Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.[K]>CN(C)C=O>[F:1][CH:2]([F:5])[CH2:3][N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: FC(F)CCl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)F
Temperature: 120 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
An amount of 21.4 g (0.214 mol) of 2,2-difluoro-1-chloroethane and 20 g (0.107 mol) of potassium phthalimide are dissolved in 95 g of N,N-dimethylformamide. The reaction mixture is stirred in an autoclave under pressure at 120° C. for 12 h. After the end of the reaction, cooling is carried out to ambient temperature and the solvent is exhaustively removed under vacuum. The remaining residue is treated with 100 ml of water and the solid is filtered off. The filter residue is washed twice with water and the product is dried under vacuum. An amount of 22.5 g of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione with a purity of only 59% is obtained. This corresponds to a yield of 59% of theory.
Reaction SMILES: [K+].[Br-].[CH3:3][C@@H:4]1[C:33]([CH3:35])([CH3:34])[O:32][C@:6]2([O:10][C@H:9]3[CH2:11][C@H:12]4[C@@H:18]5[CH2:19][CH2:20][C@H:21]6[CH2:26][C@H:25]([OH:27])[CH2:24][CH2:23][C@:22]6([CH3:28])[C@H:17]5[C:15](=[O:16])[CH2:14][C@:13]4([CH3:29])[C@H:8]3[C@:7]2([OH:31])[CH3:30])[CH2:5]1>C(Cl)(Cl)Cl>[CH3:3][C@@H:4]1[C:33]([CH3:34])([CH3:35])[O:32][C@@:6]2([O:10][C@H:9]3[CH2:11][C@H:12]4[C@@H:18]5[CH2:19][CH2:20][C@H:21]6[CH2:26][C@H:25]([OH:27])[CH2:24][CH2:23][C@:22]6([CH3:28])[C@H:17]5[C:15](=[O:16])[CH2:14][C@:13]4([CH3:29])[C@H:8]3[C@:7]2([OH:31])[CH3:30])[CH2:5]1
Reactant: C[C@H]1C[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@H](O)CC[C@]6(C)[C@H]5C(=O)C[C@]4(C)[C@H]3[C@@]2(C)O)OC1(C)C
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: C[C@H]1C[C@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@H](O)CC[C@]6(C)[C@H]5C(=O)C[C@]4(C)[C@H]3[C@@]2(C)O)OC1(C)C
Reaction time: 972 h

Procedure:
colorless crystals, mp: 240° C.; [α]D24−38.0° (c 2.41, CHCl3); 1H NMR (CDCl3) δ 5.31 (s, 1H), 5.00 (brs 1 H), 4.53 (q, J=7 Hz, 1H), 4.24 (brs 1H), 2.69 (dd, J=14.5, 3.5 Hz, 1H), 2.61 (d, J=6.5 Hz, 1H), 2.28 (m, 1H), 2.12 (m, 1H), 2.06 (m, 1H), 2.04 (s, 3H), 1.87 (m, 1H), 1.82 (m, 2H), 1.74 (m, 1H), 1.71 (m, 2H), 1.64 (m, 1H), 1.61 (dd, J=14.5, 4 Hz, 1H), 1.48 (m, 3H), 1.41 (s, 3H), 1.41 (m, 1H), 1.34 (m, 1H), 1.29 (s, 3H), 1.27 (m, 1H), 1.18 (m, 2H), 1.00 (s, 3H), 096 (s, 3H), 0.93 (d, J=7 Hz, 3H), 0.79 (m, 1H); 13C NMR (CDCl3) δ 170.6 s, 117.9 s, 101.3 d, 90.7 s, 84.7 s, 80.6 d, 70.0 d, 66.0 d, 64.3 d, 58.5 d, 56.1 s, 56.0 d, 41.1 d, 40.5 d, 39.2 t, 38.7 t, 35.9 s, 32.4 t, 33.7 t, 32.1 t, 32.1 t, 31.0 d, 29.0 q, 27.4 t, 25.6 t, 22.8 q, 21.4 q, 19.6 q, 14.4 q, 13.9 q; positive NOEs: H-6β/H-8, H-8/H-18, H-12β/H-21, H-12α/H-16, H-14/H-16, H-15β/H-18, H-16/H-17, H-17/H-21, and H-21/H-23α; IR (KBr) 3470, 3300, 1730, 1240 cm−1; EIMS m/z 500 (M−H2O), 485 (4), 442 (4), 372 (100%). The stereochemistry at C-18 was elucidated to be R configuration by positive NOEs between the proton pairs: H-18/H-8 and H-18/H-15β.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1oc(-c2ccccc2F)nc1CCl
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3F)oc2C)c1)C(=O)O
Yield: 47 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole, the title compound was obtained in 47% yield as a yellow solid. MS: (M+H)+ 423.3.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][CH2:15][O:16][C:17]1[C:18]([CH3:34])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][CH:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20]2.[CH2:35](Br)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>O1CCCC1.CCCCCC>[CH3:13][O:14][CH2:15][O:16][C:17]1[C:18]([CH3:34])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][C:22]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20]2
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)C1CCc2c(C)c(OCOC)c(C)c(C)c2O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCC1(C(=O)OCC)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
7.8 ml of a hexane solution containing 1.62 mmole/ml of butyllithium were added dropwise to a mixture of 2 g of diisopropylamine and 80 ml of tetrahydrofuran under a nitrogen stream at a temperature from -60° to -50° C. The resulting mixture was then allowed to stand for 10 minutes at room temperature, after which about 10 ml of tetrahydrofuran containing 4 g of ethyl 6-methoxymethoxy-5,7,8-trimethylchroman-2-carboxylate (prepared as described in Preparation 11) were added and the mixture was stirred for 1 hour at -60° C. About 20 ml of tetrahydrofuran containing 5 g of octyl bromide were added, and the mixture was stirred for 1 hour at -60° C. and then for 1 hour at room temperature, after which it was heated for 1 hour at 50° C. The reaction mixture was then poured into ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography eluted with benzene, to give the title compound.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15])([O-:10])=[O:9].Cl[C:20]([O:22][C@H:23]1[CH2:27][CH2:26][O:25][CH2:24]1)=[O:21].ClC([O-])=O>C1(C)C=CC=CC=1.O>[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH:15][C:20](=[O:21])[O:22][C@H:23]1[CH2:27][CH2:26][O:25][CH2:24]1)([O-:10])=[O:9]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)O[C@H]1CCOC1
Agent: Cl
Agent: O=C([O-])Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCc1cccc([N+](=O)[O-])c1)O[C@H]1CCOC1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
Added 13.84 g Na2CO3 to a 500 ml three neck round bottom flask equipped with a mechanical stirrer, addition funnel, and thermocouple. Then added 86 ml water and stirred until full dissolution at room temperature. 20 g 3-nitrobenzylamine HCl 2b was then added, followed by 154 ml toluene. The mixture was heated to 50° C. wherein a clear biphasic solution results. Added a 20% w/w solution of (S)-tetrahydrofuran-3-yl chloroformate, 2a (16 g) in toluene (80 ml) dropwise over 45 minutes wherein very little exotherm was noted. The reaction mixture was stirred for an additional 1 hour before the layers were separated at 50° C. The mixture was concentrated to ˜85 ml, cooled to 0° C. and stirred for 1 hour at 0° C. Precipitated product was collected by filtration and dried for 18 hours at 53° C. to give 26.64 g (94.4% yield, 99.90% a/a) of (S)-tetrahydrofuran-3-yl 3-nitrobenzylcarbamate (2c) as a white crystalline solid with consistent 1H NMR (500 MHz, d6-DMSO): 8.10 (m, 2H); 7.90 (m, 1H); 7.70 (d, 1H); 7.62 (t, 1H); 5.10 (br, 1H); 4.30 (d, 2H); 3.72 (m, 4H); 2.10 (m, 1H); 1.87 (m, 1H)ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])=[N:6][CH:7]=1>[Pt]>[F:17][C:9]1[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccc(F)cn2)c1
Agent: [Pt]
Product: Nc1ccc(F)c(-c2ccc(F)cn2)c1

Procedure:
By the method of Example 57, 5-fluoro-2-(2-fluoro-5-nitrophenyl)pyridine was hydrogenated over platinum to afford 4-fluoro-3-(5-fluoropyridin-2-yl)phenylamine: m/z (ES+) 207.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9]Br)[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([NH:25][C:26]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]([CH2:9][CH2:8][CH2:7][C:6]([O:5][CH2:3][CH3:4])=[O:11])[C:26]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1cc(C)cc(C)c1NC(=O)OC(C)(C)C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C(=O)OC(C)(C)C)c1c(C)cc(C)cc1C(=O)OC
Temperature: 55 °C
Reaction time: 48 h
Yield: 113.6 %

Procedure:
Charge a 22 L flask, equipped with overhead agitation, heating mantle, condenser and a N2 purge, with DMF (10 L), ethyl-4-bromobutyrate (1.07 kg, 787.8 mL, 5.32 moles), cesium carbonate (2.92 kg, 22.5 moles), and methyl 2-(tert-butoxy carbonylamino)-3,5-dimethylbenzoate (1,000.0 g, 3.54 moles). Heat the resulting mixture to about 55° C. and stir for about 48 hours. Cool; filter off the solid; and wash the solid with MTBE (2×4 L). Combine the filtrate and the MTBE washings into a 50 L flask and cool to less than about 5° C. Add water (6 L) to quench the reaction. Separate the layers. Wash the aqueous layer with MTBE (3 L); combine the organic layers; and wash the resulting organic solution with brine (2×3 L). Dry the organic solution over Na2SO4; filter; and wash the collected solids with MTBE to yield 1.582 kg of the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[CH2:12]([O:16][C:17]1[C:18]2[C:23]([C:24]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:25]3[C:30]=1[CH:29]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH3:15].ClCCl>C(N(CC)CC)C>[CH2:12]([O:16][C:17]1[C:18]2[C:23]([C:24]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:25]3[C:30]=1[CH:29]=[C:28]([S:31]([O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])(=[O:32])=[O:33])[CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH3:15]
Reactant: N#CC(=NO)c1ccccc1
Reactant: CCCCOc1c2ccccc2c(OCCCC)c2cc(S(=O)(=O)Cl)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1c2ccccc2c(OCCCC)c2cc(S(=O)(=O)ON=C(C#N)c3ccccc3)ccc12

Procedure:
A mixture of 0.50 g of 2-hydroxyimino-2-phenylacetonitrile, 1.43 g of 9,10-dibutoxyanthracene-2-sulfonyl chloride and 20 ml of dichloromethane was stirred on an ice bath, and 0.34 g of triethylamine was added.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=2)[C:16](OCC)=[O:17])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:17][CH2:16][C:15]1[CH:21]=[CH:22][N:23]=[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:14]=1
Reactant: CCOC(=O)c1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cc(CO)ccn2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(3,4,5-trimethoxyphenyl)isonicotinate (24.57 g) was dissolved in dry THF (200 mL), and to the solution lithium aluminum hydride (2.94 g) was added at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 1 hour as it is. A small amount of water and then sodium sulfate were added to the reaction mixture, and the reaction mixture was filtered through celite. The filtrate was evaporated, and the reultant crude crystals were recrystalized from ethyl acetate-hexane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[C:30](=[O:31])[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=[CH:22]5)[C:16]=4[CH3:32])=[CH:13][N:12]=[C:11]([C:33]([NH2:35])=[O:34])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:41]([O:43]CC)=[CH2:42])CCC.C(N(CC)CC)C.C(OCC)(=O)C.CCCCCC>O1CCOCC1.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>[C:41]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[C:30](=[O:31])[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=[CH:22]5)[C:16]=4[CH3:32])=[CH:13][N:12]=[C:11]([C:33]([NH2:35])=[O:34])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1)(=[O:43])[CH3:42]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(Br)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Temperature: 95 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
A mixture of 7-bromo-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.198 g, 0.378 mmol), tributyl(1-ethoxyvinyl)stannane (0.299 mL, 0.906 mmol), bis(triphenylphosphine)palladium(II) chloride (0.037 g, 0.053 mmol), triethylamine (0.068 mL, 0.491 mmol) in 1,4-dioxane (Volume: 15 mL) was heated at 95° C. for 24 hr. No reaction occurred. The starting bromo compound remained unchanged. Upon cooling to room temperature, some yellow precipitate formed. The clear solution was transferred to a pressure tube. Additional tributyl(1-ethoxyvinyl)stannane (0.6 mL, 1.82 mmol), bis(triphenylphosphine)palladium(II) chloride (0.080 g, 0.114 mmol), and triethylamine (0.11 mL, 0.789 mmol) were added. The mixture was heated at 125° C. for 16 hr. Upon cooling to room temperature, the reaction mixture was filtered through CELITE®, and the filtrate was concentrated under vacuum. The residue was diluted with THF (30 mL) and stirred with 1 N HCl solution (10 mL) at room temperature for 2 hr. The solution was concentrated under vacuum, basified with 1 N NaOH solution, and extracted with ethyl acetate (3×40 mL). The combined extract was dried over anhydrous MgSO4. The desired product (90 mg, 0.185 mmol, 48.9% yield) was isolated as a yellow solid by ISCO (24 g silica gel, solid loading, 60-90% ethyl acetate/hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:26]=2[F:25])[CH:7]=[CH:6][CH:5]=1)[C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cccc(F)c21
Reactant: COc1cccc(B(O)O)c1F
Product: COc1cccc(-c2cccc(C3(c4ccncc4)N=C(N)c4c(F)cccc43)c2)c1F
Yield: 28 %

Procedure:
The title compound was synthesized as described for Example 1 in 28% yield, starting from 1-(3-bromophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine (0.096 g, 0.25 mmol) and 2-fluoro-3-methoxybenzeneboronic acid (0.047 g, 0.28 mmol): 1H NMR (DMSO-d6) δ ppm 8.50-8.44 (m, 2 H) 7.65-7.60 (m, 1 H) 7.58-7.49 (m, 1 H) 7.45-7.37 (m, 3 H) 7.36-7.24 (m, 4 H) 7.22-7.11 (m, 2 H) 6.96-6.90 (m, 1 H) 6.64 (br. s., 2H) 3.85 (s, 3 H), MS (ES+) m/z 428 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[CH3:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[CH2:24][C:5]([C:4]1[CH:9]=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=1[O:2][CH3:1])=[O:7]
Reactant: COC(=O)c1ccc(OC)c(OC)c1OC
Reactant: Cc1c(Cl)cncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(OC)c1OC

Procedure:
Methyl 2,3,4-trimethoxybenzoate from preparation 1 (2.7 g, 10 mmol) and 3,5-dichloro-4-methylpyridine (prepared according to literature procedures) was dissolved in dry THF (40 mL). The reaction was cooled on ice and treated dropwise (during 5 minutes) with 1M lithium bis(trimethylsilyl)amide (12 mL, 12 mmol). After 1.5 hours at 0° C. the reaction was quenched with NH4Cl (sat, 100 mL). The organic products were extracted with EtOAc (2×100 mL), and the combined organic phases washed with NaCl (sat, 100 mL). The organic phase was dried over Na2SO4, evaporated in vacuo and purified by flash chromatography using a gradient of EtOAc in heptane as eluent. 2-(3,5-Dichloro-pyridin-4-yl)-1-(2,3,4-trimethoxy-phenyl)-ethanone was obtained as a white solid. 1H NMR (CDCl3) δ=8.43 (2H, s), 7.55 (1H, d), 6.69 (1H, d), 4.61 (2H, s), 4.02 (3H, s), 3.87 (3H, s), 3.84 (3H, s). Yield 2.3 g (65%).
Reaction SMILES: C1(Cl)C(=O)C(Cl)=C(Cl)C(=[O:4])C=1Cl.[C:13]([OH:23])(=O)[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O.ClC1C(Cl)=C(Cl)C=CC=1>>[O:4]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:17]1[O:23][CH:13]=[CH:14][CH:16]=1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: Clc1cccc(Cl)c1Cl
Product: c1coc(-c2ccco2)c1
Temperature: 180 °C
Reaction time: 20 h

Procedure:
A mixture of 4.9 parts of chloranil (2:3:5:6-tetrachlorobenzoquinone), 12 parts of mandelic acid and 25 parts of trichlorobenzene is stirred for 20 hours at 180° C. The mixture is cooled to 20° C. and the precipitated solid is filtered off, washed with trichlorobenzene and then crystallised from toluene. The solid is then dissolved in chloroform, the chloroform solution extracted with a 2% aqueous solution of sodium carbonate, and the chloroform then removed by distillation. 4:8-Dichloro-3:7-diphenyl-2:6-dioxo-2:6-dihydrobenzo[1:2-b:4:5-b1 ] bifuran is obtained. The product has a melting point of 310° C.-315° C., a λ max in chloroform of 457 n.m. and a molecular extinction coefficient of 45000. The n.m.r. and mass spectra are consistent with the stated structures.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.ClCCl>[CH3:1][S:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CSc1ccc2cc[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ccc2ccn(S(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a solution of 6-(methylthio)-1H-indole (1 g, 6.13 mmol), NaOH (4.90 g, 122.6 mmol) and Bu4NHSO4 (207.8 mg, 0.613 mmol) in dichloromethane (20 mL) was added benzenesulfonyl chloride (1.29 g, 7.36 mmol). The reaction mixture was stirred at rt overnight. The mixture was quenched with water (30 mL) and extracted with CH2Cl2 (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel eluted with (petroleum ether/EtOAc 10:1) to afford 6-(methylthio)-1-(phenylsulfonyl)-1H-indole (1.1 g, 59.18% yield) as a white solid. LC-MS MS (ESI) m/z 304.0 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 7.93-7.75 (m, 3H), 7.58-7.41 (m, 5H), 7.17 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 6.63-6.60 (m, 1H), 2.53 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[C].[Pd]>[CH3:16][O:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Solvent: CO
Product: COCC1CNCCO1
Temperature: 100 °C
Yield: 86.9 %

Procedure:
N-Benzyl-2-methoxymethylmorpholine (412.3 g) is dissolved in methanol (2 liters), and thereto is added 10% palladium-carbon (33 g), and the mixture is stirred under hydrogen pressure of 9 kg/cm2 at 100° C. After completion of the reaction, palladium-carbon is filtered off, and the solvent is distilled off under atmospheric pressure to give a pale yellow oily substance. The oily substance is distilled under reduced pressure to give the title compound (212.3 g) as colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=O)=[CH:4][CH:3]=1.[C:21]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(O)(C(F)(F)F)=O.O>C1(C)C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:29]([C:28]3[CH:30]=[CH:31][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=3)[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(CCC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(-n2c(-c3ccc(Br)cc3)ccc2-c2ccc(Br)cc2)cc1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
To a solution of the product from Example 26E (4.00 g, 10.10 mmol) in toluene (40 mL) was added 4-tert-butylaniline (1.81 g, 12.12 mmol) followed by TFA (2.30 g, 20.20 mmol). Mixture heated to 110° C. for 2 h. Mixture cooled to room temperature and water and diethyl ether were added. Stirred for 15 min, filtered, washed with water and diethyl ether and dried to provide the title compound as a white solid (4.61 g; 90% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:2]3[N:3]=[C:4]4[C:10]([C:11]([C:13]5([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)[CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)c2)CC1

Procedure:
4-{3-[7-(1-Methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester following general procedures as described in these Examples. MP 212-213° C., M+H=504.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:21][C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25])[CH:5]=[CH:6][C:7]=1[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH3:28]>CO>[NH2:28]/[C:24](/[CH3:25])=[CH:23]\[C:22]([NH:21][C:4]1[CH:5]=[CH:6][C:7]([N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:2]([Cl:1])[CH:3]=1)=[O:27]
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1Cl
Reactant: N
Solvent: CO
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)/C=C(/C)N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of N-(3-chloro-4-(dihexylamino)phenyl)-3-oxobutanamide (3.94 g, 10 mmol), MeOH (50 mL) and ammonia (50 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound as black oil (3.94 g, 100%).