Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]1[O:26][CH:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[OH:26][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][NH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[CH:11]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: NCCc1ccn(S(=O)(=O)c2ccccc2)c1
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1ccc(CCNCC(O)c2ccccc2)c1

Procedure:
A mixture of 2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine (1.8 g), styrene oxide (0.51 g) and acetonitrile (20 ml) were refluxed for three days. The solution was evaporated and the brown oil was purified by chromatography on silica, eluting with dichloromethane, chloroform then with increasing amounts of methanol (1→10%) in chloroform, to give the title product as a brown oil.
Reaction SMILES: [F:1][C:2]1(F)[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1(F)[F:21].FC1(F)C2C(=CC([C@H]3CC[C@H](CCC)CC3)=CC=2)C(F)=CC1F.N>C1COCC1.[Zn]>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:17]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[F:21]
Reactant: CCC[C@H]1CC[C@H](c2ccc3c(c2)C=CC(F)(F)C3(F)F)CC1
Agent: CCC[C@H]1CC[C@H](c2ccc3c(c2)C(F)=CC(F)C3(F)F)CC1
Agent: N
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc3c(F)c(F)ccc3c2)CC1
Reaction time: 27 h

Procedure:
A mixture of 1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene and 1,1,2,4-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene, 10.0 g (30.6 mmol) in THF was stirred with zinc dust (10 g, 153 mmol) and aqueous 30% NH40H at ambient temperature. After 27 h, GC analysis showed that the mixture contained <1% of the starting material. The mixture was filtered, and the zinc was washed with hexanes. The filtrate was transferred to a separatory funnel, the phases were separated, and the solvent was evaporated from the organic phase. The weight of product recovered was 8.6 g. GC analysis of the product showed that it contained 0.9% 1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene, 13.4% 1,2,4-trifluoro-6-(trans-4-propylcyclohexyl)naphthalene, and 82% 1,2-difluoro-6-(trans-4-propylcyclohexyl)naphthalene. This example shows that when ammonia is not buffered to reduce the pH, more by-products are formed compared to the reaction in which buffered ammonia is used (Example 8).
Reaction SMILES: N=C=N.[CH:4]1(/[CH:9]=[C:10](\[C:14]2[CH:15]=[N:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=2)/[C:11]([OH:13])=O)[CH2:8][CH2:7][CH2:6][CH2:5]1.C1C=CC2N(O)N=NC=2C=1.[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[NH2:37]>CN(C=O)C>[CH:4]1(/[CH:9]=[C:10](\[C:14]2[CH:15]=[N:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=2)/[C:11]([NH:37][C:33]2[S:32][CH:36]=[CH:35][N:34]=2)=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Nc1nccs1
Reactant: CSc1ccc(/C(=C\C2CCCC2)C(=O)O)cn1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cn1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A suspension of PS-carbodiimide (1.08 g, loading 1.32 mmol g−1, 1.42 mmol), (E)-3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)acrylic acid (Preparation 3, 125 mg, 475 μmol), and HOBt (128 mg, 949 μmol) in anhydrous DMF (8 mL) was stirred for 15 min at 20° C. Thiazol-2-ylamine (48 mg, 475 μmol) was added, then the mixture was stirred for 14 h at 20° C. LCMS indicated that the reaction had not gone to completion, so more thiazol-2-ylamine (95 mg, 950 μmol) was added. The mixture was stirred for an additional 64 h, before being filtered. The resin collected was washed with CH2Cl2, then the combined filtrate and washings were concentrated under reduced pressure. Column chromatography (2:11H-EtOAc) provided the title compound: RTA=3.85 min; m/z (ES+)=346.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[Br:16][C:17]1[C:23]([CH3:24])=[CH:22][C:20]([NH2:21])=[C:19]([CH3:25])[CH:18]=1.Cl>C(O)(C)C.CCOC(C)=O>[Br:16][C:17]1[C:23]([CH3:24])=[CH:22][C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[C:5]([Cl:15])=[CH:4][N:3]=2)=[C:19]([CH3:25])[CH:18]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: Cc1cc(Br)c(C)cc1N
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(Br)cc3C)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
A mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (732 mg, 3 mmol), 4-bromo-2,5-dimethylaniline (554 mg, 2 mmol) and conc. aqueous HCl (1.5 mL) in iso-propanol (15 mL) was heated in a microwave for 40 min at 130° C. LCMS showed that the reaction was not complete, and additional 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (732 mg, 3 mmol) was added to the reaction. The reaction was again heated in a microwave for an additional 60 min at 130° C. The crude reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with saturated aqueous NaHCO3 (2×20 mL) and brine (10 mL), dried over Na2CO3 and concentrated in vacuo. The crude product was purified by silica chromatography (0-10% MeOH in EtOAc gradient with 1% NH3 additive) to give N2-(4-bromo-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as an off-white solid; ESMS m/z 407.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=O)[NH:9][N:8]=1.O=P(Cl)(Cl)[Cl:23]>C(#N)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([Cl:23])=[N:9][N:8]=1
Reactant: COC(=O)CCCc1n[nH]c(=O)c2cc(OC)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)CCCc1nnc(Cl)c2cc(OC)ccc12
Yield: 73.8 %

Procedure:
A suspension of 4-(6-methoxy-4-oxo-3,4-dihydro-phthalazin-1-yl)-butyric acid methyl ester (9.23 g, 0.034 moles), prepared as described in example 113, and POCl3 (1.87 ml, 0.2 mole) in acetonitrile (100 ml) was refluxed. After 1.5 hours the mixture was dried, taken up in water and neutralised with NaHCO3. The mixture was extracted with ethyl acetate and the organic phase dried to give a residue which was chromatographed (eluent: petrolatum/ethyl acetate 7:3). There were yielded 7.4 g of the title compound (yield: 63.9%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][O:17][C:19](=[O:21])[CH3:20])[CH2:12][CH2:11]1)=[O:18])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC[C@H]1CC[C@H](CO)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1CC[C@H](CCNC(=O)OC(C)(C)C)CC1

Procedure:
A solution of 27.9 g (86.7 mmol) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-carbamic acid tert-butyl ester, 41 mL (434 mmol, 5 eq) of acetic anhydride and 35 mL (434 mmol, 5 eq) of pyridine in 140 mL of CH2Cl2 was stirred at RT for 16 h. The reaction mixture was then taken up in ether and washed with 1M HCl, sodium hydrogen carbonate solution and water. Then, the ether-phase was dried over MgSO4 and concentrated to yield 26.0 g of crude trans-acetic acid 4-(2-tert-butoxycarbonylamino-ethyl)-cyclohexylmethyl ester as colorless viscous oil, MS: 200 [(M-(tert-butoxycarbonyl))H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16].C1COCC1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:15](=[O:16])[N:8]([CH:9]([CH3:11])[CH3:10])[C:6]=2[CH:7]=1
Reactant: CC(C)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1c(=O)[nH]c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.8 %

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)isopropylamine (Step 1 of Example 9, 5.85 g, 30 mmol) and 10% Pd—C (600 mg) in MeOH was stirred under atmosphere of hydrogen gas at room temperature for 12 h. The catalyst was filtered off on a pad of Celite, and the filtrate was evaporated under reduced pressure. To the residue was added 1,1′-carbonyldiimidazole (4.5 g, 28 mmol) and THF (100 μL) and then stirred at 100° C. for 10 h. After cooling, the volatile materials were removed under reduced pressure and the residue was partitioned between ethylacetate and H2O. After extraction with ethylacetate (3 times), the combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (2:1) to give 3.47 g (60%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:20]([O:22]CC)=[O:21])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31].OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>CN(C=O)C.CS(C)=O.[Cu]I>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:20]([OH:22])=[O:21])=[CH:6][N:7]2[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(I)cc2)c2cccc(F)c2c1=O
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(Cc2ccc(N3CCCC3=O)cc2)c2cccc(F)c2c1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-fluoro-1-(4-iodobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.060 g, 0.13 mmol), pyrrolidine-2-one (0.034 g, 0.40 mmol), 8-hydroxyquinoline (1.9 mg, 0.013 mmol) and potassium carbonate (0.037 g, 0.27 mmol) in 2 mL of DMF under nitrogen was added copper(I)iodide (10 mol %). The reaction mixture was heated to 100° C. for 22 hours, then cooled to room temperature. To the mixture was added 1 N NaOH (0.30 mL, 0.30 mmol). After 2 hours, the mixture was acidified with 6 N HCl to pH ˜2, diluted with DMSO (2 mL), filtered, and purified via reverse phase HPLC to provide the title compound which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 381.1 for M+H+: 1H NMR (400 MHz, d6-DMSO) δ 9.25 (s, 1H), 7.86-7.80 (m, 1H), 7.66-7.64 (m, 3H), 7.36 (dd, J=8.1 Hz, 3.4 Hz, 1H), 7.30 (d, J=8.7 Hz, 2H), 5.81 (s, 2H), 3.78 (t, J=7.1 Hz, 2H), 2.51-2.44 (m, 2H), 2.07-2.01 (m, 2H).
Reaction SMILES: Cl.COC(=O)[C@@H](CC1C=CC=CC=1)N.C[O:16][C:17](=[O:47])[C@@H:18]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:19][C:20]([CH2:22][C:23]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:26]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:25][CH:24]=1)=[O:21]>CO.C(OCC)(=O)C>[CH2:36]([C:26]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]([CH2:22][C:20]([NH:19][C@@H:18]([C:17]([OH:47])=[O:16])[CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:21])=[CH:24][N:25]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1ncc(CC(=O)N[C@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1ncc(CC(=O)N[C@H](Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
The procedure of Example 12 (ii-iii) was followed using D-phenylalanine methyl ester hydrochloride in place lycine methyl ester hydrochloride. The intermediate N-[{2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5 -yl}methylcarbonyl]-D-phenylalanine methyl ester was a solid; mp 179°-181° C. (from methanol/ethyl acetate). The title compound was a solid; mp 178°-181° C. (from methanol/ethyl acetate).
Reaction SMILES: O[N:2]=[C:3]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]1=[O:24].[H][H]>CO>[NH2:2][CH:3]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[CH:4]1[OH:24]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(=NO)C(=O)c3ccccc32)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC(N)C(O)c3ccccc32)cc1
Yield: 106.6 %

Procedure:
To a suspension of 4-(hydroxyimino)-1-tosyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one (7.0 g) in methanol (300 mL) Raney nickel (11.0 g) was added. The reaction mixture was stirred under 1 atmosphere of hydrogen gas for 15-16 h. The reaction mixture was filtered through celite, washed with methanol (150 mL×3) and evaporated under reduced pressure to give 4-amino-1-tosyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ol (7.2 g, 95%). 1H NMR: (400 MHz, CDCl3) δ: 7.67 (2H, d, J=8.0 Hz), 7.55 (1H, d, J=7.6 Hz), 7.42 (2H, d, J=7.6 Hz 7.32 (1H, t, J=7.2 Hz), 7.22 (1H, t, J=7.6 Hz), 7.04 (1H, d, J=7.6 Hz), 5.53 (1H, b), 4.08 (2H, d, J=8.0 Hz), 3.1 (1H, m), 2.4 (3H, s), 1.7 (3H, m).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20](OC)=[O:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([CH2:20][OH:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:8][CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1nc2cc(CO)ccc2n1CC1CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
To a suspension of lithium aluminum hydride (391 mg, 8.3 mmol) in tetrahydrofuran (15 mL) was added a tetrahydrofuran solution of methyl 1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazole-5-carboxylate (Step C, 990 mg, 3.3 mmol) at 0° C. The mixture was stirred at 0° C. for 3 h. The mixture was quenched with potassium fluoride and sodium sulfate decahydrate and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2 as eluent) to afford the title compound (573 mg, 64%) as red gum.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:7]=1[F:24])C.[Li+].[OH-].Cl>CO>[Cl:12][C:11]1[C:6]([CH2:5][C:4]([OH:25])=[O:3])=[C:7]([F:24])[C:8]([NH:13][CH2:14][C:15]([F:22])([F:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:9][CH:10]=1
Reactant: CCOC(=O)Cc1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.5 g (1.26 mmol) ethyl(5-chloro-2-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetate 1-5 in 5 mL MeOH was added 1.4 mL (1.4 mmol, 1M aqueous solution) LiOH and the reaction mixture allowed to stir 16 hours at room temperature, then 0.1 mL (0.1 mmol) more LiOH was added and the mixture heated to 45° C. for 1 hour, then cooled. To this was added 0.12 mL (1.45 mmol, 12M solution) HCl and the mixture concentrated to give (5-chloro-2-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetic acid 1-6 (mixed with LiCl). 1H NMR (400 mHz, CD3OD) δ8.60 (br d, 1H, J=4.77 Hz); 7.89 (ddd, 1H, J=7.7, 7.7, and 1.65 Hz); 7.70 (s, 1H); 7.67 (br d, 1H, J=7.87 Hz); 7.46 (dd, 1H, J=4.94 and 7.69 Hz); 4.32 (t, 2H, J=13 Hz); 3.72 (d, 2H, J=1.83 Hz);
Reaction SMILES: [CH2:1]([N:8]([CH:13]([CH3:15])[CH3:14])[C:9](=O)[CH2:10][Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH:13]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][Cl:11])([CH3:15])[CH3:14]
Reactant: CC(C)N(Cc1ccccc1)C(=O)CCl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)N(CCCl)Cc1ccccc1
Yield: 50.2 %

Procedure:
A solution of 7.66 g of the N-benzyl-2-chloro-N-isopropylacetamide in 20 ml of dry diethyl ether was added dropwise to a suspension of 1.29 g of lithium aluminum hydride in 300 ml of dry diethyl ether with stirring under ice-cooling, and the mixture was heated under reflux for 4 hours. After the reaction mixture was cooled, and to the cooled reaction mixture was added dropwise water with stirring under ice-cooling. Insoluble materials were filtered off. The filtrate was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (eluent: chloroform) to obtain 3.61 g of 2-(N-isopropylbenzylamino)ethyl chloride in an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH:29](=O)[CH2:30][CH3:31]>>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][CH2:29][CH2:30][CH3:31])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Reactant: CCC=O
Product: CCCNc1cc(CC(C)C)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
The title compound was prepared from the compound of Example 32 and propionaldehyde as described for Example 58, with stirring at 0-5° C. for 2 hours. Following workup, chromatography on silica gel with 4:1 hexanes/ethyl acetate afforded the title compound as a light yellow gum.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:20])[C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25](O)[CH:24]=1>>[CH3:4][C:2]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([O:20][C:29]1[CH:30]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=1[C:27]#[N:28])[C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:1])[CH3:3]
Reactant: COc1ncccc1C(O)CCCNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)cc1O
Product: COc1ncccc1C(CCCNC(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N

Procedure:
The sub-title compound was prepared by the method of Example 1 step (b) using the product of step (b) above and 4-chloro-2-hydroxybenzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][O:15][CH2:16][C:17]([NH:1][C:2]1[CH:12]=[C:11]([NH:13][C:17](=[O:18])[CH2:16][O:15][CH3:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:18]
Reactant: CCOC(=O)c1ccc(N)cc1N
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)COC)cc1NC(=O)COC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2,4-diaminobenzoate (3.6 g) in pyridine (80 ml) is added dropwise methoxyacetyl chloride (4.0 ml) at room temperature. The mixture is stirred at room temperature for 3 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue are added water and chloroform. The organic layer is separated and washed with water and then with aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the resulting oily substance is dissolved in ethyl acetate-hexane, and the solution is allowed to stand at -30° C. for 6 hours. The precipitated crystals are separated by filtration to give the title compound (6.0 g) having the following physical properties.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl-].[NH4+].[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Fe].C(O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:34](=[O:35])[CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:28][CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CCn1ncc2c([N+](=O)[O-])cccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)CCn1ncc2c(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of dimethyl-[2-(4-nitro-indazol-1-yl)-ethyl]-amine (1.6 g, 6.8 mmol), iron powder (3.8 g, 68 mmol), and ammonium chloride (0.18 g, 3.4 mmol) in a 4:1 ethanol/H2O solution (20 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 10 mL) for 15 minutes and then filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure to provide a play yellow oil. This material was then processed with (4-phenoxy-phenyl)-acetic acid according to the procedure described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 2.85 (s, 6H), 3.62 (t, J=6.24, 2H), 3.80 (s, 2H), 4.78 (t, J=6.24, 2H), 6.99–7.01 (m, 3H), 7.13 (m, 2H), 7.36–7.40 (m, 5H), 7.45 (m, 1H), 7.71 (m, 1H), 8.40 (s, 1H), 9.61 (s, 1H); MS (DCI/NH3) m/z 415 [M+H]+.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=O)=[CH:6][C:5]=1[C:25]#[N:26]>C1COCC1>[NH2:26][CH2:25][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:4]=1[Cl:3])[CH2:8][N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Cl)c(C#N)c2)CC1
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(CN)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.4 %

Procedure:
To a 250 mL round-bottom flask fitted with a reflux condenser, rubber septum and stir bar under a positive pressure of N2 was added 10.3 mL of 1M BH3.THF complex in THF. This mixture was cooled in an ice bath. The tert-butyl 4-(4-chloro-3-cyanobenzoyl)piperazine-1-carboxylate (1.44 g, 4.12 mmol) was dissolved in 20 mL of THF and added dropwise to the reaction mixture via syringe. The ice bath was removed, replaced with a heating mantle and the reaction mixture was heated at reflux for 20 h. The reaction was cooled to RT and to the mixture was added 48 mL of 20% HOAc in water (v/v) and the mixture was stirred between pH 3-4 for 20 h. The mixture was concentrated to half its original volume with a rotary evaporator and then diluted with 20 mL of 10% citric acid. This mixture was washed once with 25 mL of EtOAc and the aqueous layer was brought to pH=11 by the addition of 52 mL of 3N NaOH. The resultant mixture was extracted with EtOAc (3×40 mL). The combined extracts were washed with 40 mL of saturated NaCl solution. The organic layer was dried over Na2SO4, filtered and concentrated to give 1.00 g of tert-butyl 4-(3-(aminomethyl)-4-chlorobenzyl)piperazine-1-carboxylate as a pale yellow oil.