Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][O:16][CH2:17][CH2:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH2:18][CH2:17][O:16][CH3:15])(=[O:21])=[O:20])=[CH:30][CH:29]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: COCCS(=O)(=O)c1ccc(C(=O)O)cc1
Product: COCCS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
A mixture of 500 mg of methyl 4-mercaptobenzoate, 1.6 g of potassium carbonate, 1.2 g of 2-bromoethylmethylether and 329 mg of tetrabutylammonium iodide in 10 mL of acetone was refluxed for 16 h. The reaction mixture was diluted with ethyl acetate, washed with H2O and concentrated. Purified by silica gel chromatography (0-50% ethyl acetate/hexane) to yield 4-(2-methoxyethylthio)benzoate. 240 mg of 4-(2-methoxyethylthio)benzoate was reacted via Procedure R to give 4-(2-methoxyethylsulfonyl)benzoate. 120 mg of 4-(2-methoxyethylsulfonyl)benzoate was hydrolyzed via Procedure M to yield 4-(2-methoxyethylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-methoxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-methoxyethylsulfonyl)benzamide. MS (Q1) 431.0 (M)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS([O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47]C[CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:45][CH2:44][N:43]4[CH2:42][CH2:41][O:40][CH2:47][CH2:48]4)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(O)cc3)nn3ccnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(OCCN4CCOCC4)cc3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 80.1 %

Procedure:
To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-yl)-6-(4-(2-morpholinoethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (40 mg, 80%). 1H NMR (300 MHz, CDCl3): δ 8.63 (s, 1H), 8.05-7.90 (m, 4 h), 7.57 (s, 1H), 7.42 (t, 1H, J=8.0 Hz), 7.04-7.01 (m, 2H), 6.22 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.30-4.19 (m, 3H), 3.80-3.77 (m, 4 h), 3.70-3.64 (m, 1H), 3.51-3.48 (m, 1H), 2.87 (t, 2H, J=5.7 Hz), 2.65-2.62 (m, 4 h), 2.17-2.05 (m, 3H), 1.78 (brs, 1H), 1.26 (d, 3H, J=6.3 Hz). LC/MS: 500 [M+H]+, tR=1.11 min. HPLC: 99.73% at 214 nm, 99.60% at 254 nm, tR=99.73% min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][NH:37][C:36](=[O:40])[CH:35]=1.C(Cl)CCl.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][NH:37][C:36](=[O:40])[CH:35]=4)=[O:26])[CH2:22][CH2:23]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCC(C(=O)O)CC3)nc3scnc23)cc1OC
Reactant: NCCc1cc[nH]c(=O)c1
Agent: Br
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(Nc2nc(N3CCC(C(=O)NCCc4cc[nH]c(=O)c4)CC3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
The mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-4-carboxylic acid (70 mg, 0.22 mmol), 4-(2-aminoethyl)pyridin-2(1H)-one hydrobromide (70 mg, 0.32 mmol), EDC (170 mg, 0.89 mmol) and 1-methyl-1H-imidazole (108 mg, 1.32 mmol) in 20 mL of DCM was stirred at room temperature overnight. Excess of DCM was removed under reduced pressure and the residue was triturated with H2O (30 mL) and EtOAc (20 mL) then dried under reduce pressure to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)piperidine-4-carboxamide (25 mg, 40%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.62 (s, 1H), 7.61 (d, 1H, J=2.4 Hz), 7.35 (d, 1H, J=7.2 Hz), 7.20 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 6.95 (d, 1H, J=8.7 Hz), 6.36-6.32 (m, 2H), 4.83-4.79 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.44 (t, 2H, J=6.8 Hz), 3.00-2.92 (m, 2H), 2.70 (t, 2H, J=6.8 Hz), 2.45 (brs, 1H), 1.80-1.64 (m, 4H). LC-MS: 536 [M+H]+, 534 [M−H]−, tR=1.38 min. HPLC: 95.70% at 214 nm, 96.10% at 254 nm, tR=3.65 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][N:6]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:10]([C:11]#[N:12])=[C:5]2[NH:4][CH2:3]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:30]>>[NH2:1][CH:2]1[CH2:7][N:6]2[N:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:17][CH:18]=3)[C:10]([C:11]([NH2:12])=[O:30])=[C:5]2[NH:4][CH2:3]1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(N)C2
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(N)C2

Procedure:
The desired product was prepared from 6-amino-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, DMSO-d6) 7.53-7.48 (m, 2H), 7.46-7.40 (m, 2H), 7.22-7.16 (m, 1H), 7.11-7.03 (m, 4H), 6.58 (br s, 1H), 4.15-4.08 (m, 1H), 3.72-3.67 (m, 1H), 3.40-3.30 (m, 2H) and 3.06-2.98 (m, 1H). MS (ESI) m/e [M+1]+ 350.2.
Reaction SMILES: C[Mg]I.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.Br[C:14]1[C:15](=[O:29])[NH:16][C:17](=[O:28])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>C(OCC)C.C1C=CC=CC=1>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]2[C:15](=[O:29])[NH:16][C:17](=[O:28])[C:18]=2[C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[CH:5]1
Reactant: O=C1NC(=O)C(c2ccc([N+](=O)[O-])cc2)=C1Br
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg]I
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1ccc([N+](=O)[O-])cc1
Yield: 0.9 %

Procedure:
1.4 ml of a 3M solution of methylmagnesium iodide in diethyl ether was added to a solution of 360 mg indole in 20 ml of benzene under nitrogen. After stirring at room temperature for 10 minutes 300 mg of 3-bromo-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione were added and the resulting mixture was heated to reflux for 4 days. After cooling the solution was evaporated and the residue was partitioned between dichloromethane and 2M hydrochloric acid. The organic phase was washed with water, dried and evaporated. The residue was purified on silica gel with dichloromethane and 1% methanol in dichloromethane and then with 20% methanol/water on Hypersil to give 3 mg of 3-(3-indolyl)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 125° C. (decomposition).
Reaction SMILES: I(O)(=O)(=O)=O.[F:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH:13]([F:15])[F:14])[C:8]=1[CH:16]=[O:17].[Cr](Cl)([O-])(=O)=[O:19].[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[F:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH:13]([F:14])[F:15])[C:8]=1[C:16]([OH:19])=[O:17]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: Cn1nc(C(F)F)c(C=O)c1F
Agent: [O-][I+3]([O-])([O-])O
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1nc(C(F)F)c(C(=O)O)c1F
Reaction time: 0.5 h

Procedure:
A suspension of 79.7 g (350 mmol) of periodic acid in 640 ml absolute acetonitrile was stirred for 30 min. To this was added 56.6 g (318 mmol) of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde at 0° C. and a solution of 1.4 g (6 mmol) of pyridinium chlorochromate in 130 ml dry acetonitrile. The reaction mixture was stirred for 2.5 hours at room temperature. 1600 ml of ethyl acetate was added to the reaction mixture and the separated organic phase was washed consecutively with brine/water(1:1), saturated sodium metabisulfite and brine. Then the organic phase was dried with sodium sulphate, and evaporated under vacuum to give the expected product as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:25][CH2:26][C:27]#[CH:28])=[N:22][CH:21]=[CH:20][CH:19]=2)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[C:27]([CH2:26][NH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][N:22]=4)[N:17]=[CH:16][C:15]=3[N+:12]([O-:14])=[O:13])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCNc1c([N+](=O)[O-])cnc2cccnc12
Reactant: ON=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Temperature: 40 °C
Reaction time: 18 h
Yield: 31.9 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (44.6 g, 257 mmol) was added to a mixture of 3-nitro-N-prop-2-ynyl[1,5]naphthyridin-4-amine (29.34 g, 129 mmol) and anhydrous triethylamine (39.5 mL, 283 mmol) in anhydrous dichloromethane (1 L). The reaction was stirred at 40° C. for 18 hours and then concentrated under reduced pressure. The residue was triturated with water; the resulting solid was isolated by filtration, washed sequentially with isopropanol and a small amount of diethyl ether, and then dried under vacuum to provide 15.02 g of N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitro[1,5]naphthyridin-4-amine as a brownish-green solid.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].Cl.Br[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>C(O)(=O)C>[N:28]1[CH:29]=[CH:30][C:25]([N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)=[CH:26][CH:27]=1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Reactant: Brc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(ccc3c2ccn3-c2ccncc2)n1
Temperature: 110 °C

Procedure:
A solution of 7.97 g. of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 500 ml. of dry dimethylformamide is stirred, under nitrogen, with 4.61 g. ca. 50% sodium hydride-mineral oil dispersion for 1.5 hours. Addition of 8.95 g. of p-bromopyridine hydrochloride is followed by heating of the reaction mixture at 110° C. for 5 hours. Glacial acetic acid (10 ml) is added and the solvent is removed in vacuo. The residue is stirred thoroughly with a mixture of excess aqueous potassium carbonate solution and 100 ml. of 1 N sodium hydroxide solution, collected, washed with water and dried. Three crystallizations from methanol and one from dimethylformamide and drying afford 0.61 g. of the title product, m.p. 328.5°-329.5° C., NMR (dDMSO): δ 7.16 (doublet, J=8 Hz, 5H), 7.22 (doublet, J=3 Hz, 9H), 7.88 (doublet, J=3 Hz, 8H), 7.96 (doublet, J=8 cps, 6H) p.p.m λmax95%EtOH 255 mμ (22,900) and 297 mμ (22,100).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH:12](OCC)[O:13]CC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)C>O1CCCC1>[C:1]([O:9][CH2:10][CH2:11][CH:12]=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CCOC(=O)c1ccccc1)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CCCOC(=O)c1ccccc1
Yield: 69.5 %

Procedure:
A solution of 57.0 grams (0.226 mole) of 3-ethoxy-4-oxahexyl benzoate in 475 ml of tetrahydrofuran and 475 ml of aqueous 10% hydrochloric acid was stirred at ambient temperature for 18 hours. After this time the reaction mixture was stirred with 700 ml of diethyl ether. The organic layer was separated, washed with water, and then was dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure yielding 28.0 grams of 3-oxopropyl benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]1([C:13]([F:16])([F:15])[F:14])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Br:19][C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([CH2:3][C:2]([F:1])([F:17])[F:18])([C:13]([F:15])([F:14])[F:16])[O:5][C:6]=2[CH:12]=1
Reactant: BrBr
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccc(Br)cc2O1

Procedure:
54.4 g of 2-(2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole were dissolved in 300 ml of carbon tetrachloride, and 0.4 g of anhydrous iron(III) chloride was added. 32 g of bromine were then added dropwise at the reflux temperature and the mixture was subsequently stirred until the reaction was complete (monitoring by gas chromatography). The mixture was then allowed to cool, and was washed with 10% strength by weight aqueous sodium hydrogen sulphide solution and water, dried with magnesium sulphate and concentrated. The residue was distilled in vacuo. The yield was 58 g (83% of theory), and the boiling point was 80° C. under 14 mbar. The characteristic absorptions in the NMR spectra were as follows: 19F-NMR: -59.2 and -84.9 ppm. 1H-NMR: 3.02 ppm.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Li]CCCC.[CH3:34][O:35][C@H:36]1[C@@H:41]([CH3:42])[CH2:40][O:39][C@H:38]([CH:43]=O)[C@@H:37]1[O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Si:46]([O:45][C@@H:37]1[C@@H:36]([O:35][CH3:34])[C@@H:41]([CH3:42])[CH2:40][O:39][C@H:38]1/[CH:43]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48]
Reactant: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C=O)OC[C@@H]1C
Reactant: CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCC/C=C\[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a stirred solution of n-octyltriphenylphosphonium bromide (2124 mg) in dry THF (10 ml) and dry HMPA (5 ml), there was added n-BuLi (4.0 ml, 1.6M in n-hexane) at 0° C. After the mixture was stirred at 0° C. for 30 min, a solution of (2S,3R,4S,5S)-4-methoxy-5-methyl-3-(tert-butyldimethylsilyloxy)tetrahydro-2H-pyran-2-carbaldehyde (497 mg) in dry THF (3 ml) was added to the resulting orange solution. The mixture was stirred at 0° C. for 30 min, and at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined ethereal extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography gave (2S,3R,4S,5S)-3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyl-2-[(Z)-1-nonenyl]tetrahydro-2H-pyran (602 mg, 72% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]([CH3:25])[C:16](=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6][CH2:5]2.I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:25][N:15]([CH2:14][CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[NH:33])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)[C:16](=[O:24])[O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(CCCN1CCCc2cc(N)ccc21)C(=O)Oc1ccccc1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(CCCN1CCCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a stirred solution of phenyl 3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)propyl(methyl)carbamate (830 mg, 2.445 mmol) in ethanol (35 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (1395 mg, 4.89 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then diluted with water and sodium carbonate (sat) and extracted with dichloromethane. The combine organics were dried, filtered and concentrated, then chromatographed in 1:1 ethyl acetate in hexanes, then ethyl acetate, followed by 5% (2M NH3 in methanol) in 1:1 ethyl acetate dichloromethane, giving the desired phenyl methyl(3-(6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (630 mg, 1.404 mmol, 57.4% yield). 1H NMR (DMSO-d6) δ 7.67 (d, J=3 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.23-7.21 (m, 1H), 7.13-7.05 (m, 3H), 6.56 (m, 2H), 6.49 (brs, 1H), 6.25 (brs, 2H), 3.50-3.45 (m, 2H), 3.38-3.32 (m, 2H), 3.23-3.19 (m, 2H), 3.06, 2.93 (2s, 3H), 2.69-2.64 (m, 2H), 1.89-1.81 (m, 4H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:36]=[CH:37][C:38]([NH:39][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:40][CH:41]=3)[N:23]=2)(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Phenyl chloroformate (0.256 mL, 2.04 mmol) was added dropwise to 4-[4-[(4-chlorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (850 mg, 1.85 mmol) and sodium hydrogen carbonate (233 mg, 2.78 mmol) in dioxane (20 mL) at RT. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2×100 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane, to give the desired material as a white solid (955 mg).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:18]3OCC[O:19]3)[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1.C1COCC1.Cl>O>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[CH:18]=[O:19])=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(C#Cc2cccc(C3OCCO3)c2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 432.5 %

Procedure:
Into a mixture of 2-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-1,3-dioxolane, (1.0 g, 3.1 mmol) and THF (5 mL) was added HCl (2N, 1 mL). The mixture was stirred at room temperature for 2 hours, poured into water and extracted with EtOAc/ethyl ether 1/1. The organic extracts were dried over MgSO4. Evaporation and purification on silica gel (ISCO) using hexanes/EtOAc (3/1) as the eluting solvents gave 3-{[4-(difluoromethoxy)phenyl]ethynyl}benzaldehyde as a yellow oil (3.65 g, 95% yield), MS m/e M+ 272; 1H NMR (400 MHz, DMSO-d6) 3.9-4.05 (m, 4H), 5.72 (s, 1H), 7.1-7.3 (m, 4H), 7.62 (m, 2H), 7.8-7.9 (m, 2H), 8.03 (s, 1H), 9.99 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:40])([CH2:36][CH2:37][CH2:38][CH3:39])[C:3](=[O:35])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].[Cl-].[Na+]>C(#N)C.O.P(=O)(O)(O)O>[F:1][C:2]([C@:3]1([OH:35])[O:11][C@@H:10]2[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C@H:6]2[CH2:5][CH2:4]1)([F:40])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCC(=O)OCc1ccccc1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCCC(F)(F)[C@@]1(O)CC[C@H]2[C@@H](CC(=O)[C@@H]2CCCCCCC(=O)OCc2ccccc2)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a solution of benzyl 7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (19) (70.49 g, 124.8 mmol) in acetonitrile (705 ml), water (70.5 ml) and 85% phosphoric acid (70.5 ml) were added and the mixture was stirred for 3 hours at approximately 20° C. The solution was supplemented with 10% aqueous sodium chloride (705 ml), and extracted three times with ethyl acetate (276 ml). The organic layers were combined and sequentially washed with 10% aqueous sodium chloride (360 ml), saturated sodium bicarbonate water (360 ml) and saturated aqueous sodium chloride (360 ml). The solution was dried with anhydrous magnesium sulfate (51 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2100 g; ethyl acetate:hexane=1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300 1000 g, ethyl acetate:hexane=1:4) to give benzyl 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydro cyclopenta[b]pyran-5-yl]heptanate (20) (52.64 g; 109.5 mmol; yield: 87.8%) as a colorless oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20](Cl)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.[I-].[Na+].C(N(CC)CC)C>O1CCOCC1>[CH:15]1[C:14]2[CH2:13][CH2:12][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:20]([N:2]3[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: COC(=O)C1=CCCNC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCCN(C2c3ccccc3CCc3ccccc32)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (crude, 150 mmol), 5-chlorodibenzosuberane (41 g, 180 mmol, 1.2 eq), sodium iodide (2.2 g, 15 mmol, 0.1 eq) and triethylamine (63 mL, 450 mmol, 3.0 eq) in dioxane (300 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, and concentrated. The crude product was passed through a silica gel plug, eluting with CH2Cl2. After concentration, the resulting solid was triturated with ether to yield 27 g (55%) of methyl 1-(10,11-dihydro5H-dibenzo[a,d][7]annulen-5-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate.