Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=[O:28])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH3:27]>>[CH2:24]([CH:23]1[C:22](=[O:28])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: CCC/C=C/C=O
Product: CCCCC1C(=O)Oc2[nH]c(-c3cc(F)ccc3F)nc2C1c1ccccc1
Yield: 90 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-hex-2-enal. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 17 as an off-white solid (103 mg, 90%). Analytical data for 17: 1H NMR (500 MHz, CDCl3) δ 9.54 (d, J=8.5 Hz, 1H), 7.88 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.35-7.27 (m, 2H), 7.12-7.03 (m, 3H), 7.01-6.93 (m, 1H), 4.29 (d, J=6.8 Hz, 1H), 3.18-3.08 (m, 1H), 1.86-1.73 (m, 1H), 1.46-1.36 (m, 2H), 1.36-1.15 (m, 4H), 0.86 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 126 MHz) δ 169.2, 159.1 (d, JCF=243.5 Hz), 155.4 (d, JCF=240.4 Hz), 149.2, 137.2, 136.3, 129.2, 128.1, 127.7, 118.5 (dd, JCF=12.8, 9.0 Hz), 117.1 (dd, JCF=25.6, 8.8 Hz), 116.5 (dd, JCF=24.7, 9.4 Hz), 114.5 (dd, JCF=27.1, 3.8 Hz), 110.6 (d, JCF=3.8 Hz), 46.0, 39.3, 29.3, 26.7, 22.4, 13.9; IR (film) cm−1 3084, 3030, 2957, 1773, 1619, 1528, 1482, 1464, 1238, 1174, 1138, 1118, 1094, 1068, 874, 812, 766, 699; LRMS (ESI): Mass calcd for [M+H]+ C22H21F2N2O2: 383.2. found 383.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 0-30 min: isocratic 12% IPA/hexanes; 30-45 min: 20% IPA/hexanes 1.0 mL/min, 280 nm), Rt1 (major)=16.8, Rt2 (minor)=37.6 min; er=>99:1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:17]S(C2C=CC(C)=CC=2)(=O)=O)=[C:9]([CH:16]=1)/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34]Br)=[CH:31][CH:30]=1>>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:10]1[C:9]2[C:8](=[CH:7][CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:16]=2)[NH:17][C:34]=1[C:33](=[O:36])[C:32]1[CH:37]=[CH:38][C:29]([Cl:28])=[CH:30][CH:31]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)/C=C/c1cc(C(C)(C)C)ccc1NS(=O)(=O)c1ccc(C)cc1
Product: COC(=O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2ccc(C(C)(C)C)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-tert-butyl-2-(p-toluenesulfonylamino)cinnamate (Example 143, step 2) and 4-chlorophenacyl bromide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[CH:7]=1)#[N:2].[NH2:27][OH:28].Cl.CCN(CC)CC>CCO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[C:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][N:6]4[CH:7]=[C:3]([C:1]([NH2:2])=[N:27][OH:28])[CH:4]=[N:5]4)[C:12]=3[CH:19]=[N:18]2)=[CH:25][CH:24]=1
Reactant: NO
Reactant: N#Cc1cnn(CC(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1cnn(CC(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)c1
Temperature: 90 °C
Yield: 60 %

Procedure:
A mixture of 2-(4-cyanopyrazol-1-yl)-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone (0.175 g, 0.50 mmol), NH2OH—HCl (0.500 g, 7.2 mmol) and NEt3 (1.00 mL, 7.1 mmol) in EtOH (3 mL) was heated at 90° C. for 5 hrs. It was then cooled to rt. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to obtain 1-[2-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-oxo-ethyl]-N′-hydroxy-pyrazole-4-carboxamidine (0.115 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[C:31]([C:33]1[CH:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1)#[N:32].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.O>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:39](=[O:40])[C:36]3[CH:35]=[CH:34][C:33]([C:31]#[N:32])=[CH:38][N:37]=3)[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
To a solution of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (2a, 0.125 g, 0.404 mmol) in DCM (3 mL) was added N,N-diisopropylethylamine (0.074 mL, 0.424 mmol, Aldrich), 5-cyanopicolinic acid (0.060 g, 0.404 mmol, Aldrich) and 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate; 0.238 mL, 0.404 mmol, Alfa Aesar). The reaction was stirred at ambient temperature for 15 minutes. The reaction was diluted with water and DCM. The organic layer was separated and washed sequentially with aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (gradient of 10-70% EtOAc in hexanes) to afford the title compound as a white solid. (0.0745 g, 0.170 mmol, 42.0% yield). MS m/z=440.0 [M+H]+. Calculated for C19H14F5N5O2: 439.34
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:45])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[CH:36][CH:35]=2)[C:15]1=[O:44])=[O:12])C(=O)OC(C)(C)C.[ClH:46]>O1CCOCC1.CCOCC>[ClH:46].[CH3:21][C@@H:20]1[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[CH:36][CH:35]=2)[C:15](=[O:44])[C@H:14]1[NH:13][C:11](=[O:12])[C@@H:10]([NH:2][CH3:1])[CH3:45]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2ccnc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2ccnc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Yield: 85.7 %

Procedure:
A rt solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-5-(quinolin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (56 mg, 87.8 μmol) in 4 M HCl in dioxane (439 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-5-(quinolin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (43.2 mg, 75.2 μmol, 85.7% yield) as a white solid. MS m/z 538 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:19])([CH:16]([CH3:18])[CH3:17])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1)#[CH:2].CO.[I:22]I.[OH-].[Na+]>O>[I:22][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:19])([CH:16]([CH3:17])[CH3:18])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1
Reactant: II
Reactant: C#Cc1ccc(C(O)(Cn2cncn2)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C(O)(Cn1cncn1)c1ccc(C#CI)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.1 g 2-(4-ethynylphenyl)-3-methyl-1-(1H-1,2,4-triazole-1-yl)butan-2-ol in 100 ml abs. CH3OH are simultaneously added, with stirring at 20°-25°, 2.6 g iodine and 10 ml 30% NaOH solution. The reaction mixture is maintained at room temperature for 24 hours, with stirring, then poured into 500 ml H2O and extracted with CH2Cl2. The organic phase is washed, dried and evaporated. The residue is stirred in hexane fraction and kept over 16 hours at rest. The precipitate is sucked off and dried to give the title compound m.p. 122° as colourless crystals.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[N:9][N:10]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[C:11]=2[CH:12]=1
Reactant: N#Cc1cc(Br)cc2[nH]ncc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ncc3c(C#N)cc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
Sodium hydride (0.108 g, 4.50 mmol) was added to a stirred solution of 6-bromo-1H-indazole-4-carbonitrile (0.5 g, 2.252 mmol) in N,N-dimethylformamide (10 ml) at room temperature. The mixture was stirred at room temperature for 10 mins when p-toluenesulphonyl chloride (0.558 g, 2.93 mmol) was then added. The pale yellow suspension was stirred for 20 mins at room temperature. The mixture was poured into stirring water (100 ml) and the precipitated product collected by filtration. The cream coloured solid was dried in vacuo at 65° C. to give the title compound (0.794 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@H:5]([NH2:17])[CH2:6][CH:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][OH:9])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:18])[C@H:5]([NH2:17])[CH2:6][CH:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][O:9][S:27]([CH3:26])(=[O:29])=[O:28])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H](N)CC(CO)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](N)CC(COS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(R)-4-BOC-amino-5-hydroxy-pentanoic acid ethyl ester (36 g, 137.8 mmol) prepared in Step A and triethylamine (38.4 mL, 275.5 mmol) were dissolved in dichloromethane (200 mL). Methanesulfonylchloride (11.7 mL, 151.5 mmol) was added in drops thereto, and the mixture was stirred for 1 h at 0° C. to room temperature. After completion of the reaction, 1N hydrochloric acid solution was added, which was then extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH2:11][C@H:12]([NH:16][C:17]([C:19]2[CH:38]=[CH:37][C:22]3[N:23]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:24]([C:26]4[CH:30]=[CH:29][O:28][CH:27]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])=[N+:2]=[N-:3].Br[CH2:40][C:41]([O:43]C)=[O:42].C([O-])([O-])=O.[Cs+].[Cs+].CO>CC(C)=O.C1COCC1>[N:1]([C:4]1[CH:5]=[C:6]([CH2:11][C@H:12]([NH:16][C:17]([C:19]2[CH:38]=[CH:37][C:22]3[N:23]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:24]([C:26]4[CH:30]=[CH:29][O:28][CH:27]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[O:10][CH2:40][C:41]([OH:43])=[O:42])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(C[C@H](NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: [N-]=[N+]=Nc1cc(C[C@H](NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)ccc1OCC(=O)O

Procedure:
(S)-3-(3-Azido-4-hydroxy-phenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionic acid (Example 146, 0.230 g, 0.44 mmol) and methyl bromoacetate (0.136 g, 0.89 mmol) were stirred in acetone (4 mL) in the presence of Cs2CO3 (0.058 g, 0.18 mmol) for 20 h at room temperature. The reaction mixture was concentrated to dryness and dissolved in water, acidify to pH 4 and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO4 and concentrated to give a brown oil. This oil was stirred in THF:MeOH (6 mL, 2:1 ratio) in the presence of LiOH monohydrate (0.18 mmol) for 3 h at room temperature. The reaction mixture was concentrated to remove most of the THF and MeOH, acidified with AcOH and purified by reversed phase C18 preparative HPLC to obtain the title compound of example 147.
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[C:5]([Cl:22])=[CH:6][C:7]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:8][CH:9]=1>O1CCOCC1.O.[Cu](I)I>[Cl:22][C:5]1[C:4]([I:1])=[CH:9][N:8]=[C:7]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=1
Reactant: O=C(c1cc(Cl)c(Br)cn1)N1CCc2cc(F)ccc21
Reactant: [I-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1cc(Cl)c(I)cn1)N1CCc2cc(F)ccc21
Temperature: 110 °C
Reaction time: 120 h

Procedure:
Under a nitrogen atmosphere 1.3 g (8.4 mmol) sodium iodide, 80 mg (0.42 mmol) copper iodide and 90 μL (0.84 mmol) N,N-dimethylene-ethylenediamine were added to 1.5 g (4.2 mmol) (5-bromo-4-chloro-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone in 15 mL 1,4-dioxane and the mixture was stirred for 5 days at 110° C. The reaction mixture was diluted with water, the precipitate formed was suction filtered and dried.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C[N:14](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([NH2:14])=[O:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C(N)=O)c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a solution of 2-methyl-2-phenylpropionic acid in 100 mL of CH2Cl2 was added 0.50 mL of DMF and oxalyl chloride (3.40 g, 26.8 mmol). The mixture was stirred at 23° C. for 4 hours then the solvent was removed under reduced pressure. The crude material was dissolved in 50 mL of THF and 30 mL of NH4OH was added. The mixture was stirred at 23° C. for 1 hour then and the mixture was concentrated under reduced pressure. The crude product was dissolved in 150 mL of EtOAc and washed with 100 mL of 2 N HCl, 100 mL NaHCO3, and 100 mL of brine. The organic phase was dried over Na2SO4 and concentrated. The product was purified by recrystallization from EtOAc/hexanes to provide 3.50 g (88% yield) of the desired product as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:11]([CH3:10])(=[O:13])=[O:12])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 3-amino-5-bromo-2-chloropyridine (stage 152.1.2, 3.59 mmol) in pyridine (7 ml) was added methanesulfonyl chloride (Fluka, Buchs, Switzerland, 0.365 ml). The RM was stirred for 22 h at rt then was added methanesulfonyl chloride (0.2 ml), the RM was stirred for 5 h at rt. Methanesulfonyl chloride (0.2 ml) was added and the RM was stirred for 17 h at rt. The RM was evaporated to dryness and then taken in EtOAc, washed with aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fractions containing product were evaporated together to give the title compound as a pink solid. (HPLC: tR 2.91 min (Method A); M+H=285, 287 MS-ES)
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH:2]=[CH2:3].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH3:30]>O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[O:12][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[O:8])[CH:2]=[CH2:3]
Reactant: CCCCBr
Reactant: C=CCc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1cc(C=O)cc(OC)c1OCCCC
Yield: 98.8 %

Procedure:
A mixture 3-allyl-4-hydroxy-5-methoxybenzaldehyde (10.25 g, 0.053 mole), of dimethylformamide (150 ml), of potassium carbonate (8.29 g, 0.06 mole) and of 1-bromobutane (8.22 g, 0.06 mole) was maintained at 40°-45° C. for 3 hours. The reaction mixture was dropped into iced water and the oil formed was extracted with dichloromethane. After washing with water, drying and evaporating off the solvent, a brown oil was obtained, which was passed through a bed of silica 60 to give a pale yellow oil of 3-allyl-4-butoxy-5-methoxybenzaldehyde (13 g, yield=91%).
Reaction SMILES: [C:1]([CH:3](O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)#[N:2].S(Cl)([Cl:24])=O.O>O1CCCC1>[Cl:24][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: N#CC(O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#CC(Cl)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 25 °C
Yield: 25.1 %

Procedure:
To a suspension of 2-[4-[cyano(hydroxy)methyl]phenyl]-5,6-dichlorobenzimidazole (275 mg, 0.865 mmol) in tetrahydrofuran (20 mL) was added thionyl chloride (0.38 mL, 5.2 mmol), and the mixture was heated to reflux for 3 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (14:1 chloroform/acetonitrile) to afford of 2-[4-[chloro(cyano)methyl]phenyl]-5,6-dichlorobenzimidazole (73 mg, 25%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[F:24][CH:25]([F:42])[C:26]1[N:34]=[CH:33][C:32]([CH2:35][NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])=[CH:31][C:27]=1[C:28](O)=[O:29].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:42][CH:25]([F:24])[C:26]1[N:34]=[CH:33][C:32]([CH2:35][NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])=[CH:31][C:27]=1[C:28]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][C:2]([F:1])=[C:3]([C:20]([F:23])([F:21])[F:22])[CH:4]=1)=[O:29]
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)ccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)Nc2cccc3c(Oc4ccc(F)c(C(F)(F)F)c4)ccnc23)c1
Yield: 7.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-44, 50 mg, 0.16 mmol), 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-66, 52 mg, 0.19 mmol), oxalyl chloride (37 mg, 0.29 mmol), DMF (1 drop) and DIPEA (74 mg, 0.57 mmol) in CH2Cl2 (2 mL) to afford 7 mg of the title product. 1H NMR (300 MHz, CDCl3): δ 10.39 (s, 1H), 8.93 (d, 1H), 8.75 (s, 1H), 8.60 (d, 1H), 8.07 (m, 2H), 7.66 (t, 1H), 7.47 (m, 1H), 7.37-7.15 (m, 2H), 6.60 (d, J=5.4 Hz, 1H), 4.63-4.60 (d, J=6.9 Hz, 2H), 2.45 (m, 1H), 1.21 (d, J=6.9 Hz, 6H); MS (m/z): 577.97 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17](O)=[O:18].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:18]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1F
Reactant: Nc1ccccc1
Solvent: O
Product: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1F
Reaction time: 0.5 h

Procedure:
Reaction of 500 mg (1.59 mmol) of the compound from Example V and 163 mg (1.75 mmol) of aniline as described for Example VI. The reaction time is about 30 min. For work-up, the reaction mixture is poured into 100 ml of water and extracted with dichloromethane (4×50 ml), and the combined organic phases are dried over sodium sulphate and concentrated. Yield: 610 mg (98% of theory). For characterization, a sample of the resulting product is recrystallized from ethanol, the main quantity is directly used further.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[Br:13]Br.O>C(Cl)Cl>[Br:13][CH:10]([CH3:11])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: O
Product: CC(Br)C(=O)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
In methylene chloride (300 ml) was dissolved 2',4'-difluoropropiophenone (55 g), to which was added bromine (50 g) dropwise, while stirring, during 30 minutes. The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added water (200 ml), and the methylene chloride layer was washed three times, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off to leave 2-bromo-2',4'-difluoropropiophenone (77 g) as a pale yellow oily product.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]1=[O:17].[CH:18](OCC)=[O:19]>C(COC)OC>[CH:18]([CH:11]([CH2:10][C:7]1[CH:8]=[CH:9][N:4]([CH3:3])[C:5](=[O:17])[CH:6]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:19]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccn(C)c(=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccn(C)c(=O)c1
Temperature: -5 °C
Reaction time: 72 h
Yield: 51.7 %

Procedure:
To a stirred suspension of 57% sodium hydride in oil (6.55 g) in dimethoxyethane (40 ml) at -5° C., was added dropwise over 40 minutes a mixture of ethyl β-(N-methyl-2-oxo-4-pyridyl)propionate (26.05 g) and ethyl formate (13.83 g) whilst maintaining the reaction temperature at -5° C. The temperature of the reaction mixture was slowly allowed to rise to ambient at which temperature it was stood for three days. The reaction mixture was poured on to ice, extracted with diethyl ether (3×100 ml) and the combined organic layers were washed with water (2×20 ml). The aqueous layer and washings were acidified to pH 4 with 2 N sulphuric acid whereupon a solid came out of solution. The mixture was kept at 0° C. for two hours, and the solid filtered off and dried in vacuo to afford ethyl α-formyl-β-(N-methyl-2-oxo-4-pyridyl)propionate (15.27 g) as a solid; recrystallisation from isopropanol afforded a solid, m.p. 164-5-165.5 ° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[CH:24]=[N:25][N:26](C3CCCCO3)[CH:27]=2)=[C:12]([F:34])[C:11]=1[F:35])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:35][C:11]1[C:12]([F:34])=[C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3cnn(C4CCCCO4)c3)c(F)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1ccc(O[C@H]2CCCC[C@@H]2c2cn[nH]c2)c(F)c1F
Yield: 34.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide (70 mg, 0.10 mmol) prepared in Example 83a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL) and methanol (1.0 mL), to yield the title compound (15 mg, 33%) as a colorless solid.