Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)(=O)C.Cl>[Br:1][CH2:14][C:13]([C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:8][CH:9]=1)=[O:15]
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: BrBr
Agent: Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
38.5 ml of bromine dissolved in 110 ml of acetic acid are added dropwise onto a suspension of 159 g of the product of Example 1 in 1.6 l of acetic acid and 1.6 ml of hydrochloric acid, the reaction mixture is then stirred for 3 h at ambient temperature. The precipitate obtained is filtered, rinsed with water and then dissolved in dichloromcthane and dried over magnesium sulphate. The dichloromethane is evaporated off, the residue is taken up in pentane and filtered to give 100 g of the expected product. A second batch is obtained by pouring the filtrate of the reaction mixture onto an icc/water mixture, then by filtering off and by treating the precipitate as previously. The two batches are then combined and recrystallised from acetic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4]C.[F:6][C:7]1[CH:8]=[C:9]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([C:31]2[CH:32]=[N:33][N:34]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:35]=2)[CH:27]=[N:26]3)[CH:10]=[C:11]([F:20])[C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:6][C:7]1[CH:8]=[C:9]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([C:31]2[CH:32]=[N:33][N:34]([CH:36]4[CH2:41][CH2:40][N:39]([C:3](=[O:4])[CH3:2])[CH2:38][CH2:37]4)[CH:35]=2)[CH:27]=[N:26]3)[CH:10]=[C:11]([F:20])[C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COCCCl
Reactant: Fc1cc(-c2cccc3ncc(-c4cnn(C5CCNCC5)c4)nc23)cc(F)c1CN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(n2cc(-c3cnc4cccc(-c5cc(F)c(CN6CCOCC6)c(F)c5)c4n3)cn2)CC1
Temperature: 95 °C

Procedure:
2-chloroethylmethyl ether (13.5 μl, 0.143 mmol) is added dropwise to a solution of 8-(3,5-Difluoro-4-morpholin-4-ylmethyl-phenyl)-2-(1-piperidin-4-yl-1H-pyrazol-4-yl)-quinoxaline (as obtained in example 98, 67 mg, 0.137 mmol), Cs2CO3 (24 mg, 0.075 mmol) in DMF (0.5 ml). The resulting mixture is heated under Ar at 95° C. for 17 h. Two products are formed in a ratio 1:1, as identified by example 122 and example 123. The reaction is quenched with water and extracted with EtOAc several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 40 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient CH2Cl2/(CH2Cl2:EtOH:NH3 90:9:1) from 1:0=>0:1) to afford example 122 and example 123.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[S:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]=2)[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[C:11]([C:13]2[S:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]=2)[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc(-c2nc3ccncc3s2)cc([N+](=O)[O-])c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)cc(-c2nc3ccncc3s2)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 17.9 %

Procedure:
3-Nitro-5-thiazolo[5,4-c]pyridin-2-yl-benzoic acid (880 mg, 2.92 mmol) was suspended in 50 mL of anhydrous THF along with NMM (0.32 mL, 2.92 mmol). The reaction mixture was cooled in an ice bath and isobutyl chloroformate (0.38 mL, 2.92 mmol) was added. The reaction mixture was stirred at 0° C. for 40 min. NaBH4 (110 mg, 2.92 mmol) was then added as a solution in 5 mL of water. The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. It was concentrated and then extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford the crude product. Purification by chromatography (Isco, gradient elution, CH2Cl2 to 9:1 CH2Cl2/MeOH) afford 150 mg of (3-nitro-5-thiazolo[5,4-c]pyridin-2-yl-phenyl)-methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]O)=[CH:27][CH:26]=1>C(#N)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: COc1ccc(CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(CNc2ccc(Cl)cc2C#N)cc1
Temperature: 70 °C
Yield: 98.8 %

Procedure:
A solution of 2-amino-5-chlorobenzonitrile (0.50 g, 3.28 mmol) in 2 mL of acetonitrile was treated with p-toluenesulfonic acid monohydrate. The reaction mixture was heated to 70° C. with stirring. 4-Methoxybenzyl alcohol (0.50, 3.61 mmol) in acetonitrile (1 mL) was added dropwise via syringe keeping the reaction temperature at 70° C. The reaction was stirred at 70° C. for 12 h, allowed to cool to ambient temperature, and concentrated in vacuo. Chromatography afforded 1 (0.884 g, 99%) as light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.36 (d, J=2.4 Hz, 1H), 7.27 (dd, J=9 Hz, 1H), 7.24 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 6.58 (d, J=9 Hz, 1H), 4.95 (br S, 1H), 4.33 (d, J=5.4 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][O:15][C:16](=[O:44])[CH2:17][CH2:18][C@H:19]([C@@H:21]1[C@:38]2([CH3:39])[C@H:24]([C@H:25]3[C@H:35]([CH2:36][C@@H:37]2[OH:40])[C@:33]2([CH3:34])[C@@H:28]([CH2:29][C@@H:30]([N:41]=[N+:42]=[N-:43])[CH2:31][CH2:32]2)[CH2:27][CH2:26]3)[CH2:23][CH2:22]1)[CH3:20].COC(=O)CC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](C[C@@H]2O)[C@]2(C)[C@@H](C[C@@H](N=[N+]=[N-])CC2)C[C@H]3O)CC1)C>CC(C)=O>[CH3:14][O:15][C:16](=[O:44])[CH2:17][CH2:18][C@H:19]([C@@H:21]1[C@:38]2([CH3:39])[C@H:24]([C@H:25]3[C@H:35]([CH2:36][C:37]2=[O:40])[C@:33]2([CH3:34])[C@@H:28]([CH2:29][C@@H:30]([N:41]=[N+:42]=[N-:43])[CH2:31][CH2:32]2)[CH2:27][CH2:26]3)[CH2:23][CH2:22]1)[CH3:20]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=[Cr](=O)=O
Agent: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Yield: 80 %

Procedure:
12.5 mL of Jones reagent (33.3 mmol Cr(VI)) are dropped into a solution of 17.8 g of (3β,5β,12α)-3-azido-12-hydroxycholan-24-oic acid methyl ester (41.1 mmol) (prepared analogously to the method described for (3β,5β,7α,12α)-3-azido-7,12-dihydroxycholan-24-oic acid methyl ester in WO-A-95/32741: example 5) in acetone (600 mL) in 90 min at room temperature. After 20 h the mixture is filtered and the solution is evaporated. The residue is dissolved in CHCl3 (400 mL) and the solution is washed with a NaHCO3 saturated aqueous solution then with H2O. The solution is dried and evaporated to give a crude which is crystallized from 96% EtOH to obtain 14.1 g of the desired product (32.9 mmol).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>[Cu]I.C(OCC)(=O)C.CS(C)=O>[CH2:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(CCc2ccccc2)cc1I
Reactant: NCCc1ccccc1
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCc2ccccc2)cc1NCCc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To dimethylsulfoxide 2.0 mL solution of 2-iodo-4-phenethylbenzoic acid 0.20 g were added phenethylamine 0.11 mL, copper (I) iodide 0.010 g, proline 0.013 g and potassium carbonate 0.16 g, and it was stirred at 60° C. for 4 hours. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate:acetic acid=90:10:1] to give 4-phenethyl-2-(phenethylamino)benzoic acid 0.12 g of white solid.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:11])[CH3:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([S:29]([O-:31])=[O:30])[CH:23]=[CH:22]3)=[CH:15][CH:14]=1.[Na+]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([S:29]([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=2[C@@H:9]([OH:11])[CH3:10])(=[O:31])=[O:30])[CH:23]=[CH:22]3)=[CH:15][CH:14]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: Cc1cccc([C@H](C)O)c1I
Agent: [Na+]
Product: Cc1cccc([C@H](C)O)c1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1

Procedure:
Prepared according to the method of Example 6 Step 4 using (1S)-1-(2-iodo-3-methylphenyl)ethanol and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate to give the title compound as a white solid (58 mg). SFC (10% MeOH, chiralpak AD-H) e.e. >99%; 1H NMR (400 MHz, d6-DMSO): δ 8.6 (1H, s), 8.35 (1H, s), 8.31 (1H, d, J=8.7 Hz), 8.17 (1H, d, J=8.7 Hz), 8.03 (1H, d, J=9.4 Hz), 7.93-7.89 (2H, m), 7.85 (1H, d, J=7.7 Hz), 7.75 (1H, m) 7.6 (1H, t, J=8.7 Hz), 7.4-7.35 (2H, t, J=7.5 Hz), 7.3 (1H, d, J=7.4 Hz) 5.9 (1H, m), 5.35 (1H, d, J=7.3 Hz), 2.5 (3H, s) 1.3 (3H, d, J=6.3 Hz); m/z (ES+) 403 [(M-OH)+].
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[N:46]1[CH:51]=[CH:50][C:49]([CH2:52][N:53]2[CH:57]=[C:56]([C:58]3[C:66]4[C:61](=[N:62][CH:63]=[C:64]([C:67]5[CH:72]=[CH:71][C:70]([CH:73]6[CH2:78][CH2:77][N:76]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:75][CH2:74]6)=[CH:69][CH:68]=5)[CH:65]=4)[N:60](S(C4C=CC(C)=CC=4)(=O)=O)[CH:59]=3)[CH:55]=[N:54]2)=[CH:48][CH:47]=1.[OH-].[Li+]>C1COCC1.CO.O>[N:46]1[CH:47]=[CH:48][C:49]([CH2:52][N:53]2[CH:57]=[C:56]([C:58]3[C:66]4[C:61](=[N:62][CH:63]=[C:64]([C:67]5[CH:68]=[CH:69][C:70]([CH:73]6[CH2:74][CH2:75][N:76]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:77][CH2:78]6)=[CH:71][CH:72]=5)[CH:65]=4)[NH:60][CH:59]=3)[CH:55]=[N:54]2)=[CH:50][CH:51]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccncc4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6ccncc6)c5)c4c3)cc2)CC1
Yield: 99.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (142 mg, 0.206 mmol) was hydrolyzed with lithium hydroxide (43 mg, 1.030 mmol) in THF/methanol/water (4/4/2 mL) to yield 120 mg (99.6% yield). MS: m/z=535.3 (M+1).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31]C)=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)=[CH:18][CH:17]=1>C1COCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Temperature: 75 °C
Reaction time: 60 h
Yield: 96.5 %

Procedure:
To 140 ml (140 mmol) 1M L-selectride in THF (Lithium-tri-sec-butylborohydride), 14.9 g (50 mmol) 1-(4-Bromo-phenyl)-5-methoxy-1H-indole were added slowly in small portions at RT. The mixture was stirred at 75° C. for 60 h, concentrated and dissolved in ether and water. The organic phase was washed with water and dried over Na2SO4. Trituration with cyclohexane yielded 13.9 g (96%) 1-(4-Bromo-phenyl)-1H-indol-5-ol as grey solid, MS: 287 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH3:12]COCC>[N+](=C)=[N-]>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CCOCC
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: C=[N+]=[N-]
Product: COC(=O)c1ccc(Cl)cc1O

Procedure:
To a solution of 4-chloro-2-hydroxybenzoic acid (5.0 g) in ether (50 ml), diazomethane in ether was added until the reaction was terminated at 0° C. The reaction mixture was concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=4:1) to give the title compound (5.4 g) having the following physical data.
Reaction SMILES: O.[CH3:2][C:3]1[C:4]([CH2:15][S:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].C(N)(N)=[O:27].OO.C(N(CC)CC)C.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN1CCCC1=O.O.O=[V].F.F.F>[CH3:2][C:3]1[C:4]([CH2:15][S:16]([C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:27])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:13])([F:12])[F:14]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: NC(N)=O
Agent: O=[V]
Agent: F
Agent: O=S([O-])([O-])=S
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 2.5 °C
Yield: 84.5 %

Procedure:
20 g (0.0538 mole) of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole hydrate were dissolved in 60 ml of 1-methyl-2-pyrrolidone (NMP) at room temperature, then 0.080 g (0.6 mmole) vanadium(V) oxytrifluoride were added and the reaction mixture was cooled to a temperature of from 0 to 5° C. 8.1 g (0.0861 mole) of hydrogen peroxide urea adduct were suspended (optionally per partes) and the reaction was carried out at a temperature of from 0 to 10° C. for half an hour then at a temperature of from 10 to 15° C. until the reaction was completed. At the end of the reaction 0.5 ml of triethylamine and a solution of 11.36 g sodium thiosulphate pentahydrate in 12 ml of water were added. The product was precipitated with water (120 ml at 20±5° C.) and filtered off to obtain 16.8 g of wet lansoprazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6](Cl)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C=C(Cl)c1ccc(C)cc1
Product: CCOC(=O)C=C(c1ccc(C)cc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 36 %

Procedure:
The title compound was synthesized from 3-chloro-3-p-tolyl-acrylic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure outlined in Example 18, step (d), in a 36% yield of E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.33 (m, 1.4H), 7.17 (m, 4.6H), 6.96 (m, 1.6H), 6.74 (m, 2.4H), 6.57 (d, 0.8H, J=0.8 Hz), 6.50 (d, 0.2H, J=0.8 Hz), 6.20 (s, 0.8H), 6.11 (s, 0.2H), 4.39 (t, 2H, J=8.0), 4.01 (m, 2H), 3.78 (t, 2H, J=4.0), 3.22 (t, 2H, J=8.0), 2.75 (t, 2H, J=8.0), 2.44 (s, 0.6H), 2.40 (s, 2.4H), 1.94 (m, 2H), 1.53 (s, 9H), 1.05 (t, 3H, J=8.0 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:22])[CH3:21]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:24][CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: CC(C)c1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CC(C)c1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 4-isopropylaniline gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.30 (s, 1H), 10.50 (s, 1H), 8.22 (d, 1H, J=5.4 Hz), 7.37 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=3 Hz), 7.18 (s, 1H), 7.15 (s, 1H), 7.06 (dd, 1H, J=3.3 and 8.7 Hz), 6.81 (d, 1H, J=8.7 Hz), 4.23 (s, 4H), 2.85 (sept., 1H, J=7.2 Hz), 1.17 (d, 6H, J=6.9 Hz); LCMS: ret. time: 24.91 min.; purity: 95%; MS (m/e): 381 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 77.5 %

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (214 mg, 0.7 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (250 mg, 1.1 mmol) according to the general procedure K. Obtained as a light yellow solid (260 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[F:9])N.[ClH:12].N([O-])=O.[Na+]>Cl[Cu].O>[F:11][C:3]1[C:2]([Cl:1])=[C:8]([F:9])[C:7]([Cl:10])=[CH:6][C:4]=1[Cl:12]
Reactant: Cl
Reactant: Nc1cc(Cl)c(F)c(Cl)c1F
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1c(Cl)cc(Cl)c(F)c1Cl
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
31.1 g of 3,5-dichloro-2,4-difluoroaniline (0.157 mol) was added to 100 ml of a solution of concentrated hydrochloric acid and water (1:1) at 70° C. The resulting mixture was stirred to be a slurry and cooled to 0-5° C. To the mixture was added 11.6 g of aqueous solution of sodium nitrite (0.165 mol) over 30 minutes. The resulting solution was added to a solution of CuCl (0.188 mol) and hydrochloric acid (100 ml). The reaction mixture was stirred for 2 hours and kept overnight. Fractions obtained by wet-distillation were extracted with toluene. The extract was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water, dried over sodium sulfate and evaporated. The residue was recrystallized from toluene to give 27.7 g of 2,4-difluoro-1,3,5-trichlorobenzene (0.127 mol) in 81.1% yield.
Reaction SMILES: Br[C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12](=[O:22])[C@@H:13]([NH:17][C:18](=[O:21])[O:19][CH3:20])[CH:14]([CH3:16])[CH3:15])=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[C:35]3[CH2:37][O:38][C:39]4[CH:63]=[C:62]5[C:42]([CH:43]=[CH:44][C:45]6[N:49]=[C:48]([CH:50]7[CH2:54][CH2:53][CH2:52][N:51]7[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[NH:47][C:46]=65)=[CH:41][C:40]=4[C:34]3=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:20][O:19][C:18]([NH:17][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[C:5]1[NH:6][C:2]([C:31]2[CH:36]=[C:35]3[CH2:37][O:38][C:39]4[CH:63]=[C:62]5[C:42]([CH:43]=[CH:44][C:45]6[N:49]=[C:48]([CH:50]7[CH2:54][CH2:53][CH2:52][N:51]7[C:55]([O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:56])[NH:47][C:46]=65)=[CH:41][C:40]=4[C:34]3=[CH:33][CH:32]=2)=[CH:3][N:4]=1)=[O:22])[CH:14]([CH3:16])[CH3:15])=[O:21]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-4
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc(C6CCCN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1)C(C)C
Temperature: 85 °C
Yield: 0.1 %

Procedure:
To a solution of methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (1.48 g, 3.97 mmol), tert-butyl 2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (1.88 g, 1.48 mmol), tetrakis(triphenyl phosphine)palladium(0) (191 mg, 0.16 mmol) and dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II) (242 mg, 0.33 mmol) in a mixture of 1,2-dimethoxyethane (37.0 mL) and dimethylformamide (6 mL) was added a solution of potassium carbonate (2M in water, 5 mL, 9.93 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield tert-butyl 2-[9-(2-{1-[N-(methoxycarbonyl)valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (1.45 mg, 59%). LCMS-ESI+: calculated for C41H47N7O673 733.86; observed [M+1]+: 734.87.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH:18]=[C:17]([C:20]#[N:21])[C:16](=[O:22])[C:15]=2[CH:23]=1)[CH3:10])(=[O:7])[CH3:6].[N-:24]=[N+:25]=[N-:26].[Na+]>O1CCCC1>[C:5]([O:8][CH:9]([C:11]1[CH:23]=[C:15]2[C:14](=[CH:13][CH:12]=1)[O:19][CH:18]=[C:17]([C:20]1[NH:26][N:25]=[N:24][N:21]=1)[C:16]2=[O:22])[CH3:10])(=[O:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC(C)c1ccc2occ(C#N)c(=O)c2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC(C)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1
Reaction time: 1.5 h

Procedure:
To a mixture of 45 parts by volume of tetrahydrofuran and 4.005 parts of anyhydrous aluminum chloride there are added 3.86 parts of 6-(1-acetoxyethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile and 2.925 parts of sodium azide, and the resulting mixture is refluxed under stirring for 1.5 hours. After cooling, the solvent is distilled off. To the solid residue are added 2.1 parts of sodium nitrite and ice-water, and the mixture is well shaken. The insoluble material is recovered by filtration and recrystallized from ethyl acetate. The procedure yields 1.88 parts of 6-(1-acetoxyethyl)-3-(1H-tetrazol-5-yl)-chromone as colorless crystals. Melting point: 231°-232° C