Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.[CH:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:50]1([S:53]([NH:56][C:37](=[O:38])[C:36]2[CH:35]=[CH:34][C:33]([C:20]3[C:21]([CH3:32])([CH3:31])[C@H:22]4[C@:17]([CH3:42])([CH2:18][CH:19]=3)[C@@H:16]3[C@:25]([CH3:30])([C@@:26]5([CH3:29])[C@H:13]([CH2:14][CH2:15]3)[C@H:12]3[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:11]3([NH:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:49])[CH2:3][CH2:4]3)[CH2:28][CH2:27]5)[CH2:24][CH2:23]4)=[CH:41][CH:40]=2)(=[O:55])=[O:54])[CH2:52][CH2:51]1
Reactant: NS(=O)(=O)C1CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)Cl)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)NS(=O)(=O)C7CC7)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoyl chloride (30 mg, 0.042 mmol), cyclopropanesulfonamide (6.15 mg, 0.051 mmol), Hunig's Base (0.022 mL, 0.127 mmol) and DMAP (2.58 mg, 0.021 mmol) in dichloromethane (1 mL) was stirred for 16 h at room temperature. The crude reaction mixture was purified by prep HPLC to provide the title compound as a white solid (4 mg, 11%). LCMS: m/e 794.53 (M+H)+, 2.44 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 7.94 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 5.38 (d, J=4.6 Hz, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 3.56-3.39 (m, 1H), 3.38-3.21 (m, 7H), 3.21-3.11 (m, 3H), 3.11-3.03 (m, 2H), 3.01-2.89 (m, 1H), 2.41-1.16 (m, 26H), 1.76 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]([O:30]CC2C=CC=CC=2)=[O:29])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:7]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:6]=2.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[C:3]([C:28]([OH:30])=[O:29])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[C:7]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:6]=2
Reactant: Cc1nc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2nc1C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2nc1C(=O)O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
The compound of Example 27A (4.9 g, 10.0 mmol) was added to a solution of potassium hydroxide (2.2 g, 40.0 mmol) in ethanol/water (80 ml/16 ml) and the mixture was stirred at 80° C. for 20 hours and then cooled (5° C.). The precipitate was collected by suction, washed with ether (4.3 g) and then suspended in water (100 ml). After correction of the pH of this suspension to 2 by the addition of 2N HCl stirring was continued at room temperature for 20 minutes and the crystallized title compound was isolated by suction, washed with water and dried in vacuo over P2O5. Yield: 3.4 g (85%); mp 198°-200° C.
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].Br[CH2:9][C:10]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]2[C:11]=1[N:12]=[C:13]([O:23][CH3:24])[C:14]([O:21][CH3:22])=[N:15]2.O>CO>[Br:20][C:18]1[CH:17]=[C:16]2[C:11]([N:12]=[C:13]([O:23][CH3:24])[C:14]([O:21][CH3:22])=[N:15]2)=[C:10]([CH:9]=[O:3])[CH:19]=1
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1nc2cc(Br)cc(C=O)c2nc1OC
Reaction time: 1 h

Procedure:
1.38 g (60 mmol) of sodium are dissolved in portions, at 0° C. under N2, in 200 ml of methanol. At 0° C., 5.85 ml (65 mmol) of 2-nitropropane are added dropwise. 18.1 g (50 mmol) of 5-(bromomethyl)-7-bromo-2,3-dimethoxy-quinoxaline are then added. The beige suspension is heated to reflux and stirred for 1 hour. The reaction mixture is poured onto 600 ml of water and the methanol is distilled off. The residue is extracted twice with ethyl acetate, and the organic phases are dried over sodium sulfate and filtered with suction. The filtrate is concentrated and the residue is dried under a high vacuum. 7-Bromo-5-formyl-2,3-dimethoxy-quinoxaline is obtained in the form of beige crystals having a melting point of 179-182° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[O:23]=[C:24]1[CH2:29][CH2:28][C:27]([CH:33]=[CH2:34])([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:34]=[CH:33]/[C:27]3([C:30]([OH:32])=[O:31])[CH2:28][CH2:29][C:24](=[O:23])[CH2:25][CH2:26]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC1(C(=O)O)CCC(=O)CC1
Reactant: C[C@H](c1ccc2ccc(Br)cc2n1)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](c1ccc2ccc(/C=C/C3(C(=O)O)CCC(=O)CC3)cc2n1)N(C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A solution of [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-methyl-carbamic acid tert-butyl ester (200 mg, 0.55 mmol), 4-oxo-1-vinyl-cyclohexanecarboxylic acid (138 mg, 0.82 mmol), palladium(II) acetate (25 mg, 0.11 mmol), tri-(o-tolyl)phosphine (50 mg, 0.16 mmol) in anhydrous 1,4-dioxane (2 mL) was treated with triethylamine (267 μL, 1.91 mmol). After stirring at 100° C. under microwave irradiation for 30 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and a 5% citric acid solution, the aqueous layer was extracted with ethyl acetate (2 x), the organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (235 mg, 94%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 1.68 (d, J=7.1 Hz, 3H), 2.07-2.22 (m, 2H), 2.44-2.70 (m, 6H), 2.75 (br s, 3H), 5.61 (br s, 1H), 6.68 (ABq, ΔδAB=0.31, JAB=16.3 Hz, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 8.05-8.12 (m, 2H). LCMS (m/z) 453.1 [M+H], Tr=2.48 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.[CH3:28][NH:29][CH3:30]>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:29]([CH3:30])[CH3:28])[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: CNC
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CN(C)c1c(F)c(N)c2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 81 %

Procedure:
5-Amino-1-(6-amino-3, 5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) and an aqueous solution (about 50%; 170 mg) of dimethylamine were added to pyridine (500 mg), and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (86 mg) as a yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=CC2C=CC=CC=2)[N:4]=1)#[N:2].[O:17]=[O+][O-]>CO.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[O:17])[N:4]=1)#[N:2]
Reactant: O=[O+][O-]
Reactant: N#Cc1ccnc(C=Cc2ccccc2)n1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccnc(C=O)n1
Temperature: 25 °C

Procedure:
2.238 g (10.81 mmol) of 4-cyano-2-(2-phenylethenyl)-pyrimidine in 150 ml of absolute methanol and 75 ml of absolute methylene chloride are cooled to -70° C. Ozone is passed through until a blue solution is produced (about 0.5 hour). Nitrogen is passed through the solution until the excess ozone has been removed (about 0.75 hour) and then 3.5 ml of dimethyl sulfide are added to the reaction mixture. The solution is allowed to warm up to room temperature and is concentrated in a rotary evaporator. The crude product is purified over silica gel (eluant: n-hexane/ethyl acetate 1:3). 1H-NMR (CDCl3): δ=10.11 (s, 1H); 9.23 (d, 1H); 7.82 (d, 1H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:37])[C:16]=3[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41][CH3:42])=[O:40])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:55][CH:56]=[CH2:57].O>CN(C=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:57][CH:56]=[CH2:55])[CH:31]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:37])[C:16]=3[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41][CH3:42])=[O:40])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6cccc(O)c6)c5)nn34)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cccc(-c2cccc(-c3cc4nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c5ccc6c(c5Cl)N(CC=C)CCO6)n4n3)c2)c1
Temperature: 50 °C
Yield: 42 %

Procedure:
To a solution of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.138 mmol) in DMF (2 mL) was added K2CO3 (38.1 mg, 0.276 mmol) followed by 3-bromoprop-1-ene (0.017 mL, 0.207 mmol) and the resulting mixture was heated at 50° C. for 16 h. After cooling to room temperature, water was added and the mixture was extracted with ether (50 mL), washed with brine, dried (Na2SO4), filtered and concentrated. Crude was then purified by biotage (5-30% EtOAc/hexane) to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-(allyloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (40 mg, 0.058 mmol, 41.9% yield) as white solid. 28 mg of starting material was also recovered. 1H NMR (500 MHz, CDCl3) δ: 8.05 (t, J=1.6 Hz, 1H), 7.84 (dt, J=7.7, 1.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.23-7.20 (m, 1H), 7.19-7.16 (m, 1H), 7.03-6.97 (m, 2H), 6.96-6.92 (m, 2H), 6.17-6.00 (m, 2H), 5.50-5.44 (m, 1H), 5.39-5.29 (m, 3H), 5.25 (dd, J=10.2, 1.6 Hz, 1H), 5.09 (s, 1H), 4.62 (dt, J=5.3, 1.4 Hz, 2H), 4.27 (t, J=4.4 Hz, 2H), 3.67 (s, 3H), 3.27-3.17 (m, 2H), 2.86 (s, 3H), 1.19 (s, 9H). LCMS (M+H)=693.4.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19](F)=[C:20]([NH2:22])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:21]=[C:20]([NH:22][S:27]([CH:24]3[CH2:26][CH2:25]3)(=[O:29])=[O:28])[CH:19]=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}amine (283 mg, 0.811 mmol) and cyclopropanesulfonyl chloride (114 mg, 0.811 mmol) the title compound was obtained as a white solid (247 mg, 67% yield). MS (ESI): 453.3 [M+H]+.
Reaction SMILES: Br[CH:2]1[CH2:19][CH:18]([OH:20])[CH2:17][C:16]2[CH:15]=[C:14]3[C:5]([C:6](=[O:28])[C:7]4[CH:8]=[CH:9][CH:10]([CH2:26][CH3:27])[C:11]5([O:25][CH2:24][CH2:23][O:22]5)[C:12]=4[C:13]3=[O:21])=[C:4]([OH:29])[C:3]1=2.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][CH:2]1[CH2:19][CH:18]([OH:20])[CH2:17][C:16]2[CH:15]=[C:14]3[C:5]([C:6](=[O:28])[C:7]4[CH:8]=[CH:9][CH:10]([CH2:26][CH3:27])[C:11]5([O:25][CH2:24][CH2:23][O:22]5)[C:12]=4[C:13]3=[O:21])=[C:4]([OH:29])[C:3]1=2
Reactant: CCC1C=CC2=C(C(=O)c3cc4c(c(O)c3C2=O)C(Br)CC(O)C4)C12OCCO2
Reactant: CN(C)CCN
Product: CCC1C=CC2=C(C(=O)c3cc4c(c(O)c3C2=O)C(NCCN(C)C)CC(O)C4)C12OCCO2

Procedure:
7-Bromo-9-(1,1-ethylenedioxy)ethyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (571 mg) prepared in the foregoing step and N,N-dimethylethylenediamine (10 ml) were subjected to reaction in a nitrogen stream while cooling with ice for 1 hour. Excess of the N,N-dimethylethylenediamine was eliminated by distillation under reduced pressure. The residue was dissolved in dichloromethane (2 ml) and ether (4 ml) was added thereto, whereby 7-(2-dimethylaminoethyl)amino-9-(1,1-ethylenedioxy)ethyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione was obtained as yellow crystals (124 mg). M.P., 192°-196° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([N:16]2[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: COc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-n2cnc(C)c2)c(C#N)c1
Yield: 72 %

Procedure:
In analogy to example 5a, 2-fluoro-5-methoxy-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 48 h at 100° C. After aqueous workup and crystallization from Ethyl acetate/diisopropylether the title compound was obtained as a white solid (yield: 72%). MS: m/e=214.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:29][CH2:30][CH2:31][CH3:32])[N:9]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]#[N:28])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])[CH3:2].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:29][CH2:30][CH2:31][CH3:32])[N:9]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:39][N:38]=[N:37][N:28]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc(C(=O)OCC)c(Cl)n1C1CCc2cc(-c3ccccc3C#N)ccc21
Solvent: Cc1ccccc1
Product: CCCCc1nc(C(=O)OCC)c(Cl)n1C1CCc2cc(-c3ccccc3-c3nnn[nH]3)ccc21
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of 2-butyl-5-chloro-1-[5-(2-cyano-phenyl)-indan-1-yl]-1H-imidazole-4-carboxylic acid ethyl ester (177 mg, 0.41 mmol) and trimethyltin azide (108 mg, 0.5 mmol) was heated in toluene (1.0 mL)for 72 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was chromatographed on SiO2 -gel using a gradient of 2% MeOH/CH2Cl2 to 15% MeOH/CH2Cl2 to give 50 mg of a colorless oil.
Reaction SMILES: C1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([C:12]([C:14]3[CH:19]=[CH:18][C:17]4[O:20]C[O:22][C:16]=4[CH:15]=3)=[O:13])=[O:11])=[CH:4][C:3]=2[O:2]1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[CH:15]=2)=[O:13])=[O:11])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: O=C(C(=O)c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(C(=O)c1ccc(O)c(O)c1)c1ccc(O)c(O)c1
Reaction time: 3.5 h
Yield: 47.2 %

Procedure:
To a stirred solution of bis(3,4-methylenedioxy)benzil (500 mg) in dry CH2Cl2 (50 ml) under nitrogen, was slowly added boron tribromide (1.6 ml) then stirring continued for a further 3.5 hours. Methanol (100 ml) was added carefully, then the solvent evaporated in vacuo to a volume of 1 ml, this addition and evaporation was repeated twice more. The product was purified by column chromatography over silica gel when elution with diethylether in dichloromethane gave 3,4,3′,4′-tetrahydroxybenzil (217 mg, 47%) as a yellow powder.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[CH:16]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:26]([Cl:34])[CH:25]=2)[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(OCC)(=O)C>[Cl:34][C:26]1[CH:25]=[C:24]([CH:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:35])[CH:29]=[CH:28][C:27]=1[S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ccn(CCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
In a flask containing N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (150 mg, 0.26 mmol) was added ethanol (5 mL) and concentrated hydrochloric acid (three drops) and was stirred at 25° C. for 30 minutes. It was then diluted with ethyl acetate (50 mL) and washed with water (1×20 mL) and saturated aqueous brine solution (1×20 mL). The organic layer was then dried over sodium sulfate and absorbed onto silica gel (2 g) and purified on Biotage Flash purification system (40S column, silica gel, 5% methanol/ethyl acetate) which afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (107 mg, 89%) as a white foam: ES-HRMS m/e calcd for C20H26N3O5SCl (M+H)+ 456.1355, observed 456.1354; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.27 (m, 2H, CH2), 1.29-1.42 (m, 1H, CH of CH2), 1.49-1.70 (m, 3H, CH of CH2 and CH2), 2.00-2.14 (m, 1H, CH), 3.20 (m, 2H, OCH2), 3.34 (s, 3H, SO2CH3), 3.67 (q, J=5.5 Hz, 2H, OCH2), 3.75-3.86 (m, 2H, OCH2), 3.95-4.08 (m, 3H, CH and NCH2), 4.83 (t, J=5.3 Hz, 1H, OH), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.54 (d, J=2.3 Hz, 1H, Ar), 7.60 (dd, Jo=8.2 Hz, Jm=1.6 Hz, 1H, Ar), 7.71 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.81 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(OCC)(=O)C>[C].[Pd].CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(/C=C/c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(CCc2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the obtained 4-((E)-2-(3,4-dimethylphenyl)vinyl)-2-(4-fluoroanilino)benzoic acid were added ethyl acetate 1.0 mL, methanol 1.0 mL and 10% palladium-carbon 10 mg sequentially, and it was stirred under hydrogen atmosphere at room temperature for 2 hours. The solvent was removed under reduced pressure after insoluble matter was filtrated to give 4-(2-(3,4-dimethylphenyl)ethyl)-2-(4-fluoroanilino)benzoic acid 2.5 mg of a white solid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:17][CH3:18])(=[O:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[Cl:19])[C:5]=1[CH2:17][CH3:18])(=[O:3])[CH3:2]
Reactant: CCc1[nH]c2cc(C(=O)OC)ccc2c1C(C)=O
Reactant: Clc1ccccc1CBr
Product: CCc1c(C(C)=O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl

Procedure:
Methyl 3-acetyl-1-(2-chlorobenzyl)-2-ethylindole-6-carboxylate (170 mg) was prepared from methyl 3-acetyl-2-ethylindole-6-carboxylate (100 mg) and 2-chlorobenzyl bromide (0.06 ml) in a similar manner to that of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([S:18][C:19]3[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:18][C:19]3[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[N:24]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)ccnc1Sc1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OC)nc(Sc2nccc(-c3ccc(Cl)cc3)c2C(=O)O)n1
Temperature: 60 °C
Yield: 0.1 %

Procedure:
16.8 g (0,040 mol) of methyl 4-(4-chlorophenyl)-2-(4,6-dimethoxypyrimidin-2-ylthio)nicotinate was dissolved in 150 ml of dimethylsulfoxide, and 35 ml (0,070 mol) of 2N sodium hydroxide added with stirring at 60° C. After stirring at 60° C. for 30 minutes, the mixture was poured into water, and washed twice with ethyl acetate. The aqueous layer was acidified with 10% hydrochloric acid, and extracted with 500 ml of ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and concentrated. The concentrate was washed with methanol and isopropyl ether to obtain 11.5 g of a white crystal of the aimed product.
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([CH3:14])[C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][O:21]1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]([OH:21])([CH3:22])[CH2:19][N:6]2[C:7]3[CH:8]=[C:9]([CH3:14])[C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:16][CH2:15][C:5]2=3)[CH:24]=1
Reactant: Cc1cc2[nH]c3c(c2cc1C)CN(C)CC3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c3c(n(CC(C)(O)c4cccnc4)c2cc1C)CCN(C)C3
Temperature: 0 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
2,7,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 1.86 mmol) was dissolved in DMF (4 mL), cooled to 0° C. and sodium hydride (224 mg, 5.60 mmol) was added portionwise at the same temperature. 3-(2-methyloxiran-2-yl)pyridine (504 mg, 3.73 mmol) in DMF (1 mL) was added to the reaction mixture and allowed to stir at RT for 12 h. After complete consumption of starting material, the reaction mixture was poured in to ice water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was crystallized with ether and hexane to obtain 400 mg 2-(pyridin-3-yl)-1-(2,7,8-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol. 1H NMR (DMSO, freebase) δ (ppm): 8.60 (s, 1H), 8.4 (d, 1H), 7.7 (d, 1H), 7.28 (t, 1H), 7.06 (s, 1H), 7.01 (s, 1H), 4.11 (dd, 2H), 3.41 (m, 2H), 2.53 (m, 2H), 2.44 (m, 2H), 2.35 (s, 3H), 2.22 (s, 6H), 1.5 (s, 3H). Separation by chiral HPLC provides enantiomers II-220a-b.