Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)[CH:8]=[CH:7][N:6]=1.Cl[CH:19]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([F:32])[CH:26]=1)[C:20]1[O:24][CH:23]=[N:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:19]([C:20]2[O:24][CH:23]=[N:22][CH:21]=2)[N:14]2[CH:15]=[CH:16][C:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=3)=[CH:12][C:13]2=[O:17])=[CH:26][C:27]=1[F:32]
Reactant: Fc1cc(C(Cl)c2cnco2)ccc1Cl
Reactant: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nccc(-c2ccn(C(c3ccc(Cl)c(F)c3)c3cnco3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
NaH (13.2 mg, 0.331 mmol; 60 wt % oil dispersion) neat as a solid was added to a stirred suspension of 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (65.9 mg, 0.301 mmol) in DMF (600 μL) at room temperature under nitrogen. After 30 minutes, the suspension had become a solution. A solution of 5-(chloro(4-chloro-3-fluorophenyl)methyl)oxazole (111 mg, 0.451 mmol) was then added as a solution in DMF (300 μL) dropwise by syringe. After stirring at room temperature overnight, TLC in ethyl acetate showed a new high rf spot, as well as a new mid rf spot (both bright blue under UV). The reaction was quenched with water (1 mL) and then partitioned between ethyl acetate (30 mL) and water with a little brine (30 mL). The organics were isolated and washed with water/brine (3×30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated to an oil. The mixture was loaded onto a Biotage 12M column with 7/3 ethyl acetate/hexanes and eluted. Two main spots eluted and corresponding fractions were pooled and concentrated. The least polar fraction appears to be alkylated on the pyridone oxygen. The second eluting spot appears to be the desired N-alkylated pyridone, which was isolated as a foam, 1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (50 mg, 39%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)=[CH:32][CH:31]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN1CCN(Cc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cc2)CC1
Yield: 56 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (200 mg, 0.644 mmol) was reacted with 4-[(4-methylpiperazin-1-yl)methyl]aniline (200 mg, 0.966 mmol) to afford the desired product (173 mg, 56%) as a yellow solid: ESI MS m/z 479 [C25H27BrN4O+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:13]([Cl:33])[CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>CO.C1COCC1.O>[Cl:33][C:13]1[CH:12]=[C:11]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9][CH2:10]2)[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])[C:14]=1[C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1(c2cc(Cl)c(-c3ccc(C(F)(F)F)cc3)c(OCC(F)(F)F)c2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2cc(Cl)c(-c3ccc(C(F)(F)F)cc3)c(OCC(F)(F)F)c2)CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentane carboxylate (0.32 g, 0.64 mmol) was dissolved in 25 mL of MeOH/THF/H2O (10:10:5, vvl), LiOH (0.163 g, 3.88 mmol) was added. The reaction mixture was stirred for 5 h at room temperature and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the 1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (0.220 g, 73%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.69 (d, 2H), 7.41 (d, 2H), 7.26 (s, 1H), 6.92 (s, 1H), 4.22 (q, 2H), 3.71 (m, 2H), 1.98 (m, 2H), 1.81 (m, 4H).
Reaction SMILES: Cl.CON.[CH3:5][N:6]([CH3:9])[CH:7]=[O:8].[H-].[Na+].CS(C1O[C:18]([C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=4)[C:25]=3[CH:40]=2)=[N:19][N:20]=1)(=O)=O>C(OCC)(=O)C.O1CCCC1>[CH3:5][N:6]([CH3:9])[C:7]1[O:8][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:37])([F:39])[F:38])[CH:30]=4)[C:25]=3[CH:40]=2)=[N:19][N:20]=1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Agent: CON
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Reaction time: 0.25 h
Yield: 12 %

Procedure:
To a mixture of O-methylhydroxylamine hydrochloride (0.59 g, 7.07 mmol), N,N-dimethylformamide (0.7 mL) and tetrahydrofuran (1.4 mL) was added sodium hydride (60% in oil, 0.31 g, 12.8 mmol) at 0° C., and the resulting mixture was stirred for 15 min. 2-(Methylsulfonyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (0.30 g, 0.71 mmol) was added to the mixture, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=7/3) and recrystallized from hexane/diisopropyl ether to give the title compound (32.7 mg, yield 12%) as colorless crystals.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[CH2:19]([NH2:22])[C:20]#[CH:21]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:22][C:19]#[C:20][CH3:21])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccccn1
Reactant: C#CCN
Solvent: CC#N
Product: CC#CNC(=C[N+](=O)[O-])NCCSCc1ccccn1

Procedure:
A mixture of the product of Step A (2.0 g; 7.03 mmoles) and propargylamine (3.44 g; 62.5 mmoles) in acetonitrile (30 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 1.5 hours then stirred at ambient temperature for 42 hours. The reaction mixture was filtered and the product collected. Recrystallization from acetonitrile gave the title compound; mp 147°-148°.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[CH3:9][C:10](O)([C:12]#[CH:13])[CH3:11].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:9][C:10]([CH3:11])([O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1)[C:12]#[CH:13]
Reactant: C#CC(C)(C)O
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#CC(C)(C)Oc1ccc(Br)cc1
Reaction time: 8 h
Yield: 15.1 %

Procedure:
69.2 g of p-bromophenol and 33.6 g of 2-methylbut-3-yn-2-ol were dissolved in 600 ml of dichloromethane and 75 ml of diethyl azodicarboxylate were added. 126 g of triphenylphosphine were added portionwise and the mixture was stirred overnight. The mixture was washed with dilute hydrochloric acid and 2M sodium hydroxide solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:10) for the elution. There was obtained an oil which was distilled to give 14.4 g of 4-(1,1-dimethyl-2-propynyloxy)bromobenzene of boiling point 96°-106° C./1 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH3:44])=[C:37]([O:45][CH2:46][CH3:47])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:46]([O:45][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][CH3:44])[CH3:47]
Reactant: CCCOc1ccc(OB([O-])[O-])cc1OCC
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 3-ethoxy-4-propoxyphenyl borate (0.16 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-(3-ethoxy-4-propoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 125) (0.16 g) as colorless crystals.
Reaction SMILES: [CH2:1]([C:5]1([CH2:68][CH2:69][CH2:70][CH3:71])[C:17]2[CH:16]=[C:15]([N:18]([C:47]3[CH:59]=[CH:58][C:57]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[C:50]([CH2:64][CH2:65][CH2:66][CH3:67])([CH2:60][CH2:61][CH2:62][CH3:63])[C:49]=4[CH:48]=3)[C:19]3[CH:31]=[C:30]4[C:22]([C:23]5[CH:24]=[CH:25][C:26]([C:40]6[S:44][C:43]([CH:45]=O)=[CH:42][CH:41]=6)=[CH:27][C:28]=5[C:29]4([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[C:72]([CH2:74][C:75]([OH:77])=[O:76])#[N:73]>C(#N)C.N1CCCCC1>[CH2:1]([C:5]1([CH2:68][CH2:69][CH2:70][CH3:71])[C:17]2[CH:16]=[C:15]([N:18]([C:47]3[CH:59]=[CH:58][C:57]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[C:50]([CH2:60][CH2:61][CH2:62][CH3:63])([CH2:64][CH2:65][CH2:66][CH3:67])[C:49]=4[CH:48]=3)[C:19]3[CH:31]=[C:30]4[C:22]([C:23]5[CH:24]=[CH:25][C:26]([C:40]6[S:44][C:43]([CH:45]=[C:74]([C:72]#[N:73])[C:75]([OH:77])=[O:76])=[CH:42][CH:41]=6)=[CH:27][C:28]=5[C:29]4([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(-c5ccc(C=O)s5)ccc3-4)cc21
Reactant: N#CCC(=O)O
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(-c5ccc(C=C(C#N)C(=O)O)s5)ccc3-4)cc21

Procedure:
As shown in Scheme 3, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31); and 2-Iodo-9H-fluorene is reacted with 1-iodobutane to form 9,9-dibutyl-2-iodo-9H-fluorene (32). Then, 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31) is reacted with 9,9-dibutyl-2-iodo-9H-fluorene (32) by Ullman coupling reaction to obtain (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33). Next, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a). Finally, in acetonitrile, 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 3-(5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophen-2-yl)-2-cyano-acrylic acid (35a).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][OH:47])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=1O>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][O:47][C:50]4[C:49]([F:48])=[CH:54][CH:53]=[CH:52][C:51]=4[F:55])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCOc4c(F)cccc4F)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C

Procedure:
This compound is prepared from compound E4 and 2,6-difluorophenol, according to the above-described procedure A. LC-MS: tR=1.24 min, ES+: 819.40.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(O)(C)(C)C.C(N(CC)CC)C.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1>ClC(Cl)C.CCOC(C)=O.CCCCCC.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncc(C(F)(F)F)c(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (5 g, 23 mmol) in dichloroethane: t-butanol (50 ml, 1:1) was added dry zinc chloride (3.7 g, 27 mmol) and triethylamine (2.52 g, 25 mmol), and the mixture was stirred at rt for 1 h (pH should not be >7). To this mixture, (S)-tert-butyl 3-aminopiperidine-1-carboxylate (4.9 g, 25 mmol) was added and stirring continued at rt for 16 h. TLC showed formation of the major compound (0.2 Rf) and a minor other isomer (0.25 Rf) and ˜10% starting material in 15% EtOAc: hexane solvent system. Solvents were evaporated, and crude was diluted with ice cold water (50 mL) and stirred for 5 min at rt to get a pale yellow gummy mass. The crude pale yellow gummy mass (6 g) was taken in 60 mL hexane and stirred for 10 min at rt to get a solid which was immediately filtered to get the pure desired compound (5 g, 57%). MS m/z: 381.1 (ES+, M+H).
Reaction SMILES: CC(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:19][CH2:18][CH2:17][C@H:12]1[C:13](OC)=[O:14])=O)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[C:13]1(=[O:14])[NH:8][CH2:9][CH2:10][N:11]2[CH2:19][CH2:18][CH2:17][C@@H:12]12
Reactant: COC(=O)[C@@H]1CCCN1CCNC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCN2CCC[C@@H]12

Procedure:
To a solution of methyl 1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-L-prolinate (D75, 1 g) in dichloromethane (20 ml) was added at r.t. TFA (5 ml) and the reaction mixture was stirred for 1 hr. The mixture was diluted with MeOH and it was filtered trough SCX cartridge. The fractions eluted with methanolic ammonia were evaporated in vacuo keeping the bath temperature at 40° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][C:13](=[O:15])[O:12][C:11](=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[NH4+:18].N>O1CCOCC1>[Si:1]([O:8][CH:9]1[CH2:14][C:13](=[O:15])[NH:18][C:11](=[O:12])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)OC(=O)C1
Reactant: [NH4+]
Agent: N
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)NC(=O)C1
Temperature: 100 °C

Procedure:
Dissolve 4.1 mmol of 4-(tert-butyldimethylsilyloxy)dihydro-2H-pyran-2,6(3H)-dione (Nagao Y et al., Chem. Lett. 1990 9: 1503) in 10 mL of dioxane in a pressure tube. Cool in an ice/water bath, add 15 mL of saturated ammonium hydroxide and treat with gaseous ammonia via bubbler for about 10 min. Cap the pressure tube and heat in a 100° C. oil bath for 17 h. Cool the mixture and concentrate in vacuo. Purify the residue by silica gel chromatography using ethyl acetate/hexanes eluant to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](Cl)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[CH3:18][CH:19]([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([C:19]([CH3:27])([CH3:18])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: CC(C)C(=O)OC(C)(C)C
Reactant: Clc1nc2ccnc(Cl)c2c2cc(Br)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C)(C)c1nc2ccnc(Cl)c2c2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of 9-bromo-1,6-dichlorobenzo[c]-1,6-naphthyridine (5 g, 15.24 mmol) in Toluene (50 ml) was added tert-butyl 2-methylpropanoate (2.64 g, 18.29 mmol). The reaction mixture was cooled to 0° C. A solution of NaHMDS (1M in THF, 3.35 g, 18.29 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was quenched with aqueous saturated ammonium chloride (50 mL), and extracted with EtOAc (1×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was adsorbed on to silica gel and purified by column chromatography on silica gel, eluting with an EtOAc/Hexanes gradient to afford tert-butyl 2-(9-bromo-1-chlorobenzo[c]-1,6-naphthyridin-6-yl)-2-methylpropanoate. LRMS (ESI) calc'd for (C20H20BrClN2O2) [M+H]+, 437.0; found 437.0.
Reaction SMILES: [C:1]([C@@H:6]([C@H:8]([C:10]([O:12][CH2:13][CH3:14])=O)[OH:9])O)([O:3]CC)=O.C(OC/C=C/CO)[C:16]1[CH:21]=[CH:20]C=[CH:18][CH:17]=1.C(OO)(C)(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].C(OCC)C>[CH2:13]([O:12][CH2:10][C@@H:8]1[O:9][C@H:6]1[CH2:1][OH:3])[C:14]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: OC/C=C/COCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: OC[C@@H]1O[C@H]1COCc1ccccc1
Temperature: -23 °C
Reaction time: 8 h

Procedure:
3.3 g of molecular sieve (powder, 3A) was suspended in 190 ml of dry dichloromethane, and 4.2 ml of isopropyl orthotitanate and 2.9 ml of diethyl L(+)-tartrate were added thereto at -23° C. under stirring. The mixture was stirred at the same temperature for 15 minutes. Then, 3 ml of a dry dichloromethane solution of 4.7 g of (E)-4-benzyloxy-2-buten-1-ol was added thereto, and the mixture was stirred at the same temperature for 5 minutes. 11 ml of tert-butylhydroperoxide (a 5.17M dichloromethane solution) was added thereto, and the mixture was stirred for further 7 hours. Then, the reaction mixture was left to stand at -23° C. overnight. 190 ml of diethyl ether and 4.2 ml of a saturated sodium sulfate aqueous solution were added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. Insolubles were removed by filtration, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 240 ml of diethyl ether. 42 ml of a 1N sodium hydroxide aqueous solution was added thereto at 0° C. under stirring, and the mixture was stirred at 0° C. for 30 minutes. The ether layer was washed sequentially with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to obtain 2.9 g of (2S, 3S)-4-benzyloxy-2,3-epoxy-1-butanol as colorless oily substance.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=[S:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2c(c3cccnc3n1-c1ccccc1)OCC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=c1c2c(c3cccnc3n1-c1ccccc1)OCC2

Procedure:
A suspension of 3,5-dihydro-5-phenyl-furo-[3,2-c][1,8]naphthyridin-4(2H)-one (3 g.) and 2,4-bis- (4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent; 5 g.) in dry toluene (100 ml.) was stirred in an atmosphere of nitrogen and heated to reflux for 6 hrs. After cooling, the organic layer was washed with water, dried and evaporated. The product was purified by chromatography over silica gel in CH2Cl2 containing increasing amounts of ethyl acetate (0-5%). The fractions containing pure product were combined, evaporated, suspended in ethanol, filtered and dried to yield the desired product, m.p. 242°-244.5° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](C)=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClCl.Cl=O.[Cl-].[C:17]([Cl:21])(Cl)([Cl:19])[Cl:18]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:17]([Cl:21])([Cl:19])[Cl:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: ClCl
Agent: [Cl-]
Product: CS(=O)(=O)c1ccc(C(Cl)(Cl)Cl)cc1

Procedure:
Methyl p-tolylsulfone (100 g, 0.59 mole), carbon tetrachloride (1500 ml) and mercuric oxide (211 g) were added to a 3-necked flask equipped with a mechanical stirrer, gas inlet, dry-ice condenser and thermometer. The mixture was stirred and maintained at 50°-60° while adding chlorine gas (scrubbed through sulfuric acid) at a rate of approximately 1600 cc/min for 35 minutes (155 g). At this point chlorine monoxide started refluxing and chloride addition was discontinued. The mixture was stirred and heated for a total of 7 hours and additional chlorine (65 g) and mercuric oxide (100 g) were added as needed to complete the reaction which can be readily monitored by N-nmr.