Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)/C=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1.[BH4-].[Na+].C([OH:24])C>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][OH:24])=[CH:7][CH:8]=2)[CH:14]=1
Reactant: CCO
Reactant: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1ccc(Cc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.41 g of the aldehyde (prepared as described in Reference Example 1), 8 ml of ethanol and 78 mg of sodium borohydride was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 4% V/V solution of ethanol in chloroform as eluent to give 0.33 g of the title compound having the following physical characteristics:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:17](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C([O-])O
Reactant: Cc1c(O)cccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(O)c1C
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 3-hydroxy-2-methylbenzoic acid (5 g, 33 mmol) and concentrated sulfuric acid (3 mL) in methanol (300 mL) was stirred at reflux for 48 hours. The mixture was cooled to room temperature and the pH was adjusted to 7 using solid sodium bicarbonate. Some methanol was evaporated and residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic portion was washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded 5.3 g, 32 mmol (97%) of methyl 3-hydroxy-2-methylbenzoate. 1H NMR (400 MHz, CDCl3): 7.41 (d, 1H), 7.13-7.09 (m, 1H), 6.94 (d, 1H), 3.89 (s, 3H), 2.46 (s, 3H). MS (EI) for C9H10O3: 167 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18]C)=[O:17])=[O:11])=[CH:6][C:5]=1[CH3:25])([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1>[CH:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([OH:18])=[O:17])=[O:11])=[CH:6][C:5]=1[CH3:25])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(NC(=O)COc2ccc(C(C)C)c(C)c2)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: Cc1cc(OCC(=O)Nc2cccc(C(=O)O)c2)ccc1C(C)C

Procedure:
A solution of methyl 3-[2-(4-isopropyl-3-methyl-phenoxy)acetylamino]benzoate (948 mg, 2.78 mmol) and lithium iodide (3.72 g, 27.8 mmol) in anhydrous pyridine (15 mL) was heated to reflux for 20 h, then cooled and evaporated. The residue was taken up in water, and extracted twice with ethyl acetate. The extracts were washed with 1 N hydrochloric acid and brine, combined, dried over magnesium sulfate, filtered and evaporated to afford a semisolid mixture. The mixture was fractionally crystallized using ether-hexane to afford the title product as a solid, collected by filtration and dried under vacuum, m.p. 188-189° C. (772 mg, 2.36 mmol, 85%). 1H NMR (300 MHz, CDCl3): δ 8.44 (1H, br s), 8.03-7.96 (2H, m), 7.79 (1H, dt, J=7.7, 1.3 Hz), 7.39 (1H, t, J=7.9 Hz), 7.14 (1H, d, J=8.8 Hz), 6.79-6.73 (2H, m), 4.54 (2H, s), 3.03 (1H, heptet, J=7.0 Hz), 2.28 (3H, s), 1.14 (6H, d, J=7.0 Hz). MS (ESI): m/e 330 (3), 329 (21), 328 (100). Elemental analysis: calc. for C19H21NO4.0.1H2O C 69.33, H 6.49, N 4.25; observed C 69.22, H 6.53, N 4.17.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:27][NH:28][CH3:29])[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH2:27][N:28]([CH3:29])[CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[CH:18]=[C:17]([O:16][CH3:15])[C:22]=1[O:23][CH3:24]
Reactant: CNCc1cc(OC)c(OC)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CN(C)CCCOc2ccc([N+](=O)[O-])cc2)cc(OC)c1OC
Yield: 76.5 %

Procedure:
A mixture of 1-(3-chloropropoxy)-4-nitrobenzene (4.6 g), 3,4,5-trimethoxy-N-methylbenzenemethanamine (4.1 g; Sigma) and potassium carbonate (2.9 g) in DMF (60 ml) was heated at 70° for 24 h. The mixture was then filtered and the filtrate evaporated. The residue was taken up in water and extracted with dichloromethane. The organic layer was washed with water, dried, evaporated and purified by column chromatography eluting with dichloromethane/methanol (99:1) to give the title compound (5.8 g) as a yellow oil. NMR includes signals at d 2.15 (3H,s,N-CH3), 3.3 (2H,s,CH2 --Ar), 3.7 (9H,s,OCH3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:32])(=[N:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])=[CH:20][CH:19]=1>>[CH2:30]([O:29][C:27]([N:26]=[S:24]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][N:3]=2)=[CH:23][CH:22]=1)([CH3:32])=[O:25])=[O:28])[CH3:31]
Reactant: OCCNc1nc(Cl)ncc1-c1cccs1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(NCCO)n2)cc1
Yield: 37 %

Procedure:
In the reaction of 2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)ethanol (200 mg, 0.8 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methyl-sulfoximide (173 mg, 0.7 mmol) according to procedure 5a, the desired product is obtained in 37% yield (120 mg) after chromatographic purification (silica gel, dichloromethane/methanol (0%-20% methanol)).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20][CH2:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26])=[CH:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][CH:11]=1)[CH3:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(CCCN)CCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCCNC(=O)c1ccccc1)CCCc1c[nH]c2ccccc12
Reaction time: 2 h

Procedure:
A solution of 10.1 g benzoyl chloride in 15 ml anhydrous methylene chloride is added dropwise with stirring for 25 minutes between 0° and 10° to a solution of 14.5 g N-[3-(3-indolyl)propyl]-N-methyl-1,3-diaminopropane in 150 ml anhydrous pyridine and the reddish clear solution is stirred for 2 hours at 0°. The reaction mixture is divided between a 2 N sodium carbonate solution and methylene chloride, and the organic phase is washed, dried and evaporated. Chromatographic purification of the resinous product on aluminium oxide using methylene chloride with 0.1 to 0.3% of methanol yields the title compound. The naphthalene-2-sulfonate-dihydrate, obtained by conventional methods, melts at 73°-74° after crystallization from methanol/water/ethyl acetate (1:1:1).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]([OH:8])=[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[CH:2]=1.[CH3:18][CH:19]1[CH2:25][C:24](=[O:26])[O:23][C:21](=[O:22])[CH2:20]1.C(N(CC)CC)C>CCOCC>[C:21]([CH2:20][CH:19]([CH3:18])[CH2:25][C:24]([O:8][C:4]1[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=1[Cl:16])=[O:26])([OH:23])=[O:22]
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reactant: CC1CC(=O)OC(=O)C1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(CC(=O)O)CC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 20 h
Yield: 23 %

Procedure:
A mixture of triclosan (22.3 g.), 3-methylglutaric anhydride (15.0 g.) and triethylamine (15 ml.) in ether (250 ml.) was stirred for 20 hours, and then washed first with 2M hydrochloric acid (50 ml.) and then with water (3×150 ml.). The ether phase was dried (MgSO4) and evaporated. A portion (20 g.) of the residual oil was purified by chromatography on silica gel using methylene chloride as eluant to give (D) as a colourless oil (7.4 g.) ; NMR (CDCl3): 0.8-1.3 (3H,d, CH3), 2.1-2.8 (5H,m,CH2CO+CH3CH), 6.7-7.6 (6H, m, aromatic H), 11.25 (1H,s, CO2H)ppm.
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[N:9]=1)([CH3:4])[CH3:3].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>>[CH3:4][C:2]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[N:19]=2)=[C:8]([C:10]2[C:11]([F:17])=[C:12]([NH:13][S:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])(=[O:34])=[O:33])[CH:14]=[CH:15][CH:16]=2)[N:9]=1)([CH3:1])[CH3:3]
Reactant: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(N)c2F)n1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3ccccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 222, Step A using 3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline (70 mg, 0.204 mmol) and 2-fluorobenzenesulfonyl chloride (0.119 mL, 0.613 mmol), the title compound was obtained as a solid (77 mg, 75% yield). 1H NMR (400 MHz, DMSO-d6) ppm 10.53 (s, 1H), 8.42 (d, J=5.31 Hz, 1H), 7.64-7.69 (m, 1H), 7.59-7.64 (m, 1H), 7.31-7.39 (m, 3H), 7.25 (dt, J=15.29, 7.74 Hz, 2H), 6.51 (d, J=5.31 Hz, 1H), 2.53 (s, 3H), 1.37 (s, 9H). MS (ESI): 502.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]1([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.CN(C)C=O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]3([CH3:30])[CH3:29])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(C)(C)C1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(C(N)=O)cnn3cc(Br)cc23)C(C)(C)C1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (310 mg, 1.129 mmol, Intermediate 2), tert-butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate (387 mg), N,N-diisopropylethylamine (0.592 mL, 3.39 mmol) and N,N-dimethylformamide (2 mL) was pumped under vacuum and backfiled with nitrogen twice. The reaction vial was sealed and heated to 90° C. for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate twice. The organic layer was washed with brine and concentrated. Silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, gave the title compound as a brown solid (0.3510 g, 67% yield). MS (ES+) m/z: 466.1, 468.1 (M+H); LC retention time: 4.488 min (analytical HPLC Method H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[C:11]1([CH:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>C(O)CCC>[C:29]1([CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][NH:28][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[N:9][N:10]=4)[N:7]=3)[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Clc1ccc2nncn2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C(OC2CCN(CCCNc3ccc4nncn4n3)CC2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 48.8 %

Procedure:
0.464 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine and 1.26 g of 4-(diphenylmethoxy)-1-piperidinepropanamine were suspended in 20 ml of 1-butanol; 0.62 ml of N-ethyldiisopropylamine was added, followed by refluxing under heating for 12 hours. After ice water and sodium hydrogen carbonate were added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated; the crystal obtained was washed with ethyl acetate and dried to yield 0.648 g of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=O.B(F)(F)F.CCOCC.B.C1COCC1.Cl>C1COCC1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:3][C@H:2]([NH2:1])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:7]1
Reactant: COc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccccn2)CC1
Agent: B
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C[C@H](N)Cc2ccccn2)CC1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of (2R)-2-Amino-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-3-pyridin-2-yl-propan-1-one (1.02 g; 3 mmol, from Example 12) in THF (10 mL) was added, dropwise, BF3.Et2O (0.37 mL; 3 mmol). The reaction mixture was heated to reflux, BH3.THF (1.0M/THF) (4.3 mL; 4.3 mmol) was added dropwise at reflux, and the mixture stirred at reflux for 2.5 hours. The mixture was cooled to 0–5° C., cautiously treated with 3N HCl (10 mL), stirred at ambient temperature for 1 hour. The mixture was heated to reflux for 5 minutes, cooled to ambient temperature, concentrated on a rotary evaporator to remove THF. The aqueous residue was washed with ether (5 mL), and the ether layer discarded. The aqueous layer was rendered basic (pH 9–10) with 2.5N NaOH, and the product extracted into ethyl acetate (25 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and the solvent removed in vacuo to yield the free base of the title compound as an amber oil (804 mg; 82%), MS EI, M+ @ m/z 326; 1H NMR, 400 MHz, DMSO-d6.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Br)[N:4]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[Li]CCCC.[CH2:32]([O:34][C:35]1[CH:36]=[C:37]([O:52][CH:53]([CH3:55])[CH3:54])[C:38]([F:51])=[C:39]([CH:50]=1)/[CH:40]=[N:41]/[C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)[CH3:33]>C1COCC1>[Br:1][C:2]1[N:6]=[C:5]([N:41]([CH2:40][C:39]2[CH:50]=[C:35]([O:34][CH2:32][CH3:33])[CH:36]=[C:37]([O:52][CH:53]([CH3:55])[CH3:54])[C:38]=2[F:51])[C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)[N:4]([C:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Reactant: Brc1nc(Br)n(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2nc(Br)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(OC(C)C)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 29.2 %

Procedure:
To a solution of Intermediate 359.1 (748 mg, 1.6 mmol) in THF (10 mL) was added BuLi (1.6 M in THF, 1.02 mL, 1.6 mmol). The mixture was stirred at −78° C. for 15 min, then a solution of Intermediate 7.3 (500 mg, 1.53 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min, before warming to 23° C., and quenching with aqueous NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) followed by preparative HPLC purification to afford 320 mg of Intermediate 359.2. LCMS (2 min gradient) RT=2.45 min, 717.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.25-1.33 (m, 9H) 3.93(q, 2H) 4.41 (m, 1H) 6.15 (d, 2H) 6.52 (m, 1H) 6.82 (m, 1H) 7.03-7.21 (m, 18H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:9][N:8]([C:20](=[O:28])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7]1)=[O:5])[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:9][N:8]([C:20](=[O:28])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCC(=O)N1CC(C(=O)OCC)C(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CCC(=O)N1CC(C(=O)OCC)C(c2ccc(N)cc2)C1
Yield: 71.5 %

Procedure:
A solution of 1-(3-ethoxycarbonyl-propionyl)-4-(4-nitro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (0.33 g, Reference Example 12) in acetic acid (5 ml) and 10% palladium on charcoal (0.1 g) was stirred under a hydrogen atmosphere (1 bar) for 20 hours then filtered through a pad of celite. The filtrate was evaporated (40° C. and 2.7 kPa) affording the title compound (0.218 g) as an oil. MS [DCI (reactant gas, ammonia)]: 363 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18](=[CH:24]O)[C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:29])=[N:3]1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>C1COCC1>[CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17](/[C:18](=[CH:24]/[NH:43][C:40]4[CH:39]=[CH:38][C:37]([N:34]5[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]5)=[CH:42][CH:41]=4)/[C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:29])=[N:3]1
Reactant: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)/C4=C\Nc3ccc(N4CCN(C)CC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
A small screw cap test tube was charged with 6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-3-hydroxymethylene-1,3-dihydro-indol-2-one (prepared below, 0.045 g, 0.117 mmol) and THF (2 mL). To the resulting solution was added 4-(4-Methyl-piperazin-1-yl)-phenylamine (23 mg, 0.117 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration. The yellow solid was dissolved in 5 mL of a solvent mixture containing 98% EtOAc/2% i-prOH and washed with water (2×5 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was columned over silica (95/5, chloroform/Hexanes w/0.5% NEt3 to afford the title compound in 39% yield (26 mg, 0.045 mmol).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.[CH3:9][N:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12](=O)[CH3:13].C([BH3-])#N.[Na+]>CO.CCCCCCC.C(OCC)(=O)C>[CH:1]1([NH:4][CH:12]([CH3:13])[CH2:11][N:10]([CH3:9])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CC(=O)CN(C)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(CN(C)c1ccccc1)NC1CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 55.6 %

Procedure:
To a cooled solution of 2.52 g (44 mmol) of cyclopropylamine and 3.3 g (55 mmol) of acetic acid, together with 10 g of 3 Å molecular sieves, in 100 ml of methanol, are added 3.6 g (22 mmol) of 1-[methyl(phenyl)amino]propan-2-one. The reaction mixture is stirred for 2.5 hrs at reflux. The reaction mixture is then cooled to 0° C. and 2.07 g (33 mmol) of sodium cyanoborohydride are slowly added and the reaction mixture is further stirred for 2 hrs at reflux. The cooled reaction mixture is then filtered over a cake of diatomaceous earth. The cake is washed twice by 80 ml of methanol and the combined methanolic extracts are concentrated under vacuum. 100 ml of water are then added to the residue and the pH is adjusted to 10 with a 0.5 N solution of sodium hydroxyde. The watery layer is extracted three times with ethyl acetate (3×50 ml). The combined organic layers are washed twice by brine and are filtered over a phase separator filter to yield after concentration 9.2 g of a yellow oil. Column chromatography (gradient heptane/ethyl acetate) yielded 2.5 g (50% yield) of N2-cyclopropyl-N1-methyl-N1-phenylpropane-1,2-diamine as a brown oil (M+H=205).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][CH2:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.[CH3:23][P:24](Cl)([CH3:26])=[O:25]>ClCCl.O>[CH3:23][P:24]([O:10][CH2:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)([CH3:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CP(C)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(COP(C)(C)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
Diisopropyl ethyl amine (124.28 g, 0.961 mol) was added dropwise to stirred solution of compound tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (150 g, 0.80 mol) in dichloromethane (500 mL) at 0° C. Dimethyl phosphinyl chloride (90 g, 0.80 mol) in dichloromethane (300 mL) was added to above reaction mixture over a period of 90 min at same temperature. Then, the reaction mixture was warmed to room temperature and continued stirring for 2 h. After completion of the reaction, the mixture was diluted with water (300 mL). The layers were separated. The organic layer was washed with brine (300 ml), dried over sodium sulfate and concentrated. The resultant concentrated product was purified via column chromatography on silica gel using chloroform/methanol (95/5) to afford tert-butyl 3-{[(dimethylphosphoryl)oxy]methyl}azetidine-1-carboxylate (146.8 g, 68.3%) as brown liquid.