Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[N:24](C(CCC)C)[N:23]=[CH:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:5][CH2:4][CH2:3][CH2:8][CH3:7])[N:23]=[CH:22]4)=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CCCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Agent: Br
Product: CCCCCn1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Yield: 97 %

Procedure:
This compound was synthesized as a white amorphous solid from 4h (41.1 mg, 0.098 mmol) in 48% aqueous HBr (1.0 mL) in 97% yield by following general procedure 1.4: 1H NMR (400 MHz, CDCl3, δH) 7.62 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 6.68 (d, J=8.5 Hz, 2H), 4.52-4.28 (m, 1H), 3.39-3.28 (m, 4H), 3.25-3.14 (m, 4H), 1.94-1.78 (m, 1H), 1.64 (ddd, J=19.7, 12.6, 5.8 Hz, 1H), 1.44-1.23 (m, 5H), 0.92 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3, δC) 152.47, 151.60, 150.98, 144.38, 134.64, 125.52, 124.54, 119.17, 116.75, 116.28, 51.48, 51.42, 49.20, 37.67, 19.87, 19.70, 14.00. MALDI-MS: 408.2 (M+H+), 430.2 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[N:24]=[C:23]2[C:18]([C:19](=[O:41])[C:20]([C:36]([O:38]CC)=[O:37])=[CH:21][N:22]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])=[CH:17][C:16]=1[F:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[N:24]=[C:23]2[C:18]([C:19](=[O:41])[C:20]([C:36]([OH:38])=[O:37])=[CH:21][N:22]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])=[CH:17][C:16]=1[F:42])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)c(F)cc2c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4C[C@@H]5C[C@H]4CN5C(=O)OC(C)(C)C)nc32)c(OC)c1

Procedure:
A solution of EXAMPLE 84A in 1:1 ethanol/1M NaOH (20 mL) was heated at 80° C. for 18 hours then cooled, poured into saturated ammonium chloride (100 mL), and filtered.
Reaction SMILES: Cl[C:2]1([F:11])[C:7](F)([F:8])[CH2:6][CH:5]=[CH:4][CH:3]1[CH3:10].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:11][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:10]
Reactant: CC1C=CCC(F)(F)C1(F)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: Cc1cccc(F)c1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-chloro-3-methyl-4,5,5-trifluorocyclohexene of 58.6 g prepared in Example 12 was added 2.5 g of benzyltriethylammonium chloride, and then the reaction mixture was heated to 80° C. followed by slowly adding 240 g of 50% aqueous sodium hydroxide solution for 1 hour. The reaction mixture was stirred for additional 3 hours at 80° C., and then the resultant was purified by steam distillation followed by separating the aqueous layer. The organic layer was dried with calcium chloride, and then 32.3 g of the desired product was collected by fractional distillation as a colorless liquid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].[C:19]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCCC1.C(OCC)C>[C:19]([N:29]1[CH2:30][CH2:31][C:32]([C:14]([CH3:16])([CH3:15])[C:13]([OH:18])=[O:17])([OH:35])[CH2:33][CH2:34]1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C(=O)O)C1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.4 %

Procedure:
To a 100 ml flask maintained under argon are added 2.22 g diisopropylamine and 15 ml tetrahydrofuran. The contents of the flask are cooled to 0° and are maintained at that temperature. A solution of 1.5 M n-butyllithium (14.7 ml) is added and the solution is stirred for five minutes. Isobutyric acid (0.88 g) is added and the mixture is stirred for 15 minutes at 20°. The mixture is cooled to -70° and a solution of 2.33 g of N-carbobenzyloxy-4-piperidone in 5 ml tetrahydrofuran is added at such a rate that the temperature remains below -50°. The mixture is allowed to warm to room temperature and is poured into 150 ml diethyl ether. This solution is extracted with two 150 ml portions of 1 N hydrochloric acid, 50 ml of water and 100 ml of 2% sodium hydroxide. The basic layer is acidified with 10 N hydrochloric acid and the resulting mixture is extracted with three 50 ml portions of diethyl ether. Evaporation of the ether affords an oil which is triturated with 50 ml hexane to give 1.65 g 2-(1-carbobenzyloxy-4-hydroxypiperidin-4-yl)-2-methylpropionic acid, an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:29]([F:32])([F:31])[F:30])=[N:5][N:6]([CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH:14]([NH:18]C(=O)OCC2C=CC=CC=2)[CH2:13][CH2:12]3)[CH:7]=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:18][CH:14]1[C:15]2[C:11](=[CH:10][C:9]([CH2:8][N:6]3[CH:7]=[C:3]([CH2:2][OH:1])[C:4]([C:29]([F:32])([F:31])[F:30])=[N:5]3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: O=C(NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Reaction time: 0.5 h

Procedure:
A suspension of palladium hydroxide (0.498 mmol, 350 mg) and benzyl 5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-1-ylcarbamate (2.69 mmol, 1.2 g) in ethanol (30 mL) was hydrogenated at 2 bar pressure for 30 min before the reaction vessel was vented and the whole filtered through a pad of dicalite. The pad was washed with EtOAc and the filtrate concentrated under reduced pressure. The residue was purified using SCX eluting with 2N NH3/MeOH to give a clear oil which solidified on standing (700 mg, 2.25 mmol, 83%). 1H NMR (400 MHz, CDCl3) δ 1.65 (m, 1H) 2.51 (m, 1H) 2.80 (m, 1H) 2.95 (m, 1H) 1.35 (t, 1H) 4.60 (s, 2H) 5.26 (s, 2H) 7.12 (d, 2H) 7.30 (d, 1H) 7.42 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]5([CH2:39][CH2:38]5)[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:40]=[CH:41][N:42]=[C:10]12.C(O)(C(F)(F)F)=O>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]5([CH2:38][CH2:39]5)[CH2:26][NH:27][CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:40]=[CH:41][N:42]=[C:10]12
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Nc3ncc4c(=O)n(-c5c(Cl)cccc5Cl)c5nccn5c4n3)ccc2C2(CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cnc(Nc3ccc4c(c3)CNCC43CC3)nc2n2ccnc2n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 109A (0.12 g, 0.2 mmol) in 3 ml dichloromethane was added excess TFA. The reaction mixture was stirred at room temperature for one hour. The mixture was concentrated and the crude material was dried over high vacuum to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.87-1.27 (m, 4H) 3.18-3.38 (m, 2H) 4.34-4.58 (m, 2H) 6.94 (d, J=8.48 Hz, 1H) 7.13 (d, J=1.70 Hz, 1H) 7.39-8.01 (m, 6H) 8.91-9.45 (m, 3H) 10.88 (s, 1H). MS (ESI+) m/z 504.2 (M+H)+.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[N:15]2)[N:12]=1)=[O:7])[CH3:4].[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH2:19])[CH:16]=[N:15]2)[N:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1nc(Cn2cc([N+](=O)[O-])cn2)cs1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc(Cn2cc(N)cn2)cs1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 4-(4-nitro-pyrazol-1-ylmethyl)-thiazole-2-carboxylic acid ethyl ester (1.77 g, 6.27 mmol), iron powder (1.06 g, 18.81 mmol) and NH4Cl (1.69 g, 31.35 mmol) in a mixture of EtOH (30.0 mL) and water (15.0 mL) was stirred at reflux for 40 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (60 mL) was added followed by 1M NaOH (50 mL). The aq. layer was extracted with CH2Cl2 (2×30 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=0.56 min; [M+H]+=253.36.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=O)[C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>C(O)CO>[Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2c(Cl)cccc2-c2ccccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Clc1cccc2c1CCCCc1ccccc1-2
Yield: 90.6 %

Procedure:
The reaction of 9-chloro-5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-5-one (3.0 g, 0.015 mole), 85% hydrazine hydrate (4.5 g, 0.076 mole), potassium hydroxide (3.0 g, 0.046 mole) and ethylene glycol (39 ml) produced an oil. The oil was purified by column chromatography on silica gel, eluted with toluene to yield 4-chloro-5,6,7,8-tetrahydrodibenzo[a,c]cyclooctene as an oil (3.3 grams).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][N:30]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1
Reactant: CN(C)CCCN(c1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Product: CN(C)CCCN(c1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1)C1CCN(S(C)(=O)=O)CC1
Yield: 90 %

Procedure:
Reaction of the above amine with methanesulfonyl chloride as in Example 21 gave N1-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediamine in 90% yield. Hydrochloride: 1H NMR (DMSO-d6) (rotamers) δ 10.17 and 10.0 (2br, 1H), 8.36 and 8.34 (2d, J=7.0 and 7.9 Hz, 1H), 7.76 and 7.74 (2t, JHF=52.8 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.57-7.53 (m, 1H), 7.46-7.43 (m, 1H), 4.70-4.56 (m, 1H), 3.84-3.71 (m, 10H), 3.62-3.53 (m, 2H), 3.13-3.06 (m, 2H), 2.94 and 2.93 (2s, 3H), 2.90-2.80 (m, 2H), 2.74 and 2.70 (2s, 6H), 1.99-1.87 (m, 6H); Anal. Calcd. for C26H38ClF2N9O3S.0.5H2O: C, 48.9; H, 6.15; N, 19.7; Cl, 5.6. Found: C, 48.9; H, 6.3; N, 19.8; Cl, 5.7%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[H-].[Na+]>C1COCC1.C(O)CCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:9][CH2:2][CH2:3][CH3:4])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Solvent: C1CCOC1
Product: CCCCOc1cc(Br)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 115 %

Procedure:
A solution of 4-bromo-2-hydroxy-benzonitrile (0.89 g, 4.45 mmol) in THF (50 mL) and 1-butanol (2.0 mL) is slowly added to NaH (0.356 g, 8.90 mmol). The mixture is stirred at room temperature for one hour and quenched with water (10 mL). The mixture is concentrated, and the residue is extracted with ethyl acetate (20 mL×2). The combined organic layers are dried over sodium sulfate and concentrated to provide 4-bromo-2-butoxy-benzonitrile (0.65 g, 57%). 1H NMR (400 MHz, CDCl3): δ 7.37-7.34 (d, 1H), 7.11-7.08 (d, 1H), 7.08 (s, 1H), 4.04-4.01 (t, 2H), 1.80 (tt, 2H), 1.50 (tt, 2H), 0.95 (t, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:32]=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:33])[CH2:11][N:10]=3)=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[CH:17][CH:16]=5)[CH:8]=2)[CH2:3][CH2:2]1.Br[C:35]1[CH:40]=[N:39][C:38]([F:41])=[CH:37][N:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:32]=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:33])[CH2:11][N:10]=3)=[C:19]([C:35]3[CH:40]=[N:39][C:38]([F:41])=[CH:37][N:36]=3)[CH:18]=[CH:17][CH:16]=5)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Fc1cnc(Br)cn1
Reactant: CC1(C)OB(c2cccc3c2CCN2C(=O)CN=C(n4cnc(C5CC5)c4)C=C32)OC1(C)C
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: [Na+]
Solvent: COCCOC
Product: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(-c4cnc(F)cn4)c3CCN12
Temperature: 90 °C
Reaction time: 0.03 h
Yield: 61.1 %

Procedure:
Example 137. A suspension of 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (100 mg, 0.225 mmol), 2-bromo-5-fluoropyrazine (90 mg, 0.51 mmol) and Pd(PPh3)4 (39 mg, 0.034 mmol) in DME (2.8 mL) was treated with a 2M aq. solution of Na2CO3 (0.6 mL, 1.12 mmol). The mixture was heated to 90° C. for 2 h, allowed to cool to RT and poured onto H2O. The mixture was extracted with DCM and the combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 25% EtOAc in heptane for 2 min, then from 25% EtOAc in heptane to 100% EtOAc in heptane in 10 min, 100% EtOAc in heptane for 5 min) to yield a solid which was crystallized from diethyl ether and afforded the title compound (57 mg). UPLC-MS: MS 415.2 (M+H+); UPLC rt 0.92 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.59-0.69 (m, 2 H), 0.72-0.82 (m, 2 H), 1.75-1.86 (m, 1 H), 2.97 (t, J=5.62 Hz, 2 H), 3.70 (t, J=6.11 Hz, 2 H), 4.24 (br. s., 2 H), 7.15 (s, 1 H), 7.43 (s, 1 H), 7.54 (t, J=7.82 Hz, 1 H), 7.69 (d, J=7.58 Hz, 1 H), 8.01-8.16 (m, 2 H), 8.58 (s, 1 H), 8.83 (d, J=8.31 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:34]=[CH:33][N:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccnc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.14 mmol) were added 2-(trifluoromethyl)pyridin-4-ylboronic acid (39 mg, 0.20 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.01 mmol) and 204 μl of a 2M aqueous solution of cesium carbonate in dioxane (2.5 ml). The mixture was stirred under argon atmosphere at 90° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography using SP1® Purification System (0% to 70% hexane/AcOEt in 25 CV, 70% AcOEt in 10 CV) to give 33 mg (48% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].O1CCCC1.[OH-].[Li+].Cl>CO>[C:9]([O:8][C:6]([NH:5][C@@H:4]([C:3]([OH:23])=[O:2])[CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)c(F)cc1F)C(=O)O

Procedure:
A solution of 2.41 g (7.5 mmol) of (R)-N-(tert-butoxycarbonyl)-2,4,5-trifluorophenylalanine methyl ester in approximately 200 mL of a mixture of tetrahydrofuran:methanol: 1N lithium hydroxide (3:1:1) was stirred at 50° C. for 4 h. The reaction was cooled, acidified with 5% hydrochloric acid (aqueous) and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound. LC-MS 220.9 (M+1-BOC).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(Br)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.6 g), triethylamine (2.8 cc) and 4-(4-bromophenyl)piperazine (4.8 g) in toluene (60 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure re (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (40 cc), 2-{3-[4-(4-bromophenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (4.3 g) is obtained, m.p. 149° C.
Reaction SMILES: Cl[C:2]1[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:12][C:3]=2[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5])[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: O=C(OCC(F)(F)F)c1ccc(OCC(F)(F)F)nc1Cl
Product: CN1CCN(c2nc(OCC(F)(F)F)ccc2C(=O)OCC(F)(F)F)CC1
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (0.71 g, yellow oil) from 2,2,2-trifluoroethyl 2-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (0.75 g, 2.04 mmol, Step-1 of Amine-37) and 1-methylpiperazine instead of morpholine by the similar manner in Step-2 of Amine-37.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].C1(CCCCO)C=CC=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH2:28][CH2:29]1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: OCCCCc1ccccc1
Product: C[C@H]1CC[C@H](N(CCCCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl) -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 4-phenyl butan-1-ol and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][C:11]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:15])[C:12](O)=[O:13].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:12](=[O:13])[C:11]([CH3:15])([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH3:10])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)(C(=O)O)N1CCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C(=O)NNc1ccc(F)cn1)N1CCCC1
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (200 mg, 1.57 mmol) in DMF (10.0 mL) was added 2-methyl-2-pyrrolidin-1-yl-propionic acid (246 mg, 1.57 mmol), EDC (332 mg, 1.73 mmol) and HOBt.H2O (21.0 mg, 0.16 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (260 mg, 62%). 1H NMR (300 MHz, CDCl3): 1.30 (6H, s), 1.76-1.84 (4H, m), 2.64-2.72 (4H, m), 6.46 (1H, br s), 6.62 (1H, dd, J 9.0, 3.6), 7.28 (1H, ddd, J 9.0, 8.0, 2.9), 8.03 (1H, d, J 2.9), 9.06 (1H, br s).
Reaction SMILES: C(OC(=O)[N:6]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=3)[N:15]=2)[CH:9]=1)C=C.C(N(C(C)C)CC)(C)C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.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>[C:31]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: C=CCOC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
tert-Butyl-(3-{2-[2-(3-chloro-4-hydroxy-phenyl)-ethylamino]pyrimidin-4-yl}-benzyl)-carbamic acid allyl ester (Intermediate 120, 168 mg) was dissolved in methylene chloride (5 mL), followed by addition of diisopropylethylamine (0.11 mL), 1,3-dimethylbarbituric acid (78 mg) then Pd(PPh3)4 (50 mg). The mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and chromatographed on silica gel with methyl chloride:methanol (95:5) to afford 120 mg of product in 86% yield. LC-MS showed the product had the expected M+H+ of 411. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 1H) 7.5 (m, 2H) 7.2 (d, 1H) 7.1 (d, 1H) 7.0 (m, 1H) 6.8 (d, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 2.8 (m, 2H) 1.3 (s, 9H).