Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:6]=1.[CH3:17][O:18][CH:19]([O:30][CH3:31])[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22](F)[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C.O>[Cl:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([NH:1][C:22]3[CH:21]=[C:20]([CH:19]([O:30][CH3:31])[O:18][CH3:17])[CH:25]=[CH:24][C:23]=3[N+:26]([O-:28])=[O:27])[S:3][C:4]=2[C:14]([NH2:16])=[O:15])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)c1
Yield: 47.5 %

Procedure:
A mixture of 3.6 g (15 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 3.9 g (17.9 mmole) of 4-(dimethoxymethyl)-2-fluoro-1-nitro-benzene (IV.2a), 7.3 g (22.5 mmole) cesium carbonate, and 30 mL of dimethylformamide was heated at 70 degrees for 18 hours. The mixture was cooled, diluted with 150 mL of ethyl acetate and 100 mL of water. The ethyl acetate layer was washed once with 100 mL of brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (50:50) to give 3.2 g of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2a).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(OC([NH:22][CH:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24](O)=[O:25])=O)(C)(C)C>>[NH2:22][CH:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24]([NH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[O:25]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: NC(=O)c1ccc(N)c2cccnc12
Product: NC(=O)c1ccc(NC(=O)C(N)c2ccccc2)c2cccnc12

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 27 by using 5-aminoquinoline-8-carboxamide coupled with 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid, followed by removal of the protecting group to afford Example 29. LC-MS (M+H=321, obsd=321).
Reaction SMILES: [Na].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>CO.C(OCC)C>[O:8]([CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc(OCc2ccncc2)cc1
Temperature: 100 °C
Yield: 88.5 %

Procedure:
To a solution of 3.5 g (0.15 mole) of sodium in 100 ml of methanol are added 14.1 g (0.15 mole) of phenol. The reaction mixture is evaporated, mixed with 50 ml of N,N-dimethyl formamide and 8.2 g (0.05 mole) of 4-chloromethylpyridine hydrochloride and the reaction mixture heated for 20 hours at 100° C. After cooling, the reaction mixture is mixed with diethyl ether, washed with a dilute aqueous solution of sodium hydroxide and with water, dried over anhydrous sodium sulfate, evaporated and the residue distilled in a vacuum. There are obtained 8.2 g of 4-phenoxymethylpyridine (88% of theory); b.p. 115°-117° C./0.1 mm Hg.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14](=[O:20])OC(C)(C)C)[CH3:2].C(O)(C(F)(F)F)=O.[Br:28][C:29]1[CH:30]=[C:31](C(O)=O)[C:32]2[CH:33]=[CH:34][N:35]([CH:38]([CH3:40])[CH3:39])[C:36]=2[CH:37]=1.CN1CCOCC1.C(Cl)CCl>ClCCl>[Br:28][C:29]1[CH:30]=[C:31]([C:14]([NH:13][CH2:12][C:5]2[C:6](=[O:11])[NH:7][C:8]([CH3:10])=[CH:9][C:4]=2[NH:3][CH2:1][CH3:2])=[O:20])[C:32]2[CH:33]=[CH:34][N:35]([CH:38]([CH3:40])[CH3:39])[C:36]=2[CH:37]=1
Reactant: CCNc1cc(C)[nH]c(=O)c1CNC(=O)OC(C)(C)C
Reactant: CC(C)n1ccc2c(C(=O)O)cc(Br)cc21
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCNc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
In a 50 mL round bottom was added 1,1-dimethylethyl {[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}carbamate (500 mg, 1.777 mmol) and Dichloromethane (DCM) (20.00 mL). TFA (1.095 mL, 14.22 mmol) was added and the reaction stirred at rt for 3.5 h. The LCMS indicated deprotection. The reaction was evaporated and evaporated from DCM. Dimethyl Sulfoxide (DMSO) (20 mL) was added to the round bottom followed by 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylic acid (501 mg, 1.777 mmol), to the solution was added N-methylmorpholine (1.172 mL, 10.66 mmol) 1-hydroxy-7-azabenzotriazole (363 mg, 2.67 mmol) and EDC (511 mg, 2.67 mmol). The reaction stirred at rt for 12 hr. The reaction was poured onto Ice water (10 mL) and was stirred for 20 min let it rest for 10 min and filter. Rinse solid with water (10 mL). Purification of solid by reverse phase Gilson HPLC (10-90% acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column 7 minutes) provided the desired product as a white solid after neutralization with 0.1N NaOH and evaporation and precipitation from water. 6-bromo-N-{[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-1H-indole-4-carboxamide (240 mg, 0.523 mmol, 29.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (s, 1H) 8.87 (m, 1H) 7.93 (s, 1H) 7.57-7.71 (m, 2H) 6.89 (d, J=3.28 Hz, 1H) 6.71 (m, 1H) 5.66 (s, 1H) 4.82 (m, 1H) 4.34 (d, J=5.81 Hz, 2H) 3.12-3.23 (m, 2H) 2.08 (s, 3H) 1.43 (d, J=6.57 Hz, 6H) 1.18 (t, 3H) MS (ES) [M+H]+ 445.1.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Br:15])[C:13]=1[CH3:14].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Br:15][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([CH:16]2[CH2:18][CH2:17]2)[C:13]=1[CH3:14]
Reactant: Cc1c(Br)cncc1Br
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(Br)cncc1C1CC1
Temperature: 100 °C

Procedure:
Cesium carbonate (2.59 g, 0.00797 mol) was added to a stirred solution of 3,5-dibromo-4-methylpyridine (1.0 g, 0.0039 mol) and cyclopropylboronic acid (0.34 g, 0.0039 mol) in the mixture of 1,4-dioxan (35 mL) and water (15 mL). The reaction mixture was purged with argon for 20 min. Next, Pd(dppf)2Cl2 (0.14 g, 0.000199 mol) was added. The reaction mixture was heated at 100° C. and for 6 h. It was cooled to room temperature, filtered through a bed of CELITE and the bed was thoroughly washed with ethyl acetate. The filtrate was concentrated under vacuum. The residue was dissolved with dichloromethane, washed with water and saturated sodium chloride solution, dried over sodium sulphate, concentrated under vacuum and purified by silica gel (60-120) column chromatography with 0-2.5% ethyl acetate in hexane to afford the title compound. 1H NMR (400 MHz, CdCl3) δ 8.51 (s, 1 H), 8.17 (s, 1 H), 2.52 (s, 3 H), 1.87-1.82 (m, 1 H), 1.03-0.99 (m, 2 H), 0.71-0.68 (m, 2 H). MS (M+1): 211.8.
Reaction SMILES: N[C:2]1C(Cl)=C(C(OCC)=O)C(C)=NC=1NCC.[NH2:18][C:19]1[C:20]([Cl:36])=[C:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:22]([CH3:30])=[N:23][C:24]=1[NH:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:26]([N:25]1[C:24]2=[N:23][C:22]([CH3:30])=[C:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:20]([Cl:36])=[C:19]2[N:18]=[CH:2]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCNc1nc(C)c(C(=O)OCC)c(Cl)c1N
Reactant: CCNc1nc(C)c(C(=O)OCC)c(Cl)c1N
Product: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Yield: 83 %

Procedure:
By replacing 5-amino-6-ethylamino-4-chloro-2-methylpyridine-3-carboxylic acid, ethyl ester in Example 1 d with 5-amino-6-butylamino-4-chloro-2-methylpyridine-3-carboxylic acid, ethyl ester, 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]-pyridine-6-carboxylic acid, ethyl ester is obtained. Yield 83%, b.p. 190°-200°/0.01.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[C:25]3[CH:21]([CH2:22][N:23]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)=[O:27])[N:24]=3)[CH2:20][CH2:19][C:18]=2[CH:39]=1.Cl[C:41]([O:43][CH3:44])=[O:42]>CCCCCC.C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[C:25]3[C:21]([C:41]([O:43][CH3:44])=[O:42])([CH2:22][N:23]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][CH:30]=4)=[O:27])[N:24]=3)[CH2:20][CH2:19][C:18]=2[CH:39]=1
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC2CCc3cc(Cl)ccc3C2=N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C12CCc3cc(Cl)ccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 50 ml of THF and 6.7 ml of diisopropylamine was cooled under N2 to -78° C. and then 17.5 ml of 2.5 M n-butyllithium in hexane was added. After 5 min. a solution of 7.8 g of the title compound of Example 4 in 15 ml of THF was added dropwise and the dark red solution that formed was stirred at -78° C. for an additional 15 min. After this time a solution of 4.6 ml of methyl chloroformate in 10 ml of THF was added dropwise and the red color dissipated rapidly. The reaction was warmed to room temperature and after 1 hr quenched with 5% aqueous sodium bicarbonate. The reaction mixture was partitioned between ether and 5% aqueous sodium bicarbonate. The ether extracts were dried over magnesium sulfate and concentrated to 14.1 g of a yellow oily solid. The crude product was triturated with ether and the resulting white precipitate was filtered and dried to afford 5.56 g of the title compound as a white solid, m.p. 234° C. to 236° C. 1H NMR(CDCl3) δ 2.1 (m, 1H), 2.75 (m, 1H) 2.95 (m, 2H), 3.71 (s, 3H), 3.75 (d, 1H, J=6Hz), 4.59 (d, 1H, J=6Hz), 7.25 (m, 2H), 7.57 (d, 2H), 7.66 (d, 2H), 7.94 (d, 1H), 8.18 (d, 1H),
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]([C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl:14]C1C([N+]([O-])=O)=CC=C(Cl)C=1C.[Br-].[K+]>>[Cl:14][C:2]1[C:3]([CH3:13])=[C:4]([C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1C#N
Agent: [Br-]
Agent: [K+]
Product: Cc1c(Cl)ccc([N+](=O)[O-])c1C#N

Procedure:
The title compound was prepared using the method described above for preparing 3-bromo-2-methyl-6-nitrobenzonitrile, except that the reaction was carried out at 210° C. and employed 2,6-dichloro-3-nitrotoluene as the starting material. The infrared spectrum of a potassium bromide pellet of the product exhibited principal absorption peaks at 3121, 2231, 1602, 1560, 1530, and 1348 receiprocal centimeters.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9](Br)[N:8]=1)[CH3:2].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1nc(Br)ccc1N
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1nc(-c2ccc(C(F)(F)F)cc2)ccc1N
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 64.5 %

Procedure:
3.0 g (E)-3-(3-Amino-6-bromo-pyridin-2-yl)-acrylic acid ethyl ester, 3.05 g 4-(Trifluoromethyl)phenylboronic acid and 3.61 g cesium carbonate were dissolved in a mixture of 21 ml dimethylformamide and 7 ml water. An argon stream was bubbled through the reaction mixture for thirty minutes then 333 mg Tetrakis(tripehnylphosphine)palladium(0) were added and the reaction mixture stirred at 110° C. for 1.5 hours. The reaction mixture was diluted by addition of 50 ml water and extracted three times with portions of 80 ml dichloromethane. The combined organic layers were dried over MgSO4 then the solvent was removed in vacuo. The residue was purified by chromatography on silica gel to obtain 2.4 g (E)-3-[3-Amino-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]acrylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[C:37]1([NH2:40])[CH2:39][CH2:38]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:32]6[N:33]=[CH:34][CH:35]=[CH:36][N:31]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: NC1(c2ncccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.1 g, 0.25 mmol, 1 eq), 1-(pyrimidin-2-yl)cyclopropanamine (0.041 g, 0.3 mmol, 1.2 eq) (60% purity), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0.086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.16 g, 1.3 mmol). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally purified by preparative HPLC. Yield: 0.15 g (14%). 1H NMR (400 MHz, DMSO-d6): δ 1.33-1.36 (m, 2H), 1.59-1.61 (m, 2H), 2.31 (s, 3H), 2.82-2.83 (d, 3H, J=4.8 Hz), 7.26-7.29 (t, 1H, J=4.8 Hz), 7.39-7.45 (m, 4H), 7.59 (s, 1H), 7.76-7.78 (d, 1H, J=8.4 Hz), 7.86-7.87 (d, 2H, J=4.4 Hz), 7.98-8.02 (m, 2H), 8.47-8.50 (m, 1H), 8.67-8.68 (d, 2H, J=4.8 Hz), 9.20 (s, 1H). LCMS: (ES+) m/z=521.2 (M+H). Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][CH2:12][C@@H:13]([C:15]([O:17][C@@H:18]1[C@@H:23]2[C@@H:24]([CH2:29][CH2:30][C@H:31]3[O:37][C:35](=[O:36])[CH2:34][C@H:33]([OH:38])[CH2:32]3)[C@@H:25]([CH3:28])[CH:26]=[CH:27][C:22]2=[CH:21][C@H:20]([CH3:39])[CH2:19]1)=[O:16])[CH3:14].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH3:14][CH:13]([CH2:12][CH3:11])[C:15]([O:17][CH:18]1[CH:23]2[C:22]([CH:27]=[CH:26][CH:25]([CH3:28])[CH:24]2[CH2:29][CH2:30][CH:31]2[CH2:32][CH:33]([OH:38])[CH2:34][CH:35]([OH:36])[O:37]2)=[CH:21][CH:20]([CH3:39])[CH2:19]1)=[O:16]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)CC(O)O3)C21
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Diisobutylaluminum hydride (1.0 M solution in dichloromethane, 99.0 ml, 99 mmol) was added dropwise to a stirred and cooled (−35° C.) solution of lovastatin (20.0 g, 49.4 mmol) in tetahydrofuran (200 ml) in a period of 1 hours. Stirring was continued for 1 hour at −35° C. Celite (20 g) and sodium sulphate decahydrate (30 g) were added. The mixture was stirred for 20 min. Cooling bath was removed and stirring was continued for 1 hour. The mixture was filtered through a pad of Celite (8.0×1.5 cm) and the solid was washed with ethyl acetate. Evaporation of the combined filtrate gave crude hemiacetals II (19.0 g, yield 99%) as a white foam (HPLC purity>96%). This was used without further purification in the next step.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:28][C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:31]=3[N:30]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8](S(C1C=CC(C)=CC=1)(=O)=O)[CH:7]=[C:6]2[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[CH3:2].[OH-].[K+]>CCO.C(Cl)Cl>[CH2:1]([C:3]1[C:4]([CH2:28][C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:31]=3[N:30]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c(-c3ccn[nH]3)cn2S(=O)(=O)c2ccc(C)cc2)c1Cc1nc2cc(C#N)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCc1cc(C)c2[nH]cc(-c3ccn[nH]3)c2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-((5-ethyl-7-methyl-3-(1H-pyrazol-5-yl)-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (63 mg, 0.118 mmol) and KOH (33.1 mg, 0.589 mmol) in EtOH (5 mL) was stirred at 100° C. for 0.5 h under microwave irradiation. The reaction mixture was diluted with CH2Cl2 and filtered through silica gel. The silica gel cake was washed with CH2Cl2/MeOH (c.a. 9/1). After concentration the resulting residue was purified by RP-HPLC (HC-A) to give the title compound. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 10.13 (br. s., 1H), 8.53 (s, 1H), 8.23 (d, J=8.60 Hz, 1H), 8.18 (br. d, J=8.60 Hz, 1H), 8.05 (s, 1H), 7.96 (d, J=2.78 Hz, 1H), 7.54 (s, 1H), 6.72 (br. s., 1H), 5.32 (br. s., 2H), 3.38 (q, J=7.60 Hz, 2H), 3.06 (s, 3H), 1.69 (t, J=7.58 Hz, 3H). HRMS calcd. for C23H20N6 (M+H)+ 381.1828. found 381.1828.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([C@@H:8]1[CH2:13][C@@H:12]2[C@@H:10]([CH2:11]2)[N:9]1[C:14]([OH:16])=O)=[O:7])[CH:3]=[CH2:4].[C:17]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH2:29]C(O)=O)[N:21]=1)(=[O:19])[CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:2]([O:5][C:6]([C@@H:8]1[CH2:13][C@@H:12]2[C@@H:10]([CH2:11]2)[N:9]1[C:14](=[O:16])[CH2:29][N:22]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]([C:17](=[O:19])[CH3:18])=[N:21]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)O
Reactant: CC(=O)c1nn(CC(=O)O)c2ncccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(C)=O)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-allyl ester hydrochloride (1.03 g, 6.43 mmol), (3-acetyl-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid (prepared as described in Part A, 1.3 g, 5.93 mmol) and HBTU (2.70 g, 7.12 mmol) in DMF (19.7 mL) was added DIPEA (3.11 mL, 17.8 mmol). The reaction mixture was stirred for 16 h at RT. DMF was evaporated. The residue was poured into NH4Cl (sat. aq. solution) and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 0:10) to give the title compound. Rf, TLC (EtOAc)=0.6; MS (LCMS): 369.0 [M+H]+, 391.0 [MH+Na]+; tR (HPLC conditions d): 2.78 min.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:5]=[CH:4][N:3]=1.[CH3:17][NH:18][NH2:19].C([O-])(=O)C.[Na+]>CC#N>[CH3:17][N:18]1[C:2]2[N:3]=[CH:4][N:5]=[C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:7]=2[CH2:8][CH:9]=[N:19]1
Reactant: CNN
Reactant: O=CCc1c(Cl)ncnc1-c1ccccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1N=CCc2c(-c3ccccn3)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.5 %

Procedure:
To a stirred solution of 2-(4-chloro-6-(pyridin-2-yl)pyrimidin-5-yl)acetaldehyde (600 mg) in dry MeCN (10 mL), methyl hydrazine (181 mg) and sodium acetate (422 mg) were added. The reaction mixture was stirred at room temperature for 3 hours and solvents were removed under reduced pressure. The resulting crude was purified by column chromatography using MeOH/CHCl3 (0.5:9.5) as eluent to afford 1-methyl-5-(pyridin-2-yl)-1,4-dihydropyrimido[4,5-c]pyridazine (350 mg) as white solid. 1H NMR (DMSO-d6): δ 3.41 (s, 3H), 3.93-3.94 (d, 2H), 6.92-6.94 (t, 1H), 7.47-7.51 (m, 1H), 7.94-7.99 (m, 1H), 8.00-8.10 (m, 1H), 8.67-8.69 (d, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:12][O-:13].[Na+]>CO>[F:11][C:4]1[C:3]([CH2:2][O:13][CH3:12])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: C[O-]
Reactant: N#Cc1cccc(CBr)c1F
Agent: [Na+]
Solvent: CO
Product: COCc1cccc(C#N)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
3-(Bromomethyl)-2-fluorobenzonitrile (Intermediate 84, 1.39 g, 6.49 mmol) was dissolved in MeOH (10 mL) and sodium methoxide (1.238 mL, 6.49 mmol) was added. The mixture was stirred at r.t. for 2 h. This mixture was concentrated and then partitioned between water and EtOAc. The organic layer was separated and then concentrated in vacuo. The resulting residue was purified by flash chromatography using EtOAc/heptanes as eluent to give the title compound (0.900 g, 84% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 3.32 (s, 3H) 4.52 (br. s, 2H) 7.42 (t, 1H) 7.77-7.84 (m, 1H) 7.86-7.92 (m, 1H); MS (EI) m/z 166 M+.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].[CH3:5][S:6][CH3:7].[F:8][B-:9]([F:12])([F:11])[F:10].[H+]>>[F:8][B-:9]([F:12])([F:11])[F:10].[CH2:1]([S+:6]([CH3:7])[CH3:5])[CH:2]=[CH2:3]
Reactant: CSC
Reactant: C=CCO
Agent: F[B-](F)(F)F
Agent: [H+]
Product: C=CC[S+](C)C
Reaction time: 144 h

Procedure:
Into a 3-neck 5-liter flask were weighed 1161.6 g (20 moles) of allyl alcohol, 950 g (15.3 moles) of dimethyl sulfide, and 1829 g (10 moles) of 48% aqueous tetrafluoroboric acid. The flask was attached to a large (1.5 liter) capacity Dean-Stark trap (initially filled with dimethyl sulfide) which was attached to a condenser. Reflux was started and an aqueous phase began to accumulate at the bottom of the Dean-Stark trap, displacing dimethyl sulfide back into the reaction mixture. Reflux was continued for six days. At the end of this period, the rate of accumulation of aqueous phase had become very small. The aqueous phase was drained into a tared bottle and weighed; the net weight of the aqueous phase was 1136.7 g. Excess dimethyl sulfide and allyl alcohol were allowed to distill at atmospheric pressure into the Dean-Stark trap until the temperature in the flask had reached 100° C. At this point, the flask was connected to a dry ice trap and vacuum was applied. The mixture in the flask was evaporated at 70° C. under magnetic stirring for one hour, with the pressure decreasing to a final value of 200 Pa. The yield of nonvolatile product was 1952 g. The nonvolatile product was a viscous liquid containing a small amount of crystals. It showed no signs of further crystallization on standing at room temperature.