Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30](Cl)=[O:31])=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]=[CH:21][CH:22]=3)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccnc2ccccc12
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccnc2ccccc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin4-amine and quinoline4-carbonyl chloride were combined to provide N4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]4-quinolinecarboxamide as a white crystalline solid, m.p. 214.5-215.2° C. 1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, J=4.3 Hz, 1H), 8.76 (t, J=5.6 Hz, 1H), 8.24 (s, 1H), 8.10-8.01 (m, 3H), 7.78 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.64 (dd, J=8.4, 1.1 Hz, 1H), 7.56 (ddd, J=8.3, 6.9, 1.4 Hz, 1H), 7.44 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.34 (d, J=4.3 Hz, 1H), 7.24 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 6.60 (broad s, 2H), 4.68 (t, J=6.9 Hz, 2H), 3.38 (q, J=7.0 Hz, 2H), 2.00 (m, 2H), 1.63 (m, 2H); MS (EI) m/e 410.1860 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:31].C(N(CC)CC)C.Cl>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[C:8]([C:10](=[O:12])[NH:31][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=2[F:23])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cn1S(C)(=O)=O
Reactant: Nc1cccc(F)c1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 1-methanesulfonyl-1H-pyrrole-2,4-dicarboxylic acid 2-methyl ester (290 mg, 1.17 mmol) in dry CH2Cl2 (5 mL) and DMF (2 drops) was added oxalyl chloride (220 mg, 1.73 mmol) at room temperature. The mixture was stirred for 1 hour and evaporated. The residue was dried on the vacuum pump for 4 hours and then dissolved in dry CH2Cl2 (5 mL). To this solution was added 2,3-difluoro-phenylamine (300 mg, 2.32 mmol) and triethylamine (240 mg, 2.37 mmol). The reaction mixture was stirred for another 1 hour then poured into 2N HCl solution. The aqueous solution was extracted with EtOAc and the combined organic layers were dried over MgSO4. After removal of solvent by evaporation, the residue was purified by flash column eluting with 20% EtOAc/hexanes to afford the title compound as a yellow solid (410 mg, 98%). MS (ES+): m/e=359.1 (M+H); LC/Method A/3.31 min.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][CH:12]=1.[NH2:16][C:17]1C=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.BrC1C=CC=CN=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(Cl)Cl.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>[N:16]1[CH:17]=[CH:22][CH:21]=[CH:20][C:19]=1[C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[NH2:6]
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Brc1ccccn1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Nc1cccc(-c2ccccn2)c1

Procedure:
3-Aminophenylboronic acid hemisulphate (5.58 g, 30 mmol), 2-bromopyridine (2.7 ml, 28 mmol), Pd(PPh3)2Cl2 (100 mg, 0.5 mol %), 2M K2CO3 (50 ml) were refluxed in 1,2-dimethoxyethane (50 ml) for 24 h under N2. The mixture was diluted with CH2Cl2 (100 ml) and washed with sat. NaHCO3 (50 ml). The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure. Flash-chromatography with CH2Cl2 as eluent gave 3-(2-pyridyl)aniline as a yellow oil, 1.0 g (21%). 3-(2-Pyridyl)aniline was transformed by Method B and Method G (using cyclohexanecarboxaldehyde). M.p. 213–216° C.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)CCC.[Cl-].[Li+].[F-].[K+]>CN(C)C=O.C(OCC)(=O)C.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>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[C:3]([CH3:28])[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)c(-c2cccs2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.4 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), tributyl(2-thienyl)tin (0.64 g) and lithium chloride (0.15 g) in N,N-dimethylformamide (10 mL) was added dichlorobis(triphenylphosphine)palladium (0.04 g), and the mixture was stirred for 12 hr under an argon atmosphere. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. A 20% aqueous potassium fluoride solution was added, and the mixture was stirred for 2 hr. The insoluble material was filtered off through celite. The organic layer of the filtrate was separated, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.38 g, 75%) as a colorless viscous oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2[O:14][CH3:15])[CH2:3][CH2:2]1.[Br:16]N1C(=O)CCC1=O>C1COCC1>[Br:16][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:7]=1[O:14][CH3:15]
Reactant: COc1cccc(OC)c1OCC1CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COc1ccc(Br)c(OC)c1OCC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
To a stirring solution of 2-(cyclopropylmethoxy)-1,3-dimethoxybenzene (500 mg, 2.40 mmol) in THF (25 mL) was added N-bromosuccinimide (430 mg, 2.40 mmol) and the resultant reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 1-Bromo-3-(cyclopropylmethoxy)-2,4-dimethoxybenzene as a solid (500 mg, 73%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](O)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][O:21][CH3:22]>CN(C=O)C>[CH3:20][O:21][CH2:22][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1cc(F)ccc1C(=O)OC
Reaction time: 48 h
Yield: 57.5 %

Procedure:
Into a DMF (200 mL) solution of methyl 4-fluoro-2-hydroxybenzoate (17.0 g, 100 mL), cooled in an ice bath, was added K2CO3 (27.6 g, 200 mmol) and chloromethymethyl ether (9.11 mL, 120 mmol) dropwise. The reaction mixture was allowed to come to room temperature slowly and was stirred 48 h. To the reaction mixture at room temperature was added additional K2CO3 (6.9 g, 50 mmol) and chloromethylmethyl ether (4.5 mL, 60 mmol), and stirring was continued for 24 h. Most of the solvent was evporated in a bath at 60° C., and the residue was partitioned between ether (250 mL) and water (250 mL). The organic layer was washed with 1 N HCl (200 mL), dried (MgSO4), and evaporated. The crude product was chromatographed over silica (eluting with 0 to 20% EtOAc in hexane gradient), giving 11.38 g (57% yield) of the named product as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.I[CH:19]([CH3:21])[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH3:17][C:14]([C:4]1[N:3]=[C:2]([Cl:1])[C:7]([CH:8]([CH:19]([CH3:21])[CH3:20])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=1)([CH3:16])[CH3:15]
Reactant: CC(C)I
Reactant: CCOC(=O)Cc1cnc(C(C)(C)C)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOC(=O)C(c1cnc(C(C)(C)C)nc1Cl)C(C)C

Procedure:
4-chloro-5-ethoxycarbonylmethyl-2-(2-methylprop-2-yl)pyrimidine was reacted with 2-iodo-propane in the presence of lithium bis(trimethylsilyl)amide according to the procedure illustrated in example 6, to give ethyl (RS)-2-[2-(2-methylprop-2-yl)-4-chloropyrimidin-5-yl]-3-methylbutyrate.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:15]([N:39]1[CH2:38][CH2:37][N:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)[CH2:41][CH2:40]1)[N:16]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Reaction time: 90 h

Procedure:
550 mg (1.39 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A) and 251 mg (1.39 mmol) of 1-(4-fluorophenyl)piperazine are stirred in the presence of a spatula tip of silica gel in 15 ml of dichloromethane for 1 hour. After 90 hours of stirring under reflux, the product is purified by chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Reaction SMILES: [CH2:1]([C:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)(C(OCC)=O)[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>C(O)C>[CH2:1]([CH:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccccc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)Cc1ccc([N+](=O)[O-])cc1
Temperature: 95 °C
Reaction time: 7 h
Yield: 59.1 %

Procedure:
A mixture of diethyl benzyl-4-nitrobenzylmalonate (24 g), KOH (14 g) and water (100 ml)-ethanol (150 ml) was stirred at 90-100° C. for 7 hours. The reaction mixture was concentrated under reduced pressure and the residue was acidified with 1N HCl and extracted with ethylacetate. The ethyl acetate layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in pyridine (100 ml) and the solution was stirred at 90° C. for 16 hours. The organic solvent was evaporated off and the residue was acidified with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residual oil was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:3, v/v) gave 2-benzyl-3-(p-nitrophenyl)propionic acid (10.5 g, 59%) as crystals. Melting point: 104-105° C.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:16])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].[NH3:17]>C1C=CC=CC=1>[CH3:16][C:4]([CH:5]=[CH:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][CH2:2][NH2:17]
Reactant: N
Reactant: CC(C)=CCCC(C)CC=CC(C)=CCBr
Solvent: c1ccccc1
Product: CC(C)=CCCC(C)CC=CC(C)=CCN
Reaction time: 4 h

Procedure:
Ten grams of 1-bromo-3,7,11-trimethyldodeca-2,4,10-triene is mixed with 50 ml. of benzene, cooled to 5°-10° and saturated with ammonia. The resulting mixture is stirred for 4 hours allowing the temperature to rise to about 20° while maintaining dry conditions. The mixture is washed with dilute sodium hydroxide and then evaporated under reduced pressure to yield 3,7,11-trimethyldodeca-2,4,10-trienylamine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([Cl:35])[CH:26]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:16]=[CH:15][N:14]3[CH:22]=2)=[CH:7][CH:6]=1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.[CH3:57][N:58]([CH3:63])[CH2:59][C:60](O)=[O:61]>C(Cl)Cl.O>[Cl:35][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH:32]([CH3:33])[CH3:34])[C:24]([NH:23][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:16]=[CH:15][N:14]3[CH:22]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][C:60](=[O:61])[CH2:59][N:58]([CH3:63])[CH3:57])=[O:36]
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)N[C@H](CNC(=O)CN(C)C)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A mixture of N-[(1S)-2-amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.912 g, 1.80 mmol), EDCI (0.69 g, 3.6 mmol), N,N-diisopropylethylamine (0.466 g, 3.6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH2Cl2) to give the title compound (0.515 g, 48%) as a pale yellow solid. MS (ES+) m/e 592 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([Cl:18])[CH:9]=2)=[CH:6][N:7]=1.Cl[CH:20]([CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[CH:34]2)[CH:21](N1C(=O)CCC1=O)O>C(O)CCC>[Cl:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:20]([CH2:30][C:31]4[CH:32]=[C:33]5[C:38](=[CH:39][CH:40]=4)[N:37]=[CH:36][CH:35]=[CH:34]5)=[CH:21][N:1]=3)[N:4]=2)[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1Cl
Reactant: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Solvent: CCCCO
Product: COC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Temperature: 110 °C
Reaction time: 22 h
Yield: 66.6 %

Procedure:
The mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)-2-chlorobenzoate (Step 2, 0.840 g, 3.17 mmol) and 1-(2-chloro-1-hydroxy-3-quinolin-6-ylpropyl)pyrrolidine-2,5-dione (1.11 g, 3.49 mmol, Example 1, Step 7) in 1-butanol (11.6 mL) was stirred at 110° C. for 22 h. The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate and hexane to yield the desired product (0.908 g). The mother liquor was concentrated to half volume. The precipitate was collected by filtration and washed with ethyl acetate and hexane to afford additional desired product (0.342 g). The total product obtained was 1.10 g (80.6%). LCMS (M+H)+: m/z=430.0/431.9.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:56]1[CH:61]=[CH:60][CH:59]=[C:58](/[CH:62]=[CH:63]/[C:64](O)=[O:65])[CH:57]=1>O>[N:56]1[CH:61]=[CH:60][CH:59]=[C:58]([CH:62]=[CH:63][C:64]([NH:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:1])([F:21])[F:22])(=[O:12])=[O:11])=[CH:14][CH:15]=2)=[O:65])[CH:57]=1
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: NCc1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C=Cc1cccnc1)NCc1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a 50 ml of flask were added (4-(2-(trifluoromethoxy)phenylsulfonyl)phenyl)methanamine (100 mg, 0.302 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (138 mg, 0.362 mmol DIEA (117 mg, 0.905 mmol), (E)-3-(pyridin-3-yl)acrylic acid (49.5 mg, 0.332 mmol) DMF (5 ml). The mixture was stirred at RT for 16 hours. The mixture was diluted with water and back extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with water (3×20 mL). The organic was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product The crude product was purified by Biotage to afford E)-3-(pyridin-3-yl)-N-(4-(2-(trifluoromethoxy)phenylsulfonyl)benzyl)acrylamide, 85 mg (61%). 1HNMR (DMSO-D6): δ 8.70 (t, 1H), 8.75 (d, 1H), 8.54 (dd, 1H), 8.21 (dd, 2H), 7.98 (dd, 1H), 7.83 (m, 2H), 7.66 (dt, 1H), 7.53 (m, 2H), 7.44 (m, 1H), 6.75 (d, 1H), 4.49 (d, 1H)
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1.C1(C2C=CC(N)=CC=2)CCCCC1.C([O-])(=O)C.[Na+]>[N+](C1C=CC=CC=1)([O-])=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:18][C:5]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[CH:2]=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)ccc(O)c21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Nc1ccc(C2CCCCC2)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(O)cccc21

Procedure:
The pleochroic dye 1-cyclohexylphenylamino, 4-hydroxyanthraquinone was prepared by combining equimolar quantities of 1-chloro-4-hydroxy anthraquinone and 4-cyclohexylaniline and heating in the presence of a catalytic amount of copper acetate (0.1 g/0.1 mole) and sodium acetate (10 g/0.1 mole) in nitrobenzene. The reaction was run and the dye separated and tested as in Example 70. The dye had an absorption maxima at 594 nm and an optical order parameter of 0.75.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:13]=1)[C:11]#[N:12])[CH2:4][CH3:5].CCN(C(C)C)C(C)C.[C:23]([C:25]1[C:32](F)=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[C:26]=1[C:34]#[N:35])#[CH:24].C([O-])(O)=O.[Na+]>CCOC(C)=O.[Cu]I.CN1C(=O)CCC1>[C:11]([C:10]1[CH:13]=[C:6]([C@H:3]([N:2]2[C:32]3[C:25](=[C:26]([C:34]#[N:35])[C:27]([C:28]#[N:29])=[CH:30][CH:31]=3)[CH:23]=[CH:24]2)[CH2:4][CH3:5])[CH:7]=[N:8][CH:9]=1)#[N:12]
Reactant: CC[C@@H](N)c1cncc(C#N)c1
Reactant: C#Cc1c(F)ccc(C#N)c1C#N
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC[C@H](c1cncc(C#N)c1)n1ccc2c(C#N)c(C#N)ccc21
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 35.1 %

Procedure:
To a solution of (R)-5-(1-aminopropyl)nicotinonitrile hydrochloride (0.081 g, 0.411 mmol) in anhyd NMP (2.0 mL) was added DIEA (0.215 mL, 1.232 mmol) via syringe. The mixture was stirred 15 min and 3-ethynyl-4-fluorophthalonitrile (0.0635 g, 0.373 mmol) was added in one portion. The mixture was stirred at rt under N2 for 36 h, poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in anhyd DMF (3 mL), CuI (0.036 g, 0.187 mmol) was added and the mixture was subjected to microwave heating (140° C.) for 30 min. The mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was diluted 1:1 with heptane and concentrated in vacuo (3× heptane chase). The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (R)-1-(1-(5-cyanopyridin-3-yl)propyl)-1H-indole-4,5-dicarbonitrile (0.0407 g, 0.131 mmol, 35.0% yield) as a yellow gum: 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=8.7 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H), 7.66 (t, J=2.1 Hz, 1H), 7.63 (d, J=3.4 Hz, 1H), 7.53 (s, 2H), 7.00 (d, J=3.4 Hz, 1H), 5.50 (dd, J=8.7, 6.8 Hz, 1H), 2.53-2.34 (m, 2H), 1.03 (t, J=7.3 Hz, 3H); MS (LCMS ES+) m/z 312 ([M+H]+, 6%), 353 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: C(O/C=C\[C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:7]=1)C.I([O-])(=O)(=O)=O.[Na+].[O:36]1CCOC[CH2:37]1>O.[Os](=O)(=O)(=O)=O>[CH:37]([C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[CH:7]=1)=[O:36]
Reactant: CCO/C=C\c1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C=O)nc(C(F)(F)F)n2)CC1
Reaction time: 24 h

Procedure:
tert-Butyl 4-{[6-[(Z)-2-ethoxyvinyl]-2-(trifluoromethyl)pyrimidin-4-yl]amino}piperidine-1-carboxylate (0.80 g, 1.9 mmol, from Step 2) was dissolved in 1,4-dioxane (56 mL) and water (14 mL), then sodium periodate (1.2 g, 5.8 mmol) was added followed by osmium tetraoxide (4 wt % in water, 0.424 mL, 0.0666 mmol). After stirring for 24 hours, the reaction mixture was partitioned between water and EtOAc, the phases were separated and the aqueous phase was extracted with additional EtOAc. The combined organic extracts were washed with water, then sat'd NaCl, dried over Na2SO4, filtered and solvent removed in vacuo. The crude product was used in the next reaction without purification. LCMS (M+H)+: 375.0; (M+H2O+H)+: 393.0.
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[CH3:7][N:8]([CH3:23])[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[NH:19][CH2:20][CH2:21]O.C([O-])(O)=O.[Na+]>O>[CH3:7][N:8]([CH3:23])[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[NH:19][CH2:20][CH2:21][Br:1]
Reactant: CN(C)c1ccc2nccc(NCCO)c2c1
Reactant: Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(C)c1ccc2nccc(NCCBr)c2c1
Temperature: 165 °C
Yield: 57 %

Procedure:
Hydrobromic acid (6.6 ml, 122 mmol) and then sulphuric acid (2.2 ml, 41.4 mmol) are added dropwise to the 6-dimethylamino-4-(β-hydroxyethylamino)quinoline 13 (4.56 g, 19.7 mmol), the reaction medium being refrigerated using a bath of cold water. The reaction medium is then heated at 165° C. for 3 h 30 min and then poured into 71 ml of cold water. The pH is then adjusted by adding NaHCO3 (pH approximately 9) and the medium is then extracted at the reflux of toluene (71 ml) for 15 min. The organic phase is then collected and the product is obtained by crystallization at −18° C. overnight, filtration, and then washing with hexane and drying under vacuum: 3.28 g (yield=57%).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][NH2:17]>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([NH:17][CH2:16][CH2:15][NH:14][CH3:13])=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: CNCCN
Reactant: COc1ccc2c(Cl)noc2c1
Product: CNCCNc1noc2cc(OC)ccc12
Temperature: 140 °C

Procedure:
To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (2.0 g) and N-methylethylenediamine (4.8 g). The reaction was heated to 140° C. over 48 hours and then cooled to room temperature. The residue was partitioned between EtOAc and brine, washed with brine (4×) and the organic phase was dried over MgSO4 and concentrated in vacuo. Flash chromatography (silica gel) eluting with 5% acetone/CH2Cl2 provided a residue upon evaporation (0.4 g) m.p. 136-137° C.