (0.335 g, 88%). MS: [M+H]+=208.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:16]([C:18](=[O:37])[C@H:19]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOC(C)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([C:13]([NH:17][NH:16][C:18](=[O:37])[C@H:19]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: NNC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)NNC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Int. A) (200 mg, 0.702 mmol) in NMP (6 ml) was treated with (R)-benzyl 2-hydrazinyl-2-oxo-1-phenylethylcarbamate (Int. JR) (231 mg, 0.772 mg) followed by portionwise addition of HATU (293 mg, 0.772 mmol). After stirring at RT for 45 minutes, the reaction mixture was added to EtOAc (50 ml) and washed with 0.1 M NaOH (50 ml). The aqueous layer was back extracted with EtOAc (25 ml). The combined organic portions were washed with water (75 ml), brine (50 ml), dried (MgSO4) and concentrated in vacuo. The crude product was loaded in MeOH onto a pre-wetted (MeOH) Isolute® PE-AX (anion exchange) cartridge. The cartridge was eluted with MeOH (70 ml) and the filtrate was concentrated in vacuo to give a yellow solid which was placed under high vacuum to give the title compound as a yellow solid;
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C@H:3]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[CH:29](I)([CH3:31])[CH3:30].C1CCN2C(=NCCC2)CC1>C(#N)C>[OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:29]([CH3:31])[CH3:30])=[O:17])[C@H:3]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC(C)I
Reactant: CCCCCCCCCC[C@@H]1[C@@H](C/C=C\CCCCCC(=O)O)[C@@H](O)C[C@H]1O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCC[C@@H]1[C@@H](C/C=C\CCCCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O

Procedure:
The compound (27-5) was reacted with isopropyl iodide and DBU in dry acetonitrile and the resultant was purified on silica gel column to give the titled compound (27-6).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cc2Cl)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of 4-(5-carboxy-3-chloro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (a) above (1.1 g, 3.22 mmol) and K2CO3 (0.67 g, 4.83 mmol) in DMF (10 mL) was added dropwise MeI (0.3 mL, 4.83 mmol) with stirring at room temperature. The reaction mixture was stirred at room temperature for 16 h, quenched with 20 mL of satd. aq. solution of NaHCO3 and extracted with EtOAc (50 mL). The organic extract was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (gradient 30% to 50% EtOAc in hexane) to give the title compound as white solid.