Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:4].[NH:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:16]([C:21](O)=[O:22])[CH2:17][C:18](=[O:20])[NH2:19].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:16]([C:21]([NH:2][C@H:3]([C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:4])=[O:22])[CH2:17][C:18](=[O:20])[NH2:19]
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
The HCl salt of H-Ala-OBzl (43 g, 200 mmol) was dissolved in DMF (500 ml) and stirred with Boc-Asn-OH (46.5 g, 200 mmol), NMM (27 ml), HOBt (54 g), and DCC (45 g) at 0° C for 1.5 hr and 25° C for 17 hr. The reaction mixture was worked up as in Example 11 to a solid which was crystallized from tetrahydrofuran and minimum petroleum ether: 62.5 g (79.4%); mp 140°-141° C; [α]D25 -31.1° (c 1, MeOH). Anal. Calcd for C19H27N3O6 (393.44): C, 58.00; H, 6.92; N, 10.68. Found: C, 57.77; H, 7.09; N, 10.52.
Reaction SMILES: C[N:2]([CH3:16])/[CH:3]=[CH:4]/[C:5]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[O:17]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1CN)[CH3:18]>CN1C(=O)N(C)CCC1>[CH3:18][O:17][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH2:16][N:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=2)[C:7]1=[NH:8]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CN(C)/C=C/c1cc([N+](=O)[O-])ccc1C#N
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(Cn2ccc3cc([N+](=O)[O-])ccc3c2=N)c(OC)c1

Procedure:
(E)-2-(2-(Dimethylamino)vinyl)-4-nitrobenzonitrile (4.6 g, 21.2 mmol) and 2,4-dimethoxylbenzylamine (4.0 mL, 1.25 equiv) in DMPU (10 mL) were heated at 140° C. for 3 h. The solvent was removed by vacuum distillation and residue was treated with hexanes/ethyl acetate (1:1). The solid was collected by filtration and washed with hexane to give 2-(2,4-dimethoxybenzyl)-6-nitroisoquinolin-1 (2H)-imine (4.6 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3 H) 3.81 (s, 3 H) 4.96 (s, 1 H) 6.28 (d, J=6.59 Hz, 1 H) 6.46 (d, J=7.47 Hz, 1 H) 6.58 (d, J=1.76 Hz, 1 H) 7.03 (d, J=8.79 Hz, 1 H) 7.27 (d, J=6.15 Hz, 1 H) 8.02 (dd, J=9.01, 2.42 Hz, 1 H) 8.31 (d, J=2.20 Hz, 1 H) 8.43 (d, J=8.35 Hz, 1 H).
Reaction SMILES: [N:1]1(C2C=CC(CC3C(Cl)=NC4C(C=3Cl)=CC(Br)=CC=4)=CC=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Cl:26][C:27]1[C:36]([CH2:37][C:38]2[CH:43]=[CH:42][C:41](S(C)(=O)=O)=[CH:40][CH:39]=2)=[C:35]([Cl:48])[C:34]2[C:29](=[C:30]([CH3:57])[CH:31]=[C:32]([C:49]([C:51]3[N:55]([CH3:56])[CH:54]=[N:53][CH:52]=3)=[O:50])[CH:33]=2)[N:28]=1>O=P(Cl)(Cl)Cl>[N:1]1([C:41]2[CH:42]=[CH:43][C:38]([CH2:37][C:36]3[C:27]([Cl:26])=[N:28][C:29]4[C:34]([C:35]=3[Cl:48])=[CH:33][C:32]([C:49]([C:51]3[N:55]([CH3:56])[CH:54]=[N:53][CH:52]=3)=[O:50])=[CH:31][C:30]=4[CH3:57])=[CH:39][CH:40]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)nc12
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: 105 °C

Procedure:
A heterogeneous mixture of 2-(4-(1H-pyrazol-1-yl)benzyl)malonic acid (2.42 g 9.29 mmol, Intermediate 4: step b), (4-amino-3-methylphenyl)(1-methyl-1H-imidazol-5-yl)methanone (2 g, 9.29 mmol, Intermediate 13: step c) and POCl3 (10 mL) was heated at 105° C. for 4 hours. The mixture was cooled to room temperature, concentrated to remove excess POCl3 and ice water was added. The mixture was treated with NH4OH (kept adding ice during addition) to a basic pH 8-9 and the aqueous was then extracted with DCM. The DCM extracts were dried (Na2SO4), evaporated in vacuo and chromatographed (DCM/EtOAc, gradient) to provide the crude product. Pure product was precipitated with MeOH, filtered and dried to provide the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:30]=[CH:29][C:17]([O:18][CH:19]([CH3:28])[C:20]([O:26][CH3:27])=[CH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:28])[C:20]([O:26][CH3:27])=[CH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:29][CH:30]=1)[CH:11]=[N:10]2
Reactant: COC(=O)C=C(OC)C(C)Oc1ccc(O)cc1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Product: COC(=O)C=C(OC)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1

Procedure:
The procedure of Example 37 is repeated using 2,6-dichloroquinoxaline and methyl 4-(4-hydroxyphenoxy)-3-methoxy-2-pentenoate as the starting materials to yield methyl 4-[4-(6-chloro-2-quinoxalyloxy)phenoxy]-3-methoxy-2-pentenoate which is treated with 35% HClO4 to yield the 3-oxo ester. Methyl 4-[4-(6-chloro-2-quinoxalyloxy)phenoxy]-3-oxopentanoate.
Reaction SMILES: [C:1]1([C:7]([NH:9][NH2:10])=[S:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=O>C(O)C>[C:1]1([C:7]2[S:8][CH:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=O
Reactant: NNC(=S)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1NN=C(c2ccccc2)S1
Yield: 112.7 %

Procedure:
A solution of benzenecarbothioic acid hydrazide (0.4g) and ethyl glyoxylate (0.4g) in ethanol (1 ml) was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the residue re-evaporated with toluene (x2) to yield the sub-title product (0.7g) as a gum.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>>[NH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:5]([O:6][CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[C:4]=1[C:2]#[N:3]
Reactant: CCCC(=O)Cl
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CCCC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 90 %

Procedure:
Prepared as in Example 209a from (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 209b) and butyryl chloride to in 90% yield as a white solid. MS 288 (MH+).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: FC1(F)CCN(CCCCl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CCC(F)(F)C4)c4ccc(OC(F)F)cc34)nc12
Yield: 71.4 %

Procedure:
N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), 1-(3-chloropropyl)-3,3-difluoropyrrolidine (34.6 mg, 188 μmol) and cesium carbonate (184 mg, 565 μmol) in dimethylformamide (2 mL) were heated in a microwave at 100° C. for 30 min. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with water 3 times then dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (91 mg, 72%). MS (M+H)+=678.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24]Cl)[CH3:21]>>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][S:1][C:2]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:21]
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCSc1nc2ccccc2c(=O)n1-c1ccccc1
Yield: 32.7 %

Procedure:
The title compound was prepared in a yield of 32.7%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3-isobutyl-2-mercapto-4(3H)-quinazoline and β-diethylaminoethyl chloride hydrochloride in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH2:41]([N:43]1[CH:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[N:44]1)[CH3:42]>O1CCCC1.O>[CH2:41]([N:43]1[CH:47]=[C:46]([S:48]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:50])=[O:49])[CH:45]=[N:44]1)[CH3:42]
Reactant: CCn1cc(S(=O)(=O)Cl)cn1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Reaction time: 0.08 h
Yield: 97.4 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 50 mg) at room temperature, and the mixture was stirred for 5 min. 15-Crown-5 (273 mg) was added. Then 1-ethyl-1H-pyrazole-4-sulfonyl chloride (181 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 290 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:19]4([CH2:20][CH2:21][O:16][CH2:17][CH2:18]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: O=C1CCOCC1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC2(CCOCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.078 g, 0.36 mmol), tetrahydro-4H-pyran-4-one (0.200 g, 2.00 mmol), p-toluenesulfonic acid monohydrate (0.076 g, 0.40 mmol) and toluene (3.0 mL) was stirred for 2 h at 90° C. The mixture was poured into aqueous sodium hydrogen carbonate (50 mL). Extraction with ethyl acetate/tetrahydrofuran (2:1, 2×30 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (12 g, silica, Combiflash, dichloromethane to 80:20 dichloromethane/methanol) to afford the title compound (0.050 g, 46%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]N1C(=O)CCC1=O>>[Cl:1][C:2]1[C:11]([CH2:12][Br:17])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl

Procedure:
80 g (0.3 mol) of methyl 2-chloro-3-methyl-4-methylsulfonylbenzoate, 54 g (0.31 mol) of N-bromosuccinimide and 1.5 g of azoisobutyronitrile are stirred at 76° C. for 6 h. The reaction mixture is filtered and freed form the solvent under reduced pressure. Yield: 104 g; m.p. 83-85° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(OC(=O)[NH:37][CH2:38][CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)(C)(C)C>>[NH2:37][CH2:38][CH:39]1[CH2:43][CH2:42][N:41]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]4[C:16]([C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:15][NH:14][C:11]4=[N:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCC(CN)C4)c3)nc12

Procedure:
1-{2-[3-(3-Aminomethyl-pyrrolidin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester following general procedures as described in these Examples. M+H=378.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9](=[O:19])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[C:14]([OH:18])[CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)C>[OH:3][CH:1]([C:4]1[O:8][C:7]2[C:9](=[O:19])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[C:14]([OH:18])[CH:13]=[CH:12][CH:11]=3)[CH3:2]
Reactant: CC(=O)c1cc2c(o1)C(=O)c1cccc(O)c1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(O)c1cc2c(o1)C(=O)c1cccc(O)c1C2=O
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a solution of 2-acetyl-5-hydroxynaphtho[2,3-b]furan-4,9-dione (694 mg, 2.73 mmol) obtained in Example 5 in chloroform (100 mL) and ethanol (25 mL) is added sodium borohydride (515 mg, 13.7 mmol) at 0° C. The mixture is stirred for 30 minutes, and then the reaction is quenched by adding 10% hydrochloric acid to the mixture. The aqueous layer is extracted with chloroform twice, and the extract is continuously washed with water and brine. The mixture is evaporated in vacuo and purified by silica gel column chromatography (eluent: chloroform) to give 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4,9-dione (516 mg, 74%) as a racemic mixture of a yellow crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]#[N:16])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:6]=2Br.O.O.[Sn](Cl)Cl.Cl>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:15]#[N:16])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: COc1ccc2cc(Br)cc(C#N)c2c1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2cc(Br)cc(C#N)c2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
To slurry of 3,8-dibromo-7-methoxy-1-naphthonitrile (1.62 kg) and Tin (II) chloride dihydrate (1.24 kg, 5.50 mol) in acetic acid (5 L) is added conc. HCl (37% wt, 2.50 L) through a dropping funnel at 100° C. during a period of 2 h. The mixture is stirred at 100° C. for 4 h. Then, the mixture is cooled to room temperature. The solid is filtered, washed with 1% wt HCl (2×1.00 L), water (1.00 L) and dried to give the title compound as a white solid (524 g, 73%). 1H NMR (CDCl3): δ8.13 (d, 1H, J=1.8 Hz), 7.93 (d, 1H, J=1.9 Hz), 7.72 (d, 1H, J=9.0 Hz),7.41 (d, 1H, J=2.4 Hz), 7.28 (dd, 1H, J=2.4 Hz, 9.0 Hz), 3.99 (s, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:35][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[N:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccnn5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cccnn5)cc4)CC3)n2CCS1
Yield: 57 %

Procedure:
A solution of the compound (292 mg, 0.58 mmol) obtained in Example 50-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (130 mg, 57%) as a colorless solid.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]([F:14])([F:13])[F:12].[NH3:15]>O1CCCC1>[NH2:15][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: N
Reactant: Fc1cc(F)c(C(F)(F)F)c(F)c1F
Solvent: C1CCOC1
Product: Nc1c(F)c(F)cc(F)c1C(F)(F)F
Temperature: 100 °C

Procedure:
110 g of 2,3,4,6-tetrafluoro-benzotrifluoride in 200 ml of tetrahydrofuran were initially introduced into a 0.7 l stainless steel autoclave and it was pressurized using 30 ml of liquid ammonia. The mixture was subsequently heated at 100° C. for 3 hours, a maximum pressure of 10 bar being adjusted. After cooling, the pressure was released and the liquid phase was subjected to a fractional distillation. 42 g of 2-amino-3,4,6-trifluorobenzotrifluoride were first obtained with a boiling point of 47° to 48° C. at 8 mbar, then after an intermediate run, 46 g of 2,5,6-trifluoro-4-amino-benzo-trifluoride with a boiling point of 75° to 78° C. at 8 mbar.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[N:16]1([C:22]2[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)[C:25](O)=[O:26])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:23]=1
Reactant: O=C(O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-morpholin-4-yl-5-trifluoromethyl-benzoic acid (CAS RN 250682-08-7) after a reaction time of 5 days. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). Colorless solid (12%). MS (ESI): m/z=456.188 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([Cl:42])[CH:41]=1>>[Cl:35][C:36]1[CH:37]=[C:38]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)[CH:39]=[C:40]([Cl:42])[CH:41]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(Cl)cc(Cl)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3,5-dichloro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.96 (d, J=6.60 Hz, 6H), 1.58 (dt, J=13.45, 6.72 Hz, 1H), 1.77 (ddd, J=13.76, 7.34, 7.03 Hz, 1H), 2.09 (ddd, J=13.45, 7.83, 7.58 Hz, 1H), 3.83 (t, J=7.70 Hz, 1H), 7.38 (t, J=1.83 Hz, 1H), 7.48 (d, J=1.71 Hz, 2H), 7.52 (s, 1H), 7.57-7.67 (m, 2H), 7.71-7.77 (m, 4H); Calcd for C25H21Cl2F3O2 (M+H) 482.33, Found 482.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>N.CO.[Ni]>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc2ncccc2c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
To a solution of quinoline-6-carbonitrile (96 g, 0.62 mol) in saturated ammonia in methanol (1 lit.), Raney-Ni (10 g) was added and the mixture was stirred at 1 atm of H2 at RT for 16 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to afford the title compound as a brown oil (80 g, 82%). 1H-NMR (δ ppm. DMSO-d6, 400 MHz): δ8.83 (dd, J=4.2, 1.7 Hz, 1H), 8.29 (d, J=8.2, 4.2 Hz, 1H), 3.90 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:32]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH2:19][Br:32])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1CBr
Yield: 100.3 %

Procedure:
To a boiling solution of 23.5 g 2-(4-methoxy-phenyl)-4-methyl-oxazole-5-carboxylic acid ethyl ester in 250 ml tetrachloro-methane were added portionwise a mixture of 5.92 g 2,2′-azobis(2-methylpropionitrile) and 19.3 g N-bromosuccinimide. The reaction mixture was refluxed for seven hours. The cooled reaction mixture was filtered over a celite pad and the solvent removed in vacuo to obtain 30.7 g of crude 4-bromomethyl-2-(4-methoxy-phenyl)-oxazole-5-carboxylic acid ethyl ester. The material was used without further purification in the next step.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[CH3:7].[C:21]([O-])(=[O:23])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH3:20])[C:13]1[CH:18]=[CH:17][C:16]([CH:21]=[O:23])=[CH:15][CH:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CCN(CCOC(C)=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CCOC(C)=O)c1ccc(C=O)cc1
Temperature: 0 °C
Yield: 84.2 %

Procedure:
After adding 55.8 g of ice-cooled phosphoryl chloride to 26.6 g of dimethylformamide, a solution of 63.0 g of the 2-(N-ethylanilino)ethyl acetate in 40 ml of dimethylformamide was slowly added at room temperature, this was caused to react for 6 hours at room temperature while stirring, and then poured into an aqueous solution of 150 g of sodium acetate under ice cooling. An organic layer was extracted with ethyl acetate and the solvent was boiled off under reduced pressure. This was refined by silica gel column chromatography to yield 60.2 g of 2-(ethyl(4-formylphenyl)amino)ethyl acetate.