Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([CH2:14][OH:15])=[C:12]([C:16]([F:19])([F:18])[F:17])[S:11][N:10]=1.O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:23]([C:34]([F:37])([F:36])[F:35])[CH:22]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([C:34]([F:35])([F:37])[F:36])[CH:22]=2)=[C:12]([C:16]([F:19])([F:17])[F:18])[S:11][N:10]=1
Reactant: Cc1ccc(-c2nsc(C(F)(F)F)c2CO)c(F)c1
Reactant: CCOC(=O)CCc1ccc(O)cc1C(F)(F)F
Product: Cc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2-fluoro-4-methylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and ethyl 3-(4-hydroxy-2-(trifluoromethyl)phenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.39-7.34 (m, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.07 (d, J=10.0 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 5.18 (s, 2H), 3.01 (t, J=7.6 Hz, 2H), 2.44 (t, J=8.4 Hz, 2H), 2.43 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H16F7NO3S, 506.1 (M−H). found 506.1.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:8][C:9]#[N:10])[CH2:5][C:6]#[N:7].S(OC)(O[CH3:15])(=O)=O>O1CCCC1>[CH3:15][O:3][CH:4]([CH2:8][C:9]#[N:10])[CH2:5][C:6]#[N:7]
Reactant: COS(=O)(=O)OC
Reactant: N#CCC(O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CC#N)CC#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Into a tetrahydrofuran solution, 0.7 g of sodium hydride was added. After cooling to 0° C., 3 g of 3-hydroxyglutaronitrile dissolved in a tetrahydrofuran solvent was slowly dropped. After completing the dropping, dimethyl sulfate was slowly added dropwise and stirred at 0° C. for 15 minutes. After stirring at room temperature for 6 hours, the reactant was extracted using water and dichloromethane and distilled under a reduced pressure to obtain 3-methoxy glutaronitrile (yield 82%).
Reaction SMILES: CC([N:5]([C@@:9]([CH3:31])([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[N:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C@:9]([CH3:31])([CH2:10][CH3:11])[NH2:5])=[CH:20][CH:19]=2)=[CH:23][C:24]=1[O:29][CH3:30]
Reactant: CC[C@](C)(C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@](C)(N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-1-methyl-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 98, 65 mg) in dry dichloromethane (3 mL) cooled to 0° C., TFA (0.700 mL, 9.08 mmol) was added dropwise. The reaction was stirred at that temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of NaHCO3 (20 mL) added at 0° C., and extracted with dichloromethane (3×7 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound as a white solid (44 mg).
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26]O>S(=O)(=O)(O)O>[CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([O:14][CH3:26])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CCCCSc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
A solution of 4-benzyl-3-n-butylthio-5-sulfamylbenzoic acid (0.85 g) in dry methanol (10 ml) and conc. sulfuric acid (0.2 ml) is refluxed for 20 hours. The methanol is removed in vacuo and the residue is triturated with 1 N sodium hydrogen carbonate (15 ml). The resulting crystalline material is collected by filtration, washed with water and dried. After recrystallization from methanol, methyl 4-benzyl-3-n-butylthio-5-sulfamylbenzoate is obtained with a melting point of 118°-120° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C.[C].[Pd]>[CH2:6]([NH:1][CH:2]([CH3:5])[CH2:3][OH:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@H](N)CO
Agent: [Pd]
Solvent: CCO
Product: CC(CO)NCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (S)-(+)-2-aminopropan-1-ol (50.0 g) and benzaldehyde (74 ml) in ethanol (500 ml) was added 5% palladium carbon (5.0 g), and the mixture was hydrogenated at room temperature under ordinary pressure for 8 hours. The reaction mixture was filtered through Celite, and concentrated under reduced pressure to give the titled compound (111.2 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:23][NH2:24].O>ClCCl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][NH2:24])=[O:5]
Reactant: NN
Reactant: O=C(O)c1ccccc1I
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: NNC(=O)c1ccccc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2-Iodobenzoic acid (3.00 g, 12.1 mmol) was dissolved in dichloromethane (150 mL), and the mixture was stirred at room temperature for 2 hours after adding 1,1′-carbonyldiimidazole (2.16 g, 13.3 mmol). Thereafter, hydrazine.monohydrate (3.52 mL, 72.6 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. Water was added after concentrating the mixture under reduced pressure, and the precipitated solid was collected by filtration, and dried under reduced pressure to give 2-iodobenzohydrazide (2.81 g, 89%).
Reaction SMILES: [Br:1][C:2]1[N:14]=[C:5]2[CH:6]=[CH:7][C:8]([C:10](OC)=[O:11])=[CH:9][N:4]2[N:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][C:2]1[N:14]=[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][N:4]2[N:3]=1
Reactant: COC(=O)c1ccc2nc(Br)nn2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc2nc(Br)nn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (3.0 g, 11.7 mmol) in DCM, is added DIBAL-H (3 equivalents) drop wise at −78° C. and the reaction mixture is warmed to room temperature and stirred for 1 hour. The reaction mixture is quenched with saturated ammonium chloride solution (20 mL) and extracted with DCM (2×50 mL). The combined organic extracts are dried over sodium sulphate, and evaporated. The crude material is triturated with n-pentane to give the title compound as a yellow solid (1.5 g, 57.6%). LCMS m/z 171 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:13]C(O)=O.OO>C1COCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: CC(=O)O
Reactant: CON(C)C(=O)c1cccnn1
Agent: OO
Solvent: C1CCOC1
Product: CC(O)c1cccnn1
Temperature: 30 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
To a solution of compound 2 (300 mg, 0.6 mmol) in THF (15 mL) was added AcOH (1 mL) and H2O2 (3 mL). The reaction mixture was stirred at 30° C. for 10 h. The mixture was quenched with saturated NaHCO3 (6 mL) and then balanced between EtOAc (2×20 mL) and water (10 mL). The organic layers were collected and concentrated in vacuo to give the residue, which was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to give compound 3 (70 mg, 35%) as a colorless oil.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>CN(C=O)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([N:9]2[CH2:8][CH:7]([CH2:6][N:31]3[CH2:30][CH2:29][C:28]([C:25]4[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=4)([OH:34])[CH2:33][CH2:32]3)[O:11][C:10]2=[O:12])=[CH:18][CH:17]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: COc1ccc(N2CC(COS(C)(=O)=O)OC2=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(N2CC(CN3CCC(O)(c4ccc(Cl)cc4)CC3)OC2=O)cc1

Procedure:
4.82 g of 5-methanesulfonyloxymethyl-3-p-methoxyphenyl-oxazolidin-2-one [m.p. 126°-128°; obtainable by reaction of p-methoxyaniline with hydroxymethyl-oxirane to give 3-p-methoxyanilino-1,2-propanediol, reaction with diethyl carbonate to give 3-p-methoxyphenyl-5-hydroxymethyl-oxazolidin-2-one (m.p. 133°-134°) and reaction with CH3SO2Cl] is heated together with 5.08 g of 4-p-chlorophenyl-4-hydroxypiperidine in 25 ml of DMF at 95°-100° for 1 hour; the mixture is cooled and worked up in a conventional manner to give 3-p-methoxyphenyl-5-(4-p-chlorophenyl-4-hydroxy-piperidinomethyl)-oxazolidin-2-one, m.p. 143°-144°.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:76][N:77]([CH3:81])[CH2:78][CH2:79][NH2:80]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([NH:80][CH2:79][CH2:78][N:77]([CH3:81])[CH3:76])=[O:27])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Reactant: CN(C)CCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1cc(F)c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)cc1F
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a mixture of 0.0606 g (0.134 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0292 g (0.216 mmole) of 1-hydroxybenzotriazole, 0.0784 g (0.207 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1083 g (0.804 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0174 g (0.198 mmole) of N,N-dimethylethylenediamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0589 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-2,5-difluoro-benzamide (I-236) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:6][C:2]=2[CH3:1])=[N:20][CH:19]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cn1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethanol (1.56 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure and ice water was added to the residue. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 5-chloromethyl-2-(5-methyl-2-phenyl-4-thiazolylmethoxy)pyridine (1.53 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 78–79° C.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[O:44]1[C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=[N:45]1>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:49]([C:48]4[O:44][N:45]=[CH:46][CH:47]=4)=[O:50])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: O=C(Cl)c1ccno1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)c1ccno1)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (38.1 mg, 0.074 mmol) in DCM (736 μL) at 0° C. was treated with triethylamine (30.8 μL, 0.221 mmol), followed by isoxazole-5-carbonyl chloride (14.2 μL, 0.147 mmol). The reaction mixture was allowed to warm to room temperature and stir for 45 min. The reaction mixture was concentrated under reduced pressure and purified directly by HPLC Method B, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column was used, using a 55% to 90% ACN gradient to give the title compound, as a TFA salt, as a tan oil (18.6 mg, 41.2%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.30 (m, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.89 (m, 2H), 3.11 (m, 2H), 3.46 (m, 2H), 3.91-4.21 (m, 3H), 4.49 (m, 1H), 4.78 (br s, 2H), 6.87 (m, 1H), 6.92 (s, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H), 8.55 (s, 1H); ESI-MS m/z [M+H]+ 499.5.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1ccc(C#N)c(N)c1
Product: Cc1ccc(C#N)c(NC(=O)NC(=O)c2ccccc2)c1

Procedure:
Prepared as in Example 1a from 2-amino-4-methylbenzonitrile and benzoyl isocyanate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.10-7.13 (m, 1H), 7.54 (t, J=7.8 Hz, 2H), 7.66 (t, J=7.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 8.02-8.04 (m, 2H), 8.07 (s, 1H), 11.32 (s, 1H), 11.44 (s, 1H). MS 280 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]([CH3:33])[CH:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:15]([CH3:33])[CH:16]2[CH2:32][CH2:31][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a suspension of tert-butyl 8-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (3.9 B: 0.19 g, 0.40 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 3.5 M). The mixture was stirred at room temperature for 2 h, then concentrated in vacuo. The residue was diluted with DCM (10 mL) and saturated Na2CO3 aqueous solution (10 mL) and then the mixture was extracted with DCM/MeOH (v/v)=10/1 (30 mL×5). The combined organic layer was dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/2N NH3 in MeOH (v/v)=5/1) to give 3.10 B as a light yellow solid (0.14 g, 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:14][O:13][C:9](=[O:12])[CH:10]=[CH:11][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: Cc1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C=Cc1cnc(C)nc1
Temperature: 150 °C
Yield: 16.8 %

Procedure:
A sealed mixture of 5-Bromo-2-methyl-pyrimidine (2.6 g, 15.03 mmol, 1 eq), methyl acrylate (1.40 eq, 1.89 ml), palladium(II)-acetate (0.013 eq, 44 mg), triphenylphosphine (0.024 eq, 95 mg), and triethylamine (1.21 eq, 2.54 ml) was heated at 150° C. (temperature on display of heating device) for 16 hours. The mixture was cooled to ambient temperature and was poured into 200 ml of water. Organic substances were extracted with EtOAc (twice, 200 ml was used in total). The gathered EtOAc layers were filtered over celite pad, were dried and the solvent was evaporated. The resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 50 g normal phase silica SNAP column and EtOAc/cyclohexane solvent system (gradient 30-80% of EtOAc in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 3-(2-Methyl-pyrimidin-5-yl)-acrylic acid methyl ester (450 mg, yield=16.80%, purity=95%). MS: [M+H]+=179.13 1H NMR (300 MHz; CDCl3) δ/ppm 2.74 (s, 3H), 3.81 (s, 3H), 6.52 (d, J=16.60 Hz, 1H), 7.58 (d, J=16.60 Hz, 1H), 8.75 (s, 2H)
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:48][C:43]2[CH:44]=[CH:45][CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N[C@@H]1CCCN(C(OC(C)(C)C)=O)C1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][C@@H:43]5[CH2:44][CH2:45][CH2:46][NH:47][CH2:42]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-tert-butyl 3-aminopiperidine-1-carboxylate, where Boc was removed using TFA in DCM. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.52 (m, 2 H) 1.52-1.77 (m, 7 H) 1.85-1.99 (m, 3 H) 2.45 (t, J=9.9 Hz, 2 H) 2.85 (d, J=12.4 Hz, 1 H) 3.01 (dd, J=11.8, 3.4 Hz, 1 H) 3.32 (s, 3 H) 3.85 (m, 1 H) 3.94 (s, 3 H) 4.05 (t, J=14.0 Hz, 3 H) 4.76 (quin, J=8.2 Hz, 1 H) 7.47 (dd, J=1.8 Hz, 1 H) 7.49 (s, 1 H) 7.97 (s, 1 H) 8.04 (d, J=7.8 Hz, 1 H) 8.26 (s, 1 H) 8.28 (d, 1 H). [M+H] calc'd for C26H33F2N7O3, 530; found 530.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][O:28][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].Cl.O>CO.O1CCCC1>[C:9]([O:8][CH2:7][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][OH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCCC(CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1)(COC(C)=O)COC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)OCCC(CCC1(CCO)CCCCC1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 51.6 %

Procedure:
To a solution of 2-(acetoxymethyl)-2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane (340 mg) in methanol (5 mL) and tetrahydrofuran (3 mL) was added 3N hydrochloric acid (2.0 mL) at room temperature. After stirring the solution at room temperature for 5.5 hours, water was added thereto. The solution was concentrated under reduced pressure to distill off methanol and tetrahydrofuran, and it was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=4:6) to give the title compound (110 mg).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([NH:18][C:19]([NH:21][C:22]2[CH:23]=[N:24][C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:26]([Cl:28])[CH:27]=2)=[O:20])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:10]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:2]([C:6]1[CH:7]=[C:8]([NH:18][C:19]([NH:21][C:22]2[CH:23]=[N:24][C:25]([N:29]3[CH2:34][CH2:33][N:32]([C:39]([C:36]4([CH3:35])[CH2:38][CH2:37]4)=[O:40])[CH2:31][CH2:30]3)=[C:26]([Cl:28])[CH:27]=2)=[O:20])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:10]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(N3CCNCC3)c(Cl)c2)cc1
Reactant: CC1(C(=O)O)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(N3CCN(C(=O)C4(C)CC4)CC3)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Over a solution of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(5-chloro-6-piperazin-1-yl-pyridin-3-yl)-urea hydrochloride (1.6 mmol, 0.7 g), in 5 mL of CH2Cl2 add 1-methyl-cyclopropanecarboxylic acid (1.6 mmol, 0.2 g), 1-hydroxy-1H-benzotriazol hydrate (1.8 mmol, 0.2 g), N-ethyl-N′-(3-domethylaminopropyl) carbodiimide hydrochloride (1.8 mmol, 0.3 g) and triethylamine (4.8 mmol, 0.7 mL). Stir the solution for 24 hours at room temperature. Add water and extract with CH2Cl2. Combine the organic layers and wash with saturated aq. sodium chloride solution, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate in gradient (from 20% to 80%). MS(ES+): m/z=550 [M+H].
Reaction SMILES: [C:1]([C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[ClH:12].[CH2:13]([O:15]CC)[CH3:14]>C(O)C.O1CCCC1>[ClH:12].[S:10]1[C:11]2[C:3]([C:1](=[NH:2])[O:15][CH2:13][CH3:14])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=[N:9]1
Reactant: CCOCC
Reactant: N#Cc1cccc2nnsc12
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=N)c1cccc2nnsc12
Reaction time: 24 h

Procedure:
7.2 g of 7-cyanobenzo-1,2,3-thiadiazole are dissolved at 45° C. in 60 ml of absolute ethanol and 20 ml of tetrahydrofuran, and the solution is cooled to 0° C. and saturated with gaseous hydrochloric acid in the course of 1 hour at 0° C. to 15° C., with the exclusion of moisture. The reaction mixture is then stored for 24 hours in the refrigerator, treated with 70 ml of absolute diethyl ether and allowed to stand for another 4 days in the refrigerator. The solid is then filtered off, washed with diethyl ether and dried. This gives 9.4 g of compound 5.2 in the form of beige crystals of m.p. 270°-272° C.