Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:13][C:1](=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([O:9][CH2:17][CH2:18][CH2:19][Cl:20])=[C:5]([O:6][CH3:7])[CH:4]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1ccc(OCCCCl)c(OC)c1
Yield: 65.1 %

Procedure:
A mixture of 50 g (0.238 mole) of ethyl homovanillate, 75 g (0.476 mole) of 1-bromo-3-chloropropane and 98.7 g (0.71 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 24 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give an oil which gradually crystallized to a semi-solid. The solid was recrystallized from ethyl ether-petroleum ether (30°-60° C.) to yield 44.4 g (65%) of white solid, m.p. 36°-38° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9](=[O:11])[N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1)=[O:5])[CH3:2].Br[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Li+].[Li+].C(#N)C.CN(C=O)C>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9](=[O:11])[N:8]([C:12]([CH3:14])([CH3:13])[CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(C(C)(C)C)c(=O)[nH]1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C(C)(C)C)c(=O)n1CC(=O)C(C)(C)C
Temperature: 100 °C

Procedure:
A solution of 3.0 g of the product of Step B, 7.41 g of 1-bromo-3,3-dimethyl-2-butanone, and 4.15 g of lithium carbonate in a 2:1 mixture of acetonitrile/DMF (90 mL) was heated at 100° C. for four h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with sat. ammonium chloride solution. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with sat. lithium chloride solution, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography afforded 1-tert-butyl-4-(3,3-dimethyl-2-oxo-butyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester as a yellow oil. MS (M+H+)=312.3.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([NH2:16])[N:15]=[C:10]2[CH:9]=[CH:8]1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH:19]1([NH:25][C:26]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:18])([CH3:17])[CH3:1])[C:11]3=[N:12][CH:13]=2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C=NC1CCCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(N)cnc21
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCCC3)cnc21
Temperature: 25 °C
Yield: 137.3 %

Procedure:
5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine (1.32 g, 4.99 mmol) was dissolved in toluene (50 mL). Cyclohexylisocyanate (6.4 mL, 49.9 mmol) was added and the reaction mixture was heated to reflux for 88 hr, cooled to RT, and concentrated, and purified by SiO2 chromatography (150 g SiO2, DCM/MeOH 0 to 5% MeOH) to give 2.67 g of impure 1-cyclohexyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a yellow solid (31% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])O[CH:8]=1.C1(=O)[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1>ClC1C=CC=CC=1Cl>[F:10][C:2]([F:1])([F:11])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:13][CH:8]=1)[C:15](=[O:18])[CH:16]=[CH:17][C:6]2=[O:9]
Reactant: O=C1C=CC(=O)C=C1
Reactant: O=c1ccc(C(F)(F)F)co1
Solvent: Clc1ccccc1Cl
Product: O=C1C=CC(=O)c2cc(C(F)(F)F)ccc21

Procedure:
A mixture of 1.64 g (0.01 mmol) of 5-trifluoromethyl-2-oxo-2H-pyrane and 5.4 g (0.05 mol) of 1,4-benzoquinone in 7 ml of 1,2-dichlorobenzene is heated for 12 hours to 180° C. The reaction mixture is then concentrated by evaporation at 90°/20 mbar, and the distillation residue is chromatographed over 150 g of silica gel 60 (eluant: 19:1 mixture of CH2Cl2 /acetone; 0.3 bar overpressure). Yield: 1.82 g (80.52%); m.p. 80°-85° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:26][CH3:27])[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24]C)[CH:16]=3)=[CH:9][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[O:28]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH2:26][CH3:27])[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([OH:24])[CH:16]=3)=[CH:11][CH:12]=1
Reactant: CCn1c(-c2ccc(N3CCCS3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCn1c(-c2ccc(N3CCCS3(=O)=O)cc2)c(C#N)c2ccc(O)cc21
Temperature: 0 °C

Procedure:
Following the procedure in example 1B step A, 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile is treated with 1M BBr3 solution in CH2Cl2 at −15° C. for 1.5 h and then poured into ice-water and filtered and dried to afford 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile in nearly quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14]CC)=[O:13])[CH:8]=2)[N:3]=1.[ClH:17]>>[ClH:17].[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc2nc(N)ccc2c1
Agent: Cl
Product: Nc1ccc2cc(C(=O)O)ccc2n1

Procedure:
330 mg of ethyl 2-aminoquinoline-6-carboxylate was stirred in 30 ml of 6 M hydrochloric acid at 80° C. overnight. The solvent was evaporated, and the residue was washed with ethyl acetate to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5](=[O:16])[C:4]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1.[OH-].[K+].CCOC(C)=O>C1COCC1.O>[N:22]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[C:5](=[O:16])[C:4]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:26]=[CH:25][CH:24]=[N:23]1
Reactant: CCOC(=O)c1c(CBr)n(C)n(-c2ccc(F)cc2)c1=O
Reactant: c1cn[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cn2cccn2)n(C)n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of ethyl 5-(bromomethyl)-2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (1.3 g, 3.6 mmol) and 1H-pyrazole (0.25 g, 3.6 mmol) in THF (50 mL) and H2O (1 mL) cooled in an ice-water bath is added solid KOH (0.2 g, 3.6 mmol) in three portions. After the reaction mixture is stirred at RT overnight, the solvent is removed. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (4:1) to give the product (0.87 g, 70% yield). MS (m/z): 345.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][C:13]#[N:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:19]([OH:21])[CH3:20].Cl>C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][C:13](=[NH:14])[O:21][CH2:19][CH3:20])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)COc1ccc(Oc2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 194.6 %

Procedure:
A solution of 15 g (0.0578 mol) of 4-(4-chlorophenoxy)-phenoxy-acetonitrile prepared as indicated in Example 29a) and of 3.7 ml (0.0637 mol) of anhydrous ethanol in 75 ml of anhydrous diethyl ether is kept at about -5° C. and a stream of dry hydrogen chloride gas is passed into it for 2 hours. Thereafter the reaction mixture is left for 4 hours at about 2° C. and 19.25 g of a white powder are isolated by filtration.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Br>CN(C)C=O>[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: Fc1ccc(CBr)c(F)c1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 51.4 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 2,4-difluoro-benzyl bromide (62 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(2,4-difluoro-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (82 mg, 51%) as an off-white solid. APCI-MS (M+H) 333.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[CH2:5][OH:6]
Reactant: COC(=O)c1cc(Br)cc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cc(Br)cc(CO)c1

Procedure:
13.5 Grams (55 mmole)) Methyl 3-bromo-5-methoxybenzoate was dissolved in ether and cooled in an ice bath. 33 ml of 1M lithium aluminum hydride was added dropwise. The reaction mix was then quenched cautiously by addition of sodium sulfate decahydrate, then water, and solid residue was removed by filtration. The ether was separated and evaporated under reduced pressure to give 11 gms of 3-bromo-5-methoxy benzyl alcohol as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O[Na])(C)(C)C.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:30]=[CH:29][CH:28]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[N:9]=1
Reactant: C1CNCCN1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCNCC2)c1
Temperature: 110 °C

Procedure:
To a solution of 5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Example 11, Step 1; 500 mg, 1.04 mmol) in toluene (10 mL) were added piperazine (86 mg, 1.04 mmol), t-BuONa (290 mg, 3 mmol), Ruphos (46 mg, 0.1 mmol) and Pd2(dba)3 (90 mg, 0.1 mmol). The reaction mixture was then heated in a sealed vial at 110° C. under inert atmosphere for 12 h. The resulting mixture was cooled, diluted with H2O (30 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=3:1 to 1:1) to give the title compound as a white solid; MS (ES+) C23H22F3N7O2 requires: 485. found: 486 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.78 (br s, 1H), 8.22 (d, J=9 Hz, 2H), 7.61 (d, J=9 Hz, 2H), 7.27 (m, 1H), 6.97 (m, 2H), 6.76 (d, J=7.5 Hz, 1H), 5.50 (s, 2H), 3.32 (m, 2H), 3.23 (m, 4H), 2.58 (s, 3H), 2.50 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].S(=O)(=O)(O)O>CO>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:28][NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=[N+]([O-])c1cccc(NN=C(c2ccc(O)cc2)c2ccc(O)cc2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of 4,4′-dihydroxybenzophenone (0.32 g, 1.5 mmol) in 10 mL of methanol was added to a solution of 3-nitrophenylhydrazine hydrochloride (0.43 g, 2.25 mmol), concentrated sulfuric acid (0.3 mL) in 10 mL of methanol at 50° C. It was stirred at 50° C. for additional 2 h. The reaction mixture was concentrated and diluted with 20 mL of water. The precipitates were separated by filtration and washed with 3% aqueous NaHCO3 and water. The crude product was recrystallized from ethanol to give 0.4 g (77% yield) of the desired compound as a yellow solid, mp 160-162° C. 1H NMR (300 MHz, d6-DMSO): δ 6.71 [d, 2H, J=8.8 Hz, Ar—H], 6.91 [d, 2H, J=8.1 Hz, Ar—H], 7.07 [d, 2H, J=8.8 Hz, Ar—H], 7.27 [d, 2H, J=8.8 Hz, Ar—H], 7.40 [dd, 1H, J=J2=8.1 Hz, Ar—H], 7.49 [d, 1H, J=8.1 Hz, Ar—H], 7.61 (dd, 1H, J1=8.4 Hz, J2=2.2 Hz, Ar—H], 7.99 [d, 1H, J=2.2 Hz, Ar—H], 9.25 [s, 1H, NH], 9.78 and 9.62 [s, 1H, OH].
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH3:31])=[CH:26][C:27]([O:29]C)=O)=[CH:20][CH:19]=1)(=[O:16])[CH3:15]>>[OH:29][C:27]1[C:20]2[C:21](=[CH:22][CH:23]=[C:18]([NH:17][C:14](=[O:16])[CH3:15])[CH:19]=2)[N:24]=[C:25]([CH3:31])[CH:26]=1
Reactant: COC(=O)C=C(C)Nc1ccc(NC(C)=O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)Nc1ccc2nc(C)cc(O)c2c1
Temperature: 252.5 °C
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
Phenyl ether (1 L) was heated to 255° C. Butenoate 3 (334 g, 1.35 mol) was carefully added portionwise while maintaining temperature 245-260° C. After the addition was complete, the yellow-orange suspension was held at 255° C. for an additional 15 min. The mixture was slowly cooled to 40° C., the solids were collected by filtration and washed with EtOAc (3×500 mL) followed by MeOH (3×500 mL) to give hydroxy quinoline 4 as yellow-orange solid (256 g, 88% yield); 1H NMR (DMSO) δ 11.52 (br, s, 1 H), 10.07 (s, 1 H), 8.24 (s, 1 H), 7.82 (d, 1 H), 7.42 (d, 1 H), 5.84 (s, 1 H), 2.31 (s, 3 H), 2.05 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[N:20]=2)[CH:14]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27]>>[CH3:24][C:21]1[N:20]=[C:19]([C:15]2[CH:14]=[C:13]([N:12]3[C:3]4[CH:4]=[CH:5][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=5[C:2]=4[NH:1][C:26](=[O:27])[C:25]3=[O:29])[CH:18]=[CH:17][CH:16]=2)[O:23][N:22]=1
Reactant: Cc1noc(-c2cccc(Nc3ccc4ccccc4c3N)c2)n1
Reactant: O=C(Cl)C(=O)Cl
Product: Cc1noc(-c2cccc(-n3c(=O)c(=O)[nH]c4c5ccccc5ccc43)c2)n1

Procedure:
1-Amino-2-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]aminonaphthalene and oxalyl chloride were used in a process similar to Example 1(3) to give the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:21][CH:20]=1)[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:8]=1[CH3:9].[H][H]>O1CCOCC1.[Pd]>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:23][CH:24]=1)[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:7][C:8]=1[CH3:9]
Reactant: [H][H]
Reactant: Cc1oc(-c2ccccc2)nc1CN(C)CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1CN(C)CCOc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 99.6 %

Procedure:
5-[4-[2-[N-methyl-N-(5-methyl-2-phenyl-4-oxazolyl)methylamino]ethoxy]phenyl methylene]thiazolidine-2,4-dione (2.5 g) obtained in example 18, was dissolved in dry 1,4-dioxane (100 ml) and was reduced with hydrogen (50 psig) in the presence of 10% palladium on charcoal (2.5 g) at ambient temperature until hydrogen uptake ceased. The solution was filtered through a bed of celite, the filter pad was washed exhaustively with dioxane and the combined filtrate was evaporated to dryness under reduced pressure to afford 2.5 g of the title compound after crystallisation from a mixture of benzene and petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25](F)[CH:24]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:41][NH2:42]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:24]=[C:25]3[C:26]([C:29]([NH2:30])=[N:41][NH:42]3)=[CH:27][CH:28]=2)[N:3]=1
Reactant: Cn1nccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1nccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 110 °C
Yield: 44.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(1-methyl-1H-pyrazol-5-yl)-3-piperidinecarboxamide (180 mg, 0.428 mmol), 3 mL of EtOH, Hunig's base (0.30 mL, 1.71 mmol), and hydrazine anhydrous (0.081 mL, 2.57 mmol) were added, and the yellow mixture was heated overnight at 110° C. in an oil bath. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was treated with EtOAc (3 mL) at 50° C. with stirring, and the clear layer of EtOAc solution was poured out. The solid layer was then treated with water (3 mL) at 50° C. with stirring, and the suspension was filtered. The light yellow colored solid was washed by water, and dried to give the title compound (82 mg) as a light yellow solid. LC-MS (ES) m/z=433 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.39-1.57 (m, 1H), 1.62-1.84 (m, 2H), 2.04 (m, 1H), 2.55-2.71 (m, 1H), 2.81-2.94 (m, 1H), 2.97-3.11 (m, 1H), 3.67 (s, 3H), 4.39-4.73 (m, 2H), 5.38 (s, 2H), 6.11 (s, 2H), 6.21 (s, 1H), 6.69 (s, 1H), 7.33 (s, 1H), 7.56-7.77 (m, 2H), 7.97 (s, 1H), 10.00 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[CH:17]=1>O1CCCC1>[SH:2][C:1]1[NH:23][C:18]2[CH:17]=[C:16]([O:15][C:14]([F:24])([F:25])[F:13])[CH:21]=[CH:20][C:19]=2[N:22]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc2nc(S)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
1,1′-thiocarbonyldiimidazole (1.13 g, 6.25 mmol) is added by portions to a solution of 4-(trifluoromethoxy)-ortho-phenylenediamine (1 g, 5.2 mmol) in 5 ml of tetrahydrofuran and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate and washed with water (2×30 ml). The organic phase is then dried over MgSO4, filtered and concentrated. The residue is triturated in diisopropylether and pentane and dried under vacuum to yield 1.26 g of 2-mercapto-5-trifluoromethoxy-benzimidazole as a yellow powder. Quantitative yield. Analytical LC/MS (method B): retention time=3.69 min. m/z=235.67 (positive ion mode).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])C>C1COCC1>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([C:25]2[N:26]=[C:21]3[CH:20]=[CH:19][C:18]([CH2:17][O:16][C:13]4[CH:14]=[CH:15][C:10]([C@@H:6]([C:7]#[C:8][CH3:9])[CH2:5][C:4]([OH:35])=[O:3])=[CH:11][CH:12]=4)=[CH:23][N:22]3[N:24]=2)=[CH:32][CH:31]=1)#[N:34]
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(C#N)cc4)nn3c2)cc1
Solvent: C1CCOC1
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCc2ccc3nc(-c4ccc(C#N)cc4)nn3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of (S)-3-{4-[2-(4-cyano-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester (0.130 g, 0.2795 mmol) in THF (10 mL) is added potassium trimethylsilanoate (0.143 g, 1.118 mmol) and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is evaporated to dryness, the residue is washed with n-pentane, redissolved in water (5 mL) and is acidified with saturated citric acid solution (pH ˜5). The precipitated solid is filtered, washed with water, and dried to give the title compound as an off-white solid (0.113 g, 56.5%). LCMS m/z 437 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:13]=[C:12]([C:23]([OH:25])=O)[CH:11]=1)#[N:2].[NH2:26][C@@H:27]([CH3:30])[CH2:28][OH:29].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[OH:29][CH2:28][C@@H:27]([NH:26][C:23]([C:12]1[CH:11]=[C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:13]=1)=[O:25])[CH3:30]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cc(C)ccc3C#N)c2)nc1
Reactant: C[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-c3cc(C)ccc3C#N)c2)nc1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 2′-cyano-5′-methyl-5-(5-methylpyridin-2-yl)biphenyl-3-carboxylic acid (30.0 mg, 0.0914 mmol), (2S)-2-Aminopropan-1-ol (13.724 mg, 0.18272 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.14474 g, 0.38068 mmol), N,N-diisopropylethylamine (0.10609 mL, 0.60908 mmol), N,N-dimethylformamide (0.260 mL, 3.35 mmol) and the reaction stirred over night at room temperature. The solvent was removed under reduced pressure and the residue purified by prep HPLC to get the compound as white solid.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.[Br:12][CH2:13][CH2:14]Br.[OH-].[Na+]>>[Br:12][CH2:13][CH2:14][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[S:1][CH2:2][CH2:3][CH2:4]2
Reactant: Oc1cccc2c1SCCC2
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Product: BrCCOc1cccc2c1SCCC2
Temperature: 100 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
1 g (6.015 mmol) of 8-thiochromanol is dissolved in 2.26 g (12.03 mmol) of 1,2-dibromoethane. 5.6 cm3 of a 1.6N NaOH solution are added dropwise. The mixture is heated to 100° C.; after 2 hours, the solution reaches pH 7. The mixture is allowed to cool. 100 cm3 of a 2N NaOH solution are added. The mixture is extracted with CH2Cl2 and then dried over MgSO4. Purification over a silica column (eluant: petroleum ether/CH2Cl2 2: 1) yields the desired compound.