Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][S:14][C:15]2[CH:27]=[C:26]([F:28])[C:18]([O:19][CH2:20][C:21](OCC)=[O:22])=[C:17]([F:29])[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[C:17]([F:29])[C:18]([O:19][CH2:20][CH2:21][OH:22])=[C:26]([F:28])[CH:27]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1c(F)cc(SCCNS(=O)(=O)c2ccc(Cl)cc2)cc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(NCCSc1cc(F)c(OCCO)c(F)c1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a mixture of ethyl 4-[2-(4-chlorophenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetate (0.46 g) and tetrahydrofuran (30 ml) was added under ice cooling lithium aluminum hydride (38 mg), and the mixture was stirred at room temperature for an hour. To the reaction mixture was added successively 10% aqueous sodium hydroxide solution (0.2 ml), ethyl acetate (30 ml) and anhydrous sodium sulfate (1 g), and the insolubles were removed by filtration. After evaporation of the filtrate under reduced pressure, the residue was chromatographed on silica gel column (eluent; ethyl acetate:hexane=1:1), and the desired fractions were collected and recrystallized from ethyl ether/isopropyl ether mixture to give 2-{4-[2-(4-chlorophenylsulfonylamino)ethylthio]-2,6-difluorophenoxy}ethanol (Compound No. 129).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)=[CH:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:20][C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:10]([C:9]2[CH:8]=[N:7][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:14][CH:13]=2)=[O:12])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(-c2ccsc2)nc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: O=C(c1ccc(-c2ccsc2)nc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D using 6-thiophen-3-yl-nicotinic acid and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine to give the title compound (35 mg). MS (ES+) 342.1 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[CH3:12][C:13]1([CH3:27])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[O:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][C:17]1([CH3:19])[C:13]([CH3:12])([CH3:27])[O:14][B:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]3[O:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[CH:7]=3)=[CH:22][CH:21]=2)[O:16]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: BrCc1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(OCc3cc4ccccc4o3)cc2)OC1(C)C
Temperature: 70 °C
Yield: 63 %

Procedure:
To 2-Bromomethyl-benzofuran (1.5 g, 7.1 mmol, 1 eq.), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.56 g, 7.1 mmol, 1 eq.), potassium carbonate (1.96 g, 14.2 mmol, 2 eq.) was dissolved in acetonitrile (50 mL) under argon and heated at 70° C. for 16 hours. After work-up and flash column chromatography, 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran is obtained. Yield: 63%. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (s, 12 H) 5.3 (s, 2 H) 7.1 (m, 3 H) 7.3 (m, 1 H) 7.3 (m, 1 H) 7.6 (m, 4 H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:43])[C:7](=[CH2:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4].CCN(CC)CC>CO>[CH2:1]([NH:5][C:6](=[O:43])[C@H:7]([CH3:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:31])[CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
3.5 g of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoic acid (N-butyl)amide are hydrogenated in 30 ml of absolute methanol in the presence of 20 mg of [Ru2Cl4 ((S)-Binap)2].NEt3 at room temperature and 25 bar for 5 hours. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The residue is purified by FC (200 g of silica gel, hexane/ethyl acetate=1:1). Title compound: Rf (hexane/ethyl acetate=1:1)=0.16; FAB-MS (M+H)+ =599.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]=[O:10].[Cl-].[NH4+].O1CC[CH2:15][CH2:14]1>>[OH:10][CH:9]([CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C:14]#[CH:15]
Reactant: C1CCOC1
Reactant: O=CCOC1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Product: C#CC(O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Acetylene gas was bubbled into tetrahydrofuran (30 ml) for 30 minutes. Ethyl magnesium bromide (25 ml) was added. 2-(Tetrahydro-2-pyranyloxy)-acetaldehyde (5.0 g, 0.035 mole) in tetrahydrofuran (25 ml) was then added. The reaction mixture was warmed to room temperature and stirred overnight. Saturated ammonium chloride aqueous solution (30 ml) was added to quench the unreacted acetylide and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated and separated by silica gel chromatography eluted with n-hexane/ethyl acetate (5:2) to give colorless oil (4.5 g, 76%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH:26]([CH3:28])[CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH:26]([CH3:28])[CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CC(C)Oc1ccc(F)cc1Br
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(F)ccc2OC(C)C)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo4-fluoro-1-isopropoxy-benzene (prepared from 2-bromo-4-fluoro-phenol, Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:17][CH2:18][CH2:19]Br.[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:19][CH2:18][Br:17])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: BrCCBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCCBr
Temperature: 50 °C
Reaction time: 9 h

Procedure:
To a solution of 5-bromosalicylaldehyde (5.00 g, 24.87 mmol) in DMF (200 ml) were added K2CO3 (4.47 mg, 32.34 mmol) and 1,2-dibromoethane (46.73 mg, 21.44 ml, 248.73 mmol), followed by stirring at 50° C. for 9 hours. After complete reaction, the solution was cooled to room temperature, cleansed with an aqueous saturated NH4Cl solution and extracted with ethyl acetate. The organic layer thus obtained was additionally washed once with an aqueous saturated NH4Cl solution. Then, the organic layer was dried over anhydrous MgSO4 and filtered, and the filtrate was concentrated in a vacuum. The residue was subjected to column chromatography (ethyl acetate/n-hexane 1/9→1/5) to afford the object compound (yellowish solid, 300 mg, 90.1%).
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].Cl>C(O)(C)C>[CH:4]([O:27][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])([CH3:5])[CH3:3]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2ccccc2)nc(-c2ncccn2)nc1OC(C)C
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 27.2 %

Procedure:
Sodium (181 mg) was added to 10 ml of isopropyl alcohol and, after one hour, 100 ml of isopropyl alcohol was added thereto followed by heating at 60° C. to dissolve. To this reaction solution was added 400 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide with stirring at room temperature. The reaction mixture was stirred at room temperature for 1.25 hours and then at 60° C. for 45 minutes followed by pouring into a mixture of 1N hydrochloric acid and ice. The solution was extracted with chloroform and the chloroform layer was dried over anhydrous magnesium sulfate followed by filtering. The filtrate was concentrated in vacuo and the resulting residue was purified by a silica gel column chromatography (ethyl acetate). The resulting amorphous substance was crystallized in ether and collected by filtration to give 57 mg of N-[6-isopropoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(=O)C(F)(F)F)[C@@H:7]([CH3:18])[CH2:6][NH:5]2.Cl[C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:8][C@@H:7]([CH3:18])[CH2:6][N:5]2[C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:10][CH:11]=1
Reactant: Clc1nc2ccccc2o1
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: C[C@H]1CN(c2nc3ccccc3o2)c2cc(Br)ccc2N1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
A mixture of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.050 g, 0.155 mmol), 2-chlorobenzo[d]oxazole (0.035 mL, 0.309 mmol), tris(dibenzylideneacetone)dipalladium (7.09 mg, 7.74 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.018 g, 0.031 mmol) (0.015 g, 0.031 mmol) and cesium carbonate (0.101 g, 0.309 mmol) in t-butanol (2.0 mL) was heated in the microwave at 100° C. for 1.5 h. A second portion of Xantphos (0.018 g, 0.031 mmol) and tris(dibenzylideneacetone)dipalladium (7.09 mg, 7.74 μmol) were added, and the mixture stirred at 100° C. for 2.5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-2-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)benzo[d]oxazole (0.016 g, 30%) as an off-white solid. MS (ESI, pos. ion) m/z 344, 346 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:13]2[C:12]([CH3:15])([CH3:14])[O:11][C:10]([CH3:17])([CH3:16])[C:9]=2[S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:18][C:7]2[S:8][C:9]3[C:10]([CH3:17])([CH3:16])[O:11][C:12]([CH3:15])([CH3:14])[C:13]=3[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:25])=[C:22]([C:29]([F:30])([F:31])[F:32])[CH:21]=1
Reactant: CCOC(=O)c1c(N)sc2c1C(C)(C)OC2(C)C
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Product: CCOC(=O)c1c(NC(=O)c2ccc(F)cc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 18A and commercially available 4-fluoro-2-(trifluoromethyl)benzoyl chloride using the procedure described for Example 1B. 1H NMR (DMSO-d6, 300 MHz) δ 1.30 (t, J=7.1 Hz, 3H), 1.49 (s, 6H), 1.54 (s, 6H), 4.30 (q, J=7.1 Hz, 2H), 7.76 (ddd, J=9.1, 8.6, 2.4 Hz, 1H), 7.88 (dd, J=9.3, 2.5 Hz, 1H), 7.96 (dd, J=8.6, 5.3 Hz, 1H), 11.48 (br s, 1H). MS (ESI+) m/z 460 (M+H)+. Anal. calcd. for C21H21F4NO4S: C, 54.90; H, 4.61; N, 3.05. Found: C, 54.84; H, 4.60; N, 3.02.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:37][CH:38]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Product: CC(C)(CC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl ]-butanamide (Example 51, Step A) and 4'-bromomethyl-1,1'-biphenyl-2-nitrile (Example 69, Step C) by the procedure described in Example 1, Step K. FAB-MS: calculated for C37H36N4O4 600; found; 601 (M+H,100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[N:3]=1.[O-:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>O>[CH3:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[N:3]=[C:2]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)cc(OC)c1OC
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: O
Product: COc1cc(Nc2nc(C)cc(Oc3ccccc3)n2)cc(OC)c1OC
Yield: 12.9 %

Procedure:
4-Chloro-6-methyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine (0.30 g, 0.97 mmol) was added to a solution of sodium phenoxide (0.97 mmol) [prepared from phenol (0.091 g, 0.97 mmol) and NaH (60% in mineral oil; 0.039 g, 0.97 mmol)], and heated to 80° for 17 h with stirring. Water was added and the mixture was extracted with CH2CH2 (2×30 ml), the organic phases were dried (MgSO4) and evaporated to a yellow oil. The residue was subjected to chromatography (silica, 2% methanol/CH2CH2) to give the title compound (0.046 g). A portion was recrystallised from methanol to give an off white crystalline solid m.p. 175°. δH (CDCl3) 2.38 (3H, s), 3.64 (6H, s), 3.77 (3H, s), 6.19 (1H, s), 6.78 (2H, s), 6.95 (1H, s), 7.15 (2H, d, J 7.5 Hz), 7.23 (1H, m) and 7.39 (2H, t, J 7.5 Hz).
Reaction SMILES: C[C:2]([CH3:17])([CH3:16])[CH:3]([NH:7][C:8]([O:10][CH:11]1[CH2:15][CH2:14][O:13][CH2:12]1)=[O:9])[C:4]([OH:6])=[O:5].NC(C1CC1)C(O)=O.O1CCC(OC(=O)OC2C=CC([N+]([O-])=O)=CC=2)C1>>[CH:2]1([CH:3]([NH:7][C:8]([O:10][CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])[C:4]([OH:6])=[O:5])[CH2:16][CH2:17]1
Reactant: CC(C)(C)C(NC(=O)OC1CCOC1)C(=O)O
Agent: NC(C(=O)O)C1CC1
Agent: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1
Product: O=C(NC(C(=O)O)C1CC1)OC1CCOC1

Procedure:
Cyclopropyl-[(tetrahydro-furan-3-yloxycarbonylamino)]-acetic acid was prepared according to the method presented in the synthesis of the intermediate 3,3-dimethyl-2-(tetrahydro-furan-3-yloxycarbonylamino)-butyric acid in Example 62. Treatment of amino-cyclopropyl-acetic acid with carbonic acid 4-nitro-phenyl ester tetrahydro-furan-3-yl ester occurred under the same conditions, adjusted for scale, to provide the desired cyclopropyl-[(tetrahydro-furan-3-yloxycarbonylamino)]-acetic acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[C:5]([F:18])=[CH:4][CH:3]=1.[NH3:19]>C(O)CO.[Cu-]=O>[NH2:19][C:2]1[N:7]=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[C:5]([F:18])=[CH:4][CH:3]=1
Reactant: N
Reactant: C[C@]1(c2nc(Br)ccc2F)N=C(N)OCC1(F)F
Agent: O=[Cu-]
Solvent: OCCO
Product: C[C@]1(c2nc(N)ccc2F)N=C(N)OCC1(F)F
Temperature: 60 °C

Procedure:
To a solution of (R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (8.73 g, 23.17 mmol) in ethylene glycol (139 ml) and aq. NH3 (w=25%, 108 ml) in an autoclave was added copper(I) oxide (497 mg, 3.47 mmol) and the mixture was warmed to 60° C. over night. After cooling to rt the mixture was extracted with EtOAc, the organic layer was washed with aq. NH3 (w=12%, 2×), the combined organic layers were washed with sat. aq. NaCl, dried with Na2SO4 and evaporated. The residue was dissolved in TBME and extracted with 1N HCl (2×). The combined aq. layers were basified by addition of solid Na2CO3 some NaCl was added and the aq. solution extracted with DCM (4×). The combined DCM extracts were dried with K2CO3 and evaporated to provide the title compound as greyish resin. The crude material was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33]>O1CCCC1>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1

Procedure:
The procedure described in Example 1 (step 1.4.) is used. Starting with 0.66 g (1.51 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl}-1-piperazinecarboxylate, obtained in step 10.2, and 3 ml (6.02 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 96/4 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 0.50 g of product is obtained in the form of a white solid.
Reaction SMILES: O.[NH3:2].[F:3][CH:4]([F:16])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl>[F:3][CH:4]([F:16])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:2])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)F
Reactant: N
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1OC(F)F

Procedure:
To a mixture of 250 ml of methylene chloride, 250 ml of water and 250 ml of 30% ammonia solution is slowly added a solution of 80.3 g of crude 2-difluoromethoxyphenylsulfonyl chloride in 50 ml of methylene chloride. After the exothermic reaction has subsided, the reaction mixture is refluxed for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from methanol yield 40.5 g of 2-difluoromethoxyphenylsulfonamide with a melting point of 128°-130° C.
Reaction SMILES: [CH:1]1([C:16]([OH:18])=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH:2]1[C:13](O)=[O:14].[OH-].[NH4+:20]>>[CH:1]12[C:16](=[O:18])[NH:20][C:13](=[O:14])[CH:2]1[C:3]1[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]2=3)[CH:6]=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: O=C(O)C1c2cccc3cccc(c23)C1C(=O)O
Agent: [OH-]
Product: O=C1NC(=O)C2c3cccc4cccc(c34)C12
Temperature: 200 °C

Procedure:
5.5 Parts of acenaphthene-1,2-dicarboxylic acid is heated in an oil bath with an excess of concentrated ammonium hydroxide. After most of the excess of ammonium hydroxide has distilled off, the temperature of the oil bath is raised to 200° C. and it is maintained at that temperature for 45 minutes. The residual material is sublimed under vacuum (0.05-0.1 mm.) using an oil bath at 280° C. The resultant solid is recrystallized from ethanol to give acenaphthene-1,2-dicarboximide melting at about 242°-246° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=3)[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C=O.[C:32]([O-])([O-])=[O:33].[K+].[K+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)([CH2:32][OH:33])[CH2:10][OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(C2(c3cccc(Br)c3)CO2)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCC(CO)(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
A mixture of the crude 2,2-bis(3-bromophenyl)oxirane (7.4 g, 20.90 mmol) and p-toluenesulfonic acid monohydrate (360 mg, 2.1 mmol) in toluene (25 mL) was stirred at 95° C. for 1 h. The solution was washed with aq NaHCO3 (10 mL) and water (20 mL). The organic layer was dried and concentrated. The residue was dissolved in EtOH (20 mL). To the solution was added formaldehyde (15.56 mL, 209 mmol, 37% aqueous solution) and K2CO3 (1.44 g, 10.45 mmol). The mixture was stirred at 85° C. for 12 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (60 mL×4). The combined organic layers were dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether˜Petroleum ether: EtOAc=2:1) to afford 4.6 g of 2,2-bis(3-bromophenyl)propane-1,3-diol (11.9 mmol, 57% after two steps). LC/MS: [M−18+1]=368. 1HNMR (CDCl3), 400 MHz: δ 2.53 (brs, 2H), 2.41 (s, 4H), 7.09-7.20 (m, 4H), 7.36-7.40 (m, 4H).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CCOC(C)=O.CCCCCC>[Br:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:16](=[O:18])[CH3:17])[CH:10]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CC(=O)Nc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(C)=O)c2cc(Br)ccn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
To a 20 mL vial charged with Sodium hydride (0.196 g, 7.76 mmol) was added dry N,N-Dimethylformamide (5.0 mL, 64 mmol), cooled with ice bath. N-(4-bromopyridin-2-yl)acetamide (1.50 g, 7.00 mmol) was added portionwise in ˜3 min. The suspension was stirred at the same temperature for 15 min and turned into a clear solution. 4-methoxybenzyl bromide (1.55 g, 7.70 mmol) was added dropwise with a syringe and rinsed down with dry N,N-Dimethylformamide (2.0 mL, 26 mmol). The mixture was stirred at r.t. for 17 hours. The mixture was poured into ice chilled saturated NaHCO3 (80 mL), extracted with EtOAc (2×100 mL), washed with water, brine, dried over anhydrous Na2SO4, filtered, evaporated in rotavpor to give a crude. Chromatograph using EtOAc/hexane (1/9 to 7/3) gave an oily product (1.80 g, yield 76.7%). LCMS: (AA) ES+, 335, 337. 1H NMR (400 MHz, d1-chloroform) δ: 8.28-8.30 (d, J=5.27 Hz, 1H), 7.43 (s, 1H), 7.31-7.33 (dd, J=5.52, 1.51 Hz, 1H), 7.13-7.15 (d, J=8.78 Hz, 2H), 6.80-6.82 (d, J=8.78 Hz, 2H), 5.05 (s, 2H), 3.77 (s, 3H), 2.12 (s, 3H).