Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH:32]([NH2:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:25])[CH2:22][CH2:23]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(C(=O)O)CC3)n3nccc3n2)cc1
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)NC(=O)C1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Yield: 8.3 %

Procedure:
A solution of 1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-4-carboxylic acid (Compound 244, 80 mg, 0.189 mmol), isopropylamine (22 mg, 0.378 mmol), EDCI (72 mg, 0.378 mmol), and HOBT (13 mg, 0.095 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 20-30% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (7.3 mg, 8%). 1H NMR (DMSO-d6) δ: 10.88 (s, 1H), 8.08 (d, J=2.3 Hz, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.74 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.42 (s, 1H), 6.34 (d, J=2.3 Hz, 1H), 4.43-4.50 (m, 3H), 3.84 (dd, J=14.3, 6.4 Hz, 2H), 3.07 (br. s., 2H), 1.73-1.87 (m, 4H), 1.45 (s, 6H), 1.05 (d, J=6.6 Hz, 6H). ESI-MS: m/z 465.0 (M+H)+.
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)Cl.[S:7]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8]1>O>[Br:1][C:8]1[S:7][C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=1
Reactant: O=C1c2ccccc2CCc2sccc21
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2CCc2sc(Br)cc21
Reaction time: 4 h
Yield: 69.5 %

Procedure:
Bromine (8.5 mL, 165 mmol) was added dropwise to a chloroform (300 mL) solution of 9,10-dihydro-1-thiabenzo[f]azulen-4-one (23.2 g, 108 mmol), and the mixture was stirred for 4 hours. Water was added to the reaction mixture, the product was extracted with ethyl acetate, the organic layer was then washed with a saturated aqueous sodium bicarbonate solution and with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate), to give 22.0 g (69%) of the captioned compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CO>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CO
Product: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CN1CCCCC1)CO2
Temperature: 120 °C
Yield: 81.5 %

Procedure:
A mixture of [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.49 g, 1.1 mmol), piperidine (1 ml, 10.1 mmol) and MeOH (2 ml) was heated under microwave radiation at 120° C. for 25 min. Purification on SCX-3 column (TEA/MeOH) and by flash column chromatography (MeOH/EtOAc) gave the title compound (0.31 g). The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et20 (0.25 g). MS m/z (rel. intensity, 70 eV) 345 (M+, 0.5), 124 (3), 99 (7), 98 (bp), 96 (2), 55 (4) [α]=−60° (MeOH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(c2ccc(N)cc2)CC1

Procedure:
10.0 g (45 mmol) 1-methyl-4-(4-nitro-phenyl)-piperazine are dissolved in 250 ml of ethanol, then combined with 2 g palladium/charcoal (10%) and hydrogenated at 5 bar hydrogen for 2 hours. Then the reaction mixture is suction filtered and the filtrate is concentrated by evaporation. The residue is recrystallised from cyclohexane. Yield: 7.7 g
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:9]1[CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[NH:6][C:7]2[C:15]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[CH:14][CH:13]=[CH:12][C:8]1=2)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(S(=O)(=O)Nc2cccc3c2Nc2ccccc2CN3)cc1
Product: COc1ccc(S(=O)(=O)Nc2cccc3c2Nc2ccccc2CN3C(C)=O)cc1

Procedure:
N-(10,11-Dihydro-5H-dibenzo(b,e)(1,4)diazepin-6-yl)-4-methoxybenzensulfonamide, which had been synthesized in the same manner as the one of Example 31, was reacted with acetic anhydride at room temperature. Then the obtained product was purified by silica gel column chromatography and thus the title compound was obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)=[O:5])#[N:2].[H-].[Na+].[C:19](N1C=CN=C1)(=[O:21])[CH3:20].Cl>O1CCCC1.C(O)(=O)C>[CH3:16][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])/[C:3](/[C:1]#[N:2])=[C:19](\[OH:21])/[CH3:20])[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(=O)n1ccnc1
Reactant: Cc1cc(NC(=O)CC#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Cyano-N-(3-methyl-4-nitrophenyl)acetamide (0.61 g; 2.8 mmol) is dissolved in tetrahydrofuran (30 ml) and sodium hydride (80% strength dispersion in oil; 0.21 g; 7 mmol) is added. The mixture is stirred at 25° C. for 15 minutes and 1-acetylimidazole (0.46 g; 4.2 mmol) is added dropwise over the course of 5 minutes and the mixture is stirred for a further 15 minutes. 2 ml of glacial acetic acid are added and the mixture is stirred at 25° C. for 1 hour and then poured into ice-cold water (100 ml). The pH of the solution is then adjusted to 1 using concentrated hydrochloric acid, and the precipitate is filtered, washed with water and brought to dryness under reduced pressure. N-(3-Methyl-4-nitrophenyl)-2-cyano-3-hydroxycrotonamide is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21]([NH2:25])=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: N
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(N)=O)n(C)n1
Yield: 20 %

Procedure:
As described for example 144, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using ammonia instead of 2-hydroxy-2-methylpropylamine, to the title compound (12 mg, 20%) which was obtained as an off white solid. MS: m/e=330.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[O:8])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[SH:29]>>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[O:8])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cc([N+](=O)[O-])c(Cl)s1
Product: O=C(c1cccc([N+](=O)[O-])c1)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1

Procedure:
Prepared according to the procedure described for example 18 from (5-chloro-4-nitro-2-thienyl)-(3-nitrophenyl)methanone (100 mg, 0.28 mmol) and 2,4-dichlorobenzenethiol (50 mg, 0.28 mmol). The title compound was obtained as a solid (35 mg, 28% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.52 (2H, m), 8.26 (1H, m), 8.24 (1H, m), 8.11 (1H, m) 8.04 (1H, m), 7.87 (1H, m), 7.74 (1H, m).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([F:33])([F:32])[C:12]1[CH:31]=[CH:30][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>C1COCC1>[F:33][C:11]([F:10])([F:32])[C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]4=[N:29][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 418 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.659 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-amine (690 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with IPE/EtOAc, dried in vacuo to give 9-{4-[4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (579.1 mg) as a slightly yellow solid. Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (505 mg) in THF (dry) (15 mL) and MeOH (15 mL) and the mixture was stirred at room temperature under hydrogen for 6 hr. Platinum(IV) oxide (30 mg), MeOH (15 mL) and THF (dry) (15 mL) were added and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (297.2 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)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: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 100 °C

Procedure:
To a round-bottomed flask equipped with a stirring bar, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.50 g, 6.72 mmol), 5-bromo-2-nitropyridine (1.64 g, 8.07 mmol), Pd(PPh3)4 (388 mg, 0.336 mmol), Na2CO3 aqueous solution (1.0 N, 20.2 mL, 20.2 mmol), dioxane (60.6 mL) were added. The reaction mixture was heated at 100° C. for 10 hrs. CH2Cl2 (200 mL) was added to the resulting mixture was washed with water (30 mL×3). CH2Cl2(200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-nitropyridine (130a) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH3:7])[S:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:23](OC(C)=C)(=[O:25])[CH3:24]>>[C:23]([O:1][C:2]1[CH:6]([CH3:7])[S:5][CH2:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:25])[CH3:24]
Reactant: COC(=O)C1CSC(C)C1=O
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)C1=C(OC(C)=O)C(C)SC1
Reaction time: 22 h

Procedure:
Methyl 4-keto-5-methyl-2,3,4,5-tetrahydrothiophene-3-carboxylate (90.83 g) and p-toluenesulphonic acid (1 g) were refluxed for 6 hours in isopropenyl acetate (214 ml) and then stood at room temperature for 22 hours.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][N:42]=1>>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][N:42]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1ccc(Br)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Product: Cc1ccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)nc1
Yield: 61 %

Procedure:
The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (100 mg, 0.106 mmol) and 2-bromo-5-methylpyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (42 mg, 61%): 1H NMR (CDCl3, 400 MHz) δ 7.64 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.47 (d, 1H, J=7.6 Hz), 7.30-7.26 (m, 2H), 7.19-7.16 (m, 3H), 7.08 (d, 1H, J=7.6 Hz), 4.85 (dd, 1H, J=7.3, 5.8 Hz), 2.60 (t, 2H, J=7.6 Hz), 2.59 (s, 3H), 1.93 (m, 2H), 1.65 (m, 2H), 1.36 (m, 4H), 0.90 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.4, 158.8, 150.9, 146.8, 142.8, 137.0, 128.4, 128.2, 125.5, 124.8, 122.5, 116.1, 68.7, 36.4, 35.9, 31.4, 29.1, 25.7, 25.7, 25.1, 24.5, 13.6, −5.0, −5.2.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.C[N+]1([O-])CCOCC1.CCOCC>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCc1ccc2[nH]cnc2c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc2[nH]cnc2c1

Procedure:
(1H-benzo[d]imidazole-5-yl)methanol (2.8 mmol, 1 eq.) was dissolved in 30 mL dichloromethane and a molecular sieve (4 A) was added. To the solution were added Tetrapropylammonium perruthenate (0.28 mmol, 0.1 eq.) and N-Methylmorpholine-N-Oxide (9.8 mmol, 3.5 eq.). After stirring the mixture for 72 hours at room temperature 50 mL of ether was added and filtrated. The solvent was removed under reduced pressure and the product was purified by means of flash-chromatography using silica gel and a ethyl acetate/MeOH-gradient.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH3:30][O:31][CH:32]([O:43][CH3:44])[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[C:35](F)[CH:34]=1>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:35]2[CH:34]=[C:33]([CH:32]([O:43][CH3:44])[O:31][CH3:30])[CH:38]=[CH:37][C:36]=2[N+:39]([O-:41])=[O:40])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:5])[CH3:2]
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Nc2cc(C(OC)OC)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Yield: 71.1 %

Procedure:
A mixture of 2.82 g (10 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester, 9.75 g (30 mmole) of cesium carbonate, 20 mL of dimethylformamide, and 2.15 g (10 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene was heated at 80 degrees for 1 hour. The cooled mixture was diluted with 200 mL of water and extracted three times with 100 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 0:100-10:90) to give 3.4 g of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid ethyl ester (VI.41a) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2[S:10][C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][N:13]=2)=[CH:6][C:5]([C@H:19]2[C@H:24]([OH:25])[C@@H:23]([OH:26])[C@H:22]([OH:27])[C@@H:21]([CH2:28][OH:29])[O:20]2)=[C:4]([OH:30])[CH:3]=1.Br[CH2:32][CH2:33][O:34][CH3:35].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][C:9]2[S:10][C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][N:13]=2)=[CH:6][C:5]([C@H:19]2[C@H:24]([OH:25])[C@@H:23]([OH:26])[C@H:22]([OH:27])[C@@H:21]([CH2:28][OH:29])[O:20]2)=[C:4]([O:30][CH2:32][CH2:33][O:34][CH3:35])[CH:3]=1
Reactant: OC[C@H]1O[C@@H](c2cc(Cc3ncc(-c4ccco4)s3)c(Cl)cc2O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1cc(Cl)c(Cc2ncc(-c3ccco3)s2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 50 °C
Reaction time: 15 h
Yield: 18.2 %

Procedure:
To a solution of phenol 63 (205 mg, 0.451 mmol) in acetone (10 mL) was added bromoethylmethyl ether (1.6 mL, 15.8 mmol) and K2CO3 (2.3 g, 15.8 mmol) at room temperature. The mixture was stirred at 50° C. for 15 h. The mixture was cooled to room temperature and filtered off through the celite. The filtrate was concentrated in vacuo. The residue was purified by prep HPLC (C18) to provide the titled compound 64 (42 mg, 19%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([N:25]2[CH:29]=[C:28]([C:30]3[C:31]4[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH:27]=[N:26]2)[CH2:19][C:20](OCC)=[O:21])[CH:15]=[CH:16][CH:17]=1.C(Cl)Cl>CCCCCC>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([N:25]2[CH:29]=[C:28]([C:30]3[C:31]4[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH:27]=[N:26]2)[CH2:19][CH:20]=[O:21])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(c1cccc(Br)c1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)c4cccc(Br)c4)c3)ncnc21
Reaction time: 4 h
Yield: 76 %

Procedure:
Diisobutylaluminum hydride in hexane (1 M, 4 mL) was added to a −78° C. solution of ethyl 3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate (600 mg, 0.001 mol) in DCM (6 mL, 0.09 mol). After stirring for 4 h, the reaction was quenched with cold methanol (300 μL), and then saturated ammonium chloride (500 μL) was added and the resulting solution was stirred for 1 h. The reaction was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography on silica gel eluting with hexane:EtOAc, (2:1 to 1:2), to give 3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (400 mg, 70%) as an oil. 1H NMR (400 MHz, CDCl3): δ 9.9 (s, 1H), 8.9 (s, 1H), 8.4 (s, 2H), 7.6 (d, 1H), 7.5 (d, 1H), 7.4 (d, 1H), 7.3-7.4 (m, 2H), 6.8 (d, 1H), 6.1 (m, 1H), 5.7 (s, 2H), 4 (m, 1H), 3.6 (m, 2H), 3.3 (dd, 1H), 1.0 (m, 2H), 0.01 (s, 9H). m/z=526, 528 (M+1).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2
Reactant: C#CCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (163 mg, 1.45 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (300 mg, 1.03 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and CuI (15 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 70° C. for 14 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 120 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]5[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=5)=[N:24][N:23]=4)=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]5[CH:33]=[CH:34][C:35]([CH2:36][N:40]6[CH2:44][CH2:43][CH2:42][CH2:41]6)=[CH:38][CH:39]=5)=[N:24][N:23]=4)=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccc(C=O)cc4)c4ccccc34)cc2)n1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccc(CN5CCCC5)cc4)c4ccccc34)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 25 mL RBF under nitrogen was charged with 4-(4-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenylamino)phthalazin-1-yl)benzaldehyde (90 mg, 0.18 mmol), pyrrolidine (125 mg, 1.8 mmol) and MeOH (3.5 mL, 0.05 M). HOAc was added (0.02 mL, 0.36 mmol) and the reaction mixture was stirred at RT for 2 hrs. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (186 mg, 0.90 mmol) was added portionwise. The mixture was stirred at RT overnight, then cooled to 0° C. and basified with aqueous sodium bicarbonate and the product was extracted into DCM. The organic layers were collected, dried over sodium sulfate, filtered and concentrated to give brown residue. The crude residue was purified by Gilson reverse phase liquid chromatography (5%-85% CH3CN/H2O+0.1% TFA). Product-containing fractions were combined and basified with aqueous sodium bicarbonate. This was extracted with EtOAc, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under high vacuum to afford N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-(pyrrolidin-1-ylmethyl)phenyl)phthalazin-1-amine as a light yellow solid. MS m/z=567 [M+H]+. Calc'd for C34H30N8O: 566.7.