Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.[CH3:11][NH:12][CH3:13]>>[OH:10][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:8]([N:12]([CH3:13])[CH3:11])=[O:9]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CNC
Product: CN(C)C(=O)Nc1ccccc1O

Procedure:
Benzoxazolinone (200 g) was stirred with 1 liter of a 33% solution of dimethylamine in industrial alcohol at 50° C. for 48 hours. The alcohol and unchanged dimethylamine were distilled off under reduced pressure at below 60° C. and the product was recrystallised from a 1:1 by volume mixture of isopropanol and light petroleum ether (b.pt. 60°-80° C.). It melted at 148° C. (decomp.) as measured on a Kofler bench.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:17])[N:10]([C@@H:18]3[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]3[O:20][C:21](=[O:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1B(O)O.[F-].[Cs+]>COCCOC.C(OCC)(=O)C.[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>[CH3:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:8]([CH2:7][C:5]1[S:6][C:2]([C:42]3[S:41][CH:45]=[CH:44][CH:43]=3)=[CH:3][CH:4]=1)=[CH:9][N:10]2[C@@H:18]1[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]1[O:20][C:21](=[O:23])[CH3:22]
Reactant: OB(O)c1cccs1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(-c4cccs4)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A mixture of 3-(5-bromothiophen-2-yl-methyl)-4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 45-(3) (190 mg), thiophene-2-boronic acid (229 mg), cesium fluoride (272 mg) and tetrakis(triphenylphosphine)-palladium(0) (34.5 mg) in 1,2-dimethoxyethane (6 ml) was refluxed for 6 hours under argon atmosphere. The reaction mixture was diluted with ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was filtered through an aminosilane-treated silica gel pad. The filtrate was evaporated under reduced pressure to give crude 4-methyl-3-(5-(2-thienyl)-thiophen-2-yl-methyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole, which was partially deacetylated. This crude compound was dissolved in chloroform (6 ml), and thereto were added successively pyridine (0.121 ml), acetic anhydride (0.141 ml) and 4-(dimethylamino)pyridine (3.7 mg). After being stirred at room temperature for 4 hour, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (80 ml), and the mixture was washed with a 10% aqueous copper (II) sulfate solution (5 ml) twice and a saturated aqueous sodium hydrogen carbonate solution (5 ml), and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-50:50) to give 4-methyl-3-(5-(2-thienyl)thiophen-2-yl-methyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole (134 mg) as a yellow powder. APCI-Mass m/Z 657 (M+NH4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].C([Li])CCCCC.[Cl:17][CH2:18][C:19]([CH2:21][Cl:22])=[O:20].Cl>C(OCC)C>[Cl:17][CH2:18][C:19]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9])([OH:20])[CH2:21][Cl:22]
Reactant: Fc1cccc(Br)c1F
Reactant: O=C(CCl)CCl
Agent: Cl
Agent: [Li]CCCCCC
Solvent: CCOCC
Product: OC(CCl)(CCl)c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 1-bromo-2,3-difluorobenzene (19.5 g, 0.10 mol) in dry diethyl ether (120 mL), under nitrogen at −78° C., was added dropwise, n-hexyllithium (2.3 M in hexane, 41.7 ml, 0.096 mol). The mixture was stirred for 1 min after which a solution of 1,3-dichloroacetone (12.2 g, 0.096 mol) in dry diethyl ether (30 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h and then brought to ambient temperature and stirred for 1 h. Aqueous hydrochloric acid (50 mL. 10%) was added and the mixture was extracted with ethylacetate (2×50 ml). The combined organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (ethylacetate/isooctane, 1:9 to 1:1) to give the title compound (11.8 g, 48%). MS m/z (rel. intensity, 70 eV) 241 (M+, 1), 193 (33), 191 (bp), 141 (11), 127 (68).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([O:16][CH:17]([F:19])[F:18])=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=1>[Fe].O>[Br:6][C:7]1[C:8]([O:16][CH:17]([F:18])[F:19])=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13]
Reactant: O=[N+]([O-])c1cccc(Br)c1OC(F)F
Agent: [Fe]
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1cccc(Br)c1OC(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
Into a 300-ml four-necked flask provided with a reflux condenser, a stirrer and a thermometer were fed 6.56 g of an iron powder, 0.49 g (4.7 mmol) of 95% sulfuric acid and 50 ml of water. The mixture was heated to 80° C. on an oil bath. Thereto was slowly added, at 80 to 85° C., 12.54 g (0.047 mol) of 3-bromo-2-difluoromethoxynitrobenzene. The temperature was increased and refluxing was conducted at 100° C. for 2 hours with heating. After completion of the reaction, azeotropic distillation was performed while 200 ml of water was added gradually. The distillate was subjected to extraction two times each using 30 ml of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and subjected to distillation to remove the solvent and obtain 8.09 g of 3-bromo-2-difluoromethoxyaniline (yield: 72.4%, purity: 99.7%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CCO>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9]1
Reactant: [H][H]
Reactant: CC(C)(O)C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(O)C1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A pressure vessel was charged with 2-(1-benzylpyrrolidin-3-yl)propan-2-ol (1.013 g, 4.62 mmol), palladium, 10 wt. % (dry basis) on activated carbon (wet) (0.904 g, 0.425 mmol) and EtOH (20 mL). The reaction vessel was pressurized (50 psi) with hydrogen and purged 3 times. The vessel was pressurized at 50 psi and allowed to stir overnight at rt. The reaction was filtered and the filtrate was concentrated to dryness.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH3:15])[C:5]2=[O:16].[NH2:17]C(N)=O>>[NH2:17][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH3:15])[C:5]2=[O:16]
Reactant: CN1C(=O)c2cc(Cl)c([N+](=O)[O-])cc2C1=O
Reactant: NC(N)=O
Product: CN1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Temperature: 150 °C
Yield: 66.1 %

Procedure:
5-Chloro-2-methyl-6-nitroisoindoline-1,3-dione (14.40 g, 59.85 mmol) and urea (35.95 g, 599 mmol) were mixed together under argon. The mixture was stirred and heated to 150° C. for 3 h and cooled to rt. The solid was washed with 200 mL of hot water (90° C.) and filtered to remove the remaining urea. The isolated yellow solid was washed twice with hot water, dried under vacuum and purified by column chromatography (silica-gel CH2Cl2/acetone=19/1 v/v) to give a yellow solid product, 8.75 g, 66.1% yield. MS: 219.6 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.39 (s, 2H), 8.26 (s, 1H), 7.40 (s, 1H), 2.99 (s, 3H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]C)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(OC1C=NC(C2C=CC(CCCCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCC.C(OC1C=NC(C2C=CC(CCCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCC>>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(CCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCc1ccc(-c2ncc(OCCCCCCCCCC)cn2)cc1
Agent: CCCCCCCCCCCc1ccc(-c2ncc(OCCCCCCCCCC)cn2)cc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCCCC)cc2)nc1

Procedure:
5-decyloxy-2-(4-hexylphenyl)pyrimidine ##STR20## 5-decyloxy-2-(4-heptylphenyl)pyrimidine ##STR21## 5-decyloxy-2-(4-octylphenyl)pyrimidine ##STR22## 5-decyloxy-2-(4-nonylphenyl)pyrimidine ##STR23## 5-decyloxy-2-(4-decylphenyl)pyrimidine ##STR24## 5-decyloxy-2-(4-undecylphenyl)pyrimidine 5-decyloxy-2-(4-dodecylphenyl)pyrimidine
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]1[CH2:11][C@H:10]([O:12][C:13]2[C:14]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:15]=3[N:16]=[C:17](Cl)[N:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH:43]=[C:42]([NH2:44])[CH:41]=[N:40]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[CH3:38][N:39]1[CH:43]=[C:42]([NH:44][C:17]2[N:18]=[C:13]([O:12][C@H:10]3[CH2:11][C@H:8]([NH:7][C:6](=[O:37])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9]3)[C:14]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:15]=3[N:16]=2)[CH:41]=[N:40]1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Oc2nc(Cl)nc3c2c(-c2ccccn2)cn3COCC[Si](C)(C)C)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(Nc2nc(O[C@H]3C[C@H](NC(=O)OC(C)(C)C)C3)c3c(-c4ccccn4)cn(COCC[Si](C)(C)C)c3n2)cn1
Temperature: 140 °C

Procedure:
To a solution tert-butyl(trans-3-{[2-chloro-5-(pyridin-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy}cyclobutyl)carbamate (439 mg, 0.804 mmol) in 1,4-dioxane (8 mL) in a microwave vial was added 1-methyl-1H-pyrazol-4-amine (78.1 mg, 0.804 mmol) followed by cesium carbonate (524 mg, 1.61 mmol), tris(dibenzylideneacetone)dipalladium(0) (73.3 mg, 0.08 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (46.3 mg, 0.08 mmol) and the resulting mixture heated in the microwave to 140° C. for 45 minutes. The reaction was cooled to rt, filtered through a celite plug and stripped to a dark oil that was purified via flash chromatography (20%-100% EtOAc I heptane, then 10% methanol in EtOAc) to afford the title compound as a tan solid (365 mg, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.03-9.14 (m, 1H) 8.44-8.55 (m, 1H) 8.00-8.09 (m, 1H) 7.81-7.92 (m, 1H) 7.74-7.80 (m, 1H) 7.57-7.64 (m, 1H) 7.42-7.48 (m, 1H) 7.21-7.32 (m, 1H) 7.11-7.20 (m, 1H) 5.45-5.53 (m, 2H) 5.35-5.42 (m, 1H) 4.02-4.15 (m, 1H) 3.74 (s, 3H) 3.45-3.56 (m, 2H) 2.28-2.39 (m, 4H) 1.31 (s, 9H) 0.74-0.81 (m, 2H) −0.20 (s, 9H). m/z (APCI+) for C30H42N8O4Si 607.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cncc(Cl)n1
Product: Clc1cncc(-c2ccccc2)n1

Procedure:
Prepared from 2,6-dichloropyrazine (1.01 g, 6.78 mmol) and phenylboronic acid (946.7 mg, 7.76 mmol) according to Method K, except the product was purified by silica gel chromatography (DCM, Rf=0.37) instead of preparative HPLC: 1H NMR (300 MHz, chloroform-D) δ ppm 7.46-7.53 (m, 3H), 7.94-7.98 (m, 2H), 8.22 (s, 1H), 8.63 (s, 1H). MS (DCI/NH3) m/z=191 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([OH:9])[CH:3]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1F
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1F
Temperature: 130 °C
Yield: 60.1 %

Procedure:
To a solution of 3-fluoro-p-cresol (2.5 g, 19.82 mmol) and 4-fluorobenzaldehyde (2.460 g, 19.82 mmol) in DMF (15 mL), was added K2CO3 (4.11 g, 29.7 mmol). The mixture was heated with a microwave condition at 130° C. for 1 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated and purified via flash chromatography to afford the title compound (2.741 g, 11.91 mmol, 60.1% yield) as a yellow oil. LCMS: rt=3.57 min, [M+H+]=231
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13](Br)[N:14]=2)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[C:25]([Si:29]([CH3:55])([CH3:54])[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[N:35]=[C:34]2[Sn](CCCC)(CCCC)CCCC)([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.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.[Cu]I>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:34]3[C:33]4[C:37](=[CH:38][CH:39]=[C:31]([O:30][Si:29]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:54])[CH3:55])[CH:32]=4)[N:36]([CH3:40])[N:35]=3)[N:14]=2)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
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: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(O[Si](C)(C)C(C)(C)C)cc34)nc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (100 mg, 0.24 mmol) and 5-(tert-butyl-dimethyl-silanyloxy)-1-methyl-3-tributylstannanyl-1H-indazole (crude from Step 4) were dissolved in DMF (2 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.012 mmol) and copper (I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 80° C. for 2 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to afford 104 mg (72%) of 2-[5-(tert-butyl-dimethyl-silanyloxy)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][CH2:68][CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:67][CH2:68][CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300 mg, 0.67 mmol), HATU (280 mg, 0.74 mmol) and N,N-diisopropylethylamine (190 mg, 1.47 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of tert-butyl (2-aminoethyl)carbamate (128 mg, 0.80 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate as white solid. Yield: 355 mg, 90%.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)[S:10][C:6]=2[C:5](=[O:16])[NH:4]C1(C)C.[ClH:19]>CO>[ClH:19].[ClH:19].[CH3:1][NH:2][C:7]1[CH:8]=[C:9]([C:11]2[CH:15]=[N:14][NH:13][CH:12]=2)[S:10][C:6]=1[C:5]([NH2:4])=[O:16]
Reactant: CN1c2cc(-c3cn[nH]c3)sc2C(=O)NC1(C)C
Agent: Cl
Solvent: CO
Product: CNc1cc(-c2cn[nH]c2)sc1C(N)=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of 1,2,2-trimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (262 mg, 1.00 mmol), 1 M HCl (5 mL) and MeOH (5 mL) was stirred at 50° C. for 1 h. The mixture was concentrated under reduced pressure to afford the title compound (292 mg, 99%) as a pale yellow solid. This material was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[N:24][CH:25]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[N:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: Fc1ccc(OCCBr)cn1
Product: N#Cc1ccc2c(cc(C(F)F)n2CCOc2ccc(F)nc2)c1Cl

Procedure:
Synthesized as described in Example 39 from 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile and 5-[(2-bromoethyl)oxy]-2-fluoropyridine: MS (ESI) m/z 366 (M+1).
Reaction SMILES: [CH:1]([CH2:3][C:4](O)=[O:5])=[CH2:2].Cl.[NH2:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12]>C(Cl)Cl>[C:4]([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:5])[CH2:3][CH:1]=[CH2:2]
Reactant: C=CCC(=O)O
Reactant: COC(=O)CC(N)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: C=CCC(=O)NC(CC(=O)OC)c1ccccc1
Temperature: -10 °C
Reaction time: 15 h
Yield: 95.4 %

Procedure:
To a solution of vinylacetic acid (861 mg, 10.0 mmol), methyl 3-amino-3-phenylpropionate hydrochloride (2.37 g, 11.0 mmol) and TEA (1.6 mL, 12 mmol) in DCM (20 mL) at -10° C. was added DEC (2.11 g, 11.0 mmol). The resulting mixture was stirred at -10° C. for 15 hours. The mixture was then washed with water, 0.1M HCl, sat. NaHCO3, sat. NaCl and dried over anhydrous MgSO4. Concentration in vacuo followed by pumping until constant weight gave 2.36 g (95%) of the desired amide as a golden oil of suitable purity for further reaction; 1H NMR (300 MHz, CDCl3) 87.28 (m, 5H), 6.78 (bd, J=7.7 Hz, 1H), 5.95 (m, 1H), 5.43 (dt, J=8.4, 5.9 Hz, 1H), 5.25 (m, 2H), 3.61 (s, 3H), 3.04 (d, J=7.0 Hz, 2H), 2.88 (dq, J=15.0, 5.9 Hz, 2H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:19]([Cl:22])=[CH:20][CH:21]=1)[C:7](C1C=CC(Cl)=C([N+]([O-])=O)C=1)=[O:8])([O-])=O.[Cl:23]C1C=CC=CC=1C(C1C=CC(Cl)=CC=1)=O>ClC1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][CH:4]=[CH:5][C:6]=1[C:7]([Cl:23])=[O:8]
Reactant: O=C(c1ccc(Cl)cc1)c1ccccc1Cl
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1cc([N+](=O)[O-])ccc1Cl
Solvent: Clc1ccccc1
Product: O=C(Cl)c1ccccc1Cl

Procedure:
For example, 3,3'-dinitro-4,4'-dichlorobenzophenone can be prepared in a yield of 95 to 98% by nitrating 4,4'-dichlorobenzophenone [E. R. Kofanov et al., J. Org. Chem. USSR, 15, 98-100 (1979)]. 5,3'-Dinitro-2,4'-dichlorobenzophenone can be prepared in a high yield by nitrating 2,4'-dichlorobenzophenone [E. H. Faith et al., J. Am. Chem. Soc., 77, 543 (1955)]. 3,3'-Dinitro-4-chlorobenzophenone can be prepared in a high yield by nitrating 4-chlorobenzophenone [G. S. Mironov et al., J. Org. Chem. USSR, 8, 1538 (1972)]. 3,4'-Dinitro-4-chlorobenzophenone can be prepared by nitrating 4-halogeno-4'-nitrobenzophenone obtained by the condensation reaction between p-nitrobenzoyl chloride and chlorobenzene [P. T. Montagne et al., Ber., 49, 2267-2270 (1916); G. S. Mironov et al., J. Org. Chem. USSR, 8, 1538-1543 (1972)]. 3,3'-Dinitro-6,4'-dichlorobenzophenone can be prepared in a high yield by nitrating 2,4'-dichlorobenzophenone obtained by the condensation reaction between 2-chlorobenzoyl chloride and chlorobenzene [H. F. Faith et al., J. Am. Chem. Soc., 77, 543 (1955)].
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[C:19]([C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)[C:18]([C:31]4[N:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:37]N1C(=O)CCC1=O>CN(C)C=O>[Br:37][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:20]=[C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:18]([C:31]3[N:32]=[CH:33][CH:34]=[CH:35][N:36]=3)=[CH:17][CH:16]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cnc(-c2ccc(-c3c4ccccc4cc4ccccc34)cc2-c2cccc3ccccc23)nc1
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2ccc(-c3ncccn3)c(-c3cccc4ccccc34)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
Dissolving 8.5 g (19 mmol) of 4-anthracen-9-yl-6-naphthalen-1-yl-phenyl-pyrimidine obtained in the foregoing step (2) into 100 milliliter of N,N-dimethylformamide, and adding 3.6 g (20 mmol) of N-bromosuccinimide, stirred at room temperature for 8 hours. After completion of the reaction, precipitated solids were separated by filtration and washed with water and methanol, thereby obtaining 7.2 g of 4-(10-bromo-anthracen-9-yl)-6-naphthalen-1-yl-phenyl-pyrimidine (yield: 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[N+:25]([O-:27])=[O:26])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c1cccc2[N+](=O)[O-]
Product: CC1c2cccc([N+](=O)[O-])c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.