Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[NH2:6][C:7]1[C:12]([S:1]([OH:5])(=[O:4])=[O:3])=[CH:11][C:10]([S:1]([OH:3])(=[O:5])=[O:4])=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1
Product: Nc1ccc(S(=O)(=O)O)cc1S(=O)(=O)O
Temperature: 200 °C

Procedure:
225.5 g (2.3 mol) of 100% strength sulphuric acid were added to 257.0 g (2.76 mol) of aniline in 460 ml of ortho oil. The suspension obtained was heated at 200° C. for 2.5 hours in a 1.3 1 enamel autoclave. After cooling, the mixture was filtered off with suction and the filter residue was dried. The 475.6 g of solid contained 80.7% of p-sulphanilic acid in addition to unchanged anilinium hydrogensulphate, based on the excess sulphuric acid employed. Aniline-2,4-disulphonic acid was not formed.
Reaction SMILES: [OH-].[Li+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=[C:5]1[C:15]([O:17]C)=[O:16].CO.Cl>O.C1COCC1>[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=[C:5]1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1ccc(-c2ccccc2)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1c(C(=O)O)ccc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
Lithium hydroxide (1.39 g, 33.2 mmol) is added to a solution of the product from Step 34b (1.43 g, 6.64 mmol) in 96 mL of a 1.25:1:1 H2O:MeOH:THF solvent mixture. The reaction is stirred at 50° C. for 2 h. Aqueous HCl (1N, 50 mL) is added and the resultant precipitate is collected by filtration, washed with water, and dried to give 0.851 g of 1-methyl-5-phenyl-1H-pyrrole-2-carboxylic acid as a tan solid (64% yield). MS for C12H11NO2 (ESI) (M−H)+ m/z 200.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10]C(OCC)C.C([Li])CCC.[B:21](OC)(OC)[O:22]C.Cl>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[B:21]([OH:22])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: COB(OC)OC
Reactant: CCOC(C)OCc1cc(F)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB1OCc2cc(F)ccc21
Temperature: -78 °C
Yield: 70.9 %

Procedure:
Dissolve 1-bromo-2-(1-ethoxy-ethoxymethyl)-4-fluoro-benzene(5.4 g, 19.5 mmol) in dry THF (100 mL) and cool to −78° C. under nitrogen. Add butyl lithium (2.5M in Hexanes, 10.2 mL, 25.4 mmol) dropwise at −78° C. Upon complete addition, stir the reaction at −78° C. for 10 minutes and then add trimethyl borate (4.4 mL, 39 mmol) and warm the reaction to room temperature. Pour the reaction into 1N HCl (100 mL) and stir for 1 hour. Extract the biphasic mixture with ether three times. Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo. Triturate the oily residue with cold hexanes to yield 2.1 g (70%) of the title compound as a white solid. 1H NMR (d6-DMSO) 9.18 (s, 1H), 7.70 (dd, J=8.2, 5.8 Hz, 1H), 7.20 (dd, J=9.5, 2.7 Hz, 1H), 7.11 (m, 1H), 4.92 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br)#[N:29]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[O:17][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[C:28]#[N:29])[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1cccc(-c2nc(C3CCC3)n3ccnc(N)c23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (500 mg, 1.78 mmol) in DMF (8.9 mL) was charged with Cs2CO3 (871 mg, 2.68 mmol) and stirred for 30 min. at rt. A solution of 2-cyanobenzyl bromide (500 mg, 1.78 mmol) in DMF was added to the reaction mixture. After 24 h at rt the reaction mixture was concentrated in vacuo and chromatographed on silica gel [Jones Flashmaster, 10 g cartridge, eluting with 50% EtOAc:hexanes to 100% EtOAc]. The product was then recrystalized with CH2Cl2 and hexanes yielding the title compound as a light red solid; 1H NMR (CDCl3, 400 MHz) δ 2.02-2.06 (m, 1H), 2.11-2.33 (m, 1H), 2.45-2.53 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.86 (m, 1H), 5.33 (s, 2H), 7.02-7.04 (m, 1H), 7.05 (dd, J=2.4 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 7.29-7.30 (m, 1H), 7.33 (q, J=3.6, 11H), 7.40-7.64 (m, 2H), 7.61-7.66 (m, 1H), 7.70-7.72 (m, 2H); MS (ES+): m/z 395.99 (100) [MH+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH:25]([NH2:28])([CH3:27])[CH3:26]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:6]
Reactant: CC(C)N
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 2.5 °C
Yield: 82940.7 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (1.002 g, 5.41 mmol) was dissolved in dichloromethane and cooled in an ice bath. DMF (0.1 mL) and oxalyl chloride (0.71 mL, 8.4 mmol) were added, and the reaction mixture was stirred at ice bath temperature (0-5° C.) for two houres. Dichloromethane (25 mL) was added, followed by isopropylamine (1.85 mL, 21.7 mmol). The ice bath was removed and the reaction mixture was stirred for 2.5 hours. The reaction mixture was washed with 25 mL of 10% aqueous NaOH solution, and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (EtOAc/hexanes 0-33%) to give 1,015 g of 2-fluoro-N-isopropyl-4-nitro-benzamide.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:50]1[C:55](=[O:56])[N:54]([CH3:57])[CH:53]=[C:52]2[CH2:58][N:59]([CH2:62][CH2:63][C:64]3[N:65]=[C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][N:67]4[CH:72]=3)[C:60](=[O:61])[C:51]=12.[NH:73]1[CH2:78][CH2:77][O:76][CH2:75][CH2:74]1>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[N:65]1[C:64]([CH2:63][CH2:62][N:59]2[C:60](=[O:61])[C:51]3[C:52](=[CH:53][N:54]([CH3:57])[C:55](=[O:56])[C:50]=3[N:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)[CH2:58]2)=[CH:72][N:67]2[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=12
Reactant: C1COCCN1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1cn3ccccc3n1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1cn3ccccc3n1)C2
Temperature: 120 °C
Yield: 20.9 %

Procedure:
Palladium diacetate (65.5 mg, 0.292 mmol), Xantphos (169 mg, 0.292 mmol) and Cs2CO3 (285 mg, 0.875 mmol) were each rapidly added in sequence to a suspension of 7-chloro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-5-methyl-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (100 mg, 0.292 mmol, see Example c5)) and morpholine (76 mg, 0.875 mmol) in dioxane (1 ml). The reaction was heated in a microwave at about 120° C. for about 40 min. The solvent was removed and the resulting mixture was purified by preparative HPLC (system: Waters 2767 PHW003, eluent: MeCN/ammonium acetate buffer (gradient: 10:90 to 35:65 over 15 min), column: Boston Analytics, C-18, 10 μm, 21×250 mm) to afford the title compound (24.1 mg, 0.061 mmol, 21.00% yield).
Reaction SMILES: [CH3:1][O:2]C(Cl)Cl.[CH3:6][C:7]1[CH:8]=[C:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:10]=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:6][C:7]1[C:8]([CH:1]=[O:2])=[C:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:10]=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14]
Reactant: COC(=O)CCCc1cc(C)c(OC)c(C)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCCc1cc(C)c(OC)c(C)c1C=O

Procedure:
Dichloromethyl methyl ether (5.3 g equiv) was added slowly to a well stirred mixture of methyl 4-(3,5-dimethyl-4-methoxyphenyl)butyrate (9.75 g) and titanium tetrachloride (31 g equiv) in dichloromethane (200 ml) at 0°-5° C. The mixture was stirred for 1 hr at 5° C. and at room temperature for 2 hrs. The mixture was poured onto ice-water which was then extracted with dichloromethane. The dried (MgSO4) organic fraction was evaporated to give methyl 4-(3,5-dimethyl-2-formyl-4-methoxyphenyl)butyrate as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.69-2.98 (6H,m); 2.31 (3H,s); 2.52 (3H,s); 3.67 (3H,s); 3.69 (3H,s); 6.91 (1H,s); 10.50 (1H,s).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:20]([CH3:32])=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][CH:23]([C:28]([O:30]C)=[O:29])[CH2:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:20]([CH3:32])=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][CH:23]([C:28]([OH:30])=[O:29])[CH2:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: COC(=O)C1Cc2ccc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(C)c2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)ccc2c1CC(C(=O)O)C2
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
Lithium hydroxide (3.3 mg, 0.0795 mmol) was added to a solution of methyl 5-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl)-4-methylindane-2-carboxylate (17.0 mg, 0.0397 mmol, from Step G) in THF (1.0 mL) and H2O (300 μL) and heated to 50° C. After 30 min, the reaction mixture was concentrated in vacuo and partitioned between EtOAc (5 mL) and 5% citric acid (2 mL). The layers were separated and organic layer was washed with H2O (3×2 mL), brine (1×2 mL) and dried over MgSO4. The mixture was filtered and the filtrated concentrated in vacuo. Purification of the residue by flash chromatography (3% CH3OH/CH2Cl2/1% HCO2H) on SiO2 afforded 15.2 mg of the title compound as a white solid: 1H NMR (500 MHz, CD3OD) δ 1.41 (d, 6H, J=6.2 Hz), 2.51 (s, 3H), 3.19-3.41 (m, 5H), 5.49 (septet, 1H, J=6.2 Hz), 7.17 (d, 1H, J=8.0 Hz), 7.78 (d, 1H, J=7.8 Hz), 8.39 (s, 1H), 8.83 (s, 1H); HPLC A: rt=4.11 min, m/z=414.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:12]=1.S(Cl)([Cl:32])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15]([Cl:32])=[O:16])[N:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CNc2nc(CCC(=O)O)nc3sc4c(c23)CCCC4)cc1Cl
Solvent: ClCCl
Product: COc1ccc(CNc2nc(CCC(=O)Cl)nc3sc4c(c23)CCCC4)cc1Cl

Procedure:
1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro [1]benzothieno-[2,3-d]pyrimidine-2-yl]propionic acid and 1.2 equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. The solvent is removed and 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-2-yl]propionyl chloride is obtained. This is transferred to aqueous ammonia, the mixture is stirred for one hour and, after customary working up, 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-2-yl]propionamide is obtained.
Reaction SMILES: [ClH:1].[C:2](=[NH:7])(OCC)[CH3:3].[OH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>C(O)C>[ClH:1].[NH:7]=[C:2]([N:12]1[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]1)[CH3:3]
Reactant: OC1CCNCC1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: CC(=N)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.46 g of ethyl acetoimidate hydrochloride was added to a solution of 4-hydroxy-piperidine (1.0 g) in 10 ml of absolute ethanol. The resulting mixture was stirred at room temperature for 6 hours and then allowed to stand for 7 days. After concentration to dryness the obtained oil spontaneously solidified. After crystallization from acetone 0.7 g of the desired product were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([C:10]#[N:11])[CH:9]=1)=[O:4].[Li+].[OH-].Cl.C(C1C=C(C(O)=O)SC=1S(C)(=O)=[O:27])#N>C1COCC1>[C:10]([C:8]1[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[S:6][C:7]=1[S:12]([CH3:15])(=[O:14])=[O:13])(=[O:27])[NH2:11]
Reactant: CS(=O)(=O)c1sc(C(=O)O)cc1C#N
Reactant: COC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1sc(C(=O)O)cc1C(N)=O

Procedure:
To 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid methyl ester (0.5 g) in THF/H20 (3:1; 16 ml) was added LiOH (0.102 g). Hydrochloric acid (2M) was added and the resulting mixture was extracted with ethyl acetate. The extracts were combined and the solvent evaporated to leave a mixture of 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid and the title compound. This mixture was used without further purification. 1H NMR (299.944 MHz, DMSO-D6) δ 3.62 (3H, s), 7.99 (1H, s).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)C.[OH-].[Na+]>O>[N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)C(C)c1ccc(-c2cn3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(-c2cn3ccccc3n2)cc1
Yield: 55.3 %

Procedure:
A mixture of 8 g of ethyl 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]-propionate, 50 ml of ethanol, 1.4 g of sodium hydroxide and 10 ml of water is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and the residue is dissolved in water. The solution is adjusted to pH 6 by addition of dilute hydrochloric acid. The crystalline precipitate is filtered off, washed with water, and recrystallized from methanol to give 4 g of 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionic acid as colorless crystals melting at 244°-246°C with decomposition. The corresponding hydrochloride melts at 210°-211°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[N:34]=[C:33]([CH3:35])[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[C:33]([CH3:35])=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=5)[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)c(C)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (70 mg, 0.18 mmol), 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (69 mg, 0.27 mmol) and tetrakis(triphenylphosphine)-palladium (0) (21 mg, 0.018 mmol) in 1,2-dimethoxyethane (2.0 mL), 2 M Na2CO3 (276 μL, 0.55 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 20 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3,4-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (45 mg, 52%). ESI-MS m/z calc. 467.5. found 468.3 (M+1)+. Retention time 1.80 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(I)cc1
Product: O=C(O)Cc1ccccc1Nc1ccc(I)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-iodoaniline to yield 2-[(4-iodophenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][N:26]([CH3:28])[CH3:27])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][N:26]([CH3:28])[CH3:27])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8]
Reactant: CN(C)Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 4-chloro-N-{[4-chloro-3-({3-cyano-5-[(dimethylamino)methyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (82 mg, 0.138 mmol) in DCM (6.0 ml) was added TFA (2.00 mL) and the reaction mixture was stirred ar RT for one hour. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-{[4-chloro-3-({3-cyano-5-[(dimethylamino)methyl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide trifluoroacetate (29 mg, 0.050 mmol, 36% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.72 (s, 1H), 7.62 (s, 1H), 7.27-7.49 (m, 4H), 4.63 (s, 2H), 4.35 (s, 2H), 2.85 (s, 6H). LC-MS (ES+) m/z 462.08, [M+H].
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C>[CH3:1][C@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([Cl:16])=[O:4]
Reactant: C[C@H](CC1CCCCC1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: C[C@H](CC1CCCCC1)C(=O)Cl
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of α(R)-methylcyclohexane-propionic acid (2.4 g, 14 mmol) in dry CH2Cl12 (30 mL) was added DMF (1 drop) and oxalyl chloride (2 g, 15 mmol). After 2 h at room temperature, the mixture was concentrated. The residue was dissolved in Et2O (10 mL). This solution was filtered. The filtrate was concentrated to provide α(R)-methylcyclohexanepropionic acid chloride as a clear yellow liquid (2.6 g, 98% yield). 1H NMR (400 MHz, CDCl3) 3.02-2.91 (m, 1H), 1.80-1.63 (m, 6H), 1.39-1.10 (m, 5H), 1.28 (d, J=7 Hz, 3H), 0.99-0.85 (m, 2H). This material was used without further purification in the coupling reaction described in the following example.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=2[C:7]1=O)=[O:5])[CH3:2].FC(F)(F)C(O)=O.B(F)(F)F.CCOCC.CS(O)(=O)=O.C([SiH](CC)CC)C>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCC1(C(=O)OCC)CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O
Agent: CC[SiH](CC)CC
Agent: CS(=O)(=O)O
Agent: FB(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCOCC
Product: CCOC(=O)CCCC1(C(=O)OCC)CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1
Temperature: 5 °C
Yield: 52.6 %

Procedure:
Compound 29 (4.76 g, 9.48 mmol) was dissolved in 45 mL of dry 1,2-dichloroethane, cooled to 5° C., and treated with trifluoroacetic acid (1.3 mL), BF3.Et2O (1.4 mL), anhydrous methanesulfonic acid (3.2 mL) and triethylsilane (5.7 mL). The reaction was allowed to slowly warm to room temperature over 18 hours. The reaction was cooled to 5° C. and cautiously quenched with saturated aqueous NaHCO3 (100 mL). The reaction mixture was extracted with ethyl acetate (100 mL) and the ethyl acetate extract was extracted with saturated aqueous NaHCO3, water, brine (2×), dried over Na2SO4, and concentrated in vacuo to give an oil. This oil was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (17:3) to give 2.43 g (53%) of compound 30 as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[C:19]2[N:10]([C:11](=[O:21])[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=32)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C([OH:27])C>O>[OH:27][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:20]=[C:19]2[N:10]([C:11](=[O:21])[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=32)[N:9]=1
Reactant: CCO
Reactant: O=c1[nH]c2ccccc2c2cc(Cc3ccccc3)nn12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c2ccccc2c2cc(C(O)c3ccccc3)nn12
Reaction time: 0.5 h

Procedure:
1.65 g (0.0057 mole) of 2-benzylpyrazolo[1,5-c]quinazolin-5(6H)-one prepared as in part B above is stirred with 880 mg (4 equiv) of sodium borohydride in absolute ethanol (125 ml) at room temperature for 3 hours. The reaction mixture is stripped to dryness and the resulting solid is suspended in water (40 ml), cooled down to 0° and treated dropwise with 1 N HCl 25 ml). The mixture is stirred for 30 minutes, diluted with water (40 ml) and stirred for another 10 minutes. The white precipitates are filtered off, washed well with water and dried overnight in a vacuum over at 70° C. to give 1.6 g of product.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]([OH:34])[CH3:33])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]([OH:34])[CH3:33])[N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)CCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Reaction time: 1.5 h
Yield: 30 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-hydroxybutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in dichloromethane (2 mL) was added drop-wise trifluoroacetic acid (1 mL) at room temperature. Then the reaction mixture was stirred for 1.5 hours. The solvent was removed under reduced pressure and the residue was purified by preparative-TLC (silica gel, petroleum ether:EtOAc=1:1) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-hydroxybutyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (22 mg, 30% over three steps) as a white solid. MS: (M+H)+=473.2; 1H NMR (300 MHz, DMSO): δ 12.86 (s, 1H), 9.11 (s, 1H), 8.42 (s, 1H), 8.24 (d, 1H, J=1.8 Hz), 7.92-7.89 (m, 2H), 7.47-7.42 (m, 1H), 7.23 (t, 1H, J=74.4 Hz), 4.75-4.61 (m, 3H), 3.65 (brs, 1H), 2.06-1.92 (m, 2H), 1.53 (s, 9H), 1.15 (d, 3H, J=6.3 Hz).