Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][C:15](OCC)=[N:14][CH2:13][CH2:12]1)=[O:10].[C:20]([NH:28][NH2:29])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:12][CH2:13][N:14]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:28][N:29]=[C:15]2[CH2:16]1)=[O:10]
Reactant: CCOC1=NCCN(C(=O)c2ccc(F)cc2Cl)C1
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCO
Product: O=C(c1ccc(F)cc1Cl)N1CCn2c(nnc2-c2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 1-[(2-chloro-4-fluorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (0.228 g, 0.8 mmol, e.g. see preparation below) and benzohydrazide (benzoylhydrazine, 0.109 g, 0.800 mmol, CAS [613-94-5], commercially available e.g. from Sigma-Aldrich or ABCR) in 1-butanol (1 ml) was heated at reflux for 18 hours. After cooling to room temperature the solvent was evaporated and the residue was purified by mass-directed automated (preparative) HPLC (MDAP). A trituration with diethyl ether was then carried out to yield 7-[(2-chloro-4-fluorophenyl)carbonyl]-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.053 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:14][O:13][C:11]([C:10]1[CH:15]=[CH:16][C:7]([C:4]2[CH:5]=[CH:6][N+:1]([O-:25])=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(-c2ccncc2)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc[n+]([O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Methyl 4-(4-pyridyl)benzoate (1.49 g) was dissolved in dichloromethane (30 ml), 70% m-chloroperbenzoic acid (3.46 g) was added, and the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium sulfite was added to conduct liquid separation. The resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the title compound (1.33 g) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]4[NH:23][N:22]=[N:21][N:20]=4)[CH:16]=[C:15]([F:24])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.[N+](=[CH2:27])=[N-]>O1CCCC1>[F:24][C:15]1[CH:14]=[C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[N:12]=2)[CH:18]=[C:17]([C:19]2[N:23]([CH3:27])[N:22]=[N:21][N:20]=2)[CH:16]=1
Reactant: C=[N+]=[N-]
Reactant: Fc1ccc(-c2noc(-c3cc(F)cc(-c4nnn[nH]4)c3)n2)nc1
Solvent: C1CCOC1
Product: Cn1nnnc1-c1cc(F)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Yield: 21.3 %

Procedure:
To a solution of 3-(5-fluoro-pyrid-2-yl)-5-[3-fluoro-5-(1H-tetraazol -5-yl)-phenyl]-1,2,4-oxadiazole (30mg, 0.092 mmol) in tetrahydrofuran (1 mL), 0.5 M diazomethane (1 mL, 0.5 mmol, ether) was added. The reaction was quenched with water and extracted with dichloromethane. The product was purified by column chromatography with 20% ethyl acetate in hexanes to give 6.7 mg (21.4%) of 5-[3-fluoro -5-(1-methyl-1H-tetraazol-5-yl)-phenyl]-3-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.87 (s, 1H), 8.70 (d, 1H), 8.29 (dd, 1H), 8.10 (m, 2H), 7.62 (dt, 1H), 4.46 (s, 3H).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=[O:16])([C:3](OCC)=[O:4])=[O:2]>C(O)C.[Pt]>[OH:16][N:15]1[C:14]2[C:9](=[CH:10][C:11]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:13]=2)[NH:8][C:1](=[O:2])[C:3]1=[O:4]
Reactant: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n(O)c1=O
Yield: 36.6 %

Procedure:
A solution of 3-ethoxalylamino-4-nitrobenzotrifluoride (0.61 g, 2 mmol) in 50 ml of 96% ethanol was hydrogenated at atmospheric pressure and room temperature in the presence of 30 mg of 5% platinum on carbon for 5 min. The catalyst was filtered off and washed with ethanol. Acetic acid (10 ml) was added to the filtrate and the solution was refluxed for 1.5 h. The mixture was evaporated to dryness, and the residue was recrystallized from ethanol/water to give 0.18 g (36%) of the title compound. M.p.>220° C. dec.; 1H-NMR (DMSO-d6): 7.40-7.70 (m, 3H, ArH), 12.1 (broad s, 1H, NH); IR (KBr): 1700, 1625 cm-1 ; MS (m/e): 246 (68%, M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[N:43]([C:6]([C:7]3[CH:16]=[CH:15][C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C#Cc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1ccc2ccccc2c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 88 %

Procedure:
The title compound was synthesized from naphthalene-2-yl-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 88% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) δ 7.85 (m, 4H), 7.50 (m, 2.6H), 7.33 (m, 1.6H), 7.12 (m, 1.8H), 6.95 (m, 1.4H), 6.74 (m, 1.6H), 6.61 (d, 0.6H, J=0.4 Hz), 6.50 (d, 0.4H, J=0.4 Hz), 6.35 (s, 0.6H), 6.23 (s, 0.4 HZ), 4.36 (t, 2H, J=8.0 Hz), 4.05 (m, 2H), 3.76 (m, 2H), 3.20 (t, 2H, J=8.0), 2.73 (t, 2H, J=8.0 Hz), (m, 2H), 1.51 (s, 9H), 1.07 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=1>CN(C)C=O.O.CO>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)[O:10][C:11]1[C:12](=[O:21])[N:13]([CH2:29][C:30]2[C:38]3[C:33](=[N:34][CH:35]=[CH:36][CH:37]=3)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=2)[CH:14]=[CH:15][C:16]=1[C:17]([F:18])([F:19])[F:20]
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)n1nc(Cn2ccc(C(F)(F)F)c(Oc3cc(Cl)cc(C#N)c3)c2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with 3-chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile (3C, 2.03 g, 6.45 mmol) and potassium carbonate (0.891 g, 6.45 mmol) was added dimethylformamide (20 mL). To this under N2 was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (2.01 g, 6.45 mmol) as a solution in dimethylformamide (10 mL). This was allowed to stir at room temperature for 16 hours. After this time the reaction mixture was diluted with water (50 mL) and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic fractions were washed with brine (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 120 gram column, eluting with 0-5% methanol in CH2Cl2 to give a solid. This was suspended in methanol (100 mL) and filtered to recover the title compound as a solid. 1H NMR (DMSO-d6) δ 8.71 (d, J=4.4 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.11 (d, J=7.1 Hz, 1H), 7.74-7.70 (m, 1H), 7.56-7.52 (m, 1H), 7.50-7.45 (m, 1H), 7.44-7.38 (m, 1H), 6.70 (d, J=7.1 Hz, 1H), 5.59 (s, 2H), 1.62 (s, 9H). LRMS (M+1)=545.8.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1F

Procedure:
In analogy to example 16.4, 2-fluoro-4-hydroxy-benzaldehyde (CAS-No: 348-27-6) was alkylated with benzylbromide/potassium carbonate in DMF to give 4-benzyloxy-2-fluoro-benzaldehyde. Off-white solid. MS 230.1 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11](Cl)(Cl)=[S:12]>C(=O)([O-])O.[Na+].O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[N:4]=[C:11]=[S:12]
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(N)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N=C=S)c(Cl)c1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a stirred solution of 2-chloro-4-methoxyaniline (7.90 g, 50.1 mmol) in saturated aqueous sodium hydrogen carbonate (40 mL) and tetrahydrofuran (40 mL) was added thiophosgene (4.99 mL, 65.1 mmol) at room temperature. After 30 min, the reaction mixture was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The resulting solid was washed with n-hexane to give the title compound as a pale red solid (6.85 g, 34.3 mmol, 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-fluoro-biphenyl-4-ol and 1-(4-chloro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 13) to afford the racemate as a white solid (84 mg, 37%)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:23][CH:22]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 2-(4-amino-1H-indazol-1-yl)-2-(4-chlorophenyl)butanoate (1.0 g, 2.9 mmol) and NMM (0.9 g, 8.7 mmol) in DCM (10 mL) was added MsCl (0.4 g, 3.2 mmol) dropwise, Then the mixture was stirred at room temperature overnight. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (50 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: PE/EA=4/1) to afford the title compound as a yellow solid. LC/MS m/z=422.1 [M+H]+.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[C:66]([CH3:67])=[CH:65][CH:64]=[C:63]([F:68])[C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([O:58]C)=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]>>[F:33][C:34]1[C:66]([CH3:67])=[CH:65][CH:64]=[C:63]([F:68])[C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([OH:58])=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4c(F)ccc(C)c4F)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: Cc1ccc(F)c(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)c1F
Yield: 78 %

Procedure:
The compound of example 166 was prepared analogous to compound of example 98 by hydrolysis of compound of example 165.
Reaction SMILES: C1(P(=O)(O[C:16]([CH3:47])=[C:17]([N:31]2[C:37](=[O:38])[CH:36]3[CH:32]2[S:33][C:34]([CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:35]3)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])OC2C=CC=CC=2)C=CC=CC=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>O1CCCC1>[O:40]([CH2:39][C:34]1[S:33][CH:32]2[CH:36]([C:37](=[O:38])[N:31]2[C:17](=[C:16]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH3:47])[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])[N:35]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(OP(=O)(Oc1ccccc1)c1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 3 h

Procedure:
To a stirred solution of phenyl 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-1-(p-nitrobenzyloxycarbonyl)-prop-1-en2-yl phenylphosphonate (1.37 g.) in tetrahydrofuran (20 ml.) at 0°-5° C. was added morpholine (0.383 ml.). After stirring for 3 hours at 0°-5° C., the solvent was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:20](=[O:21])[NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: O=C=Nc1cccnc1
Reactant: CSc1cc2c(cc1Cl)NCC2
Product: CSc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2
Yield: 81 %

Procedure:
6-Chloro-5-methylthioindoline (D48) (0.70 g, 3.51 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound (0.91 g, 81%) as a white crystalline solid m.p. 241°-242° C.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[S:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]2=[O:27])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1.O.C(OCC)C>[C@@H:23]1([N:25]2[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]2=[O:27])[S:24][C@H:20]([CH2:19][OH:18])[CH2:21][CH2:22]1
Reactant: CC(C)(C)[Si](OC[C@@H]1CC[C@H](n2ccc(N)nc2=O)S1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1ccn([C@H]2CC[C@@H](CO)S2)c(=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
The compound 13 (78 mg, 0.17 mmol) was dissolved in 4 mL tetrahydrofuran and then 1 M tetrabutylammonium fluoride in THF (0.2 mL, 0.2 mmol) and acetic acid (11.5 μm, 0.2 mmol) were added, with subsequent stirring at 25° C. overnight. The reaction was diluted with 10 mL water and 10 mL ethyl ether followed by stirring for 5 minutes. The aqueous phase was washed with 20 mL ethyl ether and concentrated in vacuo to 1 mL. The aqueous residue was eluted through a 5-mL Dowex 1×4 (-OH) column with water to remove the tetrabutyl ammonium salts. The crude product (33 mg, 87%) was refractory to recrystallization and was precipitated as an amorphous solid with ethyl acetate and ethyl ether to afford 26.5 mg (69%) of 24; mp. 83°-85° C.; FAB MS 228 (M+H)+ ;1H NMR (DMSO-d6) δ 8.0 (d, 1, H-6), 7.1 (brd, 2, NH2), 6.15 (m, 1, 1'-H), 5.74 (d, 1, H-5), 5.1 (brs, 1, 5'-OH), 4.2 (q, EtOAc), 3.64 (m, 1, 5'-H), 3.5 (m, 2, 4'-H, 5'-H), 2.18 (m, 1, 2'-H), 2.0 (m, 2, 2'-H, 3'-H), 1.99 (s, EtOAc), 1.82 (m, 1, 3'-H), 1.18 (t, EtOAc).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1.[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([CH:47]=1)[C:44](O)=[O:45])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([C:44]([N:25]2[CH2:26][CH2:27][CH:22]([N:20]3[C:19](=[O:28])[C:18]([CH3:30])([CH3:29])[C:17]([C:7]4[C:8]5[CH2:9][C:10]6([O:15][C:16]=5[C:4]([O:3][CH3:2])=[CH:5][CH:6]=4)[CH2:11][CH2:12][CH2:13][CH2:14]6)=[N:21]3)[CH2:23][CH2:24]2)=[O:45])[CH:47]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B6) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]#[C:22][C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)COc1ccc(I)cc1
Product: CCOC(=O)COc1ccc(C#Cc2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 2-(4-iodophenoxy)acetate (550 mg, 1.80 mmol) and phenylacetylene (0.17 mL, 1.80 mmol) according to the general procedure IE to give 390 mg (78%) of an orange solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.26 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.53-7.45 (m, 4H), 7.36-7.25 (m, 3H), 6.90-6.87 (m, 2H), 4.63 (s, 2H), 4.32-4.23 (dq, 2H, J=7.2 Hz, 2.1 Hz), 1.35-1.24 (tt, 3H, J=7.2 Hz, 1.5 Hz); 13CNMR (CDCl3) δ 168.6, 157.8, 133.1, 131.5, 128.3, 128.0, 123.4, 116.6, 114.7, 89.0, 88.4, 65.4, 61.5, 14.1; EI-MS m/z 280 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)CCC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 59.9 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.64 g, 1.4 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid (0.22 g, 1.4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.45 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.33 min; [M+H]+=473.1.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([B-](F)(F)F)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[K+].Cl[C:22]1[C:27]2[O:28][CH:29]([CH3:33])[C:30](=[O:32])[NH:31][C:26]=2[CH:25]=[C:24]([CH:34]=[O:35])[CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O.CC(O)C>[CH2:9]([C:22]1[C:27]2[O:28][CH:29]([CH3:33])[C:30](=[O:32])[NH:31][C:26]=2[CH:25]=[C:24]([CH:34]=[O:35])[CH:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: F[B-](F)(F)Cc1ccccc1
Reactant: CC1Oc2c(Cl)cc(C=O)cc2NC1=O
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CC1Oc2c(Cc3ccccc3)cc(C=O)cc2NC1=O
Temperature: 115 °C
Reaction time: 20 h
Yield: 28.2 %

Procedure:
To a suspension of potassium phosphate, tribasic (0.564 g, 2.66 mmol), potassium benzyltrifluoroborate (0.263 g, 1.330 mmol), 8-chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 15 (0.2 g, 0.886 mmol) in toluene (Ratio: 5.00, 20 mL) and water (Ratio: 1.000, 4.0 mL) was added PdOAc2 (0.015 g, 0.066 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.062 g, 0.133 mmol) at 23° C. The reaction was stirred at 115° C. for 20 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3×5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was reconstituted in DCM (1.0 mL) and purified via medium pressure chromatography using a gradient eluant of 1-5% MeOH:DCM. The appropriate fractions were combined and solvent was removed via rotary evaporation. The late eluting fractions were dried in vacuo to provide a yellow solid. The yellow solid was re-suspended in IPA (1.0 mL), heated at reflux to furnish a solution, cooled to room temperature, filtered, rinsed with IPA, and dried in vacuo to provide the title compound as an off-white solid (0.0704 g, 0.250 mmol, 28.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.82 Hz, 3H) 3.98 (s, 2H) 4.75-4.81 (m, 1H) 7.16-7.32 (m, 6H) 7.45 (d, J=2.02 Hz, 1H) 9.80 (s, 1H) 10.93 (s, 1H). ESI-MS: m/z 282.2 (M+H)+. mp=163.2-166.1° C.