Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[S:23][C:18]2=[N:19][CH:20]=[CH:21][N:22]=[C:17]2[CH:16]=1)=[O:14].Cl>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[S:23][C:18]2=[N:19][CH:20]=[CH:21][N:22]=[C:17]2[CH:16]=1)=[O:14]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc3nccnc3s2)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C(=O)O)cc1NC(=O)c1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of methyl 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)benzoate 49 (480 mg, 1.466 mmol) in ethanol (30 mL) was added 2NaOH (7.33 mL, 14.66 mmol). The mixture was stirred overnight at rt. The mixture was acidified with 2N HCl solution and cooled on ice. the resulting precipitation was collected to give 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)benzoic acid 50 (310 mg, 67%). NMR (400 MHz, DMSO-d6) 2.36 (s, 3H), 7.46 (d, J=7.8 Hz, 1H), 7.79 (dd, J=7.8 Hz and 1.6 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 8.54 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 10.57 (s, 1H), 13.01 (br s, 1H). (m/z)=314 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC[CH2:43][CH2:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:43][CH2:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(O)(CC)CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(CC)CCCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 89.5 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (84.3 mg, 0.145 mmol), 6-bromo-3-ethyl-3-hexanol (152 mg, 0.725 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=2:1, developed twice) to give 76.4 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from 6-bromo-3-ethyl-3-hexanol.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][NH:5][C:6]1[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:20]1([NH:26][N:27]=[C:28]([C:32](Cl)=[O:33])[C:29](Cl)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1COCC1>[C:20]1([NH:26][N:27]=[C:28]2[C:32](=[O:33])[N:5]([CH2:4][CH2:3][CH:2]([CH3:19])[CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:29]2=[O:30])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C(=NNc1ccccc1)C(=O)Cl
Reactant: CC(C)CCNc1ccccc1Nc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CCn1c(=O)c(=NNc2ccccc2)c(=O)n(-c2ccccc2)c2ccccc21
Yield: 96.8 %

Procedure:
Solutions of N1 -(3-Methylbutyl)-N2 -phenyl-1,2-benzenediamine (12.45 g) in dry THF (100 ml) and (phenylhydrazono)propandioyl dichloride (12.0 g) in dry THF (100 ml) were added dropwise concurrently to a flask of dry THF (100 ml) cooled in an ice-methanol bath under nitrogen. After 30 min more diacid chloride (1.0 g) in dry THF (30 ml) was added and the mixture was allowed to warm to 23°. After 24 h the mixture was poured into dilute HCl and extracted with EA. The combined extracts were washed with dilute sodium carbonate and saturated brine then dried and evaporated. The residue was chromatographed on TEA deactivated silica with EA as eluent to give the title compound (20.2 g) as a yellow solid, m.p. 143°
Reaction SMILES: C(O)(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.O1CC[CH2:16]OO1>OS(O)(=O)=O.O=S(=O)=O>[C:6]1([C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[CH2:16][O:8]1)=[O:7]
Reactant: C1COOOC1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C1OCc2ccccc21
Temperature: 145 °C

Procedure:
Terephthalic acid was suspended in 25-30% oleum. Trioxane was added and the mixture was heated to 140-150° C. for 4-8 hours. The reaction mixture was cooled and then quenched by cautious addition of water at less than 80° C. The resulting suspension was cooled to about 40° C. and the solid was filtered off. The filter cake was washed with water followed by propan-2-ol before slurrying the solid in propan-2-ol at reflux for 30 minutes. After cooling to 20-25° C. the product was filtered off, washed with propan-2-ol and dried at 60-70° C. under reduced pressure.
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29]CC2C=CC=CC=2)=[O:28])[CH2:18][CH2:17][CH2:16][N:15]([CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=2)[CH2:14][CH2:13]1)=[O:10])C1C=CC=CC=1.CCOCC>C(O)C.[Pd]>[C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([OH:29])=[O:28])[CH2:18][CH2:17][CH2:16][N:15]([CH2:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:14][CH2:13]1)([OH:10])=[O:8]
Reactant: O=C(CN1CCCN(CCc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: Nc1ccc(CCN2CCCN(CC(=O)O)CCNCCCN(CC(=O)O)CC2)cc1
Yield: 98.4 %

Procedure:
To a solution of compound (16) (0.86 g, 1.33 mmol) in absolute ethanol (100 ml) was added 10% Pd/C (0.26 g). The resultant mixture was stirred at an ambient temperature under H2 atmosphere for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 ml). The solvent was evaporated from the combined filtrate in vacuo to give an oily residue, which was then treated with Et2O to obtain a white solid of compound (12) (0.57 g, 98% yield). 1H NMR (500 MHz, D2O): δ 7.45-7.43 (dd, 2H), 7.38-7.36 (dd, 2H), 3.49-3.12 (m, 18H), 2.82-2.62 (m, 6H), 1.91 (brs, 4H); 13C NMR (125 MHz, D2O): δ 177.0, 176.6, 163.4, 163.1, 162.8, 162.5, 137.4, 130.4, 128.9, 123.4, 119.9, 117.5, 115.2, 112.9, 56.0, 54.9, 54.4, 53.3, 51.6, 50.5, 48.8, 47.3, 45.0, 31.5, 27.6, 22.8, 21.3; FIRMS (FAB) calculated for C22H38N5O4: 436.2924 [(M+H)+], measured value: 436.2925 [(M+H)+].
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])[CH2:9]1)(C)(C)C.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:19]=1)[O:13][C@H:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1

Procedure:
To [(1S,3S)-3-(5-fluoro-2-nitro-phenoxy)-cyclopentyl]-carbamic acid tert-butyl ester, cpd. XXXVII.1 (2.13 g) in DCM (150 ml) was added at 0° C. TFA (10 ml) and stirred at rt overnight. The reaction mixture was concentrated at rt and triturated with diisopropyl ether to give the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:17]3[CH2:26][CH2:25][C:20]4(OCC[O:21]4)[CH2:19][CH2:18]3)=[CH:8][C:9]=2[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[S:4][C:3]=1[C:27]([NH2:29])=[O:28].C(O)(=O)C.C([O-])(O)=O.[Na+]>O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:17]3[CH2:18][CH2:19][C:20](=[O:21])[CH2:25][CH2:26]3)=[CH:8][C:9]=2[O:11][CH2:12][C:13]([F:14])([F:16])[F:15])[S:4][C:3]=1[C:27]([NH2:29])=[O:28]
Reactant: NC(=O)c1sc2nc(N3CCC4(CC3)OCCO4)cc(OCC(F)(F)F)c2c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1sc2nc(N3CCC(=O)CC3)cc(OCC(F)(F)F)c2c1N
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A solution of 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-(2,2,2-trifluoro-ethoxy)-thieno[2,3-b]pyridine-2-carboxylic acid amide as a white powder (0.940 g, 2.17 mmol) in a 4:1 mixture of acetic acid: H2O (20 mL) was heated to 80° C. for 4h then cooled to room temperature and made basic by the addition of a saturated aqueous solution of NaHCO3 which caused a solid to precipitate from solution. The solid was collected by filtration and dried under reduced pressure to provide 0.680 g (80.5%) of 3-amino-6-(4-oxo-piperidin-1-yl)-4-(2,2,2-trifluoro-ethoxy)-thieno[2,3-b]pyridine-2-carboxylic acid amide as a clear oil.
Reaction SMILES: C[Si](I)(C)C.C[O:7][C:8](=[O:54])[C@H:9]([O:23][C:24]1[C:29]([Br:30])=[CH:28][C:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]4[CH:52]=[CH:51][CH:50]=[CH:49][C:39]=4[S:40][C:41]=3[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:33][CH:32]=2)=[CH:26][C:25]=1[Br:53])[CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C(Cl)Cl>O>[CH2:42]([C:41]1[S:40][C:39]2[CH:49]=[CH:50][CH:51]=[CH:52][C:38]=2[C:37]=1[C:34]1[CH:33]=[CH:32][C:31]([C:27]2[CH:28]=[C:29]([Br:30])[C:24]([O:23][C@H:9]([CH2:10][CH2:11][N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[C:8]([OH:54])=[O:7])=[C:25]([Br:53])[CH:26]=2)=[CH:36][CH:35]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COC(=O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: O
Product: O=C(O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Temperature: 50 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
Trimethylsilyl iodide (0.29 mL, 2.07 mmol) was added into a mixture of (2R)-2-[4′-(2-benzyl-benzo[b]-thiophen-3-yl)-3,5-dibromo-biphenyl-4-yloxy]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (1.1 g, 1.38 mmol), and methylene chloride (10 mL). The reaction mixture was stirred at 50° C. for 24 hours. An additional 0.29 mL of trimethylsilyl iodide was added and the mixture was stirred for 48 hours, poured into water and extracted with ethyl acetate. The organic extracts were washed with aqueous sodium bisulfite and dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexanes/EtAOc 2:1) gave white solid (0.92 g, 94% yield): mp 113-115° C.; MS m/e 778 (M−H)+;
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)c1ccc(Nc2ccccc2)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1ccc(N(c2ccccc2)c2ccc(C=O)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
4-(trimethylsilyl)-N-phenylbenzeneamine (22.8 m mol)), 4-bromobenzaldehyde (29.64 m mol)), tris(dibenzylideneaceton)dipalladium(O) (0.342 m mol)), tris-tert-butyl phosphine (0.684 m mol)), and sodium-tert-butoxide (29.64 m mol)) were dissolved in toluene (100 ml) in a 250 ml tri-neck-round bottom flask and were then stirred in a bath of 100° C. for 24 hours. After the reaction was terminated, the toluene was removed from the solution. After extraction was performed on the solution using dichloromethane and water, the resulting solution was reduced in pressure and distilled. After a silica gel column chromatography, the solvent was reduced in pressure and distilled, thereby obtaining 4-(N-(4-(trimethylsilyl)phenyl)-N-phenylamino)benzaldehyde liquid having 4.1 g.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11].C(O)(=O)C.[F:16][C:17]([F:25])([F:24])[C:18](=O)[CH2:19][C:20](=O)[CH3:21]>COCCO>[CH3:21][C:20]1[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[OH:3])[N:11]=[C:18]([C:17]([F:25])([F:24])[F:16])[CH:19]=1
Reactant: COc1ccccc1NN
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Solvent: COCCO
Product: Cc1cc(C(F)(F)F)nn1-c1ccccc1O

Procedure:
300 mg of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 1.3 ml of 2-methoxyethanol, and 2.5 ml of acetic acid and 208 μl of 1,1,1-trifluoro-2,4-pentanedione were added and heated at reflux for 1 hour and 40 minutes. The solvent was distilled off under reduced pressure, and 50 ml of ethyl acetate was added, and the organic layer was washed with 50 ml of a saturated sodium bicarbonate solution and 50 ml of saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to yield 485.6 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:45][NH2:46]>O.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:45][NH:46]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4cccc(Cl)c4)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3cccc(Cl)c3)C2)n1
Temperature: 150 °C
Yield: 77 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(3-chlorophenyl)-3-piperidinecarboxamide (190 mg, 0.421 mmol), 3 mL of EtOH, Hunig's base (0.22 mL, 1.26 mmol), and hydrazine anhydrous (0.053 mL, 1.69 mmol) were added, and the yellow mixture was heated at 150° C. for 180 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered off and the yellow filtrate was evaporated. To the resulting brown liquid was added EtOAc (1 mL), and the mixture was warmed to 50° C. Two layers formed. The top layer is EtOAc solution, and it was pipeted to a different vial. The bottom layer is the comparatively pure product. This compound was treated with water at 50° C., and a solid was formed. This material was filtered and dried to give the title compound as a light yellow solid (150 mg). LC-MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (m, 1H), 1.63-1.85 (m, 2H), 2.01 (m, 1H), 2.79-3.06 (m, 2H), 4.62-4.76 (m, 1H), 5.37 (s, 2H), 6.11 (s, 2H), 6.69 (s, 1H), 7.10 (m, 1H), 7.28 (m, 1H), 7.52 (m, 1H), 7.55 (m, 1H), 7.79 (m, 1H), 7.82 (s, 1H), 8.03 (s, 1H), 10.22 (s, 1H), 11.45-11.57 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1[CH:34]=[O:35].[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1[CH2:34][OH:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C=O)c(Cl)n3)cc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CO)c(Cl)n3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 5-(6-chloro-5-formylpyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (300 mg, 0.58 mmol) in THF (4 ml) and MeOH (1 ml) was added NaBH4 (66 mg, 1.74 mmol). The resulting mixture was stirred at RT for 3 hours then treated with NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 5-(6-chloro-5-(hydroxymethyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (300 mg, yield: 100%). MS (M+H)+: 518.
Reaction SMILES: CN(C1C=CC=CN=1)C.C[Si]([N:14]=[C:15]=[O:16])(C)C.C(Cl)Cl.[CH3:20][S:21]([C:24]1[CH:50]=[CH:49][C:27]([O:28][C:29]2[C:43]([CH:44]3[CH2:48][CH2:47][CH2:46][NH:45]3)=[CH:42][C:32]3[NH:33][C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[N:35][C:31]=3[CH:30]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>O>[CH3:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([O:28][C:29]2[C:43]([CH:44]3[CH2:48][CH2:47][CH2:46][N:45]3[C:15]([NH2:14])=[O:16])=[CH:42][C:32]3[NH:33][C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[N:35][C:31]=3[CH:30]=2)=[CH:49][CH:50]=1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 mg of dimethylaminopyridine and 0.029 ml of trimethylsilyl isocyanate were added to a methylene chloride (1 ml) solution of 17.1 mg of 5-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 162 (step 7), and the reaction liquid was stirred overnight at room temperature. Water was added to the reaction liquid, and extracted with ethyl acetate, and then washed with saturated saline. After dried and concentrated, the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid], and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14](I)[CH:13]=3)[C:6]=2[N:5]=[CH:4]1)[CH3:2].[CH2:20]([S:22]([C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([O:40][CH3:41])[CH:26]=1)(=[O:24])=[O:23])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:1]([N:3]1[C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([C:28]4[CH:29]=[CH:30][C:25]([S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])=[CH:26][C:27]=4[O:40][CH3:41])[C:15]([F:18])=[CH:16][CH:17]=3)[C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc2c(-c3ccc(F)c(I)c3)cnnc21
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCn1cnc2c(-c3ccc(F)c(-c4ccc(S(=O)(=O)CC)cc4OC)c3)cnnc21
Temperature: 100 °C
Yield: 13 %

Procedure:
A stirred solution of 7-ethyl-4-(4-fluoro-3-iodophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 10, 100 mg, 0.27 mmol), 2-(4-ethylsulfonyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 21, 88 mg, 0.27 mmol) and cesium carbonate (177 mg, 0.54 mmol) in dioxane (5 mL) and water (1 mL) was degassed with argon for 10 minutes followed by the addition of 1,1′-bis(di-tert-butylphosphino) ferrocene palladium dichloride (4.4 mg, 0.005 mmol). The resulting mixture was heated at 100° C. for 16 hours, cooled to room temperature and diluted with EtOAc (15 mL). The organic layer was washed with water (10 mL) and saturated brine solution (10 mL) then dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 afforded the title compound as off white solid in 13% yield, 15 mg.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[S:7][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[N:13]=2)=[C:9]([CH3:11])[N:10]=1.[N+]([O-])(OC(=O)C)=O.C([O-])(O)=O.[Na+]>CC(OC(C)=O)=O>[CH3:5][C:6]1[S:7][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[C:21]([N+:1]([O-:4])=[O:2])[CH:20]=3)[N:13]=2)=[C:9]([CH3:11])[N:10]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(N(C)C)cc3)n2)s1
Reactant: O=[N+]([O-])O
Agent: CC(=O)O[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N(C)C)c([N+](=O)[O-])c3)n2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.6 %

Procedure:
HNO3 (69% aq, 24 μL, 0.36 mmol) was added dropwise to Ac2O (1 mL) at room temperature, keeping the internal temperature below 25° C. The mixture was stirred at room temperature for 15 min before cooling to −5° C. in an ice-MeOH bath. Compound N-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-N′,N′-dimethyl-benzene-1,4-diamine (50 mg, 0.15 mmol) was slurried in Ac2O (1 mL) and added dropwise to the cooled solution of acetyl nitrate. The mixture was stirred with cooling for 1 h then a further 2 h at room temperature. The mixture was poured into ice-water (20 mL) and the pH was adjusted to 7-8 by addition of saturated aq NaHCO3 solution. The mixture was extracted with EtOAc. The combined organics were washed with brine, dried on MgSO4, and filtered. The solvent was evaporated in vacuo to give a dark solid, which was purified by flash chromatography, eluted with heptane/EtOAc to afford 32 mg of the title compound as a pale reddish solid. RP-HPLC: tR=12.7 min (10-70% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>95%). 1H-NMR (DMSO-d6): δ 2.62 (s, 3H, CH3), 2.64 (s, 3H, CH3), 2.74 (s, 6H, CH3), 7.09 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.23 (d, 1H, J=8.8 Hz, Ph-H), 7.77 (dd, 1H, J=8.7, 2.7 Hz, Ph-H), 8.39 (d, 1H, J=2.7 Hz), 8.51 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 9.81 (br. s, 1H, NH).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CS(C)=O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]1[N:19]=[N:20][N:21]=[C:2]1[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ccc2c(c1)c(-c1ccccc1)nc1nnnn12
Temperature: 100 °C
Yield: 96.7 %

Procedure:
The starting material may be prepared as follows: To a solution of 1.92 g of 2,6-dichloro-4-phenylquinazoline in 30 ml of dimethylsulfoxide was added 0.91 g of sodium azide. The mixture was heated at 100° C. for 1 hour with stirring and then poured into ice-water. The resulting precipitate was collected by filtration, washed with water and dried to give 1.9 g of 7-chloro-5-phenyltetrazolo[1,5-a]quinazoline. Recrystallization from chloroform-ethanol gave pale yellow needles, m.p. 209° C. (decomp.).