Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(C)C=CC(S(O)(=O)=O)=C[CH:19]=1>C(O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Oc2ccccc2)cc1
Yield: 404.9 %

Procedure:
To a suspension of (4'-phenoxyphenyl)acetic acid (0.456 g) in 4 ml of ethanol is added para-toluensulfonic acid (0.076 g) and the resulting mixture is refluxed for 2 hours. The solvent is evaporated off, the residue is dissolved in diethyl ether and the organic phase is washed with saturated aqueous solution of sodium hydrogencarbonate and then with brine. The organic phase is dried over sodium sulfate and concentrated to dryness to give 0.458 g of the product as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[CH2:36][CH:35]([CH3:37])[NH:34][C:33]2=[O:38])=[CH:29][CH:28]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH:35]([CH3:37])[CH2:36][N:32]([CH2:31][C:30]5[CH:39]=[CH:40][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:33]4=[O:38])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1ccc(CN2CC(C)NC2=O)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(C)c3)C2=O)cc1
Yield: 42.7 %

Procedure:
Using (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (155 mg) described in Preparation Example 118 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 1, 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (90 mg) was obtained. Using the obtained 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 421, the title compound (53 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[CH:5][C:4]=1[CH2:19]O.S(Cl)([Cl:25])=O>>[Cl:25][CH2:19][C:4]1[C:3]([C:2]([F:22])([F:21])[F:1])=[CH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(CCl)cn2)cc1

Procedure:
In analogy to the procedure described in example 1 g], [4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol was reacted with thionyl chloride to give the title compound as off-white crystals.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC=C(F)C=1)=[O:10].Cl>O1CCCC1.O.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1cccc(F)c1)c1cc(Br)ccc1OCc1cccc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)ccc1OCc1cccc(F)c1
Temperature: 71 °C
Reaction time: 16 h

Procedure:
Solid LiOH (0.50 g, 20.95 mmol) was added in one charge to a stirred solution of (3-fluorophenyl)methyl 5-bromo-2-{[(3-fluorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 82; 1.65 g, 3.81 mmol) in tetrahydrofuran (15 ml) and water (5 ml) in air at 20° C. The reaction mixture was stirred at 71° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 ml). 10% Aqueous HCl was added to the mixture to adjust pH to 2. The organic phase was isolated, washed with brine, dried over Na2SO4, and concentrated to yield the title compound as a white solid. 1.5 g.
Reaction SMILES: [CH:1](S(C)(=O)=O)=[CH2:2].BrBr.N12CCCN=C1CCCCC2.[OH:20][C:21]1[C:22](=[O:32])[C:23]2[C:28]([C:29](=[O:31])[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2>ClCCl>[O:20]1[CH:2]=[CH:1][C:30]2[C:29](=[O:31])[C:28]3[C:23]([C:22](=[O:32])[C:21]1=2)=[CH:24][CH:25]=[CH:26][CH:27]=3
Reactant: C=CS(C)(=O)=O
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: BrBr
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)c2occc21
Yield: 24.6 %

Procedure:
To the solution of 5 grams (47.2 mmoles) of methyl vinyl sulfone in 100 mL of dichloromethane, 7.9 grams (49.5 mmoles) of bromine was added. The mixture was refluxed for 6 hours, and then evaporated to sticky residue. To the residue solution in 150 mL of tetrahydrofuran cooled in ice bath, 7.5 grams (49.5 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was dropped slowly over 20 minutes while stirring vigorously. The reaction mixture was further stirred for 30 minutes in ice bath, then 8.2 grams (47.2 mmoles) of 2-hydroxy-1,4-naphthoquinone and 7.5 grams (49.5 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) were added. The mixture was reflux for 6 hours, and then evaporated to sticky residue. The residue was dissolved in 300 mL of dichloromethane, and washed with 300 mL of water, 300 mL of 2% aqueous citric acid solution, successively, and dried with 30 grams of anhydrous sodium sulfate. The naphtho[2,3-b]furan-4,9-dione product was purified with silica gel column using dichloromethane/hexane (3:1) as elution solvent. 2.3 grams of product (overall yield 25%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 7.17 (d, J=2, 1H), 7.86-7.91 (m, 2H), 8.09-8.13 (m, 2H), 8.32 (d, J=2.1H). Mass (M+H) is 199.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH2:13][N:12](CC4C=CC(OC)=CC=4)[C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:44]1[S:45][C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=1)CCC>>[S:45]1[C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=[C:44]1[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:13][NH:12][C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3[nH]c(-c4ccnc(Cl)n4)cc3C2=O)cc1
Product: O=C1NCC2(CCNCC2)c2[nH]c(-c3ccnc(-c4nc5ccccc5s4)n3)cc21

Procedure:
The title compound was prepared following the general procedure reported for Example 9—1 using A5 and 2-(tributylstannyl)benzo[d]thiazole, purified by semi-preparative HPLC (Method A) and isolated as TFA-salt. 1H NMR (400 MHz, DMSO-D6, 300K): δ=1.92 (2H, d J=14.1 Hz), 2.30 (2H, dt, J1=3.9 Hz, J2=14.5 Hz), 3.12 (2H, t, J=12.5 Hz), 3.31 (1H, s), 3.53 (2H, d, J=2.3 Hz), 7.42 (1H, s), 7.45 (1H, s), 7.60 (2H, m), 8.01 (1H, d J=5.5 Hz), 8.21 (2H, t, J=8.6 Hz), 8.91 (1H, d, J=5.5 Hz), 11.93 (1H, s); MS (ES) C22H20N6OS requires: 416. found: 417.1 [M+H]+.
Reaction SMILES: CCO/C(/C)=[N:5]\[O:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8].Cl(O)(=O)(=O)=O>O1CCOCC1>[C:11]1([CH3:18])[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=1[S:7]([O:6][NH2:5])(=[O:9])=[O:8]
Reactant: CCO/C(C)=N\OS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1COCCO1
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 0 °C

Procedure:
An adaptation of the method described in WO 96/01826 was used. To a solution of ethyl O-mesitylsulfonylacetohydroxamate 7 (1.7 g, 6.0 mmol) in 1,4-dioxane (10 mL) cooled in an ice bath (freezes at 8-9° C.) was added 70% perchloric acid (7.5 mL) dropwise over 15 minutes, maintaining internal temperature below 15° C. The mixture was then diluted with ice water (100 mL) to precipitate the product O-(mesitylsulfonyl)hydroxylamine 8 which was filtered off, washed thoroughly with water, and immediately dissolved in chloroform (10 mL) while still wet (CAUTION! 8 is explosive when dry!). The organic layer was separated and was passed through a plug of Na2SO4 in a fritted syringe to remove water. The so obtained solution of O-(mesitylsulfonyl)hydroxylamine 8 was added dropwise to a solution of 2-amino-4,6-dimethylpyridine 9 (0.611 g, 5.00 mmol) in chloroform (10 mL) cooled in an ice bath. The mixture was then warmed to room temperature and was stirred for 2 hours to effect conversion to intermediate 10. Into the reaction mixture was then added 1,1′-thiocarbonyldiimidazole 11 (1.16 g, 6.5 mmol) and the resulting mixture was stirred at 40° C. overnight. Volatiles were evaporated and the residue was chromatographed on silica gel (gradient elution with heptane:ethyl acetate 100:0→0:100) to yield imidazole-1-carbothioic acid (2-imino-4,6-dimethyl-2H-pyridin-1-yl)-amide 12 as an off-white solid (0.50 g, 40%) containing a minor amount of residual imidazole. 1H NMR (500 MHz, DMSO-d6): δ7.88 (s, 1H), 7.64 (s, 1H), 7.42 (br s, 2H), 6.93 (s, 1H), 6.69 (s, 1H), 6.67 (s, 1H), 2.28 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl[C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:18][N:17]([CH3:19])[S:14]([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:3]1[CH2:2][NH:1][C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)(=[O:15])=[O:16]
Reactant: Clc1cnc2ccccc2n1
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CNc1cnc2ccccc2n1
Temperature: 180 °C

Procedure:
2-(Aminomethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (0.56 mmol), 2-chloroquinoxaline (138 mg, 0.84 mmol), and Hunig's base (195 μL, 1.12 mmol) were dissolved in anhydrous THF (4.5 mL) in a microwave vial. The vial was heated in the microwave (180° C., 40 min), then poured into saturated aqueous K2CO3 solution (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phases were washed with saturated aqueous NaCl (1×50 mL), dried (Na2SO4), filtered and concentrated to give N,N-dimethyl-4-phenyl-2-((quinoxalin-2-ylamino)methyl)-1H-imidazole-1-sulfonamide.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:54]=[N+:55]=[N-:56])(C)C>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:56]=[N:55][N:54]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Nc1ccc(C#N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
To a solution of 2-[(4-cyanophenyl)amino]-2-oxoethyl acetate (3.48 g, 15.95 mmol, Intermediate 7) in tetrahydrofuran (THF) (200 mL) was added triphenylphosphine (8.37 g, 31.9 mmol), di-isopropyl azodicarboxylate (6.20 mL, 31.9 mmol) and trimethylsilylazide (4.23 mL, 31.9 mmol). The reaction mixture was stirred at room temperature for 18 hours. The majority of the solvent was removed under vacuum and the residue purified by silica chromatography (Biotage SP4, eluting 30% EtOAc in iso-hexane (5 column volumes) then a gradient from 30-40% ethyl acetate in iso-hexane (over 7 column volumes)) to yield the title compound as a white solid (2.68 g).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:23]>>[OH:23][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCC(O)c1ccccc1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCC(O)c3ccccc3)s2)c(C)[nH]c1=O
Yield: 58 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-amino-1-phenylethanol as described in Step 5, Example 24 to give the title compound as a yellow solid (58% yield). LC/MS: RT 2.68 min; m/e 419 (M+H); 1H NMR (CDCl3, δ, ppm): 11.30 (1H, br), 7.58 (1H, d), 7.40 (5H, m), 6.90 (1H, d), 5.33 (1H, br), 4.90 (1H, m), 3.47 (1H, m), 3.22 (1H, m), 2.60 (2H, q), 2.44 (3H, s), 1.22 (3H, t).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]2[N:32](C(=O)C)[C:31]3[CH:36]=[CH:37][C:38](Br)=[CH:39][C:30]=3[N:29]=2)=[N:20]1)(=O)C>O1CCCC1.C(OCC)(=O)C>[C:7]1([C:37]2[CH:38]=[CH:39][C:30]3[N:29]=[C:28]([C:21]4[NH:20][N:19]=[C:27]5[C:22]=4[CH:23]=[CH:24][CH:25]=[CH:26]5)[NH:32][C:31]=3[CH:36]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)n1nc(-c2nc3cc(Br)ccc3n2C(C)=O)c2ccccc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(-c2ccc3nc(-c4[nH]nc5ccccc45)[nH]c3c2)cc1
Temperature: 25 °C
Yield: 122.9 %

Procedure:
40 mg of sodium carbonate, 7 mg of dihydrogendichlorobis(di-tert-butylphosphonite-κP)palladate(2-) (POPd[0]) and 46 mg of phenylboronic acid are added under an argon atmosphere to a solution of 50 mg of 1-[2-(1-acetyl-1H-indazol-3-yl)-5-bromobenzimidazol-1-yl]ethanone in 800 μl of anhydrous tetrahydrofuran. The reaction mixture is brought to reflux for 3 hours and then cooled to ambient temperature. The mixture is then diluted with 3 ml of ethyl acetate and then washed with 2 times 2 ml of water. The organic phase is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. 48 mg of a brown solid are obtained, which solid is dissolved in 500 μl of tetrahydrofuran, to which 500 μl of diethylamine are added. The reaction mixture is heated at 60° C. for 4 hours and then allowed to return to ambient temperature. The mixture is then concentrated to dryness and then the brown solid obtained is purified by LC-MS to produce 12.5 mg of 3-(6-phenyl-1H-benzimidazol-2-yl)-2H-indazole (6); analytical retention time 3.10, MS 311 [M+H]+.
Reaction SMILES: B.CSC.[C:5]([NH:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)(=O)[CH3:6].CO>C1COCC1>[CH2:5]([NH:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[CH3:6]
Reactant: CC(=O)Nc1cccc(O)c1
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1cccc(O)c1
Yield: 74 %

Procedure:
A 1.0 M solution of borane-methyl sulfide in dichloromehtane (275 ml) was added dropwise to a solution of 3-acetamidophenol (161 g) in THF (800 ml) over about 1 to 2 hours. The mixture was heated to reflux temperature for about 4 hours and was then poured slowly into methanol (1 liter). The solvent was evaporated to a heavy syrup, which deposited crystals on cooling and scratching. The solid was collected by filtration and redissolved in methanol. Evaporation and recrystallization as above gave a 74% yield of the compound.
Reaction SMILES: [C:1]1([Si:7](Cl)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]([F:18])([F:17])[S:13]([OH:16])(=[O:15])=[O:14]>>[O:16]([Si:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])[S:13]([C:12]([F:18])([F:17])[F:11])(=[O:15])=[O:14]
Reactant: C[Si](C)(Cl)c1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Product: C[Si](C)(OS(=O)(=O)C(F)(F)F)c1ccccc1
Reaction time: 6 h

Procedure:
Phenyldimethylsilyl triflate was prepared by cooling 5 ml of phenyldimethylsilyl chloride to a temperature between 0° and 5° C., and then adding 4.2 ml of trifluoromethanesulfonic acid in a dropwise fashion over a period of about 30 minutes. The resulting mixture was then stirred at a temperature of between 0° and 5° C. for about 6 hours, and subsequently left to stand, with cooling, overnight. The resulting preparation could be used without any further purification.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][NH:13][NH2:14].C([O-])(=O)C.[Na+]>CC#N>[Cl:11][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[N:13]([CH3:12])[N:14]=[CH:9][CH2:8][C:7]=12
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: CNN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1N=CCc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a stirred solution of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (600 mg) in dry MeCN (10 mL), methyl hydrazine (154 mg) and sodium acetate (514 mg) were added. The reaction mixture was stirred at room temperature for 3 hours and solvents were removed under reduced pressure. The resulting oil was diluted with ethyl acetate (50 mL), washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by column chromatography using EtOAc/CHCl3 (0.4:9.6) as eluent to afford 5-chloro-1-methyl-1,4-dihydropyridazino[3,4-d]pyrimidine (310 mg) as white solid. 1H NMR (DMSO-d6): δ 3.34 (s, 3H), 3.53-3.54 (d, 2H), 6.91-6.93 (t, 1H), 8.38 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([C:19]1[CH:20]=[CH:21][C:16]([O:22][CH3:23])=[CH:17][CH:18]=1)=[O:7])#[N:2]
Reactant: COc1ccccc1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 16.5 g. of 3-cyanobenzoyl chloride were added to 80 ml. of methylene chloride. The temperature was brought to approximately 0° C. by means of an external ice bath and kept cold while 20 g. of aluminum chloride were added in portions. A solution of 10.8 g. of anisole in 20 ml. of methylene chloride were added to the reaction solution. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into a mixture of ice water/hydrochloric acid and extracted with ethyl acetate. The layers were separated and the organic layer was washed with water, dried, and concentrated in vacuo. The residue was crystallized from toluene/hexane to which a small amount ethyl acetate had been added to provide 7.7 g. of the desired subtitle intermediate, m.p. 85°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[C:5]([N:7]([CH3:14])[C@@H:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=O)=[O:6].Cl.[CH3:20][O:21][CH2:22][CH:23]1[CH2:26][NH:25][CH2:24]1.[B-]C#N.[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[C:5]([N:7]([C@@H:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][N:25]1[CH2:26][CH:23]([CH2:22][O:21][CH3:20])[CH2:24]1)[CH3:14])=[O:6]
Reactant: CC(C)[C@@H](C=O)N(C)C(=O)c1ccc(F)c(F)c1
Reactant: COCC1CNC1
Agent: Cl
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Product: COCC1CN(C[C@H](C(C)C)N(C)C(=O)c2ccc(F)c(F)c2)C1
Yield: 20.7 %

Procedure:
(S)-3,4-Difluoro-N-methyl-N-(3-methyl-1-oxobutan-2-yl)benzamide (Compound A2.3) (0.25 g, 0.98 mmol) in MeOH (1.5 mL) was added to 3-(methoxymethyl)azetidine hydrochloride (0.202 g, 1.47 mmol) and TEA (0.679 mL, 4.90 mmol) in MeOH (1.5 mL). Sodium cyanotrihydroborate (0.103 mL, 1.96 mmol) was added and the resultant mixture was stirred at rt over night. The solvent was removed and the residue diluted with DCM. The organic phase was washed with LiOH (aq., 3 mL, 1M), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated and the residue was purified a second time by preparative HPLC using Chiralpak AD 5 μm 20×250 mm column and Heptan/EtOH/TEA 80/20/0.1, as mobile phase to give the title compound (69 mg, 21%). Enantiomeric excess: 99.9%. Mixture of rotamers: (400 MHz, CD3OD) δ 0.77-0.86, 0.93, 1.06, 1.70-1.90, 2.57-2.88, 2.94-3.09, 3.22-3.36, 3.40-3.57, 4.18-4.36, 7.23-7.52, 7.63-7.74. Total no of protons: 26. HRMS (M+H)+: calculated 341.2040. found 341.2051.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:28]=[C:27]([O:29][C@@H:30]3[CH2:34][O:33][C@@H:32]4[C@H:35]([OH:38])[CH2:36][O:37][C@H:31]34)[N:26](COCC[Si](C)(C)C)[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.OS([O-])(=O)=O.[K+].[OH-].[Na+].Cl>C(O)=O.O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:28]=[C:27]([O:29][C@@H:30]3[CH2:34][O:33][C@@H:32]4[C@H:35]([OH:38])[CH2:36][O:37][C@H:31]34)[NH:26][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)NC1CCN(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)CC1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=CO
Product: CCOC(=O)NC1CCN(c2ccc(-c3nc4[nH]c(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)nc4cc3Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 1-(4-(6-chloro-2-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yloxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)piperidin-4-ylcarbamate (44 mg) and KHSO4 (2 M aqueous solution, 40 μL) in formic acid (3 mL) is stirred for 3 hours at 60° C. After diluting with water and cooling to 0° C. NaOH (10 M aqueous solution) is added until the pH >11. Tetrahydrofurane (3 mL) is added and the mixture is stirred for 1 hour at room temperature. Hydrochloric acid (4 N) is added until pH=6. Then the mixture is partitioned between water and ethylacetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=0.81 min; Mass spectrum (ESI+): m/z=544 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[N:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:18][CH2:19][CH:20](OC)OC)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]2[N:25]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CCC(=NNC(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)OC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nn1cccc1[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The product from step 2 (20.25 g, 43.68 mmol) was dissolved in 125 mL of AcOH and stirred at 40° C. for 8 h and then concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and extracted with 50 mL of water, 2×100 mL 2M aq. Na2CO3, brine, dried over Na2SO2. The mixture was filtered through a 1″×4″ pad of SiO2 (pre-wetted with EtOAc) and the pad was washed with 300 mL of EtOAc and the filtrate concentrated in vacuo to give the title compounds as a light, brown syrup that was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (bs, 1H), 7.40-7.24 (m, 5H), 6.59 (d, 1H), 5.90 (dd, 1H), 5.78 (d, 1H), 5.15-4.92 (m, 2H), 4.13 (bd, 1H), 3.99 (bd, 1H), 2.91-2.60 (m, 3H), 1.91 (m, 1H), 1.74-1.62, (m, 1H), 1.42 (s, 12H). ES-MS m/z 400.0 [M+H]+, HPLC RT (min) 3.93