Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][NH:16][C:17]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=1[N+:26]([O-])=O)([O-])=O.[H][H].[S:31](=[O:35])(=[O:34])([OH:33])[OH:32]>[Pd].CO>[S:31]([OH:35])([OH:34])(=[O:33])=[O:32].[NH2:26][C:18]1[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:17]=1[NH:16][CH2:15][CH2:14][NH:13][C:5]1[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(NCCNc2cc([N+](=O)[O-])ccc2[N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: Nc1ccc(N)c(NCCNc2cc(N)ccc2N)c1

Procedure:
150 ml of methanol were introduced into a 0.3 liter autoclave, 16.7 g (0.2 mole) of N,N'-bis-(2,5-dinitrophenyl)-1,2-diaminoethane were dissolved therein and 2 g of palladium on active carbon 10% (Degussa) were added. After the autoclave had been closed and blanketed with nitrogen, hydrogenation was carried out under a pressure of 3 bar and at a temperature of 35 to 40° C. until no more hydrogen was taken up. The mixture was emptied onto a pressure filter, the residue was dissolved in 100 ml of N-methyl pyrrolidone at 100° C., the catalyst was filtered off using a pressure filter and, after cooing of the filtrate to 5-10° C., 9.8 g (0.1 mole) of 80% sulfuric acid were added dropwise. The jelly-like precipitate was stirred with 200 ml of methanol. The crystallized product was filtered off under suction, washed with methanol and dried.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.O>C(O)(=O)C.Cl>[F:21][C:19]1[C:18]([F:22])=[C:17]([F:23])[C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:24])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)c(F)c3nc21
Temperature: 20 °C
Yield: 92.7 %

Procedure:
A suspension of 4 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 30 cm3 of acetic acid and 30 cm3 of 50% hydrochloric acid is heated at a temperature close to 100° C. for 2 hours. After cooling to about 20° C., 100 cm3 of water are added. The precipitate formed is drained, washed with 3 times 50 cm3 of water and recrystallized from 80 cm3 of dimethylformamide. 3.4 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a colourless solid melting at 350°-352° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:21][CH2:22][C:23]#[N:24])[C:9](=O)[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.CO>C1COCC1>[NH2:24][CH2:23][CH2:22][CH2:21][N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: CN(CC(=O)N(CCC#N)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCN(CCCN)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 104465.6 %

Procedure:
tert-butyl 2-((3-chlorophenyl)(2-cyanoethyl)amino)-2-oxoethyl(methyl)carbamate (500 mg, 1.4 mmol) was dissolved in anhydrous THF (10 mL) and heated to reflux under nitrogen atmosphere. A solution of BH3.MeS in THF was added drop wise and stirring was continued under reflux overnight. The resulting solution was cooled to room temperature. Methanol was added drop wise to quench the reaction. After evaporation of the solution, the crude product was purified by column chromatography to afford the pure product tert-butyl 2-((3-aminopropyl)(3-chlorophenyl)amino)ethyl(methyl)carbamate (500 g, yield 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:36])([F:35])[C:21]([C:27]1[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=1)([OH:26])[C:22]([F:25])([F:24])[F:23].[OH-].[Na+]>CO.O.C(Cl)(Cl)Cl>[F:25][C:22]([F:23])([F:24])[C:21]([C:27]1[N:32]=[C:31](/[CH:33]=[C:8]2/[C:9](=[O:12])[C:10]3[C:6]([CH2:7]/2)=[CH:5][C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[C:3]([O:2][CH3:1])[CH:11]=3)[CH:30]=[CH:29][CH:28]=1)([OH:26])[C:20]([F:36])([F:35])[F:19]
Reactant: O=Cc1cccc(C(O)(C(F)(F)F)C(F)(F)F)n1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cccc(C(O)(C(F)(F)F)C(F)(F)F)n1)C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (0.1 g, 0.40 mmol)) in MeOH/H2O (1:1) was added 6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)picolinaldehyde 262 (0.132 g, 0.485 mmol), NaOH (0.032 g, 0.80 mmol), and the reaction stirred at RT for 6 h. The reaction mass was diluted with chloroform and washed with water (3×25 ml). The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound 265 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid (E)-2-((6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)methylene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 265.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=O.P([Cl:34])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[C:6]1([N:5]=[C:3]([Cl:34])[C:2]([F:17])([F:16])[F:1])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Nc1cccc2ccccc12)C(F)(F)F
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)C(Cl)=Nc1cccc2ccccc12
Temperature: 82 °C
Yield: 86.4 %

Procedure:
Five grams (20.9 mmol) of 2,2,2-trifluoro-N-(naphthalen-1-yl)acetamide, 11.23 g (41.8 mmol) of diphenyl chlorophosphate, 4.22 g (41.8 mmol) of triethylamine, and 20 ml of acetonitrile were introduced into a 50 ml flask and reacted for 15 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 15 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.65 g of N-(naphthalen-1-yl)-2,2,2-trifluoroacetimidoyl chloride as a yellow oil (yield: 86.2%).
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:9]1[C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1cccc(F)c1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2c(F)cccc2C#N)cn1
Yield: 28 %

Procedure:
In analogy to example 5a, 2,3-difluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup and crystallization from Ethyl acetate/diisopropylether the title compound was obtained as an off-white solid (yield: 28%). 1H-NMR (300 MHz, DMSO): δ=2.19 (d, J=0.9 Hz, 3H), 7.26 (s with fine splitting, 1H), 7.71-7.89 (m, 1H), 7.86-7.94 (m, 3H)
Reaction SMILES: [N+:1]([C@@H:3]1[C@@H:6]([CH2:7][CH:8]=[CH2:9])[N:5]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:4]1=[O:18])#[C-:2].C([Li])CCC.[CH3:24][C:25]([CH3:27])=[O:26].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[OH:26][C:25]([C@:3]1([N+:1]#[C-:2])[C@@H:6]([CH2:7][CH:8]=[CH2:9])[N:5]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:4]1=[O:18])([CH3:27])[CH3:24]
Reactant: CC(C)=O
Reactant: [C-]#[N+][C@H]1C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: [C-]#[N+][C@]1(C(C)(C)O)C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (106.9 mg) in tetrahydrofuran (2.1 ml) was added dropwise a solution of n-butyl lithium (0.375 ml of 1.38M solution in hexane) at -78° C. After stirring for 15 minutes at -78° C., the reaction mixture was added with a solution of acetone (0.0385 ml) in tetrahydrofuran (0.3465 ml) at -78° C. After stirring for 25 minutes at -78° C., the reaction mixture was added with acetic acid (0.0493 ml) at -78° C., diluted with ethyl acetate (30 ml), and washed with chilled brine (10 ml), aqueous sodium bicarbonate (10 ml), brine (10 ml), and saturated aqueous sodium chloride (10 ml). After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil was chromatographed on silica gel (1.2 g) eluting with a mixture of ethyl acetate and hexane (1:5-1:3) to give methyl 2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (96.5 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[C:12](=[O:19])[S:11]2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[NH:24][C:23](=[O:27])[N:22]([CH3:28])[C:21]1=[O:29].C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[CH:37]=[CH2:38].O>CC(C)=O>[CH2:36]([N:24]1[C:23](=[O:27])[N:22]([CH3:28])[C:21](=[O:29])[N:20]([C:3]2[CH:4]=[C:5]([N:9]=[C:10]3[N:14]4[CH2:15][CH2:16][CH2:17][CH2:18][N:13]4[C:12](=[O:19])[S:11]3)[C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:25]1=[O:26])[CH:37]=[CH2:38]
Reactant: C=CCBr
Reactant: Cn1c(=O)[nH]c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCn1c(=O)n(C)c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A mixture of 1-{2-chloro-4-fluoro-5-[(tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a]pyridazin-1-ylidene)-amino]phenyl}-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (1.00 g, 2.27 mmol), potassium carbonate (0.627 g, 4.54 mmol) and allyl bromide (0.329 g, 2.72 mmol) in acetone is stirred overnight at 40° C. and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a white glass (0.8 g) which is identified by NMR spectral analyses.
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3([C:34]4[C:25](=[CH:26][C:27]5[O:32][CH2:31][CH2:30][O:29][C:28]=5[CH:33]=4)[O:24][CH2:23]3)[C:15]2=[O:35])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OC1C=CC(CN2C3C(=CC=CC=3)C3(COC4C=C5C(=CC3=4)CCO5)C2=O)=CC=1)C1C=CC=CC=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3([C:34]4[C:25](=[CH:26][C:27]5[O:32][CH2:31][CH2:30][O:29][C:28]=5[CH:33]=4)[O:24][CH2:23]3)[C:15]2=[O:35])=[CH:36][CH:37]=1
Reactant: O=C1N(Cc2ccc(OCc3ccccc3)cc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C1N(Cc2ccc(OCc3ccccc3)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(O)cc2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in Example 17 and making non-critical variations using 1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-[4-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(4-hydroxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (93%) as a colorless solid: mp 243-244° C.; 1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 7.30-7.22 (m, 1H), 7.20-7.13 (m, 3H), 7.05-6.97 (m, 2H), 6.76-6.68 (m, 2H), 6.52 (s, 1H), 6.04 (s, 1H), 4.89-4.63 (m, 4H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.6, 156.7, 154.6, 144.1, 142.1, 137.7, 131.7, 128.6, 126.4, 123.5, 122.9, 121.2, 115.3, 110.8, 109.5, 98.8, 79.3, 64.1, 63.5, 57.1, 42.5; MS (ES+) m/z 401.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([CH3:11])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])=[O:7])=[CH:9][CH:10]=1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-methyl-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.29 (s, 1H), 9.02 (d, J=2.7, 1H), 8.81 (d, J=8.7, 1H), 8.24-8.21 (m, 1H), 8.11 (s, 1H), 7.58-7.50 (m, 2H), 2.44 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH:3]=1.[CH2:8]([N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C(O)=O>C(O)C.CC(O)C>[CH3:7][N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:16]2[N:15]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)[CH2:3]1
Reactant: Clc1nc2ccccc2n1Cc1ccccc1
Reactant: CN1C=C(N)CC1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: CCO
Product: CN1CCC(Nc2nc3ccccc3n2Cc2ccccc2)C1
Temperature: 125 °C

Procedure:
To 14 g (0.14 mol) of 3-amino-N-methyl pyrroline was added 10.4 g (0.042 mol) of N-benzyl-2-chlorobenzimidazole and the reaction mixture heated to 125° C. for 2 days. The reaction mixture was partitioned between 150 mL of 1N NaOH and 100 mL of CH2Cl2. The aqueous layer was extracted again with 100 mL of CH2Cl2. The combined organic layers were washed with 100 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation and subjected to high vacuum at 100° C. for ~30 min. For purification, the residue was treated with 2 moles of oxalic acid in ethanol/2-propanol to afford 15 g (73%) of white analytically pure crystals, mp 211°-213° C. dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCN1C(=O)C(c2cc(Br)ccc2O)c2ccccc21
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one (2.22 g, 5.64 mmol) in dichloromethane (10.0 mL) were added trifluoroacetic acid (1.00 mL) and triethylsilane (1.00 mL) at ambient temperature. The reaction mixture was stirred at 50° C. for 15 hrs and concentrated in vacuo to dryness to give the title compound: MS (ES+) m/z 374 (M+1), 376 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][N:17]=2)=[O:15])=[CH:10][CH:9]=1.[OH:31]O>C1COCC1>[OH:31][C:19]1[CH:18]=[N:17][C:16]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:9][CH:10]=2)=[O:15])=[N:21][CH:20]=1
Reactant: OO
Reactant: CC1(C)OB(c2cnc(C(=O)c3ccc(OC4CCCCO4)cc3)nc2)OC1(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ncc(O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of (4-(tetrahydro-2H-pyran-2-yloxy)phenyl)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)methanone (410 mg, 1 mmol) in 20 mL of THF was added 0.5 mL 33% H2O2 and the reaction was stirred for 1 h at rt. The reaction was then quenched with aq. Na2SO3, extracted with EtOAc, washed with water and brine, dried, filtered, concentrated, and purified by column chromatography to give the desired product (240 mg, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[N:7]([NH:11][CH3:12])[CH:8]=[CH:9][CH:10]=1)=[O:5].[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:12][N:11]([N:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[Cl:1])[C:26](=[O:27])[CH2:25][NH:24][C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNn1cccc1C(=O)c1ccccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CN(C(=O)CNC(=O)OC(C)(C)C)n1cccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
2-(2-Chlorobenzoyl)-1-methylaminopyrrole (23.7 g, 0.10 mol) and tert-butoxycarbonyl glycine (19.26 g. 0.11 mol) are combined in 250 ml of dichloromethane followed by addition of dicyclohexylcarbodiimide (23.7 g, 0.115 mol) over 3 minutes. The mixture was stirred at ambient temperature for 5 hours and thereafter filtered and evaporated to give 35 g of oil. This oil was purified by HPLC (silica, 2:1 hexane-ethyl acetate) to give 28 g of solid. This material was recrystallized from ether to give 26.5 g (68%) of cubes, m.p. 131°-133°.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[C:15](C(O)=O)[C:14](NC3C=CC(C)=CC=3)=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:3][CH:2]=1.ClC1C=CC([NH:34][C:35]2[CH:43]=[C:42](C(O)=O)[C:41](NC3C=CC(Cl)=CC=3)=[CH:40][C:36]=2[C:37](O)=[O:38])=CC=1>>[CH:1]1[CH:6]=[C:5]2[C:10]([C:9]3[C:8]([NH:7][C:4]2=[CH:3][CH:2]=1)=[CH:16][C:15]1[C:37]([C:36]2[C:35]([NH:34][C:14]=1[CH:13]=3)=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 125 °C
Reaction time: 0.42 h

Procedure:
A stirred vessel is charged with 1000 parts of polyphosphoric acid containing 85.0% P2O5. Then 75 parts of 2,5-di(4-toluidino)terephthalic acid and 60 parts of 2,5-di(4-chloroanilino)terephthalic acid are introduced at 90° C. with stirring over 25 minutes. During this addition the temperature rises to 120° C. The mixture is heated to 125° C. and stirred at 125° C. for 1 hour, and ring closure takes place to form the quinacridone. The reaction mixture is subsequently metered into a static mixer, model Kenics KMR (length: 10 cm, diameter: 9 mm, 8 elements, supplier: H. Ott, Neckargmünd) with a throughput of 3.3 parts by volume per hour in a volume flow of 27 parts by volume per hour of 70% strength phosphoric acid at 95° C. and is hydrolyzed in 0.9 second (a precipitate is formed). During hydrolysis, the temperature rises to 118° C. Following the hydrolysis the phosphoric acid strength is 77.7%. This gives 4905 parts of crude pigment suspension. After cooling to 60° C., the crude pigment suspension is filtered off with suction, washed to neutrality with water and dried at 80° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]([Cl:10])=[CH:4][CH:3]=1.[CH3:11][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:11])[C:5]([Cl:10])=[CH:4][CH:3]=1
Reactant: O=Cc1nc(Br)ccc1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Br)ccc1Cl
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a solution of 6-bromo-3-chloropicolinaldehyde (10.0 g, 45.45 mmol) in 200 mL THF stirring at −78° C. under N2 was slowly added methylmagnesium bromide (3.0 M in diethyl ether, 16.63 mL, 50 mmol). The reaction was stirred at this temperature for 3 hours, and then saturated ammonium chloride was added. The mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-1% EtOAc/hexanes over 20 minutes) to provide 1-(6-bromo-3-chloropyridin-2-yl)ethanol (8.4 g, 78%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5]CC)=O.[CH:8](O)([CH2:10][CH3:11])[CH3:9]>C1(C)C=CC=CC=1>[CH2:9]([C@@:2]1([CH3:9])[NH:1][C:3](=[O:5])[CH2:2][NH:1][C:3]1=[O:5])[C:8]1[CH:11]=[CH:10][CH:8]=[CH:11][CH:10]=1
Reactant: CCC(C)O
Reactant: CCOC(=O)CN
Solvent: Cc1ccccc1
Product: C[C@]1(Cc2ccccc2)NC(=O)CNC1=O
Reaction time: 21 h
Yield: 100 %

Procedure:
A solution of α-methyl-(R)-phenylalanyl)glycine, ethyl ester (0.63 g, 2.4 mmol) in sec-butanol (14 ml) and toluene (7 ml) was stirred at reflux. After 21 h, the solvent was removed in vacuo and the residue azeotroped with toluene (3×) to afford the product (0.51 g, 100% yield) as a white solid. MS (ESI) 219 (M+H). This was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=[O:13])=[CH:9][C:8]([S:15][CH3:16])=[CH:7][CH:6]=2.[C:27](Cl)(=O)C(Cl)=O.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:27])=[O:13])=[CH:9][C:8]([S:15][CH3:16])=[CH:7][CH:6]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1ccc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(SC)cc12
Reaction time: 1 h
Yield: 68.9 %

Procedure:
DMF (5 drops) was added to a suspension of 3-methyl-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.1 g, 5.56 mmol) in dichloromethane (100 mL). Oxalyl chloride (0.731 mL, 8.35 mmol) was added slowly and the mixture was stirred for 1 h. The solvent was removed under reduced pressure, the residue was redissolved in methanol (50 mL), and triethylamine (1.55 mL, 11.13 mmol) was added slowly. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the residue was diluted with aqueous saturated NaHCO3, and the aqueous mixture was extracted with ethyl acetate (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-30% ethyl acetate/hexanes) to give methyl 3-methyl-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.5 g, 69% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.95-8.04 (m, 3H), 7.88 (d, J=8.03 Hz, 1H), 7.69-7.81 (m, 2H), 7.41 (d, J=2.01 Hz, 1H), 4.08 (s, 3H), 2.62 (s, 3H), 2.35 (s, 3H); MS (m/z) 392.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH:11]=[O:12])=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](Br)[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24]>O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][CH:6]2[C:7]([C:11]([C:19]3[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=3)=[O:12])=[C:8]([CH3:10])[O:9][CH:5]2[CH:4]=1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: COc1ccc2c(C=O)c(C)oc2c1
Agent: O=[Mn]=O
Product: COC1=CC2OC(C)=C(C(=O)c3cc(OC)c(OC)c(OC)c3)C2C=C1

Procedure:
6-Methoxy-2-methylbenzofuran-3-carbaldehyde was coupled with 3,4,5-trimethoxybromobenzene and subsequently oxidized by MnO2 in a manner similar to that described in Example 11 to afford compound 12.