Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]#[N:12])[NH:10][C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH2:19]([N:10]1[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:11]#[N:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc2nc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc2nc(Cl)ccc2n1Cc1ccccc1

Procedure:
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carbonitrile (0.10 g, 0.56 mmol, from Step 2) in DMF (1.3 mL) was treated with K2CO3 (0.12 g, 0.84 mmol) and benzyl bromide (74 μL, 0.62 mmol, Aldrich) overnight. The reaction mixture was diluted with EtOAc and washed three times with water and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded purified product. Yield: (0.12 g, 80%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1C=C(CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[C:31]([C:36]([O:38][CH3:39])=[O:37])[C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][C:24]=1[CH3:40].C(Cl)C1C=CC=CC=1>>[CH2:9]([N:33]1[C:32](=[O:35])[C:31]([C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[C:24]([CH3:40])[CH:25]=2)=[N:34]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Solvent: ClCc1ccccc1
Product: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(Cc2ccccc2)c1=O
Yield: 71 %

Procedure:
Following the procedure of Example 1 (6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and benzyl chloride were reacted to yield the title compound as yellow needles (yield: 71.0%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[CH:17]1([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[C:26](Cl)[N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Cl:30][C:29]1[C:24]([NH:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:25][C:26]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:27][CH:28]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Clc1ncc(Cl)c(NC2CCCCC2)n1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NC4CCCCC4)n3)cc2CC1

Procedure:
5-Chloro-N(4)-cyclohexyl-N(2)-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-pyrimidine-2,4-diamine was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and cyclohexyl-(2,5-dichloro-pyrimidin-4-yl)-amine in an analogous manner to Example 308c. Product isolated as a pale yellow foam (65 mg, 37%). LCMS (m/e) 430 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.87 (s, 1H), 7.40-7.30 (m, 2H), 7.07-7.00 (m, 1H), 6.97 (bs, 1H), 5.12 (d, 1H, J=4.9 Hz), 4.07-3.92 (m, 1H), 3.61-3.51 (m, 2H), 3.38 (s, 3H), 3.00-2.87 (m, 4H), 2.81-2.65 (m, 6H), 2.17-2.05 (m, 2H), 1.89-1.76 (m, 2H), 1.53-1.47 (m, 2H), 1.47-1.20 (m, 4H).
Reaction SMILES: CS([O-])(=O)=O.[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N+:11]2[C@@H:29]([CH:32]3[CH2:34][CH2:33]3)[CH2:30][O:31][C:10]1=2)[CH:7]=[CH2:8].[CH2:36]([S-:38])[CH3:37].[Na+]>>[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH:32]2[CH2:33][CH2:34]2)[CH2:30][S:38][CH2:36][CH3:37])[C:10]1=[O:31])[CH:7]=[CH2:8]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C1CC1
Reactant: CC[S-]
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSCC)C2CC2)C1=O

Procedure:
The title compound was prepared from (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium methanesulfonate (Example 349, Step A) and sodium ethanethiolate as described in Example 339.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:6]([CH:29]=1)[CH:7]([NH:14][C:15]([CH2:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+].[CH3:38]I>CN(C)C=O>[CH3:38][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[C:6]([CH:29]=1)[CH:7]([NH:14][C:15]([CH2:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CI
Reactant: CCOC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2cc(O)ccc2N2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2cc(OC)ccc2N2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
Four hundred seventy-two milligrams (1 m mol) of ethyl 4-[N-(5-hydroxy-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate were dissolved in 25 ml of absolute dimethylformamide. After addition of 50 g of 50% sodium hydride, the mixture was stirred for 30 minutes. Then, 0.5 gm of methyl iodide were added dropwise, and the resulting mixture was stirred overnight. To work the mixture up, it was poured onto ice-water and extracted with methylene chloride. The concentrated extracts were purified by column chromatography on silica gel by use of toluene/ethyl acetate (4:1) as eluant.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl.O>[CH3:1][NH:2][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3])[CH3:11]
Reactant: CC(=O)c1ccccc1N
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(C)c1ccccc1N
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Acetic acid (10 drops) was added to a solution of methylamine (10 g) in dichloromethane (150 ml) cooled to 5° C., followed by o-aminoacetophenone (3.5 g, 25.9 mmol), and the solution stirred for 10 minutes. Sodium triacetoxyborohydride (1.5 g, 38.8 mmol) was added and the reaction stirred at room temperature for 72 hours. The reaction was diluted with water, the layers separated, and the organic solution evaporated under reduced pressure to give the title compound as a yellow oil.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:17]([OH:20])(=[O:19])=[O:18].Cl.N([O-])=O.[Na+:25].[PH2](O)=O>O>[Na+:25].[CH3:16][C:8]([C:5]1[CH:4]=[C:3]([S:17]([O-:20])(=[O:19])=[O:18])[CH:2]=[CH:7][CH:6]=1)([CH3:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(c1ccccc1)c1ccc(N)c(S(=O)(=O)O)c1
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)[O-])c1
Temperature: 65 °C

Procedure:
1-Amino-4-(α,α-dimethylbenzyl)benzene-2-sulphonic acid (582.7 g) is suspended in water (41) in a 201 reaction vessel, cone. HCl is added (400 ml) and the mixture is stirred and heated at 65° C. for 20 minutes. The suspension is cooled to 20° C. and cone. HCl (400 ml) is added, followed by a solution of NaNO2 (138 g) in water (400 ml) dropwise, maintaining the temperature below 25° C. The resulting mixture is stirred at room temperature for a further 30 minutes. 50% Hypophosphorous acid (1.7 kg) is added dropwise over 30 minutes and the mixture is stirred at room temperature for 1 hour. The mixture is then warmed slowly until a temperature of 60° C. is reached and foaming has subsided to give a dark brown solution which is allowed to cool overnight and then filtered to remove a small amount of solid. The filtrate is evaporated to a volume of 41, neutralised by the gradual addition of sodium hydroxide pellets (950 g) to pH 10-11, water (31) is added and the solution warmed to 70° C. NaCl (800 g) is added and the product is allowed to crystallise. The solid is collected by filtration, washed with saturated brine and dried. After recrystallisation from 15% w/v NaCl(aq), the solid is stirred with ice water to remove salt, filtered and dried, stirred in acetone, filtered off and dried to give 3-(α,α-dimethylbenzyl)benzenesulphonic acid sodium salt. Further product is recovered from the washings.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(O)[CH3:9])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.Cl>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH2:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C)(O)c2ccc(I)cc2)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: C=C(c1ccc(I)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The side chain used in example 5 (1-(4-iodophenyl)-1-(4-methoxyphenyl)ethanol) (1.25 g, 2.86 mmol) was treated with acetic anhydride (13.49 ml, 143 mmol) and HCl conc (1.042 ml, 34.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered. The precipitate was washed well with n-heptane then dried in vacuo to obtain the title compound as white solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)=[O:5])C>CO.[OH-].[Na+]>[C:4]([CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCc1cn(-c2cccnc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1cn(-c2cccnc2)c2ccccc12

Procedure:
A solution of 2.0 g of 3-[2-(ethoxycarbonyl)ethyl]-N-(3-pyridyl)indole in 10 ml of methanol and 10 ml of 1N sodium hydroxide is refluxed for two hours, cooled, and evaporated. The residue is taken up in 10 ml of water, extracted with 10 ml of ether and adjusted to pH=6 with concentrated sulfuric acid. The resulting solid is filtered and dried to yield 3-(2-carboxyethyl)-N-(3-pyridyl)indole, m.p. 147°-149°.
Reaction SMILES: S[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]#[N:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.S(Cl)([Cl:15])=O>CN(C=O)C>[Cl:15][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]#[N:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: N#Cc1cccc2oc(S)nc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cccc2oc(Cl)nc12
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 98.7 %

Procedure:
A mixture of 2-sulfanyl-1,3-benzoxazole-4-carbonitrile (178 mg), thionyl chloride (427 mg) and DMF (0.0468 mL) was stirred at 80° C. for 5 min. The reaction mixture was concentrated under reduced pressure, ethyl acetate and THF were added, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (178 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C([O-])(O)=O.[Na+]>CCOCC.C1COCC1.C(Cl)Cl.C1C=CC=CC=1>[C:18]1([S:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[CH:5]([CH2:4][CH2:3][O:2][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:6][CH2:7][CH2:8]3)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A solution of (6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid methyl ester (5.22 g, 14.56 mmol) in anhydrous Et2O (50 mL) was cooled to 0° C. under argon, and 21.84 mL of lithium aluminum hydride (21.84 mmol) in THF was added dropwise via syringe. An additional 50 mL of dry THF was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was carefully quenched by addition of 500 mL water, and the resulting aqueous mixture was extracted twice with 250 mL of EtOAc. Evaporation of the organic layer yielded a crude oil which was purified by elution through silica gel with 1:1 hexanes:EtOAc. The solvent was evaporated to give a solid that was dissolved in 50 mL dry methylene chloride. The solution was cooled to 0° C., and pyridine (4.0 mL, 49.5 mmol) and methanesulfonyl chloride (1.69 mL, 21.84 mmol) were added. The reaction mixture was stirred for 3 hours, during which time the reaction mixture was allowed to warm to room temperature. The reaction mixture was poured into 500 mL of saturated aqueous NaHCO3, and the mixture was extracted three times with 250 mL of EtOAc. The combined organic layers were washed with water, brine, and dried on MgSO4. The solvent was removed under reduced pressure to give an oil that was dissolved in benzene and azeotroped to remove residual pyridine. Solvent was removed, and the resulting oil was dissolved in methylene chloride and eluted through silica gel with 1:1 hexanes:EtOAc. Solvent was again removed, to afford methanesulfonic acid 2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester as a white solid (4.44 g, 11.25 mmol, 77.3%) MS: 396 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH2:11][NH:10]1.[CH2:31]([N:33](CC)CC)C.N#CBr>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:31]([N:10]1[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)=[CH:13][CH:9]1[CH2:8][S:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)#[N:33]
Reactant: CCN(CC)CC
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(CSc4ncccn4)NC3)cc2)C(=O)O1
Agent: CN(C)c1ccncc1
Agent: N#CBr
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(CSc4ncccn4)N(C#N)C3)cc2)C(=O)O1
Reaction time: 1 h
Yield: 65.1 %

Procedure:
The amine (Reference Example 7, 0.103 g, 0.24 mM) in CH2Cl2 (4 ml) was treated with triethylamine (0.073 g, 0.100 ml, 0.72 mM) and 4-dimethylaminopyridine (4-DMAP) (0.003 g, 0.024 mM), followed by a suspension of cyanogen bromide (0.129 g, 1.21 mM) in CH2Cl2 (3 ml). The solution was stirred for 1 hour. The mixture was then diluted with CH2Cl2 (7 ml), washed with sat. aq. NaHCO3 (3 ml), water (3 ml), dried and evaporated to an oil which was purified by Isolute chromatography (using as eluant 6% MeOH/CH2Cl2). The resultant oil was triturated with diethyl ether to give the title product (0.071 g, 66%).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:11][NH:10][CH2:9][C:4]32[O:8][CH2:7][CH2:6][O:5]3)[CH2:2]1.Br[CH2:13][CH2:14][OH:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:15][CH2:14][CH2:13][N:10]1[CH2:11][C:3]2([CH2:1][CH2:2]2)[C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:9]1
Reactant: OCCBr
Reactant: C1COC2(CNCC23CC3)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CC2(CC2)C2(C1)OCCO2

Procedure:
The compound (B) (100 mg) was mixed with 2-Bromoethanol (100 mg) and K2CO3 (120 mg) in Acetonitrile. The reaction was refluxed overnight and filtered, the filtrate was evaporated and purified on silica gel column to give the titled product. Mass: (M+1), 200
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=[CH:4][C:3]=1[C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21].[H-].[Na+].F[C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=1>CN(C)C(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=[CH:4][C:3]=1[C:20]([N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:26][CH2:27]1)=[O:21]
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(O)CC1
Reactant: Cc1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccnc1OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 0.07 h

Procedure:
A solution of crude 4-[[4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one (2a) (50 mg, 0.131 mmol) in N,N-dimethylacetamide (1 mL) was treated with sodium hydride (60% in mineral oil; 3.8 mg, 0.157 mmol) and the reaction was left stirring at ambient temperature until effervescence had stopped. 2-fluoro-3-methylpyridine (16 mg, 0.144 mmol) was then added and the reaction mixture sealed into a microwave tube, heated to 170° C. and held at that temperature for 250 seconds before cooling to ambient temperature. The mixture was then purified by preparative HPLC to afford the desired material; m/z (LC-MS, ESI+), RT=4.22 (M+H 473.2)
Reaction SMILES: C(O[C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][N:10]=1)C.[CH3:31][NH2:32]>CO>[CH3:31][NH:32][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:11][N:10]=1
Reactant: CCOC(=O)CCCCc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cn1
Reactant: CN
Solvent: CO
Product: CNC(=O)CCCCc1ccc(CCCCN)cn1

Procedure:
A mixture of 5-6 (45 g, 110 mmol) and a saturated solution of methylamine in methanol (300 mL) in a sealed tube was heated at 70° C. for 12 hours. The mixture was cooled and concentrated to an oil. The residue was chromatographed on silica gel (10:10:1:1 EtOAc/EtOH/NH4OH/H2O) to give 5-7 as a yellow oil.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.FC(F)(F)S(O[Si:25]([CH3:28])([CH3:27])[CH3:26])(=O)=O.O.CCOCC>C(N(C(C)C)CC)(C)C>[O:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:2]1([O:1][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1C=CC(O)(CCCCOc2ccccc2)C1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: C[Si](C)(C)OC1(CCCCOc2ccccc2)C=CC(=O)C1
Reaction time: 0.33 h
Yield: 76.9 %

Procedure:
A solution of 1.2 g (4.9 mmoles) of 4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone in 10 ml of diisopropylethylamine was cooled to 0° C. in an atmosphere of nitrogen, and 20 ml (10 mmoles) of trimethylsilyl trifluoromethanesulfonate (5 M dichloromethane solution) was added. The mixture was stirred for 20 minutes. After the reaction, water was added, and the mixture was exracted with ether. The extract was washed with water and an aqueous sodium chloride solution, and then dried. The solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column (n-hexane:AcOEt=10:1) to give 1.2 g (77%) of 4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:12](=[O:14])[O:11][C:10](=[O:15])[NH:9][C:8]=2[CH:7]=[CH:6][C:5]=1[F:16].[CH3:17]I>CN(C=O)C>[Cl:3][C:4]1[C:13]2[C:12](=[O:14])[O:11][C:10](=[O:15])[N:9]([CH3:17])[C:8]=2[CH:7]=[CH:6][C:5]=1[F:16]
Reactant: O=c1[nH]c2ccc(F)c(Cl)c2c(=O)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2c(Cl)c(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a suspension of NaH (49 mg, 1.11 mmol) in DMF (2 ml) at RT was added a solution of 5-chloro-6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (synthesized in analogy to a procedure described in EP 59391) (200 mg, 0.93 mmol) in DMF (2 ml). The mixture was stirred at RT for 1 h and then methyl iodide (87 μl, 1.39 mmol) was added. The reaction mixture was then warmed up to RT and stirring was continued overnight. The mixture was quenched with water and extracted with ether. The organic phase was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:1 ethyl acetate:cyclohexane) to give the desired compound (83 mg, 39%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz): 7.56 (dd, J=9.5, 8.0 Hz, 1H), 7.10 (dd, J=9.5, 4.0 Hz, 1H), 3.59 (s, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:16]=[C:15]([NH:35][CH:36]3[CH:40]=[C:39]([CH3:41])[NH:38][N:37]3S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=2)(=O)=O)=CC=1.[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>>[CH3:52][N:53]1[CH2:58][CH2:57][N:56]([CH2:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:16]=[C:15]([NH:35][C:36]3[CH:40]=[C:39]([CH3:41])[NH:38][N:37]=3)[CH:14]=2)[CH2:55][CH2:54]1
Reactant: CC1=CC(Nc2cc(COS(=O)(=O)c3ccc(C)cc3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)N(S(=O)(=O)c2ccc(C)cc2)N1
Reactant: CN1CCNCC1
Product: Cc1cc(Nc2cc(CN3CCN(C)CC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Yield: 72.5 %

Procedure:
A mixture of 6-[(4-methylphenylsulphonyloxy)methyl]-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-2-N-[4-methylphenylsulphonyl]-1H-pyrazol-3-ylamino)pyrimidine (Method 52) (214 mg, 0.295 mmol) and 1-methylpiperazine (3.0 ml, 27.1 mmol) was heated at reflux for 4 hours. The volatiles were removed by evaporation and the residue purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2). Product containing fractions were combined and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation of give the title compound (107 mg, 71%).
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO>[CH:1]1([O:5][C:6]2[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=Cc1ccc(OC2CCC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(OC2CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a suspension of 4-hydroxybenzaldehyde (0.12 g) and cesium carbonate (0.49 g) in N,N-dimethylformamide (2 mL) was added cyclobutyl bromide (0.15 g), and the mixture was stirred at 65° C. overnight. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution, and the mixture was extracted with diethyl ether. The organic layer was washed with 0.5 mol/L aqueous sodium hydroxide solution, water and brine, and dried over an hydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-cyclobutyloxybenzaldehyde (0.13 g). To a solution of the obtained 4-cyclobutyloxybenzaldehyde (0.13 g) in methanol (10 mL) was added sodium borohydride (0.056 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-cyclobutyloxybenzyl alcohol (0.12 g).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:19]1[CH:20]=[CH:21][C:22]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=CC(=O)c1ccccc1
Reactant: CCCCCCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCCCCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and n-heptylbenzene (0.82 ml, 4 mM) were dissolved in dichloroethane (3 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-n-heptylbenzoin was obtained as crystal (386.7 mg, 61.5% yield).