Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:27][CH3:28])=[CH:8][C:9]([O:25][CH3:26])=[C:10](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:43](OC(=O)C)(=[O:45])[CH3:44]>C1COCC1>[C:43]([NH:22][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([C:14](=[O:15])/[CH:13]=[CH:12]/[C:10]2[CH:11]=[C:6]([C:5]3[S:1][C:2]4[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=4[CH:4]=3)[C:7]([O:27][CH3:28])=[CH:8][C:9]=2[O:25][CH3:26])=[CH:17][CH:18]=1)(=[O:45])[CH3:44]
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(N)=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)NC(C)=O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
A suspension of 4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide (Ex-93, 0.5 g, 1.13 mmol) in THF (15 mL) was cooled to −78° C. followed by addition of lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.3 mL, 2.3 mmol). The mixture was stirred at this temperature for 1 hour and warmed up to 0° C. Acetic anhydride (0.48 mL, 6.8 mmol) was then added dropwise. After the addition was complete the reaction mixture was warmed up to ambient temperature and stirred for 2 hours. The reaction was quenched with water. The aqueous solution was extracted with ethyl acetate. The combined extract was washed with NH4Cl, brine, dried and concentrated. The residue was purified by flash chromatography. Elution with 50% EtOAc/hexane gave the title compound as yellow solid (0.16 g, 29%), mp 228–229° C. 1H-NMR (CCDl3) δ 8.52 (s, 1H), 8.15–8.10 (m, 3H), 7.96 (d, J=7.6 Hz, 2H), 7.85–7.77 (m, 2H), 7.67 (s, 1H), 7.55 (d, J=16.7 Hz, 1H), 7.34–7.29 (m, 3H), 6.58 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 2.65 (s, 3H). MS m/z=485 (M+, 100%).
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce].[F:7][C:8]([F:25])=[CH:9][CH:10]1[CH2:14][N:13](CC2C=CC(OC)=CC=2)[C:12](=[O:24])[CH2:11]1>CC#N.O.O>[F:7][C:8]([F:25])=[CH:9][CH:10]1[CH2:14][NH:13][C:12](=[O:24])[CH2:11]1
Reactant: COc1ccc(CN2CC(C=C(F)F)CC2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1CC(C=C(F)F)CN1
Temperature: 4 °C
Reaction time: 5 h

Procedure:
In a 200 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, cerium ammonium nitrate (11.2 g, 0.02 mol, 3 eq) is added to a solution of 4-(2,2-difluoro-vinyl)-1-(4-methoxy-benzyl)-pyrrolidin-2-one a4 (1.8 g, 6.8 mmol in MeCN/H2O (respectively 70 ml/110 ml) cooled at 4° C. After 5 h at 10° C., the reaction mixture is diluted with water, extracted with AcOEt, dried on MgSO4 and concentrated in vacuo. The residue is diluted with toluene, the solid is filtrated and the solvent is evaporated. The residue is purified by chromatography on silicagel (CH2Cl2/MeOH: 99/01 (v/v)) to afford fraction A1 (0.5 g of the expected compound) and fraction B (0.7 g of a mixture of synthetic intermediates and starting materials). Fraction B is again reacted with cerium ammonium nitrate as above (CAN: 0.78 g, MeCN (30 ml), H2O (50 ml)) to afford after purification, another fraction A2 (0.3 g). Fractions A1+A2 put together give 0.8 g of 4-(2,2-difluoro-vinyl)-pyrrolidin-2-one as (81%) contaminated by traces of 4-methoxybenzoic acid.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[C:39]1([NH2:43])[CH2:42][O:41][CH2:40]1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:43][C:39]2([C:34]3[N:35]=[CH:36][CH:37]=[CH:38][N:33]=3)[CH2:42][O:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2ncccn2)COC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)COC4)ccc3C)c(F)c12
Reaction time: 8 h

Procedure:
To a yellow solution mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (30 mg, 0.071 mmol) and 3-(pyrimidin-2-yl)oxetan-3-amine hydrochloride (16 mg, 0.085 mmol) in DMF (1 ml) in a 25 ml round-bottomed flask was added benzotriazo-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (50 mg, 0.096 mmol), followed by triethylamine (TEA) (0.1 ml, 0.717 mmol), and the reaction mixture stirred for overnight. Ice cooled water was added to the reaction mixture, which was then stirred for 10-15 min. at 0° C. Precipitation was observed. The solid was collected by filtration, washed with cold water, and then dissolved in dichloromethane. The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC. Yield (12 mg, 30%).
Reaction SMILES: C[Si](C)(C)O[NH:4][OH:5].CN1CCOCC1.[CH3:15][O:16][CH:17]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:18][CH:19]=[CH:20][CH:21]=[CH:22][C:23](Cl)=[O:24]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:5][NH:4][C:23](=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH2:18][CH:17]([O:16][CH3:15])[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1
Reactant: C[Si](C)(C)ONO
Reactant: COc1ccc(C(CC=CC=CC(=O)Cl)OC)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(CC=CC=CC(=O)NO)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a stirred solution of trimethylsilyloxy hydroxylamine (132 μL, 1.08 mmol) and N-methylmorpholine (44 μL, 0.40 mmol) in CH2Cl2 (5 mL) at 0° C. was added dropwise a solution of acid chloride 5 (101 mg, 0.36 mmol) via cannula. The reaction mixture was stirred for 1 h, and then was allowed to warm to rt over 1 h. After being stirred for an additional 1 h, the reaction mixture was diluted with CHCl3: MeOH (20 mL: 1 mL), washed with saturated NaHCO3 solution and then water, and the organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash silica gel chromatography (5-10% MeOH in CHCl3) gave the desired hydroxamic acid 6 (30 mg, 30%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.20 (m, 3H), 6.87 (d, J=7.5 Hz, 2H), 5.60-6.20 (m, 3H), 4.10 (m, 1H), 3.79 (s, 3H), 3.16 (s, 3H), 2.61 (m, 1H), 2.43 (m, 1H); 13C NMR (75.4 MHz, CDCl3) δ 41.6, 55.2, 56.4, 82.7, 113.8, 117.9, 127.8, 130.4, 133.1, 139.3, 141.7, 159.2, 165.5.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[O:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[O:10]1[CH:14]=[CH:13][C:12]([C:2]2[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)=[CH:11]1
Reactant: OB(O)c1ccoc1
Reactant: O=C(O)c1ccc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccoc2)s1
Yield: 94.2 %

Procedure:
Using microwave irradiation. The general procedure was used with 5-bromothiophene carboxylic acid (206 mg, 1.00 mmol), 3-furanboronic acid (168 mg, 1.50 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (5.0 mL), 10 min, 150° C. (using microwave irradiation with cooling). The product was isolated as a white solid (183 mg, 95%). Mp=147° C. 1H NMR (400 MHz, d4-MeOH) δ: 7.89 (m, 1H), 7.65 (d, 1H, J=4.0 Hz), 7.54 (t, 1H, J=1.6 Hz), 7.15 (d, 1H, J=4.0 Hz), 6.69 (m, 1H). 13C NMR (125 MHz, d4-MeOH) δ: 165.4, 145.6, 143.7, 140.9, 135.5, 132.9, 125.2, 121.5, 109.9. IR (neat, cm−1): 3200 (br), 1672, 1287. Anal. Calcd for C9H6O3S: C, 55.66; H, 3.11. Found: C, 55.50; H, 3.32.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.CN(C1CCCCC1)C1CCCCC1.[CH3:27][Si:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31][CH2:32]Cl>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:28]([CH3:35])([CH3:34])[CH3:27])[N:9]=2)[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cc(C=O)cc2cn[nH]c12
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(C=O)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 5 h

Procedure:
To a solution of 7-methyl-1H-indazole-5-carbaldehyde (5.0 g, 31.25 mmol) and N-methyl-dicyclohexylamine (113.5 mL, 62.35 mmol) in dry tetrahydrofuran (120 mL) at 0° C., was added 2-(trimethylsilyl)ethoxymethyl chloride (6.65 mL, 39.5 mmol). The icebath was removed and stirring continued for 5 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated in vacuo. Column chromatography afforded 8.5 g (93%). 1H-NMR (CD3OD, 300 MHz) δ −0.04 (s, 9H), 0.83-1.01 (m, 2H), 2.60 (s, 3H), 3.22-3.34 (m, 2H), 3.60-3.76 (m, 2H), 5.58 (s, 2H), 7.54 (s, 1H), 8.23 (s, 1H), 8.64 (s, 1H), 9.91 (s, 1H). Mass spec.: 291.33 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.S1(=O)(=O)CCCC1.C([N:32]([C:38]([O-])=[O:39])[N:33]=[CH:34]N(C)C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:22]2[CH:34]=[N:33][NH:32][C:38]2=[O:39])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3Br)CC2)cc1
Reactant: CCN(N=CN(C)C)C(=O)[O-]
Solvent: O=S1(=O)CCCC1
Solvent: CCO
Product: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3Br)CC2)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of 54.3 parts of 3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]-benzenamine and 189 parts of tetrahydrothiophene 1,1-dioxide was added portionwise, during a 30 minutes-period, 28.6 parts of ethyl[(dimethylamino)methylene]hydrazinecarboxylate at 160° C. Upon completion, stirring and heating were continued at 170° C. till all ethanol was distilled off. After cooling to room temperature, 120 parts of 4-methyl-2-pentanone were added to dissolve the sticky residue. The whole was heated till a solution was obtained. After cooling, the supernatant phase was decanted and the residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 44.6 parts of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (int. 34).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:41]([O:43][C:44]([C:46]1[N:47]([CH3:52])[CH:48]=[C:49]([NH2:51])[N:50]=1)=[O:45])[CH3:42].C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:19])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([NH:51][C:49]4[N:50]=[C:46]([C:44]([O:43][CH2:41][CH3:42])=[O:45])[N:47]([CH3:52])[CH:48]=4)=[O:17])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1
Reactant: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Reactant: CCOC(=O)c1nc(N)cn1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(NC(=O)c2ccc3cc4n(c3c2)C(C)(C)CNC4=O)cn1C
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
To a solution of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylic acid (336 mg, 1.3 mmol, Intermediate E) in DMF (1 mL) are added N-hydroxybenzotriazole (351 mg, 2.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (498 mg, 2.6 mmol). After stifling for 10 min, 4-amino-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester (535 mg, 2.6 mmol), N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) and 4-dimethylaminopyridine (32 mg, 0.26 mmol) are added. The reaction mixture is heated at 60° C. for 16 h. DMF is removed under a stream of N2 at 40° C. and EtOAc (2 mL) and water (2 mL) are added. After stirring for 15 min, a white solid is formed and it is filtered and dried to afford the title compound (490 mg, 92%).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]>CO>[CH3:4][C:3]1([CH3:5])[S:6][CH:10]([C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[OH:13])[NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CO
Product: CC1(C)SC(c2ccccc2O)N[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
A solution containing 4.5 g (30 mmoles) of D-penicillamine and 3.16 ml (30 mmoles) of salicylaldehyde in 90 ml of 30% methanol is stirred for 3 hours. The precipitated product is filtered out, washed with 50% methanol and dried to give the title acid in a yield of 7.05 g (92.7%) which is recrystallized from methanol, m.p. 179°-181° C., [α]D =129.8° (c=0.48, dimethylformamide).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 60 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (150 mg, 0.22 mmol), copper (I) iodide (83 mg, 0.44 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (600 mg, 4.4 mmol) to a solution of 1-fluoro-4-iodo-2-nitrobenzene, (prepared as described in PREPARATION 46), (1.22 g, 4.6 mmol) in triethylamine (6.6 mL, 65.3 mmol). Stir at 60° C. for 18 h then concentrate. Purify by silica gel chromatography, eluting with a gradient of 100:0 to 90:10 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 95:5 to 60:40 hexanes:ethyl acetate, to give the title compound as a light yellow solid (650 mg, 54%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][C:43]([O:51][CH3:52])=[C:44]([O:49][CH3:50])[CH:45]=2)[O:40][C:39]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[CH:42][C:43]([O:51][CH3:52])=[C:44]([O:49][CH3:50])[CH:45]=4)[O:40][C:39]=3[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2oc(-c3ccccc3)c(I)c(=O)c2cc1OC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1OC
Yield: 86 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-6,7-dimethoxy-2-phenyl-chromen-4-one was reacted to give the title compound as a white solid (68 mg, 86%). LCMS (Method B): RT=4.81 min, [M+H]+=528.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1CSC1C=CC=C2C=1N=CC=C2.[Li+].[OH-]>CO.O>[C:3]([OH:22])(=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccccc1CSc1cccc2cccnc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1.0 eq of ester 41 and 3.0 eq. of LiOH in methanol and water was heated to 65° C. for a time sufficient for completion of the hydrolysis. The mixture was cooled to room temperature and concentrated, then diluted with H2O. The pH of the aqueous mixture was adjusted to 4.5 and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated to give the intermediate benzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:45]([O:44][CH2:43][CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1)[CH3:46]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCCc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCCc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 4-(3-ethoxypropyl)phenyl borate (0.18 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-[4-(3-ethoxypropyl)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 123) (0.25 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:6]=[CH:5]2.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:43]1[CH:44]=[C:45]([C:62]([NH2:64])=[O:63])[C:46]2[NH:47][C:48]3[CH:49]=[C:50]([N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH:51]=[CH:52][C:53]=3[C:54]=2[N:55]=1.CC1(C)C(C)(C)OB(C2C=C3C(=CC=2)N(CCN2CCOCC2)N=C3)O1.C([O-])([O-])=O.[Na+].[Na+]>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].C(Cl)Cl.COCCOC>[O:59]1[CH2:60][CH2:61][N:56]([C:50]2[CH:51]=[CH:52][C:53]3[C:54]4[N:55]=[C:43]([C:2]5[CH:3]=[C:4]6[C:8](=[CH:9][CH:10]=5)[N:7]([CH2:11][CH2:12][N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)[N:6]=[CH:5]6)[CH:44]=[C:45]([C:62]([NH2:64])=[O:63])[C:46]=4[NH:47][C:48]=3[CH:49]=2)[CH2:57][CH2:58]1
Reactant: Brc1ccc2c(cnn2CCN2CCOCC2)c1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc3c(cnn3CCN3CCOCC3)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 100 °C
Yield: 55.8 %

Procedure:
A microwave vial containing a mixture of 4-(2-(5-bromo-1H-indazol-1-yl)ethyl)morpholine (549 mg, 1.77 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (494 mg, 1.95 mmol), potassium acetate (347 mg, 3.54 mmol) and PdCl2(dppf)-CH2Cl2 adduct (72 mg, 0.088 mmol) was flushed with nitrogen. Dioxane (4.5 mL) was added, the vial was sealed and heated at 100° C. for 5 hrs. This was diluted with EtOAc, washed with water and brine, and dried over MgSO4. Removal of the solvent left crude 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)ethyl)morpholine (1 gm) as a oil which was used as such. A microwave vial containing a mixture of 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (50 mg, 0.120 mmol), crude 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)ethyl)morpholine (83 mg, 0.17 mmol), and PdCl2(dppf)-CH2Cl2 adduct (9.8 mg, 0.012 mmol), was flushed with nitrogen. DME (2 mL) and aq. Na2CO3 (0.30 mL, 0.60 mmol, 2.0 M) were added and the vial was sealed and heated at 100° for 6 hrs. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, elution gradient of 0 to 60% B over 20 min at 42 mL/min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-morpholino-2-(1-(2-morpholinoethyl)-1H-indazol-5-yl)-5H-pyrido[3,2-b]indole-4-carboxamide (35 mg, 0.067 mmol, 56% yield) as a solid. MS (ESI) m/z 526.24 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.21 (1H, s), 8.61 (1H, s), 8.55 (1H, br. s.), 8.37 (1H, dd, J=9.16, 1.53 Hz), 8.35 (1H, s), 8.19 (1H, s), 8.10 (1H, d J=8.85 Hz), 7.79-7.86 (2H, m), 7.23 (1H, d, J=1.83 Hz), 7.02 (1H, dd, J=8.70, 1.98 Hz), 4.58 (2H, t, J=6.56 Hz), 3.77-3.87 (4H, m), 3.49-3.56 (4H, m), 3.21-3.27 (4H, m), 2.82 (2H, t, J=6.56 Hz), 2.41-2.49 (4H, m).
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1.C(O)C>O>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:1]3[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)C1=CCC=CC1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)C1=CCC=CC1
Temperature: 4 °C
Yield: 33 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 1,4-cyclohexadiene-1-carboxylic acid (6.2 g), N,N'-carbonyldiimidazole (8 g) and 2-amino-7-chloro-1,8-naphthyridine (8 g). The product produced by precipitation in water (11 g; m.p. 205° C.) is dissolved in boiling ethanol (250 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (3×15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7Chloro-1,8-naphthyridin-2-yl)-1,4-cyclohexadiene-1-carboxamide (4.2 g) is produced, m.p. 210° C.