Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])#[C:28][CH2:29][CH2:30][CH3:31].C(NCC)C>[Cu]I.CN(C)C=O>[F:18][C:16]1[CH:15]=[CH:14][C:12]2[NH:13][C:9]([CH:8]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:4]3[CH:3]=[C:2]([C:31]#[C:30][CH2:29][CH2:28][CH2:27][N:32]4[C:33](=[O:42])[C:34]5[C:35](=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:36]4=[O:37])[CH:7]=[CH:6][CH:5]=3)=[N:10][C:11]=2[CH:17]=1
Reactant: CCCC#CN1C(=O)c2ccccc2C1=O
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3cc(F)ccc3[nH]2)CC1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CN1CCC(OC(c2cccc(C#CCCCN3C(=O)c4ccccc4C3=O)c2)c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A screw-capped tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole (example 437D, 418 mg), PEPPSi-sono catalyst (19 mg), copper (I) iodide (38 mg), N-pentynylphthalimide (428 mg), diethylamine (880 μL) and N,N-dimethylformamide (1.5 mL). The tube is evacuated, filled with argon and sealed. The reaction mixture is stirred at 80° C. overnight. As the reaction is not completed, PEPPSi-sono catalyst (10 mg) and N-pentynylphthalimide (214 mg) are added, and the reaction mixture is heated at 80° C. for 24 h. The mixture is diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol from 98/2/to 90/10) to give 2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione. 1H NMR: 9.65 (sl, 1H), 7.84-7.65 (m, 4H), 7.54 (s, 1H), 7.48-6.95 (m, 4H), 5.84 (s, 1H), 3.90 (t, 2H, J=6.9 Hz), 3.65-3.50 (m, 1H), 2.85-2.70 (m, 2H), 2.52 (t, 2H, J=7.0 Hz), 2.32 (s, 3H), 2.28-1.50 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[C:14]([Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=1)[Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13][C:14]=2[Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:35][CH2:34]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N(c1ccc(CBr)c([Si](C)(C)C)c1)[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)cc2[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of crude tert-butyl(4-bromomethyl-3-trimethylsilylphenyl)trimethylsilylcarbamate (2.57 g, 5.98 mmol) in THF (10 mL) was added Et3N (1.3 mL, 8.97 mmol) and 1-methylpiperazine (1.1 mL, 8.92 mmol). After stirring for 1 h at rt, aq. NaHCO3 was added, and the mixture was extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM) to provide product as a pale yellow oil (1.60 g, 71%).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13]=[O:14]>>[OH:14][CH2:13][C:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]([OH:11])=[CH:7][CH:8]=1
Reactant: C=O
Reactant: Oc1cccc2ncccc12
Agent: Cl
Product: OCc1ccc(O)c2cccnc12
Reaction time: 8 h

Procedure:
3.40 g of quinolin-5-ol is combined with 8 ml of conc. hydrochloric acid and 8 ml of 37% formalin solution while cooling with an ice bath. Then hydrogen chloride gas is piped through the reaction mixture for about two hours, while the temperature slowly rises. The reaction mixture is stirred first overnight while cooling with an ice bath, then at ambient temperature and then evaporated down in vacuo. The flask residue is taken up in water, covered with a layer of diethyl ether and adjusted to pH 10 while cooling with an ice bath and vigorously stirring with dilute ammonia solution. After another two hours' vigorous stirring at ambient temperature the organic phase is separated off and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with methylene chloride/methanol (20:1) as eluant.
Reaction SMILES: C(OC(=O)[N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[S:22][C:23]([C:27](=[O:37])[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=3)=[C:24]([NH2:26])[N:25]=2)=[CH:16][CH:15]=1)[CH2:8][CH3:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:26][C:24]1[N:25]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][NH:7][CH2:8][CH3:9])=[CH:15][CH:16]=2)[S:22][C:23]=1[C:27]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=1)=[O:37]
Reactant: CCN(CCCOc1ccc(Nc2nc(N)c(C(=O)c3ccc(OC)c(F)c3)s2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNCCCOc1ccc(Nc2nc(N)c(C(=O)c3ccc(OC)c(F)c3)s2)cc1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of (3-[4-[4-Amino-5-(3-fluoro-4-methoxybenzoyl)-thiazol-2-ylamino]-phenoxy]-propyl)-ethyl-carbamic acid tert-butyl ester (220.5 mg) (from Step A above) in dichloromethane (6 mL) at 0° C. was added trifluoroacetic acid (3 mL). After stirring for 1 hour, the mixture was concentrated and the residue was purified on HPLC to [4-Amino-2-[4-(3-ethylamino-propoxy)-phenylamino]-thiazol-5-yl]-(3-fluoro-4-methoxyphenyl)-methanone (159.8 mg, 89% yield) as a light yellow solid. HRMS, observed: 445.1707; Calcd for M+H: 445.1704.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][SH:6].CS(O[C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([C:33](=[O:35])[CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[C:25](=[CH:26][C:27](=[O:36])[CH:28]=[CH:29]1)[CH2:24][CH2:23]3)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][S:6][C@@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([C:33](=[O:35])[CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[C:25](=[CH:26][C:27](=[O:36])[CH:28]=[CH:29]1)[CH2:24][CH2:23]3
Reactant: SCc1ccc(Cl)c(Cl)c1
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCc1ccc(Cl)c(Cl)c1

Procedure:
In a manner similar to that described in Example 1A, 3,4-dichlorobenzylmercaptan is reacted with 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione to obtain the title compound of this example; m.p.=131°-133° C.; [α]D26 +150° (CHCl3); λmaxMeOH 228 nm (ε=26,000).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)=[O:33])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: COc1cccc(N=C=O)c1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(NC(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 40 °C
Yield: 6.1 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 3-methoxyphenylisocyanate (0.45 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The residue was triturated in Et2O (50 mL) for 3 h at rt, then refluxed in acetone (50 mL) for 1 h. The product was isolated by filtration and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(3-methoxy-phenyl)-urea as a white solid (0.08 g, 6% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 8.01 min (99.44%); mp: 323-325° C.; 1H NMR (DMSO-d6) δ 2.03-2.09 (m, 1H, CHH), 2.49-2.63 (m, 2H, CHH, CHH), 2.85-2.91 (m, 1H, CHH), 3.70 (s, 3H, CH3), 4.47 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 13.5 Hz, 1H, CH), 6.47-6.50 (m, 1H, Ar or NH), 6.82-6.91 (m, 2H, Ar or NH), 7.09-7.15 (m, 2H, Ar or NH), 7.78-7.91 (m, 3H, Ar or NH), 8.74 (s, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.98, 30.90, 42.57, 48.96, 54.81, 103.52, 106.72, 110.14, 121.63, 123.47, 129.36, 129.65, 131.57, 133.17, 141.49, 143.07, 148.75, 155.16, 159.60, 167.02, 167.18, 169.80, 172.72; LCMS: MH=437; Anal Calcd for C22H20N4O6: C, 58.38; H, 4.85; N, 12.38. Found: C, 58.36; H, 4.45; N, 11.98.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH2:18][P:19]([OH:22])([OH:21])=[O:20])=[CH:5][C@@H:6]([NH2:17])[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[H][H]>O.[Pd]>[OH:1][CH2:2][CH2:3][C:4]([CH2:18][P:19]([OH:22])([OH:21])=[O:20])=[CH:5][C@@H:6]([NH2:17])[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: N[C@H](C=C(CCO)CP(=O)(O)O)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: N[C@H](C=C(CCO)CP(=O)(O)O)C(=O)O
Yield: 61.7 %

Procedure:
2.5 g (7.59 mmol) of benzyl 6-hydroxy-2(R)-amino-4-phosphonomethyl-hex-3-enoate are dissolved in 35 ml of water and, after addition of 0.25 g of 10% palladium on charcoal, subjected to hydrogenolysis under normal pressure. When no more hydrogen is taken up, the catalyst is filtered off over diatomeic earth, and the filtrate is hydrophilized. 1.12 g (61% yield) of 6-hydroxy-2(R)-amino-4-phosphonomethyl-hex-3-enoic acid are thus obtained. ee=91%; αD -59° (c=1.0 H2O).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 9 (11.5 g, 31.8 mmol) and sodium azide (4.12 g, 64 mmol) in 250 ml of DMF was heated to 70° C. for 24 hours. After cooling to room temperature the solvent was removed in vacuo and the residue partitioned between chloroform and water. The organics were dried over MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by chromatography on silica gel (8:1 hexane: ethyl acetate) afforded the title compound.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[CH:10](=[N:17][NH:18][CH2:19][CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH:10](=[N:17][N:18]([CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])[CH2:19][CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC=C(C#N)C#N
Reactant: CCNN=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCN(C=C(C#N)C#N)N=Cc1ccccc1
Reaction time: 16 h

Procedure:
To a solution of 2-(ethoxymethylene)malononitrile (15.2 g, 0.124 mole) in 100 ml toluene was added Intermediate 1-benzylidene-2-ethylhydrazine (18.4 g, 0.124 mole). The mixture was allowed to stand at room temperature, and a precipitate formed. The reaction mixture was stirred for an additional 16 h. The precipitate was collected on a filter and washed with a small amount of cold ethanol to obtain 2-((2-benzylidene-1-ethylhydrazinyl)methylene)malononitrile as a solid.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[Cl:9][CH2:10][CH2:11]O>>[OH:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3]([O:5][CH2:11][CH2:10][Cl:9])=[O:4]
Reactant: CCC(C)(O)C(=O)O
Reactant: OCCCl
Product: CCC(C)(O)C(=O)OCCCl

Procedure:
2-Chloroethyl 2-hydroxy-2-methylbutyrate was prepared from 2-hydroxy-2-methylbutyric acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1: b.p. 108° C./20 mm Hg; 1H NMR δ 0.90 (t, 3H, J=7.4 Hz), δ 1.44 (s, 3H), δ ca. 1.70 (m, 1H), δ ca. 1.83 (m, 1H), δ 3.10 (s, 1H), δ 3.72 (t, 2H, J=5.6 Hz), δ 4.43 (dd, 2H, J=5.6 Hz and 1.5 Hz); HRMS calcd for C6H9ClO3Tms (M--CH3) 237.0714, obsd 237.0750.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.CC(C)([O-])C.[K+].Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:5]=1
Reactant: Clc1ncccn1
Reactant: COC(OC)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1cccc(Oc2ncccn2)c1
Temperature: 60 °C

Procedure:
A solution of 168 mg of 3-hydroxybenzaldehyde dimethyl acetal in 2 ml of anhydrous dimethylformamide was stirred under nitrogen and 220 mg of potassium tert.butoxide were added. The mixture was heated at 60° C. for 1 hour, then cooled to room temperature and 114 mg of 2-chloropyrimidine were added in portions. The mixture was heated at 150° C. for 20 hours. After cooling 20 ml of water were added and the product was extracted with ethyl acetate. The extracts were washed with 10 ml of 1M sodium hydroxide solution and 5 ml of brine and then dried over anhydrous magnesium sulphate. After filtration and evaporation of the filtrate the residual brown gum was purified by column chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution to give 3-(2-pyrimidinyloxy)-benzaldehyde dimethyl acetal as a syrup.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:30][CH2:31][O-:32].[Na+]>C(O)C>[CH2:31]([O:32][CH2:2][CH2:1][S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:30]
Reactant: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 80 °C
Yield: 58.8 %

Procedure:
The mixture of 3-[1-(ethenylsulfonyl)-4-piperidinyl]-5-phenyl-1H-indole-7-carboxamide (23 mg, 0.056 mmol), NaOEt (10 mg) in ethanol (1 mL) was refluxed at 80° C. overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (15.0 mg, 59%).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([NH:14][C:15]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].IC>CN(C=O)C>[CH3:1][O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:15]=1[NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13]
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc(F)c1NC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
To a suspension of caesium carbonate (1.3 g, 4.0 mmol) in DMF (5.0 ml) was added 2-tert-butoxycarbonylamino-3-fluorobenzoic acid from Example 19A (890 mg, 3.5 mmol) and iodomethane (230 μl, 3.8 mmol). The mixture was stirred for 18 h and evaporated in vacuo. The residue was partitioned between EtOAc and brine and the organic layer was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc;pet. ether 25:75) to give a white solid; yield 680 mg, 72%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.[CH3:20][S@@:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[NH:23])=[O:22].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:23]=[S@:21]([CH3:20])(=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: C[S@@](=N)(=O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[S@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
To a solution of 5-bromonicotinic acid (303 mg, 1.5 mmol), N,N-diisopropylethylamine (0.523 mL, 3.0 mmol), and (R)-(−)-S-methyl-S-phenylsulfoximine (233 mg, 1.5 mmol) in DMF (3.0 mL) cooled to 0° C. was added 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) (859 mg, 1.65 mmol). The solution was stirred 10 minutes, the ice bath removed, and the reaction continued at room temperature for 2.5 hours. The mixture was taken up in EtOAc and washed with H2O, Na2CO3 solution, brine, AcOH solution, H2O, Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown oil was chromatographed eluting with hexane/EtOAc to give the title compound as a yellow solid (478 mg, 94%).
Reaction SMILES: Cl.Cl[C:3]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[N:14]=[N:15][N:16]=[C:9]1[N:8]=[C:7]2[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1.[NH3:37].CC(O)C>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:3]([C:31]4[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=4)([C:24]4[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[NH2:37])[CH:5]=3)[N:10]3[N:14]=[N:15][N:16]=[C:9]3[N:8]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: N
Reactant: Cc1ccc(C(Cl)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1ccc(C(N)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of intermediate 26 (0.0083 mol) in THF (80 ml) was cooled to 5° C. under N2 flow. NH3/iPrOH (80 ml ) was added dropwise. The mixture was stirred at 5° C. for 1 hours, then brought to room temperature. The mixture was stirred at room temperature overnight, poured out into ice water and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH 96/4/0.2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 1.37 g (33%) of 5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4—methylphenyl)-tetrazolo[1,5-a]quinazoline-7-methanamine .hydrate (1:1) (intermediate 27), mp. 150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][OH:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[I:8].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(c2ccc(I)c(F)c2)=NO1
Product: CS(=O)(=O)OCC1CC(c2ccc(I)c(F)c2)=NO1

Procedure:
(5RS)-3-(3-Fluoro-4-iodophenyl)-5-hydroxymethyl-4,5-dihydroisoxazole (2 g, 6.2 mM) was treated with methanesulfonyl chloride under essentially the conditions of the equivalent intermediate of Example 4. Product was obtained as a white solid (2.18 g) without chromatography. MS (EI): 399 (M+) for C11H11FINO4S
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:22].C(N(CC)CC)C.[CH:30]([C:32]([CH3:34])=[O:33])=[CH2:31]>CC(C)=O>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:31][CH2:30][C:32](=[O:33])[CH3:34])[CH2:20][CH2:21]2)=[O:13])=[CH:4][C:3]=1[Cl:22]
Reactant: Nc1c(Cl)cc(C(=O)OCC2CCNCC2)c2c1OCCO2
Reactant: C=CC(C)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Yield: 37.1 %

Procedure:
4-Piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate (0.100 g; 10.31 mmol) was dissolved in acetone (10 ml) and treated with triethylamine (0.043 ml; 0.31 mmol) and methyl vinyl ketone (0.026 ml; 0.34 mmol). The solution was heated at reflux (18 hours), cooled and evaporated in vacuo to a yellow gum. The gum was purified by flash silica-gel chromatography with CHCl3 as eluant to yield the title compound as a colourless gum (0.050 g; 41%) which was converted to the oxalate salt.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Cl:19])[C:3]=1[NH2:20].[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33])#[N:22].N1C=CC=CC=1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:20][C:3]2[C:4]([Cl:19])=[CH:5][C:6]([C:9]([F:18])([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])=[C:7]([F:8])[C:2]=2[Cl:1])=[O:28])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33])#[N:22]
Reactant: N#Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)c(F)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)c(F)c2Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To a solution of 2,6-dichloro-3-fluoro-4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)-phenylamine (Example 3.2) (3.48 g, 10 mmol) and 4-cyano-3-nitrobenzoic acid (made as in WO 2008/074427) (3.84 g, 20 mmol) in dichloromethane (40 ml) was added pyridine (4.17 ml, 30 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (5.09 g, 20 mmol). The reaction mixture was heated to reflux for 6 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of aqueous hydrochloric acid (1N) (50 ml). The mixture was then extracted three times with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent:cyclohexane/ethyl acetate 7:3) to give 4-cyano-N-[2,6-dichloro-3-fluoro-4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)phenyl]-3-nitrobenzamide (4.76 g, 91% yield). LC-MS (Method 2): RT=2.08, [M−H]−=520.