Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)(=[O:36])=[O:35])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)(=[O:36])=[O:35])=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][C:8](=[O:16])[NH:7][C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)NC(=O)CN(CC1CC1)C2
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCCC3)n1)NC(=O)CN(CC1CC1)C2
Yield: 12.5 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-cyclopropylmethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (125 mg, 0.48 mmol) and (2,5-dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine (149 mg, 0.40 mmol) were coupled to afford 8-{5-chloro-4-[2-(pyrrolidine-1-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-4-cyclopropylmethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (30 mg, 10%) as a pale yellow solid following flash chromatography on silica gel (0-10% MeOH-EtOAc);); 1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.45 (d, J=8 Hz, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 7.98 (d, J=8 Hz, 1H), 7.62 (m, 2H), 7.35 (m, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.94 (s, 3H), 3.82 (s, 2H), 3.53 (s, 2H), 3.28 (t, J=6 Hz, 4H), 2.60 (d, J=6 Hz, 2H), 1.82 (t, J=6 Hz, 4H), 0.96 (m, 1H), 0.60 (m, 2H), 0.23 (m, 2H); MS (m/e) 599 (M+1); mp 142° C.
Reaction SMILES: [O:1]=[C:2]([O-:11])[C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[Na+].O=C([O-])[C@@H]([C@@H]([C@@H](CO)O)O)O.O=C[C@@H]([C@@H](CO)O)O.C(O)[C@@H]([C@@H](CO)O)O.[BH4-].[Na+]>O>[O:1]=[C:2]([OH:11])[C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C([O-])[C@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@H](O)CO
Agent: OC[C@@H](O)[C@@H](O)CO
Agent: [BH4-]
Solvent: O
Product: O=C(O)[C@H](O)[C@H](O)[C@H](O)CO

Procedure:
Sodium ribonate (15 mmoles) was dissolved in 20 mL of water. Cation exchange resin (Amberlite IRC747 H+ form) was added to lower the pH from 6.8 to 3.5 (or approximately 50% neutralization of the starting material). The solution was filtered to remove the cation resin, the ribonate starting material was diluted to 30 mL, and 25 mL transferred to glass cell for electrolysis. The initial ribonate solution was analyzed by HPLC against a standard and quantified to be 9.54 mmoles (0.38M). The 25 mL of starting material containing 9.54 mmoles of ribonate was stirred in the glass cell, while a constant current of 0.5 amps (100 mA/cm2) was applied. The cell voltage averaged about 6.5 volts, and the pH of the substrate increased from 3.5 to 7.6 after 2F/mole of charge was passed. Samples were taken at 603, 1206 and 1809 coulombs. The samples containing the erythrose product were reduced to erythritol with an excess amount of sodium borohydride, and analyzed for erythritol by HPLC-RI. The samples were quantified for erythritol based on a response factor determined from an erythritol standard, see Table 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1([C:20]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:20]([N:15]4[CH2:16][CH2:17][CH2:18][CH2:19]4)=[O:21])[CH2:28][CH2:27]3)=[O:14])[CH2:9][S:8]2)[CH:2]=1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(=O)C2CSC(c3cccnc3)N2)CC1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a solution of 2-(3-pyridyl)thiazolidine-4-caroxylic acid 2.1 g, 1-(pyrrolidinecarbonylmethyl)piperazine 1.8 g, 1-hydroxybenzotriazole 1.5 g and N,N-dimethylformamide 50 ml was added dicyclohexylcarbodiimide 2 g under ice-cooling, and the mixture was stirred overnight at room temperature. The resultant dicyclohexylurea was filtered off and the filtrate concentrated under reduced pressure. To the residue were added ethyl acetate 100 ml and water 10 ml, the mixture was basified by addition of sodium carbonate, sodium chloride added until saturation and allowed to stand. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture solution of ethyl acetate - methanol (6:4) to give 2.1 g of 1-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]-4-[1-(pyrrolidinyl)carbonylmethyl]piperazine.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:13]([NH:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[N:12]=2)[CH2:6][CH2:5]1.O1CCCC1.[N:39]([Sn](CCCC)(CCCC)CCCC)=[N+:40]=[N-:41]>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[NH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[C:13]([NH:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]4[NH:41][N:40]=[N:39][N:31]=4)=[CH:28][CH:27]=3)[N:12]=2)[CH2:8][CH2:9]1
Reactant: N#Cc1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(-c4nnn[nH]4)cc3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 120 °C

Procedure:
296 mg of the product obtained in Example 83 in 3 ml of toluene and 0.26 ml of azido tributyltin are mixed together at ambient temperature then the reaction medium is heated at a temperature of approximately 120° C. for 22 hours then left to return to ambient temperature. 7 ml of tetrahydrofuran is added to the suspension obtained, gaseous hydrochloric acid is bubbled through for 1 minute then nitrogen is bubbled through for 10 minutes, the product obtained is separated, followed by rinsing with ether and drying under reduced pressure at 50° C. In this way 374 mg of expected product is obtained.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[CH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][CH2:11][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: OCCCCl
Reactant: O=Cc1ccccc1O
Product: O=Cc1ccccc1OCCCO

Procedure:
Synthesized from salicylaldehyde and 3-chloropropanol as described in Example XXIXb.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:41]4[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(Cc3cc4c(=O)n([C@H]5CCCC[C@@H]5O)cnc4c4ccncc34)cn2)cn1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.070 g, 0.17 mmol) in 2 mL of THF under an atmosphere of nitrogen was added cesium carbonate (0.33 mL, 1 N aqueous, 0.33 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.052 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %). The reaction was heated at 85° C. for 20 h, and additional 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (7.0 mg, 0.014 mmol) were added. After 5 h, the reaction was cooled to rt, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 466.9 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.64 (s, 1H), 9.03 (d, J=6.0 Hz, 1H), 8.80 (d, J=5.4 Hz, 1H), 8.65 (s, 1H), 8.59 (s, 1H), 8.35 (s, 1H), 8.19 (s, 2H), 8.13 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 4.18 (br s, 1H), 3.99 (s, 2H), 3.31 (s, 3H), 2.20 (br s, 1H), 2.00 (br s, 2H), 1.87 (br s, 2H), 1.52-1.39 (m, 4H).
Reaction SMILES: N1C2C=CC=[C:9]([CH:10]=[O:11])C=2N=N1.N[C:13]1[CH:21]=[CH:20][C:16]2[NH:17][N:18]=[N:19][C:15]=2[CH:14]=1.C(=NO)C>C(Cl)Cl>[C:10]([C:13]1[CH:21]=[CH:20][C:16]2[NH:17][N:18]=[N:19][C:15]=2[CH:14]=1)(=[O:11])[CH3:9]
Reactant: O=Cc1cccc2[nH]nnc12
Reactant: Nc1ccc2[nH]nnc2c1
Solvent: CC=NO
Solvent: ClCCl
Product: CC(=O)c1ccc2[nH]nnc2c1

Procedure:
The ketone was prepared in the same manner as the benzotriazole aldehyde from 5-aminobenzotriazole and acetaldoxime. Column chromatography of the crude ketone using DCM and eluting with MeOH (0-10%) afforded the ketone in 11% yield. Rf [A] 0.3; δH(400 MHz; Acetone-d6) 2.68 (3H, s, CH3), 7.92 (1H, d, J 8.7, Ar—H), 8.07 (1H, d, 3 8.7 Ar—H), 8.62 (1H, s, Ar—H); m/z (FAB−HR) 162.06674 [(M+H)+ calc. for C8H8N3O 162.06682]. The hydrazone of the ketone was prepared from 2,4DNPH to afford an orange solid. 4,6-Dinitro-7-1H-benzotriazole [26]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.C(O)(=O)C.[CH2:18]([NH2:21])[CH2:19][CH3:20].[BH3-]C#N.[Na+]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:21][CH2:18][CH2:19][CH3:20])[CH2:8]2
Reactant: CCCN
Reactant: COc1cccc2c1CCC(=O)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCNC1CCc2c(cccc2OC)C1
Yield: 62.1 %

Procedure:
This compound was prepared following Procedure A from 5-methoxy 2-tetralone (6.0 g, 34.0 mmol), acetic acid (5.1 ml, 102 mmol), propyl amine (5.5 ml, 68 mmol), and NaCNBH3 (5.3 g, 85 mmol) to give 4.63 g of 32b (62%, free base). 1H NMR (free base) (400 MHz, CDCl3) 0.92-0.964 (t, 3H, J=7.6 Hz), 1.39 (bs, 1H), 1.49-1.61 (m, 3H), 2.05-2.10 (m, 1H), 2.53-2.62 (m, 2H), 2.66-2.70 (t, 3H, J=7.6 Hz), 2.87-2.94 (m, 2H), 2.98-3.03 (m, 1H), 3.81 (s, 3H), 6.65-6.67 (d, 1H, J=8 Hz), 6.96-6.71 (d, 1H, J=8 Hz), 7.07-7.11 (t, 1H, J=7.2 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C([Li])CCC.[CH3:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>O>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[NH:6][C:22](=[NH:23])[C:21]1[CH:24]=[CH:25][C:18]([CH3:17])=[CH:19][CH:20]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C#N)cc1
Reactant: Cc1cccc(C(C)C)c1N
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccc(C(=N)Nc2c(C)cccc2C(C)C)cc1
Reaction time: 8 h
Yield: 82.4 %

Procedure:
Procedure as described for Amidine I using the following amounts: 7.80 mL of 2-isopropyl-6-methylaniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.86 g of 4-methylbenzonitrile (50.0 mmol). After refluxing overnight, the solution was dark brown. Addition of water yielded an orange-brown solution with suspended solid. Solution was filtered and taken to dryness. The residue was treated with 100 mL of pentane stirred overnight and filtered yielding 10.98 g (83%) of beige material. 1H NMR (400 MHz, CDCl3): 7.82 (d, 2H), 7.26 (d, 2H), 7.15 (d, 1H), 7.05 (d, 1H), 6.98 (t, 1 H), 4.56 (s, 2H), 3.09 (septet, 1H), 2.42 (s, 3H), 2.15 (s, 3H), 1.21 (d, 3H), 1.16 (d, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23](O)=[O:24])[CH:20]=[CH:19][S:18]2.[CH3:28][C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:26][C:2]([CH3:1])([CH3:27])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([NH:34][C:31]1[S:32][CH:33]=[C:29]([CH3:28])[N:30]=1)=[O:24])[CH:20]=[CH:19][S:18]2
Reactant: Cc1csc(N)n1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C)cs2)c1OCC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 3 (250 mg, 0.646 mmol) with 4-methyl-1,3-thiazol-2-amine (82 mg, 0.711 mmol) in the presence of EDCI hydrochloride (247 mg, 1.292 mmol) and DMAP (36.33 mg, 0.323 mmol) in a mixture of DCM and DMF (4:1, 10 mL) to give 110 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 9H), 2.28 (s, 3H), 3.57 (s, 2H), 3.80 (s, 3H), 6.62 (s, 1H), 6.98 (d, J=7.8 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.36-7.40 (m, 2H), 7.88 (d, J=16.2 Hz, 1H), 7.98-8.20 (br m, 1H), 8.55 (br m, 1H), 12.89 (br s, 1H); ESI-MS (m/z) 483.33 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([OH:31])=O)[C:22]3=[O:32])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([NH:41][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:31])[C:22]3=[O:32])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)O)C3=O)CC2)c2ccc(Cl)cc2n1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)NCc4ccccc4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
The mixtures of (3S)-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid (50.0 mg, 0.1 mmol), benzyl amine (0.2 mL), HATU (50 mg), and diisopropylethyl amine (0.3 mL) in DMF (5 mL) was stirred at rt for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with NaHCO3 (sat.) and water, dried over Na2SO4. Concentration in vacuo followed by flash chromatography afforded the title product. LC-MS: 564 (M++1). 1H NMR (CD3OD) δ 7.82 (d, 1H), 7.45 (s, 1H), 7.25 (m, 4H), 7.20 (m, 2H), 6.30 (s, 1H), 4.65 (d, 1H), 4.40 (s, 2H), 4.15 (m, 2H), 3.75 (m, 1H), 3.65 (m, 4H), 3.30 (m, 1H), 3.10 (m, 4H), 1.96 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]([F:30])([F:29])[C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:23][NH2:24])=[S:22])[CH2:17][CH2:16]1)=[O:14].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2](=[O:8])[NH:24][NH:23][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=2[C:10]([F:29])([F:9])[F:30])[CH2:16][CH2:17]1)=[S:22])[CH3:7]
Reactant: NNC(=S)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)NNC(=S)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
Ethyl chlorooxoacetate (0.84 mL, 7.54 mmol) was added dropwise to a stirred solution of 4-(2-trifluoromethylbenzoyl)piperazine-1-carbothioic acid hydrazide (2.18 g, 6.56 mmol) and triethylamine in 8 mL of DMF at 0° C. over 15 minutes. The mixture was stirred for 1 hour, then 100 mL of ethyl acetate was added. The mixture was washed with water and brine, dried over anhydrous Na2SO4, and evaporated below 30° C. to dryness to yield oxo-{N′-[4-(2-trifluoromethylbenzoyl)piperazine-1-carbothioyl]hydrazino}acetic acid ethyl ester in quantitative yield (2.88 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([O:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]2[CH3:27])=[O:13])([CH3:10])([CH3:9])[CH3:8]>N1C=CC=CC=1>[C:7]([O:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]2[CH3:27])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC1=CC(C)(C)Nc2ccc(NC(=O)OC(C)(C)C)cc21
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Reaction time: 18 h

Procedure:
Butyryl chloride (185 l) was added dropwise to a solution of 6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (50 mg) and a catalytic amount of N,N-dimethylaminopyridine in pyridine (4 ml). After stirring for 18 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>7/3 (v/v) as eluent.
Reaction SMILES: [N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:5][CH2:4][CH:3]([C:6]([O:8]C(C)(C)C)=[O:7])[NH:2]1.Cl.CCOCC>ClCCl>[C:17]1([CH2:16][O:15][C:13]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[NH:2]2)=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
At r.t., to a 50 mL round bottomed flask containing crude 3-(1,1-dimethylethyl) 1-(phenylmethyl) 1,3-pyrazolidinedicarboxylate (88 mg) in dichloromethane (DCM) (0.5 mL), was added HCl in ether (2M) (3.59 mL, 7.18 mmol), then the reaction vessel was equipped with a glass stopper. The reaction mixture was stirred at r.t. for 48 hr. The solid was filtered and washed with ether, providing the product as an off-white solid. (58.4 mg, 71% over two steps).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)[N:10]=1.Cl[C:23]1[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=1.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:23]3[N:24]=[CH:25][CH:26]=[CH:27][C:28]=3[C:29]#[N:30])=[CH:15][CH:14]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a mixture of [4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanol (4.14 g), 2-chloro-3-cyanopyridine (1.91 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.65 g, 87%) of 2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12.C([Li])CCC.[Cl:34]N1C(=O)CCC1=O.[Cl-].N>C1COCC1>[Cl:34][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Br)c(C)nn12
Agent: N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: -78 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
Under a nitrogen atmosphere dissolve 3-(4-bromo-2-morpholin-4-yl-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (116 mg, 0.25 mmol) in THF (1.5 mL) and chill to −78° C. Add n-butyl lithium (0.1 mL. 2.5 M in hexane, 0.25 mmol) and stir at −78° C. for 30 min. Add N-chlorosuccinimide (33.4 mg, 0.25 mmol) and stir for another 30 min, slowly warming to room temperature. After stirring overnight, quench the reaction by adding a solution of saturated ammonia chloride and extract with ethyl acetate. Wash the organic layer with brine, dry over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes:dichloromethane:ethyl acetate (5:5:2) to provide the title compound (54 mg). MS (APCI) m/z (35Cl) 420.6 (M+1)+; 1H NMR (400 MHz, CDCl3): 6.44 (s, 1H), 3.79 (t, 4H, J=4.8 Hz), 3.63-3.56 (m, 1H), 3.47 (t, 4H, J=4.8 Hz), 2.55 (s, 3H), 2.45 (s, 3H), 1.88-1.75 (m, 4H), 0.87 (t, 6H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-])=O)=[CH:15][C:14]=2[Cl:23])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:14]([Cl:23])=[CH:15][C:16]([NH2:20])=[CH:17][C:18]=2[Cl:19])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Solvent: Cc1ccccc1
Product: Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
Into a 500 milliliter Parr bottle was charged 4-(4-chloro-1-naphthoxy)-3,5-dichloro- nitrobenzene (15.84 grams, 42.97 mmol) prepared in Part A and toluene (250 milliliters). The bottle was purged thoroughly with nitrogen and 5% platinum on carbon (0.50 grams) was added immediately following the purge. The reaction mixture was then hydrogenated for 1.5 hours on a rocking Parr hydrogenator at a pressure of 90-100 psi hydrogen at ambient temperature. The reaction mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure to afford pure 4-(4-chloro-1-naphthoxy)-3,5-dichloroaniline (13.99 grams, 41.31 mmol, 96%) as a white solid having a melting point of 145° C.-147° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:8][C:7](=[O:9])[CH:6]=[CH:5]1)[CH2:2][CH3:3]>[Pd].C(OCC)(=O)C.[H][H]>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C:7](=[O:9])[CH2:8]1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCC[C@H]1C=CC(=O)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H]1CCC(=O)C1
Yield: 87.4 %

Procedure:
A mixture of 2 (1.2 g, 9.7 mmol) and 10% palladium on charcoal (catalytic quantity) in ethyl acetate (30 ml) was shaken in hydrogen at 55 psi and at 30° C. for 6 hours. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane-ether, 1:0 to 9:1) to give the 3-propylcyclopentanone 3 (1.07 g, 88%). νmax(film)/cm−1 1744 (C═O).