Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1)(=O)=O.Cl.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([C:34]2[S:44][C:43]3[N:45]4[C:36](=[CH:37][N:38]=[C:39]4[CH:40]=[CH:41][CH:42]=3)[CH:35]=2)=[O:33])[CH2:27][CH2:26]1.C(N(CC)CC)C.[I-].[Na+].N12CCCNC1CCCC=C2>C(#N)C>[C:19]([O:18][C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:25]2[CH2:26][CH2:27][CH:28]([NH:31][C:32]([C:34]3[S:44][C:43]4[N:45]5[C:36](=[CH:37][N:38]=[C:39]5[CH:40]=[CH:41][CH:42]=4)[CH:35]=3)=[O:33])[CH2:29][CH2:30]2)=[CH:14][CH:13]=1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCOS(C)(=O)=O)cc1
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: C1=CN2CCCNC2CCC1
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(CCCN2CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC2)cc1
Yield: 61.3 %

Procedure:
3-(4-tert-Butoxycarbonylaminophenyl)propyl methanesulfonate (423 mg, 1.28 mmol) was added to a stirred solution of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (400 mg, 1.07 mmol), triethylamine (539 mg, 5.33 mmol), sodium iodide (192 mg, 1.28 mmol) and 1,8-diazabicyclo[5.4.0]undecene (326 mg, 2.14 mmol) in acetonitrile (20 ml) at room temperature. After refluxing under nitrogen for 1 day, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (20 g) with Ethyl acetate-Methanol (3:1) to give N-[1-[3-(4-tert-butoxycarbonylaminophenyl)propan-1-yl]piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide as purple amorphous powder (350 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([C:27]#[N:28])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:33]([NH2:36])([CH3:35])[CH3:34]>C(#N)C.O>[CH:33]([NH:36][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:29]([F:30])([F:31])[F:32])[CH:11]=2)=[O:22])=[C:16]([C:27]#[N:28])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:35])[CH3:34]
Reactant: N#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: O
Solvent: CC#N
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C#N)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 600 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-9-oxo-1,9-dihydro-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalene-5-carbonitrile in 5 mL of acetonitrile/water (4:1, v/v) is added 1.1 mL (12.9 mmol) of isopropylamine. The reaction mixture is stirred during 4 hours at ambient temperature and then concentrated in vacuo. After purification by flash chromatography (SiO2, hexanes/ethyl acetate 4:1), 250 mg (38%) of a white solid are obtained; LC/MS:518/520 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[C:11][CH2:12][OH:13])=[CH:9][C:4]=2[O:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[C:11][CH:12]=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCC#Cc1ccc2c(c1)OCO2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=CC#Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 51.6 %

Procedure:
To a solution of 3-(1,3-benzodioxol-5-yl)prop-2-yn-1-ol (242 mg, 1.37 mmol, obtained as described in Nugent et al., 1987, J. Am. Chem. Soc., 109, 2788) in anhydrous DCM (12 mL) was added MnO2 (2.70 g, 31.1 mmol) portion wise over 2 h. The resulting mixture was stirred at rt for one additional hour, then filtered on a bed of Celite and the filtrates were evaporated under reduced pressure to give 123 mg (51%) of the title compound as a brown solid. HPLC, Rt: 2.76 min (purity: 98.9%). 1H NMR (CDCl3) δ: 9.37 (s, 1H), 7.18 (m, 1H), 7.00 (m, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.03 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:14]([OH:29])[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)=O)(C)(C)C>Cl>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C@H:15]([NH:25][C:26](=[O:28])[CH3:27])[C@H:14]([OH:29])[C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCCN1
Reaction time: 1 h

Procedure:
Dissolve (R)-2-[(1S,2S)-2-Acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-piperidine-1-carboxylic acid tert-butyl ester (0.085 g, 0.21 mmol) in hydrogen chloride (4 M in 1,4-dioxane, 3 mL). Stir 1 h and concentrate to give the title compound as a foam 10 (0.077 g, 100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]2.[C:20](=N)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.CCOC(C)=O>[C:20](=[N:1][CH2:2][C:3]1[C:4]([Cl:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH:7]=[CH:6]2)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN)ccc21
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN=C(c3ccccc3)c3ccccc3)ccc21
Temperature: 40 °C
Reaction time: 96 h
Yield: 67.1 %

Procedure:
A mixture of tert-butyl 5-(aminomethyl)-4-chloro-1H-indole-1-carboxylate (1.147 g, 4.087 mmol) and benzophenone imine (0.75 mL, 4.496 mmol) in anhydrous DCM (39.3 mL) was stirred at 40° C. under N2 for 4 d. The reaction mixture was diluted with EtOAc, and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with and EtOAc/heptane gradient (0 to 70% EtOAc) to afford 1.22 g (67%) of tert-butyl 5-[(benzhydrylideneamino)methyl]-4-chloro-1H-indole-1-carboxylate (322) as an oil: 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.5 Hz, 1H), 7.82-7.77 (m, 1H), 7.69 (d, J=7.2 Hz, 2H), 7.60-7.56 (m, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.9 Hz, 2H), 7.37 (d, J=7.0 Hz, 1H), 7.33 (t, J=7.3 Hz, 2H), 7.25-7.20 (m, 2H), 6.66 (d, J=3.7 Hz, 1H), 4.75 (s, 2H), 1.66 (s, 9H); MS (ESI) m/z=445.2 [M+1]+.
Reaction SMILES: [H][H].[CH3:3][CH:4]([C:7]([CH3:12])([CH3:11])[CH2:8][C:9]#[N:10])[C:5]#[N:6].N>C(O)C>[CH3:3][CH:4]([C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][NH2:10])[CH2:5][NH2:6]
Reactant: [H][H]
Reactant: CC(C#N)C(C)(C)CC#N
Agent: N
Solvent: CCO
Product: CC(CN)C(C)(C)CCN
Temperature: 105 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
After scavenging with nitrogen and then with hydrogen, commercial hydrogen is introduced under a pressure of 170 atm and then the autoclave is heated to about 105° C. for six hours. Thereafter the autoclave is cooled, the pressure is released and the autoclave is charged with a solution of 68 grams of 2,3,3-trimethylglutaronitrile dissolved in 30 mls abs. ethanol, the scavenging with nitrogen is repeated, there are charged 160 grams of anhydrous ammonia and finally commercial hydrogen is introduced under a pressure of 165 atm approx. The autoclave, which is fitted with a magnetic stirrer, is heated to about 105° C.-108° C. the hydrogen pressure being restored as hydrogen is gradually being absorbed. After about 2 hrs. the pressure does not decrease any more and the above specified temperature is maintained for three additional hours, whereafter the autoclave is allowed to cool. The catalyst is filtered off, the solvent is distilled off and, on the raw production of the reaction, the yield in terms of 2,3,3-trimethyl pentamethylene diamine is determined by gaschromatographic methods in the presence of an internal standard (yield 65%-70%). The diamine is then purified by fractionation and, under a pressure of about 12 Torr. it boils at 105° C.-106° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[O:14]C=[N:12][C:11]=3C(OC)=O)[CH:8]=[CH:9][C:2]1=2.[ClH:19]>CO.O1CCCC1>[ClH:19].[NH2:12][CH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:2]2[O:1][CH:5]=[CH:4][C:3]=2[CH:6]=1)=[O:14]
Reactant: COC(=O)c1ncoc1-c1ccc2occc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCC(=O)c1ccc2occc2c1
Reaction time: 8 h

Procedure:
To a solution of the crude product of methyl 5-(5-benzo[b]furyl)oxazol-4-carboxylate (1.14 g) in methanol (20 ml) and tetrahydrofuran (5 ml) was added conc. hydrochloric acid (8 ml), and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with methanol-diethyl ether-acetone to obtain 5-(aminoacetyl)benzo[b]furan hydrochloride (600 mg).
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5](C(O)=O)([CH2:6]3)[CH2:4]2.OS(O)(=O)=O.[N-:20]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH2:20])([CH2:6]3)[CH2:4]2
Reactant: [N-]=[N+]=[N-]
Reactant: COC12CC3CC(C1)C(C(=O)O)(C3)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC12CC3CC(C1)C(N)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To the suspension of 1-methoxytricyclo[3.3.1.03,7]nonane-3-carboxylic acid obtained from step IV (0.39 g, 2.0 mmol) in CHCl3 (10 mL) was added conc. H2SO4 (1.0 mL, 20 mmol). Solid NaN3 (0.39 g, 6.0 mmol) was added in portions by keeping the reaction temperature below 40° C. After stirring at room temperature for 2 hrs, the reaction mixture was cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-methoxytricyclo[3.3.1.03,7]nonan-3-amine (0.23 g) in 69% yield. m/z (M+1) 168; 1H NMR (CDCl3) 300 MHz δ 3.27 (s, 3H), 2.40-2.34 (m, 1H), 2.16-2.08 (m, 1H), 1.97 (ddd, J=2.0, 6.8, 8.7 Hz, 1H), 1.92-1.53 (m, 7H), 1.51-1.38 (m, 2H).
Reaction SMILES: N[C@@H]1CCN([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)C1.[CH3:25][C@@:26]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[OH:31][C@:26]1([CH3:25])[CH2:30][CH2:29][N:28]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:27]1
Reactant: C[C@@]1(O)CCNC1
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](N)C3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@]1(O)CCN(CCCOc2ccc(-c3ccc(C#N)cc3)cc2)C1
Yield: 40 %

Procedure:
4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile (177 mg, 0.65 mmol), (3R)-3-methyl-3-pyrrolidinol (75 mg, 0.74 mmol), potassium carbonate (153 mg) and potassium iodide (184 mg) in 10 mL of DMF were heated at 110° C. for 10 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (40% yield).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=3)=[N:25][CH:26]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:47]C=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:36]=[CH:35][C:31]([C:32]([NH2:47])=[O:34])=[CH:30][CH:29]=3)=[N:25][CH:26]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(Oc3ccc(C(=O)O)cc3)nc2)c1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(Oc3ccc(C(N)=O)cc3)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Ammonium chloride (39 mg, 0.733 mmol) was added to a stirred solution of 4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]oxy}benzoic acid (114 mg, 0.244 mmol), EDC (94 mg, 0.489 mmol), HOBt (99 mg, 0.733 mmol), and diisopropylethyl amine (0.256 mL, 1.47 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 hours, diluted with water and extracted with ethyl acetate (3×). The combined organics were washed with saturated sodium bicarbonate and then brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]oxy}benzamide (89 mg, 0.191 mmol) as a white solid. MS ESI calc'd for C24H19F3N5O3 [M+H]+ 466. found 466. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.81 (d, J=5.0 Hz, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.08 (dd, J=8.8, 1.8 Hz, 1H), 7.96 (s, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.89 (s, 1H), 7.53 (s, 1H), 7.34 (s, 1H), 7.26 (d, J=4.5 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.5 Hz, 1H), 7.15 (s, 1H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:8][C:9]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][CH:11]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccccc1
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccccc1
Temperature: 120 °C

Procedure:
The mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-phenyl-propionic acid methyl ester (0.31 g, 1.0 mmol) (from Example 5a supra) and aniline (3.0 mL) (Aldrich) was heated at 120° C. for 1 hour. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel) to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-phenyl-propionic acid methyl ester as a white amorphous solid. (Yield 0.35 g, 82.3%).
Reaction SMILES: O=O.[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]>>[CH2:5]([OH:6])[C@@H:4]([OH:3])[CH:4]([OH:3])[C@H:5]([OH:6])[CH2:7][OH:8]
Reactant: OCC(O)CO
Agent: O=O
Product: OC[C@@H](O)C(O)[C@H](O)CO
Yield: 60 %

Procedure:
The following results were performed in a 2 L fermenter with 1 L working volume. In these fermentation runs, glycerol was used as carbon source. Low dissolved oxygen concentrations of 5% showed about 60% yield of arabitol based on total glycerol consumed. More aerobic conditions with dissolved oxygen concentrations above 5% were also good for cell growth rate and 5% dissolved oxygen was good for arabitol production. FIG. 9 shows total arabitol yield for 5, 10, and 20% dissolved oxygen concentrations.
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[C:25]1(=[O:39])[N:29]([CH2:30][CH2:31][C:32]#[CH:33])[C:28](=[O:34])[C:27]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:26]12>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]1(=[O:34])[N:29]([CH2:30][CH2:31][C:32]#[C:33][C:2]2[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=2)[C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:25](=[O:39])[C:26]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:27]12
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 78.8 %

Procedure:
5-Iodo-2'-deoxyuridine (354 mg, 1 mmol) was dissolved in 10 mL of dimethylformamide. Cuprous iodide (76 mg, 0.4 mmol), tetrakis (triphenylphosphine) palladium (0) (230 mg, 0.2 mmol), and triethylamine (200 mg, 2.0 mmol) were added. 4-Phthalimidobut-1-yn (300 mg, 1.5 mmol) was added all at once and the reaction kept at 60° C. for three hours. The clear yellow reaction was then evaporated and methylene chloride was added. Scratching of the flask induced crystallization of nearly all of the product which was filtered and recrystallized from 95% ethanol to give 335 mg (78%) of title compound as fine, feathery needles.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]([CH3:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.O>[Br:28][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]([CH3:20])([C:16]([F:19])([F:17])[F:18])[C:12]([F:13])([F:14])[F:15])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)CC(C)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(CS(=O)c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To 1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl)-benzene (4.13 g, 13.0 mmol) in carbon tetrachloride (50 mL) add NBS (2.31 g, 13.0 mmol), benzoyl peroxide (314 mg, 1.30 mmol) and stir overnight at reflux. Cool to ambient temperature, dilute with water and extract three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the title compound as colorless oil (2.3 g, 55%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:13][CH:14]1[O:18][N:17]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]1.C(N(CC)CC)C>ClCCl>[CH3:26][C:24]([CH3:25])([CH3:27])[C:12](=[O:11])[CH2:13][CH:14]1[O:18][N:17]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]1
Reactant: CCOC(=O)C1=NOC(CC(O)C(C)(C)C)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C1=NOC(CC(=O)C(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A solution of DMSO (3.94 mL, 55.6 mmol) in dichloromethane (90 mL) at −78° C. was treated dropwise with oxalyl chloride (20.8 mL, 2 M in dichloromethane), stirred at −78° C. for 15 minutes, treated with a solution of the product from Example 115B (6.76 g, 27.8 mmol) in dichloromethane (230 mL) over 10 minutes, stirred at −78° C. for 20 minutes, treated dropwise with triethylamine (16.7 mL, 119.5 mmol) at −78° C., and after 10 minutes the reaction was warmed to 0° C., and stirred for an additional 10 minutes. The reaction mixture was quenched with water and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 5% ethyl acetate in chloroform to give the title compound (4.9 g, 73% yield).
Reaction SMILES: BrC(Br)[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.O.C[C:18](C)=[O:19]>>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:3][CH:4]=2)[C:9]=1[CH:18]=[O:19]
Reactant: COc1ccc2cc(C(Br)Br)ccc2c1
Reactant: CC(C)=O
Solvent: O
Product: COc1ccc2ccccc2c1C=O
Temperature: 24 °C
Reaction time: 10 h

Procedure:
A solution of 2-dibromomethyl-6-methoxynaphthalene (3 g) in acetone (25 ml) was treated with water (7 ml) and the mixture stirred at 24° C. for 10 hours. The solvent was removed under vacuum and the residue dissolved in toluene (30 ml). The toluene solution was washed with saturated sodium bicarbonate solution (2×10 ml) and water (10 ml) and dried over MgSO4. The dried solution was filtered and the filtrate evaporated down to a yellowish-brown semi-solid. This was recrystallised twice from isopropanol (2×10 ml) to give 0.5 g of pure 2-methoxynaphthaldehyde as confirmed using HPLC (conditions; spheresorb C18 25 cm×4.5 mm i.d. (column), 65% acetonitrile/35% water (eluent), 1 ml/min (flowrate), 310 nm (wavelength). The samples were dissolved in acetonitrile and 20 μl injected onto the column. The retention time for 2-methoxynaphthaldehyde was about 6 minutes.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:18]
Reactant: CCO
Reactant: Oc1ccc2ccccc2c1
Agent: O=S(=O)(O)O
Product: CCOc1ccc2ccccc2c1

Procedure:
450 g of β-naphthol, 200 ml of ethanol and 50 ml of 98% sulfuric acid were mixed and after finishing the generation of heat the mixture was heated on a steam bath for 4 hours. After allowing to stand and cool, the lower layer was removed. Then the procedures wherein to the residue were added 40 ml of ethanol and 20 ml of 98% sulfuric acid, the mixture was heated on a steam bath for 3 hours and the lower layer was removed after allowing to stand and cool were repeated three times. The organic layer was washed with water to which was added an aqueous solution of sodium hydroxide (40 g of sodium hydroxide dissolved in 1 liter of water) and the mixture was warmed and shaked. While it was warm, the lower layer was removed, the upper layer was poured into an aqueous solution of sodium hydroxide and cooled to solidified. The solid was collected by filtration, washed with water and air-dried. Yield: 461 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH:15]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1ccc(C(CN2CCNCC2)c2ccc(Cl)cc2)cc1

Procedure:
4-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester was treated with HCl in ethyl acetate (saturated, 5 ml) for 1 hour, solvent removed under reduced pressure to afford the title compound as the HCl salt
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19]CC)=O)[C:9]2=[O:27])=[CH:5][CH:4]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:9](=[O:27])[C:10]3[N:14]=[CH:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([OH:19])[C:11]=3[CH:12]=[CH:13]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=CNc1cccn(Cc2ccc(OC)cc2)c1=O)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(=O)n(Cc3ccc(OC)cc3)ccc2c1O
Reaction time: 0.5 h

Procedure:
Dowtherm A (50 ml) was heated to 250° C. in a 500 ml a 3-neck rbf equipped with a temperature probe, a stir bar and a reflux condenser. Diethyl 2-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (5.00 g, 12.5 mmol) was added in one portion. The mixture was stirred for 30 mins and then was rapidly cooled down using a stream of nitrogen. At around 140° C., a solid started to crash out. Once at RT, the mixture was diluted with hexanes (100 ml) and was allowed to stand overnight. The precipitate that formed was collected by suction filtration, washed with ether and dried to give ethyl 7-(4-methoxybenzyl)-4-hydroxy-8-oxo-7,8-dihydro-1,7-naphthyridine-3-carboxylate as a yellow solid. MS (M+H)+ 355.