Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:25][CH:26]=[C:27]([C:33]([O:35]CC)=O)[C:28]([O:30]CC)=[O:29])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].O.C(OCC)(=O)C>[N+](C1C=CC=CC=1)([O-])=O>[OH:35][C:33]1[C:20]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[C:22]([O:23][CH3:24])[CH:21]=2)[N:25]=[CH:26][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)C(=CNc1ccc(OC)c(OC)c1)C(=O)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc2ncc(C(=O)O)c(O)c2cc1OC
Temperature: 150 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
10.2 g of phosphorus pentoxide were added cautiously, with mechanical stirring, to a mixture of 21.1 g of diethyl 2-[(3,4-dimethoxyphenylamino)methylene]malonate in 42 cm3 of nitrobenzene. The reaction mixture was maintained at a temperature in the region of 150° C. for 4 hours. After cooling to about 20° C. and stirring for 18 hours at this same temperature, 14 cm3 of water were added dropwise and the reaction mixture was then heated to about 110° C. for 7 hours. After cooling to a temperature in the region of 20° C., 42 cm3 of ethyl acetate were added. The suspension was stirred under these conditions for 18 hours, the phases were then separated by settling, the organic phase was filtered and the filter cake was washed with 3 times 40 cm3 of ethyl acetate, 40 cm3 of ethanol and 40 cm3 of water. 9.25 g of 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylic acid were obtained in the form of a cream-colored solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[I:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(I)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(I)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
A solution of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride (0.019 mol) in DCM (50 ml) was added slowly at 5° C. to a mixture of 1-amino-4-iodo-benzene (0.017 mol) and triethylamine (0.026 mol) in DCM (40 ml). The mixture was stirred at room temperature for 1 hour, then washed with HCl 1N, then with K2CO3 10%. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 6.1 g of N-(4-iodophenyl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 1; mp. 147° C.).
Reaction SMILES: C1(N)CCCCC1.[N+](C1C=CC(OC(N[C@@H](CC2C=CC=CC=2)C(=O)CN(C)C(N2CCC[C@H]2C(OCC2C=CC=CC=2)=O)=O)=O)=CC=1)([O-])=O.[CH:51]1([NH:57][C:58]([NH:60][C@@H:61]([CH2:84][C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[C:62](=[O:83])[CH2:63][N:64]([CH3:82])[C:65]([N:67]2[CH2:81][CH2:80][CH2:79][C@H:68]2[C:69]([O:71]CC2C=CC=CC=2)=[O:70])=[O:66])=[O:59])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1>C1(C)C=CC=CC=1>[CH:51]1([NH:57][C:58]([NH:60][C@@H:61]([CH2:84][C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[C:62](=[O:83])[CH2:63][N:64]([CH3:82])[C:65]([N:67]2[CH2:81][CH2:80][CH2:79][C@H:68]2[C:69]([OH:71])=[O:70])=[O:66])=[O:59])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]1
Reactant: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)NC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: NC1CCCCC1
Product: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)NC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Cyclohexylamine (1 ml., 8.7 ml., 8.7 mmole) is added to a cold (0°) solution of 1-[[[(S)-3-[[(4-nitrophenoxy)carbonyl]amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester (0.9 g., 1.58 mmole) in toluene in one portion. The solution turns yellow immediately and TLC indicates all starting material has been consumed. The resulting solution is washed sequentially with water, 1N hydrochloric acid, and 10% sodium bicarbonate. The organic layer is dried (MgSO4) and concentrated to a pale yellow oil. The crude product is purified (2x) by preparative layer chromatography using ethyl acetate as eluant to give 0.31 g. of 1-[[[(S)-3-[[(cyclohexylamino)carbonyl]amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester as a clear, colorless salt.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:22])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1CC
Temperature: 60 °C
Yield: 81.9 %

Procedure:
To a stirred solution of 2-ethylphenol (5 ml, 42.4 mmoles, 1 eq) in dry DMF (120 ml, 0.35M) was added potassium carbonate (6.45 g, 46.6 mmoles, 1.1 eq) and ethylbromoacetate (4.7 ml, 42.2 mmoles, 1 eq) and heated to 60° C. overnight. After cooling to room temperature the reaction mixture was partitioned between ethyl ether and 1N NaOH. The phases were separated and the organic portion was washed twice with 1N NaOH, twice with H2O, brine, dried over Na2SO4, filtered and concentrated in vacuo to yield 7.2 g (82%) of product.
Reaction SMILES: C1(C(O)=O)C2C(=CC=CC=2)C=CC=1.S(Cl)(Cl)=O.N.[CH3:19][O:20][C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:33](=O)[NH2:34])[CH:29]=2)[CH:24]=1)=[O:22].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.COP(OC)(OC)=O>[CH3:19][O:20][C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:33]#[N:34])[CH:29]=2)[CH:24]=1)=[O:22]
Reactant: COC(=O)c1ccc2cc(C(N)=O)ccc2c1
Agent: N
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: COP(=O)(OC)OC
Product: COC(=O)c1ccc2cc(C#N)ccc2c1

Procedure:
Compounds of formula II, where T is a bond, B is H, each of-e and g is C—H, f is a bond, V is a substituted carbonyl group, and Z′ is NH can be prepared as follows. Hydrolysis of naphthalene-2,6 dicarboxylic acid dimethyl ester with one equivalent of a base such as KOH, followed by acidification of the product with an acid such as HCl, affords the naphthalene mono carboxylic acid. After conversion of the carboxylic acid to an acid chloride with a reagent such as thionyl chloride and subsequent reaction with ammonia in methylene chloride, the resulting 6-carbamoyl-naphthalene-2-carboxylic acid methyl ester is reacted with triphosgene in trimethylphosphate to provide 6-cyano-naphthalene-2-carboxylic acid methyl ester. Hydrolysis of the ester with LiOH in aqueous THF solution, followed by reaction with thionyl chloride, affords 6-cyano-naphthalene-2-carbonyl chloride, which can then be coupled with alcohols or amines to provide compounds of the formula XX. The amidine, hydroxyamidine, or aminoamidine groups can be obtained from the nitrile as described previously to afford compounds the formula XXI, where R19 is H, and R22 is H, alkyl, OH, or NH2, and V is an alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, aralkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, or heteroaralkyloxycarbonyl.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[OH-].[K+]>>[CH2:2]([N:11]([CH2:2][CH2:3][CH2:4][CH3:5])[C:10]1[CH:12]=[CH:13][C:7]([Br:6])=[CH:8][CH:9]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Nc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Product: CCCCN(CCCC)c1ccc(Br)cc1
Yield: 42.6 %

Procedure:
1-Bromobutane (41.1 g, 300 mmol), 4-bromoaniline (17.2 g, 100 mmol) and KOH (16.8 g, 300 mmol) were heated at reflux under nitrogen gas for about 18 hours. After cooling, the mixture was partitioned between water and hexane and the organic layer washed with water followed by brine. After drying over MgSO4 and filtering, the solvent was evaporated and the mixture distilled under reduced pressure. Distillate fractions collected between 25-100° C. and pressure of 360-210 mTorr contained a mixture of products and starting material. The fractions collected at 100-107° C. and 200 mTorr pressure afforded 12.1 g (43%) of pure product.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][C:7](=[O:13])[C:8]([O:10]CC)=O)[CH3:2].[CH2:17]([NH2:19])[CH3:18]>C(O)C>[CH2:17]([NH:19][C:8]([C:7]([NH:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])=[O:13])=[O:10])[CH3:18]
Reactant: CCN
Reactant: CCOC(=O)C(=O)NCC(OCC)OCC
Solvent: CCO
Product: CCNC(=O)C(=O)NCC(OCC)OCC
Yield: 85.1 %

Procedure:
To a solution of 20.0 g of ethyl N-(2,2-diethoxyethyl)oxamate in 60 ml of ethanol was added 6.1 ml of 70% by weight aqueous ethylamine solution, and the mixture was subjected to reaction at room temperature for 1 hour. After the completion of the reaction, the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 17.0 g (yield: 85.1%) of N-ethyl-N'-(2,2-diethoxyethyl)oxamide having a melting point of 131°-132° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]3[CH:13]=[C:14]([CH2:22][OH:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=3)[CH:8]=2)[CH2:3]1.[CH3:24][S:25](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:27])=[O:26].N1CCCN2CCCCCC=12>C1COCC1>[OH:23][CH2:22][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=1)[CH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][C@H:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10]2
Reactant: CS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (S)-(3-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)phenyl)methanol (50, mg, 0.16 mmol) in THF (1 mL) was added perfluorophenyl methanesulfonate (39 mg, 0.15 mmol) followed by 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (34.1 mg 0.22 mmol). The reaction was allowed to stir at RT overnight before removing the solvent in vacuo. The sample was redissolved in DMSO (500 μL) before purifying by reverse phase preparative HPLC-MS to give the title compound as a clear film (11 mg, 17.2%). MS (ESI): m/z [M+H]+ 400.1
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(O)(=[O:15])C>C(OCC)C.O>[O:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:12]
Reactant: Cc1ccc2oc(=O)ccc2c1
Reactant: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc2oc(=O)ccc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
6-Methylcoumarin (400 mg, 2.50 mmol) was dissolved in 1.0 mL of diethyl ether, 1.0 mL of acetic acid, and 1.0 mL of water. After addition of ceric ammonium nitrate (5.5 g, 1.0 mmol) at room temperature, the reaction mixture was stirred at 100° C. for 1 h. The resulting mixture was diluted with water, and the solution was extracted with ethyl acetate. The extract was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25 to 50/50) to obtain the title compound as a pale yellow powder (80 mg, 18%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][N:49]([CH3:51])[CH3:50])=[CH:42][CH:41]=1>C(O)C>[CH3:50][N:49]([CH3:51])[CH2:48][CH2:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:7]2[N:8]=[CH:9][C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:5]3[N:6]=2)=[CH:41][CH:42]=1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n2nc(Nc3ccc(OCCN(C)C)cc3)ncc12
Yield: 24.2 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), {2-[(4-aminophenyl)oxy]ethyl}dimethylamine (32 mg, 0.17 mmol) and ethanol (2.5 mL) to afford N-(4-{[2-(dimethylamino)ethyl]oxy}-phenyl)-5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (16 mg) as a yellow solid. MS m/z 389 (M+1).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([Br:7])[CH:4]=[N:3]1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>CCOC(C)=O.CCCCCCC>[Br:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1cc(Br)cn1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)On1cc(Br)cn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4-bromopyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (89%, oil). HPLC-MS m/z=298.0 (M+1), Rt: 3.77 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.C([CH:14]([CH2:18][C:19](Cl)=[O:20])[C:15](Cl)=[O:16])C.[NH2:22][NH2:23]>CO>[CH3:8][C:6]1([CH3:9])[CH2:7][CH:2]([NH:1][C:15](=[O:16])[CH2:14][CH2:18][C:19]([NH:22][NH2:23])=[O:20])[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5]1
Reactant: NN
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CCC(CC(=O)Cl)C(=O)Cl
Solvent: CO
Product: CC1(C)CC(NC(=O)CCC(=O)NN)CC(C)(C)N1

Procedure:
N-(2,2,6,6-tetramethyl-4-piperidinyl)-N'-aminosuccinamide was prepared by the reaction of 4-amino-2,2,6,6-tetramethylpiperidine with ethyl succinyl chloride followed by hydrazinolysis of the resulting ester with 64% aqueous hydrazine in methanol.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:23]([CH3:24])[CH:22]3[CH2:25][CH:18]([CH2:19][CH2:20][N:21]3[CH3:26])[C:17]=2[CH:27]=1)(=[O:11])[CH3:10].C(=O)(O)[O-].[Na+]>CO.ClCCl>[C:9]([O:12][C:13]1[CH:14]=[C:15]([Br:1])[C:16]2[N:23]([CH3:24])[CH:22]3[CH2:25][CH:18]([CH2:19][CH2:20][N:21]3[CH3:26])[C:17]=2[CH:27]=1)(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc2c(c1)C1CCN(C)C(C1)N2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Oc1cc(Br)c2c(c1)C1CCN(C)C(C1)N2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.5 %

Procedure:
N-Bromosuccinimide (2.40 g) was added in three portions to a solution of 3.50 g of crude 1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol acetate in 135 ml of deoxygenated methanol. The resulting solution was stirred at room temperature for five minutes and then diluted with dichloromethane and a saturated sodium bicarbonate solution. The aqueous phase was separated and extracted with dichloromethane, and the combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. Column chromatography of the oil (silica gel elution with triethylamine-methanol-ethyl acetate) afforded 1.80 g (33%) of 10-bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol acetate as a solid.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([C:20](=[O:55])[NH:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[C:31]3[C:36]4[S:37][C:38]([C:40]5[C:45]([F:46])=[CH:44][N:43]=[C:42]([NH:47][CH2:48][CH2:49][N:50]6[CH:54]=[CH:53][N:52]=[N:51]6)[N:41]=5)=[CH:39][C:35]=4[CH:34]=[CH:33][CH:32]=3)[CH3:23])[CH3:19])C3C(=CC=CC=3)C=2C=CC=1>N1CCCCC1.C(Cl)(Cl)Cl.C(O)(C)C>[N:50]1([CH2:49][CH2:48][NH:47][C:42]2[N:41]=[C:40]([C:38]3[S:37][C:36]4[C:31]([C:25]5[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=5[C@H:22]([NH:21][C:20](=[O:55])[C@H:18]([NH2:17])[CH3:19])[CH3:23])=[CH:32][CH:33]=[CH:34][C:35]=4[CH:39]=3)[C:45]([F:46])=[CH:44][N:43]=2)[CH:54]=[CH:53][N:52]=[N:51]1
Reactant: CC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC(C)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: C[C@@H](N)C(=O)N[C@H](C)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Dissolve {1-[1-(4-fluoro-2-{2-[5-fluoro-2-(2-[1,2,3]triazol-1-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophen-7-yl}-phenyl)-ethylcarbamoyl]-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (129 mg, 167 μmol) in piperidine (5 mL). Stir the mixture at RT for 30 min and then dilute with chloroform/IPA (3/1, 100 mL). Wash the organic phase with water/aqueous saturated sodium chloride, dry over sodium sulfate, and concentrate in vacuo. Purify the crude product by FCC (10% methanol in DCM to chloroform/methanol/ammonium hydroxide (7/3/0.05) as a gradient to give the title compound as a yellow solid (72 mg, 78%). MS (ES) m/z 549 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]1[CH:15]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:16][CH:17]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:8].N1C=CC=CC=1.O=C1CCC(=O)N1[O:53][C:54](=O)[O:55][CH:56]1[CH2:72][CH:71]2[C:59]([CH3:99])([CH:60]3[CH:68]([CH2:69][CH2:70]2)[CH:67]2[C:63]([CH3:98])([CH:64]([CH:73]([CH3:97])[CH2:74][CH2:75][C:76](=[O:96])[NH:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH3:95])[CH2:65][CH2:66]2)[CH2:62][CH2:61]3)[CH2:58][CH2:57]1.CCOC(C)=O>ClCCl>[CH3:99][C:59]12[CH2:58][CH2:57][CH:56]([O:55][C:54](=[O:53])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]3[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]3[CH:15]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:16][CH:17]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:8])[CH2:72][CH:71]1[CH2:70][CH2:69][CH:68]1[CH:60]2[CH2:61][CH2:62][C:63]2([CH3:98])[CH:67]1[CH2:66][CH2:65][CH:64]2[CH:73]([CH3:97])[CH2:74][CH2:75][C:76](=[O:96])[NH:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH3:95]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)ON5C(=O)CCC5=O)CCC4(C)C3CCC12C
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)NCCCCCC(=O)N5CC(O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Temperature: 0 °C

Procedure:
Amine 5 (4.22 g, 7.9 mmol) is dissolved in anhydrous dichloromethane (25 mL) and cooled to 0° C. To the solution are added pyridine (10 mL) and compound 89 (9.3 g, 7.9 mmol) successively. The reaction temperature was brought to ambient temperature and stirred further. The completion of the reaction is ascertained by TLC (EtOAc). The reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water followed by brine. The organic layer is dried over sodium sulfate, filtered and concentrated under vacuum to afford the crude product. Compound 90 is obtained as a white solid after column chromatography over silica gel.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[N:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=[C:26]([C:33](O)=[O:34])[CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:26]2[CH:25]=[N:24][N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=23)=[O:34])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cnn2ccccc12
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnn3ccccc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Pyrazolo[1,5-a]pyridine-3-carboxylic acid. LC-MS (basic): tR=0.74 min; [M+H]+=477.4.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[NH:8]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C>[N:18]([CH2:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[NH:8]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1Cc2ccccc2C(=O)N1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Cc2ccccc2C(=O)N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Dissolve (1-oxo-3,4-dihydro-2H-isoquinolin-3-yl)methyl methanesulfonate (3 g, 11.7 mmol) in DMF (10 mL). Add NaN3; heat to 70° C. and stir overnight. Concentrate under reduced pressure; add water; and extract with EtOAc. Combine the extracts and remove the solvents under reduced pressure to provide the title compound (1.7 g, 71.5%). 1H NMR (400 mHz, CDCl3): δ 8.1 (s, 1H), 7.6 (m, 1H), 7.5 (m, 1H), 7.0 (s, 1H), 3.9 (m, 1H), 3.5 (m, 2H), 3.0 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[H-].[Na+].C(O[C:15](=O)[CH2:16][N:17]=C(C1C=CC=CC=1)C1C=CC=CC=1)C.CI>CN(C)C=O.O>[ClH:8].[Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([CH:16]([CH3:15])[NH2:17])=[N:6][CH:7]=1
Reactant: Clc1cc(Br)cnc1Cl
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CC(N)c1ncc(Br)cc1Cl
Product: Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
Under nitrogen, 4.1 g of the title compound from Step B was added to a suspension of sodium hydride (60% oil suspension) in 30 mL of dry N,N-dimethylformamide, cooled to 0° C. N-(Diphenylmethylene)glycine ethyl ester (4.6 g) was added in portions with no exotherm, and the mixture was stirred at room temperature for 3 hours. Then, 3.4 mL of methyl iodide was added at <30° C. and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with diethyl ether (2×). The combined extracts were washed with saturated brine (1×) and reduced in vacuo to an oil that was then refluxed in 50 mL of 12N HCl for 4 hours. The reaction mixture was reduced in vacuo to an oil, cooled, and slurried with diethyl ether overnight. The ether was then decanted off and the residue was dried in a vacuum oven to give 1.3 g of the desired intermediate as a solid. NMR(CDCl3; 300 MHz): 1.40 and 1.46 (2 doublets, 3H, J is 7.0 Hz), 4.7 (m, 1H), 8.48 (d, 1H, J is 1.8), 8.6 (bs, 3H), 8.79 (d, 1H, J is 1.9 Hz).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.[C:10]([CH2:12][C:13]([O:15]C)=O)#[N:11].[CH:17]([NH2:21])([CH2:19][CH3:20])[CH3:18].Cl>CO>[CH:17]([N:21]1[C:1]([OH:7])=[CH:2][C:3]([CH3:5])=[C:12]([C:10]#[N:11])[C:13]1=[O:15])([CH2:19][CH3:20])[CH3:18]
Reactant: CCC(C)N
Reactant: COC(=O)CC#N
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CO
Product: CCC(C)n1c(O)cc(C)c(C#N)c1=O

Procedure:
A mixture composed of 130 g (1 mol) of ethyl acetoacetate, 99 g (1 mol) of methyl cyanoacetate, 146 g (2 mol) of sec-butylamine and 300 ml of methanol was heated in an autoclave at 100° to 110° C. for 10 hours. After cooling, the reaction solution was neutralized with diluted hydrochloride to obtain white crystals of 1-sec-butyl-3-cyano-6-hydroxy-4-methyl-2-pyridone.