Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[C:20]1([NH:30][CH2:31][CH2:32][NH2:33])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:33][CH2:32][CH2:31][NH:30][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNc1cccc2ccccc12
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCCNc2cccc3ccccc23)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(1-naphthyl)ethylendiamine dihydrochioride and DBU in DME. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][CH:11]([F:23])[O:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH:11]([F:10])[F:23])[CH:14]=2)(=[O:21])=[O:20])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a 100 mL round-bottomed flask was added 3-amino-5-bromo-2-chloropyridine (855 mg, 4122 μmol), pyridine (5 ml), 3-(difluoromethoxy)benzenesulfonyl chloride (1000 μl, 4122 μmol). The reaction mixture was stirred at room temperature for overnight (ca 16 h). The solvent was removed in vacuo and the residue was dissolved in EtOAc (50 mL), washed with water (10 mL), saturated NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give N-(5-bromo-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (566 mg, 33% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C12H8BrClF2N2O3S: 413.9. found 414.9. 1H NMR (300 MHz, chloroform-d) δ ppm 6.53 (t, J=72.27 Hz, 1H) 6.99 (s, 1H) 7.38 (dd, J=8.18, 1.75 Hz, 1H) 7.52 (t, J=8.04 Hz, 1H) 7.58 (s, 1H) 7.62-7.68 (m, J=1.17 Hz, 1H) 8.16 (d, J=2.34 Hz, 1H) 8.21 (d, J=2.19 Hz, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:31])[N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)N4CCCC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:25](O)[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2CN1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 18 h
Yield: 75.3 %

Procedure:
To 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-one (2.2 g, 5.6 mmol) was added a solution of trifluoroacetic acid (11.0 ml) in dichloromethane (30 ml) at room temperature, under nitrogen. Triethylsilane (1.5 ml) was then added and the reaction mixture was allowed to stir for 18 hours at which time it was poured into a NaHCO3 (sat.). The layers were separated and the aqueous phase was extracted with DCM (3×). The combined organics were washed with brine and dried (Na2SO4). Filtration and concentration gave the crude product as a solid which was recrystallized from EtOAc. to give 1.6 g (79%) of the desired product as a white solid, m.p.=166°-168° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=O)[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=2)=[CH:9][CH:8]=1.C(#[N:25])C>O>[NH2:25][C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=1
Reactant: CC#N
Reactant: O=C(O)c1cc(=O)[nH]c(-c2ccc(Cl)cc2)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1cc(C(=O)O)nc(-c2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To phosphorus oxychloride (180 mL) was added 2-(4-chlorophenyl)-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step A) (81.81 g, 326 mmol). The mixture was heated to 90° C. for 2.5 h. After cooling to room temperature the reaction mixture was slowly added to 1:2 acetonitrile:water (1.5 L) while keeping the temperature between 35 and 45° C. After the reaction mixture was stirred at room temperature for 30 minutes the resulting solid was isolated by filtration and washed with water. The solid was then combined with aqueous ammonia (5%, 2.1 L) and heated to 80° C. for 18 h. After 2 days at room temperature the solid was isolated by filtration and washed with water. A second crop was obtained by cooling the filtrate and refiltering. The combined solids were dried to afford the title compound (58.8 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C:9]#[C:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:25]([S:32][C:33](=[NH:35])[NH2:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:35]=[C:33]([S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:34]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(N)SCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC#CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(SCc2ccccc2)n1

Procedure:
To a solution of [4-oxo-4-(4-trifluoromethyl-phenyl)but-2-ynyl]-carbamic acid tert-butyl ester (3.0 g, 9.17 mmol) and 2-benzyl-2-thiopseudo-urea hydrochloride (2.1 g, 10.1 mmol) in freshly distilled CH3CN (100 mL) was added K2CO3 (1.9 g, 13.8 mmol) at rt. After 12 h the resulting mixture was partitioned between H2O (75 mL) and DCM (50 mL). The layers were separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting solid was used without purification. MS (ESI): mass calcd. for C24H24F3N3O2S, 475.2; m/z found, 476.3 [M+H]+. 1H NMR (CDCl3) δ 8.15 (d, J=8.14 Hz, 2H), 7.75 (d, J=8.28 Hz, 2H), 7.51-7.47 (m, 2H), 7.39-7.31 (m, 4H), 5.52 (s, 1H), 4.51 (s, 2H), 4.43 (d, J=5.48 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][Si:2]([CH3:60])([CH3:59])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][N:13]([CH2:45][C:46]1[N:47]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:48]=[CH:49][N:50]=1)[C:14]([C:16]1[CH:44]=[CH:43][C:19]([CH2:20][N:21]([CH2:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:40][CH2:41][CH3:42])[CH2:37][CH2:38][CH3:39])C(=O)OCC2C=CC=CC=2)=[CH:18][CH:17]=1)=[O:15]>[C].[Pd]>[CH2:40]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:35][CH2:34][CH2:33][CH2:32][NH:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:14]([N:13]([CH2:45][C:46]2[N:47]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:56])([CH3:58])[CH3:57])[CH:48]=[CH:49][N:50]=2)[CH2:12][C:8]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:59])[CH3:60])[CH:11]=[CH:10][N:9]=2)=[O:15])=[CH:44][CH:43]=1)[CH2:41][CH3:42]
Reactant: CCCN(CCC)CCCCN(Cc1ccc(C(=O)N(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Product: CCCN(CCC)CCCCNCc1ccc(C(=O)N(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)cc1

Procedure:
The same procedure as a series of reactions of Example 2 was carried out, except that the compound 8 was used in place of the compound 1 and 10% palladium carbon was used in place of 20% palladium hydroxide carbon, to obtain the title compound having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][NH2:24])[CH2:16][CH3:17]>C(Cl)(Cl)Cl>[CH2:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][NH:24][C:5](=[O:7])[C:4]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:2]([Br:1])[C:3]=1[O:13][CH3:14])[CH2:16][CH3:17]
Reactant: CCCN1CCCC1CN
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Solvent: ClC(Cl)Cl
Product: CCCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1OC
Yield: 79 %

Procedure:
The title compound was prepared from 3-bromo-2,6-dimethoxybenzoic acid via the acylchloride and (-)-1-n-propyl-2-(aminomethyl)pyrrolidine in the same manner as described in Example 8. Yield 79%. M.p. 103°-104° C. [α]D20 =-85.4° (c=0.5; CHCl3).
Reaction SMILES: [F:1][C:2]([F:16])([CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:17]12([C:27]([O:15][CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([F:16])[F:1])=[O:28])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C(F)(F)C(O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(F)(F)C(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
In 60 g of methylene chloride were dissolved 9 g of ethyl 2,2-difluoro-3-hydroxy-3-phenylpropionate, prepared in Synthesis Example 1-4, and 9.5 g of 1-adamantanecarbonyl chloride. Under ice cooling, a mixture of 6 g of triethylamine, 0.5 g of 4-dimethylaminopyridine and 20 g of methylene chloride was added dropwise to the solution. The reaction solution was aged overnight, after which it was quenched with 5 wt % hydrochloric acid, washed with water, and concentrated. Methyl isobutyl ketone was added to the concentrate, which was concentrated again. There was obtained 15 g of the target compound, 2-ethoxycarbonyl-2,2-difluoro-1-phenylethyl 1-adamantanecarboxylate as colorless oily matter (yield 68%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)[CH:18]([CH3:20])[CH3:19])[CH:13]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:53]1[O:54][CH:55]=[CH:56][CH:57]=1)CCC.[Cl-].[Li+]>CN(C=O)C.O.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>[O:54]1[CH:55]=[CH:56][CH:57]=[C:53]1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]([C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)([OH:45])[CH:18]([CH3:20])[CH3:19])[CH:11]=[CH:10]2
Reactant: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(O)(c1ccc2cc(-c3ccco3)ccc2c1)c1c[nH]cn1

Procedure:
6-[1-Hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthyl trifluoromethanesulfonate (2.0 g), 2-(tributylstannyl)furan (1.26 mL), tetrakis(triphenylphosphine)palladium (115 mg) and lithium chloride (259 mg) were dissolved in DMF (10 mL) and heated at 80 for 4 h. The reaction mixture was diluted with water, extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluent; hexane:THF=4:1) and crystallized from ethyl acetate-hexane to give the titled compound (1.48 g) as a colorless powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:15][CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:2]1.[CH3:17][O:18]C=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[N:15]([CH:17]=[O:18])[CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:2]1
Reactant: O=C1NCCNC1c1c[nH]c2ccccc12
Reactant: COC=O
Product: O=CN1CCNC(=O)C1c1c[nH]c2ccccc12

Procedure:
21.5 g (0.1 mol) of 3-(3-indolyl)-piperazin-2-one (Example 30) are formylated with methylformate, as described in Example 5.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Cl[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][O:10][C:9](=[O:18])[CH:8]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][S:2]([C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][O:10][C:9](=[O:18])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)c1coc(=O)cc1Cl
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc(=O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of sodium methylsulfinate are introduced into a solution of 2.02 g of ethyl 4-chloro-2-oxo-2H-pyran-5-carboxylate in DMF, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is diluted with CH2Cl2 and extracted with saturated aqueous NaCl solution. The organic phase is dried with Na2SO4 and evaporated. The distillation residue which has crystallized out is mixed with ether, filtered off with suction and washed with ether. Yield 1.4 g (56.9% of theory); melting point: 95°-97° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[CH2:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.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>[O:20]1[C:16]2[CH:15]=[C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=5)[CH:3]=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)[CH:22]=[CH:21][C:17]=2[CH2:18][CH2:19]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OCC4)CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OCC5)CC3)n2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
A mixture of N-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-6-yl)cyclopropanecarboxamide (50.0 mg, 0.15 mmol), 2-methoxypyridine-5-boronic acid (23.0 mg, 0.15 mmol), and tetrakis(triphenylphosphine)palladium (0) (8.8 mg, 0.0076 mmol) in 1,2-dimethoxyethane (1.0 mL) and 2 M Na2CO3 (0.2 mL) was stirred at 80° C. for 16 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 20 mg (32%) of 1-(2,3-dihydrobenzofuran-6-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 401.2. found 402.0 (M+1)+. Retention time 1.94 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2.[CH3:14][S:15]SC>C1COCC1>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([S:15][CH3:14])[CH:3]=[N:4]2
Reactant: CSSC
Reactant: COc1cccc2ncc(Br)cc12
Solvent: C1CCOC1
Product: COc1cccc2ncc(SC)cc12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-bromo-5-methoxy quinoline (2.37 g, 10 mmol) prepared in stage B of example 10 in THF (25 mL) was added 2.5M n-buLi (4 mL, 10 mmol) at −78° C. The solution is stirred at −78° C. for 45 min and dimethyl disulfide (1.8 g, 20 mmol) is added. The resultant solution is stirred for 3 hours and then quenched with saturated NH4Cl (30 mL). Extraction with dichloromethane, drying, filtering and evaporation in vacuo afford the title compound
Reaction SMILES: [H-].[Na+].C([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=O)=C.[Br:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1C(OCC)=O.Cl>O1CCCC1>[Br:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:6]1[CH2:7][CH2:8][CH2:9][N:5]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=CN1CCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccccc1C1=NCCC1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
Sodium hydride (977 mmol, 23.45 g) was suspended in tetrahydrofuran (700 mL) and cooled to 5° C. with an ice-water bath. To this cold suspension was added 1-vinyl-pyrrolidin-2-one (465 mmol, 51.7 g) over approximately 20 minutes, maintaining an internal temperature reaction temp of less than 5° C. then ethyl 2-bromobenzoate (437 mmol, 100 g) was added. After the addition was complete the reaction was stirred at 5° C. for 10 minutes then refluxed for 2 hours and allowed to cool to room temperature. To the suspension was added 5N HCl (600 mL) dropwise, maintaining reaction temperature between 25° C. and 35° C. The bulk of the tetrahydrofuran was then distilled off at a temperature of 60° C. under vacuum. The resulting solution was cooled and further 5N hydrochloric acid (600 mL) was added and the mixture was refluxed overnight. The solution was then cooled with a salt-ice bath to 5° C. and basified by the careful addition of sodium hydroxide pellets (˜250 g) maintaining an internal temperature between 10 and 15° C. When reaction mixture was at pH 13, the cooling bath was removed and temperature allowed to reach room temperature. The reaction was then extracted with methylene chloride (1 L) and the aqueous layer was extracted with further methylene chloride (2×1 L). The combined methylene chloride extracts were dried with sodium sulfate, filtered and evaporated to dryness to give 5-(2-bromophenyl)-3,4-dihydro-2H-pyrrole (92.2 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[NH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1>C(#N)C>[Cl:1][CH2:2][C:3]1[N:7]=[C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]2[CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccnc(N)c1
Solvent: CC#N
Product: Cc1ccn2cc(CCl)nc2c1
Yield: 23.9 %

Procedure:
A mixture of 1,3-dichloroacetone (30.0 g) and 2-amino-4-picoline (63.9 g) in acetonitrile (210 ml) was refluxed for 1 hour. Evaporation of a solvent gave a residue, which was purified by a column chromatography on silica gel eluting with a mixture of dichloromethane and ethyl acetate (1:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-chloromethyl-7-methylimidazo[1,2-a]pyridine (10.21 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=O>C(O)(=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(CNCCc2ccoc2)cc1
Solvent: CC(=O)O
Product: c1ccc(CN2CCc3ccoc3C2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 5.603 g (27.838 mmol) of N-benzyl-2-(3-furyl)ethylamine in 50 ml of acetic acid, 2.71 g (33.4 mmol) of 37% aqueous formaldehyde was added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to yield the desired product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10](=[O:18])[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([CH3:23])([O-:22])=[O:21]>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([OH:18])([CH2:23][N+:20]([O-:22])=[O:21])[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccc(Cl)cc21
Solvent: O
Product: O=C1N(Cc2ccccc2)c2ccc(Cl)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 6 h

Procedure:
1-benzyl-5-chloroindoline-2,3-dione (0.135 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 6 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].[C:15](OC(=O)C)(=[O:17])[CH3:16].O>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14])(=[O:17])[CH3:16]
Reactant: COc1cc2c(=O)[nH]cnc2cc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Temperature: 100 °C
Yield: 76 %

Procedure:
A mixture of 7-hydroxy-6-methoxyquinazolin-4-(3H)-one (8.0 g, 41.6 mmol), pyridine (7.5 ml) and acetic anhydride (63 ml) was heated at 100° C. for 4.5 hours and left to cool to ambient temperature 18 hours. The reaction mixture was poured into ice/water (400 ml) and the resultant precipitate collected by filtration and dried in vacuo. Analysis revealed that hydrolysis of the acetate group on the 4 position of the quinazoline was incomplete. The mixture was therefore treated with water (150 ml) and pyridine (0.5 ml) at 90° C. for 15 minutes. The reaction was cooled and the solid was collected by filtration, washed with water and dried in vacuo to yield 7-(acetoxy)-6-methoxyquinazolin-4-(3H)-one (7.4 g, 76% yield):
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:15][CH2:16][CH3:17])=[C:12]([OH:14])[CH:13]=1.Cl>CCO>[CH2:15]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:13][C:12]=1[OH:14])[CH2:16][CH3:17]
Reactant: Brc1nccs1
Reactant: CCCc1ccc(N)cc1O
Agent: Cl
Solvent: CCO
Product: CCCc1ccc(Nc2nccs2)cc1O
Temperature: 90 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (1.26 mL, 14.0 mmol), 5-amino-2-propylphenol (1.1 g, 7.0 mmol) and 37% HCl solution (1.21 mL, 14.0 mmol) in 10%, aqueous EtOH solution (20 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 36% yield (588 mg).