Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21](C(=O)C(F)(F)F)=[CH:20][CH:19]=2)[N:7]=1)=[O:4].[C:32](OC(=O)CC)(=O)CC>CN(C)C1C=CN=CC=1.O>[C:18]1([N:8]2[CH:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[CH2:10][C:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:32])=[N:7]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(C2CC(NC(=O)C(F)(F)F)=NN2c2ccc(C(=O)C(F)(F)F)cc2)cc1
Reactant: CCC(=O)OC(=O)CC
Agent: CN(C)c1ccncc1
Solvent: O
Product: CCC(=O)NC1=NN(c2ccccc2)C(c2ccc(C)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of 4.5 g. of 3-amino-1-phenyl-5-p-tolyl-2-pyrazoline (prepared in Example 3), 20.0 ml. of propionic anhydride and 200 mg. of 4-dimethylaminopyridine is heated on a steam bath for 2 hours. The reaction mixture is cooled to room temperature then water is added to separate a solid. The solid is collected then is dissolved in dichloromethane. The solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated at reflux and hexane is added until turbidity appears. The mixture is cooled and filtered to collect a solid. The solid is recrystallized again from 80% ethanol. This material is dissolved in 100 ml. of methanol, then 200 mg. of potassium carbonate is added and the mixture is refluxed for 15 minutes. Water is added until turbidity appears. The mixture is cooled and filtered to collect the solid. The solid is dissolved in dichloromethane. This solution is columnized and recrystallized as described above to yield 2.4 g. of the desired product as colorless needles, m.p. 123.5° -125° C.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:35][CH3:36])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:18]>>[CH2:35]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c1C
Yield: 56.4 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (1.5 g, 7.16 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (2 g) to give 1.9 g (57%) of the title compound as an orange solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([O:14]CC)=[O:13])[N:3]=1.CO.[Li+].[OH-]>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([OH:14])=[O:13])[N:3]=1
Reactant: CCOC(=O)Cn1nc(I)c2cccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1nc(I)c2cccnc21

Procedure:
Ethyl (3-Iodo-pyrazolo[3,4-b]pyridin-1-yl)-acetate (11 g, 33 mmol, 1 equiv) was dissolved in 50 mL of THF and 50 mL of MeOH to the solution was added 40 mL of 1N LiOH for 3 h. The organic solvents were evaporated and the remaining aqueous phase was neutralized with 1N HCl to a pH of about 1 which resulted in the precipitation of the desired product as a white solid was filtered and air dried to give (3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])(C)C)[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:17])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(C)(C)O)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(CO)cc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared 2-[5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidin-7-yl]-propan-2-ol (example C.14) (28 mg, 0.1 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (24 mg, 0.10 mmol) according to general procedure II. Obtained as a yellow solid (9 mg, 20%). MS (ISP) 445.0 [(M+H)+]; mp 194-196° C.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Cl.[Cl:14][CH2:15][C:16]1[N:17]=[CH:18][S:19][CH:20]=1>>[ClH:14].[S:19]1[CH:20]=[C:16]([CH2:15][O:1][NH2:2])[N:17]=[CH:18]1
Reactant: ClCc1cscn1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Product: NOCc1cscn1

Procedure:
Prepared by a similar procedure as described for preparation 18. Starting materials: N-hydroxyphthalimide and 4-(chloromethyl)thiazole hydrochloride (TCl). 13C-NMR (DMSO-d6) δ 155.1, 149.2, 121.4, 70.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([O:20][C:19]4[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:18]=4[N:17]4[CH:26]=[CH:27][CH:28]=[C:16]34)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30].[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:18]2[N:17]3[CH:26]=[CH:27][CH:28]=[C:16]3[C:13]3([CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH:31]5[CH2:33][CH2:32]5)=[C:3]([O:29][CH3:30])[CH:4]=4)=[O:9])[CH2:11][CH2:12]3)[O:20][C:19]=2[CH:21]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)ccc1Br
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)ccc1C1CC1
Temperature: 120 °C

Procedure:
To a microwave vial was added Pd-FibreCat (42 mg, 0.0065 mmol), (4-bromo-3-methoxyphenyl)(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (63 mg, 0.13 mmol), cyclopropylboronic acid (17 mg, 0.19 mmol), DMF (0.7 mL), and K2CO3 (190 μL of 2.0 M, 0.39 mmol). The reaction vessel was purged with nitrogen and the mixture was heated at 120° C. overnight. The mixture was filtered and was purified by prep-HPLC (20-99% MeOH:H2O with HCl modifier) to give (7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-cyclopropyl-3-methoxyphenyl)methanone. ESI-MS m/z calc. 448.2, found 449.4 (M+1)+; Retention time: 3.32 minutes (4 min run).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7](=[O:16])[C:6]1=[O:17])([OH:3])=[O:2].[N+:18]([O-])([O-:20])=[O:19].[Na+]>S(=O)(=O)(O)O>[C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7](=[O:16])[C:6]1=[O:17])([OH:3])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2ccc(Cl)cc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
13.0 g (51 mmol) of 1-(carboxymethyl)-7-chloro-2,3(1H,4H)-quinoxalinedione were dissolved in 150 ml of concentrated sulfuric acid and, at 0° C., 4.3 g (51 mmol) of sodium nitrate were added a little at a time. The mixture was stirred at room temperature for 2 h and then poured into ice-water, and the precipitate was filtered off with suction to yield 10.2 g (67%) of the product. Melting point >280° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[C:13]([C:16]1[CH:17]=[C:18]([C:22](O)=[O:23])[CH:19]=[N:20][CH:21]=1)(=[O:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:13]([C:16]1[CH:17]=[C:18]([C:22]([NH:12][C:6]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=2[NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:23])[CH:19]=[N:20][CH:21]=1)(=[O:15])[CH3:14]
Reactant: Nc1ccc(F)cc1NC1CC1
Reactant: CC(=O)c1cncc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cncc(C(=O)Nc2ccc(F)cc2NC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.082 g, 0.495 mmol) in dichloromethane were added the title compound from Step A (0.090 g, 0.545 mmol), HATU (0.207 g, 0.545 mmol), HOAt (0.074 g, 0.545 mmol), and diisopropylethylamine (0.35 mL, 1.98 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 314.14 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.33 (s, 1 H), 9.29 (s, 1 H), 8.72 (s, 1 H), 8.02 (br s, 1 H), 7.19-7.16 (m, 1 H), 6.91 (d, J=10.5 Hz, 1 H), 6.50-6.47 (m, 1 H), 4.64 (br s, 1 H), 2.69 (s, 3 H), 2.45-2.44 (m, 1 H), 0.78-0.77 (m, 2 H), 0.52-0.51 (m, 2 H).
Reaction SMILES: [C:1]1([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2>>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([N:18]=[C:10]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]3=[O:9])=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Reactant: Nc1ccc2[nH]ccc2c1
Product: O=C1C(=Nc2ccc3[nH]ccc3c2)c2ccccc2N1c1ccccc1
Temperature: 140 °C
Yield: 13.9 %

Procedure:
1-phenylisatin (51.8 mg, 0.23 mmol) and 5-aminoindole (31 mg, 0.23 mmol) were mixed and heated at 140° C. for 2 h. The resulting crude product was purified by preparative TLC using ethyl acetate/hexane (6:4) as the eluent, giving the desired product as a yellow solid (10.8 mg, 14%). 1H NMR (400 MHz): δ 8.28 (s, 1H), 7.57 (t, J=7.7, 2H), 7.49–7.40 (m, 6H), 7.29–7.23 (m, 1H), 7.03 (dd, J 8.5, 1.7, 1H), 6.98 (d, J=7.6, 11H), 6.83 (d, J=8.0, 1H), 6.74, J=7.6, 1H), 6.59 (s, 1H); ESI-MS m/z found 338 (MH+).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>CC(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cc1Cl
Temperature: 70 °C
Yield: 53.3 %

Procedure:
Sodium hydroxide (40 mg) was added to a solution of ethyl 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D108) (300 mg) in iPrOH (10 mL) and water (10 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E81) (150 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.61 (2H, t), 2.97 (2H, t), 5.46 (1H, m), 7.34 (1H, d), 7.71 (2H, m), 8.12 (1H, s), 8.54 (1H, s), 8.92 (1H, s), 11.18 (1H, s), 12.05 (1H, br s). MS (ES): C21H19ClN4O4 requires 426; found 427.2 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([OH:21])=O)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([Cl:25])=[O:21])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=C(O)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
23 g (0.067 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid are dissolved in 40 ml dichloromethane and combined with three drops of dimethylformamide and 6.96 ml (0.081 mol) of oxalyl chloride, dissolved in 10 ml dichloromethane, under nitrogen at 0° C. The mixture is stirred for 3 hours at ambient temperature. Then the solvent is removed and the crude product is further reacted without any more purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)=[CH:6][CH:5]=1
Reactant: Cc1cccc(CCl)n1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Product: COC(=O)c1ccc(OCc2cccc(C)n2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E except KI (1.3 eq.) is also added from 4-hydroxy-benzoic acid methyl ester and 2-(chloromethyl)-6-methyl-pyridine hydrochloride [CAS 3099-29-4]. MS (ES+) 258.2
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:26][CH:27]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:28](O)=[O:29].CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([CH:31]([CH2:34][CH3:35])[CH:27]([OH:26])[C:28]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([NH:13][CH2:12][C:11]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:29])[CH3:33]
Reactant: CCC(CC)C(O)C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(CC)C(O)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (171 mg, 0.47 mmol), 2-hydroxy-3-ethylpentanoic acid (68 mg, 0.47 mmol), and NMM (51 μL, 0.47 mmol) in DMF (5 mL) at ambient temperature under nitrogen atmosphere was added BOP reagent (247 mg, 0.56 mmol). The mixture was stirred at ambient temperature for 18 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by preparative thick layer silica gel plate chromatography (2000 μM×20 cm×20 cm) developed with 5% MeOH in dichloromethane. Desired bands were removed and eluted with 5% MeOH in dichloromethane. The filtrate solvent was concentrated in vacuo to obtain 1-(3-ethyl-2-hydroxypentanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide was obtained as a yellow oil (200 mg; HPLC RT=3.45 min, method A; LC-MS m/z=496.1).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.[OH:20][C:21]([CH3:28])([CH3:27])[CH2:22][NH:23][C:24]([NH2:26])=[NH:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:7][N:26]=[C:24]([NH:23][CH2:22][C:21]([CH3:28])([OH:20])[CH3:27])[N:25]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(O)CNC(=N)N
Reactant: CSc1nccc(/C(=C/N(C)C)C(=O)CC2CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(methylthio)pyrimidin-4-yl)but-3-en-2-one (3) in DMF (4 mL), 1-(2-hydroxy-2-methylpropyl)guanidine (529 mg, 3.15 mmol) and potassium carbonate (872 mg, 6.31 mmol) were added, and the reaction mixture was stirred at 120° C. for 2 h. The reaction mixture was purified by a reverse-phase Gilson HPLC [30-90% organic phase over 15 min] followed by a Biotage silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a glassy solid (90 mg, 21% yield). MS (ES+): m/z=392.2/393.2/394.3 (100/40/10) [MH+]. HPLC: tR=1.12 min over 3 min. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [C:1]([CH:5]1[CH2:10]C[C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[C:23](=[O:26])(O)[O-:24].[Na+]>ClCCl>[C:1]([CH:5]1[CH2:10][O:24][C:23](=[O:26])[CH2:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C1CCCC(=O)OC1

Procedure:
This was prepared in the same manner as Lactone 1 except using 4-tert butylcyclohexanone (10 parts, 0.065 m ex. Aldrich), 3-chloroperoxybenzoic acid (17.5 parts, 0.0713M), sodium bicarbonate (11.5 parts, 0.143M) and dichloromethane (750 ml) in place of the 3-methyl cyclohexanone and amounts described for Lactone 1. The product was obtained as an oil (10.2 parts).
Reaction SMILES: CN(CCC1[C:10]2[CH:11]=[C:12]([CH2:15][C@@H:16]3[NH:21][C:19](=[O:20])[O:18][CH2:17]3)[CH:13]=[CH:14][C:9]=2[NH:8]C=1)C.[NH2:22]C1C=CC(C[C@H]2COC(=O)N2)=CC=1.N([O-])=O.[Na+].Cl>>[NH:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]2[CH2:17][O:18][C:19](=[O:20])[NH:21]2)=[CH:11][CH:10]=1)[NH2:22]
Reactant: CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Reactant: Nc1ccc(C[C@H]2COC(=O)N2)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: NNc1ccc(C[C@H]2COC(=O)N2)cc1

Procedure:
Zolmitriptan was first disclosed in U.S. Pat. No. 5,466,699 and the synthetic route comprises diazotization of (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one with sodium nitrite in presence of hydrochloric acid, followed by treatment of the diazonium salt with stannous chloride to give (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one. Further reaction of the hydrazine derivative with dimethylamino butyraldehyde diethyl acetal followed by chromatographic purification gave Zolmitriptan (I) as oil, which upon further crystallization from isopropanol gave Zolmitriptan of desired purity. (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one, in turn, was obtained from L-4-nitrophenyl alanine by treating it with thionyl chloride and methanol to give (S)-methyl-4-nitrophenyl alanate, which on reduction with sodium borohydride gave the corresponding alcohol. Further reaction of the said alcohol with phosgene in presence of potassium hydroxide followed by hydrogenation in presence of palladium on carbon gave the desired (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>O1CCCC1>[Si:9]([O:7][CH2:6][C:5]#[C:4][CH2:3][OH:8])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCC#CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC#CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
60% Sodium hydride (1.39 g) was suspended in tetrahydrofuran (50 mL), and the suspension was cooled to 0° C., a solution of but-2-yne-1,4-diol (3.0 g) in tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hr. tert-Butyldimethylsilyl chloride (5.26 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=100:0→80:20) to give the title compound (1.48 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[N:21]=3)[C:16](O)=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[N:21]=3)[C:16]([Cl:27])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1

Procedure:
A 50 mL round bottom flask was charged with 2-(4-(4-fluorophenoxy)phenyl)-6-methylisonicotinic acid (116 mg, 0.36 mmol) suspended in DCM and cooled in an ice bath for 20 minutes. Thionyl chloride (2 mL) was added to the suspension, which became a solution in about 10 minutes. The ice bath was removed and the reaction mixture was concentrated under reduced pressure to give 2-(4-(4-fluorophenoxy)phenyl)-6-methylisonicotinoyl chloride which was used without purification for the next reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:17])[CH:7]=1.[CH3:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Ag+2].C(#N)C.O>[CH2:18]([C:5]1[CH:4]=[CH:3][C:2]([C:23]2[S:24][CH:25]=[C:21]([CH3:20])[N:22]=2)=[CH:7][C:6]=1[CH:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH:10]([CH2:11][CH2:12]2)[C:9]1=[O:17])[CH3:19]
Reactant: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Reactant: Cc1cscn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CCc1ccc(-c2nc(C)cs2)cc1C1C(=O)C2CCC(C2)C1=O

Procedure:
3-(5-Bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione (200 mg, 0.62 mmol), 4-methylthiazole (74 mg, 0.75 mmol), silver carbonate (860 mg, 3.1 mmol), triphenylphosphine (16.3 mg, 62.2 umol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride (26 mg, 31.1 umol) are added to a scintillation vial and shaken with a degassed solvent mixture of acetonitrile:water 1:1 (1.5 ml) at 65° C. for 22 hours. The mixture is concentrated under reduced pressure, taken up in DMSO (1.5 ml), filtered and purified by preparative reverse-phase HPLC to give 3-[2-ethyl-5-(4-methyl-thiazol-2-yl)phenyl]bicyclo[3.2.1]octane-2,4-dione.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.CN(C=O)C.Br[CH2:36][CH3:37].O.[OH-].[Cs+]>>[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:3]2[CH:4]=[CH:5][N:1]([CH2:36][CH3:37])[N:2]=2)[N:8]=1)[CH3:29]
Reactant: CCBr
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.10 mmol; prepared as in Example 39, Step H) in dry DMF (519 μL, 0.10 mmol) was added bromoethane (11 mg, 0.10 mmol), cesium hydroxide hydrate (17 mg, 0.10 mmol) and 4 angstrom molecular sieves. The reaction mixture was stirred for one hour, filtered through an Acrodisk, rinsed with DCM and MeOH, and concentrated under a nitrogen stream to a residue. Preparative thin layer chromatography eluting with 10% MeOH, 0.5% NH4OH in CHCl3 provided the final product (10 mg). MS (ES+APCI) m/z=414 (M+H).