Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([OH:8])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[C:23]([CH3:29])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:30].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[CH2:17]([C:16]([C:21]1[CH:22]=[C:23]([CH3:29])[C:24]([OH:28])=[C:25]([CH3:27])[CH:26]=1)([C:13]1[CH:14]=[CH:15][C:10]([C:5]#[C:4][C:3]([CH2:6][CH3:7])([OH:8])[CH2:1][CH3:2])=[C:11]([CH3:30])[CH:12]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: C#CC(O)(CC)CC
Reactant: CCC(CC)(c1ccc(Br)c(C)c1)c1cc(C)c(O)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2cc(C)c(O)c(C)c2)cc1C)CC
Temperature: 160 °C
Yield: 97.3 %

Procedure:
3-Ethyl-1-pentyn-3-ol (1.4 mL, 10.88 mmol), a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (1:1) (592 mg, 0.725 mmol) and copper (I) iodide (138 mg, 0.725 mmol) were added to a solution of 4-[1-(4-bromo-3-methyl-phenyl)-1-ethyl-propyl]-2,6-dimethyl-phenol (Example 38-(2); 2.62 g, 7.25 mmol) in triethylamine (15 mL), and the mixture was stirred with microwave heating at 160° C. for three minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (2.77 g, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[S:15][C:8]=2[C:7]=1[OH:28])=[O:5])[CH3:2].C(OCC)(=O)C.[CH3:35][N:36](C)C(=O)C>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N.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]>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:35]#[N:36])[C:9]2[N:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[S:15][C:8]=2[C:7]=1[OH:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3cnn(Cc4ccccc4)c3)sc2c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2nc(-c3cnn(Cc4ccccc4)c3)sc2c1O

Procedure:
To a mixture of 2-(1-benzyl-1H-pyrazol-4-yl)-4-bromo-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (0.25 mg, 0.54 mmol), 1,1′-bis(diphenylphosphino)ferrocene (30.7 mg, 0.055 mmol), zinc dust (4.2 mg, 0.065 mmol), and zinc cyanide (38.3 mg, 0.33 mmol) in N,N-dimethylacetamide (1.11 mL) was added tris(dibenzylideneacetone)dipalladium(0)(24.9 mg, 0.027 mmol). The reaction mixture was heated at 120° C. for 5 h before ethyl acetate (70 mL) was added. The organic solution was washed with saturated ammonium chloride aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-100% ethyl acetate in hexanes to produce 0.19 g of the title compound as a light yellow solid. MS: (+) m/z 406.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[C:19](O)=[O:20]>>[O:20]=[C:19]1[C:18]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[N:1][C:2]2[C:7](=[CH:6][CH:5]=[C:4]([S:9]([OH:12])(=[O:10])=[O:11])[CH:3]=2)[NH:8]1
Reactant: O=C(O)C(=O)c1cccs1
Reactant: Nc1ccc(S(=O)(=O)O)cc1N
Product: O=c1[nH]c2ccc(S(=O)(=O)O)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with 3,4-Diamino-benzenesulfonic acid and (thiophen-2-yl)oxo-acetic acid via the method described in Example 12 to afford 2-Oxo-3-thiophen-2-yl-1,2-dihydro-quinoxaline-6-sulfonic acid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[NH2:39][C@H:40]([CH2:56][CH2:57][C:58]1[NH:62][N:61]=[N:60][N:59]=1)[C:41]([NH:43][C:44]1[CH:55]=[CH:54][C:47]2[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52][C:46]=2[CH:45]=1)=[O:42].C(O)(C(F)(F)F)=O>CN(C=O)C>[NH:62]1[C:58]([CH2:57][CH2:56][C@@H:40]([NH:39][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])[C:41](=[O:42])[NH:43][C:44]2[CH:55]=[CH:54][C:47]3[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52][C:46]=3[CH:45]=2)=[N:59][N:60]=[N:61]1
Reactant: CN1CCc2ccc(NC(=O)[C@H](N)CCc3nnn[nH]3)cc2CC1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2ccc(NC(=O)[C@@H](CCc3nnn[nH]3)NC(=O)c3ccc(Cl)s3)cc2CC1
Reaction time: 0.25 h

Procedure:
13 mg (0.08 mmol) 5-chloro-thiophene-2-carboxylic acid are dissolved in 0.5 ml DMF, mixed at room temperature with 26 mg (0.08 mmol) TBTU and 50 μl (0.45 mmol) NMM and stirred for 15 min. A solution of 32 mg (0.08 mmol) (R)-2-amino-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-4-(1H-tetrazol-5-yl)-butyramide in 1 ml DMF is added to the reaction mixture and it is stirred overnight at room temperature. The reaction mixture is acidified with TFA, separated by chromatography through RP material (eluant: water/acetonitrile 95:5=>5:95) and then freeze-dried.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.N1CCCCC1=O.CS(C)(=O)=C.[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1>>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([NH:31][CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)=[CH:33][CH:34]=1)#[N:37]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Agent: C=S(C)(C)=O
Agent: O=C1CCCCN1
Product: N#Cc1ccc(NCC2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 20.0 g (80.9 mmol) benzyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate (prepared from the protected piperidone and dimethylsulfoxonium methylide according to J. Med. Chem. 1983, 26, 855; U.S. Pat. No. 4,353,901) and 47.0 g (397.8 mmol) 4-aminobenzonitrile were heated at 160° C. for 30 hours until no starting epoxide could be detected by TLC. It was cooled to room temperature, and the excess of the aniline was removed by chromatography on silica gel with dichloromethane. The title compound was obtained after enhancing the polarity of the eluent by addition of 5% ethanol.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH2:8]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21]1[CH:22]=[C:23]([CH:27]2[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:39](O)=[O:40])[CH:33]=3)[NH:28]2)[CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH2:8]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21]1[CH:22]=[C:23]([CH:27]2[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:39]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:40])[CH:33]=3)[NH:28]2)[CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (301 mg, 7.5 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (730 mg, 7.7 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 0.77 mmol) and 1,1′-carbonyldiimidazole (310 mg, 1.9 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[3-((R)4-Benzyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (82 mg, 20%) as a white solid: LC/MS m/e calcd for C29H31N3O5S (M+H)+: 534.65, observed: 534.1.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCC1CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC1CN(Cc2ccccc2)CCC1O
Reaction time: 1 h

Procedure:
Sodium borohydride (0.4 g, 12.2 mmole) was added to the stirred solution of 1-benzyl-3-n-butylpiperidin-4-one (2.8 g, 9.3 mmole) in methanol (20 ml) at 0-5° C. over a period of 5 min, and stirring was continued for 1 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 1-benzyl-3-n-butyl-4-hydroxypiperidine as oil. Yield 2.5 g (86%), C16H25NO, m/z 248 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:21]([O-:24])(=[O:23])[CH3:22].[Na+].O>CN(C)C=O>[C:21]([O:24][CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9])(=[O:23])[CH3:22]
Reactant: Cn1nc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1OC(F)F
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl

Procedure:
A solution of 6.8 g (18 mmol) of 3-(3-bromomethyl-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole and 1.5 g (18 mmol) of sodium acetate in 20 ml of dimethylformamide was stirred overnight and then stirred into 100 ml of cold water. The product was extracted from the aqueous phase using ethyl acetate. The ethyl acetate phase was dried over magneisum sulfate and concentrated. The crude product thus obtained was purified by silica gel chromatography (eluent: hexane/ethyl acetate=9:1). Yield: 4.7 g.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:19])[CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:50])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH:40]1[CH:47]2[CH:43]([NH:44][C:45](=[O:48])[NH:46]2)[CH2:42][S:41]1.CCN(CC)CC>CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[NH:11][CH2:10][C:9](=[O:19])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:50])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH:40]1[CH:47]2[CH:43]([NH:44][C:45](=[O:48])[NH:46]2)[CH2:42][S:41]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: NCCCCCCNC(=O)CCCCCNC(=O)CCCCC1SCC2NC(=O)NC21
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NCCCCCCNC(=O)CCCCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-Butoxycarbonylamino-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (8b; 0.18 g, 0.69 mmol) dissolved in DMF (5 mL) was added slowly to a DMF solution (3 mL) containing 6-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamino]-hexanoic acid (6-amino-hexyl)-amide (7; 0.16 g, 0.27 mmol) and Et3N (0.1 mL, 0.72 mmol) while stirring at room temperature. The reaction was stopped after 3 h by evaporating DMF in vacuo, and the remaining residue was redissolved in a limited volume of a DCM/MeOH (19:1) solution and loaded to a preequilibrated silica column. The products were separated by eluting with mobile phases of 1-6.67% MeOH in DCM to afford 9 (0.10 g; 62.2%) as a yellow solid. 1H NMR (400 MHz) (CD3OD) δ: 4.30 dd, 1H, CHN), 4.15 (dd, 1H, CHN), 3.94 (d, 2H, CH2CO), 3.32 (quin, 4H, CH2NH), 2.99 (q, 2H, CH2N), 2.92 (d, 1H, CHHS), 2.75 (d, 1H, CHHS), 2.20 (t, 4H, CH2CO), 1.44-1.88 (m, 29H). 13C NMR (100.67 MHz) (CD3OD) δ: 175.9 (CO), 63.7 (CHN), 61.6 (CHN), 56.9 (CHS), 49.0 (CH2N), 41.0 (CH2CO), 40.2 (CH2N), 36.9 (CH2S), 30.1 (CH2CO), 28.6 (CH3CO), 26.7 (CH2CH2). HRMS (ESI) calculated for C29H52N6O6S, [M+Na]+ 635.3567 (calcd.), 635.3564 (found).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2Cl)(C)(C)C.[Cl:24][C:25]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:25]=1[Cl:24]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: Cc1cc(Cl)c2cccc(OCCNC(=O)OC(C)(C)C)c2n1
Product: Cc1cc(NCc2ccc(Cl)cc2Cl)c2cccc(OCCN)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 20. Starting materials were [2-(4-chloro-2-methylquinoline-8-yloxy)-ethyl]-carbamate tert-butyl ester and 2,4-dichlorobenzylamine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C[O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:15])[CH:9]=1>C(OCC)C>[OH:14][C:11]1[C:12]([N+:1]([O-:4])=[O:2])=[CH:13][C:8]([C:7]([OH:16])=[O:6])=[CH:9][C:10]=1[CH3:15]
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.4 %

Procedure:
65% aq. nitric acid solution (2.7 mL, 60 mmol) and fuming nitric acid (2.5 mL, 60 mmol) were added at −10° C. to a solution of 4-hydroxy-3-methyl-benzoic acid methyl ester (4.97 g, 29.9 mmol) in diethyl ether (60 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to afford 4-hydroxy-3-methyl-5-nitro-benzoic acid (6.27 g, 99%). Yellow solid, MS (ISP)=210.1 (M−H)−.
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]2[O:7][CH2:8][C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH:11]([CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:5]=2[CH:4]=1.I>C(O)(=O)C>[OH:2][C:3]1[CH:23]=[CH:22][C:6]2[O:7][CH2:8][C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3/[C:11](=[CH:12]/[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])/[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(CCCN(C)C)c1ccccc1CO2
Agent: I
Solvent: CC(=O)O
Product: CN(C)CC/C=C1/c2ccccc2COc2ccc(O)cc21
Temperature: 90 °C

Procedure:
A mixture of 2-methoxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]oxepin (165 mg, 0.005 mol) with glacial acetic acid (0.2 ml) and hydriodic acid (0.2 mL, 57%) was stirred and heated for 5 hr at 90° C. The product was then extracted and purified by pouring into ice water (25 mL), made alkaline with sodium hydroxide (2N) and extracted with ether (2×10 mL). The aqueous layer was then adjusted to pH 6.8 with hydrochloric acid (6N). The mixture was then brought to pH 7 by the addition of sodium bicarbonate solution (5%) and extracted with chloroform (2×10 mL). The extract was dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellowish solid. The crude reaction product was purified by preparative TLC (chloroform/toluene/methanol/ammonia, 4:3:2:1, v/v).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(CC)=O.[CH2:14]([CH:32]1[CH2:37][C:36](=[O:38])[O:35][C:33]1=[O:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].N#N>COCCOCCOC>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:33]([OH:34])[CH:32]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:37][C:36]([OH:38])=[O:35])=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Reactant: Nc1ccc(O)cc1
Agent: N#N
Solvent: CCC(C)=O
Solvent: COCCOCCOC
Product: CCCCCCCCCCCCCCCCCCC(CC(=O)O)C(O)=Nc1ccc(O)cc1
Temperature: 25 °C

Procedure:
3.7 Grams of 4-aminophenol and 80 ml of ethyl methyl ketone were charged in a 300 ml flask equipped with a stirrer and a condenser and stirred in an atmosphere of room temperature. Thereto was added 12.0 g of powdery n-octadecylsuccinic anhydride little by little in several parts, followed by stirring at 70°-75° C. for 1 hour. Then, 120 ml of diglyme was added thereto, followed by heating with gently passing N2 gas to first distill off ethyl methyl ketone and then slowly distill off diglyme. After distilling off most of diglyme (the time required: about 3 hours), 120 ml of toluene was added to the residue, followed by leaving to cool. The precipitated crystal was filtered off and washed. The crystal was recrystallized from n-propanol to obtain 10.6 g of the desired product. m.p. 133°-134° C.
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)#[C-:2].[CH3:23][C:24]1[N:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CO.C(Cl)Cl>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([C:3]3[N:1]=[CH:2][O:31][C:30]=3[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=3)=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: Cc1cccc(C=O)n1
Reactant: [C-]#[N+]C(c1ccc2c(c1)OCO2)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(-c2ocnc2-c2ccc3c(c2)OCO3)n1
Yield: 22.5 %

Procedure:
A solution of 5-[isocyano-(toluene-4-sulfonyl)-methyl]-benzo[1,3]dioxole (40 mg, 0.127 mmol), 6-methyl-pyridine-2-carbaldehyde (15.4 mg, 0.127 mmol, 1 equiv) and potassium carbonate (26 mg, 0.19 mmol, 1.5 equiv) in methanol (1 mL) was shaken at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo, and resulting residue was partitions between water (1 mL) and methylene chloride (1 mL). The organics were purified by silica gel chromatography (20% acetone in hexane) to provide 2-(4-Benzo[1,3]dioxol-5-yl-oxazol-5-yl)-6-methyl-pyridine as a colorless oil (8 mg, 22%) [LCMS: Rt-2.34 min; M+H=281.2].
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]([F:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]([F:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 75.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.030 g, 0.634 mmol) obtained in step 2 and methanesulfonamide (0.064 g, 0.676 mmol), the title compound (0.263 g, 75%) was obtained.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[F:5][C:6]([C:21]([F:24])([F:23])[F:22])([O:10][C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:7](F)=[O:8]>CCOCC>[F:5][C:6]([C:21]([F:22])([F:23])[F:24])([O:10][C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:7]([NH:4][CH2:3][CH2:1][OH:2])=[O:8]
Reactant: NCCO
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: O=C(NCCO)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 15 °C
Reaction time: 1 h
Yield: 335 %

Procedure:
A mixture of ethanolamine (13 g, 28 mmol) and ether (30 mL) was cooled to 15° C. Perfluoro-2-methyl-3-oxahexanoyl fluoride (33 g in ether 50 mL) was added dropwise to keep the reaction temperature below 25° C. After the addition, the reaction mixture was stirred at room temperature for one hour. The solid was removed by filtration and the filtrate was washed with hydrochloric acid (0.5N, 30 mL), water (2 times 30 mL), sodium hydrogen carbonate solution (0.5N, 20 mL), water (30 mL), and sodium chloride solution (saturated, 20 mL). It was then concentrated and dried in vacuum over night at room temperature to give N-(perfluoro-2-methyl-3-oxahexanoyl)-2-aminoethanol as a white solid 35 g, yield 95%. mp. 69-72° C. 1H NMR (CDCl3) δ 1.67 (bs, 1H), 3.57 (m, 2H), 3.80 (t, J=5 Hz, 2H), 6.91 (bs, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:16][CH2:17][C:18]([C:33]([F:36])([F:35])[F:34])([OH:32])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])([CH3:22])[CH3:21])[N:7]=1)(=O)C.[BH4-].[Na+]>CO.O1CCCC1>[F:29][C:27]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([C:20]([CH3:21])([CH3:22])[CH2:19][C:18]([C:33]([F:34])([F:35])[F:36])([OH:32])[CH2:17][NH:16][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[CH:15][C:6]([CH2:5][OH:4])=[N:7]3)[CH:28]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(COC(C)=O)ccc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F

Procedure:
In the reaction of 170 mg (0.34 mmol) of 1-(2-(acetoxymethyl)quinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol with 53 mg (1.38 mmol) of sodium borohydride in 1.5 ml of methanol and 0.8 ml of tetrahydrofuran, 43 mg (27% of theory) of the product is obtained (cf. Example 14).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C.CCOCC>[F:8][C:7]1[C:2](/[N:1]=[CH:12]/[N:13]([CH3:15])[CH3:14])=[N:3][C:4](=[O:9])[NH:5][CH:6]=1
Reactant: Nc1nc(O)ncc1F
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)/C=N/c1nc(=O)[nH]cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
To a magnetically stirred solution of 4-amino-5-fluoropyrimidin-2-ol (4.00 g, 31.0 mmol) in DMF (100 mL) was added N,N-dimethylformamide dimethyl acetal (DMF-DMA; 4.00 g, 34.0 mmol). The mixture was stirred at room temperature for 72 h, diluted with Et2O (200 mL), and filtered. The solid product was washed with heptane to give (E)-N′-(5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-N,N-dimethylformimidamide (5.23 g, 92%) as a white solid: mp 240-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.7 (br s, 1H), 8.59 (s, 1H), 7.7 (d, J=5.6 Hz, 1H), 3.18 (s, 3H), 3.06 (s, 3H); ESIMS m/z 185 ([M+H]+), m/z 183 ([M−H]−).