Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CC([O-])=O)#N.[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=[C:23]([C:21]#[N:22])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: N#CCC(=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1

Procedure:
[A] Synthesis of 1-benzyl-piperidin-4-ylidene)-cyanoacetate (2; FIG. 4). A solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (9400 mL), ethyl cyanoacetate (50.6 mL, 0.48 mol) and acetic acid (918.2 mL, 0.32 mol) was refluxed for 4 hr. The mixture was quenched with ice-water and extracted with diethyl ether. The combined extracts were washed with water, brine and dried over Na2SO4 to give ethyl (1-benzyl-piperidin-4-ylidene)cyanoacetate in quantitative yield. Rf=0.53 (hexane:AcOEt=1:1).
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:9]([F:20])=[C:8]2[C:3]=1[C:4](=[O:29])[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6][N:7]2[CH:21]1[CH2:23][CH2:22]1.C([Sn](C#[C:44][Si:45](C)([CH3:47])[CH3:46])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.[Pd].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.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>[CH:21]1([N:7]2[C:8]3[C:3](=[C:2]([Si:45]([CH3:47])([CH3:46])[CH3:44])[C:11]([F:12])=[C:10]([N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)[C:9]=3[F:20])[C:4](=[O:29])[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6]2)[CH2:23][CH2:22]1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCN(C)CC3)c(F)c(Br)c2c1=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCN(C)CC3)c(F)c([Si](C)(C)C)c2c1=O
Yield: 58.1 %

Procedure:
1.1 g of ethyl 5-bromo-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylate, 1.2 g of tributylstannyl-trimethylsilyl-acetylene and 0.135 g of tetrakis(triphenylphosphine)-palladium(0) are refluxed for 3 hours in 10 ml of absolute toluene. The reaction mixture is treated with a further 5 ml of toluene and filtered while hot. The product crystallizes out of the filtrate. After filtration with suction and drying, 0.63 g of the title compound is obtained (56% of theory).
Reaction SMILES: [C:1](=S)=[S:2].[NH2:4][CH2:5][CH2:6][S:7][CH2:8][C:9]1[O:13][C:12]([CH2:14][N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>CC(C)=O>[N:4]([CH2:5][CH2:6][S:7][CH2:8][C:9]1[O:13][C:12]([CH2:14][N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)=[C:1]=[S:2]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: S=C=S
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(CSCCN=C=S)o1
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A solution of carbon disulphide (4.2 g) in dry acetone (8 ml) was added dropwise to a solution of 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (10.71 g) in dry acetone (30 ml) during 15 minutes at -10° to 0°. To the stirred solution at -15° was added dropwise a solution of mercuric chloride (13.6 g) in dry acetone (20 ml) during 45 minutes. The solution was warmed to 0° and triethylamine (11.5 g) was added dropwise with stirring during 15 minutes. The mixture was refluxed for 45 minutes, the suspension filtered and the filtrate evaporated to dryness. The oily residue was dissolved in ether (150 ml), decolourising charcoal and excess anhydrous sodium sulphate were added and the suspension filtered after 2 hours. The filtrate was evaporated to dryness, the oily residue dissolved in ether and the solution chromatographed (alumina deactivated with water, 72.5 ml/kg/ether). The appropriate eluate was evaporated to give the title compound (5.05 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[CH:17]([O:20][C:21](Cl)=[O:22])([CH3:19])[CH3:18].C1(C)C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[O:22])[CH2:13][CH2:12]3)=[N:7][C:6]=12
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (2.5 g, 8.87 mmol) taken up in DCM. Isopropylchloroformate 1M in toluene (13.3 mL, 13.3 mmol), and triethylamine (2.47 mL, 17.7 mmol) added and stirred at room temperature 30 minutes. Reaction washed with water, DCM layer dried over magnesium sulfate filtered reduced in vacuo. Run on an Isco silica column with DCM:MeOH 0-5%. Product fractions were combined and reduced in vacuo to obtain 2.86 g crude product for further reaction as is. LRMS (ESI) m/z 368/370 [(M+H)]+, calc'd for C14H18BrN5O: 368.24.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[Si](N=C=S)(N=C=S)(N=C=S)[N:18]=[C:19]=[S:20].C(N)=S>C1C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:19](=[S:20])[NH2:18])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: S=C=N[Si](N=C=S)(N=C=S)N=C=S
Agent: NC=S
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: O
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (1.43 g, 0.01 mole) in benzene (20 ml) was treated with n-butyl-lithium (15% w/w, 4.5 ml, 0.01 mole) and the solution was allowed to stand at room temperature for 0.5 hours. The solution was then treated with a suspension of silicon tetraisothiocyanate (1.3 g, 0.005 mole) in benzene (5 ml) at 0° C. After 10 minutes, water (50 ml.) was added to the solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-lithio-N-(tri-isothiocyanato) silyl)thiocarboxamide causing hydrolysis to 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-tri-isothiocyanato)silyl) thiocarboxamide and subsequent hydrolysis to the title compound, and the mixture was stirred for 0.5 h at room temperature and then acidified with conc. HCl. The aqueous layer was separated, washed with ethyl acetate and the pH was adjusted to 10 with solid Na2CO3. The basic mixture was extracted with ethyl acetate (3 × 50 ml) and the combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was triturated with n-hexane to give 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (0.2 g, 10%).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[S:6](=[O:10])(=[O:9])([OH:8])[OH:7].[Cl:11][CH2:12][CH2:13][C:14]#[N:15]>C(Cl)Cl.CC(C)=O>[S:6](=[O:8])(=[O:7])([OH:10])[OH:9].[S:1]([NH:5][C:14](=[NH:15])[CH2:13][CH2:12][Cl:11])(=[O:3])(=[O:2])[NH2:4]
Reactant: NS(N)(=O)=O
Reactant: N#CCCCl
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: ClCCl
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 57.5 °C

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a solution of conc. sulfuric acid (98%, 9.8 g, 0.1 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the heating period, the mixture was cooled to room temperature, diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml), and the suspension filtered and the product dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[S:32](Cl)(=[O:35])(=[O:34])[NH2:33].O>C(Cl)Cl>[S:32](=[O:35])(=[O:34])([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:33]
Reactant: NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)Oc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.9 %

Procedure:
108 mg of 2′-nitrobiphenyl-4-ol was dissolved in 9.5 ml of methylene chloride, and 312 mg of 2,6-di-tert-butyl-4-methylpyridine and 347 mg of sulfamoyl chloride were successively added thereto under cooling with ice, followed by stirring at room temperature for 5 hours. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 149 mg of 2′-nitrobiphenyl-4-yl sulfamate.
Reaction SMILES: Br[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1.[Li+].[Cl-].[Sn](C)(C)(C)[CH3:20]>CN(C=O)C.C(Cl)Cl.O.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>[CH3:20][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1
Reactant: COC(=O)c1nc2c(cc1Br)SCC(=O)N2
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(cc1C)SCC(=O)N2
Temperature: 100 °C
Yield: 44.2 %

Procedure:
Methyl 7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (1.44 g, 4.75 mmol) was dissolved in DMF (20 mL) and treated with PdCl2(PPh3)2 (167 mg, 0.238 mmol), LiCl (604 mg, 14.2 mmol) and Me4Sn (0.66 mL, 4.75 mmol). The reaction was heated at 100° C. for 30 min, at which point the reaction was no longer proceeding. An additional 0.25 mL of Me4Sn was added and the reaction was heated for an additional 4 h. After cooling, the reaction was diluted with DCM and water. The product was extracted into DCM and the combined extract was dried (Na2SO4) and filtered and the concentrated in vacuo. Purification provided product (500 mg).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.Cl>N1C=CC=CC=1>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([CH:1]([OH:4])[CH:2]([OH:3])[S:11]([C:8]2[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=2)(=[O:13])=[O:12])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C(O)C(O)S(=O)(=O)c2ccc(C)cc2)cc1
Yield: 83 %

Procedure:
19.8 g (0.3 mol) of ethylene glycol are dissolved in 150 ml of distilled pyridine and then the solution is cooled with an ice bath. p-Toluenesulfonyl chloride (123 g, 0.65 mol) is added slowly with mechanical stirring. The temperature must remain below 20° C. during the addition. When approximately 90 g have been added, stirring becomes difficult and the mixture is diluted with 200 ml of pyridine. The reaction mixture is left stirring for 2 h 30. An aqueous HCl solution (12N HCl (170 ml) in ice (500 ml)) is added. The solid formed during this addition is filtered off. This solid is dissolved in refluxing methanol (250 ml) and then the new precipitate formed after returning to ambient temperature is filtered off. Finally, the white solid obtained is dried under vacuum and the pure product is obtained (92.4 g, yield 83%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]([OH:16])=[C:14]2[C:9]([C:10](=[O:19])[CH2:11][C:12]([CH3:18])([CH3:17])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].S(OC)(O[CH3:24])(=O)=O>[OH-].[Na+].O>[CH2:1]([O:5][C:6]1[C:15]([O:16][CH3:24])=[C:14]2[C:9]([C:10](=[O:19])[CH2:11][C:12]([CH3:17])([CH3:18])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc2c(c1O)OC(C)(C)CC2=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(OCC(C)C)ccc2c1OC(C)(C)CC2=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In 50 ml of a 10% sodium hydroxide solution under nitrogen 5.2 g (20 millimoles) of 7-isobutoxy-8-hydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 2.6 g (2 ml, 21 millimoles) of dimethyl sulfate are added and the reaction mixture is intensively stirred for 3 hours at 50° C. The mixture is diluted with 100 ml of icecold water, extracted three times with 50 ml of chloroform each, the organic phase is washed twice with 40 ml of water dried over sodium sulfate and the solvent is evaporated. Thus 5.2 g of the desired compound are obtained in the form of yellow oil, yield 93%.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.COCCCNS(C1C=CC(NC2CC(C(OC)=O)=C(NC3C=CC(S(=O)(=O)NCCCOC)=CC=3)CC=2C(OC)=O)=CC=1)(=O)=O>>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: COCCCNS(=O)(=O)c1ccc(NC2=C(C(=O)OC)CC(Nc3ccc(S(=O)(=O)NCCCOC)cc3)=C(C(=O)OC)C2)cc1
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1

Procedure:
Pigmentary 2,9-dimethylquinacridone was prepared exactly as described in comparison Example 1 except that 10% by weight, relative to the 2,5-di(4-methylanilino)terephthalic acid, of 2,5-bis[4-(3-methoxypropylsulfamoyl)anilino]-1,4-cyclohexadiene-1,4-dicarboxylic acid, dimethyl ester (6.8 g) was included in the ring-closure reaction. 2,9-Dimethylquinacridone (60.3 g) was obtained as a magenta pigment.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 92 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To 720 g of polyphosphoric acid (117%) heated at 92° C. were added 160 g of 2,5-di(4-methylanilino)terephthalic acid over a period of approximately 65 minutes, the temperature being maintained below 105° C. by adjustment of the addition rate. The reaction mixture was held at 105° C. for five hours and then cooled to 92° C. To this mixture was added 107.9 g of phosphoric acid (75%) dropwise over a period of approximately 30 minutes. The resultant melt was allowed to stir for 15 minutes at 90° C. and then poured slowly into 1120 g of methanol, the temperature being maintained below reflux using a water bath. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant presscake was reslurried in water and heated to 45° C. After the slurry was acidified to pH 2.6, an emulsion of 4.7 g of an anionic surfactant, 69.7 g of a petroleum distillate, and 160 g of water was added, and the slurry was stirred for three hours. The resultant slurry was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 143 g of 2,9-dimethylquinacridone as a magenta pigment.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.CO>O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To 320 g of polyphosphoric acid (111.8% phosphoric acid) heated at 80°-95° C. was added 0.72 g (5.1 mmole) of sodium sulfate followed by 72 g (0.1915 mole) of essentially salt-free 2,5-di(4-methylanilino)terephthalic acid. The mixture was heated at 120°-125° C. for two hours. The viscous solution was cooled to 90°-95° C. and then slowly poured into a mixture of 468 g of methanol and 52 g of water (i.e., 90% aqueous methanol) at 40° C. The temperature of the resultant slurry was allowed to rise during the addition to about 64° C., with the temperature being controlled during addition by external cooling and adjustment of melt addition rate. The slurry was heated at reflux for one hour, cooled to 60° C., and diluted with 600 g of water. After the slurry was stirred at 60° C. for 30 minutes, the solid component was collected by filtration and washed with water until acid-free. The resultant presscake was reslurried in 800 g of aqueous sodium hydroxide, then heated at about 90°-95° C. The slurry was cooled, filtered, and washed with water until free of alkali, then reslurried in water. The resultant slurry was heated at 140°-145° C. in a closed system (e.g., a pressure reactor), cooled, acidified to pH 3.5 with phosphoric acid, treated with an aqueous emulsion of sodium dioctyl sulfosuccinate and VM&P Naphtha (available from Unocal Chemicals), and stirred. The solid component was collected by filtration and washed with water. The wet cake can be oven dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give about 60 g of 2,9-dimethylquinacridone as a brilliant magenta solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[Cl:23][CH2:24][C:25](Cl)=O>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][N:10]1[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=[C:25]1[CH2:24][Cl:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Reactant: O=C(Cl)CCl
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3ccccc3c21
Yield: 72 %

Procedure:
Using the general method of Examples 43-68 Part A, tert-butyl[2-(3-aminoquinolin-4-ylamino)ethyl]carbamate (43.5 g, 144 mmol) was reacted with chloroacetyl chloride (17.72 g, 158 mmol) to provide 37.39 g of tert-butyl[2-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate.
Reaction SMILES: C[Si](C)(C)C1C=C(C=CC=1)N.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:19][C:18]1[C:13]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccnc1Cl
Reactant: C1CNCCN1
Agent: C[Si](C)(C)c1cccc(N)c1
Product: Clc1cccnc1N1CCNCC1
Yield: 86.8 %

Procedure:
Compound A-01 can be synthesized according to method 1. Just R1, R2, and R3 of Scheme 1 are respectively —Cl, —H and p-SiMe3. More specifically, compound 1 is 2,3-dichloro-pyridine (2 g); compound 2 is piperazine; compound 3 is 1-(3-chloro-2-pyridyl)piperazine (2.3 g, yield 86.8%); compound 7 is compound 7a-p-(trimethylsilyl)phenyl isocynate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:20][CH:21]=O)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([BH3-])#N.[Na+].C(O)(=O)C>CO.CCOC(C)=O>[C:15]([O:14][C:13]([N:12]([CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:20][CH2:21][NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CNCCN(CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-Butyl [2-(4-nitrophenyl)ethyl](2-oxoethyl)carbamate (0.95 g, 3.1 mmol) in MeOH (20 mL) was added ethyl aminoacetate hydrochloride (480 mg, 3.4 mmol), sodium cyanoborohydride (590 mg, 9.3 mmol) and a drop of acetic acid. The mixture was allowed to stir at RT for 16 hours. LC showed good reaction. The reaction was diluted with EtOAc, washed with aqueous sodium carbonate, dried over sodium sulfate, and purified by silica gel chromatography to furnish the title compound. LC-MS (IE, m/z): 393 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([O:28][C:29]3[C:36]([CH3:37])=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=3[CH3:38])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1C=CC=CC1=O>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([O:28][C:29]3[C:30]([CH3:38])=[CH:31][C:32]([C:33]#[N:34])=[CH:35][C:36]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(F)nc2c1ccn2Cc1ccccc1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a solution of 4-aminobenzonitrile (54 mg, 0.46 mmol) in 1-methyl-2-pyridone (1 mL) was added NaH (18 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile (34 mg, 0.091 mmol) in 1-methyl-2-pyridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 28 mg (65%) of 4-[7-benzyl-2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimethyl-benzonitrile.
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][C:5]=2[CH:4]=1)=O.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.CC(O)=O.C([BH3-])#N.[Na+]>CO>[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][CH2:1][C:3]2[CH:23]=[CH:22][C:6]3[NH:7][C:8]([C@@H:10]4[CH2:14][CH2:13][CH2:12][N:11]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][C:5]=3[CH:4]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(C=O)ccc2[nH]1
Reactant: Nc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CNc3ccc(F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of the product from Example 95A (1.0 g, 3.17 mmol), 4-fluoroaniline (304 μL, 3.17 mmol) and AcOH (150 μL) in MeOH (30 mL) was added sodium cyanoborohydride (199 mg, 3.17 mmol). The mixture was stirred at rt overnight, and was then quenched with aqueous 1N HCl followed by stirring for 5 minutes. A few drops of aqueous NH4OH were added, and the mixture was diluted with EtOAc and washed with saturated aq. NaHCO3, H2O, and brine. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound (1.3 g, 100%). MS (ESI) m/z 411 (M+H)+.