Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[Br:12]N1C(=O)CCC1=O.Br>COC(C)(C)C.C(O)(=O)C>[Br:12][C:5]1[S:1][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:3][CH:4]=1
Reactant: c1ccc(-c2cccs2)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Brc1ccc(-c2ccccn2)s1
Temperature: 35 °C
Yield: 81.7 %

Procedure:
A solution of 2-thienylpyridine (1.924 kg) and N-bromosuccinimide (2.759 kg) in tert-butyl methyl ether (20.0 kg) was agitated for 15 minutes, treated with 30% HBr in acetic acid (125 g), heated to 35° C. for about 6 hours, and filtered. The wetcake was washed with tert-butyl methyl ether (12.6 kg) while maintaining the temperature of the filtrate at 30° C. to 35° C. The filtrate was washed with 5% Na2SO3 (21 kg) and 10% Na2CO3 (22 kg), concentrated to about 20 L, and diluted with isopropanol (11 kg), which caused the product to crystallize. This procedure was repeated twice more, when NMR analysis of the mother liquor indicated absence of tert-butyl methyl ether. The suspension was concentrated to about 12 L, cooled to 0° C., and filtered. The wetcake was washed with chilled (0° C.) isopropanol (7 kg) and dried in a vacuum oven with a nitrogen purge at 60° C. to provide 2.34 kg (82%) of the desired product. MS m/z 241 (M+H)+; 1H NMR δ 8.53 (m, 1H), 7.68 (m, 1H), 7.57 (m, 1H), 7.30 (m, 1H), 7.15 (m, 1H), 7.06 (m, 1H); Anal. calcd for C9H6BrNS: C, 45.01; H, 2.50; N, 5.83. Found: C, 45.14; H, 2.45; N, 5.72.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[C:14]([CH:22]([CH3:24])[CH3:23])[CH:13]=1)=[O:11].Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[C:15]([S:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=2)(=[O:34])=[O:33])=[C:14]([CH:22]([CH3:23])[CH3:24])[CH:13]=1)=[O:11]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(S(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.639 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.197g, 0.831 mmol). Purification on Dynamax C18 (90% CH3CN/H2O) gave 0.20 g (47%) of the tide compound as a yellow solid, mp 90-95° C. 1H NMR (DMSO-d6) δ1.06 (d, 12 H), 1.85 (s, 3 H), 2.19 (s, 3 H), 3.07 (septet, 2 H), 3.91 (s, 2 H), 7.14-7.16 (m, 2 H), 7.29 (dt, 1 H), 7.44 (d, 1 H), 7.47-7.52 (m, 4 H), 8.05 (d, 1 H) (KBr) 3400, 2950, 1690, 1380 and 1190 cm31 1. mass spectrum (−EST) rnz 667/669 (M−H). Anal. Calcd. for C33H33BrO8S: C, 59.19; H, 4.97; N, 0.00. Found: C, 58.82; H, 5.13; N, 0.13.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][CH:6]=1.[CH2:7]([O:9][C:10](=[O:34])[N:11]([C:23]1[CH:28]=[C:27](Br)[N:26]=[C:25]([NH2:30])[C:24]=1[N+:31]([O-:33])=[O:32])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)[CH3:8]>[Cl-].[Cl-].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.[Pd+2]>[CH2:7]([O:9][C:10](=[O:34])[N:11]([C:23]1[CH:28]=[C:27]([C:4]2[O:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[N:26]=[C:25]([NH2:30])[C:24]=1[N+:31]([O-:33])=[O:32])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=1)[CH3:8]
Reactant: Cc1cocn1
Reactant: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(-c2nc(C)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-methyl-oxazole (36 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg) and palladium bis(triphenylphosphine)dichloride (30 mg), giving the product (44 mg) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:22])[N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:65]([NH:67][CH3:68])[CH3:66]>CC(=O)OCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:65]([N:67]([CH3:68])[C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:22])[N:3]=1)[CH3:66]
Reactant: Cc1cc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)cc(Cl)n1
Reactant: CCNC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Product: CCN(C)c1cc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)cc(C)n1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (549 mg, 1.74 mmol) and Na tert.-butylate (346 mg, 3.60 mmol) in ethyl-methylamine (10 mL), Xantphos (106 mg, 0.18 mmol) and Pd(OAc)2 (47 mg, 0.21 mmol) is added. The mixture is stirred in an autoclave at 80° C. for 24 h. The dark mixture is cooled to rt, diluted with EA (200 mL), washed three times with sat. aq. NaHCO3-solution, dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with EA containing 20% of methanol to give 4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenol (119 mg) as a yellow solid; LC-MS: tR=0.83 min; [M+1]+=339.10; 1H NMR (D6-DMSO): δ 1.12 (m, 3H), 2.26 (s, 6H), 2.43 (s, 3H), 2.88-2.98 (m, 2H), 3.07 (s, 3H), 7.00 (s, 1H), 7.08 (s, 1H), 7.67 (s br, 1H), 7.68 (s, 1H), 8.94 (s br, 1H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1)([O:3][CH3:4])=[O:2].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C([O-])(O)=O.[Na+]>[CH2:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][NH:6][CH:5]([C:1]([O:3][CH3:4])=[O:2])[CH2:10]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1CNCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCN1

Procedure:
2-Carbomethoxypiperazine was treated with benzyl chloroformate (1.0 eq) in aqueous NaHCO3 to give 1-benzyloxycarbonyl-3-carbomethoxypiperazine. This material was treated with di-tert-butyldicarbonate (1.1 eq) and triethylamine (1.0 eq) in THF to produce 1-tert-butyoxycarbonyl-4-benzyloxycarbonyl-2-carbomethoxypiperazine. Hydrogenation of this compound in methanol using 10% Pd—C gives the title compound after filtration and solvent removal.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:12]([NH:16][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
Combine 4-cyanobenzoic acid (30 mg, 2.07 mmol), tert-butylamine (0.5 mL, 4.13 mmol), triethylamine (0.4 mL, 2.89 mmol), and HATU (1.1 g, 2.89 mmol) in anhydrous DMF (7 mL). Stir at ambient temperature for 17 h. Partition the reaction mixture between brine (15 mL) and diethyl ether (15 mL), separate the organic layer, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (0.4 g, 89%). MS (ES+) m/z: 203 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH3:18])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[Cl:30].C(=O)([O-])[O-].[Na+].[Na+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]Cl>[Cl:30][C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH3:18])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc2c1C(=O)c1cccc(N)c1C2=O
Reactant: O=[N+]([O-])c1ccc(Br)c(Cl)c1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cccc2c1C(=O)c1cccc(Nc3ccc([N+](=O)[O-])cc3Cl)c1C2=O

Procedure:
12.65 parts of 1-amino-5-methoxyanthraquinone, 15.3 parts of 1-bromo-2-chloro-4-nitrobenzene, 5 parts of sodium carbonate and 1 part of copper-(I) chloride in 120 parts of nitrobenzene are stirred for 3 hours at 170°. To remove the water formed during the reaction, a stream of nitrogen is passed through the apparatus during the reaction. After cooling the reaction mixture to 25°, the 1-(2'-chloro-4'-nitroanilino)-5-methoxyanthraquinone formed is filtered off, washed with nitrobenzene, ethanol and hot water and extracted by boiling with 5% strength hydrochloric acid. The colorant is obtained in a yield of 19.5 parts, that is to say 95% of theory. It bulk-dyes polyester in an orange-coloured shade having excellent fastness properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([I:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[I:9]
Reactant: Cc1ccc(F)cc1I
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(I)c1

Procedure:
A suspension of 4-fluoro-2-iodotoluene (14.3 g, 60.6 mmol, Lancaster Synthesis), N-bromosuccinimide (16.2 g, 90.9 mmol), and benzoyl peroxide (0.74 g, 3.0 mmol) in carbon tetrachloride (500 mL) was heated to reflux for 3 days. Additional NBS (0.5 eq portions) was added as needed over this period to drive the reaction to completion. The reaction was cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (ISCO column, 110 g silica gel) eluting with 100% hexane to afford the desired product as a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:31]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[N:32]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH2:25][C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)[CH2:36][C:33]3[NH:32][N:31]=[CH:35][CH:34]=3)=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: O=Cc1cc[nH]n1
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3ccn[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (72.0 mg) obtained in Example 43-1 was dissolved in methanol (3.5 ml) and then added with pyrazole-3-carboxaldehyde (24.5 mg) and sodium cyanoborohydride (35.9 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (52.3 mg) of the subject compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: Cc1cccc(C)c1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
2,6-dimethylaniline (10 g, 82.5 mmol, 1.0 eq) was added to acetic anhydride (100 mL) at 0° C. The reaction mixture was then warmed to room temperature and stirred for 1 h. The reaction was poured into ice water and the precipitate that formed collected by filtration to give the title compound as a yellow solid (10 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC([N:16]([CH:20]([CH2:24][OH:25])[CH:21]([CH3:23])[CH3:22])[C:17](=[O:19])[OH:18])(C)C.O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:25][CH2:24][CH:20]([NH:16][C:17](=[O:19])[O:18][C:2]([CH3:7])([CH3:3])[CH3:1])[CH:21]([CH3:22])[CH3:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)C(CO)N(C(=O)O)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 123.4 %

Procedure:
4-Methylbenzenesulfonyl chloride (0.2222 mol) was added portionwise at 10° C. to a mixture of 1,1-dimethylethyl [1-(hydroxymethyl)-2-methylpropyl]carbamic acid (ester) (0.202 mol) in pyridine (65 ml). The mixture was stirred at 10° C. for 2 hours. H2O (75 ml) was added at 10° C. The precipitate was filtered off, washed with H2O and taken up in CH2Cl2. The organic solution was washed with H2O, dried, filtered and the solvent was evaporated, yielding 49 g (68%) of (±)-1,1-dimethylethyl [1-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-2-methylpropyl]carbamate; mp. 85° C. (interm. 32).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])[C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:22]1([N:25]2[CH2:30][C:29]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[O:28][CH2:27][C:26]2=[O:36])[CH2:24][CH2:23]1>CN(C)C=O.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:33]2[CH2:34][CH2:35][C:29]3([O:28][CH2:27][C:26](=[O:36])[N:25]([CH:22]4[CH2:23][CH2:24]4)[CH2:30]3)[CH2:31][CH2:32]2)[C:3]([O:5][CH3:6])=[O:4])=[C:8]([F:14])[CH:9]=1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Reactant: COC(=O)C(Br)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.9 %

Procedure:
A solution of methyl 2-bromo-2-(4-bromo-2-fluorophenyl)acetate (7.29 mmol) in N,N-dimethylformamide (30 mL) was treated with potassium carbonate (19.90 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (8.31 mmol). The reaction was stirred at room temperature for two days. The reaction solution was diluted with water (200 mL) and was extracted three times with ethyl acetate. The combined organic layers were washed five times with water and three times with brine. The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting semi-solid was diluted with dichloromethane (10 mL) and was concentrated to dryness in vacuo. This was repeated twice, at which point the resulting solid was dried under high vacuum overnight, affording the title compound as a white solid (3.05 g, 87% yield). MS(ES)+ m/e 454.8/456.9 [M+H]+ (bromide isotope pattern).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:21])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([OH:25])[C:23]#[CH:24].C(N(CC)CC)C>CC#N.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.[Cu]I>[F:19][CH:18]([F:20])[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][CH2:22][OH:25])[CH:3]=2)=[O:21])=[CH:12][CH:13]=1
Reactant: C#CCO
Reactant: O=C(C(=O)c1cccc(Br)c1)c1ccc(OC(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(C(=O)c1cccc(C#CCO)c1)c1ccc(OC(F)F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of 1-(3-bromophenyl)-2-(4-(difluoromethoxy)phenyl)ethane-1,2-dione (0.500 g, 1.41 mmol), prop-2-yn-1-ol (0.395 g, 7.04 mmol), bis(triphenylphosphine)palladium(II) chloride (0.099 g, 0.14 mmol), copper(I) iodide (0.021 g, 0.11 mmol) and triethylamine (0.62 g, 6.11 mmol) in CH3CN (3 mL) was stirred at 60° C. overnight. The solvent is removed and the material is absorbed onto celite and purified by flash chromatography (silica, 25:75 ethyl acetate/hexanes) to afford 1-(4-(difluoromethoxy)phenyl)-2-(3-(3-hydroxyprop-1-ynyl)phenyl)ethane-1,2-dione (0.326 g, 70%) as an off white solid.
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=CC=1)CCC.C[N:34](C=O)C>C1COCC1.S(Cl)(Cl)=O>[CH2:25]([N:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:32][C:19]=2[CH:20]=[C:21]([C:29]([NH2:34])=[O:30])[CH2:22][CH2:23]1)[CH:26]([CH3:28])[CH3:27]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)CN1CCC(C(N)=O)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy) phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml), thionyl chloride (0.25 ml) and DMF (1 droplet) were added at room temperature, and the mixture was stirred for 1.5 hours at room temperature. The solvent was concentrated under reduced pressure, and a solution of the residue in THF (25 ml) was added dropwise to a solution of 4-[[(1-trityl-1H-imidazol-1-yl)methyl]thio]aniline (1.13 g) in pyridine (10 ml) at 0° C. The mixture was stirred at room temperature for 20 hours, and water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1), to give 7-[4-(2-butoxyethoxy) phenyl]-N-[4-[(1-trityl-1H-imidazol-4-yl) methyl]thio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.43 g) as yellow crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH:24]=[N:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2]>C(O)(=O)C.O1CCOCC1.[OH-].[OH-].[Pd+2]>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH:24]=[N:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
A mixture of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]quinoline-6-carboxylate (Intermediate 6, 0.180 g) and palladium hydroxide on carbon (˜0.005 g) in acetic acid (2 mL) and dioxane (20 mL) was stirred at room temperature under an atmosphere of hydrogen for 2 hours. The resultant mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to give methyl 7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]quinoline-6-carboxylate (0.100 g) as a gum which was used without further characterisation.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([Cl:11])[CH:3]=1.ClC1C=C(Cl)C=CC=1C1[C:25]([C:26]2[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[CH:24][N:23]=[C:22]([NH:32][CH2:33][CH2:34][NH:35][C:36]2[N:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)[N:21]=1>>[Cl:11][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:5]=1[C:6]1[C:25]([C:26]2[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[CH:24][N:23]=[C:22]([NH:32][CH2:33][CH2:34][NH:35][C:36]2[N:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)[N:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(F)cc2Cl)n1

Procedure:
6-[(2-{[4-(2-chloro-4-fluorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]-amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 4-fluoro-2-chlorobenzoyl chloride using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]([CH:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1)=[O:19]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Agent: Cl
Product: O=C(c1ccc(F)cc1F)C1CCNCC1
Yield: 83 %

Procedure:
A mixture of 48 parts of 1-acetyl-4-(2,4-difluorobenzoyl)-piperidine and 180 parts of a hydrochloric acid solution 6N was stirred and refluxed for 5 hours. The reaction mixture was evaporated and the residue was stirred in 2-propanol. The product was filtered off and dried, yielding 39 parts (83%) of (2,4-difluorophenyl)(4-piperidinyl)methanone hydrochloride (intermediate 2).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[N:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[C:15]1([C:21]2[O:25][CH:24]=[N:23][C:22]=2[C:26](O)=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[N:11]=[C:10]([NH:12][C:26]([C:22]2[N:23]=[CH:24][O:25][C:21]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:27])[CH:9]=[N:8]1
Reactant: CC(F)(F)CCCCn1ncc(N)n1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(F)(F)CCCCn1ncc(NC(=O)c2ncoc2-c2ccccc2)n1

Procedure:
Following general procedure A, starting from 2-(5,5-difluoro-hexyl)-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([C:17](=[CH2:21])[C:18](O)=[O:19])[CH:14]([CH3:16])[CH3:15]>O>[C:1]([C:5]1[CH:10]=[C:9]2[C:8]([CH2:21][CH:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:18]2=[O:19])=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(CC(C)C)C(=O)O
Reactant: COc1ccccc1C(C)(C)C
Solvent: O
Product: COc1cc2c(cc1C(C)(C)C)C(=O)C(CC(C)C)C2
Temperature: 60 °C

Procedure:
To Iton reagent (obtained from 110 g of P4O10 and 560 ml of methanesulfonic acid at 110° C.) a mixture of 59.4 g (0.362 mol) of 1-tert-butyl-2-methoxybenzene and 51.5 g (0.402 mol) of 2-isobutylacrylic acid was added dropwise at vigorous stirring in such a rate to maintain temperature at 60±1° C. (for ca. 40 min). The resulting mixture was stirred for 40 min at 65° C., cooled to room temperature, and then poured on 1000 cm3 of ice with 1000 cm3 of water. The product was extracted by 3×500 ml of dichloromethane. The combined organic extract was washed by aqueous K2CO3, dried over Na2SO4 and then evaporated to dryness. Fractional rectification of the residue gave dark red oil, b.p. 165-174° C./5 mm Hg. This oil was recrystallized from 100 ml of hexanes. White crystals precipitated at 5° C. were collected, washed by 20 ml of cold hexanes, and dried in vacuum. Yield 24.9 g (25%) of the title product.