Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:23])[CH:21]=[CH2:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[Li]OC(C)=O.[Li+].[Cl-].Br[C:32]1[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:23])[CH2:21][CH2:22][C:32]4[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=4[C:34]([O:36][CH3:37])=[O:35])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CC(O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: COC(=O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
A degassed suspension of 1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-2-propen-1-ol (Example 80, Step 1, 50.30 g, 156 mmol), LiOAc/2H2O (41.2 g, 404 mmol), LiCl (6.84 g, 161 mmol), Pd(OAc)2 (1.00 g, 4.45 mmol) and methyl 2-bromobenzoate (33.5 g, 156 mmol) in 300 mL of DMF was stirred at 95° C. for 4 h. The mixture was cooled to r.t (room temperature) and added to 1.8 L of water. The product was extracted with hot EtOAc, dried over Na2SO4 and concentrated. It was dissolved in toluene and filtered through silica with toluene. Recrystallization in 1.2 L of EtOAc:hexanes 1:1 afforded 65.57 g of the title compound. Recrystallization of the mother liquors in 400 mL EtOAc:hexanes 1:3 afforded a further 8.30 g (86% overall yield) of the title material.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCCCCC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CCCCCCc1ccccc1
Reaction time: 3.5 h

Procedure:
A solution of 6-phenylhexanol (5.00 g, 28.0 mmol, 1 equiv) in CH2Cl2 (10 ml) was added to a solution of pyridinium chlorochromate (9.07 g, 42.1 mmol, 1.5 equiv) in CH2Cl2 (100 ml) at rt, and the mixture was stirred for 3.5 h. The reaction mixture was diluted with hexane and filtered through silica gel (20 g). The silica gel was eluted with a mixture of hexane and EtOAc (1:1). The combined filtrate was concentrated under vacuum to give 6-phenyl-1-hexional as a colorless oil, which was used as such for the next step. 1H NMR (CDCl3) δ 9.75 (t, 1H), 7.28–7.14 (m, 5H), 2.61 (T, 2H), 2.44–2.38 (m, 2H), 1.71–1.58 (m, 5H), 1.42–1.30 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:35])([CH3:34])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:33])([CH3:32])[CH:17]([F:31])[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:35])([CH3:34])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:33])([CH3:32])[CH:17]([F:31])[C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[NH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)C(F)c1ccc(-c2ccc(F)cn2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)Cc1c[nH]c(C(C)(O)C(F)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 4 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-{2-fluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (ca. 10 mg, 0.02 mmol) in methanol (2 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride then with 0-100% ethyl acetate/hexane afforded the title compound. LCMS: 386 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[CH:33]=[CH:32][C:31]=1B(O)O>>[CH3:39][O:38][C:36]([C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:28])[CH:3]=2)=[C:30]([F:29])[CH:35]=1)=[O:37]
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)c(F)c1

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 2-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=552.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O.CN(C=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(I)c(F)cc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)c(F)cc1F
Temperature: 60 °C

Procedure:
To a solution of 11 (74.0 g, 260 mmol) in toluene (370 mL) was added thionyl chloride (95 mL, 1300 mmol) in DMF (2.5 mL, 26 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to approximately 60° C. and filtered to remove insoluble material. The filtrate was concentrated under reduced pressure and residual thionyl chloride was co-evaporated with toluene (2×120 mL) to give crude 12 which was used without purification.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([F:13])[C:10]3[O:14][C:15]4[C:20]([C@@:21]5([CH2:25][O:24][C:23]([NH2:26])=[N:22]5)[C:9]=3[CH:8]=2)=[CH:19][C:18]([C:27]2[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:17][CH:16]=4)[CH2:3][CH2:2]1>[Pd]>[F:13][C:11]1[C:10]2[O:14][C:15]3[C:20]([C@@:21]4([CH2:25][O:24][C:23]([NH2:26])=[N:22]4)[C:9]=2[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:12]=1)=[CH:19][C:18]([C:27]1[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=1)=[CH:17][CH:16]=3
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(C2=CCOCC2)nc1F
Agent: [Pd]
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(C2CCOCC2)nc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of (S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (60 mg, 0.134 mmol; prepared as described in Method BB33) and 10% Pd/C (60 mg) was stirred at rt under 1 atm of H2 gas for 12 hours. The suspension was filtered through a pad of silica gel washing with a 1:1 mixture of CH2Cl2/MeOH. The filtrate was evaporated to dryness and purified by silica gel chromatography (EtOAc to EtOAc/MeOH=100:5 to 100:7) to provide (S)-1-fluoro-7-(2-fluoropyridin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[C-:17]#[N:18].[K+].OS([O-])=O.[Na+]>C1COCC1.O>[C:17]([C:2]1([OH:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)#[N:18]
Reactant: [C-]#N
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(O)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a stirred solution of phenylmethyl 3-oxo-1-pyrrolidinecarboxylate (1.0 g, 4.56 mmole) and KCN (0.81 g, 12.54 mmole) in THF (5 mL) and H2O (15 mL) at 0° C. was added NaHSO3 (1.14 g, 10.9 mmole) in H2O (5.0 mL). After 3 h, the reaction contents were concentrated in vacuo, extracted with CHCl3 (2×100 mL), and the organics dried over Na2SO4. Purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (0.92 g, 82%) as a light yellow oil: LC-MS (ES) m/e 247 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>>[Cl:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[NH:10][C:7](=[O:9])[C:6]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[C:18]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cn1cccn1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-n1cccn1
Yield: 49 %

Procedure:
from 2-(1H-pyrazol-1-yl acetic acid and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 49%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[F:17].[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[O:29])=[C:4]([F:17])[CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CNc1ccc(OCc2ccccc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1F
Temperature: 95 °C
Reaction time: 0.75 h
Yield: 26.7 %

Procedure:
N-Methyl-4-benzyloxy-2-fluoroaniline (250 mg, 1.0805 mmol) was dissolved in N,N-dimethylformamide (5.0 ml), and then sodium hydride (65 mg, 1.6207 mmol, 60% in oil) was added and the mixture was stirred at 95° C. for 45 minutes under a nitrogen atmosphere. After adding 4-fluorophenyl isocyanate (0.14 ml, 1.1836 mmol), the mixture was stirred at 85° C. for 45 minutes under a nitrogen atmosphere. There was further added 4-fluorophenyl isocyanate (0.14 ml, 0.5094 mmol), and the mixture was stirred at 85° C. for 30 minutes under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto NH silica gel and purified by NH silica gel column chromatography (hexane-ethyl acetate system) to obtain the title compound (0.105 g, 0.2881 mmol, 21.67%) as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[N:33]1([C:31](=[O:32])[CH2:30][NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCC(=O)N1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCOCC3)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)amide (39 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 2-amino-1-morpholin-4-yl-ethanone (0.28 ml), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 536. 1H NMR (DMSO-d6, 400 MHz): δ 8.50 (t, 1H), 8.10 (s, 1H), 7.92 (m, 1H), 7.79 (br, 1H), 7.74 (br, 1H), 7.50 (d, 2H), 7.38 (m, 1H), 4.16 (d, 2H), 3.66 (s, 3H), 3.62 (m, 2H), 3.58 (t, 2H), 3.52 (t, 2H), and 3.48 (t, 2H).
Reaction SMILES: N[C@H](C([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11]([OH:13])=[O:12])=O)C(C)C.CN1C2C(=CC=CC=2)C(C)=C1C(O)=O.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11]([OH:13])=[O:12]
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1c(C(=O)O)n(C)c2ccccc12
Solvent: CN(C)C=O
Product: N[C@@H](CC(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred turbid mixture of N-[valinyl]aspartic acid, α-methyl, β-tert-butyl diester (2.75 g, 9.11 mmol) and 1,3-dimethylindole-2-carboxylic acid (1.95 g, 10 10.3 mmol) in DMF (30 ml) was added 4-dimethylaminopyridine (DMAP) (1.26 g, 10.3 mmol) and EDAC (2.37 g, 12.4 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 0° C. for 1 hour and at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined extracts were washed with saturated NaHCO3 solution, water, and brine, dried over sodium sulfate, and concentrated to give a solid. The solid was triturated with ether to give N-[1,3-dimethyl-indole-2-carbonyl) valinyl]aspartic acid, α-methyl, β-tert butyl diester as a white powder (2.87 g, 67%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([CH:21]=O)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:21]([C:19]1[N:20]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:23]([F:26])([F:24])[F:25])=[N:5]3)[CH2:15][CH2:14]2)[S:17][CH:18]=1)#[CH:27]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 40 °C

Procedure:
Under argon, 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-carbaldehyde (200 mg) is dissolved in methanol (5 ml) and potassium carbonate (215 mg) and dimethyl 1-diazo-2-oxopropylphosphonate (199 mg) are added. The mixture is stirred at 40° C. After aqueous work-up, the mixture is extracted with ethyl acetate and the extracts are dried with sodium sulphate and concentrated under reduced pressure. The residue is purified chromatographically. This gives 1-[4-(4-ethynyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (67 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+:16].[Cs+]>O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([O-:11])=[O:10])[CH2:6][CH2:7]1.[Cs+:16]
Reactant: CN1CCN(CC(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CN1CCN(CC(=O)[O-])CC1
Yield: 195.9 %

Procedure:
A solution of 2-(4-methyl-1-piperazinyl)acetic acid (described in J. Med. Chem., 43, 1493 (2000); 2.5 g, 16 mmol) in water (30 ml) was cooled to 0° C., and cesium carbonate (2.6 g, 7.9 mmol) was added thereto with stirring, then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (4.49 g, 98% yield) as a pale yellow solid.
Reaction SMILES: [Li+].[Cl-].[Li]OC(C)=O.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH:19]=[CH:20][C:21]3[CH:22]=[C:23]([CH:27]([OH:30])[CH:28]=[CH2:29])[CH:24]=[CH:25][CH:26]=3)=[N:16]2)=[CH:11][CH:10]=1.I[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]([CH2:48][CH3:49])[C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.[Pd]>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH:19]=[CH:20][C:21]3[CH:22]=[C:23]([C:27](=[O:30])[CH2:28][CH2:29][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH:38]([CH2:48][CH3:49])[C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])=[O:40])[CH:24]=[CH:25][CH:26]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: C=CC(O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CCC(C(=O)OCC[Si](C)(C)C)c1ccccc1I
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC(C(=O)OCC[Si](C)(C)C)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a mixture of LiCl (3.26 g, 77 mmol), LiOAc (19.6 g, 192 mmol), n-Bu4NCl (42.7 g, 154 mmol), Pd (0Ac)2 (0.52 g, 2.3 mmol) and the allyl alcohol of Example 80, Step 1 (24.7 g, 77 mmol) under N2 was added a solution of the aryl iodide of Step 2 (30.0 g, 77 mmol) in DMF (150 mL). The suspension was degassed and purged with N2, and was then stirred at 100° C. for 1 h. The dark red solution was then poured onto a mixture of ice (300 g) and saturated NaHCO3 (300 mL). The red syrup was extracted with EtOAc. Following filtration through celite, the organic phase was washed with H2O and saturated NaCl solution. After drying (MgSO4), the solvent was removed under vacuum and the residue was purified by flash chromatography. Elution was effected with 1:20 EtOAc:hexane, followed by 1:10 EtOAc:hexane to give 37.4 g of the title compound as a white solid, mp 109°-111° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:21]([C:29]2[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:5]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47]>ClCCl.C(OCC)(=O)C>[C:46]([NH:1][C:2]1[CH:3]=[C:4]([N:21]([C:29]2[N:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][N:30]=2)[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH:5]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1)(=[O:48])[CH3:47]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N(c1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1)c1nccc(C(F)(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(-c2cnc(N3CCCNC(=O)C3)s2)cc(N(C(=O)OC(C)(C)C)c2nccc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
To a suspension of tert-butyl {3-amino-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate (125 mg, 0.227 mmol) in dichloromethane (2.5 mL) at room temperature, under nitrogen, was added triethylamine (0.079 mL, 0.569 mmol) and acetyl chloride (0.024 mL, 0.341 mmol). The mixture was stirred at room temperature for 18 h after which time a solution was obtained. The mixture was diluted with ethyl acetate and washed with water and brine, and dried over sodium sulfate. Silica gel (1 g) was added and the solution concentrated to dryness. The resulting solid was purified by silica gel chromatography (ethanol/dichloromethane eluant) to afford 80 mg (0.135 mmol, 60% yield) of tert-butyl {3-(acetylamino)-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate as an off-white solid.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:5][C:6]1[C:15]([Br:2])=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([O:17][CH3:18])=[N:13]2)=[N:8][CH:7]=1
Reactant: COc1ccc2ncc(Br)c(O)c2n1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Br)c(Br)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
Phosphorus tribromide (140 mg, 0.53 mmol, 1.3 eq) is added at 0° C. to a stirred suspension of 3-bromo-6-methoxy-[1,5]naphthyridin-4-ol (100 mg, 0.39 mmol, 1.0 eq) in N,N-dimethylformamide (1 mL). After 2 hours stirring at room temperature, the reaction mixture is poured into saturated sodium carbonate aqueous solution (50 mL). The resulting suspension is filtered and the cake is washed with water and methanol to afford 7,8-dibromo-2-methoxy-[1,5]naphthyridine as a white solid (100 mg, 80% yield).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1
Reactant: O=C1CN(c2ccc(Cc3nccs3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CN(c2ccc(Cc3nccs3)cc2O)S(=O)(=O)N1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-(2-benzyloxy-4-thiazol-2-ylmethylphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (20 mg, 0.05 mmol) in CH2Cl2 (5 mL) at −10° C. is added BBr3 (0.2 mL, 1.0 M in CH2Cl2) and the yellow mixture is stirred at −10° C. for 30 min. The reaction is quenched with water and the aqueous layer is neutralized to pH=7 with 1N NaOH. The aqueous layer is then concentrated and the residue is purified by reverse phase HPLC (CH3CN/water/0.1% TFA) to give the title compound as a light yellow solid: 1H NMR (MeO4.16 (s, 2H), 4.18 (s, 2H), 6.68 (d, J=8 Hz, 1H), 7.73 (s, 1H), 7.28 (d, J=8 Hz, 1H), 7.34 (d, J=4 Hz, 1H) 7.56 (d, J=4 Hz, 1H); (M−1)−=324.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([CH:11]=O)[C:9]=2[CH:10]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][C:2]1[N:3]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C:4]2[C:9]([CH:10]=1)=[C:8]([CH2:11][N:32]1[CH2:31][CH2:30][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH2:33]1)[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C=O)cccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc2c(CN3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1S(=O)(=O)c1ccccc1
Temperature: 130 °C
Yield: 80 %

Procedure:
2-Methyl-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (94 mg, 0.3 mmol, Intermediate 47) was dissolved in THF (dry) (4 mL) before boc-piperazine (87.7 mg, 0.5 mmol) was added followed by acetic acid (188 mg, 3.1 mmol) and sodium triacetoxyborohydride (199 mg, 0.9 mmol) was added. The reaction mixture was heated in microwave for 720 s at 130° C. The solvent was evaporated, added water and DCM. Separated the phases and extracted the aqueous phase with DCM twice. The combined organic phases were dried (MgSO4) and the solvent was evaporated. The crude product was purified by preparative HPLC (30-60). Isolated 110 mg, as an oil, yield 80%. MS (ESI+) for C25H31N3O4S m/z 470 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[C:14]([CH2:13][CH2:12][NH:11][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9])([OH:16])=[O:15]
Reactant: CC(=O)Cc1ccccc1
Reactant: NCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(Cc1ccccc1)NCCC(=O)O
Reaction time: 18 h
Yield: 60.2 %

Procedure:
Phenylacetone (100 mg, 0.745 mmol) was dissolved in anhydrous methanol (2.0 ml). Beta-alanine (398 mg, 4.47 mmol) was added, followed by sodium cyanoborohydride (94 mg, 1.49 mmol). After 18 hours of stirring under nitrogen, the reaction mixture was filtered, and the filtrate solvent was removed in vacuo. The resulting crude material was purified on four 1.0 millimeter C18 reverse-phase preparative thin layer chromatography plates eluted with H2O/methanol/acetic acid (40/60/0.4). The material obtained was dissolved in ethyl acetate (20 ml) and was extracted with 1.0M sodium bicarbonate (3×20 ml). The aqueous extracts were combined, the pH was adjusted to 4 with 1.0M hydrochloric acid, and the solvent was removed in vacuo. The resulting crystalline solid was then triturated twice with 50-milliliter portions of ethyl acetate and filtered. The filtrates were combined, and the solvent was removed in vacuo to yield 93 milligrams of N-carboxyethyl-amphetamine.