Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C:20](=[O:21])[N:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[CH:45][CH:46]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[N:43][C:44]([NH:47][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])[C:20](=[O:21])[N:19]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[C:11]=4[N:12]=3)=[CH:45][CH:46]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CS(=O)c1ncc2cc(NC(=O)OC(C)(C)C)c(=O)n(C3CCCC3)c2n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 105 °C
Yield: 16.8 %

Procedure:
(8-Cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (1.2 g, 3.06 ml, prepared according to Example 9) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.36 g, 8.48 mmol) were combined in toluene (4 ml) and heated to 105° C. for 12 hours. The resulting paste was diluted with toluene, filtered, washed with toluene and partitioned between diethyl ether and 1 N citric acid. The mixture was filtered, and the solid was washed with water and diethyl ether. The solid then was dissolved in chloroform, dried over anhydrous magnesium sulfate, filtered, and the filtrate diluted with diethyl ether, giving a solid precipitate. This solid was collected by filtration and dried in vacuo to give 4-[6-(6-tert-butoxycarbonylamino-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.311 g, 17%). MS (APCI) M++1; Calc'd, 607.3, Found, 607.2.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)c(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)c(CO)n1
Temperature: 60 °C

Procedure:
100 g of 3-hydroxy-6-methyl-2-pyridine methanol and 150 g of potassium carbonate were suspended in 400 ml of N,N-dimethylformamide. Under heating under stirring 60° C. in an oil bath, 85 ml of benzyl bromide was added dropwise thereinto. Further, after heating under stirring for 30 minutes, insoluble matters were filtered off. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was recrystallized from ethanol/hexane, to give 145 g of the target compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:3]1>CO>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:3]1
Reactant: CN1CCC(N2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Solvent: CO
Product: CN1CCC(N2CC(C)(C)c3ccc(N)cc32)CC1
Reaction time: 8 h

Procedure:
3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-6-nitro-2,3-dihydro-1H-indole (600 mg, Step E) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (100 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo to afford the title compound as an oil. MS: 260 (M+1). Calc'd. for C16H25N3−259.39.
Reaction SMILES: B.[CH2:2]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl>O1CCCC1.O>[CH2:2]([O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:20][CH:21]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 100 ml. of 1.0 M borane in tetrahydrofuran cooled in an ice bath under nitrogen is added dropwise, 27.8 g. of p-decyloxybenzoic acid in 300 ml. of tetrahydrofuran over a period of 45 minutes. The mixture is stirred at room temperature for 6 hours and poured onto ice, diluted with water and 10 ml. of concentrated hydrochloric acid. The mixture is filtered and the solid washed with water to give white crystals. Recrystallization from ethanol gives white plates, m.p. 57.5°-59° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)(=[O:34])=[O:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[S:32]([C:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:46][CH2:45][CH:44]([NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:43][CH2:42]2)=[CH:39][CH:40]=1)(=[O:33])=[O:34])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N4CCC[C@H]4C(=O)OCc4ccccc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 22, (2S)-1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid benzyl ester, according to the procedure of Example 1 as a white solid; mp 65-71° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.40-1.90 (m, 6H), 2.50-3.20 (m, 5H), 3.75-3.85 (m, 2H), 4.15 (dd, 1H), 4.40-4.50 (m, 1H), 5.19 (s, 2H), 6.80 (d, 1H), 6.92 (d, 3H), 7.15 (d, 1H), 7.40-7.50 (m, 5H), 7.52 (d, 2H); MS (ES) m/z 673.1 (MH+).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][N:12]=1.C[O:21][C:22]([CH2:24][CH:25]1[NH:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=O.C[O-].[Na+]>CS(C)=O.O=[Pt]=O>[O:21]=[C:22]1[NH:17][C:16]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[N:30]2[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH:25]2[CH2:24]1
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=[Pt]=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN2c3ncccc3NC(=O)CC2C1
Temperature: 95 °C
Reaction time: 54 h

Procedure:
Diisopropylethylamine (3.03 mL, 17.34 mmol) was added to a mixture of 2-chloro-3-nitropyridine (2.75 g, 17.34 mmol) and the product of Example 22B (4.48 g, 17.34 mmol) in dimethyl sulfoxide (20 mL). The mixture was heated at 95° C. under nitrogen for 7 hours and then cooled to room temperature. Ice water (200 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The organic phase was washed with saturated brine (60 mL), dried (MgSO4) and concentrated under vacuum to an oil (6.81 g). This material was dissolved in methanol (400 mL), and PtO2 (25 mg, 0.11 mmol) was added. The flask was evacuated and purged with nitrogen (3 cycles) and then with hydrogen (3 cycles). The suspension was stirred under hydrogen (1 atm) for 54 hours. The flask was evacuated and purged with nitrogen (3 cycles) and the black suspension was filtered through diatomaceous earth with a methanol (2×10 mL) rinse. Sodium methoxide (Aldrich, 25% in methanol, 12.01 g, 55.6 mmol) was added to the filtrate, and the mixture was heated at reflux for 41 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2, eluted with methanol-CH2Cl2 (0:100-5:95), followed by crystallization from ethanol (10 mL) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.27-2.40 (m, 1H), 2.78 (dd, J=13.5, 5.9 Hz, 1H), 2.91-3.20 (m, 3H), 3.55-3.68 (m, 1H), 3.69-3.80 (m, 1H), 3.99-4.19 (m, 2H), 6.95 (dd, J=7.7, 5.0 Hz, 1H), 7.23 (dd, J=7.7, 1.4 Hz, 1H), 7.61 (s, 1H), 8.18 (dd, J=5.0, 1.8 Hz, 1H); MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([OH:13])=O)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:28]([O:32][C:33]([CH:35]1[CH2:43][CH:42]2[CH:37]([CH2:38][CH2:39][CH2:40][CH2:41]2)[N:36]1[C:44](=[O:61])[CH:45]([NH:50][C:51](=[O:60])[CH:52]([NH2:59])[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C>[C:28]([O:32][C:33]([CH:35]1[CH2:43][CH:42]2[CH:37]([CH2:38][CH2:39][CH2:40][CH2:41]2)[N:36]1[C:44](=[O:61])[CH:45]([NH:50][C:51](=[O:60])[CH:52]([NH:59][C:11]([C:5]1[NH:6][C:7]([CH3:10])=[C:8]([CH3:9])[C:4]=1[C:1](=[O:3])[CH3:2])=[O:13])[CH:53]1[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]1)[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:34])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(=O)c1c(C(=O)O)[nH]c(C)c1C
Reactant: CC(C)(C)OC(=O)C1CC2CCCCC2N1C(=O)C(NC(=O)C(N)C1CCCCC1)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)c1c(C(=O)NC(C(=O)NC(C(=O)N2C(C(=O)OC(C)(C)C)CC3CCCCC32)C(C)(C)C)C2CCCCC2)[nH]c(C)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
3-acetyl-4,5-dimethyl-2-pyrrole carboxylic acid 10b (2.5 g, 13.7 mmol) in DMF (56 mL) was treated with EDC (2.75 g, 14.4 mmol) and HOBt (2.20 g, 14.4 mmol) and stirred at RT for 15 minutes. Amine 16b (6.23 g, 13.0 mmol) in DMF (10 mL) was added, the reaction mixture stirred at RT and monitored by HPLC. The mixture was concentrated in vacuo, then dissolved in EtOAc. 1.0N glycine sodium salt aqueous solution was added until all excess amino ester 16b was consumed (several hours). The mixture was washed with 1N HCl (3×), brine, bicarb (3×), and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification through a short plug of silica gel (25%EA/Hex) afforded 7.08 g, (85%) of 1-(2-{2-[(3-acetyl-4,5-dimethyl-1H-pyrrole-2-carbonyl)-amino]-2-cyclohexyl-acetylamino}-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic acid tert-butyl ester 17b.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].N#N>CCO.C(Cl)Cl.[Pd]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2]2
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Agent: [Pd]
Agent: N#N
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (Step b, 18 g, 68 mmol) in EtOH (200 mL) stirred under N2 was introduced Pd/C 10% (2 g). The N2 atmosphere was replaced by H2 and the mixture was vigourously stirred at RT under H2 atmosphere (balloon) overnight. The mixture was diluted with DCM and filtered. The catalyst was washed several times with DCM. The solvents were removed under vacuum. The solid residue was suspended in EtOH and the filtered to give ethyl 6-methoxyquinoline-3-carboxylate.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[C:16](=[O:29])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:38].[Na+].C([O-])(O)=O.[Na+]>C(#N)C.O.OS(O)(=O)=O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([N:15]2[C:16](=[O:29])[C:17]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]=3[N:19]=[C:14]2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:38])[NH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:35][CH:34]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1ccc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)c[nH]1
Temperature: 100 °C

Procedure:
To a solution of 6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (28.1 mg, 0.057 mmol) in acetonitrile (0.5 mL) is added a solution of NaNO2 (5.4 mg, 0.078 mmol) in H2O (0.5 mL) at 0° C., followed by addition of one drop of concentrated H2SO4. The reaction mixture is then heated at 100° C. for 30 minutes, cooled down to 0° C., neutralized by saturated NaHCO3 to pH= 4-5, and extracted with ethyl acetate. The organic layer is concentrated and purified by preparative LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.14 (d, 2H), 7.91 (dd, 1H), 7.75 (d, 1H), 7.52 (t, 2H), 7.44 (d, 2H), 7.36 (m, 5H), 7.13 (d, 2H), 6.88 (d, 1H); HPLC-MS calculated for C28H18ClN5O2 (M+H+) 492.1. Found: 492.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.C(Cl)Cl.N>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:35]([C:34]3[CH:33]=[CH:32][C:31]([CH2:30][N:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)=[CH:38][CH:37]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2nccs2)CC1
Temperature: 85 °C
Yield: 40.2 %

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-2-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.088 g, 0.22 mmol) and EtOH (2.5 mL), 4-(morpholinomethyl)-benzaldehyde (0.045 g, 0.24 mmol) in EtOH (2.5 mL) was added, followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.66 mL, 0.66 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.049 g, 40%); 1H-NMR (500 Mz, DMSO-d6): δ 2.33-2.43 (m, 4H), 2.72-2.79 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.70 (t, J=4.5 Hz, 4H), 3.95 (s, 2H, NCH2), 7.48 (d, J=8.5 Hz, 2H, ArH), 7.69 (d, J=3.5 Hz, 1H, thiazole 5-H), 7.75 (d, J=3.0 Hz, 1H, thiazole 4-H), 8.15 (d, J=8.0 Hz, 2H, ArH), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.49 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.37 min—554/556 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 554.1341, calculated for C25H29BrN7OS (M+H)+: 554.1338.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][OH:18])[C:10]=3[OH:19])[N:8]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>C1COCC1>[C:29]([O:18][CH2:17][C:11]1[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]([N:7]2[N:6]=[C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]3=[N:8]2)[C:10]=1[OH:19])(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: C=C(C)C(=O)Cl
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: -5 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 3.98 g (13.0 mmol) 2-(5-chloro-2H-benzo[d][1,2,3]triazol-2-yl)-6-(hydroxymethyl)-4-methoxyphenol in 60 ml anhydrous THF. Triethylamine (6.4 ml) was added and the mixture was cooled to −10-0° C. Methacryloyl chloride (1.62 g, 15.5 mmol) was added dropwise and the mixture was stirred for 1 hr at −10-0° C. followed by 20 hours at ambient temperature. The solid was filtered and rinsed with 100 ml diethyl ether. The organic layer was washed with 1 N HCl and water, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to yield a yellow oil which was recrystallized in ethanol to give 1.73 g (34%) of a light yellow solid. 1H NMR (CDCl3) delta: 11.00 (s, 1H, Ar—OH), 7.92 (s, 1H, Ar—H benzotriazole), 7.88 (s, 1H, Ar—H phenol), 7.87 (d, 1H, Ar—H benzotriazole), 7.45 (d, 1H, Ar—H benzotriazole), 7.06 (s, 1H, Ar—H phenol), 6.21 (s, 1H, C═C—H trans), 5.62 (s, 1H, C═C—H cis), 5.38 (s, 2H, Ar—CH2), 3.89 (s, 3H, Ar—OCH3), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Br:8][CH2:9][CH2:10][OH:11].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:8][CH2:9][CH2:10][O:11][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCCBr
Temperature: 0 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
2,2-Dimethylpropionyl chloride (10 mL, 81.2 mmol) was added over 10 min to an ice-cooled solution of 2-bromoethanol (5.48 mL, 77.4 mmol) and DIPEA (20.8 mL, 121.8 mmol) in DCM (150 mL). The reaction mixture was stirred in the ice bath for a further 15 min, then at RT for 16 h. The reaction mixture was washed successively with 1M HCl, saturated aqueous NaHCO3 and water. The organic fraction was dried (Na2SO4) then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 1-6% EtOAc in cyclohexane) affording the title compound as a colourless oil (10.58 g, 65%). 1H NMR (CDCl3, 300 MHz): 4.37 (2H, t, J=6.0 Hz), 3.52 (2H, t, J=6.0 Hz), 1.23 (9H, s).
Reaction SMILES: [Cl:1][C:2]([Cl:22])([Cl:21])[CH2:3][O:4][C:5]([CH2:7][O:8][N:9]=[C:10]([C:18](=[O:20])[CH3:19])[C:11]([O:13]C(C)(C)C)=[O:12])=[O:6].[Br:23]Br>C(O)(=O)C>[Br:23][CH2:19][C:18](=[O:20])[C:10](=[N:9][O:8][CH2:7][C:5]([O:4][CH2:3][C:2]([Cl:22])([Cl:21])[Cl:1])=[O:6])[C:11]([OH:13])=[O:12]
Reactant: CC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)OC(C)(C)C
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CON=C(C(=O)O)C(=O)CBr)OCC(Cl)(Cl)Cl
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
To a solution of tert-butyl 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyrate (29.5 g) in acetic acid (59 ml) was added bromine (23.2 g) at 52° C., and the mixture was stirred at 52° to 68° C. for 15 minutes. After removal of the acetic acid from the reaction mixture under reduced pressure, the residual oil was dissolved in ethyl acetate (400 ml). The solution was washed with 10% hydrochloric acid (20 ml) and a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave 4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid (30.7 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[CH3:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1)([CH3:15])[C:13]#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([C:18]3[CH:17]=[C:16]([C:12]([CH3:15])([CH3:11])[C:13]#[N:14])[CH:21]=[CH:20][CH:19]=3)=[C:3]2[CH:10]=[N:9]1
Reactant: Ic1ccnc2[nH]ncc12
Reactant: CC(C)(C#N)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
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: [Na+]
Solvent: COCCOC
Product: CC(C)(C#N)c1cccc(-c2ccnc3[nH]ncc23)c1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A suspension of 4-iodo-1H-pyrazolo[3,4-b]pyridine (50 mg, 0.204 mmol), 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanenitrile (66 mg, 0.245 mmol), 2 M aqueous solution of sodium carbonate (0.31 ml, 0.612 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mol %, 12 mg, 0.01 mmol), in ethylene glycol dimethyl ether (2.5 ml) was heated under microwave irradiation at 150° C. for 30 minutes. The mixture was cooled down to room temperature, filtered through a path of celite and evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (28.4 mg, 53% yield).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:12][C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:8][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]c(-c4ccccc4)n3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-phenyl-1H-imidazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 403.2 (M+H)+.
Reaction SMILES: ClCCCC(Cl)=[O:6].[OH-].[Na+].Cl[CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1(O)[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][C:19]2[CH:25]=[CH:26][C:27]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[CH:28][C:18]1=2)=[O:15]>C(Cl)Cl>[CH3:24][C:21]1([CH3:23])[O:20][C:19]2[CH:25]=[CH:26][C:27]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[CH:28][C:18]=2[C@@H:17]([N:16]2[CH2:11][CH2:12][CH2:13][C:14]2=[O:15])[C@@H:22]1[OH:6]
Reactant: O=C(Cl)CCCCl
Reactant: CC1(C)CC(O)(NC(=O)CCCCl)c2cc(S(=O)(=O)c3ccccc3)ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2[C@@H](N2CCCC2=O)[C@@H]1O

Procedure:
A solution of 3-bromo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-4-ol in ethanol is shaken under a pressure of 8 bar of NH3 at 50° in an autoclave for 8 hours. The mixture is cooled and then evaporated to dryness and recrystallized from ethyl acetate. 4-Amino-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-3-ol of melting point: 160°-163°C. is obtained and is immediately subjected to acylation with 4-chlorobutyryl chloride. For this purpose, the substance is dissolved together with the acid chloride in CH2Cl2 and stirred in a two-phase mixture with 2N sodium hydroxide solution at room temperature for 24 hours. The usual working up results in 4-(4-chlorobutyrylamino)-3,4-di-hydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-4-ol of melting point 155°-157° C. Cyclization to give the title compound is carried out by dissolving the substance in tetrahydrofuran, addition of a stoichiometric amount of 80% NaH suspension in oil and stirring the mixture at room temperature for 24 hours. The final product is identical to the product obtained by process b). Melting point: 200°-201° C. If 4-amino-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-3-ol is subjected to racemate resolution, it is possible to obtain from its (+) enantiomer the pure (+) enantiomer from Example 5a with the data indicated there.