Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][CH:8]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH2:22][CH3:23])[CH:15]=[CH:14][CH:13]=1)[C:9]#[N:10].O.[OH-].[Na+]>C1COCC1>[CH2:22]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[C:12]([CH2:11][CH:8]([NH2:7])[CH2:9][NH2:10])=[CH:13][CH:14]=[CH:15]2)[CH3:23]
Reactant: CCc1cccc2cccc(CC(N)C#N)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc2cccc(CC(N)CN)c12
Temperature: 0 °C
Reaction time: 5 h
Yield: 28.2 %

Procedure:
A suspension of LiAlH4 (117 mg) in THF (2 ml) was cooled to 0° C. and treated under an argon atmosphere with a solution of (RS)-2-amino-3-(8-ethyl-naphthalen-1-yl)-propionitrile (230 mg) in THF (4 ml). The reaction mixture was stirred for 5 hrs at r.t., then treated sequentially at 0° C. with 0.1 ml H2O, 0.1 ml 4N NaOH and 0.5 ml H2O. After stirring for 30 min, the solid was filtered off and washed with THF. The filtrate was concentrated. The crude product was isolated by column chromatography (silica gel; eluent: CH2Cl2→CH2Cl2/MeOH 9:1) to give 3-(8-ethyl-naphthalen-1-yl)-propane-1,2-diamine (66 mg) as light brown oil. MS (ISP): 229.3 ((M+H)+).
Reaction SMILES: Cl[CH:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH:7]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]3[CH2:5][C:4]=2[NH:3]1.[C:17]1([CH:23]([NH2:25])[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:17]1([CH:23]([NH:25][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH:7]4[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]4[CH2:5][C:4]=3[N:3]=2)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(N)c1ccccc1
Reactant: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(Nc1ccc2c(n1)CC1CCCCC1C2=O)c1ccccc1
Yield: 23.9 %

Procedure:
To a solution of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H-benzo[g]quinolin-5-one (0.4 g, 1.7 mmol) and 1-phenyl-ethylamine (0.266 g, 2.2 mmol) in toluene (2 ml) under an argon atmosphere was added sodium tert-amylate (0.223 g, 2.03 mmol) and bis(tri-tert-butylphosphine)palladium (0.043 g, 0.084 mmol). The mixture was heated at reflux for 8 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.13 g, 24%) as a colorless solid.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([NH:54][NH2:55])=[CH:50][CH:49]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:51]3[CH:52]=[N:53][C:48]([CH3:47])=[CH:49][CH:50]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Reactant: Cc1ccc(NN)cn1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: Cc1ccc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)cn1

Procedure:
656 g (1.35 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 359 mg (2.02 mmol) of 6-methylpyridin-3-yl-hydrazine hydrochloride. After hydrolysis, 53 mg (9% of theory) of the title compound is obtained.
Reaction SMILES: ClC1C=C2C(C3N=C(N[C@H]4CCC[C@@H](N)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=[N:6]C=1.C(OC([N:43]1[CH2:48][CH2:47][O:46][CH:45]([C:49]([OH:51])=O)[CH2:44]1)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[OH-].[Li+]>C(Cl)Cl>[NH:43]1[CH2:48][CH2:47][O:46][CH:45]([C:49]([NH2:6])=[O:51])[CH2:44]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(Cl)cnc32)cc1
Agent: On1nnc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)C1CNCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)—N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine (0.06 g, 0.12 mmol) in CH2Cl2 (3 mL) was added 4-tert-butoxycarbonylmorpholine-2-carboxylic acid (40.4 mg, 0.17 mmol), EDC (0.03 g, 0.14 mmol), HOBt (0.02 g, 0.12 mmol) and iPr2NEt (0.06 g, 0.47 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) and allowed to stir at room temperature for 2 hours. The resulting solution was concentrated in vacuo, dissolved in THF (4 mL) and treated with 1N aqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture was heated in the microwave to 130° C. for 20 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% MeOH/H2O with 6 mM HCl over 15 minutes. The purified fractions were concentrated to provide the bis-hydrochloride of N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2, 3-1)]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]morpholine-2-carboxamide.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][Si](C)(C)C)=[N:30][CH:31]=2)=[CH:22][CH:21]=1.O>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C[Si](C)(C)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reaction time: 3 h

Procedure:
Under an argon atmosphere 6.6 g (21.0 mmol) TBAF are added to a solution of 5.8 g (20.3 mmol) 5-(4-chloro-phenyl)-2-trimethylsilanylethynyl-pyridine in 200 mL DCM at 0° C. The reaction solution is stirred for 3 h, while the reaction temperature slowly rises to RT. It is added to 50 mL water and the organic phase is extracted four times with 50 mL water, dried over MgSO4 and filtered over activated charcoal. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (PE/EtOAc 1:1).
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.CCC([O-])(C)C.[Na+].C1(C)C=CC=CC=1>CS(C)=O>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 75.8 %

Procedure:
18.2 g (0.05 mole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone, 33.0 g (0.30 mole) of sodium tert-pentoxide and 100 ml of toluene were subjected to the treatments described sub letter (a). After addition of 15 ml of DMSO, heating at 110° for 4 hours and final treatments as indicated hereinabove, there were isolated 7.75 g (76% yield) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:23]=1[NH2:24]>>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([NH:24][C:23]3[C:25]([O:31][CH3:32])=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:22]=3[O:21][CH3:20])=[O:12])[C:4]=2[CH:3]=1
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: COc1cc(OC)c(NC(=O)C2c3ccccc3COc3ccc(C)cc32)c(OC)c1
Yield: 40.8 %

Procedure:
The similar procedures as in Example 1 were repeated except using 2.32 g of Compound A and 1.85 g of 2,4,6-trimethoxyaniline in place of aniline to obtain 1.56 g of Compound 10 as amorphous.
Reaction SMILES: [NH2:1][C@@H:2]1[C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][N:18]=2)[C:14]2[CH:13]=[CH:12][C:11]([NH:21][C:22](=[O:25])[O:23][CH3:24])=[CH:10][C:9]=2[NH:8][C:7](=[O:26])[C@H:6]([CH3:27])[CH2:5][CH2:4][CH2:3]1.C(C1C=CC(C2O[N:37]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=CC=1)#N>ClCCl>[C:42]([O:41][C:39]([NH:37][NH:1][C@@H:2]1[C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][N:18]=2)[C:14]2[CH:13]=[CH:12][C:11]([NH:21][C:22](=[O:25])[O:23][CH3:24])=[CH:10][C:9]=2[NH:8][C:7](=[O:26])[C@H:6]([CH3:27])[CH2:5][CH2:4][CH2:3]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](N)c1cc-2ccn1
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](NNC(=O)OC(C)(C)C)c1cc-2ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A modified procedure described by Vidal (Chem. Eur. J., 1997, 3(10), 1691) was used. To a cooled (0° C.) pink suspension of 11A (0.060 g, 0.163 mmol) in dichloromethane (1.30 mL) was added dropwise a clear, colorless solution of tert-butyl 3-(4-cyanophenyl)-1,2-oxaziridine-2-carboxylate (0.050 g, 0.204 mmol) in dichloromethane (0.651 ml). The resulting suspension was allowed to warm to rt and stir overnight. After 24 h, the majority of the solid went into solution and the solution had become a yellow color. The reaction was concentrated. Purification by normal phase chromatography gave 11B (0.033 g, 42%) as a pale yellow solid. MS (ESI) m/z: 484.2 (M+H)+. 1H NMR (500 MHz, CD3OD) δ 8.58 (d, J=5.0 Hz, 1H), 7.57 (s, 1H), 7.51-7.46 (m, 3H), 7.35 (dd, J=5.0, 1.7 Hz, 1H), 4.29 (dd, J=8.5, 5.2 Hz, 1H), 3.78 (s, 3H), 2.57-2.48 (m, 1H), 1.92-1.80 (m, 1H), 1.73-1.59 (m, 3H), 1.41 (s, 9H), 1.23-1.11 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.79-0.65 (m, 1H).
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([C:9](=[O:11])[CH3:10])=[CH:7][N:8]=1.[CH2:12](O)[CH2:13][OH:14].COC(OC)OC>C([O-])(O)=O.[Na+]>[Br:3][C:4]1[S:5][C:6]([C:9]2([CH3:10])[O:14][CH2:13][CH2:12][O:11]2)=[CH:7][N:8]=1
Reactant: CC(=O)c1cnc(Br)s1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cnc(Br)s2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-(2-bromo-thiazol-5-yl)-ethanone (2.20 g, 10.68 mmol) in ethylene glycol (11.46 mL, 205.53 mmol) was treated with trimethylorthoformate (2.39 mL, 21.76 mmol) followed by LiBF4 (204 mg, 2.14 mmol). The reaction mixture was heated at 95° C. for 2 days. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (3:1 hept-EA)=0.80. LC-MS-conditions 01: tR=0.84 min, [M+H]+=251.85.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=1[CH:9]=O)C>C(O)(=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:7]2[O:6][C:5]([CH:4]=[O:3])=[CH:9][C:8]=2[CH:11]=1
Reactant: CCOC(COc1ccc(F)cc1C=O)OCC
Solvent: CC(=O)O
Product: O=Cc1cc2cc(F)ccc2o1
Yield: 27.4 %

Procedure:
A stirred solution of 12 (300 mg, 4.0 mmol) in acetic acid (10 mL) was refluxed for 24 h. After cooling, the solution was evaporated to dryness. The crude product was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give the 13 (180 mg, 94%) as a white solid, 1H NMR (500 MHz, CDCl3): δ: 9.89 (1H, s, CHO), 7.57 (2H, m, ArH), 7.41 (1H, d, J=7.20 Hz), 7.26 (1H, d, J=6.94 Hz, H-4). 13C NMR CDEPT 135, (500 MHz, CDCl3): δ: 179.74 (CHO), 117.73 (C-3), 117.25 (C-7), 113.81 (C-6), 108.68 (C-4).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[C:3]=1[CH3:20].[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[NH:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[N:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[C:3]=2[CH3:20])[CH2:23]1
Reactant: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Br
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidin-2-one (55.0 mg, 0.160 mmol) and 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine in toluene to give 1-(4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-quinolinyl)-2-pyrrolidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.67 (1H, d, J=2.3 Hz), 7.54 (1H, ddd, J=9.2, 2.4, 1.3 Hz), 7.05 (1H, ddd, J=12.3, 8.6, 2.5 Hz), 6.14 (1H, d, J=2.2 Hz), 4.26-4.41 (1H, m), 4.07-4.12 (1H, m), 4.04 (1H, d, J=9.2 Hz), 3.69-3.83 (5H, m), 3.12-3.18 (4H, m), 2.63-2.71 (2H, m), 2.27-2.40 (2H, m), 2.18 (3H, s), 1.70 (3H, s), 1.67 (3H, s). Mass Spectrum (ESI) m/e=494.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:23]([F:25])[F:24]>CN(C)C=O>[F:24][CH:23]([F:25])[O:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: FC(F)Cl
Reactant: COC(=O)c1ccc(O)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(F)F)c2ncccc12

Procedure:
1.0 g (5.0 mmol) of methyl 8-hydroxy-5-quinolinecarboxylate was dissolved in 20 ml of dimethylformamide, 0.76 g (5.5 mmol) of potassium carbonate was added and 14 g of chlorodifluoromethane were introduced at 40° C. over a period of 2 hours. Solid components were then filtered off, the solvent was removed and the residue was washed with water and dried. This gave 0.75 g of a brown powder;
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.Cl.[NH2:12][OH:13].O.[OH-].[NH4+]>C(O)C>[CH3:1][C:2]([NH:12][OH:13])=[C:4]1[CH:5]=[CH:6][C:7](=[O:10])[CH:8]=[CH:9]1
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(NO)=C1C=CC(=O)C=C1
Yield: 99.9 %

Procedure:
A solution was prepared by adding 13.6 g (0.1 mol) of 4-hydroxyacetophenone, 7.6 g (0.11 mol) of hydroxylamine hydrochloride, and 10 g of water to 40 mL of ethanol. To the solution was added 5.0 g of 30% ammonium hydroxide which was then heated at reflux for 2 h. The ethanol was removed on a rotary evaporator to yield a yellow oil. An extractive work-up afforded 15.1 g (99%) of 4-hydroxyacetophenone oxime.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:13]([CH:18]=2)[C:14]([O:16]C)=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>>[N:1]1([CH2:6][CH:7]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:13]([CH:18]=2)[C:14]([OH:16])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1cc(OC(Cn2ccnc2)c2nccs2)ccc1CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(OC(Cn2ccnc2)c2nccs2)ccc1CCc1ccc(F)cc1

Procedure:
Methyl 5-[2-(imidazol-1-yl)-1-(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoate was hydrolysed using aqueous sodium hydroxide solution to give 5-[2-(imidazol-1-yl)-1-(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoic acid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:8][C:9](OCC)=O)(=[O:7])[CH:4]([CH3:6])[CH3:5].Br[CH2:15][C:16](C)=[CH:17][CH2:18][CH2:19][C:20]([CH3:27])=[CH:21][CH2:22][O:23]C(=O)C>CCOCC>[CH3:27][C:20]([CH2:19][CH2:18][CH:17]=[C:16]([CH3:15])[CH2:9][CH2:8][C:3](=[O:7])[CH:4]([CH3:5])[CH3:6])=[CH:21][CH2:22][OH:23]
Reactant: CC(=O)OCC=C(C)CCC=C(C)CBr
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=CCO)CCC=C(C)CCC(=O)C(C)C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a suspension of sodium hydride (1.9 g) in ether (40 ml) while cooling with ice, ethyl isobutyroylacetate (5.2 g) is added, and 1-bromo-8-acetoxy-2,6-dimethyl-2,6-octadiene (8 g) is dropwise added thereto. The reaction is carried out with reflux for 8 hours. The ether layer is separated from the reaction mixture, washed with water, dried and evaporated. The oily product (9.9 g) is added to a solution of potassium hydroxide (6.3 g) ethanol (120 g), and refluxing is continued for about 1 hour. The resultant mixture is added to the ice water, made acidic with 10% sulfuric acid and extracted with ether. The ether extract is washed with saturated aqueous solution of sodium chloride, aqueous solution of sodium hydrogen carbonate and water in order, and then the ether is evaporated therefrom. The residue (7.2 g) is dissolved in benzene and purified by chromatography on silica gel to give 3,7,11,-trimethyl-2,6-dodecadien-10-on-1-ol (6.2 g). NMR (carbon tetrachloride): δ 1.05 (d), 1.59 (s), 2.0 (s), 21.-2.7 (m), 3.52 (s), 3.95 (d), 4.8-5.4 (m).
Reaction SMILES: C(N1CC[N:7]([CH2:10][CH2:11][CH2:12]N)CC1)(C)C.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH:23]([CH:27]([CH3:29])[CH3:28])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:12][CH2:11][CH2:10][NH2:7])[CH:23]([CH:27]([CH3:29])[CH3:28])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC(C)N1CCN(CCCN)CC1
Product: CC(C)C1CN(C(=O)OC(C)(C)C)CCN1CCCN

Procedure:
Using the method of 3-(4-isopropylpiperazin-1-yl)-propylamine, the title compound is synthesized from racemic 3-isopropyl-piperazine-1-carboxylic acid tert-butyl ester and isolated as a tan oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O.O>C(Cl)(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NC(C)(C)c1ccc(CO)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide (18.24 g) in chloroform (180 ml) was added dropwise thionyl chloride (7.07 ml) over 10 min under ice-cooling and the mixture was stirred at room temperature for 20 hr. The reaction mixture was poured into water (1000 ml) and the organic layer was separated. The organic layer was washed with aqueous sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (19.17 g) as pale-yellow crystals, m.p.=124-125° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]3[C:13]([CH:19]=[O:20])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=3)[C:5]=12.Cl[C:22]([F:27])([F:26])C([O-])=O.[Na+]>CC#N>[F:26][CH:22]([F:27])[O:18][C:15]1[CH:14]=[C:13]([C:12]([O:11][CH2:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][N:16]=1)[CH:19]=[O:20]
Reactant: O=Cc1cc(=O)[nH]cc1OCc1cccn2ccnc12
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1cc(OC(F)F)ncc1OCc1cccn2ccnc12
Temperature: 25 °C
Yield: 5.1 %

Procedure:
To 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (100 mg, 0.37 mmol, 1 equiv) in CH3CN (10 mL) was added sodium 2-chloro-2,2-difluoroacetate (84.5 mg, 0.56 mmol, 1.5 eq.). The mixture was stirred at rt O/N and concentrated. The crude was purified on silica gel using 10% MeOH/DCM as eluent to give 2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde (6.0 mg, 5%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.14 (s, 1H), 8.10 (d, J=7.0 Hz, 1H), 7.61 (s, 2H), 7.44 (t, J=60.0 Hz, 1H), 7.24-7.27 (m, 2H), 6.79 (t, J=7.0 Hz, 1H), 5.63 (s, 2H). LRMS (M+H+) m/z 320.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[S:35][CH:34]=[C:33]([CH2:36]O)[CH:32]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.C(N(S(F)(F)[F:44])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:44][CH2:36][C:33]1[CH:32]=[C:31]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][N:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)=[N:22][N:23]=2)[S:35][CH:34]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(-c5cc(CO)cs5)c5ccccc45)cc3)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5cc(CF)cs5)c5ccccc45)cc3)ccnc2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with (5-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)thiophen-3-yl)methanol (71 mg, 140 μmol) and 2.8 mL DCM, and the mixture was cooled to 0° C. under nitrogen. (Diethylamino) trifluorosulfur (55 μl, 420 μmol) was added, and the mixture was stirred at 0° C. for 20 min and was then allowed to warm to RT. After another 0.5 h, saturated NaHCO3 was added and the mixture was stirred for 10 min. The solids were filtered, and the crude material was purified by silica gel chromatography, 90/10/1 DCM/MeOH/NH4OH in DCM, followed by reverse phase chromatography, Gilson, 10-90% 0.1% TFA/ACN in water, to provide the titled compound. MS: [M+H]=510.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].[N:11]1[C:18]([Cl:19])=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13]>C1COCC1>[Cl:13][C:12]1[N:11]=[C:18]([Cl:19])[N:17]=[C:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=2)[N:14]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2nc(Cl)nc(Cl)n2)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A solution formed by dissolving 4-bromostyrene (18.3 g, 0.1 mol) and magnesium (2.64 g, 0.11 mol) into THF (200 mL) was stirred at 30° C. for two hours, and then, refluxed for two hours. This solution was added to a solution of cyanuric chloride (21.58 g, 0.120 mol) into THF (200 mL) at −20° C., and the mixture was stirred at −20° C. for five hours. The solvent was distilled off under a reduced pressure, the remaining solid was dissolved into dichloromethane and washed with water twice. The organic layer was dried over anhydride MgSO4, and the solvent was distilled off.
Reaction SMILES: [CH2:1]([C:4]1[CH:24]=[C:23]([S:25]([NH:28][CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:8]([O:10]C)=[O:9])[CH2:2][CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.CO.[NH4+].[OH-].Cl>CO.C1COCC1.ClCCl>[CH2:1]([C:4]1[CH:24]=[C:23]([S:25]([NH:28][CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:8]([OH:10])=[O:9])[CH2:2][CH3:3]
Reactant: CCCc1cc(S(=O)(=O)NC)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCc1cc(S(=O)(=O)NC)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
To a solution of 0.372 g (0.884 mmol) of the product of Step D dissolved in 3.0 mL of methanol was added 212 μL (1.06 mmol) of a 5.0N aqueous sodium hydroxide solution which resulted in a cloudy suspension. The reaction was warmed to assist solution, methanol (1 mL) was added followed by dichloromethane (0.5 mL), however a clear solution was not obtained. Additional 5N sodium hydroxide solution was added (212 μL), and finally 0.5 mL of THF was added which resulted in a clear solution. After stirring an additional 15 hours at room temperature, TLC analysis (CHCl3 -MeOH-NH4OH 80:15:1) indicated complete hydrolysis of the starting material and the reaction was adjusted to pH=7 with 6N HCl. The reaction mixture was then concentrated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with CHCl3 -MeOH-HOAc (92:7:1). Combination of the purified fractions and drying in vacuo afforded 0.335 g (93%) of the title compound as an amorphous solid.