Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:19])[N:14]([CH:16]1[CH2:18][CH2:17]1)[CH3:15])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:16]1([N:14]([CH3:15])[C:13]([C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:19])[CH2:18][CH2:17]1
Reactant: CN(C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)[C@H]1CCCN1)C1CC1

Procedure:
A solution of (R)-2-(cyclopropyl-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (958 mg, 3.57 mmol) in 50% TFA in DCM (5 mL) was stirred at rt for 4 hours. The reaction was concentrated and purified to give (R)-pyrrolidine-2-carboxylic acid cyclopropyl-methyl-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49](O)#[C:50][CH2:51][CH2:52][OH:53].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:49][C:50]#[C:51][CH2:52][OH:53])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Reactant: OC#CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CC#CCO)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (393 mg), 1,4-butyne diol (0.45 gm) and diethyl azodicarboxylate (0.18 mL). The mixture is stirred at room temperature overnight, concentrated under reduced pressure and adsorbed onto silica gel. The crude product is purified by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from methanol-acetonitrile to afford 0.16 gm of the title compound as a white solid.
Reaction SMILES: O[Li].O.C([O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.Cl.CC(C)([O-])C.[K+]>C1COCC1.O>[F:26][C:21]([F:27])([C:22]([F:23])([F:25])[F:24])[CH2:20][CH:17]1[CH2:18][CH2:19][CH:14]([C:12]([OH:13])=[O:11])[CH2:15][CH2:16]1
Reactant: O=C(OCc1ccccc1)C1CCC(CC(F)(F)C(F)(F)F)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCC(CC(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
LiOH.H2O (3.8 mg, 0.091 mmol) was added to a solution of 4-(2,2,3,3,3-pentafluoro-propyl)-cyclohexanecarboxylic acid benzyl ester (cis:trans=11:1) (11.4 mg, 0.0325 mmol) in THF (0.15 ml)-H2O (0.15 mL). The mixture was stirred at room temperature for 16 hours, and then adjusted to pH 2 with a 1 N aqueous HCl solution and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was dissolved in tert-butanol (0.4 ml), and potassium tert-butoxide (10 mg, 0.089 mmol) was added. The mixture was stirred at room temperature for two hours, and then adjusted to pH 3 with a 1 N aqueous HCl solution and extracted with dichloromethane. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane/ethyl acetate=5/1) to give 4-(2,2,3,3,3-pentafluoro-propyl)-cyclohexanecarboxylic acid (cis:trans=9:1) (8.5 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([C:16](OC)=O)[C:12]([O:14][CH3:15])=[O:13].[C:20](#[N:23])[CH:21]=C.CO[Na]>CO>[C:20]([CH2:21][CH2:16][CH:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[C:12]([O:14][CH3:15])=[O:13])#[N:23]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reactant: C=CC#N
Agent: CO[Na]
Solvent: CO
Product: COC(=O)C(CCC#N)c1ccc([N+](=O)[O-])cc1F
Yield: 64.9 %

Procedure:
To a solution of compound 65 (3 g, 11 mmol) and acrylonitrile (3.2 mL, 51 mmol) in absolute CH3OH (50 mL) was added a catalytic amount of CH3ONa (71 mg, 1.32 mmol) at room temperature with stirring under N2. The mixture was stirred at room temperature for overnight under N2. The mixture was diluted with aqNaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified with silica gel column chromatography (PE:EtOAc=5:1) to give compound 66 (1.9 g, 64%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([NH2:14])=[O:13])[C:8]([CH3:15])=[C:7]1[CH3:16])[CH:2]=[CH2:3].[CH2:17]([O:20]N1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C(C)(C)C)(C)C)C=C>>[CH2:1]([O:4][N:5]1[C:17](=[O:20])[N:10]2[CH2:11][C@H:6]1[C:7]([CH3:16])=[C:8]([CH3:15])[C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Reactant: C=CCON[C@H]1CN[C@H](C(N)=O)C(C)=C1C
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C(C)[C@H]2C(N)=O
Yield: 66.5 %

Procedure:
The title compound was prepared from (2S,5R)-5-(allyloxyamino)-3,4-dimethyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 197, 0.31 g, 1.38 mmol) following the procedure described for Intermediate 13. Silica gel chromatography (0%-70% ethyl acetate/hexanes) afforded the desired product as a white solid (0.23 g, 66.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:32])[N:9]([CH2:30][CH3:31])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41](Br)[CH:40]=1>>[CH3:35][O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:40]=[C:41]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]=2[CH2:10][N:9]([C:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][CH:33]=2)=[O:32])[CH2:30][CH3:31])[CH:42]=[C:43]([Cl:45])[CH:44]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid 4-chloro-benzyl ester and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:8][C:9]=2[CH3:11])[S:4][C:3]=1[C:22]([NH2:24])=[O:23].Cl[C:26]([O:29]C(Cl)=O)(Cl)Cl.N>O1CCOCC1.O>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:7]2[CH:8]=[C:9]([CH3:11])[C:10]3[C:2]4[NH:1][C:26](=[O:29])[NH:24][C:22](=[O:23])[C:3]=4[S:4][C:5]=3[N:6]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(-c2cc(C)c3c(N)c(C(N)=O)sc3n2)cc1OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cc(C)c3c(n2)sc2c(=O)[nH]c(=O)[nH]c23)cc1OC
Yield: 95.8 %

Procedure:
3.0 g (8.7 mmol) 3-amino-6-(3,4-dimethoxyphenyl)-4-methyl-thieno[2,3-b]pyridine-2-carboxamide is suspended in 100 ml absolute dioxane. Then, 1.1 ml (8.7 mmol) chloroformic acid trichloromethylester (diphosgene) is added and refluxed for 3 h. Following cooling, the precipitate is sucked off and then suspended in 50 ml water. The suspension is adjusted to pH 8 using concentrated ammonia solution and the precipitate is sucked off, washed with some water, suck dried and in vacuo at 50° C. 3.08 g (96%) 7-(3,4-dimethoxyphenyl)-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-2,4-dione is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:14][CH2:15]S(C)(=O)=O)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:51]=[CH:50][C:32]([CH2:33][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[C:35]2[C:43]2([OH:49])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:14][CH2:15][N:46]2[CH2:47][CH2:48][C:43]([C:35]3[N:34]([CH2:33][C:32]4[CH:50]=[CH:51][C:29]([F:28])=[CH:30][CH:31]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)([OH:49])[CH2:44][CH2:45]2)([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Reactant: CS(=O)(=O)CCC1(Cc2ccccc2)CCCN(Cc2ccccc2)C1=O
Product: O=C1N(Cc2ccccc2)CCCC1(CCN1CCC(O)(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1)Cc1ccccc1

Procedure:
Prepare by the method of Example 6.6.2 using 1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-piperidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.66 (silica gel, 10% methanol/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:6]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(C(C)(C)C)cc3)c3ccc(F)cc23)CC1

Procedure:
(23.0 mg, 42%), from 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4b, 29.4 mg, 0.128 mmol) and 4-t-butylphenylsulfonyl chloride (59.6 mg, 0.26 mmol); HRMS-FAB+ for C24H28N2O2SF calculated MH+ : 427.18555; found: 427.18680.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:21]2[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1ccnn1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(Cn2nccc2NC2CCC3(CC2)OCCO3)cc1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of 1-benzyl-1H-pyrazol-5-amine (43.3 g) in acetic acid (500 mL) was added 1,4-dioxaspiro[4.5]decan-8-one (47 g) at room temperature, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (64 g) was added by small portions at room temperature, and the mixture was stirred for 18 hr. Acetic acid was evaporated, and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a small amount of ethyl acetate, and the mixture was crystallized using diisopropyl ether. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the title compound as a pale-yellow solid (61 g, 78%).
Reaction SMILES: C([C:3]1[C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[CH:7][CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:4]=1[C:27]([OH:29])=[O:28])C.[OH-].[Na+].CO.Cl>O>[CH2:10]([O:9][C:8]1[CH:3]=[C:4]([C:27]([OH:29])=[O:28])[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][CH:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: C=CCCCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A solution of 6.46 g (16.4 mM) of ethyl p-(10-undecenyl)oxybiphenylcarboxylic acid and 2.18 g (54.6 mM) of sodium hydroxide in 4 ml of water was mixed with 30 ml of methanol, followed by 3 hours of refluxing at 50° C. After the reaction, 20 ml of distilled water was added to the reaction mixture, followed by distilling-off of methanol and acidification with 6M-HCl to obtain a crude product. The crude product was filtered and dried in a desiccator under reduced pressure to obtain 5.56 g (15.2 mM) of p-(10-undecenyl)oxybiphenylcarboxylic acid (Yield: 92.8%).
Reaction SMILES: [N:1]1O[C:3]([O-])=[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][N+:5]=12.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#C>C1(C)C(C)=CC=CC=1>[N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[CH:3][C:12]=1[C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [O-]c1on[n+]2c1CCCC2
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2n(n1)CCCC2

Procedure:
A mixture of 4,5,6,7-tetrahydro[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate (Heterocycles; 1990; 31; 481), (13.0 g, 93 mmol), and ethyl propiolate (28.5 ml, 278 mmol), in xylene (250 ml) was heated under reflux for 2 hours. The cooled mixture was evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using ether as the eluant, to afford the title compound as an oil, 5.82 g.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[CH2:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[CH2:32][C:33]1[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[C:35]([C:43]([F:46])([F:44])[F:45])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: FC(F)(F)c1cc(CN2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)cc(C(F)(F)F)c1

Procedure:
280 mg (28 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-bis-(trifluoromethyl)benzyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 65 mg (1.71 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR51## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.35, FD-MS: M+ =557.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:31]=[CH:30][C:20]4[N:21]=[C:22]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])[S:23][C:19]=4[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:33]1C=C(C2C=CC3N=C(NC(NCC)=O)SC=3C=2)C=CC=1.C(N(CC)CC)C.C1(C)C=CC=C(N=C=O)C=1>C1(C)C=CC=CC=1>[C:5]1([CH3:33])[CH:4]=[CH:3][CH:2]=[C:1]([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:31]=[CH:30][C:20]4[N:21]=[C:22]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])[S:23][C:19]=4[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:6]=1
Reactant: CCNC(=O)Nc1nc2ccc(-c3cccc(N)c3)cc2s1
Reactant: CCNC(=O)Nc1nc2ccc(-c3cccc(NC(=O)Nc4ccccc4)c3)cc2s1
Agent: Cc1cccc(N=C=O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(-c3cccc(NC(=O)Nc4cccc(C)c4)c3)cc2s1
Yield: 26 %

Procedure:
Similar to the synthesis of 1-(6-(3-phenylaminocarbonylaminophenyl)-2-benzothiazolyl)-3-ethylurea, a mixture of 1-(6-(3-aminophenyl)-2-benzothiazolyl)-3-ethylurea, triethylamine, and 3-tolyl isocyanate in toluene was reacted to give the desired compound 0.023 g (26%). LC/MS 446.2 (M+1); LC retention time 3.76 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].[C:7](N=[N+]=[N-])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>O.O1CCOCC1>[C:7]([NH:1][CH2:2][CH2:3][OH:4])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a cooled, stirred solution of 2-aminoethanol (5.9 ml, 0.098 mol) and sodium hydroxide (3.6 g, 0.098 mol) in water-dioxane (1:1), was added drop-wise Boc-azide (10 ml, 0.081 mol). The reaction was stirred at room temperature overnight. The dioxane was then removed under vacuum, and the water layer extracted several times with ethyl acetate. The organic layer was dried over sodium sulphate and then, evaporated to dryness under vacuum to get the product (N-Boc)-2-aminoethanol (5.37 g, 41% yield), which was used in further steps without purification.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH:10](O)[CH3:11])=[C:5]([O:13][CH3:14])[C:4]=1[CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:2].S(Cl)([Cl:28])=O>C(Cl)Cl.CN(C)C=O>[Cl:28][CH:10]([C:6]1[C:5]([O:13][CH3:14])=[C:4]([CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=1)[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C(C)O)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
The tert-butyl 3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylate (2.1 g, 6.4 mmol) was taken up in methylene chloride (50.0 mL) and N,N-dimethylformamide (0.59 mL), cooled in an ice bath and the thionyl chloride (0.56 mL, 7.7 mmol) was added slowly. After stirring for 2 hrs the reaction was complete by LC/MS and was partitioned between ethyl acetate and water. The combined organic layer was washed with water saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give crude tert-butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate as an oil (2.2 g, 100%). LCMS calculated for C15H18ClN2O3(M+H)+: m/z=309.1; found: 309.1.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=1)=[O:6])[CH3:2].[C:16]([C:19]1[C:20](=[O:30])[O:21][C:22]([OH:29])=[C:23]([C:26](=O)[CH3:27])[C:24]=1[OH:25])(=[O:18])[CH3:17]>[Pd].C(O)C>[C:16]([C:19]1[C:20](=[O:30])[O:21][C:22](=[O:29])[C:23](=[C:26]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5](=[O:6])[NH:4][O:3][CH2:1][CH3:2])[CH:8]=2)[CH3:27])[C:24]=1[OH:25])(=[O:18])[CH3:17]
Reactant: CCONC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: [Pd]
Solvent: CCO
Product: CCONC(=O)c1cccc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)c1
Reaction time: 1 h

Procedure:
A solution of 2.0 g. (0.0095 mol) of 3-ethoxycarbamoylnitrobenzene in 100 ml. of 2B ethanol was hydrogenated over 200 mg. of 10% palladium-on-carbon at 50 psi. Reduction was complete in 1 hour, the catalyst was filtered and to the filtrate was added 1.71 g. (0.0095 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyranone. The mixture was heated under reflux for 1.5 hours, cooled, and the product filtered to yield 5-acetyl-4-hydroxy-3-[1-(3-ethoxycarbamoylphenylamino)ethylidene]-2H-pyran-2,6-(3H)-dione, m.p. 162°-164° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[OH:16]/[N:17]=[C:18](\Cl)/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25]>C(O)C>[CH2:7]([O:6][C:1]([C:2]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[N:17][O:16][C:3]=1[CH3:4])=[O:5])[CH3:8]
Reactant: CC#CC(=O)OCC
Reactant: O/N=C(\Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2F)noc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
To a solution of ethyl 2-butynoate (65.5 mL, 562 mmol) and triethylamine (80.7 mL, 576 mmol) in ethanol (600 mL) was added, at 0-4° C. over 2 h, 500 mL of a solution of (E)- and/or (Z)-N-hydroxy-2-fluoro-benzenecarboximidoyl chloride (83.3 g 480 mmol) in ethanol (900 mL). Ethyl 2-butynoate (44.6 ml, 383 mmol) in ethanol (125 mL) was added at 0° C., then the remaining 400 ml of the (E)- and/or (Z)-N-hydroxy-2-fluoro-benzenecarboximidoyl chloride solution were added over a 1 h period. The resulting mixture was then stirred for 48 h at room temperature and evaporated. The mixture was then poured onto HCl (1.2 L), and extracted with tert-butyl methyl ether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 9:1) afforded the title product (73.6 g, 62%) which was obtained as a yellow oil, MS: m/e=250.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[C:14]([O:18][C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].[N+:29](=[CH2:31])=[N-:30]>C1COCC1.C1(C)C=CC=CC=1>[C:14]([O:18][C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23](=[O:25])[CH:31]=[N+:29]=[N-:30])=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
Triethylamine (14.6 ml) and ethyl chloroformate (10.6 ml) were added to a solution of N-(tert-butoxycarbonyl)-L-proline (21.5 g) in THF (330 ml) at -20° C., and the mixture was stirred for 30 minutes. Then, diazomethane (0.6M, diethyl ether solution, 120 ml) was added, and the mixture was stirred overnight. Toluene was added to the reaction mixture, washed with a saturated aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated to give the title compound (26.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])[NH:30][NH2:31].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.[Cu]I.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N:30]([C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH2:31])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: CC(C)(C)OC(=O)NN
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cn(-c2ccc(N(N)C(=O)OC(C)(C)C)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (2.44 g, 5.0 mmol), tert-butyl carbazate (0.727 g, 5.5 mmol), CuI (0.0095 g, 0.05 mmol), 1,10-phenanthroline (0.072 g, 0.4 mmol), and Cs2CO3 (2.28 g, 7.0 mmol) in DMF (25 mL) was stirred for 5 h at 100° C. under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt three times. The combined extracts were washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and crystallized from hexane/AcOEt to give the title compound (2.04 g, 83% yield) as a pale yellow solid: mp 163-165° C.; 1H NMR (300 MHz, CDCl3): δ ppm 1.58 (9H, s), 3.90 (3H, s), 4.36 (2H, s), 6.31 (1H, t, J=9.0 Hz), 7.28-7.45 (7H, m), 7.55 (1H, dd, J=2.3, 14.3 Hz), 7.78 (2H, d, J=1.9 Hz). Anal. Calcd for C25H25FN6O4: C, 60.97; H, 5.12; N, 17.06. Found: C, 61.20; H, 5.13; N, 16.81.