Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]([OH:30])[C:10]2[N:11]([N:14]=[C:15]([CH2:17][CH2:18][C:19]3[N:23]([CH3:24])[N:22]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:20]=3)[N:16]=2)[C:12]=1[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[C:9]([O:30][CH2:2][CH2:3][O:4][CH3:5])[C:10]2[N:11]([N:14]=[C:15]([CH2:17][CH2:18][C:19]3[N:23]([CH3:24])[N:22]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:20]=3)[N:16]=2)[C:12]=1[CH3:13]
Reactant: Cc1c(Cl)cc(O)c2nc(CCc3nc(N4CCCC4)nn3C)nn12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(Cl)c(C)n2nc(CCc3nc(N4CCCC4)nn3C)nc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
1-Bromo-2-methoxyethane (10.7 mg, 7.26 μl, 77.3 μmol, Eq: 1.2) was added to 6-chloro-5-methyl-2-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)ethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-ol (23.3 mg, 64.4 μmol, Eq: 1.00) and K2CO3 (26.7 mg, 193 μmol, Eq: 3) in dimethylformamide (1 ml). The mixture was stirred at 50° C. for 2 h. The crude material was purified by preparative HPLC to give the desired product (7 mg, 25%) as a white powder. MS: m/z=420.6 (M+H+)
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[C:11]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:24][CH:23]=3)[C:10]=2[F:38])=[CH:6][C:5]=1[O:41]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:40]=[CH:39][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]([F:20])([F:18])[F:19])=[C:11]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=3)[C:10]=2[F:38])=[CH:6][C:5]=1[OH:41]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c(F)c(F)c2C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2c(F)c(F)c(C(F)(F)F)c(Oc3ccc(C(=O)O)cc3)c2F)cc1O
Reaction time: 8 h
Yield: 95 %

Procedure:
40.4 g of the 4-(4-nitro-3-benzyloxyphenoxy)-2-(4-benzyloxycarbonylphenoxy)-1-trifluoromethyl-3,5,6-tri-fluorobenzene (0.06 mol) prepared as described in Example 10 are dissolved in 500 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 4 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The orange solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: [N:1]1([C:6]2[CH2:7][CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH3:19]>CN(C=O)C>[N:1]1([C:6]2[CH2:7][CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16](=[O:18])[NH2:19])=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Reactant: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Reaction time: 5 h

Procedure:
To a suspension of 1,2-dihydro-3-(1-imidazolyl)-6-carboxy-naphthalene (500 mg) in DMF (10 ml) SOCl2 (2 ml) was added. Cooling in an ice bath, NH3 was passed through the reaction mixture, with stirring, for 5 hours. The reaction mixture was allowed to stand for 12 hours. The ammonium salt was filtered off and Et2O was added giving a precipitate which was chromatographed on silica gel with CHCl3 :CH3OH:CH3COOH (45:5:2.5) as eluant; 350 mg of 1,2-dihydro-3-(1-imidazolyl)-6-carbamoyl-naphthalene were obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:32])=[C:18]([NH:20][C:21]([C:23]4[N:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]5=[N:25][CH:24]=4)=[O:22])[CH:19]=3)[N:10]=2)[CH2:6][C:5]([F:8])([F:7])[CH2:4]1.Cl[C:34]([O:36][CH3:37])=[O:35]>N1C=CC=CC=1>[F:7][C:5]1([F:8])[CH2:6][C:3]([NH:2][C:34](=[O:35])[O:36][CH3:37])([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:32])=[C:18]([NH:20][C:21]([C:23]4[N:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]5=[N:25][CH:24]=4)=[O:22])[CH:19]=3)[N:10]=2)[CH2:4]1
Reactant: Cc1ccc(-c2noc(C3(N)CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)NC1(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccccn45)c3)no2)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of N-(5-(5-(1-amino-3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride (166) in anhydrous pyridine (1 mL) at 0° C. was added drop-wise methyl chloroformate (19 uL, 0.26 mmol). The reaction was stirred to room temperature for 20 minutes. The crude was concentrated and purified by preparative HPLC to yield methyl (3,3-difluoro-1-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)carbamate (F174). MS m/z 483.1 (M+1)+.
Reaction SMILES: [O:1]=[C:2]([N:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[CH2:6][C:5]1=[O:22].Br[CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:37]=1>CN(C=O)C.C1(C)C=CC=CC=1>[O:22]=[C:5]1[N:4]([CH2:3][C:2](=[O:1])[N:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[CH:6]1[CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:37]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: O=C(CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)N1CCCCc2ccccc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(CC(=O)N3CCCCc4ccccc43)c3ccccc3N(c3ccccc3)C2=O)c2ccccc21

Procedure:
To a stirring solution of 1-[2-oxo-2-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)ethyl]-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (1.0 g, 2.28 mM) in 15 mL DMF at 0° C. was added 1.1 equiv. of 0.5 M solution of KN(TMS)2 in toluene. The resulting solution was stirred 10–30 min, then a solution of tert-butyl 3-(bromomethyl)-1H-indazole-1-carboxylate (0.78 g, 2.5 mM) in 3 mL DMF was added. The resulting solution was stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture was then poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer was separated, dried (MgSO4), and the solvents removed in vacuo. The resultant material was purified by silica gel flash column chromatography using hexanes/EtOAc 1/1 providing 1.4 g of white solid.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:28][C:27]3=[CH:29][N:30]([CH2:41]O)[C:31](=[O:40])[C:32]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[C:26]3[NH:25][C:24]=2[CH:43]=1>N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:28][C:27]3=[CH:29][N:30]([CH2:41][O:4][C:3](=[O:5])[CH:2]([CH3:1])[CH:6]([CH3:9])[CH2:7][CH3:8])[C:31](=[O:40])[C:32]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[C:26]3[NH:25][C:24]=2[CH:43]=1
Reactant: CCC(C)C(C)C(=O)O
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Cl)cc1N2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C)C(C)C(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1cc(Cl)ccc1S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of 2.06 g. of 2,3-dimethylvaleric acid (15.8 mmol). in 30 ml. of methylene chloride was cooled in a cold water bath and treated with 2.0 g. of oxalyl chloride (15.8 mmol.). The resulting solution was stirred at room temperature for 2 hours, then the methylene chloride was removed under reduced pressure. The resulting residue was added dropwise to a cold, stirred suspension of 1.2 g. of 7-chloro-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (3.1 mmol.) in 25 ml. of pyridine. After stirring for 35 minutes, the mixture was poured onto ice-water and allowed to stand for 16 hours at room temperature, resulting in the formation of a yellow precipitate, which was collected, washed with water, air-dried, then purified using flash chromatography on silica gel, employing a mixture of 5% ethyl acetate: 95% methylene chloride as the eluent. Fractions containing the product were combined and triturated with ether to yield 7-chloro-4-(4-chlorophenyl)-2-[(2,3-dimethyl-1-oxopentoxy)methyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a pale yellow crystalline solid (1.18 g; 76% yield) having the structural formula, ##STR22## a melting point in the range of 165°-173° C. and the following elemental analysis:
Reaction SMILES: Br[C:2]1[C:3]([O:13]C(C)(C)C)=[N:4][C:5]([O:8]C(C)(C)C)=[N:6][CH:7]=1.C([Li])CCC.[CH2:23]([C:25]1[O:26][C:27]2[CH2:34][CH2:33][C:32]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:31]=3[C:30](=O)[C:28]=2[N:29]=1)[CH3:24]>O1CCCC1.[Cl-].[Na+].O>[CH2:23]([C:25]1[O:26][C:27]2[CH:34]=[CH:33][C:32]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:31]=3[CH:30]([C:2]3[C:3](=[O:13])[NH:4][C:5](=[O:8])[NH:6][CH:7]=3)[C:28]=2[N:29]=1)[CH3:24]
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Reactant: CCc1nc2c(o1)CCc1cc(C)ccc1C2=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
To a solution of the product of step (vi) (1.74 g) in dry tetrahydrofuran (20 ml) at −78° C. was added n-butyllithium (2.3 ml of a 2.5M solution in hexanes) dropwise. After 0.5 hours a solution of the product from step (v) (1.26 g) in tetrahydrofuran (10 ml) was added. The reaction mixture was allowed to warm to room temperature and saturated brine was added. The mixture was extracted with ethyl acetate, the organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic acid (20 ml) and the solution was heated at reflux for 64 hours. The solvent was evaporated under reduced pressure and the residue was then dissolved in trifluoroacetic acid (20 ml) and the solution heated at reflux for 64 hours. The solvent was evaporated under reduced pressure. Purification was by trituration with diethyl ether and filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[CH:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.Br[C:21]1[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[C:18][C:21]4[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:23][CH:22]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(Cl)cc3)cn12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3ccc(S(N)(=O)=O)s3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-ethynyl-8-methyl-imidazo[1,2-a]pyridine (example C.21) (267 mg, 1 mmol) and commercially available 5-bromothiophene-2-sulfonamide (230 mg, 1 mmol) according to general procedure II. Obtained as a light brown solid (158 mg, 44%). MS (ISP) 427.9 [(M+H)+], 429.9 [(M+2+H)+]; mp 265-266° C.
Reaction SMILES: [H-].[Na+].C(S)C.Cl.C[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:20][CH:19]2[CH2:18][NH:17][CH2:16]3)=[CH:11][CH:10]=1.CN(C)[CH:23]=[O:24]>>[CH:23]([N:17]1[CH2:18][CH:19]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)([CH2:20]2)[CH2:16]1)=[O:24]
Reactant: CN(C)C=O
Reactant: COc1ccc(C23CNCC2C3)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Product: O=CN1CC2CC2(c2ccc(O)cc2)C1

Procedure:
To a slurry of 7.2 g (0.15 mol) of sodium hydride (50% oil dispersion) in 170 ml of N,N-dimethylformamide at 0°-5° is added a solution of 10.1 ml of ethanethiol in 85 ml of N,N-dimethylformamide over a 15 minute period. An additional 3.16 g portion of sodium hydride is added followed gy 14.4 g of 1-(p-methoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride. After the addition of 40 ml of N,N-dimethylformamide, the mixture is refluxed for 4 hours and the solvent is then removed. The residue is dissolved in 150 ml of water and mineral oil is extracted with ether. The aqueous solution is made acidic with acetic acid and the precipitated crystals are collected by filtration to give 9.8 g of 3-formyl-1-(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane as tan crystals, m.p. 166°-167°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].N1C=CC=CC=1>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
3-(4-Benzyloxyphenyl) propionic acid prepared in Example S (30 g, 117 mmol) was taken up in 300 mL of thionyl chloride. The reaction was kept under reflux for 5 hours, then cooled and concentrated. The residue was dissolved in 300 mL of CH2Cl2 and treated with N,O-dimethylhydroxyamine hydrochloride (14.1 g, 146 mmol) and 60 mL of pyridine at 0° C. The reaction was stirred overnight. The reaction was quenched with dilute HCl and extracted into EtOAc, and the organic layer was washed with sodium bicarbonate solution and dilute HCl and dried. The organic layer was dried (MgSO4) and concentrated. The residue was used further as crude reaction mixture or purified by flash silica gel column chromatography, eluting with EtOAc:hexane (1:9, then switching to 2:3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]([C:21]2[S:22][C:23]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:24][C:25]=2[CH2:26][CH2:27]O)=[O:20])[CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:17])[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CCOCC>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:23]2[S:22][C:21]3[C:19](=[O:20])[N:18]([C:5]4[CH:6]=[CH:7][C:8]([NH:9][C:10](=[O:17])[CH2:11][N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:27][CH2:26][C:25]=3[CH:24]=2)=[CH:34][CH:33]=1
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2CCO)ccc1NC(=O)CN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
Dissolve 5-(4-chloro-phenyl)-3-(2-hydroxy-ethyl)-thiophene-2-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-yl-acetylamino)-phenyl]-amide (623 μmol, 320 mg) and tri-n-butylphosphine (934 μmol, 233 μL) in tetrahydrofuran (5 mL) then add dropwise via syringe diisopropyl azodicarboxylate (934 μmol, 185 μL). Stir the mixture at room temperature for 4 h. Dilute the mixture with 15 mL of Et2O, filter the resulting solid, and dry under vacuum at 60° C. to afford 195 mg (63%) of N-{4-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-phenyl}-2-pyrrolidin-1-yl-acetamide. Prepare the hydrochloride salt of the free base using 1N HCl in ethanol. Dilute the salt solution in ether then filter off the product. Dry in vacuo to obtain the title compound. MS/ES m/z (35Cl) 496.2 [M+H]+.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].O[CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)n1cnc(CO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cnc(CON2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (2.70 g, 16.6 mmol), tert-butyl 4-(hydroxymethyl)-1H-imidazole-1-carboxylate 120 (Bull. Chem. Soc., Japan, 2002, Vol 75, No 11, 2517-2526, 1.64 g, 8.27 mmol) and triphenylphosphine (4.34 g, 16.6 mmol) in THF (100 mL) was added DIAD (3.52 mL, 18.2 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 121 (1.7 g, 61.96) as a white foam.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH2:24]([N:29]=[C:30]=[O:31])[CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:30](=[O:31])[NH:29][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2OCCC1(CO)CO
Reactant: CCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCNC(=O)OCC1(CO)CCOc2ccccc2C1=O

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]oxepin-5-one (260 mg, 1.17 mmol) in 15 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.18 ml, 1.3 mmol) and n-pentyl isocyanate (332 μl, 2.57 mmol). The mixture was heated to reflux for 24 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 210 mg (54%).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)=[O:34]>O1CCOCC1>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:33]([O:35][C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)=[O:34])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(OC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a suspension of 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine (63 mg, 0.2 mmol) in dioxane (10 ml) was added diisopropylethylamine (33 μl, 0.2 mmol) and p-tolyl chloroformate (0.2 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/30), yielding the pure title compound as yellowish solid (60 mg, 67%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].CO.OS(O)(=O)=O.[C:17]([O-])(O)=O.[Na+]>C1COCC1>[CH3:17][O:8][C:7](=[O:9])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A 500 g sample of L-pyroglutamic acid was added to 2.8 L of anhydrous methanol, 28 mL of H2SO4 was added, and the mixture was stirred for 4 hr at 60° C. The reaction mixture was cooled to room temperature, 262 g of NaHCO3 was added, and the mixture was stirred for an additional 16 hr. The mixture was dried by addition of 314 g of Na2SO4 with stirring for 1 hr, then the mixture was filtered and the solvent was evaporated under vacuum to yield a pale yellow oil. The oil was dissolved in THF, and a small amount of unreacted acid was filtered off. The THF was removed under vacuum, and the residual oil was dried by azeotropic distillation with toluene.
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH3:7])=O.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15]C=C[CH:18]=2)[CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CO>[NH2:20][C@@H:10]1[C:11]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:6]([OH:5])[CH2:18][CH2:19]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@H]1CCCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CO
Product: N[C@H]1CC[C@@H](O)c2ccccc21
Reaction time: 18 h
Yield: 99.4 %

Procedure:
Ethyl trifluoroacetate (24.2 mL, 204 mmol) was added dropwise to a solution of (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (Alfa Aesar; 25.0 g, 170 mmol) and triethylamine (35.5 mL, 255 mmol) in MeOH (250 mL) at RT and stirred for 18 h. The mixture was concentrated to approximately ⅓ of its volume and then partitioned between DCM (200 mL) and water (200 mL). The aqueous layer was extracted into DCM (3×) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound (41.1 g, 169 mmol, 99%). 1H NMR (400 MHz, CDCl3): 1.80-1.95 (3H, m), 2.05-2.15 (1H, m), 2.75-2.90 (2H, m), 5.18-5.25 (1H, q, J 5.0 Hz), 6.38-6.48 (1H, br s), 7.12-7.16 (1H, m), 7.20-7.26 (3H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:18][CH2:19][C:20]#[CH:21])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1>>[Br:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:18][CH2:19][C:20]#[C:21][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(Br)cccc2o1
Product: Brc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 45 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (63 mg, 0.40 mmol) and 4-bromo-2-(but-3-ynyl)-benzo[d]oxazole (100 mg, 0.40 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 60 mg (0.18 mmol, 46%) of 4-bromo-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid with a purity of 85%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.CCN(CC)CC.[CH:20](OCC)=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][CH:20]=[O:21])=[CH:5][CH:4]=1
Reactant: CCOC=O
Reactant: COc1ccc(SCCN)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(SCCNC=O)cc1

Procedure:
A solution of compound 1 (550 mg) and Et3N (1 mL) in HCO2Et (20 mL) was refluxed for 12 h. The mixture was cooled down and washed with 1 N HCl and sat. NaHCO3. The solvents were removed by evaporation under reduced pressure to give product 14 as solid: 606 mg. The crude product appeared to be pure by TLC and NMR and used for the next step reaction without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([OH:25])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:3].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:3][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=O)c1ccccc1-2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CN(C)CCNc1nc2cc(OC(=O)C(C)(C)C)ccc2c2c1C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a solution of 6-(((dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno[2,1-c]quinoline-7-on obtained in example 3 (100 mg, 0.3 mmol) in dichloromethane (10 ml) was added 4-dimethylaminopyridine (100 mg, 0.8 mmol) and pivaloyl chloride (37 μl, 0.3 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water to wash the organic layer, which was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent; chloroform:ethanol=10:1(v/v)) and crystallized from hexane to give 105 mg (yield: 80.0%) of title compound. The physicochemical properties thereof are shown in table 1.