Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH:23]=[CH:22][CH:21]=[N:20]1>O.[Cu](I)I>[CH2:8]([C:6]1[C:5]([O:10][CH3:11])=[N:4][C:3]([CH3:12])=[C:2]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[CH:7]=1)[CH3:9]
Reactant: c1cn[nH]c1
Reactant: CCc1cc(Br)c(C)nc1OC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc(-n2cccn2)c(C)nc1OC
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Into each of 2 microwave vials is added 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (200 mg, 0.869 mmol), potassium carbonate (180 mg, 1.30 mmol), copper iodide (16 mg, 0.084 mmol) and pyrazole (59 mg, 0.869 mmol). The vials are flushed with N2 before anhydrous dimethylformamide (5.5 mL) is added and then sealed. The first reaction is heated in the CEM Discover microwave at 160° C. for 20 minutes. LC/MS shows the reaction is incomplete. The reaction is re-microwaved to 180° C. for 20 min and LC/MS suggests that the reaction is approximately 50% complete. The reaction is re-microwaved at 185° C. for 20 min then 185° C. for 30 min and LC/MS shows the reaction is largely complete. Reaction 2 is heated in the microwave to 185° C. for 1.5 hr and LC/MS shows the reaction is almost complete. The 2 reactions are combined and diluted with water and extracted with 3 portions of dichloromethane. The combined organic layers are washed with 2 portions of aqueous sodium hydroxide (1M), then dried over magnesium sulfate and evaporated to give a dark oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined and the solvent evaporated. The residue is further purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:ethyl acetate (19:1) then dichloromethane:heptane (1:1, increasing to 1:0). Clean fractions containing the product are combined and evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(pyrazol-1-yl)pyridine as a yellow oil (102 mg, 27% yield). MS: m/e=218 (M+H); NMR (CDCl3): 7.70 (1H, d), 7.53 (1H, d), 7.37 (1H, s), 6.44 (1H, t), 3.99 (3H, s), 2.59 (2H, q), 2.29 (3H, s), 1.10 (3H, t)
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][OH:9].[C:14]([OH:25])(=O)[CH2:15][CH2:16][S:17][S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>C(C(C)=O)C(C)C>[C:21]([O:23][CH2:8][CH:7]([NH2:6])[CH2:10][CH2:11][CH2:12][CH3:13])(=[O:22])[CH2:20][CH2:19][S:18][S:17][CH2:16][CH2:15][C:14]([O:9][CH2:8][CH:7]([NH2:6])[CH2:10][CH2:11][CH2:12][CH3:13])=[O:25]
Reactant: O=C(O)CCSSCCC(=O)O
Reactant: CCCCC(N)CO
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: CCCCC(N)COC(=O)CCSSCCC(=O)OCC(N)CCCC
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
6.1 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 7.0 g of 2-amino-1-hexanol (manufactured by Aldrich Co., Ltd.). After stifling for 10 minutes, 6.3 g of 3,3′-dithiodipropionic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the resulting mixture was heated to 120° C. The mixture was then stirred at 120 to 129° C. for a further 3 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 100 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stifling for 1 hour, the precipitated crystals were collected by filtration and dried at 50° C., yielding the methanesulfonate salt of di(2-aminohexyl) 3,3′-dithiodipropionate.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:18])[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9]1)C.Cl>O.C(O)C>[C:14]([N:11]1[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([OH:18])=[O:5])[CH2:13][CH2:12]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)CC1CCN(C(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)N1CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
To a solution of NaOH in water/ethanol (v/v=40/10, 50 mL) (1-tert-butyl-piperidin-4-yl)-acetic acid ethyl ester (4.03 g, 17.8 mmol) was added and the mixture was stirred at r.t. overnight. 1 N aq. HCl was added to adjust the pH to 5. Volotiles were evaporated in vacuo, the residue was diluted with methanol (30 mL), and the insoluble inorganic salts were removed by filtration. The filtrate was concentrated and purified by column chromatography on silica gel (CH2Cl2/MeOH=20/1 to 5/1) to give 0.7 g of title compound as a light grey powder. 1H NMR (400 MHz, DMSO-d6): 3.15-3.08 (br m, 2H), 2.30 (br t, J=11.2 Hz, 2H), 2.05 (d, J=6.4 Hz, 2H), 1.71-1.68 (m, 3H), 1.30-1.27 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C:36]1([O:39]C(=O)C)[CH2:38][CH2:37]1)=[O:35]>>[OH:39][C:36]1([C:34]([N:2]2[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:27]6[O:26][CH2:25][O:24][C:23]=6[CH:22]=[CH:21][C:20]=5[O:28][CH2:29][CH:30]5[CH2:32][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3]2)=[O:35])[CH2:38][CH2:37]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: O=C(N[C@H]1CCN(C(=O)C2(O)CC2)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH2:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18].[H-].[Na+]>>[CH2:17]([O:19][C:20](=[O:23])[CH2:21][CH:8]([C:7](=[O:16])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[O:10])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: O=C(CC(=O)c1ccco1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccco1

Procedure:
Following a procedure analogous to that set out in Example 49, 40 grams 1-phenyl-3-(2-furyl)-1,3-propanedione were alkylated by reaction with 36 grams bromoacetic acid-ethyl ester and 23 grams of a 20% suspension of sodium hydride in paraffin oil to form 3-benzoyl-3-(2-furoyl)-propionic acid-ethyl ester, which was further reacted with 28 grams phenylhydrazine in glacial acetic acid to form the respective pyrazol-4-acetic acid-ethyl esters, which without being separated, were saponified in accordance with a procedure analogous to that described in Example (1b).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2[N:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14].C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>CN(C1C=CN=CC=1)C.ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2[N:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: COc1ccc(N(C)c2nc(C)nc3ccc(N)cc23)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(C)c2nc(C)nc3ccc(NC(C)=O)cc23)cc1

Procedure:
The title compound was prepared from (6-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (30 mg, 0.102 mmol), triethylamine (0.021 ml, 0.153 mmol), acetyl chloride (0.011 ml, 0.153 mmol) and DMAP (1 mg) in 5 ml of dichloromethane similar to example 28 to give 3 mg (9%) of paint brown solids. 1H NMR (CDCl3): 7.71 (s, 2H), 7.19 (s, 1H), 7.12-7.09 (m, 2H), 6.93-6.91 (m, 3H), 3.84 (s, 3H), 3.56 (s, 3H), 2.71 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].CN(C)[CH:8]=[CH:9][C:10](=O)[CH:11]([O:14][CH3:15])[O:12][CH3:13].C[O-].[Na+]>CO>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:10]1[CH:9]=[CH:8][N:5]=[C:2]([CH3:3])[N:4]=1
Reactant: COC(OC)C(=O)C=CN(C)C
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccnc(C)n1
Temperature: 40 °C
Yield: 91.3 %

Procedure:
Acetamidine hydrochloride (3 mol) and 4-dimethylamino-1,1-dimethoxy-but-3-en-2-one (2 mol) were mixed in methanol (500 ml) and the reaction mixture was warmed to 40° C. A solution of sodium methoxide in methanol (558 g, 30%) was added quickly and a brown suspension was formed. The reaction mixture was heated under reflux for 2 h, cooled to room temperature overnight followed by evaporation of methanol under reduced pressure. The resulting residue was taken up in dichloromethane (500 ml) and washed several times with water (100 mL). The solvent was removed to give 307 g of black oil. The distillation of this oil gave a colourless liquid of boiling point 55-58° C. (0.5 mbar).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:9][C:8]1[CH:11]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:13][CH3:14])=[CH:6][C:7]=1[CH3:12]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Product: COc1cc(C)c(C=C2C(=O)Nc3ccc(F)cc32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.25 g of 5-fluoro-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:29][Li]>C1COCC1>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([OH:14])([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[CH3:29])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C(=O)O)c(O)c3)ccc21
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(C)(O)COc3ccc(C(=O)O)c(O)c3)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 g (2.6 mmol) of 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoic acid and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 5.3 ml (8.3 mmol) of a solution of methyl lithium in THF (1.6M) are added dropwise at -78° C. and the reaction mixture is stirred for 12 hours at room temperature. It is poured into ice-water, acidified to pH=1 and extracted with ethyl ether, and the organic phase is separated, dried over magnesium sulphate and evaporated. The residue obtained is recrystalised in cyclohexane and 900 mg (86%) of the expected product of melting point 170°-171° C. are collected.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[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])[CH:3]1OC.C[Si]([C:24]#[N:25])(C)C.B(F)(F)F.CCOCC>C(Cl)Cl>[C:24]([CH:3]1[C:2]([CH3:19])([CH3:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])#[N:25]
Reactant: C[Si](C)(C)C#N
Reactant: COC1N(C(=O)OCc2ccccc2)CCC1(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CCN(C(=O)OCc2ccccc2)C1C#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
In a 500 ml flask was dissolved phenylmethyl 3,3-dimethyl-2-(methyloxy)-1-pyrrolidinecarboxylate (0.0426 mol, 11.2 g) in 200 ml methylene chloride under argon. After the solution was cooled to −78° C., trimethylsilyl cyanide (0.0640 mol, 6.32 g) was added followed by boron triflouride etherate (0.0640 mol, 9.09 g). After 1 hr of stirring, the reaction was quenched with saturated aqueous sodium bicarbonate and allowed to warm to 20° C. After 2 hr of vigorous stirring, the aqueous phase was separated and extracted with methylene chloride (2×100 ml). All organics were combined, dried over MgSO4, filtered and concentrated yielding 10.8 g (98%) of phenylmethyl 2-cyano-3,3-dimethyl-1-pyrrolidinecarboxylate as a clear oil which was used without further purification. LCMS (ESI+)=259 m/z (MH+). 1H NMR (400 MHz, CDCl3)— rotamers δ 7.44-7.35 (m, 5H), 5.21 and 5.20 (s, 2H), 4.26 and 4.17 (s, 1H), 3.64-3.51 (m, 2H), 2.01-1.95 (m, 1H), 1.80-1.74 (m, 1H), 1.36 (s, 3H), 1.16 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH2:22])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])C>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][S:28]([CH3:26])(=[O:30])=[O:29])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Nc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-aminopyridin-4-yl)propoxy]pyridine (0.15 g, 0.42 mmol) obtained in Example 25 is dissolved in methylene chloride (5 ml) and pyridine (0.34 ml), and thereto is added ethylsulfonyl chloride (0.04 ml, 0.50 mmol) under ice-cooling, and the mixture is stirred for 3 hours. To the mixture is added ice-water (20 ml), and the mixture is extracted with ethyl acetate (50 ml×2). The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution (20 ml×2) and a saturated brine (20 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent: chloroform/methanol), and further recrystallized from diethyl ether to give the title compound (0.07 g) as colorless crystals, m.p. 131-133° C.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[F:11][C:5]1[CH:4]=[C:3]([CH:1]2[CH2:2][O:20]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C=Cc1ccc(C#N)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1ccc(C2CO2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-ethenyl-2-fluorobenzonitrile (18.0 g, 122 mmol) in 200 mL of DCM was slowly added mCPBA (74.8 g, 367.347 mmol) in portions at 0° C. The mixture was warmed to room temperature and stirred overnight. The solution was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers was washed with brine and then concentrated. The residue was purified via column chromatography to give 2-fluoro-4-oxiran-2-ylbenzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.59˜7.62 (m, 1H), 7.12˜7.22 (m, 2H), 3.89˜3.91 (m, 1H), 3.20˜3.22 (m, 1H), 2.72˜2.74 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12](O)=[O:13])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12]([Cl:20])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)C/C(=C\C(=O)O)c2cc(F)ccc21
Solvent: ClCCl
Product: CC1(C)C/C(=C\C(=O)Cl)c2cc(F)ccc21
Temperature: 25 °C

Procedure:
To an ice cold, stirred suspension of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetic acid (9.0 g, 0.0409 mol) in dichloromethane (200 ml) was added oxalyl chloride (15.6 g, 0.123 mol, Aldrich). The stirring suspension was allowed to warm to 25° C. during 2 h. The resulting solution was concentrated by spin evaporation in vacuo with the addition of dichloromethane (4×75 ml) to give (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetyl chloride as an uncharacterized oil. Dichloromethane (approximately 70 g) was added to dissolve this residual oil and the resulting solution was divided equally and used without other purification in Examples 15i, 16 and 17.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([F:20])=[C:15](Br)[C:14]=2[O:22][CH3:23])[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][CH:35]=[C:36]([CH:39]=2)[C:37]#[N:38])O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([F:20])=[C:15]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([C:37]#[N:38])[CH:39]=3)[C:14]=2[O:22][CH3:23])[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: COc1c(C(C)Nc2ncnc(N)c2C#N)cc(Cl)c(F)c1Br
Reactant: CC1(C)OB(c2cncc(C#N)c2)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: C1COCCO1
Solvent: O
Product: COc1c(C(C)Nc2ncnc(N)c2C#N)cc(Cl)c(F)c1-c1cncc(C#N)c1
Temperature: 90 °C
Yield: 37 %

Procedure:
Into a microwave vial was added 4-amino-6-{[1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]amino}pyrimidine-5-carbonitrile (8.0 mg, 0.020 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (5.51 mg, 0.0240 mmol), a solution of sodium carbonate (48 μL, 0.050 mmol) in water (48 μL), 1,4-dioxane (0.2 mL, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol). The mixture was bubbled with N2 for 5 minutes and heated at 90° C. for 2 h. Purification by preparative LCMS (pH 10) gave the desired compound (37% yield). LCMS calculated for C20H16ClFN7O (M+H)+: m/z=424.1. found: 424.1.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH3:15])[N:8]=[CH:7][N:6]=1>C1COCC1>[CH3:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]([S:2][CH3:1])=[N:6][CH:7]=[N:8]2
Reactant: Cc1cccc2ncnc(Cl)c12
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ncnc2cccc(C)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To a suspension of sodium thiomethoxide (0.806 g, 11.5 mmol) in THF (40 ml) at 0° C. was added 1B (1.368 g, 7.66 mmol) in THF (25 ml). The mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to about 15 ml, and water (100 ml) was added. The slurry was stirred at 0° C. for 30 min. The solid was collected by filtration, washed with water and dried to give 1C (1.209 g, 83%) as a solid. The compound has an analytical HPLC retention time=1.899 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=191+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3S(C3C=CC=CC=3)(=O)=O)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:48][CH2:47][N:46]([CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:44]4)=[CH:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:11])=[O:10].[OH-].[Na+]>C(O)(C)C.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:44][CH2:45][N:46]([CH:49]([CH3:50])[CH3:51])[CH2:47][CH2:48]4)=[CH:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:10])=[O:11]
Reactant: COc1ncc(-c2cc(-c3ncc(CN4CCN(C(C)C)CC4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: COc1ncc(-c2cc(-c3ncc(CN4CCN(C(C)C)CC4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
2,4-Difluoro-N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide (81 mg, 0.106 mmol) was suspended in isopropanol (2 ml) and 2M sodium hydroxide (aq) (0.53 ml, 1.060 mmol) was added. The reaction mixture was stirred at RT for 2 h, the solvent removed and the residue dissolved in water (1 ml) and acidified to pH˜6 by the addition of 2M hydrogen chloride (aq). The resultant suspension was extracted with dichloromethane (3×2 ml), the organic layer separated (hydrophobic frit) and concentrated in vacuo to give a brown solid which dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method H). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (45 mg).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH2:23][OH:24])[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28].[H-].[Na+].O>CS(C)=O>[C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH2:23][O:24][CH2:26][C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])[O:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Reactant: CCCN(CCC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCC)C(=O)COCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A mixture of 4.9 g (0.015 mole) of 6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinemethanol and 2.84 g (0.016 mole) of 2-chloro-N,N-dipropylacetamide are dissolved in 100 ml of dry DMSO and the mixture stirred at room temperature under nitrogen. Slowly, 0.88 g of sodium hydride (0.0183 mole, 50% oil dispersion) is added to the DMSO mixture and the reaction allowed to stir at ambient temperature (22°). After stirring for 10 minutes, an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1/2 hour, the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted and washed with 6×300 ml portions of water. The product is then extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 6×300 ml portions of water. The CHCl3 layer is separated and dried over anhydrous Na2SO4 overnight. The CHCl3 is removed in vacuo yielding the crude product as a dark oil. The resulting oil is purified on a neutral Alumina III column (200 g), eluting with 2% methanol/chloroform, yielding 4.6 g (69%) of the desired product, 2-[[6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinyl]methoxy]-N,N-dipropylacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[CH2:12][NH:13][C:14]([O:16][CH3:17])=[O:15].[H-].C([Al+]CC(C)C)C(C)C.Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:15])[O:16][CH3:17]
Reactant: COC(=O)NCc1cc(C(=O)OC)ccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)NCc1cc(CO)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10.3 g of methyl 4-chloro-3-(methoxycarbonylaminomethyl)benzoate was dissolved in 80 ml of anhydrous tetrahydrofuran, 100 ml of diisobutylaluminum hydride (0.95 M hexane solution) was dropwise added thereto in an atmosphere of nitrogen at from −50° C. to −30° C., and after completion of the dropwise addition, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, diluted hydrochloric acid was dropwise added to the reaction mixture at 0° C., water was added thereto, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, eluent: hexane/ethyl acetate=1/1) to obtain 6.5 .g of methyl N-(2-chloro-5-hydroxymethylbenzyl)carbamate as white crystals.