Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20]([SnH:24]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].C(Cl)(Cl)(Cl)Cl>O1CCCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])/[C:16](=[CH:15]/[C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=1)/[C:17]([NH2:19])=[O:18])[CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(N)=O)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/c1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(N)=O
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid amide (1.13 g, 4.12 mmol) prepared in Reference Synthetic Example 8 was dissolved in tetrahydrofuran (23 ml) in nitrogen atmosphere, and tetrakistriphenylphosphine palladium(0) (95.2 mg, 0.082 mmol) was added under cooling with ice, and then a tetrahydrofuran solution (17 ml) of tri-n-butyltin hydride (5.2 ml, 19.3 mmol) was dropwise added. After stirring for 30 minutes, carbon tetrachloride was added to terminate the reaction, and potassium fluoride was added, followed by stirring for 30 minutes. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give (E)-2-(tributylstannyl)-3-(4-tert-butyldimethylsilyloxyphenyl)acrylamide (1.51 g, 65%) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[S:12]([NH2:15])(=[O:14])=[O:13].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:18][N:19]([CH3:21])[CH:20]=[N:15][S:12]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:9]([O-:11])=[O:10])(=[O:14])=[O:13]
Reactant: COC(OC)N(C)C
Reactant: COc1cccc([N+](=O)[O-])c1S(N)(=O)=O
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1S(=O)(=O)N=CN(C)C

Procedure:
A solution of 2-methoxy-6-nitro-benzenesulfonamide (904 mg, 3.89 mmol) and N,N-dimethyl-formamide dimethyl-acetal (0.78 mL, 5.83 mmol) in DMF (20 mL) is heated for 30 min to 60° C. Evaporation of volatiles at 50° C. under reduced pressure, addition of MeOH to the solid residue, and filtration gives N-[1-dimethylamino-methylidene]-2-nitro-6-methoxy-benzenesulfonamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]3[CH2:18][CH2:17][O:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[C:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:21]([CH:20]([CH2:17][CH2:18][CH:15]([OH:16])[C@H:12]1[CH2:11][CH2:10][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1)[C:19]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:22][CH3:23]
Reactant: CCc1ccc([C@H]2CC[C@H](C3CCO3)CC2)cc1
Reactant: CCCCC(=O)OC(C)(C)C
Product: CCCC(CCC(O)[C@H]1CC[C@H](c2ccc(CC)cc2)CC1)C(=O)OC(C)(C)C

Procedure:
Reaction operations were carried out according to the first step of Example 1 by using 2-(trans-4-(4-ethylphenyl)cyclohexyl)oxetane (42) (7.5 g, 30.9 mmol) and tert-butyl pentanoate (43) (15.6 g, 98.9 mmol) as starting materials to obtain tert-butyl 2-propyl-5-hydroxy-5-(trans-4-(4-ethylphenyl)cyclohexyl)pentanoate (44) (11.6 g, 28.8 mmol). The yield based on the compound (42) was 93%.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.C(C1NC=CN=1)([C:17]1[NH:18][CH:19]=CN=1)=O.CNC>O1CCCC1>[CH3:17][N:18]([CH3:19])[C:12](=[O:14])[CH2:11][CH2:10][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[NH:1][CH:2]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)CCc1c[nH]c2c1CCCC2
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCc1c[nH]c2c1CCCC2
Reaction time: 2 h
Yield: 70 %

Procedure:
3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (9.7 g) in 100 mL of tetrahydrofuran was stirred with 8.1 g of carbonyl diimidazole for 1 hour. Dimethylamine (2.5 g) was added and the mixture stirred for 2 hours. The solvent was evaporated and the residue taken up in ethyl acetate, washed with water, 0.1 N hydrochloric acid, water, and brine, dried over sodium sulfate and evaporated to give 7.7 g (70% yield) of 3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid dimethyl amide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.O>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(O)c1
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cccc(O)c1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 3-hydroxyphenylacetic acid (3.04 g, 20.0 mmol) in tetrahydrofuran (30 ml) was added at 0° C. borane-tetrahydrofuran complex (1M, 30.0 ml, 30.0 mmol) under an atmosphere of nitrogen. The mixture was stirred for 1 hour, followed by addition of water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the subject compound (2.76 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CC[N:14]([CH:18]([CH3:20])[CH3:19])C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:9][C:4]2[CH:3]=[CH:2][CH:19]=[C:18]([NH2:14])[CH:20]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cccc(Nc2ccc(Br)cc2[N+](=O)[O-])c1
Temperature: 120 °C
Yield: 126.3 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitro-benzene (1.14 ml, 9.25 mmol), benzene-1,3-diamiine (1.96 g, 18.1 mmol) and DIPEA (1.93 ml, 11.1 mmol) in dry NMP (5 ml) was deoxygenated by evacuate/fill N2 (×3), then stirred and heated at 120° C. under N2 for 18 hours. After cooling to RT the mixture was partitioned between EtOAc and 0.5N HCl. The organic layer was washed with H2O (×1), brine (×1) then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (10→40% EtOAc/petrol) to give the title compound (1.8 g) as a red solid. 1H NMR (400 MHz, DMSO-d6): 9.28 (1H, s), 8.20 (1H, d), 7.63 (1H, dd), 7.14 (1H, d), 7.07 (1H, t), 6.49 (1H, s), 6.48-6.39 (2H, m), 5.24 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[F:13].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1.[N:44](OCCC(C)C)=O>ClCCCl>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([C:9](=[O:11])[CH3:10])[N:44]=[CH:12]2
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1ccc(Br)c(F)c1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2c(F)c(Br)ccc21
Temperature: 65 °C

Procedure:
N-(4-Bromo-3-fluoro-2-methylphenyl)acetamide (36 mmol) was suspended in 1,2 dichloroethane (150 mL) and acetic anhydride (108 mmol), potassium acetate (74 mmol), 18-Crown-6 (1.4 mmol) and isopentyl nitrite (79 mmol) were added sequentially. The mixture was heated at 65° C. for 24 h, cooled to rt and washed with sat. NaHCO3. The organic layer was dried (Na2SO4) and concentrated and the residue was purified by flash chromatography (0-20% EtOAc/hexanes). 1-(5-Bromo-4-fluoroindazol-1-yl)ethanone was obtained as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4](=[O:16])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:5]2[CH:6]=[N:7][C:2]([NH:36][CH:33]3[CH2:34][CH2:35][N:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[CH2:31][CH2:32]3)=[N:3][C:4]2=[O:16])=[CH:10][CH:11]=1
Reactant: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Reactant: NC1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1nc(NC2CCN(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 52.5 %

Procedure:
To a chloroform solution (1.1 mL) of 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one (59 mg, 0.23 mmol) synthesized in Reference Synthesis Example 11, potassium carbonate (80 mg, 0.58 mmol) and 1-(4-fluorophenyl)piperidine-4-amine (66 mg, 0.34 mmol) synthesized in Reference Synthesis Example 83 were added and the resultant mixture was stirred at room temperature for 30 minutes. After the completion of the reaction, water was added to the reaction solution and extraction with chloroform from the resultant reaction solution was performed. The organic layer was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/5→0/1 and next, ethyl acetate/methanol=19/1 (v/v)) to obtain the title compound (50 mg, yield: 52%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[C:12]([F:13])=[C:11]([F:14])[C:8]([CH:9]=[O:10])=[C:7]([F:15])[C:6]=1[F:16].CO>O>[C:1]([CH:9]([OH:10])[C:8]1[C:7]([F:15])=[C:6]([F:16])[C:5]([CH3:4])=[C:12]([F:13])[C:11]=1[F:14])#[N:2]
Reactant: Cc1c(F)c(F)c(C=O)c(F)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(F)c(F)c(C(O)C#N)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
1.66 g of sodium cyanide were introduced into a mixture of 4 g of 4-methyl-2,3,5,6-tetrafluorobenzaldehyde, 4 g of 4-methyl-2,3,5,6-tetrafluorobenzaldehyde, 70 ml of methyl alcohol and 20 ml of water and the mixture was cooled to 0° C. The reaction mixture was stirred for 1 hour at 0° C. and was poured into water. Extraction was carried out with ether and the ethereal phases were dried and evaporated to dryness under reduced pressure to obtain 4.54 g of the product melting at 124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9].O1CCCC1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[C:35](Cl)[CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:32]=[C:33]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])[CH:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
1-(2-Chloro-phenyl)-ethanol (31.4 mg, 0.20 mmol) was dissolved into 1.7 mL of anhydrous tetrahydrofuran and treated with sodium hydride (8.0 mg, 60% dispersion in mineral oil, 0.20 mmol). This was stirred under nitrogen for 1 hour at ambient temperature, then the reaction was treated with 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (I-2a) (50 mg, 0.17 mmol) in one portion. The resultant mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature, the reaction was poured into water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (7:13 ethyl acetate:hexanes) to afford 64.3 mg of the title product (I-2b).
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)=O.[C:20]([NH2:24])(=[S:23])[CH2:21][CH3:22].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:21]([C:20]1[S:23][C:3]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=2)=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[N:24]=1)[CH3:22]
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(F)c2)c1
Reactant: CCC(N)=S
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(F)c2)s1
Yield: 38.1 %

Procedure:
A solution of 2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide (11 g, 29 mmol) and thiopropionamide (2.7 g, 30 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 14 hrs. Aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) to give the title compound (3.3 g, yield 38%).
Reaction SMILES: O[Li].O.[F:4][C:5]1([F:15])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([NH2:14])[C:7]=2[O:6]1.[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[C:20]=1Cl)([O-:18])=[O:17].Cl>CS(C)=O.O>[F:15][C:5]1([F:4])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([NH:14][C:20]3[C:21]([C:28]([F:30])([F:31])[F:29])=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=3[N+:16]([O-:18])=[O:17])[C:7]=2[O:6]1
Reactant: Nc1cccc2c1OC(F)(F)O2
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cccc3c2OC(F)(F)O3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
20.8 g of LiOH.H2O are added at 0° C. to a solution of 24.5 g of 2,2-difluoro-4-amino-1,3-benzodioxole in 70 ml of dimethyl sulfoxide. The mixture is then stirred for 20 minutes. Subsequently, a solution of 38.3 g of 2,4-dinitro-6-trifluoromethylchlorobenzene in 70 ml of dimethyl sulfoxide is added, and the resultant reaction mixture is stirred at 0° C. for 20 minutes and then heated to room temperature. After 5 hours, the mixture is poured into 350 ml of water, acidified with dilute hydrochloric acid and extracted several times with diethyl ether. The combined ether phases are washed three times with a 5% solution of sodium carbonate and then with 5% hydrochloric acid and dried over sodium sulfate, and the solvent is evaporated off in vacuo. The residue comprises 51.6 g of orange-brown crystals which are recrystallised in toluene. Yield: 41.6 g; melting point: 144°-146° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].CC(C)N=C=NC(C)C>CN(C=O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]([F:40])([F:41])[F:39])[CH2:34][CH2:33]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: O=C(NCc1ccc(F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to the procedure in Example 76 using N-(4-fluoro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (191 mg; 0.60 mmol), 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (185 mg; 0.60 mmol), DIC (76 mg; 0.60 mmol) and DMF (3 mL).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]#[CH:20])(=O)=O)=CC=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:18]([O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]#[CH:20]
Reactant: Nc1ccccc1
Reactant: C#CCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Product: C#CCOCCOCCNc1ccccc1
Yield: 53.1 %

Procedure:
2-(2-(prop-2-ynyloxy)ethoxy)ethyl 4-methylbenzenesulfonate (s-8)2 (100 mg, 0.335 mmol, 0.31 equiv.) was dissolved in aniline (102 mg, 1.10 mmol, 1 equiv.). The reaction was allowed to proceed at 100° C. in a sealed reaction vessel for 5 hours, after which time it was chromatographed (Silica Gel, 25 g RediSep pre-packed column, 0% EtOAc:Hexanes→20% EtOAc:Hexanes) to yield N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)aniline (s-9) as a brown oil (39.0 mg, 53.1%). IR (thin film) 3393 (m), 3278 (m), 3052 (w), 2865 (m), 2115 (w), 1603 (s), 1506 (s), 1461 (w), 1320 (w), 1277 (m), 1099 (s), 1030 (w), 750 (s), 693 (s); 1H NMR (500 MHz, CDCl3) δ 7.22-7.16 (m, 2H), 6.72 (t, J=7.3 Hz, 1H), 6.67-6.63 (m, 2H), 4.22 (d, J=2.4 Hz, 2H), 4.12 (s, 1H), 3.74-3.70 (m, 4H), 3.70-3.66 (m, 2H), 3.32 (t, J=5.2 Hz, 2H), 2.46 (t, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) 148.7, 129.6, 117.9, 113.5, 80.0, 75.1, 70.5, 70.1, 69.5, 58.9, 43.9. HRMS (ES+) calc'd for C13H17NO2 (M+H) m/z 220.1293 Found 220.1327.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7](=O)[CH2:8][CH3:9])[CH3:2].O.[NH2:17][NH2:18]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([CH2:12][CH3:13])=[N:17][NH:18][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCOC(=O)CC(C(=O)CC)C(=O)CC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1c(CC)n[nH]c1CC
Yield: 98.4 %

Procedure:
Combine 4-oxo-3-propionylhexanoic acid ethyl ester (2.49 g, 11.6 mmol) and hydrazine hydrate (0.70 g, 13.9 mmol) in glacial acetic acid (20 mL) and stir at room temperature for 88 hr. Concentrate to an oil. Partition this residue between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). Separate the organic layer; dry (sodium sulfate), filter and concentrate to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (2.4 g, 98%). 1H-NMR (400 MHz, CDCl3) δ 8.64 (bs, 1H), 4.08 (q, 2H), 3.35 (s, 2H), 2.61 (q, 4H), 1.21 (m, 9H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][C:12]=2[C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=2)[CH:5]=1.O.[OH-].[Na+]>C1COCC1>[CH3:25][C:21]1[CH:20]=[C:19]([NH:18][C:17]([C:12]2[N:13]=[C:14]([CH3:16])[S:15][C:11]=2[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=2)=[O:26])[CH:24]=[CH:23][N:22]=1
Reactant: COC(=O)c1cccc(Nc2sc(C)nc2C(=O)Nc2ccnc(C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)c2nc(C)sc2Nc2cccc(CO)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
3-[2-Methyl-4-(2-methyl-pyridin-4-ylcarbamoyl)-thiazol-5-ylamino]-benzoic acid methyl ester (example 222, 0.425 g, 1.11 mmol) was dissolved in 15 mL dry THF. Lithiumalumiumhydride (0.169 g, 4.44 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. Water (0.169 mL), 15% NaOH (0.169 mL) and again water (0.507 mL) was slowly added and the reaction mixture was filtered and evaporated. The crude material was recrystallized from ethyl acetate and dichloromethane to yield the title compound as a yellow solid (0.257 g, 65%), MS (ISP): m/e=355.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[N:17](COCC[Si](C)(C)C)[C:15]=4[N:16]=3)=[N:9][N:8]([CH2:31][CH2:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:31][CH2:32][C:33]([F:38])([F:37])[CH:34]([F:35])[F:36])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2nc(-c3nn(CCC(F)(F)C(F)F)c4ncc(F)cc34)nnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)F)c4ncc(F)cc34)nnc21
Temperature: 45 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
96 mg (0.173 mmol) of the compound from Example 37A were stirred in dichloromethane (4 ml) and trifluoroacetic acid (1 ml) at room temperature for 4.5 h. The mixture was then concentrated to dryness. The residue was stirred in ethanol/2N hydrochloric acid (4:1, 15 ml) at 45° C. for 3 h. This was followed by concentration to dryness. Purification by preparative HPLC (methanol:water (+1% trifluoroacetic acid) gradient) gave 31 mg of the title compound (42% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16](I)[CH:17]=[CH:18][CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=2)[CH:7]=1
Reactant: COc1ccc(Br)cc1B(O)O
Reactant: Clc1cccc(I)c1
Product: COc1ccc(Br)cc1-c1cccc(Cl)c1
Reaction time: 16 h
Yield: 99 %

Procedure:
I-208 was synthesized from 5-bromo-2-methoxyphenylboronic acid (2.00 g, 8.66 mmol) and 3-chloroiodobenzene (2.48 g, 10.4 mmol) using the same conditions as for I-207. The reaction time was extended to 16 h. The methanol was removed under vacuum, and the residue dissolved in ethyl acetate (100 mL), washed with water (100 mL), and the aqueous wash extracted with ethyl acetate (100 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2×200 mL), water (2×200 mL) and brine (150 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum to give I-208 (2.56 g, 99% yield). 1H NMR (400 MHz, CDCl3) 7.49-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.36-7.31 (m, 3H), 6.85 (d, J=8.4 Hz, 1H), 3.80 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1C=CC=CC=1.Cl>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:10])=[O:9]
Reactant: NC1CCCCC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(NC1CCCCC1)c1ccccc1Br
Reaction time: 3 h

Procedure:
To a 20 mL vial were added a stirbar, 2-bromobenzene-1-sulfonyl chloride (1.053 g, 4.12 mmol), cyclohexylamine (431 mg, 4.34 mmol) and dry pyridine (5 mL). The mixture was stirred for 3 hours before adding it to a separatory funnel containing 1 N HCl and EtOAc. The layers were mixed thoroughly and then separated. The organic layer was then washed with water followed by sat. NaHCO3, dried over MgSO4, filtered and evaporated to dryness to give the title compound. MS (ESI): mass calcd. for C12H16NO2SBr 317.01, m/z found 318.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.14 (dd, J=7.9, 1.7, 1H), 7.71 (dd, J=7.9, 1.2, 1H), 7.49-7.42 (m, 1H), 7.42-7.35 (m, 1H), 5.05 (d, J=7.7, 1H), 3.19-3.04 (m, 1H), 1.79-1.66 (m, 2H), 1.66-1.57 (m, 2H), 1.52-1.44 (m, 1H), 1.28-1.04 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(=O)C.CN(C)[CH:19]=[C:20]([C:26]1[N:27]=[N:28][N:29]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:30]=1)[C:21](OCC)=[O:22]>O>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:29]2[N:28]=[N:27][C:26]([C:20]3[C:21](=[O:22])[N:12]4[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]4=[N:1][CH:19]=3)=[N:30]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(=CN(C)C)c1nnn(Cc2ccc(OC)cc2)n1
Reactant: CCOC(=O)c1ccnc(N)c1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccn2c(=O)c(-c3nnn(Cc4ccc(OC)cc4)n3)cnc2c1
Temperature: 130 °C
Yield: 53.9 %

Procedure:
Ethyl 2-aminoisonicotinate (6.5 g, 39.23 mmol) was added with acetic acid (500 ml) and ethyl 3-(dimethylamino)-2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-2-propenoate (13 g, 39.23 mmol) and refluxed by heating at 130° C. for 5 hours. The reaction solution was returned to room temperature and poured into water, and this was extracted with chloroform. The resulting organic layer was washed with saturated brine, and the collected organic layer was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure and subjected to azeotropy with toluene, and the resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=80:1→50:1→30:1) to obtain 8.6 g of the title compound.