Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:26])[C:17]2[N:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[S:20][CH:21]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([N:14]2[CH2:15][CH:16]([C:17]3[N:18]=[C:19]([C:22]([F:24])([F:25])[F:23])[S:20][CH:21]=3)[O:26][CH:28]2[C:27]([O:31][CH3:32])=[O:30])[CH3:13])=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=O
Reactant: COC(=O)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Product: COC(=O)c1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC2C(=O)OC)cc1

Procedure:
Prepared analogously to Example 18 by reaction of N-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with methyl glyoxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][C:24](=[O:27])[CH2:25]I)=[O:12])=[CH:5]2.C(=O)([O-])[O-:29].[Na+].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][C:24](=[O:27])[CH2:25][OH:29])=[O:12])=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: O=C(CI)NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(CO)NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 86.8 %

Procedure:
5-Chloro-N-{1-[(iodoacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-1H-indole-2-carboxamide (Method 7a; 60 mg, 0.12 mmol) and sodium carbonate (100 mg) were dissolved in 1:1 dioxane:water (5 mL) and heated to reflux for 20 hours. The reaction was cooled, water (10 mL) added, filtered and the filter cake washed with water (3×1 mL) and dried to give the title compound (40 mg, 85%) as a white powder.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.Cl>O>[NH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1cc(C(=O)O)c(NC(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: COc1cc(C(=O)O)c(N)cc1[N+](=O)[O-]
Yield: 49.5 %

Procedure:
7.5 g of 2-acetylamino-5-methoxy-4-nitrobenzoic acid (crude mixture from stage c) were heated to reflux in 50 ml of water and 20 ml of concentrated hydrochloric acid for 3 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/isopropanol =9/1). 3.1 g (50%) of the desired product were obtained.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]4)[CH:17]=3)[N:12]=2)[CH3:10])[CH2:6]1)=[O:4].[OH-].[Li+].O1CCCC1.O>>[C:28]([C@H:25]1[CH2:24][CH2:23][C@H:22]([O:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([CH:9]([N:7]2[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]2)[CH3:10])[CH:20]=[CH:19]3)[CH2:27][CH2:26]1)([CH3:29])([CH3:30])[CH3:31]
Reactant: COC(=O)C1CN(C(C)c2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3n2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1)N1CC(C(=O)O)C1

Procedure:
A solution of 1-{1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethyl}-azetidine-3-carboxylic acid methyl ester (57.2 mg, 0.135 mmol) and Lithium hydroxide (20.9 mg, 0.874 mmol) in Tetrahydrofuran (2 mL, 20 mmol) and Water (0.5 mL, 30 mmol) was stirred at r.t. overnight. LCMS showed a single desired product peak RT 1.60 min M+1 at m/z 413.30, 100%. The solvent was concentrated and neutralized with citric acid and concentrated and Purified on HPLC to give product (26.2 mg, 37%). 1H NMR (300 MHz, MeOD) d=8.25 (d, J=8.3 Hz, 1H), 7.94 (d, J=9.4 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.37 (dd, J=2.6, 9.1 Hz, 1H), 7.28 (d, J=3.0 Hz, 1H), 4.54-4.43 (m, 2H), 4.42-4.18 (m, 3H), 3.78-3.59 (m, 1H), 2.25 (d, J=10.2 Hz, 2H), 1.89 (d, J=11.3 Hz, 2H), 1.57 (d, J=6.8 Hz, 3H), 1.51-0.99 (m, 6H), 0.89 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>CC(N(C)C)=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:16]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NC(=O)c1ccccc1N
Reactant: COc1cccc(C=O)c1
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Temperature: 0 °C
Yield: 16.3 %

Procedure:
2-Aminobenzamide (30) (1.0 g, 7.3 mmol) and 3-methoxybenzaldehyde (34) (1.0 g, 7.3 mmol) were heated with stirring in DMAC (20 ml) at 80° C. for 2 h and then poured into ice water (200 ml). The precipitate was collected, washed with water, then dried and purified by column chromatography (silica gel-ethyl acetate/n-hexane) to afford 43 (0.3 g, 15.0%) and 61 (1.4 g, 75.2%) as pale yellow powder. Yield, mp, and spectral data are given in Table 1.
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][CH2:7][C:8]2=O.[Li][C:15]#[N:16].C(P(=O)(OCC)OCC)#N.O>C1COCC1>[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]=[C:8]2[C:15]#[N:16]
Reactant: COc1cccc2c1CCCC2=O
Reactant: [Li]C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CCC=C2C#N
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 339.9 %

Procedure:
5-Methoxy-1-tetralone (8.80 g) was dissolved in 50 ml of anhydrous THF and cooled to 5° C. under N2 atmosphere. LiCN (0.50 g.) was added to the stirred solution, followed by dropwise addition of diethyl cyanophosphonate (9.1 ml) over 10 min. After 45 min at 5° C., the reaction was poured into 200 ml H2O and extracted with EtOAc (3×100 ml). The combined organic extracts were washed with water (3×150 ml), saturated NaCl (150 ml), dried (MgSO4), and evaporated under reduced pressure. The resulting colorless oil was dissolved in benzene (100 ml) and p-toluenesulfonic acid (0.50 g) was added. The reaction was stirred at reflux for 2 hr, cooled to room temperature, and poured into 5% NaHCO3 solution (150 ml). The reaction was extracted with Et2O (2×100 ml) and the combined organic extracts were washed with saturated NaCl solution (150 ml), dried (MgSO 4), and evaporated under reduced pressure to yield 9.55 g of a white solid. The product was recrystallized from MeOH to yield 7.81 g of the product as white needles.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[NH:6][C:5]2[CH:10]=[C:11]([CH3:12])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: Cc1cc2[nH]c(=O)[nH]c2cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2[nH]c(Cl)nc2cc1Cl

Procedure:
The benzimidazol-2-one from step (a) above (10.6 g, 58 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 201.3 (M+1).
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[CH:17][C:10]=23)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(OC([NH:46][CH2:47][CH2:48][CH:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[Cl:59])[C:50](O)=[O:51])=O)(C)(C)C.C(N(CC)CC)C>CN(C=O)C>[ClH:59].[ClH:1].[NH2:46][CH2:47][CH2:48][CH:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[Cl:59])[C:50]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[CH:17][C:10]=23)[CH2:8][CH2:7]1)=[O:51]
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccccc1Cl
Reactant: c1nc(N2CCNCC2)c2cn[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NCCC(C(=O)N1CCN(c2ncnc3[nH]ncc23)CC1)c1ccccc1Cl
Reaction time: 4 h
Yield: 133.1 %

Procedure:
The 4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine bis-hydrochloride salt (60 mg, 0.22 mmol), HOBt (29 mg, 0.22 mmol), EDCI (46 mg, 0.24 mmol), and 4-tert-butoxycarbonylamino-2-(2-chlorophenyl)-butyric acid [prepared by procedures described in Example 61 (68 mg. 0.22 mmol)] were suspended/dissolved in 1.5 mL of DMF then treated with triethylamine (121 μL, 0.87 mmol). The mixture was allowed to stir for four hours to completion then partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 1 mL of 1,4-dioxane and treated with 1 mL of 4M HCl in 1,4-dioxane. The solution stirred overnight to completion at room temperature and diluted with diethyl ether to afford a precipitate. This material was broken up to afford a suspended granular solid which was stirred for 30 minutes. The suspension was filtered, washed with diethyl ether, and dried over a stream of nitrogen to afford the 4-amino-2-(2-chlorophenyl)-1-[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperazin-1-yl]-butan-1-one bis-hydrochloride salt as a tan solid (69.2 mg, 67%). 1H NMR (D6O, 400 MHz) δ 8.52 (brs, 1H), 8.31 (s, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.12 (m, 3H), 4.42 (t, J=6.8 Hz, 1H), 4.11 (m, 1H), 3.98 (m, 3H), 3.70 (m, 2H), 3.61 (m, 1H), 3.41 (m, 1H), 2.96 (m, 1H), 2.80 (m, 1H), 2.21 (m, 1H), 1.94 (m, 1H). LCMS (APCI+) m/z 400 [M+H]+; Rt=1.52 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13](OC(C)=O)=[O:14]>>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[C:13]([CH3:12])=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CC(=O)O)cc1
Product: CC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
The mixture of 100 g (4-amino-phenyl)-acetic acid and 200 ml acetanhydride is heated at the steam cone for 15 minutes and evaporated. The residue is stirred with 500 ml hot water until complete dissolution occurs. The solution is cooled and the precipitate formed filtered off, to yield the (4-acetamino-phenyl)-acetic acid melting at 168°-170°.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=O)=[CH:15][CH:14]=1)([O-])=O>C1(C)C=CC=CC=1>[NH2:10][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:20])[C:7](=[O:9])[C:4]2[CH:3]=[CH:2][C:1]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)C1CCCCC1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N)cc1
Reaction time: 8 h

Procedure:
4-Cyclohexylcarboxylic acid (5.0 g) and 4-nitrophenylisocyanate (4.0 g) were stirred in toluene (150 ml) for 3 hours and then left to stand overnight. The precipitate was filtered off with suction and washed with diethyl ether. The resulting amide was ethylated by method F and hydrogenated by method B. This resulted in the product with the molecular weight of 308.43 (C20H24N2O); MS (ESI): 309 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[CH3:30][O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=2[O:31][CH3:30])[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)N[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Yield: 7.7 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 2-methoxy-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (5.2 mg, 7.7%) as light yellow oil. MS m/e=524.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.Br[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:15][CH:14]=2)=[C:4]([F:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Reactant: OB(O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cc3F)nc2)CC1
Yield: 41.5 %

Procedure:
1,1-Dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.23 g, ˜90% purity, 42%) was prepared as a white solid from (4-bromo-2-fluorophenyl)boronic acid (0.30 g, 1.36 mmol), 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.44 g, 1.19 mmol), 2M Na2CO3 (2 mL), and PdCl2(PPh3)2 (85 mg, 0.12 mmol) in DME (4 mL) in a manner similar to Example 21, Step 3. The material was purified by chromatography on a silica gel column eluted with 20% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=2.7 Hz), 7.90-7.85 (m, 1H), 7.72 (d, 1H, J=8.8 Hz), 7.45-7.30 (m, 2H), 7.30-7.25 (m, 1H), 4.25-4.10 (m, 2H), 3.99 (d, 2H, J=6.4 Hz), 2.95-2.80 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.25 (m, 2H); LRMS (ESI), m/z 465/467 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[OH:10][C@H:11]([CH3:15])[C:12](O)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:12]([C@H:11]([OH:10])[CH3:15])=[N:9][N:8]=2)[N:3]=1
Reactant: C[C@@H](O)C(=O)O
Reactant: NNc1ccc(Cl)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)c1nnc2ccc(Cl)nn12

Procedure:
A mixture of 3-chloro-6-hydrazinopyridazine (1.44 g, 9.96 mmol), (R)-2-hydroxypropanoic acid (0.90 g, 10 mmol, i.e. D-lactic acid) and p-TsOH.H2O (2.37 g, 12.4 mmol) in toluene was refluxed overnight. Some oil was formed at the bottom of the flask. LC-MS of this oil showed the desired product was formed. Toluene was poured off, and the oil residue was suspended in water (10 mL), then basified with 3 N aq. NaOH to pH=10. This aqueous solution was extracted with EtOAc (3×30 mL), and the combined organic phases were washed with brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation under reduced pressure afforded the title compound as an off-white solid. MS (ES+): 199/201 (3/1) [MH+]. 1H NMR (400 MHz, CDCl3): δ=1.88 (d, J=6.8 Hz, 3H), 2.97 (d, J=6.8 Hz, 1H, —OH), 5.51 (m, 1H), 7.15 (d, J=9.6 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH:19]=[CH:20][CH:21]=1>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([NH:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)CCc1cccc(F)c1
Reactant: COC(=O)/C=C(/C)N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)/C=C(/C)NC(=O)CCc1cccc(F)c1
Yield: 50.9 %

Procedure:
To a solution of (Z)-methyl 3-aminobut-2-enoate (1.70 g, 14.8 mmol) and pyridine (1.30 g, 16.4 mmol) in DCM (25 mL) was added a solution of 3-(3-fluorophenyl)propanoyl chloride (2.77 g, 14.8 mmol) in DCM (5 mL) dropwise with stirring. At the end of addition, the mixture was stirred further at rt for 1 h. It was then washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a white solid (2.00 g, 51%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)=O.[NH2:29][OH:30]>CO.O>[OH:30][N:29]=[CH:1][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1
Reactant: NO
Reactant: Cc1c(C=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Solvent: O
Solvent: CO
Product: Cc1c(C=NO)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a slurry of 6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 8) (37 mg, 0.1 mmol) in MeOH (1 ml) was added H2NOH (50% wt. in H2O, 14 μl 0.2 mmol) at rt. The heterogeneous mixture was stirred overnight, then diluted with H2O (5 ml) and filtered, the solid was dissolved in MeOH, which was concentrated to give title compound (30 mg, 78%) as a yellow powder. It has a retention time of 6.18 min (standard LCl method, 8 min run). MS Found: (M+H)+=384.2
Reaction SMILES: [CH2:1]([C:3]([CH3:5])=[O:4])[CH3:2].[OH:6][CH2:7][CH:8]([CH2:10]O)[OH:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC>[CH3:5][C:3]1([CH2:1][CH3:2])[O:9][CH:8]([CH2:7][OH:6])[CH2:10][O:4]1
Reactant: CCC(C)=O
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: CCC1(C)OCC(CO)O1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
In a reaction vessel having a capacity of 3 L and equipped with a thermometer, a reflux condenser, a Dean-Stark trap, a calcium chloride tube and a stirrer, methyl ethyl ketone (400 g, 5,547 mol), glycerin (561.91 g, 6.102 mol), paratoluene-sulfonic acid monohydrate (21.10 g, 0.1109 mol) and hexane (400 mL) were charged. The contents were heated under stirring and a reaction was conducted at 67 to 74° C. for 30 hours to distill off a calculated amount of water. After completion of the reaction, the reaction mixture was cooled to 60° C., followed by the addition of sodium carbonate (23.51 g, 0.2218 mol) for neutralization. After the resulting mixture was stirred at 60° C. for 30 minutes, the temperature was gradually raised up to 120° C. to recover hexane (400 mL). Filtration was then conducted to obtain the titled product in a crude form (894.74 g). Using a Biglew tube (20 cm×1.5 cm in diameter), distillation was conducted under reduced pressure to obtain the titled compound (725.14 g, yield: 89.4%). By a gas chromatographic analysis, the purity of the compound was found to be 99.1 wt. %. b.p. 101 to 104° C./17 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:12])[CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCC(=O)Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 70B (478 mg, 2.1 mmol) in 5 mL MeOH at 0° C., was added NaBH4 (110 mg, 2.98 mmol). The solution was stirred at rt for 30 min, then was diluted with EtOAc and washed with H2O and brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-30% EtOAc/hexanes) afforded 70C (460 mg, 96%). MS (ESI) m/z 221.2 (M-OH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5](I)=[C:4]([CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([B:18]([OH:21])[OH:19])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)cc(CC)c1I
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(Br)cc(CC)c1B(O)O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 4-bromo-2,6-diethyl-1-iodobenzene (10 g, 0.029 mol) in tetrahydrofuran (100 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 22.2 ml, 0.035 mol) dropwise maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then trimethyl borate (17.98 g, 0.17 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×300 ml) and the organic fractions are combined, washed with brine, dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2,6-diethylphenylboronic acid (5 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=O)=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:24][NH2:25]>>[F:1][C:2]1[CH:9]=[C:8]2[C:7]([C:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[N:24][NH:25]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NN
Reactant: N#Cc1cc(C(=O)c2ccc3ccccc3c2)c(F)cc1F
Solvent: O
Product: N#Cc1cc2c(-c3ccc4ccccc4c3)n[nH]c2cc1F

Procedure:
A total of 2.1 g of 2,4-difluoro-5-(naphthalene-2-carbonyl)-benzonitrile was allowed to react with hydrazine monohydrate by the procedure of Production Example II-10-c and thereby yielded 1.6 g of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[BH4-].[Na+].Cl>CO>[OH:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCCl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 50 mg of 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid in 3 mL of methanol was added 50 mg of NaBH4. The mixture was stirred for 30 minutes, acidified with 2N HCl, and the methanol was removed in vacuo. The concentrate was extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated to afford 4-(1-hydroxy-4-chlorobutyl)-α,α-dimethylphenylacetic acid.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:5].[OH-].[Na+].Cl>CO.C1COCC1>[CH3:29][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:8])([CH3:5])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1CCCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(NC(=O)c1ccc2ccccc2c1CCCCc1ccccc1)C(=O)O
Yield: 67.3 %

Procedure:
40 mg 2-methyl-2-{[1-(4-phenyl-butyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester were reacted with 150 μl of 2 M sodium hydroxide in 1 ml methanol and 1 ml THF for 1 h at 60° C. The reaction mixture was then acidified with 2 M hydrochloric acid and the precipitated product was collected by filtration and dried in vacuo to yield 26 mg of 2-methyl-2-{[1-(4-phenyl-butyl)-naphthalene-2-carbonyl]-amino}-propionic acid.