Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[OH:3][CH2:4][C:5]1[N:6]=[N:7][N:8]([CH3:10])[CH:9]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CCN(CC)CC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:11]([O:3][CH2:4][C:5]1[N:6]=[N:7][N:8]([CH3:10])[CH:9]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: Cn1cc(CO)nn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1cc(CO[Si](C)(C)C(C)(C)C)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxymethyl-1-methyl-1H-[1,2,3]triazole hydrochloride hydrate (WO-A-9850385) (7.0 g, 41.8 mmol), tert-butyldimethylsilyl chloride (6.3 g, 41.8 mmol), Et3N (11.6 ml, 83.6 mmol) and 4-(dimethylamino)pyridine (255 mg, 5 mol %) in CH2Cl2 (250 ml) was stirred at room temperature overnight under N2. Iso-hexanes (400 ml) were added and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and the mixture was purified by column chromatography on silica using 10-100% Et2O/iso-hexanes as eluent to yield the desired protected alcohol (8.90 g, 94%). 1H NMR (360 MHz, CDCl3) δ 7.35 (1H, s), 4.73 (2H, s), 3.98 (3H, s), 0.81(9H, s), 0.00 (6H, s).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:15]=[CH:14]3)=[CH:5][CH:4]=1.[ClH:28].N1C=CC=CC=1>O>[ClH:28].[OH:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:15]=[CH:14]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/c2ccc3c(=O)n(CCCN(C)C)ncc3c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN(C)CCCn1ncc2cc(/C=C/c3ccc(O)cc3)ccc2c1=O
Temperature: 180 °C
Reaction time: 7 h

Procedure:
Trans-6-[2-(4-Methoxyphenyl)ethenyl]-2-[3-(dimethylamino)propyl]-phthalazin-1(2H)-one (prepared as in Example XIV) (46.6 gm, 0.122 mole) and 245 gm pyridine hydrochloride were heated together with stirring at 180° C. for 7 hours. The hot melt was added to 1200 ml water and stirred over night. The product was filtered off and washed with three 400 ml portions of water. The damp product was slurried in 350 ml of tetrahydrofuran plus 350 ml methanol, acidified with gaseous HCl, filtered and washed with ethanol. The product, which weighed 36 gm, was recrystallized from 275 ml water. Wgt=30.2 gm, mp=283°-283° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([SH:8])[CH2:5][N:4]1[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].C(N(CC)CC)C.C[Si](C)(C)Cl.[S:27](Cl)(=[O:30])(=[O:29])[NH2:28]>ClCCl>[CH2:12]([O:11][C:9]([N:4]1[CH2:5][C@@H:6]([SH:8])[CH2:7][C@H:3]1[CH2:2][NH:1][S:27](=[O:30])(=[O:29])[NH2:28])=[O:10])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CN
Reactant: NS(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNS(N)(=O)=O
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To a solution of (2S,4S)-2-aminomethyl-1-allyloxycarbonyl-4-mercaptopyrrolidine (2.80 g: ca. 13.14 mmole) in dichloromethane (66 ml) at -50° C., triethylamine (4.02 ml: 28.91 mmole) and trimethylchlorosilane (3.76 ml: 28.91 mmole) are added dropwise over 15 minutes. The mixture is stirred at the same temperature for 20 minutes. To the reaction mixture triethylamine (0.92 ml: 6.57 mmole) and a solution of sulfamoyl chloride (19.37 mmole) in dichloromethane (6.8 ml) are added dropwise over 20 minutes at -70° C., and the mixture is stirred for 30 minutes. To the reaction mixture triethylamine (3.84 ml: 27.59 mmole) is again added over 1 hour at -50° C. The reaction mixture is kept at the same temperature overnight and concentrated in vacuo. The residual oil is purified by silica gel chromatography (ethyl acetate) to give (2S,4S)-1-allyloxycarbonyl-2-(sulfamoylamino)methyl-4-mercaptopyrrolidine (2.64 g). Yield: 68%. White powder. NMR δ(CDCl3) ppm: 1.4 to 1.6(m, 1H), 1.83(d, J=6.2 Hz, 1H), 2.5 to 2.7(m, 1H), 3.11(dd, J=8.2 Hz, J=11.6 Hz, 1H), 3.3 to 3.4(m, 1H), 3.71(dd, J=2.9 Hz, J=15.2 Hz, 1H), 4.13(dd, J=7.3 Hz, J=11.7 Hz, 1H), 4.16(dd, J=10.3, 14.9 Hz, 1H), 4.3 to 4.6 (m, 3H), 4.7(m, 2H), 5.2 to 5.4(m, 4H), 5.8 to 6.0(m, 2H), 6.0(m, 2H). IR ν (CHCl3) cm-1 : 1684, 1158.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.Cl.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:39])[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:21][CH2:20]1>ClCCl>[CH:16]1[C:3]2[CH:2]([N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:39])[CH2:31][CH2:32][C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[CH2:21][CH2:20]3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Reactant: ClC1c2ccccc2COc2ccccc21
Agent: Cl
Solvent: ClCCl
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C2c3ccccc3COc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.46 g (15 mmol) 11-chloro-6,11-dihydrodibenzo[b,e]oxepine are dissolved in 90 ml absolute dichloromethane and 5.43 g (15 mmol) N-(4-piperidin-4-yl-butyl)-3-pyridin-3-yl-propionamide dihydrochloride is added. 5.0 g (49.5 mmol) TEA is dissolved in 20 ml absolute dichloromethane and added dropwise under ice cooling. The mixture is stirred for two days at RT without further cooling. Subsequently, the batch is washed twice, each with 50 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5) and after drawing off the solvent, is first crystallized twice, each from 10 ml 1-chlorobutane and subsequently once from 10 ml acetic acid ethyl ester. Colorless crystals with a MP of 110-112° C. in a yield of 0.2 g (3%) are recovered
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]#[N:13])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N1CCOCC1)C>CN(C)C=O.O1CCCC1>[C:12]([CH2:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)#[N:13]
Reactant: N#CCc1ccc(N)c2[nH]ncc12
Reactant: CS(=O)(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(CC#N)c2cn[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 1.7 g of 2-(7-amino-1H-indazol-4-yl)acetonitrile in 15 ml of dimethylformamide and 5 ml of tetrahydrofuran is combined with 0.96 ml of methanesulfonyl chloride and 1.56 ml of N-ethylmorpholine and agitated for 16 hours at room temperature. The mixture is concentrated, chromatographed over silica gel with methanol/dichloromethane (1:3), and recrystallized from methanol, thus producing 2.2 g of N-(4-cyanomethyl-1H-indazol-7-yl)methanesulfonamide, mp 223°-225° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(N(CC)C(C)C)(C)C.O>CC(N(C)C)=O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)c(N)c1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)cc(Nc2cc(C)ccc2NC(=O)OC(C)(C)C)n1
Temperature: 100 °C
Reaction time: 7 h
Yield: 51.2 %

Procedure:
4,6-Dichloro-2-(methylsulfanyl)pyrimidine (50 mg) and tert-butyl (2-amino-4-methylphenyl)carbamate (57 mg) were dissolved in dimethylacetamide (250 μL), and N,N-diisopropyl ethylamine (69 μL) was added thereto, followed by stirring at 100° C. for 7 hours. After the completion of the reaction, the mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The extracts were washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain a desired compound tert-butyl (2-{[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]amino}-4-methylphenyl)carbamate (50 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]>>[CH3:28][S:29]([C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.45 g, 1.0 mmol) and commercially available 3-methanesulfonyl-phenylboronic acid (0.22 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.45 g, 86%). MS (ISP) 523.0 [(M+H)+]; mp 183.5° C.
Reaction SMILES: [Cl:1][C:2]([N:4]1[CH2:8][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])=[O:3].[CH3:12]C1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O>>[Cl:1][C:2]([N:4]1[CH2:8][CH2:12][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])=[O:3]
Reactant: O=C(Cl)N1CS(=O)(=O)NC1=O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Product: O=C(Cl)N1CCS(=O)(=O)NC1=O

Procedure:
1-chlorocarbonyl-4-thia-imidazolidin-2-on-4,4-dioxide are reacted with 0.05 mol of ampicillin,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:29]([N:28]([CH3:32])[CH3:27])=[O:30])[C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([C:29]([N:28]([CH3:32])[CH3:27])=[O:30])[C:14]=3[CH3:16])[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(N2C(=O)c3nn(C(=O)N(C)C)c(C)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Product: Cc1nn(C(=O)N(C)C)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O

Procedure:
A mixture of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 27) (200 mg, 0.542 mmol) and dimethylcarbamic chloride (0.06 mL, 0.651 mmol) in pyridine (2 mL) for 8 h at 100° C. The reaction mixture was concentrated, diluted in CH2Cl2/water, and extracted twice with CH2Cl2. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography (1% ammonia/5% MeOH/CH2Cl2), subsequent preparative achiral SFC (column: Reprosil 70 NH2, 250×30 mm, 5 μm, Dr Maisch; eluent: MeOH/scCO2; gradient: 1 min 15% MeOH, 15-20% MeOH in 6 min, 20-50% MeOH in 1 min, 1.5 min 50% MeOH; flow: 100 mL/min) and trituration of the resulting products in diethyl ether to afford 68 mg of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-N,N,3-trimethyl-6-oxo-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxamide (Example 142) and 62 mg of the title compound. tR: 0.85 min (LC-MS 2); ESI-MS: 440.1 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.95 (s, 3H) 2.15 (s, 3H) 2.95 (s, 3H) 3.08 (s, 3H) 3.38 (s, 3H) 6.22 (s, 1H) 7.33 (d, J=8.42 Hz, 2H) 7.37-7.48 (m, 3H) 7.79 (d, J=2.64 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:12]([NH:14][CH3:15])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][CH2:12][NH:14][CH3:15])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CNC(=O)CC(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccccc1)c1ccc2[nH]ncc2c1

Procedure:
[3-(1H-Indazol-5-yl)-3-phenyl-propyl]-methyl-amineCCVI was prepared as a hydrochloride salt from 3-(1H-indazol-5-yl)-N-methyl-3-phenyl-propionamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=266.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[N:7]([CH3:14])[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Na+].[I-].Cl[CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=1)=[O:28]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=2)=[O:28])[CH2:10][CH2:9]1)[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Cc1cc(NC(=O)NCCCl)cc(C)n1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc(C)n1
Temperature: 50 °C
Reaction time: 336 h

Procedure:
A suspension of methyl-piperidin-4-yl-carbamic acid tert-butyl ester (3.57 g, 16.7 mmol), NaHCO3 (6.7 g, 79 mmol), NaI (1.5 g, 10 mmol) and 1-(2-chloro-ethyl)-3-(2,6-dimethyl-pyridin-4-yl)-urea (Example D1, 2.14 g 9.4 mmol) in THF (30 mL) is stirred at 50° C. for 14 days. The mixture is quenched with Na2CO3 (50 mL) and extracted with CH2Cl2 (5×50 mL). The organic extracts are washed with sat. aq. Na2CO3 (30 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by FC to provide the title compound.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:25]3[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:24]=3[N:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClCCl>CN(C)C=O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[C:25]3[CH:33]=[CH:34][C:35]([C:37]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:38])=[CH:36][C:24]=3[N:23]=2)=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Yield: 57.5 %

Procedure:
Methanesulfonamide (0.0188 g, 0.198 mmol), sodium hydride, and the acid chloride of 49 (0.0083 g, 0.019 mmol) were reacted in dimethylformamide and dichloromethane according to the procedure described for example 8. The crude material was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a white solid (0.0055 g, 52%). 1H NMR (CDCl3) δ 8.68 (s, 1H), 8.17 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 7.69 (d, 2H, J=8.5 Hz), 7.48-7.37 (m, 5H), 7.24 (d, 2H, J=8.7 Hz), 5.18 (s, 2H), 4.57 (m, 1H), 3.34 (s, 3H), 2.34 (br m, 2H), 2.06 (br m, 4H), 1.85 (br m, 1H), 1.39 (br m, 3H); ESI-MS m/e 504.3 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:34]>C(#N)C>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18]([NH2:34])[N:19]=2)=[N:6]1
Reactant: N
Reactant: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
690 mg (1.768 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-(trifluoromethyl)-1,2,4-triazin-5-ol were admixed with 9 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was diluted with 50 ml of dry acetonitrile and, with ice-cooling, stirred into 123 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 48 h at RT and for 24 h at 50° C. After cooling, the acetonitrile was removed on a rotary evaporator, water was added, the precipitate was filtered off with suction and the filtercake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 125 mg (18% of theory) of the target compound.
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[NH:28]1[C:32]([CH2:33][C:34]([OH:36])=[O:35])=[N:31][N:30]=[N:29]1>C1COCC1.CCOC(C)=O>[C:2]([N:28]1[C:32]([CH2:33][C:34]([OH:36])=[O:35])=[N:31][N:30]=[N:29]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)Cc1nnn[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
In an argon atmosphere, TrCl (936 mg, 3 mmol) and Et3N (556 μL, 3 mmol) were added to a solution of 1H-tetrazole-5-acetic acid (128 mg, 1 mmol) in THF (10 mL) and stirred for 3 hours at room temperature. The reaction mixture was diluted with EtOAc, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated at a reduced pressure. The resulting residue was purified by neutral flash silica gel column chromatography (1.5×6, MeOH in CH2Cl2 0-0.5%) to give 2-(1-trityl-1H-tetrazol-5-yl)acetic acid (62 mg, 18%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:20])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[O:5]1.I[CH2:22][CH3:23]>C1COCC1>[CH2:22]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([B:6]3[O:5][C:4]([CH3:20])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)[CH3:23]
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Temperature: 0 °C

Procedure:
To a 0° C. suspension of NaH (43 mg, 1.81 mmol) in THF (4 mL) was added a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (400 mg, 1.65 mmol, Aldrich) in THF (4 mL). The reaction mixture was maintained at 0° C. for 15 min, iodoethane (0.200 mL, 2.47 mmol) was added and the reaction was heated at 50° C. for 30 min. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated. Chromatography over silica eluting with 1-8% EtOAc/hexanes afforded the title compound as a white solid. LC-MS: calculated for C16H22BNO2 271.16, observed m/e 273.2 (M+H)+ (Rt 2.09 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12](#N)[CH3:13].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].[Cl-].[NH4+]>CO>[C:10]([C:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH2:17][CH2:16][C:15]([O:19][CH2:12][CH3:13])=[O:18])[CH2:17][CH2:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])#[N:11]
Reactant: COc1ccc(CC#N)cn1
Reactant: CC#N
Reactant: C=CC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)CCC(C#N)(CCC(=O)OCC)c1ccc(OC)nc1
Temperature: 25 °C

Procedure:
2.775 g (18.73 mmol) of (6-methoxypyridin-3-yl)acetonitrile (WO2004/111031) are introduced into 125 ml of anhydrous acetonitrile in a 250 ml round-bottomed flask under an argon atmosphere. 0.87 ml (1.87 mmol) of Triton B (40% in methanol) is added, the reaction mixture is brought to reflux and 20.40 ml (187.30 mmol) of ethyl acrylate are added dropwise. The reaction medium is subsequently stirred at reflux for 48 hours, cooled to ambient temperature and concentrated under reduced pressure. The residue thus obtained is poured into a saturated aqueous ammonium chloride solution and extracted twice with dichloromethane. The organic phases are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 90/10/1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7][CH:8]2[CH2:11][C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl.C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)CC1CC(=O)c2ccc(F)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: NC(=O)/C=C1\CC(=O)c2ccc(F)cc21
Temperature: 120 °C
Yield: 109.7 %

Procedure:
A mixture of 2-(6-fluoro-3-oxo-1-indanyl)acetamide (0.750 g, 0.0036 mol), N-bromosuccinimide (0.750 g, 0.0042 mol, Aldrich), benzoyl peroxide (0.270 g, 0.0011 mol, Aldrich) in tetrachloromethane (37 ml) and benzene (37 ml) was stirred while heating with an oil bath at 120° C. for 20 min. This reaction was combined with a similarly run reaction (except 0.0024 mol scale). The solution was slurried with Silica Gel 60 and the volatiles were removed by spin evaporation in vacuo. This silica gel was then applied to a column of Silica Gel 60 (51×450 mm) wet with dichloromethane and the product was removed by elution with methanol:dichloromethane (3:97). After the volatiles were removed from the combined fractions containing product by spin evaporation in vacuo, the residue was recrystallized from methanol to give 0.81 g (58%) of (E)-2-(6-fluoro-3-oxo-1-indanylidene)acetamide: m.p., 235° C. (dec.):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([C:14]([OH:16])=O)[C:10]=1[CH3:17].C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].CCN(C(C)C)C(C)C>ClCCl.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([C:14]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:35][CH:34]=2)=[O:16])[C:10]=1[CH3:17]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)O)c[nH]c1-c1ccc(F)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a suspension of 5-(2-chloro-4-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylic acid (0.61 g, 2.4 mmol) in dichloromethane (30 ml) was added oxalyl chloride (0.41 ml, 4.8 mmol). The mixture was stirred at room temperature for 2.0 h, after which time the solvent was removed on a rotary evaporator. To this brown residue was added THF (40 ml), 4-(methanesulfonyl)aniline hydrochloride (495 mg, 2.38 mmol), and DIEA (1.6 ml, 9.5 mmol). The solution was stirred at room temperature for 20 h. The reaction mixture was concentrated on a rotary evaporator and 2N HCl (30 ml) was added to the residue. The solid was filtered and washed with 2N HCl, water and IPE to give the title compound (812 mg, 84%) as a brown solid.