Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:11]([CH3:10])[S:12]([CH3:15])(=[O:14])=[O:13])#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: CNS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccccc1C#N)S(C)(=O)=O
Temperature: 80 °C

Procedure:
To a round bottom flask was added 2-fluoro-benzonitrile (1.0 g, 8.2 mmol), N-Methyl-methanesulfonamide (1.0 g, 9.2 mmol), potassium carbonate (1.7 g, 12 mmol) and N,N-dimethylformamide (5 mL). The mixture was heated at 80° C. for 18 hours. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (75 mL). The organic layer was washed with water (2×25 mL) and saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated to a waxy solid. The recovered solid was triturated with hexane, filtered and dried. N-(2-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a pale yellow solid (0.74 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72 (d, J=7.7 Hz, 1H), 7.70-7.64 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 3.40 (s, 3H), 3.13 (s, 3H). MS=211 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4([CH3:28])[CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[N:13]([C@@H:12]1[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3([CH3:28])[CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCOC(=O)Cl
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)cc1
Product: CCCCOC(=O)N(C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-{(3R,4S)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid butyl ester was prepared from rac-{4-[(3S,4R)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using butyl chloroformate instead of 4-fluoro-phenyl chloroformate and was obtained as a light yellow foam. MS m/e: 504.2 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@H:4]([O:12][C:13]1[C:18]([Br:19])=[CH:17][C:16]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([OH:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:15][C:14]=1[Br:38])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[CH3:44][O:45][C:46](=[O:49])[CH2:47]Br.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:39])[CH:4]([O:12][C:13]1[C:18]([Br:19])=[CH:17][C:16]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([O:37][CH2:47][C:46]([O:45][CH3:44])=[O:49])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:15][C:14]=1[Br:38])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(O)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c2ccccc2c(-c2cc(Br)c(OC(Cc3ccccc3)C(=O)OC)c(Br)c2)c2c1sc1ccccc12
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of (R)-2-[2,6-dibromo-4-(6-hydroxy-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-phenoxy]-3-phenyl-propionic acid methyl ester (0.60 g, 0.906 mmol) in anhydrous N,N-dimethylformamide was added potassuim carbonate (0.376 g, 2.72 mmol, 3 eq) and methylbromoacetate (0.26 mL, 2.72 mmol, 3 eq) at room temperature under a dry nitrogen atmosphere. After stirring for 24 hours the reaction mixture was combined with water (60 mL) the organics were extracted with diethyl ether (2×100 mL). The extracts were combined and washed with water (2×100 mL) and brine (100 mL). Silica gel was added and the solvents removed. The adsorbate was twice flash chromatographed (eluent 88/12 petroleum ether/ethyl acetate and 85/15 ethyl ether/ethyl acetate) to provide the title compound as a white solid (0.493 g, 73%): NMR (CDCl3); δ8.38 (d, J=8 Hz, 1 H), 7.81 (d, J =Hz, 1 H), 7.64-7.59 (m, 3 H), 7.55 (d, J=8 Hz, 1 H), 7.48 (ddd, J=8, 7, 1 Hz, 1 H), 7.43-7.26 (m, 6 H), 7.16 (ddd, J=8,7,1 Hz, 1 H), 6.79 (d, J=8 Hz, 1 H), 5.25 (dd, J=8, 6 Hz, 1 H), 4.94 (s, 2 H), 3.92 (s, 3 H), 3.76 (s, 3 H), 3.57 (septet, J=7 Hz, 2 H); MS (EI): [M+], 2 bromine isotope pattern, 732 (1.8%), 734 (4%), 736 (0.8%); Anal. Calc. for C35H26Br2O6S:, 57.24, H, 3.57, N, 0.00. Found: C, 57.01, H, 3.42, N, -0.07.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[C:12](=[O:19])[O:11][C:10]=2[CH:20]=1.[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[CH3:22].C(N(CC)CC)C>O1CCCC1>[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=4[C:12](=[O:19])[O:11][C:10]=3[CH:20]=2)[CH2:27][CH2:26]1)(=[O:23])[CH3:22]
Reactant: CC(=O)NC1CCNCC1
Reactant: O=c1oc2cc(OCCCBr)ccc2c2c1CCCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCCC4)CC1

Procedure:
A mixture of 17.3 g. (0.051 mole) 3-(3-bromopropoxy)-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one, 7.3 g. (0.051 mole) 4-acetamidopiperidine, 5.2 g. triethylamine and 100 ml. tetrahydrofuran is heated under reflux for 14 hours and then cooled and filtered. The precipitate obtained is washed with tetrahydrofuran and water and dried in a vacuum. There are obtained 11.3 g. (55% of theory) of the desired compound (m.p. 167°-168° C.) which is identical to the compound of Example 23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CN2CCCC2)cc1
Yield: 36.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(pyrrolidin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), pyrrolidine (0.076 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 3 to 20% ethanol in dichloromethane) furnished 0.028 g (36%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1COCC1.C(N(CC)CC)C.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@@H:19]([NH:23][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC[C@H](NC(=O)C(C)(C)C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
To a stirred solution of (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylpentan-2-amine (91a, 13 mg, 0.03 mmol) dissolved in dry THF (150 μmol) were added, at r.t., triethylamine (27.8 μl, 0.20 mmol) and pivaloyl chloride (12.3 ul, 0.1 mmo). The reaction was stirred over night. The solvent was removed under reduced pressure, and the product purified by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([O:54][C@@H:55]1[C@@H:61]([O:62][C:63](=[O:65])[CH3:64])[C@H:60]([O:66][C:67](=[O:69])[CH3:68])[CH2:59][S:58][CH:56]1O)(=[O:53])[CH3:52]>C1COCC1>[C:51]([O:54][C@@H:55]1[C@@H:61]([O:62][C:63](=[O:65])[CH3:64])[C@H:60]([O:66][C:67](=[O:69])[CH3:68])[CH2:59][S:58][C@H:56]1[O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:12][CH:13]=1)(=[O:53])[CH3:52]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 3 %

Procedure:
A solution of 2.66 g (11.41 mM) of 6-hydroxy-1H-indole-1-carboxylic acid tert-butyl ester in 50 ml of THF, 4.16 g (20.6 mM) of diisopropylazodicarboxylate and 5.39 g (20.6 mM) of triphenylphosphine are added to a solution of 4.34 g (14.84 mM) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranose in 150 ml of THF. The reaction mixture is stirred at 50° C. for 4 hours and then concentrated under reduced pressure. The evaporation residue is solubilized in ethyl acetate and the organic phase is washed with a 1N solution of sodium hydroxide and then with a concentrated aqueous solution of ammonium chloride. The organic phase is subsequently dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by silica gel chromatography, elution being carried out with a methylcyclohexane/ethyl acetate mixture (gradient of 9/1 to 7/3; v/v). The residue obtained is subsequently purified by C18-grafted silica chromatography, elution being carried out with an acetonitrile/water mixture (6/4; v/v). The desired product is obtained in the form of a white solid with a yield of 3%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21]C(=O)C)=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:25]=1.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29].P>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH:29][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:25]=1
Reactant: CC(=O)OCCCOc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2cc(OCCCO)ccc21
Yield: 42 %

Procedure:
In accordance with general method O, 0.65 g (1.8 mmol) of acetic acid 3-(8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxy)-propyl ester, 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)2, 0.17 g of phosphine ligand and 0.74 g (7.7 mmol) of Na—O-tert-butylate are reacted in 10 ml of toluene and 2 ml of tert-BuOH. Yield: 42%; m.p.: 154° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:49][O:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:54]3[CH2:55][CH2:56][CH:51]([O:50][CH3:49])[CH2:52][CH2:53]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: COC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methoxy piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[CH:22]1[C:27]([S:28]C2C=CN=CC=2)=[CH:26][CH:25]=[N:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[N:24]1[CH:25]=[CH:26][C:27]([S:28][O:9][C:8](=[O:10])[C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)=[CH:22][CH:23]=1
Reactant: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)O)n1
Reactant: c1cc(Sc2ccncc2)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)OSc2ccncc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
31.0 g of 6-chloro-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoic acid, 22.0 g of 4,4'-dipyridylsulfide and 26.2 g of triphenylphosphine were suspended in 250 ml of toluene, and were violently stirred at room temperature for 2 hours. The reaction mixture was filtered, and the toluene was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to obtain 36.0 g of the above identified compound as a white crystal (yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7]([CH2:15][OH:16])([C:11]([O:13]C)=[O:12])[C:6]=2[CH:17]=1.[OH-].[Na+]>C(Cl)Cl.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7]([CH2:15][OH:16])([C:11]([OH:13])=[O:12])[C:6]=2[CH:17]=1
Reactant: COC(=O)C1(CO)CCOc2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1(CO)CCOc2ccc(F)cc21
Temperature: 25 °C
Yield: 41.2 %

Procedure:
To a solution of 7 g (0.029 mole) Methyl 6-fluoro-3,4-dihydro-4-(hydroxymethyl)-2H-benzopyran-4-carboxylate in 200 mL of McOH was added 7.2 mL of 5N NaOH. The reaction was heated on a steam bath overnight then cooled to room temperature. The MeOH was evaporated and the residue dissolved in water then acidified to pH 4.0 with concentrated HCl. The aqueous was extracted with EtOAc and the EtOAc layer was dried over Na2SO4, filtered and evaporated to give 6 g of crude product. Chromatography on 160 g of silica gel eluting with CH2Cl2 /ether gave 2.7 g of product, m.p. 134°-135° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:10])[O:4][N:3]=1.Cl.O1CCOCC1>CCOC(C)=O>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:11][CH2:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[O:10])[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CCc2cc(O)no2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(CCc1cc(O)no1)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate (step 1) (539 mg, 1.525 mmol) in EtOAc (15 mL) was added 4N HCl in dioxane (15 ml, 60.0 mmol). The suspension was stirred at RT for 2 hrs and then concentrated under reduced pressure to give 3-(3-hydroxyisoxazol-5-yl)-N-(piperidin-4-ylmethyl)propanamide as a gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[C:5]#[N:6].N1C=CC=CC=1.[Cl:18][CH2:19][O:20][C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([Br:11])[C:9]=1[O:10][C:21](=[O:22])[O:20][CH2:19][Cl:18]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Reactant: O=C(Cl)OCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1cc(Br)c(OC(=O)OCCl)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
To a suspension of 3,5-dibromo-4-hydroxybenzonitrile (10.0 g, 36.1 mmol) in 180 mL of chloroform was added pyridine (2.92 ml, 36.1 mmol). Chloromethylchloroformate (5.2 mL 60 mmol) was then added over 5 min. The mixture was allowed to stir at room temperature for 12 h. The reaction was then washed with 1% HCl aq, water, and brine. The organic layer was then dried over sodium sulfate, filtered, and evaporated to afford a white solid (12.5 g) in 94% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.87 (d, 2H), 7.90 (s, 2H). 13C-NMR (300 MHz, CDCl3) δ (ppm): 73.58, 113.87, 115.68, 119.01, 136.40, 149.53, 149.71. Mp=83-85° C.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([NH:25][CH3:26])=[O:24])[CH:17]=[CH:16]2.[CH:27]1[N:31]=[CH:30][N:29]2[CH2:32][CH2:33][C:34](=[O:35])[C:28]=12.[Cl-].[NH4+]>C1COCC1>[OH:35][C:34]1([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C:23]([NH:25][CH3:26])=[O:24])[CH:17]=[CH:16]3)[C:28]2[N:29]([CH:30]=[N:31][CH:27]=2)[CH2:32][CH2:33]1
Reactant: O=C1CCn2cncc21
Reactant: CNC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Reaction time: 1 h
Yield: 36.6 %

Procedure:
Dry THF (150 ml) was cooled to −65° C. in a dry ice-acetone bath under an argon atmosphere and n-butyl lithium hexane solution (1.6M: 45.2 ml) was added. A solution of 6-bromo-N-methyl-2-naphthamide (8.68 g) in dry THF (700 ml) cooled to 10° C. was added to this solution at not more than −55° C., and the mixture was stirred for 1 h. A dry THF solution (60 ml) of 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (3.65 g) was added dropwise. The mixture was stirred at the same temperature for 1.5 h and saturated aqueous ammonium chloride solution (120 ml) was added to stop the reaction. The solvent was evaporated under reduced pressure and an ethanol-soluble material was extracted from the resulting residue and the solvent was evaporated again. The residue was purified by flash silica gel column chromatography (eluent, chloroform/methanol containing ammonia (7%), 19/1→9/1). The eluate was recrystallized from methanol to give the title compound (3.36 g) as colorless crystals.
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.O>CN(C)C=O>[I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][N:5]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:6]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2 g (6.3 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole were dissolved in 20 ml of dry dimethylformamide and 2.46 g (7.5 mmol) of cesium carbonate and 0.85 ml (6.3 mmol) of p-methoxybenzyl chloride were added successively. The reaction mixture was heated at 70° C. under stirring for 5 hours. Water was then added and the product extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent evaporated under reduced pressure. 2.4 g (86%) of the title compound crystallized from a mixture diethylether-diisopropylether.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].ClC(OCC(C)C)=O.C([N:47](CC)CC)C.N>ClCCl>[CH2:35]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH2:47])=[O:18])=[CH:10][CH:11]=1)=[O:5])[CH3:36]
Reactant: CCN(CC)CC
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C(=O)O)c2)N2CCN(Cc3ccccc3)CC2)cc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C(N)=O)c2)N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of INTERMEDIATE 9 (100 mg, 0.21 mmol) in dichloromethane (3 mL) at −20° C. was added isobutyl chloroformate (41 μL, 0.31 mmol) and triethylamine (43 μL, 0.31 mmol). After 10 minutes a solution of ammonia in dichloromethane (1.5M, 4.5 mL, 3 mmol) was added. Reacton was warmed to room temperature and washed with brine. The organic layer was dried (MgSO4), filtered and concentrated to give COMPOUND 1.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[CH:19])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br[C:22]1[S:23][CH:24]=[C:25]([C:27]([NH:29][C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])[N:26]=1.C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:22]3[S:23][CH:24]=[C:25]([C:27]([NH:29][C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])[N:26]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1csc(Br)n1)C(=O)OCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1csc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)n1)C(=O)OCC
Yield: 67.5 %

Procedure:
To a 100 mL 14/20 round bottom flask under an argon atmosphere were added 0.316 g (1.17 mmol) of 2 -pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine suspended in 10 mL of acetonitrile, followed by the addition of 0.47 g (1.2 mmol) of diethyl N-(2-bromo-4-thiazolylcarbonyl)-L-glutamate, 0.14 g (0.12 mmol) of tetrakis(triphenylphosphine)palladium (0), 0.046 g (0.24 mmol) of copper (I) iodide, and 0.35 mL (2.5 mmol) of triethylamine with an additional 10 mL of acetonitrile. The reaction was heated to reflux for 2 hours The volatiles were removed in vacuo, and the residue purified using silica gel flash chromatography, eluting with a step gradient of 100% chloroform to 2% methanol/chloroform to give 0.46 g (67%) of diethyl N-{2-[2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl]-4-thiazolylcarbonyl}-L-glutamate as an off-white solid, m.p. 201-202° C. (dec). Rf =0.28 (4% methanol/chloroform). 1H NMR (300 MHz, DMSO-d6) δ 1.12-1.29 (m, 15H), 2.05-2.15 (m, 1H), 2.37 (t, J=7.2 Hz, 2H), 3.98-4.13 (m, 4H), 4.45-4.49 (m, 1H), 8.47 (s, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.84 (d, J=8.1 Hz, 1H), 9.07 (d, J=1.9 Hz, 1H)