Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[CH3:32][S-:33].[Na+]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[S:33][CH3:32])=[CH:13][CH:14]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: C[S-]
Agent: [Na+]
Product: CSc1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.15 g, 0.35 mmol, intermediate 14) was dissolved in sodium thiomethoxide (5 mL). The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.875 min; LCMS MH+-THP 395.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>ClCCCl.ClC(Cl)C.[Cl-].[Zn+2].[Cl-]>[F:13][C:11]1[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=[C:7]([OH:6])[C:12]=1[C:25](=[O:26])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1cc(F)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(CC(=O)c2c(O)cc(OC)cc2F)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To 1,2-dichloroethane (40 mL) were added anhydrous aluminum chloride (4.27 g) and zinc chloride (436 mg), followed by stirring 15 min. Under ice-cooling, a solution of 1,3-dimethoxy-5-fluorobenzene (5 g) in 1,2-dichloroethane (15 mL) was added. The mixture was cooled to −10° C. and 4-methoxyphenylacetyl chloride (4.9 mL) in dichloroethane (10 mL) was added drop-wise. The mixture was stirred 30 min at −10° C., and 1 h at room temperature and then heated to reflux for 2 h. The mixture was cooled at 0° C., poured carefully into ice-water and extracted twice with dichloromethane. The dichloromethane layer was dried over MgSO4 and evaporated in vacuo to give the title compound (9.1 g); 1H NMR (CDCl3): 13.23 (s, 1H), 7.17 (d, 2H, J=8.4 Hz), 6.88 (d, 2H, J=8.4 Hz), 6.24 (d, 1H, J=2.1 Hz), 6.18 (dd, 1H, J=13.8 Hz, J′=2.1 Hz), 4.20 (d, 2H, J=3.9 Hz), 3.82 (s, 3H), 3.80 (s, 3H); MS: 291 (MH+); containing 1-(4-fluoro-2-hydroxy-6-methoxyphenyl)-2-(4-methoxyphenyl)ethanone as a by-product. 1H NMR (CDCl3): 13.62 (s, 1H), 7.2–6.0 (6H), 4.29 (s, 2H), 3.90 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[NH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>ClCCl.CO.[Pd]>[CH3:41][S:38]([CH2:37][CH2:36][NH:35][CH2:33][C:31]1[O:32][C:28]([C:25]2[CH:24]=[CH:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([NH:17][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=5)=[C:2]([Cl:1])[CH:3]=4)[C:27]=3[CH:26]=2)=[CH:29][CH:30]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
The suspension of 5-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl]-2-furaldehyde (5 g, 10.6 mmoL) in dichloromethane (50 mL) was charged with a solution of 2-aminoethylmethylsulfone (3.2 g, 11.7 mmoL) in methanol (25 mL) slowly under constant stirring at room temperature. The reaction mixture was stirred for 2-4 hours until reaction completion and then was charged with 5% Pd—C (750 mg) and stirred under a hydrogen atmosphere using balloon pressure for 12-16 hours until reaction completion. The obtained mixture was filtered through Celite® pad and rinsed with methanol (5 mL) and dichloromethane (15 mL) mixture. The filtrate was distilled to low volume and the obtained solution was charged with methanol (25 mL). The reaction mixture was stirred for 2-6 hours and the yellow solid which precipitated out was filtered and washed with methanol (10 mL). The solid obtained was dried under vacuum at 40-45° C. to furnish Lapatinib freebase (5 g, Yield=85%, HPLC purity>99%).
Reaction SMILES: C[O:2][C:3]([CH:5]([N:9]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11](OCC2C=CC=CC=2)[C:10]1=[O:27])[CH:6]([CH3:8])[CH3:7])=[O:4].C([OH:30])C>[Pd]>[OH:30][C@@:5]([C:3]([OH:2])=[O:4])([CH:6]([CH3:8])[CH3:7])[NH:9][C:10](=[O:27])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCO
Reactant: COC(=O)C(C(C)C)N1C(=O)C(OCc2ccccc2)C1c1ccccc1
Agent: [Pd]
Product: CC(C)[C@](O)(NC(=O)CCc1ccccc1)C(=O)O
Reaction time: 38 h
Yield: 93.7 %

Procedure:
According to the same procedure as in Example 1, 1-(1-methoxycarbonyl-2-methylpropyl)-3-benzyloxy-4-phenylazetidin-2-one (560 mg.) was subjected to hydrogenolysis at room temperature in ethanol (30 ml.) under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (170 mg.). The reaction was completed in 38 hours. The same after-treatment as in Example 1 was followed to give methyl ester of α-hydroxy-β-phenylpropionylvaline (400 mg., yield: 93.7%), which was an oil.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1O)=[CH:30][C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2>C(#N)C>[Br:1][C:32]1[C:31]2[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[CH:30]=2)[N:25]=[CH:24][C:23]=1[Cl:22]
Reactant: COc1cc2ncc(Cl)c(O)c2cc1OC
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc2ncc(Cl)c(Br)c2cc1OC
Temperature: 20 °C
Yield: 83.3 %

Procedure:
19 g of triphenylphosphine dibromide were added to a solution of 5.39 g of 3-chloro-4-hydroxy-6,7-dimethoxyquinoline in 270 cm3 of acetonitrile, with stirring and at a temperature in the region of 20° C. The reaction mixture was heated at about 80° C. for 8.25 hours. After cooling to a temperature in the region of 20° C., the insoluble material was filtered off. 5.67 g of 4-bromo-3-chloro-6,7-dimethoxyquinoline were obtained in the form of a gray solid.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22](O)=[O:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].Cl.[NH:30]([CH2:32][C:33]([OH:35])=[O:34])[CH3:31].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:17]([C:22]([N:30]([CH2:32][C:33]([OH:35])=[O:34])[CH3:31])=[O:23])([CH2:18][CH2:19]3)[CH2:20][CH2:21]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CNCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)N(C)CC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a stirred mixture of 0.100 g (0.257 mmol) of 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (Example 13), 0.039 g (0.257 mmol) of sarcosine hydrochloride, 0.143 ml (1.03 mmol) of NEt3, and 2 ml anhydrous acetonitrile was added 0.103 g (0.270 mmol) of HATU. The reaction solution was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo and combined with 10 ml EtOAc and 10 ml of 10% citric acid. The aqueous layer was separated and washed twice with 10-ml portions of EtOAc. The combined organic fractions were washed with 10-ml portions of sat'd NaHCO3 and brine and conc'd in vacuo. The resultant solid was dissolved in a mixture of 5 ml of MeOH and 5 ml of 1 N NaOH and stirred for 16 h. The reaction solution was conc'd in vacuo, taken up in 10 ml of water, and washed twice with 10-ml portions of CH2Cl2. The aqueous layer was acidified with conc'd HCl and the resultant precipitate collected by suction filtration to give 0.094 g (77% yield) of an off-white solid. (MH+=460.18)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=O)=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (96.6 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:21]=2[CH3:30])=[C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:8]=[C:9]([C:10]#[N:11])[N:4]2[N:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[C:21]=2[CH3:30])=[C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:8]=[C:9]([C:10]3[N:31]=[N:32][NH:33][N:11]=3)[N:4]2[N:3]=1
Reactant: Cc1nn2c(C#N)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn2c(-c3nn[nH]n3)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Yield: 42.6 %

Procedure:
To a 5 mL microwave vial was added in 2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidine-7-carbonitrile (68 mg, 0.164 mmol), sodium azide (85 mg, 1.310 mmol) and ammonium chloride (70.0 mg, 1.310 mmol) in N,N-Dimethylformamide (DMF) (1 mL). The reaction was subjected to microwave irradiation at 180° C. for 15 min. The reaction mixture was added to a saturated NH4Cl solution and extracted with DCM (30 mL×2). The combined organic phases were dried and concentrated. The residue was purified on silica column (20˜60% EtOAc/Hexane) and then (5% MeOH/DCM) to give the titled product (32 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H) 2.46 (s, 3H) 3.47-3.79 (m, 8H) 4.01 (s, 2H) 7.15-7.34 (m, 2H) 7.40 (d, J=8.15 Hz, 1H) 7.53 (d, J=7.74 Hz, 1H); LC/MS: MS (ES+) m/e 459.3 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NCC[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[CH3:23])[CH2:19][CH2:18][CH2:17]2>>[C:1]1([CH2:7][C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[CH3:23])[CH2:19][CH2:18][CH2:17]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc2c(cc1CCN)CCC2
Reactant: O=C(Cl)Cc1ccccc1
Product: Cc1cc2c(cc1C(=O)Cc1ccccc1)CCC2

Procedure:
Phenylacetyl chloride was reacted with 5-aminoethyl-6-methylindan to produce the desired product. After recrystallization from benzene it melted at 125.5°-127° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.Br[C:60]1N=C(C(=O)NCC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=CC=3OC)N=2)=CC=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH2:10][CH3:60])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:50])([CH3:51])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(O)OCC)cc2OC)ncc1C(F)(F)F
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Product: CCNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(OCC)OCC3(Cn4cc(B5OC(C)(C)C(C)(C)O5)cn4)COC3)cc2OC)ncc1C(F)(F)F
Yield: 34 %

Procedure:
Racemic Compound 45A was prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(ethylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 45B, 78.1 mg, 0.123 mmol) to afford 37.7 mg of the title compound (34%). MS (ESI): m/z=909.40/991.51 [M+H]+. UPLC: tR=1.60 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](N(OC)C)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9]
Reactant: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C#Cc1c(Cl)cc(C=O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: -78 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
A solution of 4-chloro-6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-5-ethynyl-3′-fluoro-N-methoxy-N-methylbiphenyl-2-carboxamide (0.50 g, 1.2 mmol) in tetrahydroduran (5 mL) at −78° C. was treated with 1.0 M lithium aluminum hydride in tetrahydroduran (2.5 mL, 2.5 mmol) dropwise and stirred at −78° C. for 2 hours. The reaction mixture was quenched with water (0.5 mL) at −78° C., diluted with ethyl acetate (50 mL), and warmed to 20° C. The organic layer was separated, washed with 1 M HCl (30 mL), water and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0%-20%) gave the desired product (0.20 g, 47%). LCMS for C19H18ClFN3O (M+H)+: m/z=358.1; Found: 357.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)CCc1ccc(OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COc1ccc(CCC=O)cc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A solution of ester 12d (0.8346 g, 4.3 mmol) in 15 mL dry CH2Cl2 was cooled to -78° C. and treated with DIBAL (1.0M solution in dry CH2Cl2, 4.3 mL, 4.3 mmol, 1.0 equiv), upon completion by tlc the reaction was quenched immediately with 4.0 mL dry CH3OH. The reaction mixture was diluted with 15 mL saturated aqueous sodium potassium tartrate and warmed gradually to room temperature, partitioned, and extracted with CH2Cl2 (3×20 mL). The combined extracts were washed with saturated aqueous sodium potassium tartrate (3×25 mL), dried (MgSO4), filtered and concentrated in vacuo. SGC chromatotron (SiO2, 4 mm, 20-35% EtOAc/hexanes) afforded 13d (0.702 g, 0.706 g theoretical, 99%). For 13d: 1H NMR (CDCl3, 250 MHz) d 9.78 (d, 1H, J=1.4 Hz, CHO), 7.09 (d, 2H, J=8.6 Hz, Ar C2-H and C6-H), 6.82 (d, 2H, J=8.6 Hz, Ar C3-H and C5-H), 3.76 (s, 3H, OCH3), 2.87 (dd, 2H, J=6.9, 8.3 Hz, ArCH2), 2.72 (ddd, 2H, J=1.4, 6.9, 8.3 Hz, CH2 (C=O)); 13C NMR (CDCl3, 125 MHz) d 201.7, 158.0, 132.3, 129.1, 113.9, 55.1, 45.4, 27.2; IR (neat) nmax 2935, 2835, 1722, 1611, 1583, 1513, 1464, 1442, 1301, 1247, 1178, 1034, 831 cm-1. See FIG. 18h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH:5]=[CH:6][CH2:7]O.S(Cl)(Cl)=O.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1/[CH:5]=[CH:6]/[CH2:7][N:17]1[CH2:22][CH2:21][N:20]([CH2:7]/[CH:6]=[CH:5]/[C:4]2[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: COc1ccccc1C=CCO
Solvent: O=S(Cl)Cl
Product: COc1ccccc1/C=C/CN1CCN(C/C=C/c2ccccc2OC)CC1

Procedure:
2-Methoxy-cinnamylalcohol (1.44 g) was chlorinated using thionylchloride. Subsequently, reaction with piperazine and other treatments were performed as described in Preparation Example 2, to thereby obtain 314 mg of a salt as colorless prisms.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=[O:9])[CH2:4][C:5]([O:7]C)=O.[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[CH3:10][C:2]([CH3:1])([CH3:11])[C:3](=[O:9])[CH2:4][C:5]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=1[Cl:12])=[O:7]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)CC(=O)C(C)(C)C
Product: CC(C)(C)C(=O)CC(=O)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 83.9 %

Procedure:
Methyl 4,4-dimethyl-3-oxopentanoate (100 g, 0.632 mol) and 2,4-dichloroaniline (100 g, 0,617 mol) were heated at reflux for 6 hours in xylenes (reagent grade, dried over 4A molecular sieves, 150 mL) in a flask equipped with mechanical stirrer and distillation apparatus. 100 mL of distillate was collected during this period. The reaction mixture was then cooled to room temperature and petroleum ether (500 mL) was added with stirring. The mixture was cooled further with an ice bath, and the crystals which had formed were collected by filtration and washed with petroleum ether. A second crop was collected after concentration of the filtrate. The combined materials were dried under high vacuum to give N-[4,4,-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline (152.8 g, 84% yield) as a white solid which melted at 77°-78° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(C(C)=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCI
Reactant: Oc1cccc(C#Cc2ccc3ccc(Br)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1

Procedure:
A solution of the phenol from Step 3 (470 mg), methyl ethyl ketone (10 mL), milled potassium carbonate (600 mg) and ethyl 4-iodo-butyrate (421 mg) was refluxed overnight The solids were filtered, and the filtrate was evaporated. The residue was purified by flash chromatography using toluene-ethyl acetate (10:0.3) to afford the title product as yellow solid: m.p. 61°-63° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:31]1[CH2:32][CH2:33][CH:28]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30]1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCC(Cc4ccccc4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.1 %

Procedure:
In a 50 ml flask were placed 2.5 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 6.4 g of 4-benzylpiperidine and 25 ml of hexamethylphosphoric triamide and the mixture was stirred at 160° C. in an argon gas atmosphere for 7 hours. After disappearance of the starting materials was confirmed by thin layer chromatography, hexamethylphosphoric triamide was removed using a vacuum pump followed by cooling to room temperature. To the residue was added ethyl acetate and then several drops of concentrated hydrochloric acid and the mixture was allowed to stand in a refrigerator for 1 day. The crystals which formed were collected by filtration and recrystallized from dimethylformamide to give 0.45 g of 9-fluoro-8-(4-benzyl-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 230°-232° C., white rhombic crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:10]([N:12]1[CH2:16][CH:15]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:14][CH:13]1[C:30]([OH:32])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39]([C:41]1([NH2:47])[CH2:43][CH:42]1[CH2:44][C:45]#[N:46])=[O:40]>>[CH3:37][O:38][C:39]([C:41]1([NH:47][C:30]([CH:13]2[CH2:14][CH:15]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[CH:21]=[CH:20][N:19]=3)[CH2:16][N:12]2[C:10](=[O:11])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:33]([CH3:35])([CH3:34])[CH3:36])=[O:32])[CH2:43][CH:42]1[CH2:44][C:45]#[N:46])=[O:40]
Reactant: COC(=O)C1(N)CC1CC#N
Reactant: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C3)nccc2c1
Product: COC(=O)C1(NC(=O)C2CC(Oc3nccc4cc(OC)ccc34)CN2C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)CC1CC#N

Procedure:
1-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-cyanomethyl-cyclopropanecarboxylic acid methyl ester was prepared according to the method presented in the synthesis of compound 31. Treatment of 1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carboxylic acid (387 mg, 0.69 mmol) and 1-amino-2-cyanomethyl-cyclopropanecarboxylic acid methyl ester occurred under the same conditions, adjusted for scale, to afford the desired methyl ester (349 mg, 74%). LCMS found 638.0 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:8]([C:20]([NH2:22])=[O:21])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.C(O)C.[C].[Pd]>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:8]([C:20]([NH2:22])=[O:21])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(/C=C/c2c(C(N)=O)cnn2C(C)(C)C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CCc2c(C(N)=O)cnn2C(C)(C)C)cc1
Yield: 98.1 %

Procedure:
A mixed solution of the compound (80 mg, 0.27 mmol) obtained in step 1, 10% palladium carbon (28.4 mg, 0.27 mmol) in THF (15 mL) and ethanol (15 mL) was stirred under 1 atm hydrogen atmosphere at room temperature for 6 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 1-tert-butyl-5-(4-methoxyphenethyl)-1H-pyrazole-4-carboxamide (80 mg, 0.265 mmol, 99%) as a white powder.