Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:4].[CH:19]([NH2:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:22][CH:19]([CH3:21])[CH3:20])=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)N
Reactant: COC(=O)NC=Cc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: COC(=O)NC=Cc1ccc(OCC(O)CNC(C)C)cc1

Procedure:
9.4 g (0.038 mol) of 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane are dissolved in 200 ml of isopropanol, 3.25 ml (0.038 mol) of isopropylamine are added and thereafter the mixture is heated to the boil for 3 hours, under a reflux condenser. It is then evaporated in vacuo and the resulting crude base is crystallised from acetoneether. 1-[p-(2-Methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylamino-propane of melting point 128°-129°C is obtained.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:34])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:34][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:14]=[C:13]2[CH:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=2)(=[O:22])=[O:23])[CH2:19][CH2:20]1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cccc(S(C)(=O)=O)c3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cccc(S(=O)(=O)N2CCC(c3cc(CC(=O)O)cc4ccc(F)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
To a stirred solution of {6-fluoro-4-[1-(3-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (115 mg, 0.22 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (46 mg, 1.1 mmol) in water (1.5 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {6-fluoro-4-[1-(3-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (90 mg, 80%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (br s, 1H), 8.34 (d, J=7.8 Hz, 1H), 8.23 (s, 1H), 8.18 (d, J=7.8 Hz, 1H), 7.98-8.04 (m, 1H), 7.95 (dd, J=9.3, 6.4 Hz, 1H), 7.86 (d, J=12.7 Hz, 1H), 7.69 (s, 1H), 7.35-7.41 (m, 2H), 3.87 (d, J=10.3 Hz, 2H), 3.71 (s, 2H), 3.39 (s, 3H), 2.66 (d, J=10.3 Hz, 2H), 1.89-1.96 (m, 2H), 1.73-1.83 (m, 1H); MS cald. for C24H25FNO6S2 [(M−H)−]: 506, obsd. 506.2.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46]O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[I:50]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][I:50])[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: II
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CI)c3)c2)c1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-yl]methyl}-N′-{[6-fluoro-3′-(hydroxymethyl)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (0.0997 g, 0.15 mmol) in DCM (1.0 mL) was added iodine (0.0381 g, 0.15 mmol), and PS-PPh3 (0.0818 g, 0.18 mmol). This mixture was stirred at room temperature for 28 h, filtered and concentrated to afford N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[6-fluoro-3′-(iodomethyl)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide which was carried on to the next step of the reaction directly.
Reaction SMILES: [P].[Br:2]Br.[CH3:4][CH:5]([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7]>>[Br:2][C:5]([CH3:4])([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7]
Reactant: CC(C(=O)O)C(=O)O
Reactant: BrBr
Agent: [P]
Product: CC(Br)(C(=O)O)C(=O)O

Procedure:
Phosphorus and Bromine is added into dry 2-methylmalonic acid according to the procedure of Braun, in Berichte 42, p. 839 (1909) to form 2-Bromo-2-methyl malonic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[NH:28]1[CH2:35][CH2:34][CH2:33][C@@H:29]1[C:30]([OH:32])=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][N:28]1[CH2:35][CH2:34][CH2:33][C@@H:29]1[C:30]([OH:32])=[O:31]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=C(O)[C@H]1CCCN1
Product: O=C(O)[C@H]1CCCN1Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (96.1 mg, 0.257 mmol) and D-(+)-proline (88.6 mg, 0.770 mmol) according to Reference R and the general procedure for reductive amination to give (R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)pyrrolidine-2-carboxylic acid as a light yellow solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.2 (M++1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26](Cl)[C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[O:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:15][CH2:14]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(C(Cl)c2ccsc2)cc1
Reactant: OCCN1CCN(CCCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Fc1ccc(C(OCCN2CCN(CCCc3ccccc3)CC2)c2ccsc2)cc1

Procedure:
A mixture of 1.1 g (0.0044 mol) 4-(3-phenylpropyl)-1-piperazine-ethanol, 1.0 g (0.0044 mol)(4-fluorophenyl)-(3-thienyl)methyl chloride (as prepared in step A), 1.22 g (0.0088 mol) potassium carbonate and 50 ml toluene was stirred and heated to reflux for 16 h. The reaction mixture was cooled, diluted with toluene and washed with water. The toluene layer was then extracted with 10% tartaric acid. The aqueous phase was separated and rendered basic by addition of 4N sodium hydroxide in excess and extracted with toluene. Evaporation gave the crude product as an oil, which was purified on a silica column (eluent was toluene/ethanol 2:1). The pure fraction was evaporated, redissolved in diethyl ether and treated with a solution of hydrogen chloride in ether. The precipitate was filtered off and recrystallized from isopropanol. The yield was 0.265 g (=12%) of the title compound as the dihydrochloride. M.p. 212°-15° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[CH3:12][C:13]1[O:14][C:15]([CH3:21])=[CH:16][C:17]=1[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[CH3:8][C:6]1([CH3:9])[CH2:7][CH:2]([NH:1][C:18]([C:17]2[CH:16]=[C:15]([CH3:21])[O:14][C:13]=2[CH3:12])=[O:19])[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5]1
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)NC2CC(C)(C)NC(C)(C)C2)c(C)o1

Procedure:
156 g (1 mole) of 4-amino-2,2,6,6-tetramethylpiperidine and 79 g (0.5 mole) of 2,5-dimethylfuran-3-carbonyl chloride in 1 l of toluene are refluxed for 24 hours, after which the precipitate is filtered off, the toluene solution is extracted by shaking with NaHCO3 solution and water, and is dried and evaporated down, and the residue is recrystallized from cyclohexane to give a product of melting point 116°-118° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH2:54])[CH3:50]>CN(C=O)C.O>[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH:54][C:12]([C:11]1[CH:10]=[N:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1)=[O:14])[CH3:50]
Reactant: O=C(O)c1ccc(Nc2ccccc2)nc1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)nc1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred solution of 6-phenylamino-nicotinic acid (0.1 g, 0.00047 mol) in DMF (2 mL), was added DIPEA (0.181 g, 0.001401 mol), HOBt (0.0756 g, 0.00056 mol) and EDCI.HCl (0.107 g, 0.00056 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.0782 g, 0.00056 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.135 g (97%) of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid ethyl ester. LCMS: 299.13 (M+1)+, 99%. To a stirred solution of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid ethyl ester (0.135 g, 0.00045 mol) in a mixture of THF (5 mL), methanol (7 mL) and H2O (2 mL) was added LiOH.H2O (0.0568 g, 0.00135 mol) at ambient temperature and the resulting mixture was stirred for 2 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.078 g (64%) of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[CH2:23][C:24]([OH:26])=[O:25])=[CH:4][CH:3]=1.[CH2:29](O)[CH3:30]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[CH2:23][C:24]([O:26][CH2:29][CH3:30])=[O:25])=[CH:27][CH:28]=1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c1nc(CC(=O)O)n2Cc1ccc(Cl)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1nc2c(c(=O)n(CCCO)c(=O)n2C)n1Cc1ccc(Cl)cc1
Yield: 40 %

Procedure:
Step 3 Crude 2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)acetic acid (0.14 g, 0.36 mmol) was dissolved in ethanol (5 mL) and concentrated sulfuric acid (1 drop). The reaction was heated at reflux for 1 h. The reaction was cooled, evaporated under reduced pressure to remove the ethanol then diluted with water (50 mL) and extracted with ethyl acetate (3×40 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to a light golden oil. The oil was purified using a 12 g silica gel flash column and eluted with 20% ethyl acetate/hexanes to give ethyl 2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)acetate (0.062, 40% yield) as a light tan solid. LCMS retention time=2.804 min and 99% purity, LCMS MH+ 435. 1H NMR (CDCl3) δ 7.21 (dd, 4H, J=8 Hz and 84 Hz), 5.57 (s, 2H), 4.11-4.23 (m, 4H), 3.77 (s, 2H), 3.59 (s, 3H), 3.50-3.56 (m, 2H), 3.32-3.39 (m, 1H), 1.86-1.94 (m, 2H), 1.25 (t, 3H, J=8 Hz).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].N1C=CN=C1.[CH2:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCC>[CH:1]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[O:23][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])[CH3:2]
Reactant: CCCCCCO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: CCCCCCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 250 ml, three-necked flask was fitted with a large magnetic, egg-shaped stir bar, a small, pressure-equalizing addition funnel, a thermocouple connected to a THERM-O-WATCH®, a reflux condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 32.46 grams (0.168 mole, 1.01 equivalents) of triisopropylsilyl chloride, 11.69 grams (0.172 mole, 1.03 equivalents) of imidazole, and 100 mls of hexane. 1-Hexanol, 17.03 grams (0.167 mole, 1.00 equivalent), was then added dropwise to the resultant slurry. A very mild exotherm was detected. The total feed time was five minutes. A heavy, white precipitate formed after a few more minutes stirring. The reaction mixture became very hard to stir. Therefore, an additional 25 mls of hexane was added to the reaction. The progress of the reaction was monitored by gas chromatography (GC). An aliquot of the clear supernatant was injected into the GC. The sample at 2.33 hours indicated the conversion to the desired product was 73.0%. The reaction mixture was heated to 40° C. with a heating mantle, controlled by the THERM-O-WATCH®. After stirring overnight at 40° C., the conversion had increased to 87.2%. The temperature was increased to 60° C. After seven hours at 60° C., the conversion was 90.0%. The reaction mixture was heated to reflux overnight, under a blanket of argon. The temperature was decreased to 60° C., and the reaction was analyzed by GC. The conversion was 95.2%. The reaction mixture was held at 60° C. for an additional seven hours, then the reaction mixture was allowed to stir at room temperature over the weekend. The conversion had reached 98.1%. The reaction mixture was transferred to a small, dry, Chemglass pressure filter. The tiltrate was collected in a dry, 500 ml flask. The filter cake was rinsed with additional hexane (2×100 ml). The solvent was removed on the rotary evaporator, with the bath temperature set at 40° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)nc23)CC1
Yield: 73.4 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.058 mMol) 4-trifluoromethylbenzoyl chloride, 0.013 gm (73%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: Br[C:2]1[C:3]([CH3:26])=[N:4][C:5]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:6][CH:7]=1.[Cu](C#N)[C:28]#[N:29].CN1CCCC1=O>C(OCC)(=O)C>[CH3:26][C:3]1[N:4]=[C:5]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:15])([F:14])[F:16])[CH2:9]2)[CH:6]=[CH:7][C:2]=1[C:28]#[N:29]
Reactant: Cc1nc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1nc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C#N
Temperature: 200 °C
Yield: 45 %

Procedure:
3-Bromo-2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-pyridine (3.3 g) and copper cyanide (I) (0.65 g) were added to N-methyl-2-pyrrolidinone (10 ml). The mixture was heated for 4 hours at 200° C. using a microwave reactor (trade name: INITIATOR™, manufactured by Biotage). Upon the completion of the reaction, the reaction mixture was diluted with ethyl acetate and the precipitate was filtered off through a short silica gel layer. The filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]nicotinonitrile (1.1 g).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH2:10][O:11][CH:12]([C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1(P([CH:46]2[CH2:51][CH2:50]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:50]1([C:2]2[CH:9]=[C:8]([CH2:10][O:11][CH:12]([C:17]3[S:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[N:19][C:18]=3[CH3:32])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:51][CH2:46]1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(OCc1ccc(C#N)c(Br)c1)C(F)(F)F
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)C1CC1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(OCc1ccc(C#N)c(C2CC2)c1)C(F)(F)F
Temperature: 10 °C
Yield: 365.3 %

Procedure:
147 mg 2-Bromo-4-{2,2,2-trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile, 15 mg Tricyclohexylphosphine, 71 mg Cyclopropylboronic acid and 224 mg Tripotassiumphosphate monohydrate were dissolved in a mixture of 2 ml toluene and 0.2 ml water. The reaction mixture was degassed and 62 mg palladium(II) acetate were added and the reaction mixture heated under microwave irradiation at 10° C. for 2.5 hours. The cooled reaction mixture was diluted by addition of 50 ml ethyl acetate and filtered. The filtrate was evaporated and the residue purified by reverse phase HPLC to obtain 97 mg 2-Cyclopropyl-4-{2,2,2-trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[F:55]C1C=C(C=CC=1)C[Zn+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([F:55])[CH:29]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(C[Zn+])c1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Cl-]
Product: Fc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Yield: 32 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (3-fluorobenzyl)zinc(II) chloride in 32% yield.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=O)[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[CH3:51][O:52][CH2:53][CH2:54][NH2:55]>CO>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]/[C:16](=[N:55]\[CH2:54][CH2:53][O:52][CH3:51])/[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: COCCN
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Solvent: CO
Product: COCC/N=C1\C=C(N[C@H]2O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]2OC)C(=O)c2cc3c(c(O)c21)C(=O)[C@]1(OC)[C@H](O)Cc2cc(C)c(C(=O)OC)c(O)c2[C@]1(O)C3=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in methanol (3 mL) was added 2-methoxyethanamine (107 mg, 1.43 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 h. The reaction was quenched by adding saturated ammonium chloride solution (15 mL). Then it was extracted with chloroform (75 mL) and washed with water (2×25 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-9-(2-methoxyethylimino)-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (33.8 mg, 31.2%) as a dark blue solid: 1H NMR (500 MHz, CDCl3) δ 11.95 (s, 1H), 7.93 (s, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.49 (s, 1H), 6.05 (s, 1H), 5.27 (s, 1H), 4.99 (t, J=8.0 Hz, 1H), 4.74-4.69 (m, 2H), 3.83 (s, 4H), 3.79 (s, 4H), 3.72-3.69 (m, 4H), 3.65-3.59 (m, 4H), 3.57-3.55 (m, 1H), 3.40 (s, 3H), 3.37 (s, 3H), 3.14 (t, J=9.1 Hz, 1H), 2.48 (d, J=3.8 Hz, 1H), 2.37 (s, 3H), 1.58 (br s, 1H), 1.37 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 755 (M+H); HPLC 88.9% (AUC), tR=11.14 min.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[N:21]1([C:27]2[CH:36]=[N:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)(C)C>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:24]2[CH2:25][CH2:26][N:21]([C:27]3[CH:36]=[N:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[CH2:22][CH2:23]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)O[C@H](C)c1nccc(N2CCN(c3cnc4ccccc4n3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 7.3 g, 36.2 mmol) in isopropanol (240 mL) was added triethylamine (10.1 mL, 72.4 mmol) followed by 2-(1-piperazinyl)quinoxaline (10.1 g, 47.1 mmol; J. Med. Chem. 1981, 24, 93). This mixture was stirred at room temperature overnight then concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (5×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanol/chloroform) to give 12.4 g (91%) of the title compound of Example 1, Step A as a yellow foam. 1H NMR (CDCl3, 250 MHz) δ 8.61 (s, 1H), 8.27 (d, 1H), 7.91 (dd, 1H), 7.72 (dd, 1H), 7.61 (td, 1H), 7.44 (td, 1H), 6.43 (d, 1H), 5.70 (q, 1H), 3.96-3.84 (c, 8H), 2.18 (s, 3H), 1.61 (d, 3H); MS (CI/NH3) 379 (MH+).