Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[N+:14]([O-])=O)[CH:2]=[CH2:3].[CH2:17](N)[CH2:18][CH2:19][CH3:20]>C(O)(C)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH:14][CH2:17][CH2:18][CH2:19][CH3:20])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: CCCCN
Solvent: CC(C)O
Product: C=CCOc1cccc([N+](=O)[O-])c1NCCCC
Reaction time: 2 h

Procedure:
A mixture of 9.0 g of 1-allyloxy-2,3-dinitrobenzene and 40 ml of n-butylamine in 400 ml of isopropanol is heated under reflux, and stirred, for two hours. After evaporating off the solvent and the excess n-butylamine under reduced pressure, the resulting oil is dried at 50°/0.01 mm Hg for 2 hours. The 1-allyloxy-2-butylamino-3-nitrobenzene which is thus obtained can be further used without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3c(F)cccc3F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Difluoro-benzoyl chloride (45 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H31F2N3O3+H: 520, observed: 520.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:31](=[O:41])[N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[N:4][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][C:9]=2[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:6]=1[CH3:7].[OH-].[Na+]>CCO.C1COCC1>[Cl:1][C:2]1[C:3]([C:31](=[O:41])[N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[N:4][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of ethyl 4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (930 mg, 1.61 mmol) in EtOH (5.0 mL) and THF (5.0 mL) was added 2N NaOH (4.0 mL, 8.03 mmol). The resulting reaction mixture was stirred at 40° C. for 1 h, cooled to room temperature and quenched with 6N HCl. The solution was extracted with CHCl3 (3×), and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (885 mg, 99%), which was used without further purification. 1H NMR (DMSO-d6, 2:1 mixture of amide rotamers) δ 8.32 (s, 0.5H), 8.14 (dd, J=8.36, 1.98 Hz, 1H), 8.07-7.98 (m, 1H), 7.83-7.72 (m, 1H), 7.28-7.06 (m, 3H), 7.03-6.93 (m, 0.5H), 4.86-4.68 (m, 0.5H), 4.65-4.47 (m, 1H), 4.42-4.24 (m, 0.5H), 3.88-3.70 (m, 0.5H), 3.66-3.34 (m, 3.5H), 3.23-3.06 (m, 1H), 3.04-2.94 (m, 1H), 2.87-2.70 (m, 2H), 2.26 (s, 2H), 2.21 (s, 1H), 1.47-1.34 (m, 0.5H), 1.33-1.06 (m, 5.5H), 1.01-0.91 (m, 2H), 0.88-0.82 (m, 3H), 0.70-0.62 (m, 3H); MS(ESI+) m/z 551.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH2:20][OH:21])[NH:6][C:7]=1[C:8]1[C:9]([CH3:19])=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=1)[C:13]([O:15]C)=[O:14])#[N:2].[OH-].[Na+]>CO.O>[C:1]([C:3]1[N:4]=[C:5]([CH2:20][OH:21])[NH:6][C:7]=1[C:8]1[C:9]([CH3:19])=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=1)[C:13]([OH:15])=[O:14])#[N:2]
Reactant: COC(=O)c1cc(-c2[nH]c(CO)nc2C#N)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(-c2[nH]c(CO)nc2C#N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of methyl 5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 219.6, 100 mg, 0.35 mmol) in methanol (10 mL) and a solution of NaOH (0.14 g, 3.5 mmol) in water (5 mL). The reaction mixture was stirred for 15 h at room temperature, then concentrated under reduced pressure. The pH of the solution was adjusted to 1-2 with hydrogen chloride (4 M). The resulting mixture was concentrated under reduced pressure. Methanol (5 mL) was added to the residue. The salt was filtered off, and the filtrate was concentrated under reduced pressure to give 200 mg (crude) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:9]([CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH:10]=[O:11])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC[C@@H](Cc1cc(F)ccc1F)N(Cc1ccccc1)Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@@H](Cc1cc(F)ccc1F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 1.5 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-Dibenzylamino-3-(2,5-difluoro-phenyl)-propan-1-ol (5.10 g, 13.9 mmol) in DMSO (1 mL) and Triethylamine (7.83 mL, 56.2 mmol) at −9° C. is added a solution of Sulfur Trioxide Pyridine Complex (4.43 g, 27.3 mmol) in DMSO (19.6 mL) over a period of 60 min, the reaction temperature is maintained below 4° C. The reaction is allowed to stir an additional 15 min at 0-3° C. after which the reaction is quenched by addition of water (50 mL) over a period of 60 min, the reaction temperature is maintained below 10° C. The product is extracted into MTBE, the organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.FC(F)(F)S(O[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH:24]=[O:25])[CH:17]=1)(=O)=O>>[CH3:23][O:22][C:20]1[CH:19]=[C:18]([CH:17]=[C:16]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:21]=1)[CH:24]=[O:25]
Reactant: OB(O)c1ccncc1
Reactant: COc1cc(C=O)cc(OS(=O)(=O)C(F)(F)F)c1
Product: COc1cc(C=O)cc(-c2ccncc2)c1

Procedure:
Pyridine-4-boronic acid (50 mg, 0.35 mmol) is coupled to aryl triflate 241 (66 mg, 0.23 mmol) using Method A to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:15]=2)[C:10]([C:24](=[O:30])[C:25]([O:27]CC)=[O:26])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:15]=2)[C:10]([C:24](=[O:30])[C:25]([OH:27])=[O:26])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3cccc(Cl)c3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3cccc(Cl)c3)ccc12
Yield: 60.3 %

Procedure:
{1-Benzyl-6-(3-chlorophenyl)-1H-indol-3-yl](oxo)acetic acid was prepared from ethyl [1-benzyl-6-(3-chlorophenyl)-1H-indol-3-yl](oxo)acetate (0.489 g, 1.17 mmol), and potassium hydroxide (0.214 g, 3.81 mmol) in THF (10 mL) and water (10 mL), according to the procedure described in Step 4 of Example 5. Crystallization from acetonitrile and drying for 24 hours at 94° C. furnished the title compound as a yellow solid (0.275 g, 60%), mp: 186-188° C. Mass spectrum (−ESI, [M−H]−) m/z 388; 1HNMR (500 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.7 (s, 1H), 8.25 (d, 1H, J=8.4 Hz), 8.0 (d, 1H, J=0.76 Hz),7.75 (t, 1H, J=1.8 Hz), 7.65-7.7 (m, 2H), 7.5 (t, 1H, J=7.9 Hz), 7.4 (m, 1H), 7.3-7.4 (m, 4H), 7.25-7.3 (m, 1H), and 5.7 ppm (s, 1H). Elemental Analysis for C23H16ClNO3.0.05 H2O: Calculated: C, 70.70; H, 4.15; N, 3.58. Found: C, 70.45; H, 3.97; N, 3.71.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)[CH:3]=1.[NH2:26][C:27]1C=C(C=CN=1)C#N>>[C:27]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)[CH:3]=1)#[N:26]
Reactant: N#Cc1ccnc(N)c1
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3cc(F)ccn3)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(C(=O)Nc3cc(C#N)ccn3)cc2)OC1(C)C
Yield: 99 %

Procedure:
This compound was prepared, in an analogous manner as described in Intermediate 4, starting from 2-aminoisonicotinonitrile, to afford the title compound (1.3 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:11].[N:13]#[C:14]Br.C(O)C>O>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:11][C:14]([NH2:13])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: N#CBr
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc2nc(N)oc12
Yield: 76 %

Procedure:
A mixture of 913 mg (5.46 mmol) 3-amino-2-hydroxy-benzoic acid methyl ester, 894 mg (8.19 mmol) of cyanogen bromide, 14.4 mL of ethanol and 1.6 mL of water was heated under reflux for 1 h. Ethanol was evaporated under reduced pressure and 20 mL of 2 N aq. Na2CO3 was added to the residue. The precipitated solid was filtered and washed with water. The remaining product was treated with methanol and the soluble filtrate containing the product was evaporated in vacuo to provide 797 mg (4.15 mmol, 76%) of 2-amino-benzooxazole-7-carboxylic acid methyl ester. LCMS: 193 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[N:7]([CH:13]3[CH2:15][CH2:14]3)[C:6]=2[N:16]=1.[H-].[Na+].[N+:20](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O.O1CCOCC1>[NH2:20][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([F:17])[C:2]([Cl:1])=[N:16][C:6]=2[N:7]([CH:13]2[CH2:15][CH2:14]2)[C:8]1=[O:12]
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc(Cl)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nn1c(=O)c2cc(F)c(Cl)nc2n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A solution of 3.83 g (15 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example 23i) in 50 mL of dimethylformamide-dioxane (1:1) is cooled to 0° C. and treated portionwise with 0.8 g (20 mmol) of 60% sodium hydride/mineral oil. The reaction is stirred to room temperature for 30 minutes, re-cooled to 0° C. and 3.2 g (16 mmol) of 2,4-dinitrophenylhydroxylamine is added all at once. After stirring at room temperature overnight, the dioxane is removed in vacuo and the residue is diluted to 300 mL with ice and water and stirred at 5° C. for 1 hour. The precipitate is removed by filtration, washed with water, ether and dried in vacuo to give 2.65 g of the title compound, mp 192-194° C. A second crop, (0.6 g) could be isolated by evaporating the filtrate and triturating the residue with petroleum ether.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:7]([F:30])=[CH:8][C:9]([Cl:29])=[C:10]([N:12]2[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]2=[O:28])[CH:11]=1.C(N(CC)CC)C>O1CCCC1>[Cl:29][C:9]1[CH:8]=[C:7]([F:30])[C:6]([N:5]=[C:1]=[S:2])=[CH:11][C:10]=1[N:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]1=[O:28]
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N=C=S)c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thiophosgene (0.50 mL, 6.5 mmol) is added over 45 minutes to a solution of isopropyl 3-(5-amino-2-chloro-4-fluorophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (2.5 g, 6.5 mmol), and triethylamine (1.8 mL, 13.0 mmol) in tetrahydrofuran. The reaction mixture is stirred at room temperature for 4 hours, diluted with tetrahydrofuran, and filtered. The filtrate is concentrated in vacuo to give the title product as an orange oil which is identified by NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].O>C1C=CC=CC=1>[CH2:11]([N:13]([CH2:14][CH3:15])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)[CH3:12]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCNCC
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC)C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a 50 ml flask fitted with a stirrer, condenser, drying tube and an addition funnel is added m-fluorobenzoyl chloride (15.9 g, 0.10 mole) and benzene (100 ml). Then a solution of diethylamine (14.6 g, 0.20 mole) in benzene (100 ml) is added dropwise over 1 hour and the reaction mixture allowed to stir at room temperature overnight. Water (150 ml) is then added rapidly and after trituration for a few minutes, the benzene layer is decanted and washed repeatedly with water (5×150 ml), dried (anhyd. Na2SO4) and the solvent removed under vacuum to afford 18 grams of N,N-diethyl-3-fluorobenzamide as a yellow oil. Elemental analysis calculated for C11H14FNO: C, 67.70; H, 7.22; F, 9.72; N, 7.16; Found: C, 66.40; H, 7.08; F, 9.65; N, 6.92
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[N:5]=[C:4]([CH3:11])[CH:3]=1.CO.[NH3:14]>>[NH2:14][C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[N:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)c(C#N)c(O)n1
Reactant: N
Solvent: CO
Product: Cc1cc(N)c(C#N)c(O)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a pressure vessel were added 4-chloro-2-hydroxy-6-methylnicotinonitrile (600 mg, 3.6 mmol), ammonia methanol solution (7 mol/L, 15 mL) and magnetic stirrer. The pressure vessel was sealed, and stirred at 100° C. for 16 hours. After being cooled to room temperature, the solvent and excess ammonia were removed by rotary evaporation. The residue was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 4-amino-2-hydroxy-6-methylnicotinonitrile (350 mg, 66% yield) as a brown solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6]2)=O.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[N:21]1([CH2:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6]3)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Reaction time: 8 h

Procedure:
In 100 mL of 1,2-dichloroethane, 5.0 g (18 mmol) of (R)-tert-butyl 6-formyl-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate and 3.1 g (36 mmol) of piperidine were combined. Next, 7.6 g (36 mmol) of sodium triacetoxy borohydride was added and the mix was stirred under nitrogen overnight. The mix was then dissolved in 100 mL of ethyl acetate, washed with 25 mL of saturated sodium bicarbonate, washed with 25 mL of brine, dried with sodium sulfate and concentrated to yield the crude material.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([OH:32])=[CH:29][CH:30]=2)[N:25]([CH3:33])[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][C:2]3[C:11]4[CH2:10][N:9]([CH2:12][C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)[C:8](=[O:21])[NH:7][C:6]=4[N:5]=[CH:4][CH:3]=3)=[CH:29][CH:30]=2)[N:25]([CH3:33])[N:24]=1
Reactant: Cn1nc(N)c2ccc(O)cc21
Reactant: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(Oc4ccc5c(N)nn(C)c5c4)ccnc3NC2=O)cc1
Temperature: 130 °C
Yield: 70.4 %

Procedure:
Suspended 5-chloro-3-(4-methoxy-benzyl)-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-2-one (400.00 mg; 1.32 mmol; 1.00 eq.), 3-amino-1-methyl-1h-indazol-6-ol (268.61 mg; 1.65 mmol; 1.25 eq.) and cesium carbonate (858.15 mg; 2.63 mmol; 2.00 eq.) in DMF (4.00 ml). Heated in a microwave at 130° C. for 90 min. The reaction was concentrated, redissolved in DMSO (20 mL) and filtered through celite. Purified filtrate via prep HPLC to afford 400 mg (56%) of compound 276 as a tan solid. LC-MS (M+H=431, obsd.=431)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]([F:23])([F:22])[F:21])=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH:24]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]([F:23])([F:21])[F:22])=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:24]2)[CH:7]=1
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2OC(F)(F)F)C1=O
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2OC(F)(F)F)C1=O
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of 4-[1-(5-bromo-2-trifluoromethoxyphenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (7.06 g, 18.00 mmol) in methanol (300 ml) at 35° C. is added 50% aqueous hydrogen peroxide (1.80 ml, 27.00 mmol), immediately followed by 2M aqueous lithium hydroxide (1.80 ml, 3.60 mmol). After stirring at this temperature for 1 hour the reaction mixture is allowed to cool, then quenched with 10% sodium metabisulfite solution (negative KI-starch indicator test). The reaction mixture is extracted with diethyl ether (×3), then the organic phase is further washed with saturated aqueous sodium bicarbonate (×2) then brine. All organics are combined, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford 2-(5-bromo-2-trifluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (6.34 g, 86%) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:9]2[CH:8]=[CH:13][CH:12]=[CH:11][C:10]=2[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: C1CNCCN1
Reactant: Brc1ccccc1C1CCCCC1
Product: c1ccc(N2CCNCC2)c(C2CCCCC2)c1

Procedure:
The title compound was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 1-bromo-2-cyclohexyl-benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Si:10]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[NH2:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a solution of 3-aminobenzyl alcohol (2.00 g, 16.2 mmol) and tert-butyldimethylsilyl chloride (2.90 g, 19.4 mmol) in CH2Cl2 (32.5 mL) was added triethylamine (7.45 mL, 53.5 mmol). The reaction mixture was stirred for 18 hours at ambient temperature and was then partitioned between ethyl acetate and H2O. The organic phase was washed twice with H2O, twice with brine, dried over MgSO4, filtered, and concentrated in vacuo. 3-(O-t-butyldimethylsilyloxymethyl)aniline (2.18 g, 57%) was obtained as a yellow oil by chromatography on silica gel (30% ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3) δ7.10 (1H, t, J=7.5 Hz), 6.67-6.72 (2H, m), 6.56 (1H, br d, J=7.5 Hz), 4.66 (2H, s), 3.63 (2H, br s), 0.94 (9H, s), 0.09 (6H, s). MS m/e 238 (M+H)+, 255 (M+NH4)30 .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[N-:18]=[N+:19]=[N-:20].[Na+].C(O)(=O)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]2[NH:20][N:19]=[N:18][N:12]=2)=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(OCc2cccc(Cl)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCO
Product: Clc1cccc(COc2ccc(-c3nnn[nH]3)cc2)c1

Procedure:
To a solution of 5×10-2 mole of 4-(3-chloro benzyloxy) benzonitrile in 20 ml of butanol are added 6.6×10-2 mole of sodium azide and 6.6×10-2 of acetic acid. Then the reaction mixture is heated to reflux for four days. 1 g of sodium azide, 2 g of acetic acid and 10 ml of butanol are added and the medium is again heated for two days at reflux. After concentrating by evaporating the solvent, the residue is taken up in 20 ml of 10% aqueous NaOH. After filtration, the aqueous phase is extracted with ether. By acidification of the alkaline solution using HCl 2N, the expected compound precipitates and is recrystallized in methanol.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].[Cl:34]([O-:38])(=[O:37])(=[O:36])=[O:35].[Li+]>C(O)(=O)C>[Cl:34]([O-:38])(=[O:37])(=[O:36])=[O:35].[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S+:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CCCC(=O)c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Product: c1ccc(-c2cccc(-c3ccccc3)[s+]2)cc1
Yield: 24 %

Procedure:
The 1,5-diphenyl-1,5-pentanedione prepared in step 1 (10 mmol, 2.52 g) is mixed with phosphorus pentasulfide (15 mmol, 3.34 g), acetic acid (60 mL) and lithium perchlorate (60 mmol, 6.40 g) in a 100 mL two-necked round-bottomed flask, and then refluxed for 3 hours. The solution then becomes orange and a white precipitate forms. The precipitate is removed by filtration on a sinter funnel and then washed with hot acetic acid. The solution is concentrated on a rotary evaporator and recrystallized by addition of ether (500 mL). The precipitate obtained is filtered off on a sinter funnel and then dried on a rotary evaporator. The product obtained is a yellow solid in a mass of 850 mg. The reaction yield is 24%.