Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH:19]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:18]3[C:29]([CH3:36])=[C:30]([OH:35])[C:31]([CH3:34])=[C:32]([CH3:33])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH:19]([C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:18]3[C:29]([CH3:36])=[C:30]([O:35][CH2:43][C:42]4[CH:45]=[CH:46][C:39]([O:38][CH3:37])=[CH:40][CH:41]=4)[C:31]([CH3:34])=[C:32]([CH3:33])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(Cc3ccccc3)CC1)O2
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C2(CCN(Cc4ccccc4)CC2)O3)cc1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 81.4 mg, 1.81 mmol) was added to a solution of 1′-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (824.0 mg. 1.81 mmol) in N,N-dimethylformamide (15 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (319.9 mg, 2.04 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain the title compound (539 mg, yield 52%). This was amorphous.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[N:16]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:15]2=[N:14][C:13]=1[CH3:30])=O)C.O.[OH-].[Na+]>O1CCCC1>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][O:21][C:20]1[C:15]2[N:16]([C:12]([CH2:10][OH:9])=[C:13]([CH3:30])[N:14]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3F)cccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(OCc3ccccc3F)cccn2c1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled suspension of 1.56 g of lithium aluminium hydride in 200 ml tetrahydrofuran (THF) there was added 15.0 g of 8-(2-fluorobenzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester in portions so that the temperature remained below 10° C. After stirring at 0°-5° C. for an additional 1 hr., 1.6 ml water was added dropwise at 0°-10° C., followed by 1.6 ml15 % aqueous sodium hydroxide and then 4.8 ml water. The mixture was allowed to warm to room temperature with stirring, and was then suction-filtered in a sintered glass funnel. The solids left in the funnelwere thoroughly washed with 200 ml hot tetrahydrofuran and 4×150 ml hot chloroform. The filtrate and washings were combined, evaporated in vacuo, and the solid residue crystallized from acetonitrile to give the desired compound (m.p. 151°-153° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.Br[C:17]([CH3:21])([CH3:20])[CH:18]=[CH2:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[C:17]([CH3:21])([CH3:20])[CH:18]=[CH2:19])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C=CC(C)(C)Br
Product: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 178, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-bromo-3-methyl-but-1-ene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)([O-:3])=[O:2].C([Sn](CCCC)(CCCC)[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)CCC>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.CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1Br
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
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1ccco1
Yield: 27 %

Procedure:
A DMF solution of 2-nitrobromobenzene (2.02 g), 2-tributylstannylfuran (3.31 mL), and tetrakis(triphenylphosphine)palladium was heated at 97° C. under N2 overnight. The mixture was evaporated to a small volume. The residue was suspended in 40 mL of water. This mixture was extracted with two 50 mL portions of Et2O. The combined extracts were dried and evaporated. This oil was purified by chromatography on silica gel with 10% EtOAc/hexanes to yield 0.51 g (27%) of 2-(2-nitrophenyl)furan. [This compound was reported in Smith et al.; J. Am. Chem. Soc. 1953, 75, 6335.]
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.[CH3:20][N:21]([CH3:32])[S:22]([C:25]1[CH:26]=[N:27][CH:28]=[C:29](Br)[CH:30]=1)(=[O:24])=[O:23]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:29]2[CH:28]=[N:27][CH:26]=[C:25]([S:22]([N:21]([CH3:32])[CH3:20])(=[O:23])=[O:24])[CH:30]=2)[CH:11]=1)#[N:16]
Reactant: CN(C)S(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: CN(C)S(=O)(=O)c1cncc(C#Cc2cc(C#N)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 5-bromo-pyridine-3-sulfonic acid dimethylamide (Intermediate 32), the title compound was obtained as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:39]=[CH:38][CH:37]=[CH:36][C:10]=1[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][C:24]#[CH:25])=[CH:19][CH:20]=2)[C:15]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[N:14][C:13]1=[O:35].[CH3:40][NH:41][CH3:42]>>[CH3:40][N:41]([CH3:42])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:39]=[CH:38][CH:37]=[CH:36][C:10]=1[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][C:24]#[CH:25])=[CH:19][CH:20]=2)[C:15]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[N:14][C:13]1=[O:35]
Reactant: CNC
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1OCCCCCCCl
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1OCCCCCCN(C)C
Temperature: 60 °C

Procedure:
A mixture of 50 mg (92.1 μmol) 1-[2-(6-chloro-hexyloxy)-benzyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one and 160 μl ethanolic dimethylamine solution (33%) is heated at 60° C. for 18 h. Extraction with dichloromethane and aqueous 0.1 M NaOH yields the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C@H:5]1[C@H:12]2[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH2:7][CH2:6]1)[OH:4].[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:15][C:16]1[C:21]([NH:1][CH2:2][C@H:3]([C@H:5]2[C@H:12]3[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]3)[CH2:7][CH2:6]2)[OH:4])=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: CC1(C)O[C@H]2[C@H]([C@H](O)CN)CC[C@H]2O1
Reactant: Clc1nccnc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CNc3nccnc3Cl)CC[C@H]2O1

Procedure:
(S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (2-6) (3.22 g, 15.0 mmol, 1.0 eq) was dissolved in dioxane (150 mL). 2,3-Dichloropyrazine (4.46 g, 29.9 mmol, 2 equiv) was added followed by triethylamine (8.34 mL, 59.8 mmol, 4 equiv) and the reaction mixture was heated to reflux overnight. Concentration and purification via flash chromatography on a silica gel column (ethyl acetate/hexanes) yielded desired (S)-2-(3-chloropyrazin-2-ylamino)-1-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (2-7) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.88 (dd, J=5.5, 2.7 Hz, 1H); 7.60 (d, J=2.7 Hz, 1H); 5.74 (d, J=31.9 Hz, 1H); 4.68-4.63 (m, 1H); 4.34 (t, J=5.4 Hz, 1H); 3.88 (ddd, J=14.5, 6.7, 2.5 Hz, 1H); 3.81-3.69 (m, 2H); 3.63-3.46 (m, 2H); 2.15-2.04 (m, 1H); 2.03-1.88 (m, 1H); 1.83-1.72 (m, 1H); 1.69-1.52 (m, 1H); 1.50 (d, J=13.2 Hz, 3H); 1.32 (d, J=4.5 Hz, 3H). LRMS m/z (M+H) 313.9 found, 314.1 required.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH2:10])(=[O:9])=[O:8].[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.Cl>CC(C)=O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH:10][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:22])(=[O:9])=[O:8]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1ccsc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccsc1S(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Yield: 57.1 %

Procedure:
The procedure of Example 4B was followed with the 3-methyl-2-thiophenesulfonamide (1.6 g, 9.0 mmole), 1N NaOH (9.0 ml), acetone (10 ml), 4-chlorophenyl isocyanate (1.4 g, 9.2 mmole), 1N HCl (9.5 ml) to provide the named product (1.7 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:22])=[N:19][C:20]=1[CH3:21].C(#N)C>ClCCl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:22][C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[C:20]([CH3:21])[N:19]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Cc1ccc(N)nc1C
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C)c(C)n1
Temperature: 140 °C
Reaction time: 20 h
Yield: 46.7 %

Procedure:
A heavy walled sealable tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol) and 5,6-dimethylpyridin-2-amine (249 mg, 2.04 mmol). To the mixture was added acetonitrile (8.00 mL) and the reaction mixture was heated with stirring in an oil bath at 140° C. for 20 h. After cooling to room temperature the residue was suspended in dichloromethane and purified by flash chromatography (silica 20-45 μM, 40 g, Thomson) eluting with 0 to 10% over 20 min, acetone/dichloromethane to give ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (195 mg, 46.8%) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 10.54 (s, 1H), 9.14 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 4.55 (q, J=7.2 Hz, 2H), 2.50 (s, 3H), 2.26 (s, 3H), 1.50 (t, J=7.2 Hz, 3H); LC-MS 307.0 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21].CN(C)[CH:24]=[O:25]>C1COCC1>[Br:13][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:24]=[O:25]
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(F)c1Br
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To solution of diisopropylamine (13.29 mL, 93 mmol) in THF (300 mL) at −78° C., was added n-butyllithium (34.2 mL of 2.5M in hexanes, 85 mmol), dropwise over 10 mins. The mixture was stirred at −78° C. for 15 mins and then 2-bromo-1,4-difluorobenzene (15 g, 78 mmol) in THF (100 mL) was added dropwise over 15 mins maintaining the temperature below −65° C. After stirring for 1 hr at −78° C., N,N-dimethylformamide (6.62 mL, 85 mmol) was added via syringe. The mixture was stirred at −78° C. for 30 mins and then quenched with sat. NH4Cl solution and the mixture was allowed to reach room temperature. The product was extracted into ether and the extracts were dried (Na2SO4) and evaporated. Chromatography (silica, 0-100% dichloromethane in hexane) gave the title compound (D14) as a yellow solid (12.73 g)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][OH:26])=[NH:24])=[C:21]([F:29])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:47](OC1C=CC=CC=1)=[O:48]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]2[NH:24][C:47](=[O:48])[O:26][N:25]=2)=[C:21]([F:29])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(NO)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCOCc3ccccc3)cc2F)no1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 0.62 g of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-N-hydroxy-benzamidine in 17 mL of dichloromethane at 0° C., under argon, were added 0.23 mL of pyridine and 154 μL of phenyl chloroformate. The reaction mixture was stirred for 10 min at 0° C. followed by 1 h at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was taken up into 10 mL of acetonitrile under argon and 0.165 mL of 1,4-diazabicyclo[5.4.0]undec-7-ene (DBU) was added. The reaction mixture was stirred at room temperature overnight then warmed to 40° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up into dichloromethane and a 1M aqueous solution of NaH2PO4 was added. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 770 mg of crude product as a yellow powder. Purification by column chromatography on silica gel (heptane 1/ethyl acetate 1) gave 150 mg followed by column washing with 100% MeOH gave 320 mg of the title compound. In total, 470 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one as white powder was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[CH3:46][NH:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][N:56]2[CH2:60][CH2:59][CH2:58][CH2:57]2)[CH:50]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]([CH3:46])[CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][N:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)[CH:50]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1cccc(CN2CCCC2)c1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3cccc(CN4CCCC4)c3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AD using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.16 mmol), CDI (48 mg, 0.29 mmol), DIPEA (0.17 mL, 0.97 mmol) and N-methyl-1-[3-(pyrrolidin-1-ylmethyl)phenyl]methanamine (31 mg, 0.14 mmol) in DCE (1.2 mL).
Reaction SMILES: Cl[C:2]1[N:25]=[C:5]2[C:6]([N:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[CH3:11])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:24][N:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:10]([CH3:11])[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:39][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[CH:38][CH:37]=3)[N:25]=2)[CH:9]=[CH:8][CH:7]=1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CN(Cc1ccccc1N(C)S(C)(=O)=O)c1cccn2nc(Cl)nc12
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(N(C)Cc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
185 b) N-Methyl-N-{2-[(methyl-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino}-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-amino)-methyl]-phenyl}-methanesulfonamide was prepared from N-(2-{[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-methyl-amino]-methyl}-phenyl)-N-methyl-methanesulfonamide (75.0 mg, 0.197 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (42.0 mg, 0.220 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (18.0 mg, 0.0329 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.023 g, 21%). 7.94 (d, J=6.6 Hz, 1H), 7.56-7.51 (m, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.35-7.28 (m, 3H), 6.88 (d, J=8.1 Hz, 2H), 6.70 (t, J=7.3 Hz, 1H), 6.57-6.50 (m, 2H), 5.35-5.23 (m, 1H), 5.12-5.00 (m, 1H), 3.23 (s, 3H), 3.15-3.10 (m, 4H), 3.07 (s, 3H), 2.99 (s, 3H), 2.63-2.58 (m, 4H), 2.36 (s, 3H). MS=535 (MH)+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:2]1.[O-]CC.[Na+].O.Cl>C(O)C>[C:6]([CH:5]([C:4]([CH:1]1[CH2:2][CH2:3]1)=[O:8])[C:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])=[O:20])#[N:7]
Reactant: COc1cc(SC)ccc1C(=O)c1cnoc1C1CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(SC)ccc1C(=O)C(C#N)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Cyclopropyl-4-[2-methoxy-4-(methylsulphenyl)benzoyl]-isoxazole (1.0 g) was added to a solution of sodium ethoxide in ethanol (prepared from sodium (0.12 g) and ethanol). The mixture was stirred at room temperature for 2 hours, poured into water and acidified to pH 1 by addition of hydrochloric acid. The resultant suspension was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether and filtered to give 2-cyano-3-cyclopropyl-1-[2-methoxy-4-(methylsulphenyl)phenyl]propan-1,3-dione, COMPOUND 651, (0.88 g) as a cream solid, m.p. 108°-109° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([CH3:12])=[N:7]2.[CH3:14]I.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([CH2:12][CH3:14])=[N:7]2
Reactant: CI
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2cccc(Br)c2nc1Cl
Temperature: -78 °C
Reaction time: 0.12 h
Yield: 54.3 %

Procedure:
LDA(Aldrich) (1.7M in heptane/THF/ethylbenzene; 0.60 mL, 1.01 mmol) was added (dropwise, over 1 min) to a solution of 5-bromo-3-chloro-2-methylquinoxaline (126e) (238 mg, 0.92 mmol) in THF (8.0 mL) in an oven-dried flask under argon at −78° C., and the resulting solution was stirred at −78° C. for 7 min. Methyl iodide (0.12 mL, 1.85 mmol) was then added, and the resulting solution was stirred at −78° C. for 15 min, then warmed to 23° C. and stir at 23° C. for 16 h. The reaction mixture was subsequently cooled to 0° C., water (0.5 mL) was added, and the reaction mixture was concentrated onto silica gel and chromatographically purified (silica gel, 0-15% EtOAc/hexanes) to provide 5-bromo-3-chloro-2-ethylquinoxaline (136 mg, 0.50 mmol, 54% yield) as a light-orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (1H, d, J=3.1 Hz), 8.02 (1H, d, J=2.3 Hz), 7.60 (1H, t, J=8.0 Hz), 3.20 (2H, q, J=7.4 Hz), 1.44 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 271.0/272.9 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH:2]=[CH2:3].[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O1CCCC1>[CH2:1]([N:4]([C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
4.6 g (0.02 mole) of N-allyl-2,4-dichlorobenzamide was added to 1.2 g (0.024 mole) of 50% sodium hydride in 20 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 30 minutes to react them. Then, 4.2 g (0.024 mole) of p-toluenesulfonyl chloride was added, and reacted at room temperature for 1 hour. The tetrahydrofuran was distilled off under reduced pressure. After adding cold water to the residual oil, it was extracted with benzene, dried over anhydrous magnesium sulfate, and concentrated to afford an oily substance. It was purified by silica gel chromatography to afford compound No. 42 shown in Table 2 in a yield of 68%. Its refractive index and elemental analysis values are also shown in Table 2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:17]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][C:18]=1[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C.CCCCCC>[CH:17]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][C:18]=1[N:30]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:18]3[CH:19]=[CH:20][C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[C:25]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(Nc2ccc3oc4ccccc4c3c2)cc1
Reactant: Brc1ccc(C=Cc2ccc(Br)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C(=Cc1ccc(N(c2ccccc2)c2ccc3oc4ccccc4c3c2)cc1)c1ccc(N(c2ccccc2)c2ccc3oc4ccccc4c3c2)cc1

Procedure:
The Rf values of the object of the synthesis, 4,4′-dibromostilbene, and (dibenzofuran-2-yl)-phenylamine were respectively 0.37, 0.62, and 0.31, which were found by silica gel thin layer chromatography (TLC) (ethyl acetate:hexane (1:10) as the developing solvent).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:17]([O:19][C:20]([N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:23]Cl)=[O:21])[CH3:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:17]([O:19][C:20]([N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:23][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:21])[CH3:18]
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CCOC(=O)CN(SCl)C(=O)OCC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2)C(=O)OCC
Reaction time: 24 h

Procedure:
2.2 g (0.01 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate, 2.4 g (0.01 mole) of N-ethoxycarbonyl-N-ethoxycarbonylmethylaminosulfenyl chloride obtained in Example 17, and 3.2 g (0.04 mole) of pyridine were dissolved in 30 ml of chloroform, and the resulting solution was stirred for 24 hours at 20° to 30° C. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The chloroform layer was dried and concentrated under reduced pressure to obtain an oily product which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities.