Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[CH2:28][CH2:29][CH2:30][CH2:31][NH2:32]>C1COCC1>[ClH:10].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:14]([NH:13][C:11]([C:4]1[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=1)=[O:12])=[NH:17]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: COc1ccc(CCCCN)c(OC)c1
Agent: I
Solvent: C1CCOC1
Product: COc1ccc(CCCCNC(=N)NC(=O)c2nc(Cl)c(N)nc2N)c(OC)c1
Product: Cl
Yield: 181.3 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methyl-pseudothiourea hydroiodide (0.3 g, 0.77 mmol) was added to an anhydrous THF solution (30 mL) of 79 (0.4 g, 1.9 mmol). The reaction mixture was stirred at reflux for 3 h then the solvent was evaporated. The residue was washed with ethyl acetate (2×20 mL) then treated with 3% HCl (15 mL). The yellow solid that formed was separated, washed with water and dried overnight to provide compound 80 (0.32 g, 90%).1H NMR (300 MHz, DMSO-d6) δ 1.57 (s, 4H), 2.50 (br s, 2H), 3.35 (br s, 2H), 3.73 (s, 3H), 3.76 (s, 3H), 6.43 (m, 1H), 6.52 (s, 1H), 7.02 (m, 1H), 7.45 (br s, 2H) 8.99 (br s, 1H), 9.03 (m, 1H), 10.56 (s, 1H). APCI MS m/z 422 [C18H24ClN7O3+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23]O)=[CH:21][C:20]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:25]4[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:33])[F:35])=[CH:29][CH:30]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as yellow crystals.
Reaction SMILES: Br[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH2:3]1.[Mg].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#N.C(OCC)(=[O:32])C>O1CCCC1.O>[Br:21][C:22]1[CH:23]=[C:24]([C:25]([C:4]2[CH:3]=[C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: BrC1(c2ccccc2)C=C(c2ccccc2)C=CC1
Reactant: CCOC(C)=O
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cccc(Br)c1)c1cc(-c2ccccc2)cc(-c2ccccc2)c1
Temperature: -40 °C

Procedure:
A solution of 20.0 g (64.7 mmol) of 3-bromo-[3,1′;5,1″]terphenyl in 300 ml of tetrahydrofuran is slowly added dropwise to 1.7 g (71.2 mmol) of magnesium turnings, and the mixture is heated under reflux for 3 h. The solution is then cooled to −40° C., and a solution of 11.8 g (65 mmol) of 3-bromobenzonitrile in 100 ml of tetrahydrofuran is added dropwise. After the addition, the solution is heated under reflux for 6 h. After cooling, 600 ml of ethyl acetate and 400 ml of water are added, and the organic phase is separated off, washed three times with 200 ml of water, dried using sodium sulfate and subsequently evaporated to dryness. The residue is recrystallised from ethanol and subsequently dried under reduced pressure. The yield is 21.7 g (53 mmol), corresponding to 81.3% of theory.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12](=[O:17])[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:10]=1)=[O:8]>C1COCC1>[C:7]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12](=[O:17])[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[N:10]=1)(=[O:8])[CH3:1]
Reactant: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1C(=O)N(C)OC
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1C(C)=O
Reaction time: 1 h
Yield: 45.3 %

Procedure:
MeMgBr (1 M solution in THF, 4 mL, 12 mmol) was added dropwise at −78° C. to a solution of N,4-dimethoxy-N-methyl-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridazine-3-carboxamide (1.43 g, 4 mmol) in THF (15 mL). After stirring for 1 h, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (1/1) and recrystallized from hexane/AcOEt to give the title compound (566 mg, 45% yield) as a white solid: mp 136-138° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.57 (3H, s), 3.93 (3H, s), 6.31 (1H, s), 7.63 (1H, t, J=7.9 Hz), 7.69 (1H, d, J=7.9 Hz), 7.84-7.88 (1H, m), 7.91 (1H, s). Anal. Calcd for C14H11F3N2O3: C, 53.85; H, 3.55; N, 8.97. Found: C, 53.96; H, 3.57; N, 8.96.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10][CH3:11])[CH:5]=[O:6].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13].CCN(CC)CC>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:13][CH2:12][C:14](=[O:15])[CH3:16])[CH:7]=[CH:8][C:9]=1[S:10][CH3:11]
Reactant: CSc1ccc(C=O)cc1F
Reactant: C=CC(C)=O
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1ccc(C(=O)CCC(C)=O)cc1F
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a stirred solution of 3-fluoro-4-(methylthio)benzaldehyde (3.04 g, 17.9 mmol) in ethanol (12 mL) was added methyl vinyl ketone (1.3 mL, 15.5 mmol), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.84 g, 3.1 mmol), and Et3N (4.32 mL, 31 mmol) at room temperature. After stirring for 2 hours, volatiles were removed by evaporation. The residue was taken up with ethyl acetate (200 mL), and washed with water (120 mL), dil. aqueous HCl (120 mL), water (120 mL), brine (120 mL), dried over MgSO4, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to provide 1-[3-fluoro-4-(methylthio)phenyl]pentane-1,4-dione (2.7 g, 73% yield). To a stirred suspension of 1-[3-fluoro-4-(methylthio)phenyl]pentane-1,4-dione (2.7 g, 11.25 mmol) in methanol (50 mL) was added Oxone (14.14 g, 23 mmol) in water (50 mL) at room temperature. After stirring for 5 hours, the mixture was diluted with water. The whole was extracted with CH2Cl2 (50 mL×4), the combined organic layer washed with brine, dried over MgSO4, and evaporated in vacuo to give the subtitle compound (2.8 g, 66% yield).
Reaction SMILES: COC1C=CC(C[N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH3:19])=[C:12]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[C:25]([NH:30][CH3:31])[N:24]=[CH:23]5)[C:11]=3[CH:10]=[CH:9]2)=CC=1.C(O)(C(F)(F)F)=O.Cl>>[CH3:19][C:13]1[CH:14]=[N:15][C:16]2[C:17](=[O:18])[NH:8][CH:9]=[CH:10][C:11]=2[C:12]=1[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([NH:30][CH3:31])[N:24]=[CH:23]2
Reactant: CNc1ncc2cc(-c3c(C)cnc4c(=O)n(Cc5ccc(OC)cc5)ccc34)ccc2n1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncc2cc(-c3c(C)cnc4c(=O)[nH]ccc34)ccc2n1
Temperature: 175 °C

Procedure:
7-(4-Methoxybenzyl)-3-methyl-4-(2-(methylamino)quinazolin-6-yl)-1,7-naphthyridin-8(7H)-one (0.900 g, 2.06 mmol) was taken in a clear microwave vial and treated with 14 ml of TFA and 1 ml of cone HCl. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 175° C. for 45 minutes. The volatiles were evaporated under reduced pressure and residual TFA/water was azeotroped with toluene. The residue was taken up in DCM/2M MeOH and loaded unto silica. The residue was purified by column chromatography on silica gel using a gradient of 3 to 12% MeOH in DCM to give 3-methyl-4-(2-(methylamino)quinazolin-6-yl)-1,7-naphthyridin-8(7H)-one as a yellow solid. MS(M+H)+ 318.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH3:41])[CH:34]=[C:35]([O:39]C)[C:36]=1[O:37][CH3:38]>ClCCCl>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:34]1[C:35]([OH:39])=[C:36]([O:37][CH3:38])[C:31]([O:30][CH3:29])=[CH:32][C:33]=1[CH3:41])=[O:23]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(C)c(C(=O)CCCCCCCCCCCCCCCCCO)c(O)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a solution of 18-acetoxy-n-octadecanoyl chloride (11 g) in 1,2-dichloroethane (50 ml) is added aluminum chloride (7 g) and the mixture is stirred at room temperature for 2 hours. This reaction mixture is cooled to 5° C. and a solution of 3,4,5-trimethoxytoluene (6.2 g) in 1,2-dichloroethane (20 ml) is added. The mixture is stirred at room temperature for 72 hours. Then, this reaction mixture is heated to 50° C.-60° C. and stirred for 30 minutes. After cooling, ice-water is added to the reaction mixture and the product is extracted with dichloromethane. The dichloromethane layer is washed with water and the solvent is distilled off to recover an oil (12.1 g). This oil is dissolved in methanol (150 ml) followed by addition of sodium hydroxide (5.2 g). The mixture is stirred at room temperature for 2 hours, at the end of which time it is neutralized with 5N-HCl and the solvent is distilled off. The resultant crude crystals are rinsed with water and recrystallized from dichloromethane-ether (1:1). The above procedure yields 6-(18-hydroxy-1-oxooctadecyl)-2,3-dimethoxy-5-methylphenol (6.4 g) as colorless needles, m.p. 101° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][NH:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[C@H:16]([NH:20][C:21]([C:23]3[S:24][C:25]4[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:17][N:18]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:19]1)=[O:13])=[CH:6]2
Reactant: COC(=O)CBr
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CNC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
The compound (230 mg) obtained in Example 95 and potassium carbonate (90 mg) were dissolved in N,N-dimethylformamide (4.6 mL), and the mixture was cooled with ice. Methyl bromoacetate (0.062 mL) was added, and the resultant mixture was stirred for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine and then dried over sodium sulfate anhydrate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) and powdered with methanol-water to give the title compound (190 mg).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:34])[CH3:33])[N:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:34])[CH3:33])[N:27]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)C#N)n2)c(C(N)=O)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C#N)c1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (110 mg, 222 μmol) in CH2Cl2 (3.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol) and the reaction mixture stirred to room temperature for 18 h. Solvents evaporated and residue purified by flash column (spherical silica 20-45 μM, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (50 mg, 57% yield) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 11.47 (s, 1H), 8.76 (s, 1H), 8.06 (d, J=3.0 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 5.60-5.77 (m, 2H), 4.25 (br. s., 1H), 3.11-3.24 (m, 1H), 1.32-1.92 (m, 16H); LC-MS 395.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][C:10]1([CH3:17])[O:14][CH:13]([CH2:15][OH:16])[CH2:12][O:11]1.[Na].O>ClCCl>[CH3:9][C:10]1([CH3:17])[O:14][CH:13]([CH2:15][O:16][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:12][O:11]1
Reactant: Nc1cc(Cl)ccn1
Reactant: CC1(C)OCC(CO)O1
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: CC1(C)OCC(COc2ccnc(N)c2)O1
Temperature: 145 °C
Yield: 80 %

Procedure:
A sealed tube containing 4-chloro-2-pyridinamine (4 g, 31.2 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (8.4 g, 60.6 mmol), and sodium (1.46 g, 63.5 mmol) was heated at 145° C. for 8 hours. The mixture was cooled to ambient temperature; water (25 mL) and dichloromethane (50 mL) were added. The organic phase was separated, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica-gel to give 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine as a pale yellow solid (5.6 g).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:16])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28])=O>CO>[CH2:1]([N:3]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[CH:18][S:16]/[C:4]/1=[N:5]\[C:6]1[CH:7]=[CH:8][C:9]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNC(=S)Nc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccccc1C(=O)CBr
Solvent: CO
Product: CCn1c(-c2ccccc2OC)cs/c1=N\c1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(3-ethylthioureido)benzenesulfonic acid (1-4) (50 mg, 0.19 mmol) and 2-bromo-1-(2-methoxyphenyl)ethanone (30 mg, 0.13 mmol) in MeOH (1 mL) is heated to 80° C. for 1 hour and then cooled to room temperature and concentrated. The residual is purified by preparative LC/MS to provide (Z)-4-(3-ethyl-4-(2-methoxyphenyl)thiazol-2(3H)-ylideneamino)benzenesulfonic acid (1-5) as white solid. HPLC-MS calculated for C18H18N2O4S2 (M+H+) 391.1. found 391.1.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1)[C:2]([CH3:4])=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].[NH2:23]/[C:24](/[CH3:35])=[CH:25]\[C:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[O:27]>C(O)(C)C>[CH3:4][C:2]1[NH:23][C:24]([CH3:35])=[C:25]([C:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[O:27])[CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:1]=1[C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1
Reactant: CC(=O)Cc1nc(CCl)no1
Reactant: CCCOCCOC(=O)/C=C(/C)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: CCCOCCOC(=O)C1=C(C)NC(C)=C(c2nc(CCl)no2)C1c1cccc([N+](=O)[O-])c1
Yield: 95.1 %

Procedure:
A mixture of 530 mg of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole, 450 mg of 3-nitrobenzaldehyde and 560 mg of 2-(n-propoxy)ethyl 3-aminocrotonate in 3 ml of isopropyl alcohol was heated under reflux for 8 hours. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel using benzene-acetonitrile (10:1) as eluent to give 1.35 g of 2-(n-propoxy)ethyl 1,4-dihydro-2,6-dimethyl-3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carboxylate. Recrystallization from n-hexane-isopropylalcohol afforded pale yellow crystals, m.p. 129°-130° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH:2]2[C:7]([OH:9])=[O:8])(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCOCC2C(=O)O)cc1

Procedure:
3-Morpholinecarboxylic acid is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give 4-[(4-methoxyphenyl) sulfonyl]-3-morpholinecarboxylic acid.
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[N:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>P(Cl)(Cl)(Cl)=O>[ClH:18].[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:3]3[CH:11]=[N:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ncnc2ccncc12
Reactant: Nc1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cl
Product: Clc1cccc(Nc2ncnc3ccncc23)c1
Temperature: 85 °C
Yield: 2.3 %

Procedure:
To 4-hydroxy-pyrido[4,3-d]pyrimidine (0.13 g, 0.90 mmol) in phosphorus oxychloride (2 ml) was added dry pyridine (0.15 ml, 1.8 mmol). A condenser and CaCl2 drying tube were attached and the suspension was refluxed for 3 hours. The final, clear solution was concentrated in vacuo (CaCl2 drying tube) and followed by a toluene chase. The resulting 4-chloro-pyrido[4,3-d]pyrimidine was dissolved in dry pyridine (1.5 ml). 3-Chloroaniline (0.096 ml, 0.90 mmol) was added, and the mixture was heated in an 85° C. oil bath for 23 hours. The reaction was cooled to ambient temperature and concentrated in vacuo. The oily residue was partitioned between CH2Cl2 and H2O, filtered, and the H2O phase extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (5 g, 40 μm mesh) using 5% methano/CH2Cl2 to afford the title compound as an off-white solid (3 mg, 1.3%). LC-MS: 257 (MH+); anal. RP18-HPLC RT: 3.85 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Br)cc(OCc2ccccc2)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccccc2)c1
Yield: 48.6 %

Procedure:
(3-Benzyloxy-5-bromophenyl)-acetic acid ethyl ester (0.250 g, 0.72 mmol), benzene boronic acid (0.10 g, 0.86 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.04 mmol) were suspended in a mixture of K2CO3 solution (0.72 ml, 1.44 mmol, 2M aq) and DME (2 ml). This reaction mixture was irradiated in a CEM microwave at 120° C. for 30 min. The reaction mixture was diluted with water and extracted with Et2O (×3). The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give (5-benzyloxy-biphenyl-3-yl)-acetic acid ethyl ester (0.12 g, 0.35 mmol) as a colourless gum in 48% yield. 1H NMR (CDCl3) δ 7.59-7.54 (m, 2H), 7.48-7.30 (m, 8H), 7.13-7.11 (m, 2H), 6.94-6.91 (m, 1H), 5.12 (s, 2H), 4.16 (q, 2H), 3.64 (s, 2H), 1.27 (t, 3H).
Reaction SMILES: O=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][N:4]=1.N1C=CC=CC=1.Cl.[NH2:28][OH:29]>C(O)C>[OH:29][N:28]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][N:4]=1
Reactant: O=C(c1ccccc1)c1nsc2nc3ccccc3n12
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1nsc2nc3ccccc3n12
Yield: 89.2 %

Procedure:
To a solution of 0.5 g (1.79 mmol) of 3-(oxophenylmethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole in 7 mL of ethanol was added 0.5 mL (6.46 mmol) of pyridine and 0.5 g (7.20 mmol) of hydroxylamine hydrochloride. The mixture was refluxed for overnight. The precipitate was collected by filtration, and washed with methanol and dichloromethane to give the crude product, which was recrystallized from methanol to yield 0.47 g (89%) of the title compound as white crystals. mp 247° C.; 1H NMR (DMSO-d6)δ 11.89 (s, 1H), 7.81 (d, 1H), 7.73 (dd, 2H), 7.45-7.53 (m, 5H), 7.32 (t, 1H) ppm; 13C NMR (CDCl3)δ 168.25, 155.24, 150.52, 147.95, 136.94, 135.67, 134.30(2C), 133.03, 131.52(2C), 130.35, 127.26, 124.28, 116.91 ppm; IR (KBr)δ 2731, 1549, 1475, 1450, 1251, 1194, 983, 753, 736 cm-1HRMS calcd for C15H10N4OS 294.0575, found 294.0583
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1.[CH:50]1([C:54](Cl)=[O:55])[CH2:53][CH2:52][CH2:51]1.N1C=CC=[CH:59][CH:58]=1>CCOC(C)=O>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([C@@H:32]([O:31][C:4]2[N:3]=[C:2]([NH:1][C:54]([CH:50]3[CH2:53][CH2:52][CH2:51]3)=[O:55])[N:7]=[C:6]([N:8]3[CH2:30][CH2:29][C:11]4([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:17])[C@H:13]([C:26]([O:28][CH2:58][CH3:59])=[O:27])[CH2:12]4)[CH2:10][CH2:9]3)[CH:5]=2)[C:33]([F:35])([F:34])[F:36])=[C:38]([N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[CH:39]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Reactant: c1ccncc1
Reactant: O=C(Cl)C1CCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(NC(=O)C4CCC4)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (300 mg, 0.412 mmol) in pyridine (1.0 mL) was added cyclobutanecarbonyl chloride (54 mg, 0.045 mmol). The reaction mixture was stirred at RT for 3 h, then diluted with EtOAc, and washed with 0.5 N HCl. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification on a 40 g Isco RediSep silica cartridge (EtOAc/heptane) provides (S)-2-benzyl 3-ethyl 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(cyclobutanecarboxamido) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.