Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]#[N:21]>C(O)C.N1CCCCC1>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:20]#[N:21]
Reactant: N#CCc1ccccn1
Reactant: COc1ccc(C=O)cc1OC
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=C(C#N)c2ccccn2)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2.0 g (12.0 mmole) 3,4-dimethoxybenzaldehyde in 75 ml absolute ethanol are added 1.56 g (13.3 mmole) 2-pyridylacetonitrile and 12 drops piperidine. The reaction flask is equipped with a condenser and a drying tube (using anhydrous CaSO4), and the reaction is stirred and heated. After refluxing for 6 hours, the reaction is allowed to cool to room temperature and stirred overnight for 16 hours. The solvent is removed by rotary evaporation, and the residue purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 4:1. The yellow solid is recrystallized from acetone-hexane to give 2-(2-pyridyl)-3-(3,4-dimethoxy-phenyl)-2-propenenitrile, m.p. 112°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH:24]=3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[H][H]>CC(O)=O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2oc(-c3ccc(F)cc3)nc2-c2ccccn2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2oc(-c3ccc(F)cc3)nc2-c2ccccn2)CC1

Procedure:
A mixture of tert-butyl 4-[2-(4-fluorophenyl)-4-(pyridin-2-yl)-1,3-oxazol-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate (0.2 g, 0.475 mmol) and Pd/C (0.10 g, 10%, 0.095 mmol) in AcOH (20 ml) was hydrogenated on a shaker at 45 psi hydrogen for 2 days. Then the catalyst was filtered off, and the filtrate was concentrated. The resulting residue was purified by reverse phase HPLC to give the title compound. LC-MS m/e 424.25 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([F:15])[C:8]([F:16])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:19])=O.CN(C)C=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([F:15])[C:8]([F:16])=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
In 37 ml of toluene was dissolved 30 g (0.124 mole) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid, and 35 ml of thionyl chloride and 0.5 ml of N,N-dimethylformamide were added thereto. The mixture was refluxed by heating for 4 hours. After the reaction, toluene and excess thionyl chloride were removed under reduced pressure to obtain 2,4,5-trifluoro-3-difluoromethoxybenzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][C:9]=1[NH:10]2.[CH3:29][C:30]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32]>>[NH2:32][C:31]1[C:30]([CH3:29])=[C:36]([C:2]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]3[C:3]=2[C:4]2[CH2:5][CH2:6][CH:7]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:8][C:9]=2[NH:10]3)[CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(NC(=O)OCc1ccccc1)CC3
Product: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3c(c12)CCC(NC(=O)OCc1ccccc1)C3

Procedure:
Using the procedure of Example 3-2, benzyl 5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate (Intermediate 50-4(a), 300 mg, 0.678 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate 50-1, 237 mg, 1.017 mmol) were converted into benzyl 5-(3-amino-2-methylphenyl)-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate, TFA salt, isolated as a white solid after preparative HPLC purification (60 mg, 15%). 1H NMR (400 MHz, methanol-d4) δ 7.63 (1 H, dd, J=7.7, 2.9 Hz), 7.18-7.46 (8 H, m), 6.82 (1H, dd, J=7.5, 2.8 Hz), 5.10 (2 H, s), 3.90 (1 H, br. s.), 3.14 (1 H, d, J=4.8 Hz), 2.72 (1H, br. s.), 1.77-2.19 (6 H, m), 1.51-1.68 (1 H, m). Mass spectrum m/z 469.3 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH2:28])=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH:28][C:9](=[O:11])[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Agent: Cl
Product: O=C(Cc1ccccn1)Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Yield: 45.1 %

Procedure:
2-Pyridylacetic acid hydrochloride (44 mg, 0.25 mmol) and the product from Example 99A (62 mg, 0.25 mmol) were processed as described in Example 98 to afford 41 mg (45%) of the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 8.85 (dd, J=7.0, 1.7 Hz, 1H), 8.55 (dd, J=4.1, 1.7 Hz, 1H), 8.47-8.53 (m, 1H), 7.77-7.86 (m, 1H), 7.68-7.71 (m, 2H), 7.40-7.48 (m, 1H), 7.31-7.40 (m, 3H), 7.05 (dd, J=7.0, 4.1 Hz, 1H), 3.97 (s, 2H); MS (ESI) m/z 364 (M+H)+; Anal. calculated for C19H14ClN5O: C, 62.73; H, 3.88; N, 19.25. Found C, 62.65; H, 3.65; N, 19.19.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C:21]([O-:24])(=[O:23])[CH3:22].[Na+]>CN(C=O)C.O>[C:21]([O:24][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:10](=[O:11])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=[CH:3][C:2]=1[Br:1])(=[O:23])[CH3:22]
Reactant: CCOc1ccc(C(=O)c2ccc(CBr)c(Br)c2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)c2ccc(COC(C)=O)c(Br)c2)cc1
Temperature: 68 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
To a solution of (3-bromo-4-(bromomethyl)phenyl)(4-ethoxyphenyl)methanone (0.456 g, 1.15 mmol) in 15 mL of DMF was added sodium acetate (0.188 g, 2.29 mmol). After being stirred for 2.5 h at 68° C., the mixture was diluted with 15 mL of H2O and extracted 3× with ethyl acetate. The combined organic layers were washed once with saturated NH4Cl, once with saturated brine and dried over Na2SO4. Concentration under reduced pressure gave 0.412 g of the crude product, which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.95 (d, J=1.2 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.68 (dd, J=1.2, 8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 5.25 (s, 2H), 4.12 (q, J=7.0 Hz, 2H), 1.46 (t, J=7.0 Hz, 3H); MS ESI (m/z) 377 (M+1)+, calc. 376.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1.C(N(CC)CC)C>C(OCC)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:1](=[O:3])[CH3:2])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1
Reactant: CC1(C)c2cc(Br)ccc2OC1O
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC1Oc2ccc(Br)cc2C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
Acetyl chloride (2.0 g) in diethyl ether (10 ml) was added dropwise to a stirred, cooled solution of 5-bromo-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (5.0 g), prepared as in Example 5(e), and triethylamine (2.5 g) in diethyl ether (40 ml). After stirring for 3 hours at room temperature the mixture was washed with water three times, dried over magnesium sulphate and run down to yield 5 g of crude product, mp 73°-80° C., which was recrystallised from petroleum ether (80°-100° C.) with charcoaling to give 4 g of pure product, mp 83°-85° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]([CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:2]([F:1])([F:30])[C:3]([N:5]([CH2:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCOC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N(CC1CNCCO1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a solution of tert-butyl 2-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)morpholine-4-carboxylate (820 mg, 1.914 mmol) in dichloromethane (DCM) (8 mL) was added TFA (2 mL, 26.0 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dried under vacuum to give 533 mg of product as colorless oil. MS: (M+H)+=329.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.28-1.83 (m, 2H), 2.40-2.98 (m, 5H), 3.45-3.95 (m, 5H), 7.06-7.39 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
To a solution of 1B (1.636 g, 5 mmol) in DCE (16 mL) at RT was added benzaldehyde (1 mL, 10 mmol), followed by NaB(OAc)3H (2.97 g, 14 mmol) and AcOH (0.6 mL, 10 mmol). The reaction mixture was stirred at RT for 16 h, then quenched with aqueous NaHCO3 (40 mL) and extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with 0-20% of EtOAc in hexane to give the title compound (1.70 g, 81%) as a white foam.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].C(=O)([O-])[O-:18].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:18])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C([O-])[O-]
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 93.4 %

Procedure:
Into a 500 ml glass reactor equipped with a reflux condenser and a stirrer, 100 g (0.413 mol) of the 3,4,5,6-tetrafluorophthaloyldifluoride separated by distillation from the mixture of Example 2, 43.8 g (0.413 mol) of sodium carbonate and 200 g of xylene were charged, and the mixture was reacted at 130° C. for 1.5 hours with vigorous stirring. Then, the inorganic substance was removed by filtration, and the residue was separated by distillation to obtain 84.9 g of tetrafluorophthalic anhydride. The yield was 93.4%.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:5]([F:17])=[C:6]([CH:12]=[C:13]([F:16])[C:14]=1F)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:19]=[N+:20]=[N-:21].[Na+].C(OCC)(=O)C.Cl>CS(C)=O>[N:19]([C:14]1[C:13]([F:16])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([F:17])[C:4]=1[O:3][CH:2]([F:18])[F:1])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)c(N=[N+]=[N-])c(OC(F)F)c1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In 66 ml of dimethyl sulfoxide was dissolved 13.2 g of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoate, and to this solution was added 7.3 g of sodium azide, after which the resulting mixture was stirred at room temperature for five hours. The reaction mixture was added to a mixed solvent of 150 ml of ethyl acetate and 150 ml of ice water and the pH was adjusted to 2 with 6N hydrochloric acid, after which the organic layer formed was separated, then washed successively with water and a saturated saline solution, and thereafter dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluent: n-hexane:ethyl acetate=10:1), to obtain 13.9 g of colorless, oily ethyl 4-azido-2,5-difluoro-3-difluorome-thoxybenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]C(C)(C)C.[CH3:32][C:33]1[CH:40]=[C:39]2[O:41][CH2:42][O:43][C:38]2=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:35]([OH:36])[C:34]1[CH:37]=[C:38]2[O:43][CH2:42][O:41][C:39]2=[CH:40][C:33]=1[CH3:32])(=[O:9])=[O:10]
Reactant: Cc1cc2c(cc1C=O)OCO2
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 36.7 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxy-methyl)thieno [2,3-b]pyridine-3-sulfonamide (0.31 g, 0.75 mmoles)[Example 4(A)], THF (4 ml), t-BuLi (1.7 M, 0.53 ml, 0.90 mmoles) and 2-methyl-4,5-(methylenedioxy)benzaldehyde (0.15 g, 0.90 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 0.16 g (38%) of the title compound.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[F:10][C:9]1[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: C1COCCN1
Reactant: O=Cc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccc(F)c1N1CCOCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A 100 mL round-bottom flask was charged with 2,3-difluorobenzaldehyde (2.00 g, 14.1 mmol, 1.00 equiv), morpholine (1.84 g, 21.1 mmol, 1.50 equiv), potassium carbonate (4.90 g, 35.4 mmol, 2.52 equiv), and dimethyl sulfoxide (20 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (50 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/20) to yield 0.840 g (28% yield) of 3-fluoro-2-(morpholin-4-yl)benzaldehyde as a yellow solid. 1H NMR 300 MHz, (CDCl3) δ 10.54 (s, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.18-7.34 (m, 2H), 3.85 (br, 4H), 3.23 (br, 4H). LCMS (ESI, m/z): 210 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][C@H:11]1[C@@H:16]([O:17][CH3:18])[CH2:15][CH2:14][CH2:13][N:12]1[C:19]([C:21]1[N:22]=[C:23]([CH3:33])[S:24][C:25]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:20]>>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:9][CH2:10][C@H:11]2[C@@H:16]([O:17][CH3:18])[CH2:15][CH2:14][CH2:13][N:12]2[C:19]([C:21]2[N:22]=[C:23]([CH3:33])[S:24][C:25]=2[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[O:20])=[N:7][CH:6]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: CO[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CN
Product: CO[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example 16 using 2,5-dichloropyrimidine and rac-cis-(2-(aminomethyl)-3-methoxypiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 476.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:8]3.C(N(CC)CC)C.C([O:29][C:30](=O)[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])C>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:30](=[O:29])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[N:8]3
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: Cc1nc2cccc3nc(SCCCCCN)c1n23
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3nc(SCCCCCNC(=O)C(F)(F)C(F)(F)F)c1n23
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 275 mg (1.00 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 30 ml of acetonitrile were added 0.19 ml (1.36 mmol) of triethylamine and 231 mg (1.20 mmol) of pentafluoropropionic acid ethyl ester. The mixture was stirred for 15 hours at room temperature, and the the solvent was distilled off. To the residue was added ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 245 mg (58.1%, a pale brown solid) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:9][N:8]=1)=[O:5].[CH2:33]([N:35]([CH2:50][CH3:51])[CH2:36][CH2:37][N:38]([CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45])[CH3:39])[CH3:34].CCN=C=NCCCN(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:50]([N:35]([CH2:33][CH3:34])[CH2:36][CH2:37][N:38]([CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([NH:1][C:2]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)=[CH:9][N:8]=1)=[O:5])=[O:45])[CH3:39])[CH3:51]
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncc(-c2cccc(C(F)(F)F)c2)cn1
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncc(-c3cccc(C(F)(F)F)c3)cn2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 10.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)benzamide (200 mg, 0.45 mmol, 1.00 equiv) in dichloromethane (5 mL), 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (120 mg, 0.45 mmol, 1.00 equiv), EDCI (130 mg, 0.68 mmol, 1.50 equiv), and 4-dimethylaminopyridine (83 mg, 0.68 mmol, 1.50 equiv). The resulting solution was stirred for 10 h at 25° C. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 32.2 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 11.45 (s, 1H), 11.29 (s, 1H), 9.18 (s, 2H), 8.12-8.21 (m, 3H), 8.03 (s, 1H), 7.89-7.91 (d, J=6.6 Hz, 1H), 7.75-7.84 (m, 2H), 7.62-7.66 (m, 2H), 7.51 (s, 1H), 7.28-7.31 (d, J=8.1 Hz, 1H), 3.37 (s, 2H), 3.26 (s, 4H), 3.10-3.18 (m, 4H), 1.58-1.68 (m, 6H), 1.15-1.20 (m, 6H). MS (ES, m/z): 688.00 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][N:8]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH:25]=[O:26]>C1COCC1>[C:18]([O:17][C:15]([NH:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[CH3:22])=[N:8][CH:9]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)nc1
Reactant: CC(C)(C)CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Reaction time: 0.58 h
Yield: 55 %

Procedure:
Add slowly butyllithium (1.088 mL, 1.741 mmol, 1.6M solution in hexane) to a solution of 2-bromo-5-tert-butoxycarbonylaminomethyl-pyridine (200 mg, 0.696 mmol) in anhydrous THF (10 mL) at −78° C. Stir the mixture at this temperature for 35 min. Add 3,3-dimethylbutyraldehyde (0.219 mL, 1.741 mmol) and stir the mixture at −78° C. for 3 h. Quench the reaction mixture at −78° C. with brine. Extract the aqueous phase with EtOAc (3×15 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify The crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (3:2) to afford the desired intermediate as a colorless oil (118 mg, 55%). MS (ES+) m/z: 309 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:15]=[N:14][N:13]([CH3:16])[C:12]=1[C:17]([OH:19])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:42]1([C:48]2[N:49]=[C:50]3[CH:55]=[C:54]([NH2:56])[N:53]=[CH:52][N:51]3[CH:57]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[C:42]1([C:48]2[N:49]=[C:50]3[CH:55]=[C:54]([NH:56][C:17]([C:12]4[N:13]([CH3:16])[N:14]=[CH:15][C:11]=4[Cl:10])=[O:19])[N:53]=[CH:52][N:51]3[CH:57]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Nc1cc2nc(-c3ccccc3)cn2cn1
Reactant: Cn1ncc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc(Cl)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.7 %

Procedure:
DMF (8 ml) and diisopropylethylamine (738 mg) were added to 4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (916 mg, 5.7 mmol) and TBTU (1.83 g), and the mixture was stirred at r.t. (10 min). 2-Phenyl-imidazo[1,2-c]pyrimidin-7-ylamine (400 mg, 1.9 mmol) was added and the mixture was stirred at r.t. overnight. The reaction mixture was then poured on water (35 ml), and the mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and evaporated. The title compound (45 mg, 6.7%) was isolated from the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40), followed by preparative, inverse-phase HPLC (Agilent Zorbax XdB-C18 column, time per run ˜7 min, flow rate 30 ml/min, solvent gradient H2O/CH3CN=95:5-5:95). MS (m/e)=353.1 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)([O-])=O.[CH3:20][C:21]([Mg]Br)=[CH:22][CH3:23].[Cl-].[NH4+]>O1CCCC1>[CH3:20][C:21]1[NH:1][C:4]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[C:22]=1[CH3:23]
Reactant: CC=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1cnccc1N1CCc2ccccc2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)ccnc2c1C
Temperature: -20 °C
Reaction time: 5 h
Yield: 38.7 %

Procedure:
2-(3-Nitropyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline (5 g, 19.58 mmol) prepared in Preparation 1 was dissolved in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 80 ml, 117.5 mmol) was added at −78° C. to the solution, which was then stirred for 5 hours at −20° C. 20 ml of 20% ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methylene chloride/methanol=10/10/1, (v/v/v)) to give the titled compound as a pale yellow solid (2.1 g, 25.3%).