Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](OC(ON=C(C#N)C(N)=O)=O)[CH3:24].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:23]([O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:24]
Reactant: CCOC(=O)ON=C(C#N)C(N)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 103.6 %

Procedure:
To a suspension of N-benzyloxycarbonyl-L-phenylalanine (1.5 g) and 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (0.95 g) in ethyl acetate (20 ml), a solution of triethylamine (0.7 ml) in ethyl acetate (5 ml) is dropwise added at -10°C, and the resulting mixture is stirred at the same temperature for 20 minutes and then at room temperature for 2 hours. After allowed to stand over night, the reaction mixture is treated as in Example A to give N-benzyloxycarbonyl-L-phenylalanine ethyl ester (1.7 g) as an oil.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:35](O)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)Cl.N1(C2C=CN=CC=2)CCCC1>[C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:18])[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
13.2 parts by weight of 1-carbobenzoxypiperidine-4-carboxylic acid are dissolved in 150 parts by volume of methylene chloride, 8 parts by volume of n-octanol and 0.7 part by weight of 4-pyrrolidinopyridine are added, and the mixture is cooled to 0 to 5° C. 12.0 parts by weight of dicyclohexylcarbodiimide are added, and the mixture is stirred at 5° C. for 2 hours and at room temperature for 4 hours. The mixture is left to stand overnight, the precipitated dicyclohexylurea is filtered off with suction (11.3 parts by weight), the solvent is stripped off in vacuo, the residue is stirred with diisopropyl ether in order to remove residual dicyclohexylurea and filtered, and the solvent is stripped off. 21 parts by weight of an oily residue are obtained. The residue is chromatographed on 1070 parts by weight of silica gel using CH2Cl2 /5% of methanol. 9.8 parts by weight of the compound (A) are obtained as an oil. ##STR42## 4-decyloxyphenoxy(4-benzoyl) chloroformate =(B)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16](SC)SC)[C:4]=2[CH:3]=1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:4][CH2:3][CH2:2][CH2:14][CH3:13])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]=2[CH:3]=1
Reactant: CSC(SC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CCCCCCCCCCCC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCC(CCCCCCCCCCCC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of 2,7-dibromo-9-(bis-methylsulfanyl-methylene)fluorene (4.28, 10 mmol) in dry THF (70 ml) at 0° C. under nitrogen, was added a solution of lithium tetrachlorocuprate (2 ml of a 0.1M solution in THF, 2 mol %). A solution of dodecylmagnesium bromide (22 ml of a 1.0M solution in diethyl ether, 0.022 mol) was added dropwise over 15 min. The reaction was stirred for 3 h at 0-5° C. before quenching with 5% NaOH (100 ml). The reaction was stirred for 10 min and then filtered through celite. The organic layer was separated and the aqueous layer further washed with ethyl acetate (100 ml). The combined organics were washed with brine (100 ml), dried (sodium sulfate), and concentrated under reduced pressure. The crude oil was further purified by filtration through a plug of silica (5 cm×5 cm) covered with a layer of basic alumina (1 cm×5 cm), eluting with petrol. After concentration the residue was recrystallized from isohexane to afford 4.2 of the product as white crystals (62%). Purity (HPLC>98%). 1H and 13C NMR spectra as expected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].Cl.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH:32][CH3:33])[CH2:26][CH2:25]1.N1C=CC=CC=1>ClCCl>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[N:24]1[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][N:32]([CH3:33])[S:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:12])=[O:11])[CH2:28][CH2:29]1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: CNCCN1CCN(c2nc3ccccc3[nH]2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)N(C)CCN2CCN(c3nc4ccccc4[nH]3)CC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.7 %

Procedure:
A mixture of 2,4-dichloro-5-methylbenzenesulphonyl chloride (81 mg, 0.31 mmol), {2-[4-(1H-Benzimidazol-2-yl)-piperazin-1-yl]-ethyl}-methyl-amine hydrochloride salt (D23) (80 mg, 0.31 mmol) and pyridine (0.5 ml) in dry dichloromethane (5 ml) was stirred at room temperature for 17 h. The mixture was then diluted with dichloromethane (30 ml), washed with aqueous sodium bicarbonate (1×10 ml) and dried.(MgSO4). The solvent was evaporated and the residue was co-evaporated with toluene (5 ml). Column chromatography of the residue (eluting with methanol-dichloromethane gradient) gave the product as a yellowish solid (25 mg, 17%); MS: m/z (MH+)=482.
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: CC(C)(C)OC(=O)NCC#CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: N=C(N)SCc1ccccc1
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: C(N(CC)CC)C.[C:8]([CH:10]1[C@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][C@@H:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])[CH2:12][NH:11]1)#[N:9].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+]>ClCCl>[C:33]([N:11]1[CH2:12][C@H:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])[CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]1[C:8]#[N:9])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.8 %

Procedure:
Triethylamine (1.29 mL, 9.25 mmol) was added to a solution of tert-butyl [(3R,6S)-2-cyano-6-(2,3-difluorophenyl)azepan-3-yl]carbamate (0.65 g, 1.85 mmol) in dichloromethane (20 mL) at 0° C. Acetic anhydride (0.53 mL, 5.55 mmol) was added and the mixture was allowed to warm to ambient temperature. After 16 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (99% dichloromethane/ethyl acetate→70% dichloromethane/ethyl acetate) gave the title compound (144 mg). MS 394.1 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[CH2:16])#[N:11]>C(Cl)Cl>[NH2:9][C:3]1[C:2](/[CH:16]=[CH:15]/[C:14]2[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=2)[C:10]#[N:11])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1
Reactant: C=Cc1cccc(C#N)c1
Reactant: Nc1ncc(Cl)cc1Br
Solvent: ClCCl
Product: N#Cc1cccc(/C=C/c2cc(Cl)cnc2N)c1

Procedure:
The title compound was prepared from 3-bromo-5-chloro-2-pyridinamine and 3-cyanostyrene. Methylene chloride extracts of the crude reaction mixture were concentrated and the desired product purified by column chromatography on silica gel eluting with methylene chloride—methanol (98:2) to give a yellow solid:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][C:13]1([CH2:16][CH2:17][O:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23]([O:29][C:30]4[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]5[C:40](=[O:52])[N:41]([C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)[N:42]([CH3:45])[C:43]=5[CH3:44])=[O:38])=[CH:32][C:31]=4[F:53])=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:54]>C(OCC)(=O)C>[ClH:54].[NH2:8][CH2:9][C:10]([O:12][C:13]1([CH2:16][CH2:17][O:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23]([O:29][C:30]4[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]5[C:40](=[O:52])[N:41]([C:46]6[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=6)[N:42]([CH3:45])[C:43]=5[CH3:44])=[O:38])=[CH:32][C:31]=4[F:53])=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCC5(OC(=O)CNC(=O)OC(C)(C)C)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCC5(OC(=O)CN)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a solution of 1-(2-(4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)quinolin-7-yloxy)ethyl)cyclopropyl 2-(tert-butoxy-carbonylamino)acetate (190 mg, 0.262 mmol) in 8 mL of ethyl acetate was added a solution of HCl in EtOAc (0.93 mol/L, 5 mL) dropwise. The reaction mixture was stirred at rt for 30 minutes and then filtered. The solid was washed with ethyl acetate (20 mL×3) to afford the title compound as a white solid (54 mg, 30.3%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:24])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[N+:21]([O-])=O)[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:9]([O:11][C:12](=[O:24])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:16][C:15]=1[NH2:21])[CH3:10]
Reactant: O=Cc1ccc(Cl)s1
Reactant: CCOC(=O)Nc1ccc(N)cc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Nc1ccc(NCc2ccc(Cl)s2)cc1N
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
A solution of 5-chlorothiophene-2-carbaldehyde (240 μL, 111 μmol, 463 mM in 1,2-dichloroethane) was added to a solution of 4-amino-2-nitrophenylcarbamic acid ethyl ester (240 μL, 111 μmol, 463 mM in 1,2-dichloroethane). Sodium triacetoxyborohydride (118 mg, 555 μmol) was added, and the resulting mixture was stirred for 3.5 hours at 40° C. The mixture was allowed to cool to ambient temperature, and water (100 μL) was added. The mixture was filtered through silica gel (500 mg) and the column was washed with 1,2-dichloroethane (3 mL). The combined organic phases were evaporated to dryness in vacuo. The resulting solid was dissolved in ethanol (3 mL). Iron (19 mg) was added to one-third of the resulting solution (1 mL), followed by an aqueous solution of hydrochloric acid (96 μL, 6M). The resulting mixture was placed in an ultrasonic bath for 10 minutes. Then, saturated aqueous sodium bicarbonate solution (2 mL) was added. The mixture was extracted with ethyl acetate (3 mL). The organic phase was washed with water (3 mL) and brine (3 mL), dried over magnesium sulphate, filtered, and evaporated to dryness in vacuo. The resulting product was dissolved in 190 μL dimethylsulfoxide and subjected to preparative LC-MS purification. The resulting solution was evaporated to dryness in vacuo. Yield (6.8 mg, 56%). LC-MS (m/z) (M+H)+ 326.1 RT=1.90 (UV, ELSD) 92%, 99%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH2:18]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:14][C@@H:13]([CH3:16])[CH2:12][N:7]2[C:6]3[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Reactant: CCCCC1CCNCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(F)cc32)CC1
Yield: 58 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04)_(0.873 g, 2.50 mmol) and 4-Butylpiperidine (0.371 g, 2.63 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF08) (0.53 g, 58%). 1H NMR (CDCl3) d 7.01 (d, J=10.0 Hz, 1H), 6.92-6.88 (m, 1H), 6.68-6.64 (m, 1H), 5.57 (q, J=32.4 Hz, J=15.2 Hz, 2H), 4.02-3.83 (m, 2H), 2.92-2.70 (m, 2H), 2.23-2.10 (m, 2H), 2.04-1.97 (m, 2H), 1.81 (t, J=10.8 Hz, 1H), 1.72-1.61 (m, 2H), 1.36-1.19 (m, 9H), 0.90-0.88 (m, 6H); 13C NMR (CDCl3) d 164.8, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.3 Hz), 130.0 (d, J=10.4 Hz), 117.6 (d, J=9.6 Hz), 109.4 (d, J=23.1 Hz), 103.5 (d, J=29.3 Hz), 67.8, 64.1, 56.0, 54.3, 45.7, 36.5, 36.0, 33.0, 32.5, 29.5, 29.2, 23.1, 17.1, 14.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl.CCCCCC>[F:11][C:12]([F:20])([F:19])[C:13]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([OH:14])[C:15]([F:18])([F:17])[F:16]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 64 %

Procedure:
Aniline (10.35 ml, 0.1 mol) and 250 mg of p-toluenesulfonic acid catalyst are placed in a two-necked flask surmounted by a condenser. Hexafluoroacetone trihydrate is added dropwise (15.8 ml, 1.1 eq.) and the bath (graphite) is brought to 180° C. for 14 h. The product AHFHP (4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)aniline) is obtained by recrystallization from a dichloromethane/hexane mixture, in the form of a white powder (yield 52%). 1 g of nitrosonium tetrafluoroborate (NOBF4) (8.56 mmol, 1.1 eq.) is then placed in a round-bottomed flask dried under argon and is dissolved with 10 ml of anhydrous acetonitrile ACN. The whole mixture is brought to −30° C. by means of an acetone-liquid nitrogen bath and then 7.78 mmol of the arylamine precursor, solubilized in the minimum amount of ACN (5 to 30 ml), are added dropwise. The mixture is allowed to return to ambient temperature, and the product is precipitated from 100 ml of cold ether, filtered off on a frit and washed with cold ether. The white powder obtained is recrystallized with an ACN/Et2O mixture and obtained with a yield of 64%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([O:23][CH:24](CC)Br)[CH2:21]C.O>CC(C)=O.CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:21][CH2:20][O:23][CH3:24])[N:3]=1
Reactant: CCC(Br)OC(Br)CC
Reactant: Oc1cccc2nc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: COCCOc1cccc2nc(Cl)ccc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
2-Chloro-5-hydroxy-quinoline (0.30 g, 1.67 mmol) was dissolved in aceton (10 mL). Potassium carbonate (370 mg, 2.7 mmol) and bromo-ethyl-methylether (250 □L, 2.7 mmol) were added. The reaction mixture was stirred for 18 h at 50° C. After addition of water the reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases were dried on sodium sulfate. After evaporation of the solvent a brown oil was obtained which was subjected to column chromatography (silica gel, heptane:ethyl acetate 9:1, 4:1) to yield 2-chloro-5-(2-methoxy-ethoxy)-quinoline as a colorless oil (120 mg, 30%); MS: m/e=238.8 (M+H+).
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[I:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1ccc(I)nc1
Solvent: CO
Product: COC(=O)c1ccc(I)nc1
Yield: 43 %

Procedure:
A solution of 6-iodo-pyridine-3-carboxylic acid (J. Am. Chem. Soc. 72, 1032, (1950)), 1.2 g of trimethyl o-formate and 0.2 g of p-toluenesulphonic acid in 75 ml of methanol is held at reflux for 2 hrs. The reaction mixture is concentrated and the residue is taken up in 50 ml of diethyl ether. The ether phase is washed twice with 50 ml of 2N aqueous sodium hydroxide solution each time and twice with 50 ml of saturated, aqueous sodium chloride solution each time, dried over magnesium sulphate and concentrated. The residue is recrystallized from 30 ml of hot methanol. 1.15 g (43%) of methyl 6-iodo-pyridine-3-carboxylate are isolated as a colourless solid. M.p. 134°-135°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.Cl.[OH-].[Na+]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cccc(F)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(F)c1Cl

Procedure:
19.6 g. of 2-chloro-3-fluoronitrobenzene (0.11 mole) is reduced with stannous chloride (118 g., 0.63 mole) in 180 ml. of concentrated hydrochloric acid. The solution is basified with aqueous sodium hydroxide and extracted with chloroform to yield 2-chloro-3-fluoroaniline.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:7]=1[C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[NH:10]2.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=[C:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=[C:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]3[C:7]=2[C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[NH:10]3)[CH2:34][CH2:35]1
Reactant: Cc1ccc(OCCCCl)c2c1NC(=O)C2(C)C
Reactant: C(=C1CCNCC1)c1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCCN2CCC(=Cc3ccc4ccccc4n3)CC2)c2c1NC(=O)C2(C)C
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
4-(3-Chloropropoxy)-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-one (268 mg) and 4-(2-quinolylmethylene)piperidine (224 mg) were dissolved in DMF (10 ml), and potassium carbonate (145 mg) and potassium iodide (173 mg) were added to the solution. The mixture was stirred at 100° C. for 90 minutes under argon and concentrated under reduced pressure. Chloroform was added to the residue. The mixture was washed with water, dried over magnesium sulfate anhydrate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developer: chloroform-methanol (20:1)), to thereby obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])=[CH:17][C:16]=2[C:30]#[N:31])=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)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>[C:30]([C:16]1[CH:17]=[C:18]([S:21]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)(=[O:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[N:7][C:2]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=2)=[CH:3][CH:4]=1)#[N:31]
Reactant: Cn1cc(-c2nc(Cl)ccc2Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)cn1
Reactant: OB(O)c1cccc(F)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: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc(-c3cccc(F)c3)ccc2Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)cn1
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
10 mg (0.02 mmol) of 4-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.4 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.63 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (45% yield) of the title compound.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH:15]=[C:16](Cl)[CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.[OH-].[K+]>O>[NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)=Cc1cc(C)nc(Nc2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Temperature: 60 °C
Yield: 55.5 %

Procedure:
Into a 100 ml reaction flask equipped with a stirrer and a thermometer, 5.2 g (0.02 mol) of 2-anilino-4-methyl-6-(2-chloropropen-1-yl)pyrimidine and 40 ml of t-butanol were charged, and the mixture was heated to 60° C. Then, 4.49 g (0.08 mol) of potassium hydroxide powder was added thereto, and the mixture was reacted for 6 hours. After completion of the reaction, the mixture was put into water and extracted with toluene. The toluene layer was washed with water and concentrated, and then it was subjected to column chromatography to obtain 2.48 g of 2-anilino-4-methyl-6-(1-propynyl)pyrimidine as slightly yellow crystals. The yield was 55.5%.