Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([Cl:13])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.Cl.CC1(C)C(C)(C)OB([C:25]2[CH:37]=[CH:36][C:28]([CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:27][CH:26]=2)O1>C(#N)C.[F-].[K+]>[Cl:13][C:10]1[N:11]=[CH:12][C:7]2[NH:6][C:5]3[N:14]=[CH:15][C:2]([C:25]4[CH:26]=[CH:27][C:28]([CH2:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:36][CH:37]=4)=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: CC1(C)OB(c2ccc(CN3CCCCC3)cc2)OC1(C)C
Reactant: Clc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Clc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 140 °C
Yield: 65 %

Procedure:
A degassed mixture of 3-bromo-6-chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (1.00 g, 3.55 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine hydrochloride (1.24 g, 3.67 mmol) and 1,1′-[bis(diphenylphosphino) ferrocene]dichloro palladium(II) (0.29 g, 0.35 mmol) in acetonitrile (20 mL) and 2N aqueous potassium fluoride solution (10 mL) was heated under microwave irradiation at 140° C. for 30 minutes. The cooled reaction mixture was concentrated under reduced pressure and taken up in DCM/methanol and loaded onto an SCX-2 cartridge (20 g) which was then washed with methanol (50 mL) then 2N ammonia in methanol (50 mL). The combined basic fractions were concentrated in vacuo and the residue purified by flash chromatography (silica, 80 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a pink solid (0.87 g, 66%). 1H NMR (DMSO-D6, 400 MHz): 12.38 (s, 1H), 9.03 (d, J=2.3 Hz, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.71 (d, J=1.0 Hz, 1H), 8.38 (d, J=0.9 Hz, 1H), 7.75 (d, J=7.9 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 3.49 (s, 2H), 2.39-2.33 (m, 4H), 1.56-1.48 (m, 4H), 1.45-1.37 (m, 2H). LCMS (Method B): RT=2.27 min, M+H+=377.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]([N:13]=[C:14]=[O:15])([CH3:12])[CH2:10]I)[CH:3]=1.C([OH:20])(C)(C)C>CN(C)C=O.F[B-](F)(F)F.[Ag+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]2([CH3:12])[CH2:10][O:20][C:14](=[O:15])[NH:13]2)[CH:3]=1
Reactant: CC(CI)(N=C=O)c1cc(Br)ccc1F
Reactant: CC(C)(C)O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1(c2cc(Br)ccc2F)COC(=O)N1
Temperature: 80 °C

Procedure:
A solution of the crude (RS)-4-bromo-1-fluoro-2-(2-iodo-1-isocyanato-1-methyl-ethyl)-benzene (20.0 g, 52 mmol) in N,N-dimethylformamide (180 ml) and tert-butanol (7.7 ml, 104 mmol) was treated with silver tetrafluoroborate (11.15 g, 57 mmol). The yellow suspension was heated at 80° C. for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure. After chromatography on silica gel using a using a gradient of heptane and ethyl acetate=100/0 to 40/60 as the eluent, the (RS)-4-(5-bromo-2-fluoro-phenyl) -4-methyl-oxazolidin-2-one (intermediate C4A) was obtained as a white solid (28.49 g, 53.5% of theory).
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[Na+].[Na+].[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[N:26][C:27]=3[NH:37][NH2:38])[N:22]=2)=[CH:17][CH:16]=1>CCO>[O:12]1[CH2:13][CH2:14][O:10][CH:11]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:29][C:28]3[C:27]4=[N:37][N:38]=[C:2]([NH2:1])[N:26]4[CH:25]=[CH:24][C:23]=3[N:22]=2)=[CH:17][CH:16]=1
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5OCCO5)cc4)nc3ccn12
Reaction time: 3 h

Procedure:
To dry EtOH (1 mL) was added cyanogen bromide (0.104 mL, 0.52 mmol, 5M in MeCN) followed by sodium carbonate (96 mg, 0.91 mmol). [2-(4-[1,3]Dioxolan-2-yl-phenyl)-3-phenyl-[1,6]naphthyridin-5-yl]-hydrazine (3-4, 100 mg, 0.26 mmol) was added and the mixture was stirred for 3 h. The reaction mixture was concentrated in vacuo and the resulting solid was used without further purification. LRMS m/z (M+1) Calcd: 410.2. Found 410.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH:16]1(Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=2[S:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1ccc(SC)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Reaction time: 0.42 h

Procedure:
A stirred solution of methyl 3-hydroxy-4-(methylthio)benzoate (1.98 g; that is prepared as described in Reference Example 53) in dry dimethylformamide (40 mL) is treated with sodium hydride (0.44 g of a 60% dispersion in mineral oil; 11 mmol) and the solution is stirred for a further 25 minutes. The reaction mixture is treated with cyclopentyl bromide (1.64 g), stirred at 60° C. for 3 hours, and then concentrated. The resulting residue is partitioned between dichloromethane (50 mL) and water (50 mL), the aqueous layer is extracted with dichloromethane (50 mL), and the combined organic layers are dried and concentrated, to give a red oil. The oil is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:9 v/v), to give methyl 3-cyclopentyloxy-4-(methylthio)benzoate (1.9 g), m.p. 53°-55° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:22])[C:18]([CH3:21])=[C:19]([CH3:20])[C:6]1=2)=[O:4].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:22][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:6]=2[C:19]([CH3:20])=[C:18]1[CH3:21]
Reactant: CN1CCNCC1
Reactant: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2C(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2C(=O)CN1CCN(C)CC1

Procedure:
289 g of 4-chloroacetyl-1,2,3-trimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one, 200 mg of N-methylpiperazine and 10 ml of dry dioxane are warmed at 70° to 80° C. for 2.5 hours. 10 ml of saturated aqueous sodium bicarbonate solution are added thereto, and the resulting mixture is extracted several times with ethyl acetate. The combined extracts are dried over sodium sulfate and concentrated in vacuo. The resulting oil is taken up in a little dioxane/acetonitrile and is brought to crystallization.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(Cl)Cl>O1CCOCC1>[CH2:1]([NH:4][C:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: CC(=O)Nc1c(-c2ccccc2)sc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCNc1c(-c2ccccc2)sc2ccccc12
Reaction time: 1 h

Procedure:
10.7 g (40 mmol) of 3-acetamido-2-phenyl-benzo(b)thiophene and 3.8 g (0.1 mol) of LiAlH4 in 200 milliliters of absolute dioxan is refluxed with stirring for 1 hour. The cooled reaction mixture is mixed with water to decompose the excess LiAlH4 and, after the addition of 300 milliliters of CH2Cl2, it is stirred for a further 15 minutes. After centrifuging with the addition of hyflo, the organic phase is dried over potassium carbonate and evaporated: 3-ethylamino-2-phenyl-benzo(b)thiophene in the form of a crude oily product. It is dissolved in a little chloroform and converted into the hydrochloride by hydrochloric gas: 10.9 g (94% of theory) of colourless sticks in ethanol, decomposition from 205° C. (in sealed tube).
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH2:18][O:19][C:20](=[O:21])[C:13]=3[CH:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Br:29])[CH:23]=3)[C:11]=2[C:10](=[O:30])[CH2:9]1)C1C=CC=CC=1.[Cl:31]C(OC=C)=O>C(Cl)Cl>[ClH:31].[Br:29][C:24]1[CH:23]=[C:22]([CH:12]2[C:11]3[C:10](=[O:30])[CH2:9][NH:8][CH2:17][C:16]=3[NH:15][C:14]3[CH2:18][O:19][C:20](=[O:21])[C:13]2=3)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: O=C1CN(Cc2ccccc2)CC2=C1C(c1ccc(F)c(Br)c1)C1=C(COC1=O)N2
Reactant: C=COC(=O)Cl
Solvent: ClCCl
Product: Cl
Product: O=C1CNCC2=C1C(c1ccc(F)c(Br)c1)C1=C(COC1=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.7 %

Procedure:
A solution of product from Example 39B (0.35 g, 0.75 mmol) in methylene chloride (10 ml) was treated with vinyl chloroformate (0.1 mL, 1.2 mmol), stirred at ambient temperature for 16 hours, concentrated to dryness, treated with ethanol (10 mL), treated with 6N HCl (3 mL), refluxed for 5 hours and concentrated to dryness. Purification of the residue on silica gel (10:90:1 ethanol/methylene chloride/saturated ammonium hydroxide) provided the title compound (0.08 g) which was converted the HCl salt.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:20][C:21]#[N:22].[NH4+]>CO>[OH:19][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][C:11]([S:20][C:21]#[N:22])=[CH:10][C:9]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CO
Product: N#CSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
2,6-Diphenylphenol (100 g, 0.406 mole) and ammonium thiocyanate (67.99 g, 0.893 mole) were suspended in methanol (150 ml) in a three-necked round bottom flask equipped with magnetic stirrer, thermometer and bubbler. The reaction mixture was cooled to -5° C. in an acetone/ice bath and chlorine gas bubbled through the solution for three hours. Maintaining the temperature below 10° C., ammonia gas was bubbled through the reaction for 2 hours. The contents of the flask were then poured into iced distilled water (250 ml) and allowed to stand for 12 hours in the refrigerator. After filtering, the solid was dried in vacuo at 45° C. for 12 hours. The title compound was purified by chromatography on silica and recrystallized from hexane, m.p. about 104-106.5° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[C:22]([C:34]([CH3:36])=[CH2:35])[C:21]=2[O:37][CH3:38])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[NH2:8][C:9]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH:34]([CH3:36])[CH3:35])[C:21]=2[O:37][CH3:38])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2
Reactant: [H][H]
Reactant: C=C(C)c1c(OCc2ccccc2)ccc(Oc2c(C)cc(N(Cc3ccccc3)Cc3ccccc3)c3c2CCC3)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1c(Oc2c(C)cc(N)c3c2CCC3)ccc(O)c1C(C)C
Yield: 98.9 %

Procedure:
To a solution of dibenzyl[7-(4-benzyloxy-3-isopropenyl-2-methoxyphenoxy)-6-methylindan-4-yl]amine (7.97 g) in tetrahydrofuran (80 mL) was added 10% Pd/C (4.00 g). The mixture was stirred at room temperature under an atmospheric pressure of hydrogen overnight. The insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to dryness to give the title compound (4.33 g).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6](C2C=CC=CC=2)=[O:7])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.OC1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1>C(#N)C>[CH3:45][C:44]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[O:7])=[CH:14][CH:15]=1)([CH2:47][CH3:48])[C:43]#[CH:42]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C#CC(C)(CC)Oc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a solution of 3-methyl-1-pentyn-3-ol 6 (0.319 mL, 2.83 mmol) in acetonitrile (3 mL) at 0° C. was added DBU (0.55 mL, 3.69 mmol). Then TFAA (0.34 mL, 2.46 mmol) was added drop wise and the solution was stirred at 0° C. for 30 min. To a solution of 4-hydroxybenzaldehyde (300 mg, 2.46 mmol) in acetonitrile at 0° C. was added DBU (0.55 mL 3.69 mmol) and CuCl2.2H2O (0.42 mg, 0.0025 mmol). The first mixture was added to the second mixture over a period of five min. The reaction was stirred overnight. The solvent was removed by rotary evaporation and the residue diluted with DCM. Then the organic layer washed with 1M HCl, 1M NaOH, sat NaHCO3 and brine, dried over MgSO4 and concentrated in vacuum to give 170 mg (32%) of product. 1H NMR (CDCl3): δ 9.91 (s, 1H), 7.83-7.81 (m, 2H), 7.36-7.34 (m, 2H), 2.69 (s, 1H), 2.06-1.92 (m, 2H), 1.66 (s, 3H), 1.12 ppm (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O[CH:20](C1OC(C)=CC(=O)C=1O)C.C(Br)C1C=CC=CC=1>>[OH:1][CH:2]([C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:20]
Reactant: Cc1cc(=O)c(O)c(C(C)O)o1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Agent: BrCc1ccccc1
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(C)O)o1

Procedure:
The title compound was prepared by the method outlined for 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one, using 8.5 g (50 mmol, 1 eq.) of 2-(1-hydroxyethyl)-3-hydroxy-6methyl-pyran-4(1H)-one and 9.5 g benzyl bromide (55 mmol, 1.1 eq.) to yield the pure product 10 g (77.7%) after recrystallisation from CH2Cl2/Pet. ether 40/60, as a white crystalline solid. m.p 91-92° C.
Reaction SMILES: [CH: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[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16]([NH:18][NH2:19])=[O:17].C(N(CC)CC)C.[C:33](Br)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(N(C)C)=O>[CH: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[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16]([NH:18][NH:19][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:17]
Reactant: O=C(Br)c1ccccc1
Reactant: NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 3-[(2-naphthyl)methoxy]-5-nitrobenzhydrazide (0.30 g, 0.89 mmol) and triethylamine (0.14 mL, 0.98 mmol) in DMA (25 mL) at room temperature was added benzoyl bromide (0.11 mL, 0.89 mmol), and stirring was continued overnight. Yellowish solution was poured onto ice-water (50 g) and set aside for 24 h. Precipitate formed was filtered, washed with water, and air-dried. Off-white solid, yield 0.34 g (87%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.92 (s, 1H); 10.66 (s, 1H); 8.12-7.89 (m, 8H); 7.67-7.50 (m, 6H); 5.53 (s, 2H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([O:11][CH3:12])[CH:4]=1)=[CH2:2].[Br:13]N1C(=O)CCC1=O.[OH2:21]>O1CCOCC1>[Br:13][CH2:2][CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([O:11][CH3:12])[CH:4]=1)[OH:21]
Reactant: C=Cc1cc(OC)c(C#N)cn1
Reactant: O=C1CCC(=O)N1Br
Reactant: O
Solvent: C1COCCO1
Product: COc1cc(C(O)CBr)ncc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-ethenyl-4-methoxypyridine-3-carbonitrile (80.0 mg, 0.499 mmol) in 1,4-dioxane (8 mL) and H2O (4 mL) was treated with N-bromosuccinimide (89.0 mg, 0.499 mmol, 1.0 equiv). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into H2O (8 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated aqueous NaCl (1×30 mL), dried over Na2SO4. Evaporation of the solvent gave an oil that was purified over SiO2 (0-30% EtOAc/hexanes as eluent) yielding 6-(2-bromo-1-hydroxyethyl)-4-methoxypyridine-3-carbonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]=1I)=[CH:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([Mg]Cl)(C)C.[Li+].[Cl-].[C:45](=[O:47])=[O:46]>C1COCC1>[CH3:2][CH2:1][O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]=1[C:45]([OH:47])=[O:46])=[CH:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[CH:10][CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1c(I)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC2CCCC2)cc1
Reactant: O=C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(=O)O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(4-Cyclopentyloxyphenyl)-3-iodo-5-(4-trifluoromethylphenyl)indole-2-carboxylic acid ethyl ester (310 mg, 0.5 mmol; see step (c) above) in THF (2 mL) was added dropwise to i-PrMgCl.LiCl (1.0 M in THF, 500 μL, 0.5 mmol) at −40° C. After 15 min at −40° C., a stream of dry CO2 was passed through the mixture for 5 min and the mixture was allowed to warm to rt. The mixture was partitioned between EtOAc (10 mL) and NH4Cl (aq, sat). The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with H2O and brine, dried (Na2SO4) concentrated and purified by chromatography, followed by recrystallisation from EtOAc/petroleum ether to give the title compound. Yield 70 mg (26%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:54][CH2:55][CH:56]1[CH2:60][O:59][C:58]([CH3:62])([CH3:61])[O:57]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:54][CH2:55][CH:56]4[CH2:60][O:59][C:58]([CH3:62])([CH3:61])[O:57]4)[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OCC(CCOS(C)(=O)=O)O1
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCC4COC(C)(C)O4)c4ccc(OC(F)F)cc34)nc12
Temperature: 65 °C

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (5 mL) was added 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate (42 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 2 hours. After cooling to room temperature, the mixture was poured into water, filtered, the filter cake washed with water and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide. The crude product was used in the next step without purification. MS: (M+H)+=771.0.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])=[N:6][CH:7]=1.[C:45]1(B(O)O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCO.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:45]1([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:12][C@H:11]([S:13][C:14]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C@H:9]3[CH2:33][O:34][CH2:35][C:36]3[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=3[F:44])=[N:6][CH:7]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncc(Br)cn2)cc1F
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: CCO
Solvent: COCCOC
Product: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncc(-c3ccccc3)cn2)cc1F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
A solution of 1.35 g (2 mmol) (2S,4R)-5-Bromo-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine in 12 ml dimethoxyethane were added to a suspension of 0.116 g (0.1 mmol) tetrakis(triphenylphosphine)palladium in 1.4 ml dimethoxyethane and stirred for 15 min. 0.29 g (2.4 mmol) Phenylboronic acid in 3.4 ml EtOH was then added and after 10 min, 8.8 ml of a aqueous 2 M Na2CO3 solution. The reaction was heated for 2 h at 90° C., evaporated and extracted wit H2O/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (toluene) gave 0.48 g (36%) (2S,4R)-5-Phenyl-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, MS: 674 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2Br)=[O:8])[CH3:2].C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)CCC>CN(C=O)C.C(OCC)(=O)C.O.C1(P([Pd-2](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(Br)c2sc1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(-c3ccccc3)c2sc1=O
Yield: 83.4 %

Procedure:
[(8-Bromo-6-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (22(d)) (500 mg, 1.2 mmol) was dissolved in anhydrous DMF (5 mL). To the solution was added Tributyl-phenyl-stannane (467 uL, 1.43 mmol), bis(triphenylphosphino) palladium(II) dichloride (100 mg, 0.12 mmol) and 4A molecular sieves. The reaction was sealed and the solution was heated to 120 C for 45 minutes. The reaction was cooled, diluted with ethyl acetate (25 mL) and water (25 mL). The organic phase was separated, dried over magnesium sulfate and concentrated residue in vacuo. The residue was filtered through silica to provide the title compound (418 mg) which was used directly without further purification.