Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[O:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN2CCN(Cc3ccccc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CN2CCN(CC3CNCCO3)CC2)cc1
Yield: 225 %

Procedure:
To a solution of tert-butyl 2-((4-benzylpiperazin-1-yl)methyl)morpholine-4-carboxylate (600 mg) in CH2Cl2 (10 ml) is added trifluoroacetic acid (1.8 ml), and the mixture is stirred over night. The solvent is removed under reduced pressure to give 2-((4-benzylpiperazin-1-yl)methyl)morpholine*3 TFA (990 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC

Procedure:
A mixture of methyl 2-methoxy-4-methylbenzoate (5.0 g), N-bromosuccinimide (4.94 g), 2,2′-azobis(isobutyronitrile) (0.23 g) and carbon tetrachloride (50 ml) was heated for 40 minutes under reflux. The mixture was cooled and the precipitate was filtered off. The filtrate was concentrated to give methyl 4-bromomethyl-2-methoxybenzoate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[N:22]=[C:21](SC)[NH:20][C:19](=[O:25])[CH:18]=1>N1C=CC=CC=1>[CH3:16][C:17]1[NH:22][C:21]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[N:20][C:19](=[O:25])[CH:18]=1
Reactant: CSc1nc(C)cc(=O)[nH]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: c1ccncc1
Product: Cc1cc(=O)nc(Nc2ccc(C3=NNC(=O)CC3C)cc2)[nH]1
Yield: 34.9 %

Procedure:
A stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (2.6 g) and 6-methyl-2-methylthiopyrimidin-4-one (3 g) in dry pyridine (40 ml) was heated under reflux for 72 hours. The volume was reduced by evaporation and the crude product (3.16 g) was collected and washed with ethanol. Recrystallisation twice from dimethylformamide gave the title compound (1.39 g), m.p. 314°-318° C. (dec).
Reaction SMILES: [H-].[Na+].C[C:4](OS(C1C=CC(C)=CC=1)(=O)=O)([CH2:21][CH2:22][CH3:23])[CH2:5][C:6]1[C:15]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[OH:20].O.[CH2:36]1COCC1>C(OCC)(=O)C>[CH3:36][C:22]1([CH3:23])[CH2:21][CH2:4][CH2:5][C:6]2[C:15]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=2[O:20]1
Reactant: C1CCOC1
Reactant: CCCC(C)(Cc1c(NC(C)=O)ccc(C(=O)OC)c1O)OS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)c2c1OC(C)(C)CCC2

Procedure:
To a mixture of 2.2 g sodium hydride (60%) and 20 ml THF is added dropwise at 0° C. a solution of 15 g of methyl 3-(2'-methyl-2'-tosyloxypentyl)-4-acetylaminosalicylate in 10 ml THF. This is allowed to come to room temperature over several hours, then chilled and 2 ml H2O added slowly. This is then diluted with ethyl acetate, the salts filtered off, washed with water and brine, dried and concentrated to dryness to obtain methyl 2,2-dimethyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24][NH2:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(N(CC)CC)C.[C:37](O)(=[O:40])[CH2:38][CH3:39]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:27])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24][NH:25][C:37](=[O:40])[CH2:38][CH3:39])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CCC(=O)O
Reactant: NCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
1-{2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoro-methyl)-1,3-thiazol-5-yl}methanamine (0.1 g) and triethylamine (0.05 g) were added to dichloromethane (20 mL), followed by the dropwise addition of dichloromethane solution (10 mL) comprising anhydrous propionic acid (0.05 g) under ice cooling. After the dropwise addition was completed, the reaction solution was stirred at room temperature for one hour. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (0.1 g, 90%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: OCCO
Reactant: O=Cc1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: c1cc(C2OCCO2)cs1
Temperature: 25 °C

Procedure:
A solution of 28.04 g (250 mmol) of 3-thiophenecarboxaldehyde, 20.2 g (330 mmole) of ethyleneglycol, 10 mg (0.05 mmole) of p-toluenesulfonic acid monohydrate and 25 ml of benzene was heated to reflux untill the calculated amount of water was removed via a Dean-Stark trap (5 hours). The reaction mixture was allowed to cool to room temperature and was washed with 30 ml of saturated NaHCO3 solution. The organic layer was dried over MgSO4 and the solvent was removed by evaporation to give the title compound as a clear colorles oil.
Reaction SMILES: N[C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([Br:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=[O:16].[Na+]>S(=O)(=O)(O)O>[Br:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:16])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(Br)c(C)c(C)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cc(Br)c(C)c(C)c1O
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 91.4 %

Procedure:
To an aqueous solution (160 mL) of methyl 2-amino-5-bromo-3,4-dimethylbenzoate (28.0 g) in 25% sulfuric acid was added dropwise an aqueous solution (80.0 mL) of sodium nitrite (11.2 g) over 50 min at the internal temperature of 2-3° C. under ice-cooling. Then, 5% aqueous sulfuric acid solution (1600 mL) was added dropwise thereto over 50 min at 0-15° C. The reaction mixture was stirred at 100° C. for 2 hr. The reaction mixture was allowed to be cooled to room temperature, and the precipitate was collected by filtration, and washed with water to give the title compound (25.7 g).
Reaction SMILES: P([O-])([O-])[O-].[C:5]([O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=O)[CH3:6].[CH2:17](O)[CH2:18]CC.C(OC(OCCCC)=CCC)CCC>[Pd]>[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH:5]=[CH:6][CH2:17][CH3:18])(=[O:16])[CH3:15]
Reactant: CCCCO
Reactant: CC(=O)OC/C=C\COC(C)=O
Agent: [Pd]
Agent: CCC=C(OCCCC)OCCCC
Agent: [O-]P([O-])[O-]
Product: CCC=COCCCCOC(C)=O
Reaction time: 5 h
Yield: 25.7 %

Procedure:
The reaction was carried out by adding 0.0020 g (0.0040 mmol) of trisdibenzylideneacetone dipalladium having a palladium content of 21.5 wt % and 0.0173 g (0.0162 mmol) of the above (L-6) bidentate phosphite in an amount of 4 equivalents to a container substituted with nitrogen, adding 1.418 g (8.233 mmol) of cis-1,4-diacetoxy-2-butene and 2.327 g (31.395 mmol) of 1-butanol thereto under nitrogen atmosphere, and heating the resultant mixture at 100° C. After reacting 5 hours, the resultant solution composition was analyzed by gas chromatography, and it was found that cis-1,4-diacetoxy-2-butene was converted at a conversion rate of 97.5%, and 71.8% of dibutoxybutene and 25.7% of acetoxybutoxybutene were produced.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.[CH3:20][S@@:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[NH:23])=[O:22].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:23]=[S@:21]([CH3:20])(=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: C[S@@](=N)(=O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[S@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
To a solution of 5-bromonicotinic acid (303 mg, 1.5 mmol), N,N-diisopropylethylamine (0.523 mL, 3.0 mmol), and (R)-(−)-S-methyl-S-phenylsulfoximine (233 mg, 1.5 mmol) in DMF (3.0 mL) cooled to 0° C. was added 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) (859 mg, 1.65 mmol). The solution was stirred 10 minutes, the ice bath removed, and the reaction continued at room temperature for 2.5 hours. The mixture was taken up in EtOAc and washed with H2O, Na2CO3 solution, brine, AcOH solution, H2O, Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown oil was chromatographed eluting with hexane/EtOAc to give the title compound as a yellow solid (478 mg, 94%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][OH:8].[C:9](=S)=[S:10].Cl>C(O)C.O>[OH:8][CH2:7][CH2:6][N:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:9]1=[S:10]
Reactant: NCCCNCCO
Reactant: S=C=S
Agent: Cl
Solvent: CCO
Solvent: O
Product: OCCN1CCCNC1=S

Procedure:
2-(3-Aminopropylamino)ethanol (118 ml) is dissolved in 1:1 ethyl alcohol-water (340 ml) and heated to 40°-50° C. Carbon disulfide (60 ml) is added dropwise over a period of about 15 minutes. An exothermic reaction occurs after about half of the amount of carbon disulfide is added. After the addition of all the carbon disulfide, the mixture is refluxed for about 1 hour. Concentrated hydrochloric acid (8 ml) is then added, and the reaction mixture is refluxed overnight. After cooling in an ice bath, the crystalline solid which separates is filtered, washed with isopropyl alcohol and t-butyl methyl ether, and dried to give 129-4 g of 1-(2-hydroxyethyl)-3,4,5,6-tetrahydropyrimidine-2-thione, melting point 112°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.N#N.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.O>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:30]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:34][CH:33]=1)=[O:31]
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc2cc(OC)ccc2c1
Agent: N#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OC)ccc2c1
Temperature: 0 °C

Procedure:
Dissolve 2,6-dimethoxynaphthalene (1.0 eq.) in CH2Cl2 (5 volume eq.) at ambient temperature in a dry round bottom flask equipped with stir bar, temperature probe and N2 line. Cool the solution to 0° C. with an ice bath, and add 4-(2-piperidin-1-yl-ethoxy)-benzoyl chloride (1.1 eq.). Add aluminum chloride (2.0 eq.). Once the reaction is determined to be complete, quench the reaction slowly with 1 N NaOH and dilute with additional water and CH2Cl2. Wash the aqueous layer with CH2Cl2 (20 mL). Combine the organic extracts and wash with brine and dry (Na2SO4). Recrystallize the crude product from methanol to give (2,6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:10]=1>>[CH:1]1([O:7][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(OC3CCCCC3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from cyclohexanol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-cyclohexyloxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 353(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:23])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)NC(C)C)c2)=C(C)C1=O
Yield: 21.5 %

Procedure:
4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (73 mg, 0.20 mmol) obtained in Example 62 and isopropylamine (0.019 ml, 0.30 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (17 mg, 0.043 mmol, yield 21%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][S:35]([C:38]1[CH:53]=[CH:52][C:41]([O:42][C:43]2[N:48]=[CH:47][N:46]=[C:45]3[NH:49][N:50]=[CH:51][C:44]=23)=[CH:40][CH:39]=1)(=[O:37])=[O:36].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:49]2[C:45]3=[N:46][CH:47]=[N:48][C:43]([O:42][C:41]4[CH:40]=[CH:39][C:38]([S:35]([CH3:34])(=[O:36])=[O:37])=[CH:53][CH:52]=4)=[C:44]3[CH:51]=[N:50]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3[nH]ncc23)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
Boc-3-hydroxypiperidine (Alfa Aesar, Ward Hill, Mass., USA; 80 mg, 0.4 mmol) and triphenylphosphine (136 mg, 0.52 mmol) were added to a solution of 4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 31; 100 mg, 0.34 mmol) in tetrahydrofuran (1 mL). The mixture was cooled to 0° C., and then diisopropylazodicarboxylate (102 μL, 0.52 mmol) was added. The mixture was stirred overnight, then silica gel (˜500 mg) was added, the solvents were evaporated and the product was eluted from a silica gel column with 50% ethyl acetate/hexanes to give 3-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (10.5 mg, 6.5%) as a solid.
Reaction SMILES: [O:1]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:13][S:14]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:4]=1)(=[O:16])=[O:15]
Reactant: COC(=O)COc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Temperature: -2.5 °C
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
Methyl phenoxyacetate (99.9 g, 0.6 mol) was added dropwise to chlorosulfonic acid (279.6 g, 159.5 mL, 2.4 mol) at −5° C. at such a rate to maintain internal temperature between 0 to −5° C. (addition took about 60 min). Some solid formed during this addition. The cooling bath was removed and the reaction mixture was stirred at room temperature for an additional 1.5 hr. The reaction mixture was poured into a vigorously stirring mixture of dichloromethane (900 mL) and methanol (100 mL) at 0° C. After 15 min the cooling bath was removed and the resulting mixture was stirred at room temperature for 1 hr. The resulting mixture was washed with ice cold water (2×250 mL). The combined aqueous layers were back extracted with dichloromethane (1×250 mL). The combined organic layers were washed with brine (1×200 mL), dried over anhydrous magnesium sulfate (15 g) and concentrated under reduced pressure to give 132 g (83%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[Na].[CH3:15][SH:16]>C(Cl)Cl.CN1C(=O)CCC1>[CH3:15][S:16][CH2:3][CH:2]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[OH:1]
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Reactant: CS
Agent: [Na]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CSCC(O)C1CCC2(CC1)OCCO2
Temperature: 80 °C

Procedure:
8-(oxiran-2-yl)-1,4-dioxaspiro[4.5]decane (202 mg, 1.10 mmol), prepared in the previous step, in DCM (20 mL) was dissolved in NMP (20 mL) and methanethiol sodium salt (297 mg, 4.24 mmol) was added. The mixture was stirred, heating to 80° C. under argon overnight and then cooled to ambient temperature and poured onto water. After extraction with ethyl acetate, the organic layers were concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0-50% ether) to afford the product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.C(N(CC)CC)C.C(O)(=O)C(O)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:34]1>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:33]2[CH2:38][CH2:37][CH2:36][C@@H:35]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:34]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCNC1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](CNC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.478 g, 1.76 mmol) in CH2Cl2 was added triethylamine (0.98 mL, 0.712 g, 7.04 mmol), and the mixture was cooled to 0° C. To the reaction mixture was added tert-butyl ((R)-piperidin-3-yl)methylcarbamate oxalate (prepared analogously to 2-(7-Methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol, oxalate salt, see Example 130; 700 mg, 2.3 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was quenched with water, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-2% EtOAc in CH2Cl2 gave tert-butyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (700 mg, 88%). LC/MS: nm/z 449.5 (M+H)+ at 2.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][CH3:23].[CH2:27](Br)[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].[F-].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:24]([O:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29])=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C(=O)O
Reactant: O=C(CBr)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C(=O)OCC(=O)c1ccccc1
Reaction time: 8.5 h

Procedure:
A mixture of 2.11 g. of N-[4-bromo-3-(1-carboxybutyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 11.19 g. of phenacyl bromide, 0.64 g. of potassium fluoride and 10 ml. of acetonitrile was refluxed with stirring for 8.5 hours and the reaction mixture was cooled and the precipitate was separated by a filtration. The filtrate was concentrated under a reduced pressure and the residue was purified by a chromatography on a column of silica gel (developing solvent of benzene) to obtain 2.20 g. of Compound No. 141 shown in Table 1.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=[C:8]([F:27])[C:7]=1[C:28]([NH2:30])=[O:29].O>C(Cl)Cl>[F:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=[C:8]([F:27])[C:7]=1[C:28]([NH2:30])=[O:29]
Reactant: COc1ccc(-c2noc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(O)cc3)no2)c1F
Yield: 65 %

Procedure:
(Method L) Boron tribromide solution (1.0 M in CH2Cl2, 1.5 ml, 1.5 mmol, 2 equiv.) was added slowly, dropwise to stirred suspension of 2,6-difluoro-3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]methoxybenzenecarboxamide (272 mg, 0.75 mmol, 1 equiv.) in CH2Cl2 (5 ml), at r.t., under N2. The reaction mixture was stirred at r.t. for 4 h and poured into water (20 ml). CH2Cl2 (10 ml) was added and the biphasic mixture was stirred for 30 min. at r.t. The white un-dissolved solid was filtered, washed with water and Et2O, to give 170 mg (65% yield), mp 209-210° C., HPLC-MS (method 1): m/z 348 [M+H]+, Rt=3.00 min.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:22][CH2:21][C:20]([C:28](O)=[O:29])=[CH:19][C:18]=3[CH:31]=2)=[CH:10][CH:9]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:36][N:37]([CH:39]=O)[CH3:38]>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:22][CH2:21][C:20]([C:28]([NH:23][C:17]4[CH:18]=[CH:31][C:14]([CH2:39][N:37]([CH3:36])[CH:38]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:15][CH:16]=4)=[O:29])=[CH:19][C:18]=3[CH:31]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In THF (5 ml) was dissolved 7-[4-(3-ethoxypropoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.20 g). To the solution were added, under ice-cooling, thionyl chloride (0.06 ml) and DMF (catalytic amount), and the mixture was stirred at room temperature for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (15 ml). The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.11 g) and triethylamine (0.19 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-(3-ethoxypropoxy)phenyl)-1-methanesulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 8) (0.22 g) as colorless crystals.