Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[P:3]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([N:5]([CH3:7])[CH3:6])=[O:4].[I:21]I>C1COCC1>[CH3:20][N:2]([CH3:1])[P:3]([O:8][C:9]1[C:10]([I:21])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([N:5]([CH3:6])[CH3:7])=[O:4]
Reactant: II
Reactant: CCOC(=O)c1cccc(OP(=O)(N(C)C)N(C)C)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OP(=O)(N(C)C)N(C)C)c1I
Temperature: 0 °C
Yield: 77.9 %

Procedure:
A dry and nitrogen-flushed 25-ml Schlenk flask, equipped with a magnetic stirring bar and a septum, was charged ethyl 3-{[bis(dimethylamino)phosphoryl]oxy}benzoate 44 (300 mg, 1.00 mmol) in dry THF (3 ml). After cooling to 0° C., a freshly prepared (TMP)Mg(Bt).2LiCl solution (4.33 ml, 0.3 M in THF, 1.3 mmol) was added dropwise and the reaction mixture was stirred at the same temperature. The completion of the metalation (10 min) was checked by GC-analysis of reaction aliquots quenched with a solution of I2 in dry THF. Iodine (508 mg, 2.0 mmol) dissolved in dry THF (2 ml) was then added at 0° C. and the resulting mixture warmed to room temperature. After stirring for 1 hour, the reaction mixture was quenched with sat. aq. Na2S2O3, extracted with ether (3×20 ml) and dried over Na2SO4. After filtration, the solvent was removed in vacuo. Purification by flash-chromatography using ethyl acetate as eluent furnished ethyl 3-{[bis(dimethylamino)phosphoryl]oxy}-2-iodobenzoate 44a (332 mg, 78%) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:22].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.O>[CH2:15]([O:14][C:7]1[C:8]2[NH:9][C:10](=[O:13])[S:11][C:12]=2[C:4]([C:1](=[O:3])[CH2:2][Br:22])=[CH:5][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)sc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)sc12
Temperature: 80 °C
Yield: 93.3 %

Procedure:
To a solution of 7-acetyl-4-(benzyloxy)-1,3-benzothiazol-2(3H)-one (68 mg) in dry THF (3 ml) under nitrogen, was added phenyltrimethylammonium tribromide (90 mg) and the mixture heated at 80° C. under nitrogen for 2 h. The mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a 5 g silica SPE cartridge, eluting with stepped gradient of 10% to 100% ethyl acetate-cyclohexane mixtures, to give the title compound (49 mg).
Reaction SMILES: Br[C:2]1[C:11]([OH:12])=[C:10]([CH3:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[O:7]2.[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18].O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[CH3:15][C:6]1([CH3:16])[CH2:5][CH2:4][C:3]2[C:8](=[C:9]([CH3:14])[C:10]([CH3:13])=[C:11]([OH:12])[C:2]=2[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=2)[O:7]1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1c(C)c2c(c(Br)c1O)CCC(C)(C)O2
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: O
Solvent: COCCOC
Product: Cc1c(C)c2c(c(-c3cccc([N+](=O)[O-])c3)c1O)CCC(C)(C)O2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2,2,7,8-tetramethyl-chroman-6-ol (400 mg, 1.40 mmol), 3-nitrophenyl boronic acid (300 mg, and Pd(PPh3)4 (100 mg, 5% mol) in glycol dimethyl ether (DME, 20 mL) and 2M Na2CO3 solution (5 mL) was stirred at 120° C. for 3-5 h. After pouring it into water, the mixture was extracted with EtOAc. The EtOAc layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 10% EtOAc in hexane to give a yellow solid (140 mg). 1H NMR (300 MHz, CDCl3): 8.25-8.16 (μ, 2H), 6.76 (μ, 2H), 4.13 (σ, 1H, OH), 2.27 (μ, 2H), 2.21, 2.19 (2ρ, 6H), 1.68 (μ, 2H), 1.32 (σ, 6H) ppm. 13C NMR (75 MHz, CDCl3) δ: 167.36, 148.79, 145.85, 143.34, 138.27, 136.95, 130.10, 126.51, 125.56, 122.76, 122.29, 115.84, 73.10, 32.83, 27.07, 26.71, 12.95, 12.24, 12.14 ppm. MS: m/z: 328 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[S:17][C:16]([C:18]([O:20]C)=[O:19])=[C:15]([S:22](=[O:29])(=[O:28])[NH:23][C:24]([F:27])([F:26])[F:25])[CH:14]=1.[OH-].[Na+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[C:15]([S:22](=[O:28])(=[O:29])[NH:23][C:24]([F:25])([F:27])[F:26])[CH:14]=1
Reactant: COC(=O)c1sc(OCc2ccc3ccccc3n2)cc1S(=O)(=O)NC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1sc(OCc2ccc3ccccc3n2)cc1S(=O)(=O)NC(F)(F)F
Temperature: 0 °C
Reaction time: 7 h

Procedure:
38.0 g (0.085 mol) of methyl 5-(2-quinolinylmethoxy)-3-(1,1,1-trifluoromethylsulphamoyl)-2-thiophenecarboxylate are dissolved in 350 ml of methanol and about 100 ml of 2N sodium hydroxide solution are added. The reaction mixture is heated under reflux and with stirring for 7 hours. The reaction solution is concentrated to 20% of its volume and diluted with 500 ml of water. The aqueous phase is extracted four times with a total of 500 ml of ether. The aqueous phase is cooled to 0° C. with stirring and acidified with 0.5N hydrochloric acid. The product precipitated in this way is filtered off with suction, digested twice with 50 ml of ice-cold ether each time and dried at 60° C./1 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:15])[CH:12]=2)[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:4].[C:23]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][C:30]3[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=3)[CH:12]=2)[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:4]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)C1Cc2cc(O)ccc2CN1C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)C1Cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2CN1C(=O)OC(C)(C)C
Yield: 49.2 %

Procedure:
6-Hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (0.5 g, 1.62 mmol) in DCM (15 mL) was treated with copper acetate (0.59 g, 3.3 mmol), 4-tert-butylphenylboronic acid (0.87 g, 4.8 mmol), and TEA (1.0 mL, 7.9 mmol) by the general procedure G. The crude product was purified by flash column chromatography on silica gel using Hexanes:EtOAc (70:30) to give 0.35 g of 6-(4-tert-butyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester which was deprotected using general procedure N to give 6-(4-tert-butyl-phenoxy)-1,2,3,4-tetrahydro-isoquinoline-(3S)-carboxylic acid methyl ester hydrochloride salt (0.27 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[Br-].[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[Zn+].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: [Zn+]c1nccs1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4nccs4)cc3C)c(C)nc12
Yield: 70 %

Procedure:
Using a procedure similar to Example 32, 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.46 g, 1.17 mmol), 0.5 M 2-thiazolylzinc bromide in THF (4.7 mL, 2.35 mmol) and PdCl2(dppf) (0.043 g, 0.059 mmol) furnish the title compound (0.32 g, 0.81 mmol, 70%). 1H NMR (CDCl3), δ 0.90 (t, J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.18 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.31-3.40 (m, 1H), 7.70 (s, 1H), 7.27 (d, J=3.6 Hz, 1H), 7.47 (s, 1H), 7.78 (d, J=3.6 Hz, 1H). LC/MS (m/z): calcd. for C21H24N4S2 (M+H)+: 397.7; found: 397.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10]([N:12]([CH2:24][CH3:25])[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH3:11]>[N+](C1C=CC=CC=1)([O-])=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:20]([C:19]3[CH:22]=[CH:23][C:16]([O:15][CH2:14][CH2:13][N:12]([CH2:24][CH3:25])[CH2:10][CH3:11])=[CH:17][CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN(CC)CCOc1ccc(C=O)cc1
Reactant: Nc1cc(Br)cnc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)CCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
3.31 g 5-bromo-2,3-diaminopyridine and 3.90 g 4-(2-diethylamino-ethoxy)benzaldehyde in 120 ml nitrobenzene were heated to 140-150° C. for 24 hrs. The solvent was removed by vacuum distillation. The residue was dispersed in ethyl acetate and the crude product was isolated by filtration and washed thoroughly with more ethyl acetate.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[NH:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=1)[NH2:28]>>[CH3:24][N:23]([CH3:25])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[N:28]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: Cc1cc(NN)ccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(S(=O)(=O)N(C)C)c3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=437.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[C:6]([NH2:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH2:22][O:23][CH2:24][CH2:25]I>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[C:6]([N:13]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)c2oc(N)nc12
Reactant: ICCOCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2oc(N)nc12
Temperature: 60 °C
Yield: 52.5 %

Procedure:
To a stirred solution of 800 mg (4.47 mmol) 4-methoxy-benzooxazole-2,7-diamine in 40 ml DMF at room temperature were added 2.47 g (17.9 mmol) potassium carbonate and 2.18 g (6.70 mmol) 1-iodo-2-(2-iodo-ethoxy)-ethane and the mixture heated at 60° C. for 48 h. After cooling to room temperature the mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Flash chromatography (2/98 methanol/dichloromethane, then 10/90 methanol/dichloromethane) afforded 585 mg (53%) 4-methoxy-7-morpholin-4-yl-benzooxazol-2-ylamine as a light brown solid. ES-MS m/e (%): 250 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1.[S:35]1[CH:39]=[N:38][N:37]=[C:36]1[NH2:40].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:36]4[S:35][CH:39]=[N:38][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nncs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(5-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE XXXX, 464.57 mg, 0.901 mmol), 1,3,4-thiadiazol-2-amine (182 mg, 1.801 mmol), and cesium carbonate (880 mg, 2.70 mmol). DMF (4503 μl) was added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g SNAP Ultra column, 0-7% MeOH/DCM) to give 1-(5-chloro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (378 mg, 0.873 mmol, 97% yield) as a light-yellow foam. m/z (ESI) 433.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[C:6]([NH2:8])[CH:7]=1.[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>C1C(Cl)=CC=C(Cl)C=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14](=[O:15])[NH:8]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Br)ccc1-n1ccnc1
Solvent: CCOC(C)=O
Solvent: Clc1ccc(Cl)cc1
Product: O=c1[nH]c2cc(Br)ccc2n2ccnc12
Temperature: 25 °C
Yield: 69.5 %

Procedure:
To a solution of 5-bromo-2-imidazol-1-yl-phenylamine (5.00 g; 21 mmol; 1 eq) in anhydrous dichlorobenzene (410 mL), is added carbonyldiimidazole (6.94 g; 42 mmol; 2 eq) under argon atmosphere. This reaction mixture is allowed to stir under reflux for 2 hours. The initial crystal clear solution quickly turns black after heating and become non homogeneous. This crude reaction mixture is allowed to cool to room temperature and the grey powder formed during the reaction is filtered off on a fritted glass. The filtrate is cooled down to 0° C. overnight to afford a second batch of grey powder. The combined 6.5 g of grey solid is transferred in a 1 L flask, diluted in fresh ethyl acetate (500 mL) and heated to gentle reflux for ten minutes. Hot filtration followed by concentration afforded the title compound as a grey powder (3.85 g; 14.6 mmol; 69%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([O:26][CH3:27])[C:3]=1[OH:28].O[C@@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([O:33]C)=[O:32].BrBr>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([O:26][CH3:27])[C:3]=1[O:28][C@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([OH:33])=[O:32]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: COc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1O
Agent: BrBr
Product: COc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1O[C@H](Cc1ccccc1)C(=O)O

Procedure:
Prepared from 2-bromo-4-(6-bromo-benzo [b]naphtho [2,3-d]thiophen-11-yl)-6-methoxy-phenol (Example 193) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96) according to the procedure in Example 113. White solid: mp >103° C. (dec.): NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.83 (ddd, J=8, 7, 1 Hz, 1 H), 7.67 (ddd, J=8, 7, 1 Hz, 1 H), 7.57-7.26 (m, 9 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.89 (ddd, J=8, 1, 1 Hz, 1H), 6.79 (ddd, J=8, 7, 1 Hz, 1H), 5.29 (t, 1H), 3.76, 3.74 (ds, 3 H), 3.39-3.46 (m, 2 H); MS (EI): [M+], 2 bromine isotope pattern, 660; Anal. Calc. for C32H22Br2O4S: C, 58.02, H, 3.35, N, 0.00. Found: C, 58.04, H, 3.73, N, 0.02.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6]2[C:8]3[C:13]([CH2:14][CH2:15][CH3:16])=[CH:12][C:11](=[O:17])[O:10][C:9]=3[CH:18]=[C:19]([O:20]C(=O)CC)[C:5]=2[CH:4]=[CH:3]1.C([O-])(O)=O.[Na+].O>CO>[CH3:25][C:2]1([CH3:1])[O:7][C:6]2[C:8]3[C:13]([CH2:14][CH2:15][CH3:16])=[CH:12][C:11](=[O:17])[O:10][C:9]=3[CH:18]=[C:19]([OH:20])[C:5]=2[CH:4]=[CH:3]1
Reactant: CCCc1cc(=O)oc2cc(OC(=O)CC)c3c(c12)OC(C)(C)C=C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCc1cc(=O)oc2cc(O)c3c(c12)OC(C)(C)C=C3
Temperature: 25 °C
Reaction time: 7 h
Yield: 52.1 %

Procedure:
To a solution of ester 5a (223 mg, 0.65 mmol) in 15 mL of MeOH were added saturated aqueous solution of NaHCO3 (7 mL) and water (7 mL). The reaction mixture was stirred at room temperature under nitrogen for 7 h until TLC indicated complete consumption of the starting material. The reaction mixture was then acidified with 10% aqueous HCl (100 mL), and extracted with EtOAc (50 mL). The organic solution was washed with brine (100 mL) and dried with Na2SO4. Evaporation of the solvent yielded the crude product that was purified by preparative TLC to afford 97 mg (52% yield) of 6 as a solid. mp 190-192° C.; 1H NMR (DMSO-d6) δ 0.99 (3H, t, J=7.3 Hz), 1.45 (6H, s), 1.59 (2H, m), 2.83 (2H, t, J=7.6 Hz), 5.66 (1H, d, J=9.9 Hz), 5.92 (1H, s), 6.34 (1H, s), 6.57 (1H, d, J=9.9 Hz), 10.77 (1H, s); 13C NMR (DMSO-d6) δ 13.7, 22.9, 27.2, 37.5, 77.5, 95.7, 102.2, 106.1, 109.9, 116.3, 127.1, 151.7, 155.7, 156.4, 157.8, 160.0, 188.9; IR (film): 3185, 1686, 1582, 1381, 1157 cm−1; MS m/e: 287 (M+1); Anal. Calcd. for C17H18O4: C, 71.31; H, 6.34. Found: C, 71.39; H, 6.40.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][CH:6]3[C:5]=2[CH:4]=1)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8](/[CH:34]=[C:35](/[C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)\[CH3:36])[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC(=CBr)c1ccncc1
Reactant: CCc1ccc2c(c1)C1CN(C)CCC1N2
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCc1ccc2c(c1)c1c(n2/C=C(\C)c2ccncc2)CCN(C)C1
Temperature: 25 °C

Procedure:
8-Ethyl-2-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (200 mg, 0.9345 mmol), potassium phosphate (396 mg, 1.8 mmol), copper (I) iodide (21 mg, 0.18 mmol), L-proline (17 mg, 0.09345 mmol) and 4-(1-bromoprop-1-en-2-yl)pyridine (277 mg, 1.40 mmol) were mixed in DMF and the reaction mixture was purged with nitrogen. The contents were cooled to RT and poured into water. The precipitate obtained was filtered, dried and purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.58 (d, 2H), 7.70 (d, 2H), 7.36 (s, 1H), 7.22 (s, 1H), 7.05 (m, 2H), 3.75 (s, 2H), 2.95 (m, 2H), 2.85 (m, 2H), 2.70 (q, 2H), 2.38 (s, 3H), 2.00 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:32])[C:12](=[O:31])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([O:23][Si](C(C)(C)C)(C)C)[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.C(OCC)C.C(N(CC)CC)C>CO.O>[C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:32])[C:12](=[O:31])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([OH:23])[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)O[Si](C)(C)C(C)(C)C)c(=O)n1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CO
Product: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)O)c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a stirring solution of (R)-8-acetyl-7,8-dihydro-1-methyl-3-(5-tert-butyldimethylsilyloxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (200 mg, 0.43 mmol) in methanol (20 ml) was added a 1.0 M solution of hydrogen chloride in diethylether (0.4 ml, 0.40 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was treated with triethyamine (0.1 ml). Concentration under reduced pressure gave a white solid which was treated with water (20 ml) and stirred for 1 hour. The solid was filtered, washed with water, and dried under vacuum to provide (R)-8-acetyl-7,8-dihydro-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (CT-30260) (135 mg, 90% yield) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH3:15])[CH2:8][CH2:7][CH2:6]1)=[O:4].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([SH:25])=[N:22][C:21]=2[CH:26]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([S:25][CH2:2][C:3]([N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][C:13]=4[CH3:15])[CH2:8][CH2:7][CH2:6]3)=[O:4])=[N:22][C:21]=2[CH:26]=1
Reactant: Cc1cccc2c1N(C(=O)CCl)CCC2
Reactant: Sc1nc2cc(Cl)ccc2s1
Product: Cc1cccc2c1N(C(=O)CSc1nc3cc(Cl)ccc3s1)CCC2
Yield: 56 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 2 as the electrophile and 5-chloro-2-mercaptobenzothiazole as the nucleophile to yield 15 (3.60 g, 56%): MS m/z: 393 (M+H)+. Anal. Calcd. For, C19H17ClN2OS2.0.2H2O: C, 58.14; H, 4.47; N, 7.14; S, 16.33; Cl, 9.03. Found: C, 57.90; H, 4.40; N, 7.17; S, 16.47; Cl, 9.24.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[C:25]=1[F:33])#[N:17]>>[F:33][C:25]1[C:26]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]3=[N:4][CH:3]=2)=[CH:27][CH:28]=[CH:29][C:24]=1[C:19]1[C:18]([C:16]#[N:17])=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1ccccc1-c1cccc(B(O)O)c1F
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4ccccc4C#N)c3F)cnc2c1F
Yield: 30 %

Procedure:
2-(3-Bromo-8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 2′-cyano-2-fluorobiphenyl-3-boronic acid (prepared as described in WO 02/38568) as described in Example 1 to give 2′-fluoro-3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as an off-white solid (55 mg, 30%): δH (360 MHz, CDCl3) 2.36 (6H, d, J 1), 7.83 (1H, t, J 7), 8.03-8.26 (5H, m), 8.32-8.36 (1H, m), 8.39 (1H, s), 8.44 (1H, d, J 8), 8.69 (1H, q, J 4); m/z (ES+) 390 [MH+].
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.C(=O)=O.CC(C)=O.C[O:17][C:18]([C:20]1([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]1)=O.C(#N)C>C1COCC1>[O:17]=[C:18]([C:20]1([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]1)[CH2:2][C:3]#[N:5]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1(C(F)(F)F)CC1
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CC(C)=O
Product: N#CCC(=O)C1(C(F)(F)F)CC1
Temperature: 22 °C
Yield: 97 %

Procedure:
Add 2 M LDA solution in THF (19.15 mL, 38.3 mmol) to a dry ice-acetone cooled solution of 1-trifluoromethyl-cyclopropane-1-carboxylic acid methyl ester (2.93 g, 17.4 mmol) and acetonitrile (1.43 g mL, 34.8 mmol) in THF (30 mL). Stir reaction mixture at −70° C. for 1.5 hours and then allow to warm to 22° C. for 2 hours. Concentrate, add hexanes, and filter to give a yellow solid. Wash with hexanes and treat with diethyl ether (250 mL) then 2 N HCl (150 mL). Extract aq. layer with diethyl ether (4×100 mL). Dry the combined organic phases over sodium sulfate. Removal of solvent provides 3-Oxo-3-(1-trifluoromethyl-cyclopropyl)-propionitrile (2.99 g, 97% yield). MS (ES−): m/z=176.1 [M+H].