Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: C#CC[C@H](C)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@H](C)O)c21

Procedure:
Using Method C above, (S)-pent-4-yn-2-ol (44 mg, 0.52 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as a solvent at 80° C. for 7 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient and trituration with Et2O. (Yield 30 mg, 65%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][C:4](=[CH:6][C:7]#[N:8])[CH2:3]1.[F:9][C:10]1[C:24]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:22]=[CH:21][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)=[O:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:9][C:10]1[C:24]([C:25]([F:27])([F:26])[F:28])=[N:23][CH:22]=[CH:21][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH:17]([N:2]2[CH2:5][C:4](=[CH:6][C:7]#[N:8])[CH2:3]2)[CH2:18][CH2:19]1)=[O:13]
Reactant: N#CC=C1CNC1
Reactant: O=C1CCN(C(=O)c2ccnc(C(F)(F)F)c2F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: N#CC=C1CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a 0.25-L flask equipped with a nitrogen inlet, a thermocouple, and a magnetic stirrer were added 2-(azetidin-3-ylidene)acetonitrile hydrochloride (2a, 4.5 g, 34.46 mmol), 1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-one (7, 10 g, 34.46 mmol, 1.0 equiv), and methylenechloride (100 mL) at ambient temperature and the resulting mixture was then treated with sodium triacetoxyborohydride (14.6 g, 68.93 mmol, 2.0 equiv) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours before being quenched with saturated sodium bicarbonate (NaHCO3) aqueous solution (50 mL). The two phases were separated and the aqueous phase was extracted with dichloromethane (200 mL). The combined organic phase was washed with water (50 mL) and brine (50 mL) and concentrated under reduced pressure to afford the crude desired product (10), which was purified by column chromatography (SiO2, O-10% of ethyl acetate in hexane gradient elution) to afford 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile (10, 9.5 g, 12.7 g theoretical, 74.8%) as a white solid. For 10: 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=4.7 Hz, 1H), 7.54 (t, J=4.6 Hz, 1H), 5.29 (p, J=2.4 Hz, 1H), 4.18-4.08 (m, 1H), 4.08-4.03 (m, 2H), 3.98-3.94 (m, 2H), 3.57-3.39 (m, 2H), 3.17-3.04 (m, 1H), 2.56 (tt, J=7.4, 3.5 Hz, 1H), 1.86-1.77 (m, 1H), 1.75-1.64 (m, 1H), 1.54-1.43 (m, 1H), 1.43-1.31 (m, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ 161.34, 160.73, 152.62 (d, J=269.1 Hz), 145.75 (d, J=6.1 Hz), 136.73 (qd, J=36.1, 12.0 Hz), 134.56 (d, J=16.9 Hz), 126.89, 120.58 (qd, J=275.0, 4.9 Hz), 115.11, 92.04, 62.05, 60.57 (2C), 44.47, 39.42, 29.38, 28.47 ppm; C17H16F4N4O (MW 368.33), LCMS (EI) m/e 369 (M++H).
Reaction SMILES: [CH2:1]([C:5]12[CH2:11][C:9]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)([CH2:10]1)[C:8](=[O:21])[N:7]([CH2:22][CH2:23][CH3:24])[C:6]2=[O:25])[CH:2]([CH3:4])[CH3:3].CCCCCC.CCOCC>C(OCC)(=O)C.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]23[CH2:11][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([CH2:10]2)[C:6](=[O:25])[N:7]([CH2:22][CH2:23][CH3:24])[C:8]3=[O:21])=[CH:17][CH:16]=1
Reactant: CCCN1C(=O)C2(CC(C)C)CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCN1C(=O)C2(CC(C)C)CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 12a, 5.2 g of 5-isobutyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 100 ml of ethyl acetate are hydrogenated in the presence of 0.5 g of 5% palladium-on-carbon and worked up. Melting point 86.5°-87° (from n-hexane/ether).
Reaction SMILES: C([N:8]([CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1)CC1C=CC=CC=1)C1C=CC=CC=1.CO.N#N.O.NN>[Pd].O>[NH2:8][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1
Reactant: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Agent: N#N
Agent: NN
Solvent: CO
Solvent: O
Product: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
Compound 4 (0.95 g, 2 mmol) and 10% Pd—C (0.02 mmol) were added to 20 mL of methyl alcohol and the air was replaced with N2. Hydrazine hydrate (4 mmol) was added and on the mixture was stirred at 0° C. for 24 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to provide 0.52 g of white solid in 88% yield. HPLC: 99%.
Reaction SMILES: [I-].[Br:2][C:3]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:4]=1[CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[C:33]([O:37][C@@H:38]([C:44]1[C:45]([CH3:87])=[N:46][C:47]2[N:48]([N:82]=[C:83]([CH:85]=O)[CH:84]=2)[C:49]=1[N:50]1[CH2:55][CH2:54][C:53]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][C@H:62]([O:64][Si:65]([C:78]([CH3:81])([CH3:80])[CH3:79])([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH3:63])([CH3:56])[CH2:52][CH2:51]1)[C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[Br:2][C:3]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:4]=1[CH2:5][CH:6]=[CH:85][C:83]1[CH:84]=[C:47]2[N:46]=[C:45]([CH3:87])[C:44]([C@H:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:49]([N:50]3[CH2:55][CH2:54][C:53]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][C@H:62]([O:64][Si:65]([C:78]([CH3:79])([CH3:80])[CH3:81])([C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[C:72]4[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=4)[CH3:63])([CH3:56])[CH2:52][CH2:51]3)[N:48]2[N:82]=1
Reactant: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Br)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3Br)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.6 %

Procedure:
To a suspension of (2-bromo-4-fluorophenethyl)triphenylphosphonium, iodide salt (705 mg, 1.193 mmol) in THF (8 ml) at 0° C. was added NaH (48.9 mg, 1.223 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to −78° C. and (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (460 mg, 0.597 mmol) dissolved in THF (8 ml) was added dropwise and the mixture was stirred at −78° C. for 1 h then warmed to rt and stirred 1 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-30% EtOAc/hexane) to afford (S)-ethyl 2-(2-(3-(2-bromo-4-fluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (500 mg, 0.523 mmol, 88% yield) as inseparable mixture of E and Z isomers. LCMS (M+2H)=957.2.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:26])[N:19]([CH2:23][CH2:24]O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.C(OC([N:40]1[CH2:44][CH2:43][NH:42][S:41]1(=[O:46])=[O:45])=O)(C)(C)C>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:26])[N:19]([CH2:23][CH2:24][N:40]5[CH2:44][CH2:43][NH:42][S:41]5(=[O:46])=[O:45])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:30])[F:32])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCO
Reactant: CC(C)(C)OC(=O)N1CCNS1(=O)=O
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCNS1(=O)=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(1,1-dioxido-1,2,5-thiadiazolidin-2-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylene)-3-(2-hydroxyethyl)thiazolidine-2,4-dione and 1,1-dioxo-1λ6-[1,2,5]thiadiazolidine-2-carboxylic acid tert-butyl ester (compound described in Chemistry—A European Journal 2004, 10(22), 5581-5606) according to General Procedure C followed by deprotection (Procedure M).
Reaction SMILES: O=[C:2]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][C:24]1[C:25]([NH2:30])=[N:26][NH:27][C:28]=1[NH2:29].CCOCC.Cl>C(O)(=O)C.CO>[ClH:15].[NH2:29][C:28]1[C:24]([CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=2[Cl:15])=[C:25]2[N:30]=[C:2]([CH:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[CH:3]=[C:4]([OH:6])[N:26]2[N:27]=1
Reactant: Nc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nn2c(O)cc(C3CCOCC3)nc2c1Cc1cccc(Cl)c1Cl
Reaction time: 3 h
Yield: 51.4 %

Procedure:
To a mixture of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.100 g, 0.498 mmol) and 4-[(2,3-dichlorophenyl)methyl]-1H-pyrazole-3,5-diamine (0.128 g, 0.498 mmol) was added in Acetic Acid (2 mL). The reaction vessel was subjected to MW irradiation at 100° C. for 40 min then 70° C. for 180 min. The mixture was concentrated. The residue was purified by reversed phase HPLC (25% CH3CN (0.1% TFA)/Water (0.1% TFA)) and then repurified (10˜50% CH3CN (0.1% TFA)/Water (0.1% TFA) to give the product. 1 M ether/HCl (3 mL) was added to the solution of the product in MeOH (10 mL). The mixture was stirred for 3 h. The solvent was removed to give the titled product as solid (55 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.84 (m, 4H) 2.63-2.83 (m, 1H) 3.22-3.46 (m, 2H) 3.93 (m, 2H) 4.01 (s, 2H) 5.63 (s, 1H) 6.90 (d, J=7.07 Hz, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.43-7.59 (m, 1H) 11.92 (br. s., 1H). LC/MS: MS (ES+) m/e 393.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:15])=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:23][CH:24]([CH3:30])/[CH:25]=[CH:26]/[C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[C:4]([CH3:15])=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][N:12]([C:27](=[O:28])/[CH:26]=[CH:25]/[CH:24]([CH3:30])[CH3:23])[CH2:13][CH2:14]1
Reactant: COc1c(N2CCNCC2)ccnc1C
Reactant: CC(C)/C=C/C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(N2CCN(C(=O)/C=C/C(C)C)CC2)ccnc1C
Yield: 7 %

Procedure:
1-(3-Methoxy-2-methyl-4-pyridyl)piperazine (20.7 mg, 0.1 mmol) was dissolved in dichloromethane (1 ml), triethylamine was added (1 ml of a 0.12 M solution in dichloromethane) followed by a solution of (E)-4-methylpent-2-enoyl chloride (1 ml, 0.12 M in dichloromethane). The mixture was shaken briefly, washed with 5% sodium bicarbonate solution (2×), water and evaporated to dryness. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 2.2 mg of a solid (0.007 mmol, 7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[NH:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH2:17][OH:18].CN1CCCC1=O.C(OCC)(=O)C>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:21][CH2:20][CH2:19][CH:16]2[CH2:17][OH:18])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: OC[C@@H]1CCCN1
Reactant: COC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCCC2CO)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h
Yield: 15.4 %

Procedure:
A mixture of 4-chloro-2-nitrobenzoic acid methyl ester 100 mg, prolinol 235 mg and 1-methyl-2-pyrrolidinone 3 ml is stirred at 100° C. for 3 hours. After cooling to room temperature, ethyl acetate and water are added to the mixture. The organic layer is washed with water (twice) and brine, and dried over sodium sulfate. After removal of the sodium sulfate, the filtrate is concentrated in vacuo, and the residue is purified with preparative thin-layer chromatography (two plates, solvent; hexane:ethyl acetate=1:1) to give 4-(2-hydroxymethyl-1-pyrrolidinyl)-2-nitrobenzoic acid methyl ester 20 mg as a yellow oil.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41](/[C:44](/[CH3:48])=[CH:45]/[CH2:46]O)=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>C1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:43]=[CH:42][C:41](/[C:44](/[CH3:48])=[CH:45]/[CH2:46][O:30][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][C@H:17]([O:16][CH2:14][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=3)=[CH:40][CH:39]=2)=[CH:36][CH:37]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Cl)cc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Azodicarboxylic dipiperidide (0.731 g, 2.9 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.71 ml, 0.58 g, 2.9 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.483 g, 2.03 mmol) and (E)-3-(4′-chloro-biphenyl-4-yl)-but-2-en-1-ol (0.500 g, 1.93 mmol) in dry benzene (15 ml), the mixture warmed to room temperature, and stirred for 3 h. The resulting mixture was diluted with water and ethyl acetate (30 ml each), the aqueous layer collected and further extracted with ethyl acetate (30 ml). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica (20% ethyl acetate in n-heptane eluent) to give (E)-(S)-ethyl 3-{4-[3-(4′-chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate as a gum; 0.69 g (75%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH2:30])[CH2:28][CH2:27][O:26][CH2:25]1)[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C(Cl)Cl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:29]([NH:30][C:40](=[O:43])[CH:41]=[CH2:42])[CH2:28][CH2:27][O:26][CH2:25]1)[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COCC[C@@H]4N)ncc3c2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1CCOC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
(3S,4S)—N3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)tetrahydro-2H-pyran-3,4-diamine (0.060 g, 0.134 mmol) was taken up in CH2Cl2 (2 ml) and cooled to 0° C., followed by addition of DIEA (0.023 ml, 0.134 mmol) and then acryloyl chloride (0.012 ml, 0.147 mmol) slowly. The reaction was stirred at 0° C. for 30 minutes, then the mixture was loaded directly onto silica and purified by flash chromotography using 0-10% CH2Cl2/MeOH. N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide (0.041 g, 0.081 mmol, 61% yield) was recovered as an off white solid. MS (ES+) C24H24Cl2N4O4 requires: 502, found: 503 [M+H]+.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[OH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH2:17][C@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)[CH:13]=2)[C:8]1=[O:23]>O.O.C1COCC1>[OH:2][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH2:17][C@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)[CH:13]=2)[C:8](=[O:23])[O:6]1
Reactant: O=C1c2ccc(OC[C@H]3CCCO3)cc2CC1O
Reactant: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(O)Cc2cc(OC[C@H]3CCCO3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of periodic acid in water (0.5 M; 5.2 mL) was added at 0° C. to a solution of 2-hydroxy-5-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-indan-1-one (581 mg) in water/THF 1:1 (12 mL) and the solution was stirred at 0° C. for 1 h. After adding water it was extracted with ether, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. In this way the product was obtained with molecular weight 264.28 (C14H16O5); MS (ESI): 265 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH:7]=[CH:6][C:5]=1[NH:20][C:21](=[O:24])[CH2:22][CH3:23].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH:7]=[CH:6][C:5]=1[NH:20][C:21](=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)Nc1ccc(Sc2ccccc2[N+](=O)[O-])cc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1ccc(Sc2ccccc2N)cc1C(=O)OC

Procedure:
A mixture of 5-(2-nitro-phenylsulfanyl)-2-propionylamino-benzoic acid methyl ester (110 mg, 0.31 mmol, prepared according to Sevbo et al. 1976) and palladium-on-charcoal (10%, 25 mg) in ethyl acetate (5 mL) was stirred in an atmosphere of hydrogen (1 atm) at room temperature for 2 hours. The catalyst was filtered off and the solvent was removed by evaporation to yield the title compound quantitatively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH3:21]N(C)C=O.C[Br:27]>C(OCC)(=O)C>[Br-:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H](C)N(C)[C@@H](C)c2ccccc2)c1
Reactant: CN(C)C=O
Reactant: CBr
Solvent: CCOC(C)=O
Product: COc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1
Product: [Br-]
Temperature: 60 °C
Yield: 69 %

Procedure:
Mix 5.5 g (0.02 mol) of (S)-1-(3-methoxyphenyl)-N-methyl-N—((S)-1-phenylethyl)ethanamine (formula IV) with 12 ml N,N-dimethylformamide and 9.5 g (0.1 mol) of methyl bromide at room temperature, heat the mixture to 60° C. for 24 hours. Let it cool to room temperature, and add 100 ml of ethyl acetate. A light yellow solid is produced. Filter and dry it to receive 5.0 g light yellow solid with a yield of 69%.
Reaction SMILES: [CH2:1]=O.[NH2:3][CH2:4][C@@:5]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([OH:16])[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>C1C=CC=CC=1>[Si:9]([O:8][CH2:7][CH2:6][C@:5]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[O:16][CH2:1][NH:3][CH2:4]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: C=O
Reactant: CC(C)(C)[Si](C)(C)OCC[C@](O)(CN)c1ccc(F)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC[C@@]1(c2ccc(F)cc2)CNCO1
Yield: 104.2 %

Procedure:
Paraformaldehyde (18.50 g, 0.617 mol) was added to a solution of (2R)-1-amino-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)butan-2-ol (128.92 g, 0.411 mol) in benzene (1000 mL), a water separator was mounted, and the mixture was stirred at reflux temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give 139.43 g of crude (5R)-5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-(4-fluorophenyl)-1,3-oxazolidine as a brown oily substance.
Reaction SMILES: [C:1]([CH2:5][OH:6])([F:4])([F:3])[F:2].N1C=CC=CC=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].Cl.N1C=CC=CC=1>>[C:1]([CH2:5][O:6][S:14]([CH3:13])(=[O:16])=[O:15])([F:4])([F:3])[F:2]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(F)(F)F

Procedure:
A 10-L four-neck flask was equipped with a refluxing pipe and a dropping funnel to serve as a reactor. To the flask were added CF3CH2OH (337.1 g; 3.37 mol) and pyridine (306.31 g; 3.88 mol) in an ice bath, and the mixture was stirred. Using the dropping funnel, methanesulfonyl chloride (364.15 g; 3.20 mol) was dropped, with care for heat generation. The reaction solution changed its color gradually to milky white as pyridine hydrochloride was produced. After the end of the reaction, the reaction solution was washed with a 1 N HCl aqueous solution. The washed solution was separated to collect an organic layer.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:59]1([C@H:65]([NH2:67])[CH3:66])[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.C(Cl)[Cl:69]>O.C(OCC)(=O)C>[Cl:69][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:67][C@@H:65]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH3:66])=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:27][CH:28]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: ClCCl
Reactant: C[C@@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1)c1ccccc1
Reaction time: 48 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.263 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (76 mg, 0.394 mmol), and 1-Hydroxybenzotriazole (53 mg, 0.394 mmol) were dissolved in 3.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (68.9 μL, 0.504 mmol) and (R)-1-phenylethanamine (64 μL, 0.504 mmol) were added. The reaction was allowed to stir for 48 hours. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with saturated citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was triturated in methanol, filtered and dried under vacuum to obtain pure product as a white solid. Yield: 32.9 mg (White solid)