Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:8]2[CH:9]=[CH:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](NC(=O)CC4C=CC(F)=CC=4)=[O:20])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:44]=[CH:43][CH:42]=[C:41](C(O)=O)[C:40]2=[O:48])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[ClH:1].[NH2:2][C:3]1[C:8]2[CH:9]=[CH:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:41]4[C:40](=[O:48])[N:39]([C:36]5[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=5)[CH:44]=[CH:43][CH:42]=4)=[O:20])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: Nc1nccc2c1ccn2-c1ccc(NC(=O)NC(=O)Cc2ccc(F)cc2)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc2c1ccn2-c1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Reaction time: 8 h
Yield: 14.7 %

Procedure:
Bis-tert-butyl 1-(4-aminophenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl-dicarbamate (Compound B of Example 3, 0.18 g, 0.043 mmol, 1.0 eq) was added to a solution of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.011 g, 0.047 mmol, 1.1 eq) and TBTU (0.018, 0.047 mmol, 1.1 eq) in DMF (0.50 mL) at room temperature. Diisopropylethylamine (0.008 mL, 0.047 mmol, 1.1 eq) was added to the reaction mixture and stirring was continued for 8 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (YMC C-18 column, 30 min. gradient 25-90% aq. MeOH with 0.1% TFA). The appropriate fractions were concentrated in vacuo and the residue treated with anhydrous HCl (4 N in dioxane) at 0° C. The solution was concentrated in vacuo and the later procedure repeated three times. The residue was triturated with Et2O, discarding the filtrate and the solid was dried in vacuo to afford the title compound (0.003 g, 17%) as a white solid. 1H NMR (CD3OD) δ 7.85-7.87 (m, 2H), 7.56-7.63 (m, 3H), 7.24-7.46 (m, 6H), 7.03-7.09 (m, 3H), 6.94 (br m, 1H); MS(ESI+) m/z 440 (M+H)+, calc: 440.1523, found: 440.1517.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]([O:14]CC)=[O:13])[O:9][C:10]=1[CH3:11].[OH-].[Na+].O>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]([OH:14])=[O:13])[O:9][C:10]=1[CH3:11]
Reactant: CCOC(=O)c1nc(Cc2cccc(Br)c2)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(C(=O)O)nc1Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of ethyl 4-(3-bromobenzyl)-5-methyloxazole-2-carboxylate (500 mg, 1.5 mmol) and 2 N NaOH (2 mL, 4 mmol) in EtOH (6 mL)/H2O (2 mL) was stirred at 0° C. for 2 h. The mixture was neutralized with aqueous critic acid (10%), concentrated and purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 0.01% TFA) to afford 4-(3-bromobenzyl)-5-methyloxazole-2-carboxylic acid as a yellow oil (320 mg, 65%). MS (ES+) C12H10BrNO3 requires: 295, 297, found: 296 [M+H]+, 298 [M+2+H]+(1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18](I)[CH:19]=[CH:20][C:13]=3[O:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:31]([OH:34])[C:32]#[CH:33]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18]([C:33]#[C:32][CH2:31][OH:34])[CH:19]=[CH:20][C:13]=3[O:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1noc2ccc(I)cc2c1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1noc2ccc(C#CCO)cc2c1=O
Temperature: 25 °C

Procedure:
Under an argon atmosphere, a mixture of N-(4-chlorobenzyl)-6-iodo-4-oxo-4H-1,2-benzoxazine-3-carboxamide (Preparation 18, 0.117 g), dichlorobis (triphenyl-phosphine)palladium (12.8 mg), copper(I) iodide (3.7 mg), and triethylamine (1 mL) in THF (6 mL) is cooled in an ice-brine bath. A solution of propargyl alcohol (32 mg) in THF (3 mL) is added slowly via a syringe to the reaction mixture. The reaction mixture is stirred at ice-brine temperature for 2 h and then allowed to warm to room temperature overnight. The mixture is concentrated in vacuo and the residue is flash chromatographed on silica gel (230-400 mesh, 8 g), eluting with 1% methanol in dichloromethane, pooling desirable fractions and concentrating in vacuo provides the title compound as a pale yellow solid. Physical characteristics: m.p. 117-120° C.: 1H NMR (400 MHz, DMSO-d6) δ4.35, 4.50, 5.55, 7.42, 7.77, 7.97, 9.4; 13C NMR (DMSO-d6) δ49.2, 49.3, 67.8, 79.4, 81.8, 91.8, 117.5, 119.8, 120.2, 126.6, 128.3, 129.0, 131.6, 137.2, 138.8, 155.2, 159.2, 160.3, 165.2; MS (FAB) m/z 369 (MH+, 99); HRMS (FAB) m/z 369.0645 (C19H13ClN2O4+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].CCN(CC)CC.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([Si:26]([CH3:28])([CH3:27])[O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14])([CH3:25])([CH3:24])[CH3:22]
Reactant: COc1cc2c(cc1O)C(=O)CCC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(=O)CCC2
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a well-stirred solution of 7-Hydroxy-6-methoxy-1-tetralone (80.0 mg, 0.42 mmol) in CH2Cl2, was added Et3N (47 mg, 0.46 mmol), followed by DMAP (5.1 mg, 0.042 mmol) and TBSCl (69 mg, 0.46 mmol) at 0° C. under dry nitogen. After 2 h (at rt), the mixture was partitioned between CH2Cl2 and water. The organic layer was dried over anhydrous sodium sulfate, and after filtration, the organic layer was concentrated in vacuo to provide a yellow oil. 7-[(tertButyldimethylsilyl)oxy]-6-methoxy-1-tetralone (122 mg, 0.40 mmol, 95%) was obtained following purification by column chromatography. 1H-NMR (CDCl3, 300 MHz) 0.15 (s, 6H), 0.99 (s, 9H),2.11 (m, 2H), 2.58 (t, J=6.1 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 3.86 (s, 3H), 6.63 (s, 1H), 7.56 (s, 1H).
Reaction SMILES: C(N[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:8]([CH3:21])([CH3:20])[CH2:7]1)CCC.[N:22]1[C:29]([Cl:30])=[N:28][C:26]([Cl:27])=[N:25][C:23]=1Cl.C(=O)(O)[O-].[Na+]>>[OH:19][C:16]([CH3:17])([CH3:18])[CH2:15][O:14][N:9]1[C:8]([CH3:20])([CH3:21])[CH2:7][CH:6]([CH2:11][CH2:6][CH2:7][CH2:8][NH:9][C:23]2[N:22]=[C:29]([Cl:30])[N:28]=[C:26]([Cl:27])[N:25]=2)[CH2:11][C:10]1([CH3:12])[CH3:13]
Reactant: CCCCNC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(Cl)n2)CC1(C)C

Procedure:
The compound prepared in Example 23B is reacted with an equimolar amount of cyanuric chloride and sodium bicarbonate at 0° C. to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:16](=[O:19])[NH:17][N:18]=2)=[CH:10][CH:9]=1.Cl[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(#N)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:17]1[C:16](=[O:19])[N:15]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:14]([C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)=[N:18]1)[CH3:35]
Reactant: COc1ccc(Cn2c(-c3ccc(Cl)cc3)n[nH]c2=O)cc1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccc(OC)cc2)c1=O

Procedure:
2.54 g (18.4 mmol) of potassium carbonate are added to 2.90 g (9.18 mmol) of 5-(4-chlorophenyl)-4-(4-methoxyphenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 55A and 1.13 g (9.18 mmol) of ethyl chloroacetate in 60 ml acetonitrile and the mixture is heated under reflux overnight with stirring. It is then concentrated, the residue is partitioned between ethyl acetate and water and the aqueous phase extracted three times more with ethyl acetate. By evaporation of the organic phases, combined and dried over magnesium sulphate, 3.58 g (97% of theory) of the target compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.B(O)O.C(=O)(O)[O-].[Na+].O.[CH2:38](O)[CH3:39]>C1(C)C=CC=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([C:5]5[N:6]([CH3:8])[N:7]=[CH:39][CH:38]=5)[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: CCO
Reactant: Cc1cc(-c2cnc3c(NCC(C)C)cc(Cl)nn23)ccc1C(=O)NC1CC1
Agent: O=C([O-])O
Agent: OBO
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(-c2cnc3c(NCC(C)C)cc(-c4ccnn4C)nn23)ccc1C(=O)NC1CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a mixture of 100 mg (251 μmol) 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, 95 mg (750 μmol) 1-methyl-1H-pyrazol-5-yl) boronic acid, 35 mg Tetrakis(triphenylphosphin)palladium in 2 mL of ethanol and 2 mL of toluene was added 0.5 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then water and was added and the organic layer was washed with water and brine, concentrated and purified by chromatography to give 99 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]([NH:28][OH:29])=[NH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH2:38][C:39](Cl)=O)[CH:34]=[CH:35][C:36]=1[Cl:37]>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]1[N:27]=[C:39]([CH2:38][C:33]2[CH:34]=[CH:35][C:36]([Cl:37])=[C:31]([Cl:30])[CH:32]=2)[O:29][N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: N=C(NO)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Product: O=c1c(OCc2ccccc2)c(-c2noc(Cc3ccc(Cl)c(Cl)c3)n2)nc2ccc(N3CCOCC3)cn12

Procedure:
Using the product of example 20 and 3,4-dichlorophenylacetyl chloride following the procedure of example 21.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]([CH2:24][OH:25])[C@H:11]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Cl[S:47]([NH2:50])(=[O:49])=[O:48]>C(#N)C>[C:1]([O:9][C@H:10]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]([CH2:24][O:25][S:47]([NH2:50])(=[O:49])=[O:48])[C@H:11]1[O:26][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)Cl
Reactant: O=C(N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccncc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: NS(=O)(=O)OC[C@H]1C[C@@H](NC(=O)c2ccncc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
To a solution of (1S,2R,3R,5R)-3-(hydroxymethyl)-5-(isonicotinoylamino)cyclopentane-1,2-diyl dibenzoate (160. mg, 0.350 mmol) in ACN (10.0 mL) at 0° C. was added DBU (0.0600 mL, 0.401 mmol) and the mixture was stirred for 15 min. A freshly prepared 1.40 M solution of chlorosulfonamide (0.500 mL, 0.700 mmol, as prepared in Example 1d) was then added dropwise via syringe and the mixture was stirred for 2.5 h at 0° C. before being allowed to warm to rt. The mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in E)CM to afford the title compound (50.0 mg, 27%). LC/MS: Rt=1.57 min, ES+ 540. (FA standard).
Reaction SMILES: Br.O=[C:3]1[CH:12]([CH2:13][C:14]([O:16]C)=O)[CH2:11][CH2:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]1=2.[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.Cl.C1(C)C=CC(NN)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:26][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:14](=[O:16])[CH2:13][CH:12]3[C:3]([C:4]4[CH:5]=[CH:6][N:7]=[CH:8][C:9]=4[CH2:10][CH2:11]3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(NN)cc1
Reactant: COC(=O)CC1CCc2cnccc2C1=O
Agent: Br
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1ccc(N2N=C3c4ccncc4CCC3CC2=O)cc1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
Methyl 5,6,7,8-tetrahydro-5-oxoisoquinoline-6-acetate hydrobromide (1.2 g) (Wu et al, Synthetic Communications 24, 273 (1994)) 4-tolylhydrazine (0.5 g) and 4-tolylhydrazine hydrochloride (0.19 g) in xylene (20 ml) were heated under reflux for 3 hours. The reaction mixture was allowed to cool to room temperature and the volatiles removed. The residue was dissolved in dichloromethane-methanol, washed with sodium hydrogen carbonate solution twice and then brine. The organic phase was dried, filtered and concentrated to a dark oil. The crude product was adsorbed onto silica and chromatographed eluting with 7:3 dichloromethane:ethyl acetate. The resultant oil was triturated with ether and recrystallised from isopropanol to give the title compound (0.3 g).
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][C:14]=3[C:22]([F:25])([F:24])[F:23])=O)(C)(C)C.[ClH:29]>>[ClH:29].[CH2:19]([C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:26])[N:11]3[CH2:27][CH2:28][NH:8][CH2:9][C@H:10]32)=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:15]=1)[CH2:20][CH3:21]
Reactant: CCCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Product: CCCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 0.08 h
Yield: 89 %

Procedure:
To N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-propyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (25 mg, 0.06 mmol) was added concentrated aqueous hydrogen chloride (1 mL). After 5 min, the solution was concentrated, diluted with water, and lypholized to give the desired product as an off-white solid (19 mg, 89%). %). MS (ESI) 299.3 (M−Cl).
Reaction SMILES: [CH2:1]([N:8]([CH3:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][C:19](=O)[CH3:20]>>[CH2:1]([N:8]([CH3:16])[C:9]1[C:19]([CH3:20])=[CH:18][N:11]2[C:10]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: CN(Cc1ccccc1)Cc1ccccn1
Product: Cc1cn2ccccc2c1N(C)Cc1ccccc1
Yield: 34 %

Procedure:
This compound is obtained according to the same procedure as the compound of Preparation I, using the Tschitschibabin reaction and starting with 2.47 g of N-benzyl-N-methyl-N-[(pyridin-2-yl)methyl]amine and chloroacetone. 970 mg of a yellow oil are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc3cnccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
6-Aminoisoquinoline (3.348 g, Synthesis, 733 (1975)) was dissolved in pyridine (30 ml). To the mixture was added 4-toluenesulfonyl chloride (5.13 g), followed by stirring at room temperature overnight. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from ethanol, to give the title compound (5.958 g, 85%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][NH:5][C:6]1[C:7]([NH2:30])=[N:8][C:9]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)=[N:10][C:11]=1[NH2:12].C1N=CN([C:40](N2C=NC=C2)=[O:41])C=1.C(N(CC)CC)C>CN(C)C=O>[NH2:30][C:7]1[N:8]=[C:9]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)[N:10]=[C:11]2[C:6]=1[N:5]([CH2:4][C:3]1[CH:31]=[CH:32][CH:33]=[CH:34][C:2]=1[F:1])[C:40](=[O:41])[NH:12]2
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1NCc1ccccc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(Cc3ccccc3F)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
268 mg (0.48 mmol) of the compound from example 66A were initially charged in dimethylformamide (2.6 ml), then 389 mg (2.40 mmol) of N,N-carbonyldiimidazole and 0.80 ml (5.75 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. Subsequently, 380 mg (2.34 mmol) of N,N-carbonyldiimidazole were added and the mixture was stirred again at 100° C. overnight. The reaction mixture was purified directly by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient). This gave 130 mg (56% of theory) of the title compound.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6])#[N:2].[K+].Cl[CH2:14][C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[C:1]([C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:14][C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1)=[O:6])#[N:2]
Reactant: N#Cc1ncccc1C(=O)[O-]
Reactant: Cc1nc(CCl)cs1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(COC(=O)c2cccnc2C#N)cs1
Yield: 40.9 %

Procedure:
A mixture of potassium 2-cyanonicotinate (4.1 g; 0.022 mole), 4-chloromethyl-2-methylthiazole (2.95 g; 0.02 mole) and 18-crown-6-ether (0.13 g; 0.0005 mole) in acetonitrile (50 cc) is brought to reflux for 8 hours. The solvent is then evaporated off and the residue taken up in water and extracted with dichloromethane. After drying, evaporation of the dichloromethane and purification by chromatography on a silica column, Compound 1(2.12 g; 41%; m.p. 93° C.) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[C:35]([N:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:24]([O:26][CH3:27])=[O:25])=[CH:12][CH:11]=3)[CH2:19][CH2:20]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNCC3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(C(=O)c4ccccc4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(piperazin-1-yl)quinoxaline-6-carboxylate (180 mg, 0.49 mmol) in dichloromethane (10 ml) was added Et3N (200 mg, 2 mmol) followed by benzoyl chloride (170 mg, 1.18 mmol) dropwise. The resulting solution was stirred for 1 hour at room temperature and then quenched by the addition of ice-water (150 ml) and extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-(4-benzoylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (130 mg, 56%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:2]=1.[H-].[Na+].[Cl:21][C:22]1[C:23]([F:31])=[C:24]([C:27]([F:30])=[CH:28][CH:29]=1)[CH2:25]Br.O>CN(C=O)C>[Cl:21][C:22]1[C:23]([F:31])=[C:24]([C:27]([F:30])=[CH:28][CH:29]=1)[CH2:25][N:12]1[C:13]2[CH:1]=[N:2][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: Fc1ccc(Cl)c(F)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1
Reaction time: 22 h
Yield: 75 %

Procedure:
To a stirred solution of ethyl 9H-β-carboline-3-carboxylate (440 mg, 1.83 mmol) in DMF (5 mL) under a nitrogen atmosphere was added NaH (73.3 mg, 60% in mineral oil, 1.83 mmol) portionwise, followed by 3-chloro-2,6-difluorobenzyl bromide (442 mg, 1.83 mmol). Stirring was continued for 22 hours at ambient temperature, water (30 mL) was then added to the mixture. The precipitate was filtered, washed with water and dried to give the title product (0.55 g, 68%). 1H NMR (400 MHz, CD3OD): δ 9.04 (1H, s), 8.86 (1H, s), 8.26 (1H, d, J=8 Hz), 6.98–7.69 (5H, m), 5.82 (2H, s), 4.44 (2H, q, J=8 Hz), 1.43 (3H, t, J=8 Hz).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH2:43][C:44]([OH:46])=[O:45])[C:24]1=[O:47])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:51]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH2:43][C:44]([O:46][CH3:51])=[O:45])[C:24]1=[O:47])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-((3S,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid (741 mg, 1.076 mmol; Example 127, Step B) in 10 mL of a 10% solution of MeOH in DCM at room temperature was added TMS-diazomethane (2.0M in ether) (807 μL, 1.614 mmol). Evolution of gas was observed and the yellow mixture was stirred at room temperature for 45 min. More TMS-diazomethane (2.0M in ether) (807 μL, 1.614 mmol) was added and the reaction was stirred at room temperature for 45 min. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (24 g column; eluent: 0 to 30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.[OH-].[K+].Cl>C(O)C>[OH:13][C:5]1[C:4]([C:1](=[O:3])/[CH:2]=[CH:19]/[C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=2)=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(=O)c1cccc(C(=O)O)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(C(=O)/C=C/c2cccc(C(F)(F)F)c2)c1O
Temperature: 0 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
3-acetyl-2-hydroxybenzoic acid 32 (0.9 g, 5 mmol) and 3-(trifluoromethyl)benzaldehyde 33 (0.96 g, 5.5 mmol) were dissolved in 100 mL ethanol. After addition of the same volume of 25% aq KOH, the reaction mixture was stirred for 24 h. The mixture was poured into ice-water and the PH was adjusted to 2 with conc. HCl. The precipitate was filtered, washed with H2O and dried to give 34 (0.8 g, 47% yield)