Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]([N:18]=[C:19]([CH3:23])[C:20](=O)[CH3:21])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[C:29]1([C:35]2[N:36]([NH2:46])[C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]([N:18]=[C:19]([C:20](=[N:46][N:36]3[C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:38][CH:39]=[C:35]3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH3:21])[CH3:23])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nn1c(-c2ccccc2)ccc1-c1ccccc1
Reactant: CC(=O)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=Nn1c(-c2ccccc2)ccc1-c1ccccc1)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.6 %

Procedure:
A suspension of 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one (2.45 g, 8.1 mmol) in toluene (28 mL) was treated with DMF (14 mL), 2,5-diphenyl-pyrrol-1-ylamine (1.99 g, 8.5 mmol) and p-toluene sulfonic acid (73 mg). The resulting suspension was fitted with a Dean Stark trap and heated to reflux in an oil bath for 21 h, then cooled to rt and allowed to stand under Ar for 4 days. The desired compound did not crystallize, therefore the solution was concentrated in vacuo. Approximately half of the residue was purified by flash chromatography (SiO2, 5-100% EtOAc/heptane) to afford some pure desired 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane (780 mg) and some desired contaminated with starting 2,5-diphenyl-pyrrol-1-ylamine. The remaining crude residue was flash chromatographed (SiO2, 33-50% CH2Cl2/heptane) in an attempt to remove excess amino pyrrole. No separation was achieved, therefore all of the fractions were combined, together with the impure material from the first column and concentrated in vacuo. This mixture was suspended in toluene (15 mL) and treated with DMF (5 mL), 2,3-butanedione (0.81 mL, 9.24 mmol) and p-toluene sulfonic acid (7 mg). The resulting suspension was heated to 70° C. in an oil bath, and stirred under Ar for 3 h, then cooled to rt and concentrated in vacuo. The resulting solid was washed with water, heptane and toluene (to remove 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one and 2,3-butanedione) and dried in vacuo to afford 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane (1.42 g) as a yellow solid. Overall, 2.2 g (52% based on 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one) of 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane was isolated as a yellow solid: 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.71 (s, 6H), 6.44 (s, 4H), 7.22-7.36 (m, 20H).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12]C(C)C(Cl)=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[Mg].C(OCC)(=O)CC(OCC)=O>CCOCC>[CH2:31]([O:30][C:22](=[O:29])[CH:23]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:32]
Reactant: CC(Oc1ccc(Oc2ccc(C#N)cc2)cc1)C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(Oc1ccc(Oc2ccc(C#N)cc2)cc1)C(=O)OCC
Yield: 72 %

Procedure:
A mixture of 30 g of 2-[4'-(4"-cyano-phenoxy)-phenoxy]-propionyl chloride and 30 ml of ether is added dropwise to a 35% etheral solution of magnesium diethyl malonate prepared from 17.6 g of diethyl malonate. The addition of the acid chloride having been completed the reaction mixture is heated to boiling for an hour and worked up as described in Example 1. Thus 30 g of the desired compound are obtained in the form of a viscous oil which solidifies on standing and melts at 42°-46° C. Yield 72%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:26]([C:48]([OH:50])=O)[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:47])[NH:32][S:33]([C:36]1[C:45]([CH3:46])=[C:43]([CH3:44])[C:40]([O:41][CH3:42])=[CH:39][C:37]=1[CH3:38])(=[O:35])=[O:34].[NH:58]1[CH2:67][CH2:66][CH2:65][C@H:59]1[C:60]([NH:62][CH2:63][CH3:64])=[O:61].Cl.C(N(CC)CC)C>CC(N(C)C)=O>[NH:25]([C:51]([O:53][C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])[C@H:26]([C:48]([N:58]1[CH2:67][CH2:66][CH2:65][C@H:59]1[C:60]([NH:62][CH2:63][CH3:64])=[O:61])=[O:50])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:47])[NH:32][S:33]([C:36]1[C:45]([CH3:46])=[C:43]([CH3:44])[C:40]([O:41][CH3:42])=[CH:39][C:37]=1[CH3:38])(=[O:34])=[O:35]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Reactant: CCNC(=O)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C)NC(=O)OC(C)(C)C
Yield: 131.6 %

Procedure:
According to the general procedure for HBTU promoted coupling solutions of 31.5 g Boc-Arg(Mtr)-OH in DMAC, 24.79 g HBTU in DMAC, 11.56 g H-Pro-NHEt.HCl in DMAC and 19.60 g triethylamine in DMAC were premixed and fed into the reactor at 50° C. using a residence time of 1.1 min to yield 52 g crude material which was used in the next step without purification. The calculated yield from HPLC analysis was 99%.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+]=[N-])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Yield: 70.1 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-azido-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (28 mg) and triphenylphosphine (9 mg) in 1 ml of wet toluene was stirred at 70° C. overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative tlc on silica gel (1000 microns, 1% NH4OH in 5% i-PrOH/CH2Cl2) to give 19 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@H:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:23]>>[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH:23][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-methyl-L-valine methyl ester hydrochloride (1:1) (CAN 63038-27-7) as starting materials, MS (ESI) 361.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21](=[O:29])[N:20]=3)=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>CO>[O:29]=[C:21]1[N:20]=[C:19]([NH:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:12][CH:13]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1
Reactant: COC(=O)c1ccccc1-c1ccc(CNc2nc(=O)[nH]c3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1-c1ccc(CNc2nc(=O)[nH]c3ccccc23)cc1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of 0.26 g of 4'-[[(1,2-dihydro-2-oxo-4-quinazolinyl)amino]methyl][1,1'-biphenyl]-2-carboxylic acid methyl ester in 5.0 mL of methanol was added 15 mL of 0.1N aqueous sodium hydroxide. The solution was warmed to ~90° C. for 3 days. After cooling to room temperature the solution was neutralized with 0.1N HCl and the resulting precipitate was filtered off and washed with water. After drying, the solid was purified on silica gel chromatography to yield 0.160 g (64%) of the desired product. The product was characterized as its sodium salt: 1H NMR (DMSO-d6, 400 MHz) δ 10.69 (s, 1H), 9.00 (t, J=5.8 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.52 (m, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.28 (m, 3H), 7.14 (m, 5H), 4.68 (d, J=5.6 Hz, 2H); negative FAB MS m/e 392 (M-H); 370 (M-Na). Anal. Calcd for C22H16N3NaO3.1H2O: C, 64.23; H, 4.41; N, 10.21. Found: C, 64.43; H, 4.19; N, 9.82.
Reaction SMILES: C(O)C.[C:4]([C:7]1[C:15]2[S:14][C:13](=[O:16])[NH:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)(=[O:6])[CH3:5].I([Cl:21])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>O>[Cl:21][CH2:5][C:4]([C:7]1[C:15]2[S:14][C:13](=[O:16])[NH:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(CCl)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 78 °C

Procedure:
Ethanol (1500 mL) was added to a mixture of 7-acetyl-4-hydroxy-3H-benzothiazol-2-one (150 g) (WO2004/016578) and benzyltrimethylammonium dichloroiodate (374 g) in a flask fitted with an overhead stirrer. The mixture was heated to 78° C. for 1 h and left to cool to room temperature overnight. The mixture was poured into water (2 L), and the precipitate collected by filtration, washed with water, filtered to near dryness, and suspended in ethyl acetate. The mixture was heated to reflux and allowed to cool to room temperature with stirring. The solid was collected by filtration, washed with cold ethyl acetate (200 mL) then re-suspended in diethyl ether (1 L). The solid was collected, filtered again and washed with ether (200 mL) and dried in vacuo to give the subtitled compound. Yield 164 g.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:7][CH2:6][CH:5]1[CH2:8][OH:9])[CH3:3].[O:10]([C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][CH:2]([N:4]1[CH2:7][CH2:6][CH:5]1[CH2:8][O:9][C:20]1[CH:21]=[CH:22][C:17]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:18][CH:19]=1)[CH3:3]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)N1CCC1CO
Product: CC(C)N1CCC1COc1ccc(Oc2ccccc2)cc1

Procedure:
The title compound is prepared from 1-(1-methylethyl)-2-azetidinemethanol and 4-phenoxyphenol according to the procedures of Example 8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCNC1
Yield: 91.2 %

Procedure:
A solution of (R)-tert-butyl 3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (100 mg) in 20% TFA/CH2Cl2 was stirred at 0° C. for 30 min. The mixture was neutralized by addition of satd aq NaHCO3, extracted with CH2Cl2 (3×) and dried over Na2SO4. Evaporation of the solvent gave (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (70 mg, 91%), which was used without further purification. 1H NMR (400 MHz, CDCl3): 0.90(m, 1H), 1.52-1.24 (m, 6H), 1.78 (m, 1H), 1.83 (m, 1H), 1.93 (m, 1H), 2.21 (m, 1H), 2.40 (m, 1H), 2.83 (m, 1H), 3.00 (m, 1H), 3.12 (s, 3H), 3.31 (m, 2H), 3.63 (m, 1H), 7.06 (m, 1H), 7.30 (m, 1H), 7.55 (t, 1H). MS (E/Z): 330 (M+H+).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH:10]=[CH2:11]>C(O)(C)C>[C:1]1([CH2:7][CH:8]=[CH:9][CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC=C
Reactant: Cc1ccccc1
Solvent: CC(C)O
Product: CCC=CCc1ccccc1
Temperature: 110 °C
Yield: 77.2 %

Procedure:
The powdery catalyst that had been prepared in the same manner as in Example 1 was incorporated with 1000 g of toluene that had been dehydrated with molecular sieve, in a stream of nitrogen with heating to 110° C. Subsequently 70 g of 1,3-butadiene was introduced into the reaction system with vigorous stirring for one (1) hour to carry out the reaction. After cooling the system, the catalyst was deactivated by adding isopropyl alcohol thereto and then the reaction liquid was sampled for analysis by gas chromatography- As a result, the objective phenyl-2-pentene was obtained in a yield of 77.2%.
Reaction SMILES: [CH2:1]([N:13]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>[Pd].C(OCC)(=O)C>[CH2:1]([N:13]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH:25]([OH:30])[C:26]([F:27])([F:28])[F:29])=[CH:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(/C=C/C(O)C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(O)C(F)(F)F)cc1
Reaction time: 6 h
Yield: 93.6 %

Procedure:
A mixture of 4-[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1-yl]phenoxy]ethylamino] butanoic acid, ethyl ester (3.5 g, 6.46 mmol), palladium on activated carbon (10%, 0.6 g) and ethyl acetate (250 ml) was hydrogenated under 30 psi for 6 h. After filtration, the solvent was removed in vacuo to give the title compound (3.3 g, 94%) as a colorless oil.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC([O-])(C)C.[K+].Cl[C:24]1[CH:29]=[C:28]([C:30]([NH2:32])=[O:31])[N:27]=[C:26]([C:33]([NH2:35])=[O:34])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:30]([C:28]1[CH:29]=[C:24]([O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:10][C:11]=2[F:16])[CH:25]=[C:26]([C:33](=[O:34])[NH2:35])[N:27]=1)(=[O:31])[NH2:32]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Reactant: NC(=O)c1cc(Cl)cc(C(N)=O)n1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2cc(C(N)=O)nc(C(N)=O)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A solution of N-Boc-4-amino-2-fluorophenol (228 mg, 1.0 mmol) in DMF (2 mL) was treated with t-BuOK (124 mg, 1.1 mmol) and the mixture stirred at room temperature for 2 h. The mixture was treated with 4-chloropyridine-2,6-dicarboxamide (200 mg, 1.0 mmol) and K2CO3 (35 mg, 0.5 mmol) and heated at 80° C. for 1.5 h. The mixture was concentrated in vacuo, treated with EtOAc (10 mL) and H2O (10 mL) and filtered to remove the insoluble material. The EtOAc phase was washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the residue by flash column chromatography on SiO2 eluting with 30-100% EtOAc/hexanes gave the title compound (170 mg, 44%) as a white solid containing 10% of the starting chloropyridine. 1H NMR (DMSO-d6) δ 9.77 (s, 1H), 8.86 (s, 2H), 7.87 (s, 1H), 7.63 (d, 1H, J=12.1 Hz), 7.55 (s, 2H), 7.38-7.31 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[O:19][C:18]2[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:17]=2[O:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[Cl:24][C:22]1[C:21]([Cl:25])=[CH:20][C:18]2[O:19][CH:14]([CH2:13][CH2:12][N:26]3[CH2:27][CH2:28][CH:29]([N:32]4[CH2:36][CH2:35][NH:34][C:33]4=[O:37])[CH2:30][CH2:31]3)[CH2:15][O:16][C:17]=2[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3cc(Cl)c(Cl)cc3O2)cc1
Reactant: O=C1NCCN1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1NCCN1C1CCN(CCC2COc3cc(Cl)c(Cl)cc3O2)CC1

Procedure:
The mixture of 4.0 g of 2-(2-tosyloxyethyl)-6,7-dichloro-1,4-benzodioxan, 1.69 g of 1-(4-piperidyl)-2-imidazolidinone, 10 g of ahydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is stirred and refluxed for 2 days. It is filtered, evaporated and the residue recrystallized from acetone, to yield the 1-[1-[2-(6,7-dichloro-1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone melting at 165°.
Reaction SMILES: N.[C:2]1(=[O:18])[N:6]([CH:7]([CH3:12])[CH2:8][CH2:9][C:10]#[N:11])[C:5](=[O:13])[C:4]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:3]12.[SH2:19]>CO>[C:5]1(=[O:13])[N:6]([CH:7]([CH3:12])[CH2:8][CH2:9][C:10]([NH2:11])=[S:19])[C:2](=[O:18])[C:3]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:4]12
Reactant: S
Reactant: CC(CCC#N)N1C(=O)c2ccccc2C1=O
Agent: N
Solvent: CO
Product: CC(CCC(N)=S)N1C(=O)c2ccccc2C1=O

Procedure:
Liquid ammonia (20 g) and 4-phthalimidovaleronitrile (67 g) is added to a cooled solution of hydrogen sulphide (50 g) in methyl alcohol (500 ml). The sealed reaction vessel is the heated at 40° for 3 days with stirring. Concentration followed by recrystallization from isopropyl acetate yields 4-phthalimidothiovaleramide, m.p. 143°-146° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[CH2:17][C:16](=O)[CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:16]2[CH2:17][O:14][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)CC1
Reaction time: 17 h
Yield: 59.5 %

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (1.56 g, 8.38 mmol) and oxetan-3-one (500 mg, 6.94 mmol) DCE (60 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (2.34 g, 11.04 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: MeOH; 100:0 to 99:1 to 98:2) to afford 4-Oxetan-3-ylpiperazine-1-carboxylic acid tert-butyl ester as a white solid (1.0 g, 59%). 1H NMR (CDCl3, 400 MHz) δ 4.69-4.58 (m, 4H); 3.51-3.44 (m, 5H); 2.27 (m, 4H) and 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:40]=[CH:39][C:8]([O:9][C:10]2[CH:11]=[C:12]([C:22]3[N:23](C(OC(C)(C)C)=O)[C:24]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[CH:25][CH:26]=3)[CH:13]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:15]=2)=[CH:7][CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:20][O:19][CH2:18][C@H:17]([CH3:21])[O:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:13]=1)[O:9][C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:40][CH:39]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reaction time: 2 h
Yield: 112.8 %

Procedure:
t-Butyl 2-{3-[4-(methoxycarbonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70 mg, 0.124 mmol) synthesized in Example (38e) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (2.0 mL) was added dropwise with stirring under nitrogen atmosphere, and stirring was carried out at room temperature for 2 hours. The solvent was distilled off under reduced pressure, followed by dilution with ethyl acetate (30 mL), a saturated aqueous sodium hydrogencarbonate solution (20 mL) was added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired compound (65 mg, yield ˜100%) as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[N:23]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:24]3[CH:25]=[CH:26][N:22]([CH3:21])[N:23]=3)=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cn1ccc(C(=O)Cl)n1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccn(C)n2)CC1
Reaction time: 2 h

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 1-methyl-1H-pyrazole-3-carbonyl chloride (0.022 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and the resulting mixture was stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired porduct (32 mg, 78%). LCMS calculated for C20H21ClN5O2 (M+H)+: m/z=398.1; Found: 398.1.