Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[C:13]([CH:17]=1)[C:14]([O:16][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
To a solution of 5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoic acid (23.80 g, 61.06 mmol) in DMF (200 mL) was added potassium bicarbonate (9.16 g, 91.6 mmol) followed by benzyl bromide (8.0 mL, 67.37 mmol). The mixture was stirred for 5 h at room temperature and water (300 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v), the corresponding product was obtained as white solid (27.82 g, 95% yield). 1H NMR (400 MHz, CDCl3): δ 8.56 (s, 1H), 7.52 (dd, J=8.5, 2.1 Hz, 1H), 7.40 (m, 11H), 7.15 (m, 1H), 6.88 (m, 1H), 6.74 (m, 1H), 5.34 (s, 2H), 5.16 (s, 2H).
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH2:22][CH3:23].[Li]CCCC.CCCCCC.Cl>C(OCC)(=O)C>[CH2:22]([S:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[B:1]([OH:6])[OH:2])[CH3:23]
Reactant: CCSc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCSc1ccccc1B(O)O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
9.5 g (50 mmol) of triisopropyl borate are added to a solution of 10.9 g (50.0 mmol) of 1-bromo-2-ethylsulfanylbenzene kept at −70° C. 33.3 ml of a 15% solution of BuLi in hexane (55 mmol) are then added. The mixture is stirred at −70° C. for a further 30 minutes, then 1 N hydrochloric acid and ethyl acetate are added. The organic phase is separated off, dried and evaporated. The residue is taken up in diethyl ether and filtered. A colourless solid is obtained; FAB 182
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:29]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:29]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CCCNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C1Nc2ccc(Cl)cc2[C@](CCCNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
N-{3-[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]propyl}-4-fluorobenzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]([C:5]1[CH:10]=[C:9](I)[CH:8]=[CH:7][C:6]=1[NH:12][C:13]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[O:4].[CH2:32](C([Sn])=C(CCCC)CCCC)[CH2:33]CC>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:31])[C:3]([C:5]1[CH:10]=[C:9]([CH:32]=[CH2:33])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[O:4]
Reactant: CN(C)C(=O)c1cc(I)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
To a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-iodophenyl)amide (1.32 g) in toluene (15 mL) were added tributylvinyltin (935 mg) and tetrakistriphenylphosphine palladium(0) (142 mg), and the mixture was stirred at 140° C. for 1.5 hours under heating. The reaction solution was allowed to stand for cooling down to room temperature, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1, v/v) to give the title compound (783 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[N:18]1([C:24]2[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=2)[O:27][CH2:28][C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)(C)C>[CH3:11][N:6]1[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[N:21]1[CH2:22][CH2:23][N:18]([C:24]2[CH:39]=[CH:38][CH:37]=[C:26]([O:27][CH2:28][C:29](=[O:30])[N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[CH:25]=2)[CH2:19][CH2:20]1
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Reactant: O=C(COc1cccc(N2CCNCC2)c1)N1CCCCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2nc3c(N4CCN(c5cccc(OCC(=O)N6CCCCC6)c5)CC4)ncnc3n2C)cn1
Temperature: 25 °C
Yield: 9.9 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 2-(3-(piperazin-1-yl)phenoxy)-1-(piperidin-1-yl)ethanone (45.5 mg, 0.15 mmol), and triethylamine (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 6.1 mg (10% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.27-8.25 (m, 1H), 8.05 (s, 1H), 7.12 (t, 1H), 6.62 (dd, 1H), 6.55 (t, 1H), 6.39-6.35 (m, 1H), 4.73 (s, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 3.46-3.37 (m, 4H), 3.30-3.24 (m, 6H), 3.17 (d, 2H), 1.63-1.48 (m, 4H), 1.43 (s, 2H). MS (EI) for C27H33N9O2: 516.7 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Li]CCCC.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[C:27]([C:26]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: Brc1ccccc1P(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccccc1P(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of (2-bromophenyl)diphenylphosphine (II-a) (0.50 mmol) in dry THF (2 mL) was added dropwise under argon at −78° C. n-BuLi (0.55 mmol). The resulting solution was stirred at this temperature during one hour and pivaloyl chloride (0.80 mmol) was then added dropwise. After stirring at room temperature overnight, the reaction mixture was quenched with water (10 mL) and extracted with methylene chloride (3×10 mL). The organic phases were dried over MgSO4, filtered and the solvent evaporated giving a residue which was purified by column chromatography on silica gel using petroleum ether/ethyl acetate 3:1 as eluent. White solid; Yield 78%; Rf 0.43 (petroleum ether/ethyl acetate 3:1); IR (neat) 3049, 2967, 2928, 2867, 1686, 1585, 1477, 1458, 1431, 1389, 1361, 1283, 1192, 967, 947, 778, 741, 691 cm−1; 1H NMR (300MHz, CDCl3) δ 1.35 (s, 9H, CH3), 7.18-7.22 (m, 1H, Harom), 7.25-7.40 (m, 13H, Harom); 13C NMR (75.5 MHz, CDCl3) δ 27.7 (d, J=3.3 Hz, CH3), 44.7 (C(CH3)3), 124.8 (d, J=8.6 Hz, Carom), 128.3 (Carom), 128.5 (d, J=4.9 Hz, Carom), 128.7 (Carom), 133.3 (Carom), 133.5 (Carom), 134.6 (d, J=15.8 Hz, Carom), 134.8 (d, J=2.2 Hz, Carom), 137.0 (d, J=10.4 Hz, Carom), 148.0 (d, J=35.8 Hz, Carom); 31P NMR (121 MHz, CDCl3) δ −10.4; HRMS calcd for C23H23PONa [M+Na]+369.1379, found 369.1382.
Reaction SMILES: C([O:4][C:5](=[O:76])[CH2:6][C@H:7]([OH:75])[C@H:8]([NH:12][C:13](=[O:74])[C@H:14]([NH:36][C:37](=[O:73])[C@H:38]([NH:43][C:44](=[O:72])[CH2:45][C@@H:46]([OH:71])/[CH:47]=[CH:48]/[CH2:49][CH2:50][S:51][C:52]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:15][S:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([CH3:11])[CH3:10])C=C.N1CCOCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:75][C@H:7]([C@H:8]([NH:12][C:13](=[O:74])[C@H:14]([NH:36][C:37](=[O:73])[C@H:38]([NH:43][C:44](=[O:72])[CH2:45][C@@H:46]([OH:71])/[CH:47]=[CH:48]/[CH2:49][CH2:50][S:51][C:52]([C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:39][CH:40]([CH3:41])[CH3:42])[CH2:15][S:16][C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:9]([CH3:11])[CH3:10])[CH2:6][C:5]([OH:76])=[O:4]
Reactant: C=CCOC(=O)C[C@H](O)[C@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](CC(C)C)NC(=O)C[C@@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCN1
Product: CC(C)C[C@@H](NC(=O)C[C@@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(C)C)[C@@H](O)CC(=O)O
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a solution of 4C (168 mg, 0.158 mmol) in dry CH3OH (5 mL) at rt was added morpholine (27.6 μl, 0.48 mmol) followed by Pd(PPh3)4 (18.3 mg, 0.016 mmol). After stirring for 2 h the solvent was evaporated, the product rinsed with CH2Cl2 and washed with 1 M HCl (10 mL), sat NaHCO3 (10 mL) and sat. NaCl (10 mL) solutions. The organic layer was then dried with MgSO4 and filtered, the solvent was removed in vacuo and the crude product was washed with hexane (3×20 mL) and purified by flash chromatography (1-20% CH3OH/CHCl3) to give 5C (101 mg, 0.1 mmol, 63%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1>CO.C1COCC1.[OH-].[Pd+2].[OH-].[C]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.6 %

Procedure:
Oxazolyl chloride (4.0 mL, 45.9 mmol) and several drops of DMF were added to a solution of dichloromethane (5 mL) containing 4-benzyloxybenzoic acid (2.29 g, 10.0 mmol) under ice-cooling, and then dichloromethane (2.5 mL) was further added thereto. The mixture was stirred at room temperature for 2.5 hours, and the solvent was evaporated. The resulting residue was dissolved in dichloromethane (20 mL), and glycine methyl ester hydrochloride (1.39 g, 11.1 mmol) and N-ethyl-N,N-diisopropylamine (4.4 mL, 25.2 mmol) were added thereto under ice-cooling. The mixture was stirred at room temperature for 18 hours, and then water was added thereto to terminate the reaction. The mixture was extracted with dichloromethane, and the organic layers were combined and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 3:4 to 0:1, v/v) to give N-[4-(benzyloxy)benzoyl]glycine methyl ester. Then, 1.66 g of this ester was dissolved in a solvent mixture of methanol (8 mL) and THF (8 mL). To the resulting mixture, 20% palladium hydroxide-carbon (168 mg) was added. The mixture was vigorously stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite and then concentrated to give 1.19 g of the title compound (white powder, yield: 85%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:10]2)=[C:4]([F:25])[CH:3]=1.[ClH:26]>C(O)C>[ClH:26].[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10]2)=[C:4]([F:25])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(c2cc(F)c(Br)cc2F)C1
Agent: Cl
Solvent: CCO
Product: NC1CCC(c2cc(F)c(Br)cc2F)C1

Procedure:
A solution of 20.3 g (50 mmol) of 2-[3-(4-bromo-2,5-difluorophenyl)cyclopentyl]-1H-isoindole-1,3-(2H)-dione in 100 ml of concentrated hydrochloric acid and 100 ml of ethanol was heated at reflux for 4 hours. The ethanol was allowed to evaporate and the aqueous acid mixture was heated at reflux for 4 additional hours. The solution was filtered through a fiber glass pad to remove some insoluble material and the filtrate was evaporated in vacuo. The residue was triturated with ethanol which was also removed in vacuo to give 13.1 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5](Br)[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]3[N:17]([CH2:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:18](=[O:31])[N:19]([CH2:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:20](=[O:23])[C:21]=3[N:22]=2)=[CH:10][CH:9]=1)Br)C.CC(C)([O-])C.[K+].C>C(O)(C)(C)C.O>[CH:25]1([CH2:24][N:19]2[C:20](=[O:23])[C:21]3[N:22]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([C:6]#[C:5][C:4]([OH:40])=[O:3])=[CH:13][CH:12]=4)[NH:15][C:16]=3[N:17]([CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:18]2=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C#Cc1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
2.8 g (4.1 mmol) 3-[4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]phenyl}2,3-dibromo-propionic acid ethyl ester (part a of this example) was added to 56 mL of 1M potassium t-butoxide in t-butanol (Aldrich) at room temperature. The mixture was stirred at room temperature for 2.5 hours, then 0.10 mL water was added. The solution was stirred for an additional hour then 1 g charcoal was added in 250 mL water. The mixture was stirred for 30 minutes then filtered. The filtrate was acidified with conc. hydrochloric acid (pH=1), then the resulting suspension was stirred for 15 minutes, filtered then washed with 3×50 mL water. The solid was dried under reduced pressure to give 1.63 g (81%) of title compound; 1H-NMR (DMSO-d6) δ: 8.15 (d, J=8.0 Hz, phenyl CH, 2H), 7.73 (d, J=8.0 Hz, phenyl CH, 2H), 3.87 (d, J=6.6 Hz, CH2N, 2H), 3.74 (d, J=6.8 Hz, CH2N, 2H), 1.88 (br s, c-hexyl CH, 1H), 1.4-1.8 (m, c-hexyl CH, CH2, 11H), 0.8-1.2 (m, c-hexyl CH2, 10 H); MS (ES—): 487 (M-1), 443 (M-1-CO2).
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]([C:15](OCC)=[O:16])=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+]>O1CCCC1>[OH:16][CH2:15][C:7]1[N:6]=[C:5]2[C:14](=[C:13]3[C:8]=1[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH2:1][CH2:2][CH2:3][CH2:4]2
Reactant: CCOC(=O)c1nc2c(c3ccccc13)CCCC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nc2c(c3ccccc13)CCCC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 350 mg of ethyl 1,2,3,4-tetrahydro-phenanthridin-6-yl-carboxylate in 10 ml of tetrahydrofuran is added dropwise within five minutes to a suspension of 37 mg of lithium borohydride in 15 ml of tetrahydrofuran, wherein cooling with an ice bath. Then the ice bath is removed and the reaction mixture is stirred for a further 2.5 hours at ambient temperature. For working up, 2 ml of 1 M citric acid are added to the brown reaction solution wherein cooling with an ice bath. The mixture is stirred with 100 ml of ethyl acetate and 50 ml of water and adjusted to pH 10 with 4 N sodium hydroxide solution. The organic phase is separated off, washed with water, dried over magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with ethyl acetate/petroleum ether (1:4 to 1:1) as eluant.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11].C1(O)C=CC=CC=1>C(O)(=O)C>[N+:10]([C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([Cl:1])[C:7]=1[Cl:8])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(Cl)c1Cl
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)c(Cl)c1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution was prepared from 200 g of 2,3-dichlorophenol and 540 ml of glacial acetic acid. The solution was cooled, and a solution of 58 ml of 90% nitric acid in 160 ml of glacial acetic acid was added in dropwise fashion with stirring to the solution of the phenol. After half of the solution of the phenol had been added, the reaction mixture was allowed to warm to ambient temperature. It was stirred for 15 minutes at ambient temperature after all of the dichlorophenol had been added. The reaction mixture was then poured over 3,000 ml of an ice/water mixture. The yellowish product which precipitated was collected. The product was heated in a sublimation apparatus over a 4 day period at 80° C. at 4 torr. to remove any 2-nitro-5,6-dichlorophenol formed as a by-product in the above nitration. The residue was recrystallized from toluene to yield 80.3 g of 4-nitro-2,3-dichlorophenol; m.p.=148°-150° C.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].Br[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23]>>[NH2:1][C:2]1[C:3]([C:4]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: Fc1cccc(F)c1Br
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Product: Nc1nc(Cl)ccc1C(=O)c1c(F)cccc1F

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 2-bromo-1,3-difluorobenzene (Aldrich) using the procedure described in Example 7. HRMS, observed: 268.0217, Calcd for M+: 268.0215.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([SH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[O-]CC.[Na+].[CH:20]12[O:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25]2.O>C(O)C>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:15][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[OH:26])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:1])[CH3:3]
Reactant: C1CCC2OC2C1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1
Reaction time: 1 h

Procedure:
3,5-Bis(1,1-dimethylethyl)benzenethiol (Example 2) (5.0 g, 0.0225 moles) was added to freshly prepared sodium ethoxide (0.0230 moles) in absolute ethyl alcohol (50 ml). After stirring for 1 hour, cyclohexene oxide (2.2 g; 0.0225 moles) was added by syringe over 5 minutes, and the reaction mixture was stirred for 60 hours at room temperature. Water (100 ml) was added, and the reaction mixture was extracted twice with 75 ml of ethyl acetate. The combined ethyl acetate extracts were washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated to give the title product as a yellow solid, which was recrystallized from cold pentane. The structure assignment was supported by NMR spectroscopy. The title compound was used in Example 4.
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.CCN(CC)CC.[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[C:2]([N+:6]([O-:7])=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([Br:8])=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)[N+]([O-])=Cc1ccc(Br)cc1

Procedure:
By anaolgy to the procedure for the synthesis described above, 5.024 g (40.0 mmol) of N-tert-butylhydroxylamine hydrochloride (1) were reacted with 6.476 g (35.0 mmol) of 4-bromobenzaldehyde (2c) in 100 mL of anhydrous toluene, and in the presence of 4.554 g (45 mmol, 6.27 mL) of Et3N and 8.425 g (70.0 mmol) of MgSO4. Purification of the crude yellow oil by column chromatography (silica gel, EtOAc/hexanes=1:6 to 1:3) yielded 8.95 g (quant.) of colorless crystals. Rf: 0.25 (EtOAc/hexanes=1:4, UV254-quenching). 1H NMR (300 MHz, CDCl3, room temp.): δ8.14 (dt, J=8.7,2.4 Hz, 2H, Ar-H), 7.49 (dt, superimposed, J=8.7,2.4 Hz, 2H, Ar-H), 7.48 (s, superimposed, 1H, HC(═N)), 1.56 (s, 9H, C(CH3)3) ppm. 13C NMR (75 MHz, CDCl3, room temp.): δ131.53, 130.06, 129.81, 128.92, 123.73, 71.09, 28.20 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([OH:12])[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19]O)=[N:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([O:12][CH2:19][C:17]3[O:18][C:14]([CH3:13])=[CH:15][N:16]=3)[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cnc(CO)o1
Reactant: Oc1cnc2c(Cl)nccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cnc(COc2cnc3c(Cl)nccc3n2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 5-chloropyrido[3,4-b]pyrazin-2-ol (200 mg, 1.1 mmol) and (5-methyloxazol-2-yl)methanol (187 mg, 1.6 mmol) in tetrahydrofuran (5 mL) was added triphenylphosphine (433 mg, 1.6 mmol). The reaction mixture was cooled to 0° C. and diisopropyl azodicarboxylate (0.33 mL, 1.6 mmol) was added slowly. The reaction was stirred at 0° C. for 1 hour, and then allowed to warm to ambient temperature overnight. After 16 hours, the reaction was quenched with water and extracted into ethyl acetate. The organic layer was concentrated, and the crude product was purified by column chromatography, eluting with 20-80% (3:1 ethyl acetate/ethanol) in heptane. The less-polar isomer was isolated to provide the title compound (120 mg, 0.43 mmol, 79% yield) as a white solid. LC/MS (ESI+) m/z: 277.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][CH2:9][CH2:10][O:11][C:3]=12.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[N:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[N:21]([CH:23]1[CH2:24][CH2:25][N:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[O:8][CH2:9][CH2:10][O:11][C:3]=23)[CH2:27][CH2:28]1)[CH3:22]
Reactant: Clc1ccnc2c1OCCO2
Reactant: CN(C1CCNCC1)C1Cc2ccccc2C1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CN(C1CCN(c2ccnc3c2OCCO3)CC1)C1Cc2ccccc2C1
Temperature: 130 °C
Yield: 8.5 %

Procedure:
1.1 g (6.5 mmol) of 8-chloro-2,3-dihydro-1,4-dioxino[2,3-b]pyridine, 3 g (13 mmol) of 4[N-(indan-2-yl)-N-methylamino]piperidine and 5 ml of pyridine are placed in a reactor. The whole is heated at 130° C. for 8 hours. After cooling, the whole is taken up in toluene and concentrated. The residue is chromatographed on 130 g of silica (eluant: CH2Cl2 /CH3OH/NH4OH, 95/5/0.5) to yield the expected product which melts (MK) at 167-170° C. Yield=8.5%.