Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1.Cl.[NH2:31][NH:32][C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:33]([NH:32][N:31]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1)(=[O:34])[NH2:35]
Reactant: NNC(N)=O
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=O)NN=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Yield: 47.4 %

Procedure:
A mixture of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (231 mg), semicarbazide hydrochloride (101 mg), potassium carbonate (125 mg), water (2 ml), and ethanol (10 ml) was heated under reflux for 4 hours. Ethanol was evaporated in vacuo and the residue was partitioned between dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (30 ml). After an additional extraction with dichloromethane, the combined extracts were washed with brine (20 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to give colorless crystals of 3-[2-(2-carbamoylhydrazonocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (125.8 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: N#CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: N#CCc1cccc(NC(=O)c2cccc(-c3ccc(Cl)cc3)n2)c1

Procedure:
The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to 4-chloro-phenylboronic acid (81 mg, 0.52 mmol) using Method E. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:34]1[CH2:37][CH2:36][CH2:35]1>C(Cl)(Cl)Cl>[N:34]1([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([CH:17]4[CH2:22][O:21][CH2:20][CH2:19][O:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:37][CH2:36][CH2:35]1
Reactant: C1CNC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CCC4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and azetidine. [α]D20=+25.5° (c=0.26, CHCl3), ES-MS m/e (%): 427 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][NH:24][CH3:25])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][N:24]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[CH3:25])=[CH:21][CH:20]=1
Reactant: CNCc1ccc(OC)cc1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: COc1ccc(CN(C)C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 72.4 %

Procedure:
3.0 g (13.6 mmol) of 1-(4-nitrophenyl)-4-piperidone and 2.0 g (13.6 mmol) of N-(4-methoxybenzyl)-N-methylamine were reacted in a similar manner to Example 1. 3.5 g of 4-(N-(4-methoxybenzyl)-N-methylamino)-1-(4-nitrophenyl)piperidine were obtained. Melting point 144°-145° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1)#N.C(O)=[O:20]>[Ni]>[O:13]=[C:12]1[CH2:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8][C:7]2[CH:18]=[C:3]([CH:1]=[O:20])[CH:4]=[CH:5][C:6]1=2
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1CC2=O
Reactant: O=CO
Agent: [Ni]
Product: O=Cc1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C

Procedure:
Heat a mixture of 5.0 gm. of 3-cyano-10,11-dihydro-11-oxodibenzo[b,f]thiepin and 4.0 gm. of Raney nickel alloy in 60 ml. of 75% (v/v) aqueous formic acid at reflux for 1.5 hours. Cool to room temperature and filter. Concentrate to small volume and extract with methylene chloride. Wash the extract with water and with 1N sodium bicarbonate until neutral. Dry the neutral extract over sodium sulfate and concentrate to dryness to obtain the title product.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([F:7])[F:6])=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[F:7][C:5]([F:6])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCC(F)(F)c1ccccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCC(F)(F)c1ccccn1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To the solution of 2-(2-azido-1,1-difluoro-ethyl)-pyridine (example 59c, 1 g, 5.4 mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon (0.5 g). The reaction was carried out under H2 in a balloon at room temperature for 2 h. after removal of catalyst, the solvent was concentrated to afford 2,2-difluoro-2-pyridin-2-yl-ethylamine (0.84 g, 98%) as a light yellow oil. LC-MS m/e 158 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:12][S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[O:21])=[CH:18][CH:17]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(Cl)c1ccc(CCBr)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)NC(=O)c2ccc(CCBr)cc2)cc1

Procedure:
A mixture of 18.72 g (0.10 mol) of 4-methoxybenzenesulfonamide, 24.75 g (0.10 mol) of 4-(2-bromoethyl)benzoyl chloride and 200 ml of toluene was stirred and heated to reflux at which time solution was achieved. The solution was heated at reflux for 16.5 hrs. The vapors emitted from the condenser were acidic during reaction. After this time, the solution was cooled and concentrated to an oil. The oil was dissolved in 3:7 heptane:toluene and cooled. Solid crystallized and was collected, washed with ligroine and dried.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:25]([F:28])([F:27])[F:26])[O:16][N:15]=[C:14]([C:17]3[S:21][C:20]([CH:22]=[O:23])=[C:19]([CH3:24])[CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1>O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:25]([F:27])([F:26])[F:28])[O:16][N:15]=[C:14]([C:17]3[S:21][C:20]([CH:22]([OH:23])[CH3:1])=[C:19]([CH3:24])[CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylmagnesium bromid (1.80 ml, 3M in diethyl ether) is added to a solution of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carbaldehyde (Example 1, (ii) step B, 2 g) in tetrahydrofuran (39 ml) under nitrogen at 0° C. The mixture is slowly warmed to room temperature and stirred overnight. After 21 hours, the reaction is quenched with a saturated aqueous solution of NH4Cl in water. The mixture is extracted two times with ethyl acetate. The organic phases are combined, dried over MgSO4 and concentrated in vacuo to yield 1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethanol (2.1 g) as a yellowish foam. The crude product obtained is used without further purification. MS (HPLC/MS): 424 (MH+). Retention time: 2.03 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:5])[CH3:2].C(N(CC)CC)C.[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[F:37])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:36]([F:37])=[C:28]([F:27])[CH:29]=1)=[O:5])[CH3:2]
Reactant: CCCCNc1nc2n(c1C(=O)OCC)CCCC2
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(C(=O)c1ccc(F)c(F)c1)c1nc2n(c1C(=O)OCC)CCCC2
Temperature: 0 °C

Procedure:
Compound F (3.2 g, 12.1 mmol) and triethylamine (2.54 mL, 18.1 mmol, 1.5 eq.) were dissolved in DCM (70 mL) and the solution was cooled to 0° C. 3,4-difluorobenzoylchloride (1.66 mL, 13.3 mmol, 1.1 eq.) was added dropwise. After 90 minutes the reaction mixture was diluted with DCM (130 mL) and washed with 0.5 M KHSO4 in water (200 mL), saturated aqueous NaHCO3 solution (200 mL) and saturated aqueous NaCl solution (200 mL). The combined organic phases were dried over sodium sulphate and the solvent was removed under vacuum and the untreated product 2-[butyl-(3,4-difluoro-benzoyl)-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester was used directly in the next stage.
Reaction SMILES: [CH3:1][C:2]1[N:11]([N:12]2[C:24](=[O:25])[C:22]3[C:23]4[N:15]([C:16]([O:26][CH3:27])=[CH:17][C:18]=4[CH2:19][CH2:20][CH:21]=3)[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:13]2)[C:10](=[O:34])[C:9]2[C:4](=[CH:5][C:6]([C:35]([O:37]C)=[O:36])=[CH:7][CH:8]=2)[N:3]=1.O.[OH-].[K+]>C1COCC1>[CH3:1][C:2]1[N:11]([N:12]2[C:24](=[O:25])[C:22]3[C:23]4[N:15]([C:16]([O:26][CH3:27])=[CH:17][C:18]=4[CH2:19][CH2:20][CH:21]=3)[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:13]2)[C:10](=[O:34])[C:9]2[C:4](=[CH:5][C:6]([C:35]([OH:37])=[O:36])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc2c(=O)n(N3C=C(c4ccccc4)n4c(OC)cc5c4C(=CCC5)C3=O)c(C)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c3n1C(c1ccccc1)=CN(n1c(C)nc4cc(C(=O)O)ccc4c1=O)C(=O)C3=CCC2
Temperature: 22.5 °C
Reaction time: 5 h

Procedure:
1.3 g of product of Example 2B (2.55 mmol) are dissolved in 55 ml of THF, 18 ml of water containing 0.33 g of potassium hydroxide are added and the mixture is stirred at 20-25° C. for 5 h. Ice is added and the mixture is acidified to pH=5. It is extracted with CH2Cl2. The extracts are purified by chromatography. 0.55 g obtained. Yld: 44%. Decomposition starting at 225° C.—TLC (DM5): Rf=0.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:29](C(C)C)CC)(C)C.CS(Cl)(=O)=O>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24][NH2:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CN)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
To a 0° C. solution of 1.30 g of 1-(benzyloxycarbonyl)-2-hydroxymethyl-4-(tert-butyloxycarbonyl)-piperazine in 20 mL of CH2Cl2 was added 720 mg of diisopropylethylamine, then 510 mg of methanesulfonyl chloride. The mixture was allowed to warm to room temperature over 2 h, then diluted with 50 mL of EtOAc and washed with 25 mL of saturated NaHCO3, 2×25 mL of 1N HCl, 25 mL of saturated NaHCO3, and 25 mL of brine. The organic phase was dried over MgSO4 and concentrated to a yellow oil. This oil was dissolved in 10 mL of DMF and 360 mg of sodium azide was added. The mixture was heated to 100° C. and stirred overnight at this temperature, then cooled, diluted with 25 mL of EtOAc, and washed with 3×10 mL of water and 10 ml of brine. The organic phase was dried over MgSO4 and concentrated to an oily yellow solid. Of this solid, 475 mg was dissolved in 5 mL of 9:1 THF-water and 398 mg of triphenylphosphine was added. The mixture was heated to 50° C. and stirred at this temperature for 16 h, then cooled, poured into 30 mL of 1N HCl, and extracted with 2×10 mL of EtOAc. The aqueous phase was made very basic (pH>12) by addition of 5N NaOH, then extracted with 5×20 mL of EtOAc. The combined organic extracts were dried over MgSO4, and concentrated to yield 48 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ7.28-7.40 (m, 5H), 5.15 (ABq, J=12.4 Hz, 2H), 3.82-4.22 (m, 4H), 2.66-3.30 (m, 5H), 1.45 (br s, 9H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3](CS([O-])(=O)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[F:1][C:2]([F:16])([F:15])[CH:3]([N:17]=[N+:18]=[N-:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)([O-])CC(c1ccccc1)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(c1ccccc1)C(F)(F)F
Temperature: 60 °C
Reaction time: 48 h
Yield: 38.4 %

Procedure:
To a solution of α-(trifluoromethyl)benzylmesylate (2.8 g, 11.0 mmol) in DMF (15 mL), sodium azide (7.38 g, 110 mmol) was added. The reaction mixture was stirred at 60° C. for 48 hours. Then the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel gave the desired product (849 mg, 37%). EI-MS m/z 202 (M+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:13][NH:14][O:15][CH3:16].Cl.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][O:15][N:14]([CH3:13])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)=[O:11]
Reactant: CNOC
Reactant: O=C(Cl)c1ccc2occc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzofuran-5-carbonyl chloride (1 g, 5.54 mmol) in dry DCM (40 ml) is treated with N,O-dimethylhydroxylamine.HCl (0.594 g, 6.09 mmol) followed by triethylamine (1.930 ml, 13.84 mmol). After stirring at RT overnight, the mixture is diluted with DCM and washed with H2O, 1M HCl, 1M NaOH, brine, dried (MgSO4) and evaporated down to give a brown oil which is used without further purification; MS: m/z 206.1 [M+H]+
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[N:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccncc1
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccncc3)c12

Procedure:
The title compound, white solid (44 mg, 63%), MS (ISP) m/z=282.3 [(M+H)+], mp 323.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available pyridine-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[OH:5][C:6]1[CH:11]=[C:10]([OH:12])[N:9]=[C:8]([SH:13])[N:7]=1.[OH-].[Na+]>O>[OH:5][C:6]1[CH:11]=[C:10]([OH:12])[N:9]=[C:8]([S:13][CH2:1][CH2:2][CH3:3])[N:7]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: CCCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCSc1nc(O)cc(O)n1

Procedure:
Propyl iodide (136 ml) was added to a suspension of 4,6-dihydroxy-2-mercaptopyrimidine (200 g) in water (800 ml), containing sodium hydroxide (55.6 g). The reaction mixture was stirred for 2 weeks then concentrated to half volume, 2N hydrochloric acid was added and the subtitle compound was isolated by filtration (167 g).
Reaction SMILES: [H-].[Na+].[Cl-].[Cl:4][C:5]1[CH:6]=[C:7]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.[CH2:32]1[O:42][C:35]2([CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]2)[O:34][CH2:33]1.O>CS(C)=O>[Cl:11][C:9]1[CH:8]=[C:7]([CH:12]=[C:38]2[CH2:39][CH2:40][C:35]3([O:42][CH2:32][CH2:33][O:34]3)[CH2:36][CH2:37]2)[CH:6]=[C:5]([Cl:4])[CH:10]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Clc1cc(Cl)cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1cc(Cl)cc(C=C2CCC3(CC2)OCCO3)c1
Temperature: 90 °C
Yield: 32.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 4.2 grams (0.11 mole) of sodium hydride (60% in mineral oil) in 200 mL of anhydrous dimethyl sulfoxide was heated to about 90° C. where it was maintained for 10 minutes. After this time the reaction mixture was cooled to 25° C., and 46.0 grams (0.10 mole) of 3,5-dichlorophenylmethyltriphenylphosphonium chloride was added, followed by 14.0 grams (0.10 mole) of 1,4-cyclohexanedione mono-ethylene ketal. Upon completion of addition the reaction mixture was again warmed to 90° C., then it was allowed to cool to ambient temperature. After this time the reaction mixture was poured into 400 mL of water, and the mixture was extracted with two 250 mL portions of diethyl ether. The combined extracts were then washed with two 100 mL portions of water. The organic layer was concentrated under reduced pressure to an oily solid residue. The oily solid was taken up in a solution of 90 mL of petroleum ether and 10 mL of diethyl ether, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using 10% diethyl ether in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 9.7 grams of 8-(3,5-dichlorophenylmethylene)-1,4-dioxaspiro[4.5]decane, mp about 66° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][CH:23]=2)[O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[N:30][NH:31]2)=[CH:27][CH:26]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([NH:24][C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:13]=[C:14]([CH:21]=[CH:22][CH:23]=4)[O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:33]=2)[CH:29]=[N:30]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CNC(=O)COc1cccc(Nc2nc(Cl)nc3[nH]ccc23)c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CNC(=O)COc1cccc(Nc2nc(Nc3ccc4cn[nH]c4c3)nc3[nH]ccc23)c1
Temperature: 115 °C
Yield: 8.7 %

Procedure:
To a mixture of 2-(3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy-N-methylacetamide (0.062 g) in nBuOH (0.6 mL) was added 6-aminoindazole (0.028 g) and TMSCl (0.013 mL). After heating at 115° C. for 15 h, the mixture was purified by prep HPLC to give 2-(3-(2-(1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy-N-methylacetamide (0.007 g, MS calcd for C22H20N8O2 428.4. found [MH] 429.1; UV 238.1, 311.6 nm).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:9][C:8]([C:23]2[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([CH:32]=O)=[CH:27][CH:26]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:41].[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:17])[CH3:18])=[CH:9][C:8]([C:23]2[N:24]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([CH2:32][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:27][CH:26]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:41]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCC3)ccc21
Yield: 65.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-5-[3-(tert-butyldimethylsiloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (71.8 mg, 0.120 mmol) was dissolved in acetonitrile (2.5 mL), and the solution was treated with pyrrolidine (0.100 mL, 1.198 mmol), acetic acid (0.069 mL, 1.198 mmol) and sodium triacetoxyborohydride (76.3 mg, 0.360 mmol), followed by purification by flash column chromatography (chloroform/methanol=19/1, 4/1) to obtain 4-chloro-5-[3-(tert-butyldimethylsiloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (51.4 mg, yield 66%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccccc2-c2ccccc2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
2-[(Biphenyl-2-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (525 mg, 1.36 mmol) is dissolved in EtOH (15 mL), and solid KOH (1.42 g, 24.7 mmol) and water (1.5 mL) are added. The mixture is stirred at RT for 30 minutes then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with concentrated HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (246) as white solid (453 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1.Cl.[CH3:18][O:19][NH2:20]>N1C=CC=CC=1>[CH3:18][O:19][N:20]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1
Reactant: CON
Reactant: O=C(Cc1cnccn1)c1ccccc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(Cc1cnccn1)c1ccccc1Cl

Procedure:
3 g of 2'-chloro-2-(2-pyrazinyl)-acetophenone and 0.8 g of O-methylhydroxylamine hydrochloride are dissolved in 10 ml of pyridine and the mixture is heated at 80° for 30 minutes. The pyridine is then removed under reduced pressure and water is added to the crude product. Thereupon, the mixture is extracted with ethyl acetate and the organic phase is dried over sodium sulfate and concentrated to yield 2'-chloro-2-(2-pyrazinyl)-acetophenone O-methyl oxime as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[C:11]([F:13])[C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[F:14].[C-:15]#[N:16].[Na+].O>CS(C)=O>[C:15]([CH2:2][C:3]1[CH:12]=[C:11]([F:13])[C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[F:14])#[N:16]
Reactant: Fc1cc(CCl)c(F)c2c1OCCO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cc(F)c2c(c1F)OCCO2
Reaction time: 1 h

Procedure:
6-Chloromethyl-5,8-difluoro-1,4-benzodioxane (36.9 g, 0.183 mole) is dissolved in 500 ml of dimethylsulfoxide and 11.2 g (0.23 mole) of sodium cyanide added. This is stirred at 25° for 1 hour, and then poured into cold water. Extraction with ether, washing the extract with water, drying and concentration gives 6-cyanomethyl-5,8-difluoro-1,4-benzodioxane.