Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:32][C:33]3([CH3:37])[CH2:36][O:35][CH2:34]3)[C:17]([NH:19][C:20]3[CH:31]=[CH:30][C:23]([C:24]([O:26]CC=C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.CNC1C=CC=CC=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:32][C:33]3([CH3:37])[CH2:34][O:35][CH2:36]3)[C:17]([NH:19][C:20]3[CH:31]=[CH:30][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: C=CCOC(=O)c1ccc(NC(=O)C(CC2(C)COC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CNc1ccccc1
Solvent: C1CCOC1
Product: COc1cn(C(CC2(C)COC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
25 mg (44 μmol) of allyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoyl}amino)benzoate (racemate) and 48.2 μl (445 μmol) of N-methylaniline were initially charged in 1 ml of tetrahydrofuran, and the resulting solution was degassed. 5 mg (4 μmol) of tetrakis(triphenylphosphine)palladium(0) were then added, and the mixture was stirred at room temperature for another 30 min. The reaction solution was purified directly by preparative HPLC (neutral) and the title compound was obtained after final preparative thin-layer chromatography (ethyl acetate/cyclohexane=1:1). Yield: 10.1 mg (purity 92%, 42% of theory)
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([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.CCOC(C)=O>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:11]=[CH:10][C:9]4[C:8](=[O:12])[CH:7]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]5[CH2:5][C:4]=4[N:3]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2ccc(N3CCN(c4ccccc4)CC3)nc2CC2CCCCC12
Yield: 247.4 %

Procedure:
A mixture of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H-benzo[g]quinolin-5-one (0.29 g, 0.123 mmol) and 1-phenylpiperazine (2.0 g, 12.3 mmol) was stirred at 100° C. for 1 h (TLC control; hexane-EtOAc, 2:1). Then the mixture was separated by column chromatography on silica gel to give the title compound (0.11 g, 25%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]=[N+:12]=[N-:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
A solution of 4-methoxybenzyl chloride 1000 (51.8 g, 331.0 mmol) in anhydrous DMF (200 mL) was treated with solid sodium azide (21.5 g, 331.0 mmol, 1.0 equiv) at 25° C., and the resulting mixture was stirred at 25° C. for 24 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (400 mL) and ethyl acetate (EtOAc, 400 mL) at room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic extracts were washed with H2O (2×200 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The crude 4-methoxybenzyl azide (51.2 g, 53.95 g theoretical, 94.9% yield) was obtained as colorless oil, which by HPLC and 1H NMR was found to be essentially pure and was directly used in the subsequent reaction without further purifications. For 4-methoxybenzyl azide 1001: 1H NMR (300 MHz, CDCl3) δ 3.84 (s, 3H, ArOCH3), 4.29 (s, 2H, Ar—CH2), 6.96 (d, 2H, J=8.7 Hz), 7.28 (d, 2H, J=7.8 Hz).
Reaction SMILES: [CH:1](=[N:10][NH2:11])[C@H:2]([C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].[H][H]>C(O)C.O.[Pt]=O>[NH:10]([CH2:1][C@H:2]([C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3])[NH2:11]
Reactant: [H][H]
Reactant: NN=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=[Pt]
Solvent: O
Solvent: CCO
Product: NNC[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A 1.5 portion of D-arabinose hydrazone in 40 ml of ethanol and 20 ml of water was reduced with 200 mg of platinum oxide and hydrogen for 4 hours. The mixture was then filtered and the filtrate evaporated to dryness. The residue was dissolved in 40 ml of methanol and then evaporated to dryness, giving 1.24 g of 1-deoxy-1-hydrazino-D-arabinitol.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[N:10]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccc(C(F)(F)F)nc1Cl

Procedure:
To a stirred solution of e 2-chloro-6-(trifluoromethyl)nicotinic acid (Int-15) (40 g, 1.0 eq.) in THF (400 mL) was added BH3-THF (266.6 mL, 1.5 eq) at room temperature. The progress of the reaction was monitored by TLC. After 16 h the reaction mixture was concentrated under reduced pressure to remove THF. The resulting reaction mixture was diluted with 10% NaHCO3 (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with water (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to get crude [2-chloro-6-(trifluoromethyl)pyridin-3-yl]methanol (Int-16) as light yellow liquid, 32 g (85.5%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([Cl:33])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:33])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 50 °C
Reaction time: 14 h
Yield: 65.3 %

Procedure:
To methyl 4-[(2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]-2-chlorobenzoate (0.465 mmol, 224.8 mg), methanol (20 mL) was added, and 1 M aqueous sodium hydroxide (2.3 mmol, 2.3 mL) was added. After 5 hours of stirring at 50° C., 14 hours of stirring at room temperature and 4 hours of stirring at 50° C., 1 M hydrochloric acid (2.3 mmol, 2.3 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the crude desired product as a yellow solid (193.3 mg). Further, 169 mg of the crude desired product was dissolved in THF (35 mL) and stirred at room temperature for 2 days. The insolubles were filtered off, and the filtrate was concentrated and dried by means of a vacuum pump. After addition of chloroform, the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (142.3 mg, yield 75%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:33][CH2:32]1>>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:33][CH2:32]3)=[CH:18][C:10]1=2
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: C1CC(N2CCOCC2)CCN1
Product: CC1(C)c2cc(N3CCC(N4CCOCC4)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 4-piperidin-4-yl morpholine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=1
Reactant: C1CCNC1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Yield: 20.6 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (Example 38a) (0.222 mmol) in DMF (4 mL) was reacted with K2CO3 (61 mg, 0.444 mmol) and pyrrolidine (92 uL, 1.11 mmol) to afford the title compound (23.5 mg, 21% for 2 steps).
Reaction SMILES: [OH:1][C:2]1([CH3:18])[CH:8](Br)[CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:6][C:4](=[O:5])[CH2:3]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([CH3:18])[CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(CCc2ccccc2)C1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(CCc2ccccc2)C1
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of 200 mg of 3-hydroxy-3-methyl-4-bromo-7-phenyl-5-heptanolide in 2 ml of anhydrous tetrahydrofuran was added 500 mg of tri-n-butyltin hydride and the mixture was allowed to stand overnight at room temperature. After completion of the reaction, tetrahydrofuran was evaporated and n-hexane was added to the residue to precipitate an oily substance, which was purified by a thin layer chromatography (silica gel) affording 82 mg of the desired compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([NH:23][C@H:24]([C:31]([OH:33])=O)[CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>C(OCC)(=O)C.C(O)(=O)C>[C:34]([O:38][C:39](=[O:42])[CH2:40][NH:41][C:31](=[O:33])[C@H:24]([CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)[NH:23][C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CC(C)(C)OC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CNC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.2 %

Procedure:
Dicyclohexyl carbodiimide (226 mg) was added to a solution of 273 mg of Nα -t-butoxycarbonyl-β-(4-thiazolyl)-L-alanine and 132 mg of glycine t-butylester in 5 ml of ethyl acetate at 0° C. The reaction solution was stirred at 0° C. for 0.5 hour, then at ambient temperature for 18 hours. 4 drops of glacial acetic acid was then added to the reaction mixture and the mixture filtered. The filtrate was concentrated under vacuum to provide 426 mg of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=1[O:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=4[O:30][CH3:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCN1CCC(c2noc3cc(Cl)ccc23)CC1
Yield: 98.2 %

Procedure:
A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2 benzisoxazole (4.6 g, 19 mmol), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (4.3 g, 19 mmol), K2CO3 (2.8 g), a few crystals of KI and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to yield 8.0 g of yellow solid. The solid was chromatographed on a Waters Prep 500 LC (silica columns, eluting with methylene chloride/methanol, 5%). Concentration of the appropriate fractions yielded 3.2 g of a light yellow solid, which upon recrystallization from ethyl acetate afforded 2.3 g (28%) of 1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxyl-3-methoxyphenyl]ethanone as a pale yellow solid, m.p.=133-135° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[C:14]([OH:16])=[O:15])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(F)ccc1C=O
Solvent: c1ccncc1
Product: COc1cc(F)ccc1/C=C/C(=O)O
Yield: 95.8 %

Procedure:
A solution of 4-fluoro-2-methoxybenzaldehyde (1.0 g, 6.49 mmol) and malonic acid (1.350 g, 12.98 mmol) in pyridine (10 mL) was refluxed for 16 h. After concentration the residue was taken into water. The solid was filtered, washed with water, then dried to give (E)-3-(4-fluoro-2-methoxyphenyl)acrylic acid (1.22 g, 96% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.03 (d, J=16.1 Hz, 1H), 7.53 (dd, J=8.5, 6.8 Hz, 1H), 6.75-6.65 (m, 2H), 6.52 (d, J=16.1 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:15]=[CH:14][N:13]=1.[CH3:24][C:25]1[N:26]([C:30]2[CH:31]=[C:32]([NH2:40])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[CH:27]=[CH:28][N:29]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:40][C:32]2[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:30]([N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[CH3:24])[CH:31]=2)=[O:8])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:15]=[CH:14][N:13]=1
Reactant: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Reactant: Cc1cn(-c2ccnc(Nc3cc(C(=O)O)ccc3C)n2)cn1
Product: Cc1cn(-c2ccnc(Nc3cc(C(=O)Nc4cc(-n5ccnc5C)cc(C(F)(F)F)c4)ccc3C)n2)cn1

Procedure:
4-methyl-3-[4-(4-methylimidazol-1-yl)pyrimidin-2-yl-amino]benzoic acid and 3-(2-methylimidazol-1-yl)-5-trifluoromethyl-phenylamine prepared in Preparation 31 were used according to the similar procedure to Example 1 to give the titled compound as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
3-Bromo-4-chlorobenzoic acid (1.0 g, 4.24 mmol, 1.0 eq) was dissolved in dry DMF and stirred for 10 minutes. The solution was cooled to 0° C. and treated with N,O-dimethyl hydroxylamine hydrochloride (0.828 mg, 8.48 mmol, 2.0 eq), 1-hydroxybenzotrizole (860 mg, 6.36 mmol, 1.5 eq), N,N-diisopropyl ethylamine (820 mg, 6.37 mmol, 1.5 eq), and EDC HCl (1.2 g, 6.37 mmol, 1.5 eq). The reaction mixture was stirred for 12 h, evaporated under reduced pressure and diluted with water (25 mL). The aqueous layer was extracted with ethyl acetate. The organic layer was dried under anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane to afford the desired product (1 g, 85%). 1H NMR (400 MHz, CD3OD) δ 3.34 (s, 3H), 3.57 (s, 3H), 7.47-7.49 (d, 1H), 7.71-7.74 (d, 1H), 7.85-7.88 (d, 1H). MS (ESI): 278.2 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH2:12][Br:13])=[CH:10][C:5]=2[S:4][C:3]1=[O:15].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][Br:13])=[CH:10][C:5]=2[S:4][C:3]1=[O:15]
Reactant: Cn1c(=O)sc2cc(C(=O)CBr)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)sc2cc(CCBr)ccc21
Temperature: 25 °C

Procedure:
0.15 tool of 3-methyl-6-bromoacetylbenzothiazolin-2-one (42.9 g) is dissolved in 1 mol of trifluoroacetic acid (77 cm3) in a 250 cm3 groundneck flask. 0.33 mol of triethylsilane (52.70 cm3) is introduced dropwise using a dropping funnel, with magnetic stirring. A calcium chloride drying tube is fitted and stirring is maintained for the required time at room temperature. The reaction mixture is poured into 500 cm3 of ice-cold water. The precipitate obtained is filtered off, washed with water until the wash liquors are neutral, dried and then recrystallized.
Reaction SMILES: I[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1.[CH3:22][NH:23][CH3:24]>[Cu]Br>[CH3:22][N:23]([CH3:24])[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(I)nn1
Reactant: CNC
Agent: [Cu]Br
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N(C)C)nn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8 %

Procedure:
3-Iodo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine (500 mg, 1.3 mmol) was dissolved in an ethanolic solution of dimethylamine (7.5 mL of a 33% solution, excess). After addition of copper(I) bromide (219 mg, 1.5 mmol) the mixture was stirred for 72 h at room temperature followed by heating to 50° C. for 3 h. Then the solvent was evaporated and the residue was stirred with ethyl acetate and saturated aqueous Seignette salt solution. The organic phase was dried with sodium sulfate and evaporated. Chromatography (SiO2, heptane/ethyl acetate=100:0 to 10:90) afforded the title compound as a light yellow oil (30 mg, 8%). MS: m/e=311.1 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]1([CH:27]=O)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][N:23]([CH2:27][CH:24]2[CH2:26][CH2:25]2)[CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:26][CH2:25]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: O=CC1CC1
Product: c1cc(C2(CN(CC3CC3)CC3CC3)CCOCC2)ccc1OCCCN1CCCC1
Yield: 51 %

Procedure:
The title compound (169 mg, 51%) was prepared from {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine free base and cyclopropane carboxaldehyde similarly to the procedure used for example 54. 3 equivalents of cyclopropane carboxaldehyde were required for the synthesis of this Example. 1H NMR (400 MHz, CDCl3) δ −0.04 (q, 4H), 0.39 (q, 4H), 0.71-0.76 (m, 2H), 1.80-1.86 (m, 4H), 1.94-2.12 (m, 6H), 2.16 (d, 4H), 2.55-2.72 (m, 8H), 3.51 (t, 2H), 3.75-3.79 (m, 2H), 4.04 (t, 2H), 6.88 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 427.3306 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])C=O.[OH:12][CH:13](C1C=CC(OC(F)(F)F)=C(C=1)C#N)[CH3:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:7]([CH:13]([OH:12])[CH3:14])=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC(O)c1ccc(OC(F)(F)F)c(C#N)c1
Reactant: COc1ccc(C=O)cc1Br
Product: COc1cc(C(C)O)ccc1Br

Procedure:
This compound was prepared from 3-bromo-4-methoxybenzaldehyde in the same manner of Compound 21.
Reaction SMILES: [Cl:1][C:2]1[C:8](I)=[C:7]([Cl:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].CO[CH2:19][CH2:20]OC.O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[C:8]([CH:19]=[CH2:20])=[C:7]([Cl:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(Cl)c(I)c1Cl
Reactant: COCCOC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1c(Cl)ccc(N)c1Cl
Temperature: 80 °C

Procedure:
To a solution of 2,4-dichloro-3-iodoaniline (9.0 g, 31 mmol) in DME/water (180 mLU60 mL) is added vinyl triboroxine pyridine complex (5.0 g, 20.8 mmol) and K2CO3 (8.5 g, 62.0 mmol). The reaction mixture is stirred and N2 is bubbled in for 15 min. Tetrakis(triphenylphosphine) palladium(0) (1.8 g, 1.6 mmol) is added at room temperature and N2 is bubbled in for additional 20 min. The reaction mixture is heated to 80° C. and stirred for 18 hours, when the GC-MS showed the reaction is complete. The mixture is filtered and washed with ether (400 mL) and water (50 mL). The organic layer is separated and washed with brine and dried over MgSO4. The solvents were removed and the residue is purified through a flash chromatographic column with a gradient of hexanes/ether to give 2,4-dichloro-3-vinylaniline.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=34)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.Cl.Cl.[CH3:31][N:32]1[CH2:39][CH2:38][CH2:37][C:33]21[CH2:36][NH:35][CH2:34]2.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:28][O:27][C:4]1[CH:3]=[C:2]([N:35]2[CH2:36][C:33]3([N:32]([CH3:31])[CH2:39][CH2:38][CH2:37]3)[CH2:34]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=23)[CH:15]=[CH:14][N:13]=1
Reactant: CN1CCCC12CNC2
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 83.9 %

Procedure:
N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 300 mg, 0.78 mmol), 8-methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 118 mg, 0.94 mmol) and DIPEA (0.162 mL, 0.94 mmol) were heated at 100° C. in DMA (4 mL) for 1.75 h. The mixture was then absorbed onto an SCX column, then the column was washed with CH3OH and then eluted with 1:1 7M methanolic ammonia in CH2Cl2. Fractions that contained the desired product were combined and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (321 mg, 84%) as an orange foam; 1H NMR: 1.62-1.74 (2H, m), 1.74-1.85 (2H, m), 1.91-2.00 (2H, m), 2.00-2.06 (2H, m), 2.38 (3H, s), 2.65 (2H, t), 3.03 (2H, t), 3.71 (2H, d), 3.95 (3H, s), 4.04-4.15 (4H, m), 6.27 (1H, s), 7.01 (1H, d), 8.01 (1H, s), 8.09 (1H, s), 8.33 (1H, d), 8.54 (1H, s); m/z: ES′ MH+ 491.6.