Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[CH2:16][NH:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:23][S:20]([CH2:19][CH2:18][NH:17][CH2:16][C:15]1[CH:14]=[C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:40][C:37]4[CH:36]=[CH:35][C:34]([N:31]5[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]5)=[CH:39][CH:38]=4)=[N:5]3)=[CH:10][CH:11]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(CNCCS(C)(=O)=O)c3)n2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(CNCCS(C)(=O)=O)c5)n4n3)cc2)CC1

Procedure:
Into a microwave vial, [3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-(2-methanesulfonyl-ethyl)-amine (0.100 g, 0.000255 mol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.214 g, 0.00112 mol), 1-Methoxy-2-propanol (0.613 mL) and N,N-Diisopropylethylamine (0.133 mL, 0.000764 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 15% methanol). The collected fractions afforded (7-{3-[(2-Methanesulfonyl-ethylamino)-methyl]-phenyl}-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine a yellow solid (41 mg, 31%). LCMS (E/I+) 520.16 (M+H). NMR 1H (DMSO-d6)-9.76 (ns, 1H), 9.37 (s, 1H), 9.20 (bs, 2H), 8.99 (s, 1H), 8.42 (d, 2H, J=7.45 Hz), 8.16 (s, 1H), 7.61-7.72 (m, 3H), 7.51 (d, 1H, J=7.45 Hz), 7.15 (d, 1H, J=4.47 Hz), 6.91-7.04 (m, 4H), 4.31 (s, 2H), 3.76 (d, 2H, J=12.66 Hz), 3.34-3.63 (m, 6H0, 3.08-3.24 (m, 5H), 2.82-3.00 (m, 5H).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH2:12]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][C@H:23]1[CH2:32][O:33][CH2:34][C:35]([NH:37][C:38]([NH2:40])=[O:39])=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO>O1CCCC1>[CH2:12]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24][C@H:23]1[CH2:32][O:33][CH2:34][CH2:35][NH:37][C:38]([NH2:40])=[O:39])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)NC(N)=O)N(C(=O)OCc2ccccc2)C1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCCNC(N)=O)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a suspension of sodium borohydride (0.1 g) in tetrahydrofuran (10 ml) was added boron trifluoride etherate (0.3 ml) with stirring at 0°-10° C. After 30 minutes, a solution of (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2- [(ureidocarbonylmethyl)oxymethyl]pyrrolidine (0.63 g) in tetrahydrofuran (5 ml) was added to the mixture at 0°-10° C. The mixture was stirred at the same condition for 2 hours and at ambient temperature for 15 hours. Methanol (5 ml) was added to the mixture at 0°-10° C. The mixture was stirred at ambient temperature for 3 hours and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (25 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (0.24 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)(C)C>[CH3:11][NH:12][C:13]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[S:14]
Reactant: NCCOCc1c[nH]cn1
Reactant: CN=C=S
Solvent: CC(C)O
Product: CNC(=S)NCCOCc1c[nH]cn1
Yield: 23.5 %

Procedure:
4-(2-Aminoethoxymethyl)imidazole (2.24 g.) was caused to react with methylisothiocyanate (1.21 g.) in isopropyl alcohol (25 ml.) in the usual way. The crude product was purified by chromatography on a column of silica gel with ethyl acetate as eluant and subsequently on a dry column of alumina, using chloroform. The final product was recrystallised from ethyl acetate to give N-methyl-N'-[2-(4-imidazolylmethoxy)ethyl]thiourea (0.80 g.), m.p. 96°-98°.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1.CO.O>C1OC1CC>[F:37][C:38]1[CH:45]=[CH:44][C:41](/[CH:42]=[C:15](/[C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]3([CH3:13])[CH3:14])\[CH3:16])=[CH:40][CH:39]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC1CO1
Agent: [Br-]
Solvent: CO
Solvent: O
Product: C/C(=C\c1ccc(F)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 53.9 %

Procedure:
45 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide are suspended in 200 ml of 1,2-butylene oxide. After the addition of 8 g of 4-fluorobenzaldehyde the mixture is boiled at reflux for 16 hours. After cooling the clear, yellowish solution is poured into 1 of methanol/water (6:4) and extracted repeatedly with hexane. The organic phase is washed three times with water and, after drying over sodium sulphate, evaporated. The crystalline residue can be recrystallized from hexane and gives 11.2 g of (E)-6-(p-fluoro-α-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in colourless crystals, melting point 99°-101°.
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].P(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1[NH:4][C:5]([CH3:13])=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:2]=1
Reactant: COc1ccccc1-c1nc(C)c(-c2cccnc2)n1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: COc1ccccc1-c1nc(-c2cccnc2)c(C)[nH]1
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a solution of 1-hydroxy-2-(2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.5 g) in N,N-dimethylformamide (10 ml) was added phosphorus trichloride (0.31 ml) under ice-cooling. The mixture was stirred for 2 hours at 5° to 10° C. The mixture was poured into water (100 ml), and neutralized with aqueous sodium bicarbonate. The precipitate was collected, washed with water, and dried to give 2-(2-methoxyphenyl)-5-methyl-4-(3-pyridyl)imidazole (0.31 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.[CH:14]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[C:7]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1cncnc1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1cncnc1Cl
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a stirred, cooled (−78° C. solution of 5.8 g (29 mmol) of ethyl (4-chloro-5-pyrimidinyl)acetate (see i-48, Step A) in 75 mL of anhydrous THF under an atmosphere of nitrogen was added 15.2 mL (30.4 mmol) of a 2.0 M solution of lithium diisopropylamide in anhydrous THF. The resulting mixture was stirred for 15 min then 2.26 mL (36.1 mmol) of iodomethane was added over 5 min. The reaction mixture was stirred for 15 min, allowed to warm to −20° C. over 45 min, then warmed to 0° C. for 15 min. The reaction mixture was then quenched with a saturated ammonium chloride solution and extracted with 50 mL of dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 20% ethyl acetate in hexanes mixture to afford the title compound (1.9 g, 31%). 1H-NMR (500 MHz, CD3OD) δ: 8.88 (s 1H), 8.74 (s, 1H), 4.17 (m, 2H), 1.58 (d, J=7 Hz, 3H). LC-MS: m/z (E/S) 215 (MH)+.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Br[CH:22]1[C@@H:26]([F:27])[C@H:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:24]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[S:23]1>C(Cl)Cl>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]([CH:22]2[C@@H:26]([F:27])[C@H:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C@@H:24]([CH2:37][O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=3)[S:23]2)[C:2](=[O:3])[N:4]=1
Reactant: F[C@@H]1C(Br)S[C@H](COCc2ccc(Cl)cc2)[C@H]1OCc1ccc(Cl)cc1
Reactant: Nc1cc[nH]c(=O)n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: Nc1ccn(C2S[C@H](COCc3ccc(Cl)cc3)[C@@H](OCc3ccc(Cl)cc3)[C@@H]2F)c(=O)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To another reaction vessel, 0.12 g of cytosine and 0.53 mL of N,O-bis(trimethylsilyl)acetamide were added in a nitrogen atmosphere, and the obtained mixture was then stirred at 80° C. for 2 hours. After cooling in air, a methylene chloride solution containing (3S,4S,5R)-2-bromo-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolane was added to the reaction mixture, and the obtained mixture was then stirred 60° C. for 2 hours. Thereafter, methylene chloride was added to the reaction mixture, and the thus obtained mixture was washed with a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 80/20), so as to obtain 0.18 g of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolane in the form of a light yellow solid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:26])=[CH:18][C:17]=3[F:36])[CH:12]=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:26])=[CH:18][C:17]=2[F:36])[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nccc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)n1
Temperature: 85 °C
Yield: 62.6 %

Procedure:
A mixture of N1-(4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide (Example 14, 25 mg, 0.048 mmol), anisole (52 mg, 0.48 mmol) in TFA (1 mL) was heated at 85° C. for 6 h. The TFA was removed under vacuum and the residue partitioned between EtOAc and saturated aq. NaHCO3 solution. The EtOAc phase was washed with brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography on SiO2 using EtOAc then 1-2% MeOH in CH2Cl2 as eluents gave the title compound (12 mg, 63%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.51 (s, 1H), 8.02 (s, 1H), 7.66 (dd, 1H, J=12.6, 2.0 Hz), 7.42-7.31 (m, 2H), 7.32-7.27 (m, 1H), 7.23 (t, 2H, J=8.6 Hz), 7.16 (t, 2H, J=9.1 Hz), 6.91 (s, 2H), 3.73 (s, 2H); MS (ESI+) m/z 400.11 (M+H)+.
Reaction SMILES: COC1C=C2C(=CC=1OC)N=C[N:7]=C2SC1C=C(C=CC=1)N.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:35][C:36](=[O:44])OC2C=CC=CC=2)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:35][C:36](=[O:44])[NH2:7])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: COc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(NC(N)=O)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from the previous step (94 mg, 0.3 mmol) in THF (3 mL) was added phenyl 3-methoxy-5-(trifluoromethyl)phenylcarbamate from Example 115A (140 mg, 0.45 mmol), diisopropylethylamine (80 uL, 0.45 mmol), and 4-dimethylaminopyridine (4 mg, 0.03 mmol). The solution was stirred at 50° C. overnight, allowed to cool to room temperature, and diluted with EtOAc. The solid was then filtered to give 14346,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-methoxy-5-(trifluoromethyl)phenyl)urea (89 mg, 0.17 mmol, 56%). 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.48 (s, 1H), 7.44 (t, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 7.29-7.24 (m, 2H), 6.85 (s, 1H), 3.99 (s, 6H), 3.81 (s, 3H); LC-MS (ESI) m/z 531 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f23) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8](O)=[O:9])([OH:3])=[O:2].[C:16](=O)([O-])[O-].[K+].[K+].S([O:27][CH3:28])(OC)(=O)=O>CN(C)C=O>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([O:27][CH3:28])=[O:9])([O:3][CH3:16])=[O:2]
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C=Nc1cc(Cl)ccc1C(=O)OC
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
17 g (66 mmol) of N-carboxymethylene-4-chloroanthranilic acid are dissolved in 175 g of N,N-dimethylformamide, and 22.5 g (162 mmol) of potassium carbonate are added. At 80° C., 56 g (444 mmol) of dimethyl sulfate are added dropwise in 3 portions over the course of 2 h, and the mixture is then stirred for 30 min. The excess dimethyl sulfate is destroyed by adding ammonia. The product is precipitated by cooling, filtered off and washed with water. 16.1 g (62.5 mmol; 95%) of methyl N-carbomethoxymethylene-4-chloroanthranilate are isolated.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:24])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:15]([N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1)=[O:16])([CH3:14])[CH2:6][CH2:5]2.[O:25]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:25][C:7]([CH3:14])([C:15]([N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1)=[O:16])[CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:24]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCC(O)CC1)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)N2CCC(O)CC2)=C(C)C1=O
Yield: 90 %

Procedure:
Oxidation as described in protocol B, using 100 mg (0.302 mmol) of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-hydroxypiperidin-1-yl)methanone and 364 mg CAN (0.664 mmol) yielded 95 mg of a yellow syrup.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22]C(C#N)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-:26].[Na+].Cl.[CH2:29]([OH:32])[CH2:30]O>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:30]([C:29]([OH:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: OCCO
Reactant: [OH-]
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
To 30 ml of methyl isobutyl ketone were added 3 g of 4-hydroxy-4'-cyanobiphenyl, 21.4 g of 1-bromodecane and 2.5 g of potassium carbonate, and the mixture was reacted under reflux for 30 hours. The reaction mixture was cooled and insoluble substances were removed by filtration. The filtrate was concentrated under a reduced pressure, ethanol was added to the residue and recrystallization was carried out to obtain 5 g of 4-decyloxy-4'-cyanobiphenyl. Thus, 4.1 g of this 4-decyloxy-4'-cyanobiphenyl was dissolved in 25 ml of ethylene glycol, 2.5 ml of 2N sodium hydroxide was added to the solution, and a reaction was carried out under reflux for 4 hours. The reaction liquid was put into dilute hydrochloric acid cooled by ice, and the precipitate was recovered by filtration, washed with water and ethanol, and dried. The dried product was recrystallized from chloroform to obtain 3.0 g of 4'-decyloxybiphenyl-4-carboxylic acid. Then, 20 g of thionyl chloride was dropped into this carboxylic acid and the mixture was reacted under reflux for 2 hours. Unreacted thionyl chloride was removed by distillation under a reduced pressure and 4'-decyloxybiphenyl-4-carboxylic acid chloride was quantitatively recovered.
Reaction SMILES: C([Li])(CC)C.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[C:23]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[CH2:35]([N:42]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C@@H:43]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH:44]=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)C.C(O)(=O)C>[C:26]([O:25][C:23]([N:30]1[CH2:31][CH2:32][CH2:33][C@@H:34]1[C@@H:44]([OH:45])[C@@H:43]([N:42]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: [Li]C(C)CC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h
Yield: 60.1 %

Procedure:
Add sec-butyllithium (1.29 mL, 1.8 mmol) dropwise to a solution of (−)-sparteine (0.44 mL, 1.36 mmol) in diethyl ether (10 mL) over 3 min at −78° C. Add N-Boc-pyrrolidine (0.245 mL, 1.4 mmol) in diethyl ether (2 mL) dropwise over 10 min. Stir 2 h, add 2-(S)-dibenzylamino-3-phenylpropionaldehyde (0.69 g, 2.1 mmol) in diethyl ether (1.8 mL) over 5 min and stir 20 min. Add acetic acid (0.16 mL) and warn to room temperature. Add saturated aqueous sodium chloride (20 mL), separate layers, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a foam (0.421 g, 60%).
Reaction SMILES: [C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH2:30])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2].[H-].[Na+].I[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>CN(C)C=O>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][CH2:6][CH2:7][N:8]([CH3:9])[CH3:10])(=[O:3])[CH3:2]
Reactant: CCCCCI
Reactant: CC(=O)N(CCCN(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CCCN(C)C)C(C)=O)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 64.7 %

Procedure:
1.01 g (2.33 mmol) of the above 2-[4-[N-acetyl-N-(3-dimethylaminopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 20 mL of dimethylformamide under argon atmosphere, 190 mg (4.75 mmol) of sodium hydride (60% oil dispersion) and 0.61 mL (4.7 mmol) of 1-iodopentane were added under ice-cooling and the mixture was stirred at room temperature for 50 minutes. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1-9:1) to give 759 mg of 2-[4-[N-acetyl-N-(3-dimethylaminopropyl)amino]-3-fluorophenyl]-6,8-difluoro-5-pentylamino-4H-1-benzopyran-4-one (yield: 65%).
Reaction SMILES: C([O:5][C:6](=O)[C@@H:7]([O:9][C:10]1[CH:33]=[CH:32][C:13]2[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]=2[CH:11]=1)[CH:17]=[C:16]([C:22]1[N:23]([CH2:27][C:28]([F:31])([F:30])[F:29])[N:24]=[CH:25][N:26]=1)[N:15]=3)[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C[N:43](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[CH2:27][N:23]1[C:22]([C:16]2[N:15]=[C:14]3[C:13]4[CH:32]=[CH:33][C:10]([O:9][C@@H:7]([CH3:8])[C:6]([NH2:43])=[O:5])=[CH:11][C:12]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:26][CH:25]=[N:24]1
Reactant: C[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A solution of (S)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid tert-butyl ester was dissolved in DCM (3 mL), TFA (0.5 mL) added and the reaction mixture stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMF (3 mL). HATU (217 mg, 0.56 mmol), ammonium chloride (46 mg, 0.85 mmol) and triethylamine (119 μL, 0.85 mmol) were added and the reaction mixture stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2 gradient 0-10% methanol in EtOAc) then reverse phase preparative HPLC (C-18, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) then to yield 486 as a white solid (57 mg, 47%). LCMS: RT=3.52 min, [M+H]+=423; 1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.95 (1H, s), 7.51 (1H, br s), 7.22 (1H, br s), 6.73 (1H, dd, J=8.9, 2.6 Hz), 6.50 (1H, d, J=2.6 Hz), 5.86 (1H, q, J=8.9 Hz), 4.64 (1H, q, J=6.6 Hz), 4.51-4.38 (4H, m), 1.40 (1H, d, J=6.4 Hz)