Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:17]1[O:19][CH2:18]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:21]([O:20][CH2:16][CH:17]([OH:19])[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][CH:17]([OH:19])[CH2:16][O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: CCCCOCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOCC(O)COc1ccc(Cc2ccc(OCC(O)COCCCC)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Bis(p-hydroxyphenyl)methane (303 g; 1.5 moles), butyl glycidyl ether of epoxide content 7.45 equiv./kg (402.7 g; 6 equiv.), and benzyltrimethylammonium chloride (3 g) were stirred together and heated to 100° C., at which temperature an exothermic reaction commenced. The mixture was kept at 120° C. by moderate cooling and then, when the temperature of the mixture began to fall, heating was resumed, keeping the temperature at 120° C. for 1 hour and 150° C. for 4 hours. The mixture was cooled, and its epoxide content was found to be 0.1 equiv./kg, indicating that the reaction was virtually complete.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:8]=[C:9]1/[C:10](=[O:20])[C:11]2[C:16]([CH2:17]/1)=[CH:15][C:14]([CH3:18])=[C:13]([CH3:19])[CH:12]=2>[Pt]>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH3:19])=[C:14]([CH3:18])[CH:15]=2)[C:10]1=[O:20]
Reactant: Cc1cc2c(cc1C)C(=O)/C(=C/c1ccncc1Br)C2
Agent: [Pt]
Product: Cc1cc2c(cc1C)C(=O)C(Cc1ccncc1Br)C2

Procedure:
The title compound 107 is prepared according to the procedure reported in Example 37.2 with compound 92 (0.44 g, 1.35 mmol) and Pt/C (5 wt % loading, 44 mg) as reactants. White solid. (Yield 0.39 g, 89%).
Reaction SMILES: [K+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O-:14])=O)=[CH:5][CH:4]=1.Cl.[NH2:26][CH2:27][C:28]#[N:29]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:29][CH2:28][C:27]#[N:26])=[O:14])=[CH:7][CH:8]=1
Reactant: N#CCN
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)c1ccccn1)C(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CC(C)CC(OC(c1ccc(Br)cc1)c1ccccn1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 17, step 3, 2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-4-methylpentanoic acid potassium salt from step 3 (662 mg, 1.59 mmol) was coupled with aminoacetonitrile HCl Salt. The crude residue obtained was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:29])([CH3:28])[CH2:12][C@@H:13]([C@H:22]1[O:26][C:25](=[O:27])[CH2:24][CH2:23]1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[CH2:40]([C@@H:24]1[CH2:23][C@@H:22]([C@@H:13]([NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:12][C:11]([CH3:29])([CH3:28])[CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:26][C:25]1=[O:27])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(CCOCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCC(=O)O1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CCOCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Reaction time: 0.5 h

Procedure:
A solution of 1.76 g of 5(S)-[5-benzyloxy-1(S)-tert-butoxycarbonylamino-3,3-dimethylpentyl]-2-oxo-tetrahydrofuran in 30 ml of tetrahydrofuran is added to a mixture of 9.14 ml of a 1M lithiumbis(trimethylsilyl)amide solution in tetrahydrofuran and 30 ml of tetrahydrofuran at -78° C. under argon and the mixture is stirred for 30 min. 0.63 ml of benzyl bromide in 30 ml of tetrahydrofuran are then added dropwise. After the mixture has been stirred at -78° C. for 3.5 h, the reaction is quenched by addition of 1.6 ml of propionic acid and the mixture is diluted with diethyl ether. The organic phase is washed with a 10% aqueous citric acid solution and a 1M sodium bicarbonate solution, dried over sodium sulfate and concentrated. Purification over silica gel (mobile phase D) gives the title compound: Rf (D)=0.23; FAB-MS: (M+H)+ =496.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@@H:35]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@H:37]([N:48]2[CH:53]=[CH:52][C:51](=[O:54])[NH:50][C:49]2=[O:55])[O:36]1)[CH:6]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:29])[C@H:13]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:14]C(=O)OCC1C=CC=CC=1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([O:4][C@@H:5]([C@@H:35]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@@H:37]([N:48]2[CH:53]=[CH:52][C:51](=[O:54])[NH:50][C:49]2=[O:55])[O:36]1)[CH:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:29])[C@@H:13]([NH2:14])[CH2:25][CH:26]([CH3:27])[CH3:28])[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(NCCCNC(=O)[C@@H](N)CC(C)C)[C@@H](OC(C)=O)[C@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 103.9 %

Procedure:
Ethyl (5S)-12-[(R)-(acetyloxy)[(2R,3R,4R,5S)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]methyl}-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-1-oate (88 mg, 0.114 mmole, obtained from Example 38) was hydrogenated using 10% palladium on carbon in methanol (2 ml) under atmospheric pressure to provide ethyl (3R)-3-(acetyloxy)-2-[(3-{[(2S)-2-amino-4-methylpentanoyl]amino}propyl)amino]-3-[(2R,3R,4R,5S)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate (76 mg, 95%) as a white glassy solid.
Reaction SMILES: [CH:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:14][C:15]=1[F:22]
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Solvent: CCO
Product: CCOC(=O)C(c1ccc(N)c(F)c1)C1CCCCC1

Procedure:
The ethyl 2-cyclohexyl-2-(3-fluoro-4-nitrophenyl)acetate was dissolved in a 1:1 mix of EtOH and EE (420 ml) and hydrogenated in an H-cube (1 bar, 25° C., 1 ml/min and 0.25 mol/L). After removal of the solvent and drying, 5 g (quantitative turnover) of product could be obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:15][C:10]1[C:9]([C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=Cc1cc(-c2cccnc2F)c(Br)s1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cc(-c2cccnc2F)c(Sc2ccccc2)s1
Yield: 99 %

Procedure:
With 5-bromo-4-(2-fluoropyridin-3-yl)thiophene-2-carbaldehyde (2.86 g) as a starting material, and using thiophenol (1.33 mL) and potassium carbonate (2.21 g), an operation similar to that of Reference Example 1 was performed to give the title compound as a pale-yellow oil (yield 3.11 g, yield 99%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](F)=[O:9])=[CH:6][CH:5]=1.[N-:15]=[N+:16]=[N-:17].[Na+].C1OCCOCCOCCOCCOCCOC1.C(#N)C>C(OCC)C>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:15]=[N+:16]=[N-:17])=[O:9])=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(F)c1ccc(OC(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: [N-]=[N+]=NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
A mixture of 5 grams (24 mmol) of 4-(trifluoromethoxy)benzoyl fluoride, 1.87 grams (29 mmol) of sodium azide, 0.2 grams of 18-Crown-6 ether, and 20 ml. of acetonitrile was stirred at room temperature for two hours under an atmosphere of dry nitrogen. The reaction mixture was diluted with diethyl ether, filtered and concentrated under reduced pressure, with a bath temperature of 40° C., to give the title compound as a turbid oil. IR showed adsorptions at 2280, 2240 and 1695 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH:10]([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:21])=[C:4]([CH3:8])[C:3]=1[O:9][CH:10]([F:11])[F:12]
Reactant: Cc1nccc(Cl)c1OC(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(OC(F)F)c(Cl)cc[n+]1[O-]
Temperature: 5 °C
Reaction time: 12 h
Yield: 94.3 %

Procedure:
76.38 g of 4-chloro-3-difluoromethoxy-2-methylpyridine (XIX) was dissolved in 2500 ml of anhydrous dichloromethane, to which 93.62 g of 3-chloro-perbenzoic acid was added under cooling with ice, and the resulting mixture was stirred at 5° C. for 12 hours. The resulting organic layer was washed with 5% sodium carbonate solution, and thereafter, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 77.97 g of 4-chloro-3-difloromethoxy-2-methylpyridine N-oxide (VI).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24](O)=[O:25])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH:7][C:24](=[O:25])[CH2:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[N:14][CH:15]=2)[S:5][CH:6]=1
Reactant: O=C(O)Cc1cncc2ccccc12
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cncc2ccccc12)Nc1scc(Br)c1-c1nnc[nH]1
Reaction time: 3 h
Yield: 15 %

Procedure:
To a solution of 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (50 mg, 0.2 mmol) and 2-(isoquinolin-4-yl)acetic acid (56 mg, 0.3 mmol) in methylene chloride (2 mL) were added Hunig's base (i.e., N,N-diisopropylethylamine) (71 uL, 0.4 mmol) and HBTU (133 mg, 0.35 mmol). The heterogeneous reaction mixture was homogenous after 3 h. The reaction was quenched with saturated aqueous ammonium chloride and the aqueous was extracted with methylene chloride. The organic phase was washed with brine and dried over sodium sulfate. The resulting solution was concentrated to provide a pale red solid, which was purified by column chromatography using 3.5% MeOH/CH2Cl2. LCMS: retention time 1.955 min using analytical method [7] with an M+Na of 414.0. 19.0 mg (15% yield): white solid. 1H-NMR (300 MHz, CDCl3) δ 9.34 (s, 1H), 8.66 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.75 (m, 1H), 7.65 (m, 2H), 6.88 (d, J=0.5 Hz, 1H), 4.30 (s, 2H). 13C-NMR (75 MHz, CDCl3) δ 168.3, 153.2, 144.8, 142.8, 135.0, 131.5, 128.7, 128.4, 127.8, 123.5, 122.9, 116.2, 104.7, 38.7.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([OH:28])=[C:14]([C:23]([O:25]CC)=O)[C:15](=[O:22])[N:16]2[CH3:21]>CCCCCCC>[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([OH:28])=[C:14]([C:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:25])[C:15](=[O:22])[N:16]2[CH3:21]
Reactant: CCNc1ccccc1
Reactant: CCOC(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O
Solvent: CCCCCCC
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
N-ethylbenzenamine (430 mg, 3.55 mmol, 2.00 equiv) was added dropwise to ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (500 mg, 1.78 mmol, 1.00 equiv) dissolved in heptane (10 ml). The resulting mixture was heated about 100° C. and the volatiles were removed by distillation over a period of about 7 hours. After cooling to ambient temperature, the resulting crystals were collected by filtration, washed with heptane, and purified by silica gel chromatography (ethyl acetate/petroleum ether 1:3) to afford the title product as a white solid (0.38 g, yield: 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:54]=[C:55]([F:57])[CH:56]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:11]=[C:10]2[NH:35][C:36](=[O:53])[C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)=[CH:39][C:38]=1[N+:50]([O-:52])=[O:51])=[O:6].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:54]=[C:55]([F:57])[CH:56]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH:35][C:36](=[O:53])[C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]2)=[CH:39][C:38]=1[N+:50]([O-:52])=[O:51])=[O:6]
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(C(=O)c5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(C(=O)c5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of N-[5-(3,5-Difluoro-benzoyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide (2.76 g, 3.62 mmol), trifluoroacetic acid (5.6 mL) and dichloromethane (56 mL) was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue taken up with dichloromethane and washed with a saturated solution of sodium hydrogen-carbonate. The organic phase was evaporated to dryness. The residue was redissolved in ethyl acetate and washed twice with brine. The resulting organic phase was dried over sodium sulfate and evaporated to dryness. Purification of the crude by chromatography over silica gel (DCM/MeOH) and trituration of the so obtained compound from diethyl ether afforded 1.47 g of the title compound (78% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:19]([NH:21][CH:22]3[CH2:24][CH2:23]3)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.[I-].[K+].Cl.[O:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH:22]1([NH:21][C:19](=[O:20])[C:18]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:16]([N:11]3[CH:10]=[CH:9][C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:35]5[CH2:36][CH2:37][CH2:38][O:32][CH2:33][CH2:34]5)=[CH:6][CH:7]=4)[C:12]3=[O:15])[CH:17]=2)[CH2:24][CH2:23]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCCl)cc2c1=O
Reactant: C1CNCCOC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCN3CCCOCC3)cc2c1=O
Temperature: 150 °C
Yield: 65.3 %

Procedure:
3-[7-(2-Chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide (0.15 g), potassium iodide (0.13 g), 1,4-oxazepane hydrochloride (0.34 g), and N,N′-diisopropylethylamine (0.8 ml) were stirred in DMA (3 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using a gradient of ethyl acetate to 15% methanol/ethyl acetate gave N-cyclopropyl-4-methyl-3-[7-[2-(1,4-oxazepan-4-yl)ethoxy]-1-oxoisoquinolin-2(1H)-yl]benzamide (0.114 g) as a white solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.80 (m, 2H), 2.10 (s, 3H), 2.76 (m, 4H), 2.85 (m, 1H), 2.92 (t, 2H), 3.61 (m, 2H), 3.66 (t, 2H), 4.19 (m, 2H), 6.72 (d, 1H), 7.21 (d, 1H), 7.41 (d, 1H), 7.49 (d, 1H), 7.69 (s, 1H), 7.71 (d, 1H), 7.74 (s, 1H), 7.88 (d, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 462.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(=O)(O)[O-].[Na+]>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[S:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Sc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Sc1ccccc1

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g), thiophenol (10.25 ml), and 1N sodium bicarbonate (300 ml) was refluxed for 3 hours. After cooling, the precipitated sodium salt of 3-nitro-4-phenylthio-5-sulphamyl-benzoic acid was filtered off. The sodium salt was dissolved in hot water (200 ml), and 3-nitro-4-phenylthio-5-sulphamyl-benzoic acid was precipitated by the addition of 4N hydrochloric acid until the pH was 1. After isolation and recrystallization from aqueous ethanol, the acid was obtained with a melting point of 245°-247° C.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:24]([NH2:26])=[O:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:33][C:34]1[C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36]>C1(C)C(CCO)=CC=CC=1>[NH2:36][C:35]1[C:34]([CH3:33])=[C:40]([C:2]2[C:14]3[C:13]4[C:8](=[CH:9][C:10]([C:15]([N:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[O:16])=[CH:11][CH:12]=4)[NH:7][C:6]=3[C:5]([C:24]([NH2:26])=[O:25])=[CH:4][CH:3]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(Br)c23)CC1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Yield: 64.9 %

Procedure:
A suspension of 4-bromo-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 1-1, 300 mg, 0.722 mmol), tetrakis-(triphenylphosphine)palladium (33.4 mg, 0.029 mmol), 2 M aqueous sodium carbonate (0.9 mL, 1.806 mmol), and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate 50-1, 253 mg, 1.084 mmol) in toluene-ethanol (4:1, 15 mL) was purged with nitrogen for 5 min and then heated at reflux for 7.5 h. The mixture was concentrated and the residue was partitioned between chloroform and water. The aqueous phase was extracted with chloroform and the combined organic phases were washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with DCM-2 M methanolic ammonia, gradient from 100:0 to 95:5) to provide 4-(3-amino-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a white solid (207 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H) 8.16 (br. s., 1H) 7.97 (d, J=7.91 Hz, 1H) 7.78 (s, 1H) 7.48 (br. s., 1H) 7.08 (t, J=7.80 Hz, 1H) 6.81-6.97 (m, 4H) 6.49-6.65 (m, 1H) 3.12-3.25 (m, 4H) 2.92-3.10 (m, 4H) 2.76 (s, 3H) 1.70 (s, 3H). Mass spectrum m/z 442.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:47])[CH3:46])=[CH:41][CH:40]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:36]1[CH2:37][CH2:38][N:33]([C:39]2[CH:40]=[CH:41][C:42]([C:45](=[O:47])[CH3:46])=[CH:43][CH:44]=2)[CH2:34][CH2:35]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: CC(=O)c1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1
Yield: 8.1 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(4-piperazine-1-yl-phenyl)-ethanone instead of 2-piperazin-1-yl-benzonitrile, to the title compound (5.8 mg, 8.1%) as light yellow oil. MS m/e=559.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[NH3:24]>CO>[NH2:24][C:6]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:2]([Cl:1])[N:3]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:5]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Reactant: N
Solvent: CO
Product: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1Cl
Reaction time: 8 h

Procedure:
2.09 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine (EP-A- 0 526 708) were suspended in 75 ml of methanol and 150 ml of ammonia were condensed at 75° C. using a feedpipe. The reaction mixture was left to come to room temperature overnight, concentrated in a water-jet vacuum and the residue was partitioned between a small amount of water and methylene chloride (500 ml). The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was triturated with ether, the resulting solid was separated and dried in a high vacuum. The 4-amino-6-chloro-5-(2-methoxy-phenoxy )-2,2'-bipyrimidine was thus obtained as a fine, almost white powder. MS: 329 (M).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:15]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.C(OC([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(C)(C)C>>[CH2:31]([C@@H:26]1[NH:25][CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([O:7][CH:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[CH:15]=2)[CH2:27]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Reactant: COc1ccc(Br)cc1OC1CCN(C)CC1
Product: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCN(C)CC1

Procedure:
The title compound was prepared by the method outlined for Example 1 using 4-(5-bromo-2-methoxy-phenoxy)-1-methyl-piperidine as the aryl halide and 2(S)-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component. The title compound was isolated as an orange oil. 1H NMR (MeOH-d4) 7.33-7.29 (m, 2H), 7.25-7.22 (m, 3H), 6.85 (d, J=8.8, 1H), 6.55 (d, J=2.8, 1H), 6.50 (dd, J=8.8, 2.8, 1H), 4.24 (m, 1H), 3.74 (s, 3H), 3.35-3.27 (m, 2H), 3.05-3.00 (m, 2H), 2.91-2.85 (m, 1H), 2.74-2.65 (m, 5H), 2.36 (m, 3H), 2.28 (s, 3H), 1.90 (m, 2H), 1.78 (m, 2H). LC/MS (Method B) 0.97 min, [M+1]+ 396.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=3C(OCC)=O)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.[C:41](=[O:44])([O-])[O-:42].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:28]([C:41]([OH:42])=[O:44])=[CH:27][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccccc1NC(=O)C(CC1CCOCC1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1cn(C(CC2CCOCC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.07 g (1.89 mmol) of ethyl ({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoate (racemate) in 24 ml of methanol/water (4/1) were reacted with 1.24 g (3.79 mmol) of caesium carbonate according to General Method 4. Yield: 1.24 g (purity 73%, 88% of theory)