Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:6]([CH:8]([CH:10]([C:20]([NH2:22])=[O:21])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH3:9])[CH:7]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:6]([CH:8]([CH:10]([C:20]([NH2:22])=[O:21])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH3:9])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(c1cc(O)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(N2CCCCC2)c(C(C)C(C(N)=O)c2ccc(C(=O)O)cc2)c1
Reaction time: 96 h

Procedure:
An amount of 0.35 gm (0.915 m mol) of 4-[(1-(5-hydroxy-2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid was heated together with 0.103 ml (1.098 m mol) of acetic anhydride on a steam bath, and after standing for four days at 20° C., the reaction mixture was recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]([CH2:22][C:23]([OH:25])=O)[N:10]=1.N#N.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:42][OH:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]([CH2:22][C:23]([NH:42][OH:43])=[O:25])[N:10]=1
Reactant: NO
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nn(CC(=O)O)c(=O)c2c1
Agent: Cl
Agent: N#N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nn(CC(=O)NO)c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
A solution of [4(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1-oxo-1H-phthalazin-2-yl]-acetic acid (0.61 g, 1.55 mmoles), prepared as described in example 90, in dry DMF (25 ml), pH under N2, was added with 1,1′-carbonyldiimidazole (0.38 g, 2.32 mmoles). The mixture was stirred at room temperature for 4 hours then cooled, added with hydroxylamine hydrochloride (0.18 g, 2.55 mmoles) and stirred overnight. A precipitate formed and the solution was dried under vacuum, then taken up in 10% NaOH. The stirring was kept on for 2 hours, then the solid was filtered, washed with water, then with acetone and ethyl ether. It was taken up in 5% HCl and stirred for 1 hour, then filtered and washed with water, acetone and ethyl ether. The solid was dried under vacuum at 50° C., crystallised from acetic acid (60 ml) and dried under vacuum at 40° C. to give 0.3 g of the title compound (yield: 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]2[C:20]([O:22]C)=[O:21])=[CH:4][CH:3]=1.O.[OH-].[Li+].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]2[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)N(C)C)cn1CC(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(C(=O)O)n(CC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.4 %

Procedure:
To a solution of methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylate (90 mg, 0.26 mmol) in THF (1 mL) was added lithium hydroxide monohydrate (22 mg, 0.52 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 18 h (monitored by LCMS). A aqueous solution of NaOH (1 M) (25 mL) was added and the mixture washed with EtOAc (25 mL) to remove the remaining starting material. The aqueous layer was then acidified to pH 2-3 with an aqueous solution of HCl (1 M) and extracted with a mixture of 20% of propan-2-ol/DCM (2×25 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylic acid as a yellow solid (90 mg, quantitative yield). ESI-MI m/z [M+H]+ 335.1.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH:39]C(OC(C)(C)C)=O)[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2].CCN(C(C)C)C(C)C>ClCCl>[CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH2:39])[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2]
Reactant: C=Cc1cccc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1cccc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](N)C(C)C)N2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
*(S)-1-{(S)-2-((S)-2-Amino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 3-vinyl-benzyl ester was prepared by adding TMS (OTf) (0.17 ml, 0.64 mmol) to a solution of 10a (400 mg, 0.49 mmol) in anhydrous dichloromethane (20 ml) at 0° C. The reaction was stirred for 2 hours at 0° C., quenched by adding iPr2NEt (0.45 ml, 2.56 mmol) and concentrated in vacuo to yield a white solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12](=O)(OC(Cl)(Cl)Cl)[O:13]C(Cl)(Cl)Cl>C1COCC1>[I:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:12](=[O:13])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(I)cc2c(=O)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 212.5 %

Procedure:
10 g (0.038 mol) of 5-iodoanthranilic acid were dissolved in 180 ml of THF, and 3.76 g (0.0127 mol) of bis(trichloromethyl) carbonate dissolved in 20 ml of THF were added. The mixture was then stirred at room temperature for 1 h and at 50° C. for 2 h. After cooling, the precipitate was filtered off with suction and dried. 7.8 g (71%) of 5-iodoisatoic anhydride were obtained as white crystals.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[S:12][C:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:15]=1>CCOCC>[C:1]1([NH:7][C:8]([NH:10][C:11]2[S:12][C:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1sc(N)nc1-c1ccc(Cl)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)Cc1sc(NC(=O)Nc2ccccc2)nc1-c1ccc(Cl)cc1

Procedure:
2 Grams of phenylisocyanate in 50 c.c. ether are added to a suspension of 5 g. of ethyl (2-amino-4-p-chlorophenyl-thiazol-5-yl)-acetate in 200 c.c. of anhydrous ether. After 24 hours the precipitated solid is filtered off, m.p. 192°-93°C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:8]1[CH2:17][CH2:16][C:11]2([CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1.[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][CH:24]([CH2:35][C:36]1[NH:37][CH:38]=[CH:39][N:40]=1)[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)=[O:26]>>[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][CH:24]([CH2:35][C:36]1[NH:37][CH:38]=[CH:39][N:40]=1)[C:25]([C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:14]2[CH2:13][CH2:12][C:11]3([CH2:10][CH2:9][N:8]([CH2:7][C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])[CH2:17][CH2:16]3)[CH2:15]2)=[CH:33][CH:34]=1)=[O:26]
Reactant: O=Cc1ccc(C(=O)C(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: Cc1ccsc1CN1CCC2(CCNC2)CC1
Product: Cc1ccsc1CN1CCC2(CC1)CCN(Cc1ccc(C(=O)C(Cc3ncc[nH]3)Cc3ncc[nH]3)cc1)C2
Yield: 14.7 %

Procedure:
Using the compound (64 mg) produced in Example 13 and the compound (54 mg) produced in Example 11, the same operation as in Example 12 was performed. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol:28% aqueous ammonia=100:10:2) to obtain the title compound (14 mg) having the following physical properties.
Reaction SMILES: P(CCCC)(CCCC)CCCC.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:28][C:29]([F:49])([F:48])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[C:40]([CH:42]([OH:47])[CH2:43][CH2:44][CH2:45][CH3:46])[CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.O[C:51]1[CH:65]=[CH:64][C:54]([O:55][C:56]([CH3:63])([CH3:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58])=[C:53]([CH3:66])[CH:52]=1>C1COCC1>[CH3:63][C:56]([O:55][C:54]1[CH:64]=[CH:65][C:51]([O:47][CH:42]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:48])([F:28])[F:49])=[CH:35][CH:34]=3)[N:41]=2)[CH2:43][CH2:44][CH2:45][CH3:46])=[CH:52][C:53]=1[CH3:66])([CH3:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OC(C)(C)C(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
To a solution of nBu3P (47 μL, 0.19 mmol) in dry THF (2 mL), at 0° C. (ice/water bath) under nitrogen was added DIAD (37 mL, 0.19 mmol). After stirring for 10 minutes 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (50 mg, 0.16 mmol) was added, followed after another 20 minutes by ethyl 2-(4-hydroxy-2-methylphenoxy)-2-methylpropanoate (39 mg, 0.16 mmol). The mixture was then allowed to warm to rt over 16 hours and was then reduced under vacuum and the residue partitioned between EtOAc and water. The layers were separated and the organic layer washed with water (2×) then brine, dried (Na2SO4) and reduced to give a brown gum. Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with cyclohexane:EtOAc (19:1) afforded the title compound as a colourless gum (9 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1>CS(C)=O>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Nc1cncnc1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(Nc2cncnc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.3 %

Procedure:
To 5 ml of dimethyl sulfoxide (DMSO) containing 0.34 g of potassium tert-butoxide was added 0.29 g of 5-aminopyrimidine, followed by stirring at room temperature for about 15 minutes. To the reaction mixture was added dropwise 1 ml of a DMSO solution containing 0.33 g of p-fluorobenzotrifluoride, followed by heating at 60° C. for about 40 minutes. The reaction mixture was allowed to cool and poured into 150 ml of ice-water. The thus formed white crystals were collected by filtration and dried to obtain 0.17 g of 5-(4-trifluoromethylphenyl)aminopyrimidine.
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.[CH3:24][C:25]1[N:26]2[CH:35]=[CH:34][N:33]=[C:27]2[S:28][C:29]=1[C:30](O)=[O:31]>>[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:30]([C:29]2[S:28][C:27]3=[N:33][CH:34]=[CH:35][N:26]3[C:25]=2[CH3:24])=[O:31])=[O:8])[N:6]=1
Reactant: Cc1c(C(=O)O)sc2nccn12
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1c(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(N)sc2-c2cccc(F)c2)sc2nccn12

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 3-Methyl-imidazo[2,1-b]thiazole-2-carboxylic acid. LC-MS (basic): tR=0.73 min; [M+H]+=497.3.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12]O.[OH-].[Na+].O>C(O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=1[Cl:1])#[N:12]
Reactant: Cc1cccc(C=O)c1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.3 %

Procedure:
To a solution of 2-chloro-3-methylbenzaldehyde (19.4 g) in ethanol (45 ml) was added an aqueous hydroxylamine hydrochloride (9.7 g) solution (12 ml), and an aqueous sodium hydroxide (6.9 g) solution (10 ml) was added. The mixture was stirred at room temperature for 1.5 hours. Water (500 ml) was added and the precipitated crystals were collected by filtration. The obtained white crystals (16.1 g) were dissolved in acetic anhydride (50 ml) and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give 2-cyano-6-methylchlorobenzene (10.9 g) as a white solid. A suspension of 2-cyano-6-methylchlorobenzene (10.9 g), N-bromosuccinimide (12.8 g) and benzoyl peroxide (523 mg) in carbon tetrachloride (100 ml) was heated under reflux for 3.5 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (20:1)) to give 2-chloro-3-cyanobenzaldehyde (12.8 g) as a colorless oil. Subsequently, the title compound was prepared from 2-chloro-3-cyanobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1)=[O:8])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)c1
Yield: 79.9 %

Procedure:
Ethanol (50 ml) is added to 10% Pd-C (0.1 g) and thereto is added 1-[4-(3-nitrobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.73 g). The mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After completion of the reduction, 10% Pd-C is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane and the extract is dried over magnesium sulfate. The solvent is distilled off under reduced pressure and recrystallized from methanol to give 1-[4-(3-aminobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.54 g) as white powder, m.p. 205.5-206.5° C.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=1.C([O-])([O-])=O.[K+].[K+].[C:36]([O:40][CH3:41])(=[O:39])[C:37]#[CH:38].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:23]([O:22][C:17]1[C:16]2[N:15]([N:14]=[CH:38][C:37]=2[C:36]([O:40][CH3:41])=[O:39])[CH:20]=[C:19]([Cl:21])[CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[n+]1cc(Cl)cc(OCc2ccccc2)c1
Reactant: C#CC(=O)OC
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnn2cc(Cl)cc(OCc3ccccc3)c12
Reaction time: 0.08 h

Procedure:
To a solution of 1-amino-3-(benzyloxy)-5-chloropyridin-1-ium 2,4,6-trimethylbenzenesulfonate (2.18 g, 5.01 mmol) in DMF (50.0 mL) was added K2CO3 (1.73 g, 12.5 mmol) and the reaction was stirred for 5 minutes. Methyl propiolate (2.11 g, 25.1 mmol) was added and the reaction was stirred overnight open to air to afford a mixture of diastereomers. EtOAc and a saturated aqueous solution of NaHCO3 were added, the layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (5-20% EtOAc in hexanes) to afford methyl 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridine-3-carboxylate, which was the first eluting diastereomer.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[S:28]1[CH2:34][C:32](=[O:33])[NH:31][C:29]1=[S:30]>C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[C:34]4[S:28][C:29](=[S:30])[NH:31][C:32]4=[O:33])=[CH:17][CH:16]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCc2cccc(-c3ccccc3)c2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2cccc(-c3ccccc3)c2)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(3-phenylphenyl)methoxy]benzaldehyde (3.2 g, 10 mmol) was dissolved in acetic acid. To this solution, while stirring, were added sodium acetate (2.87 g, 35 mmol) and rhodanine (1.33 g, 10 mmol). This mixture was heated to reflux and maintained at this temperature. The progress of this reaction was monitored by thin layer chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-])=O)=[C:17]([C:19](=[O:22])[CH:20]=[CH2:21])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:23])=[C:17]([C:19](=[O:22])[CH2:20][CH3:21])[CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC(=O)c1cc(OCCCNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)c1cc(OCCCNC(=O)OC(C)(C)C)ccc1N
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
1-[5'-(3"-t-butoxycarbonylaminopropyloxy)-2'-nitrophenyl)-2-propen-1-one (325 mg) is dissolved in ethanol (15 ml) and thereto is added 10% palladium-carbon (40 mg), and the mixture is stirred under hydrogen atmosphere for 1.5 hour. After removing the catalyst by filtration, the filtrate is concentrated and purified with a silica gel column chromatography to give 1-[5'-(3"-t-butoxycarbonylaminopropyloxy)-2'-aminophenyl]propan-1-one (248 mg) as yellow powders.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]([F:16])([F:17])[CH2:3][NH:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNCC(F)(F)F
Reaction time: 8 h
Yield: 73.5 %

Procedure:
The compound (6.57 g, 25.6 mmol) obtained in step A was dissolved in tetrahydrofuran (100 ml), and the mixture was stirred under ice-cooling. Then, a suspension of lithium aluminum hydride (1.94 g, 51.2 mmol) in tetrahydrofuran (50 ml) was slowly added dropwise. Thereafter, the mixture was stood overnight at room temperature. The reaction mixture was ice-cooled again, water (2 ml), 1N aqueous sodium hydroxide solution (4 ml) and water (2 ml) were added in this order with stirring, and the mixture was stirred at room temperature for 5 hr. The insoluble material was filtered off through celite, and the obtained solution was concentrated under reduced pressure to give the title compound (4.56 g, yield 74%) as a yellow oil.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[CH3:16][C:17]([N+:22]([O-:24])=[O:23])([CH2:20]O)[CH2:18][OH:19].N1C=CC=CC=1>C(Cl)(Cl)Cl>[S:9]([O:19][CH2:18][C:17]([CH3:20])([N+:22]([O-:24])=[O:23])[CH2:16][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(CO)(CO)[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(COS(=O)(=O)C(F)(F)F)(COS(=O)(=O)C(F)(F)F)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of triflic anhydride (16.5 ml, 0.1 mol) in chloroform (50 ml) is added a solution of 2-methyl-2-nitro-1,3-propanediol (6.75 g, 0.05 mol) and pyridine (8.85 ml, 0.11 mol) in chloroform (50 ml) with external cooling to ensure a temperature of between 0° and 5° C. during the addition. After the addition the cooling bath is removed and the reaction stirred for 18 hours at ambient temperature. The reaction mixture is transferred to a separating funnel and washed with water. The organic layer is dried (Na2SO4), filtered and evaporated to dryness. The crude product is purified by chromatography using a 4:1 mixture of Hexane:Ethyl acetate as eluant; the product is obtained as a solid with melting point 50-52° C.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH:16]([NH2:18])[CH3:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:33]=[CH:32][C:24]2[O:25][C@@H:26]([C:29](O)=[O:30])[CH2:27][O:28][C:23]=2[CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([CH:16]([NH:18][C:29]([C@@H:26]3[O:25][C:24]4[CH:32]=[CH:33][C:21]([C:20]([F:35])([F:19])[F:34])=[CH:22][C:23]=4[O:28][CH2:27]3)=[O:30])[CH3:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: O=C(O)[C@H]1COc2cc(C(F)(F)F)ccc2O1
Reactant: CC(N)c1ccc2c(cnn2C2CCCCO2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)[C@H]1COc2cc(C(F)(F)F)ccc2O1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethanamine (66 mg, 0.27 mmol), (R)-6-trifluoromethyl-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acid (60.6 mg, 0.25 mmol), 4-dimethylaminopyridine (2.5 mg, 0.02 mmol) and N,N-diisopropylethylamine (153 μL, 0.88 mmol) in anhydrous DMF (4 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (102 mg, 0.27 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was poured into saturated NaHCO3 solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. The residue was dissolved in Methanol (20 mL) and 2N HCl (5 mL) was added. The reaction mixture was heated at 60° C. for 2 hours, then cooled and the methanol removed under vacuum. The remaining aqueous product was poured into saturated NaHCO3 solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 3% MeOH in DCM over 30 minutes) gave the product (43 mg) as a solid. m/z=391.8 (M+1), r.t.=2.96 and 3.04 mins. 1H NMR (400 MHz; DMSO-d6) δ 12.99 (1H, d), 8.68-8.60 (1H, m), 8.04 (0.5H, s), 7.94-7.87 (0.5H, m), 7.69 (0.5H, s), 7.53-7.16 (5H, m), 7.08-7.04 (0.5H, m), 5.12-4.90 (2H, m), 4.47-4.30 (2H, m), 1.46-1.41 (3H, m).