Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([NH:20][CH2:21][OH:22])=[O:19])=[C:16]([CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(Cl)=O.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:27])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([NH:20][CH2:21][O:22][CH2:9][C:26]([F:29])([F:28])[F:27])=[O:19])=[C:16]([CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCOCC(F)(F)F
Temperature: 25 °C
Yield: 119.3 %

Procedure:
In a solution of 1.70 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-(hydroxymethyl) benzoic acid amide in 20 ml of dichloromethane, 0.68 g of thionyl chloride was added with stirring at room temperature, stirred at the same temperature for 2 hours, then the solvent was distilled off under reduced pressure, and the residue was dissolved in 10 ml of tetrahydrofuran. In 0.33 g of 60% oily sodium hydride suspended in 30 ml of tetrahydrofuran, 1.50 g of 2,2,2-trifluoroethanol was added dropwise with stirring under ice cooling, and stirred at the same temperature for 10 minutes. Then, the solution of benzoic acid chloride in tetrahydrofuran prepared above was added dropwise in the reaction mixture with stirring under ice cooling, after the completion of the addition, continued to stir at room temperature for 1 hour. After the completion of the reaction, 50 ml of water was added in the reaction mixture, extracted with ethyl acetate (70 ml×1), and the organic phase was dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 1.20 g of the aimed product as colorless resinous substance.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[CH2:10]2)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.O>O1CCCC1>[F:29][CH:27]([F:28])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]([N:11]2[C:12](=[O:14])[C:13]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[CH2:10]2)[CH2:16][C:17]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:18])=[CH:21][C:22]=1[O:30][CH2:31][CH3:32]
Reactant: C1COCCN1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(CC(=O)N2CCOCC2)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (300 mg, 0.67 mmol) in tetrahydrofurane was added carbonyldiimidazole (130 mg, 0.80 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added morpholine (0.1 ml, 1.0 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (250 mg, 72%): mp, 164–166° C.; 1HNMR (CDCl3): 1.43 (t, J=7.5 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 3.04 (dd, J=6, 10 Hz, 1H, CHHCO), 3.54–3.72 (m, 9H, morpholine ring+CHHCO), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.27 (d, J=17 Hz, 1H, CHHN), 4.44 (d, J=17 Hz, 1H, CHHN), 5.54–5.59 (m, 1H, CHN), 6.85 (t, JH-F=75 Hz, 1H, OCF2H), 6.94–7.16 (m, 3H, Ar), 7.14 (d, J=8 Hz, 1H, Ar), 7.46 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=7.5 Hz, 1H, Ar), 10.60 (s, 1H, NHCO). 13C NMR (CDCl3): 15.3, 25.6, 36.5, 42.8, 46.9, 49.8, 54.7, 65.5, 67.2, 67.4, 112.6, 114.1, 116.7, 117.6, 118.3, 118.4, 119.9, 120.8, 123.5, 133.9, 138.5, 140.5, 142.2, 151.5, 166.7, 169.7, 170.4; Anal. Calcd. for C26H29F2N3O6: C, 60.34; H, 5.65; N, 8.12. Found: C, 60.04; H, 5.71; N, 8.19.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[S:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33]>CCO>[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH:37][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)[N:11]=1)[CH3:33]
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CNc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1
Temperature: 25 °C

Procedure:
The product from Example 24a (47 mg, 0.10 mmol) was reacted with the glycine ethyl ester hydrochloride (84 mg, 0.10 mmol) in 2 mL of EtOH in a sealed tube at 150° C. for 1 h. Cooled to room temperature and concentrated. Adjusted to pH 7 with 1M HCl and extracted with EtOAc, dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid solid (12 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.22 (t, J=6.99 Hz, 3H) 2.04 (s, 3H) 2.33 (s, 3H) 4.15 (q, J=7.23 Hz, 2H) 4.27 (d, J=6.25 Hz, 2H) 6.08 (d, J=6.99 Hz, 1H) 7.04 (d, J=5.52 Hz, 1H) 7.07 (d, J=6.62 Hz, 1H) 7.19-7.30 (m, 4H) 7.57 (d, J=8.46 Hz, 2H) 8.04 (t, J=6.62 Hz, 1H) 8.53 (d, J=9.19 Hz, 1H) 8.72 (t, J=5.88 Hz, 1H) 10.08 (s, 1H) 10.43 (s, 1H) 13.43 (d, J=5.88 Hz, 1H); MS (ESI+) m/z 502 (M+H−TFA)+.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1.N[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1.[CH:26](Cl)(Cl)Cl>>[CH3:13][C:12]([NH:11][S:8]([C:7]1[C:2]([NH:3][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)=[CH:26][C:4]([S:16][CH3:17])=[N:5][CH:6]=1)(=[O:10])=[O:9])([CH3:15])[CH3:14]
Reactant: ClC(Cl)Cl
Reactant: Cc1cccc(N)c1
Reactant: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(Cl)n1
Product: CSc1cc(Nc2cccc(C)c2)c(S(=O)(=O)NC(C)(C)C)cn1
Temperature: 25 °C
Yield: 97 %

Procedure:
4-Chloro-N-(1,1-dimethylethyl)-2-(methylthio)-5-pyrimidinesulfonamide (1.45 g, 4.91 mmol) was dissolved in chloroform (15 mL). m-Toluidine (1.08 mL, 10.7 mmol, 2.05x) was added, and the mixture was refluxed for 90 minutes. The reaction was cooled to ambient temperature, the chloroform removed under reduced pressure, and the residue crystallized from ethanol and water to yield 1.74 g (4.75 mmoles, 97%) of pale yellow needles, m.p. 177.5°-178° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:13][C:14]#[N:15])(=[O:12])=[O:11])=[CH:5][CH:4]=1.[F:18][C:19]([S:22][CH2:23][CH2:24]OS(C(F)(F)F)(=O)=O)([F:21])[F:20]>>[F:17][C:2]([F:1])([F:16])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH:13]([CH2:24][CH2:23][S:22][C:19]([F:21])([F:20])[F:18])[C:14]#[N:15])(=[O:11])=[O:12])=[CH:5][CH:4]=1
Reactant: N#CCS(=O)(=O)Cc1ccc(C(F)(F)F)nc1
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)Cc1ccc(C(F)(F)F)nc1

Procedure:
Compound II-9 was prepared from (6-trifluoromethyl-pyridin-3-ylmethanesulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: C(OC(N1CC(=C)CC1C1NC(C2C=CC(C3C=CC4C(=CC=C(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)C=4)C=3)=CC=2)=CN=1)=O)(C)(C)C.[C:56]([O:60][C:61]([N:63]1[CH2:67][CH2:66][CH2:65][CH:64]1[C:68]1[NH:69][C:70]([C:73]2[CH:82]=[CH:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78](Br)[CH:79]=3)[CH:74]=2)=[CH:71][N:72]=1)=[O:62])([CH3:59])([CH3:58])[CH3:57].[CH3:84][O:85][C:86](=[O:121])[NH:87][CH:88]([C:92]([N:94]1[CH:99]([C:100]2[NH:101][C:102]([C:105]3[CH:110]=[CH:109][C:108](B4OC(C)(C)C(C)(C)O4)=[CH:107][CH:106]=3)=[CH:103][N:104]=2)[CH:98]2[CH2:120][CH:95]1[CH2:96][CH2:97]2)=[O:93])[CH:89]([CH3:91])[CH3:90]>>[C:56]([O:60][C:61]([N:63]1[CH2:67][CH2:66][CH2:65][CH:64]1[C:68]1[NH:69][C:70]([C:73]2[CH:82]=[CH:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78]([C:108]4[CH:107]=[CH:106][C:105]([C:102]5[NH:101][C:100]([CH:99]6[CH:98]7[CH2:120][CH:95]([CH2:96][CH2:97]7)[N:94]6[C:92](=[O:93])[CH:88]([NH:87][C:86]([O:85][CH3:84])=[O:121])[CH:89]([CH3:91])[CH3:90])=[N:104][CH:103]=5)=[CH:110][CH:109]=4)[CH:79]=3)[CH:74]=2)=[CH:71][N:72]=1)=[O:62])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Yield: 70.6 %

Procedure:
This compound was synthesized using the procedure used to make 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.200 g, 0.452 mmol) and [2-Methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester (0.283 g, 0.543 mmol) to give 2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.242 g, 71% yield). LCMS-ESI+: calc'd for C44H51N7O5: 757.40 (M+); Found: 758.50 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:26]I>ClCCl.C(Cl)(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([N:18]2[CH:2]([CH2:3][I:26])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])=[CH:24][CH:23]=1
Reactant: II
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine (0.3 g, 0.85 mmol) (from Example 16, Step E, supra) in dichloromethane (50 mL) was added I2 (0.53 g, 4.2 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with chloroform (100 mL), and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (2:1:0.01) as eluent to give the desired 4-(4-chloro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as a white solid. (Yield 0.15 g, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O.C(N(CC)CC)C>ClCCl.C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@H:10]([OH:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
(3S)-3-tert-Butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (1.49 g, 5.0 mmol), 90% formic acid (0.224 ml, 5.25 mmol), and triethylamine (0.730 ml, 5.25 mmol) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (3.4 mg, 0.005 mmol, s/c=1000) in dichloromethane (10.0 ml), followed by stirring at room temperature for 1 hour. Dichloromethane (20.0 ml) was added to the reaction mixture, and the stirring was continued for 1 hour at room temperature. After completion of the reaction, the reaction mixture was quantitatively analyzed by HPLC to confirm production of a desired compound, (2S, 3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.50 g; yield: 99.9%). The production ratio of the desired (2S,3S)-form to the isomeric (2R,3S)-form, (2S,3S):(2R,3S), was found to be 12.5:1. The resulting dichloromethane solution was evaporated, and the residue was crystallized from a mixed solvent of water, toluene and ethanol (1:1:3) to give a mixture at a (2S,3S) to (2R,3S) ratio of 99.6:0.4 in a yield of 80%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:9](C([Sn])=C(CCCC)CCCC)[CH2:10]CC>CN(C=O)C.C1COCC1.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>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([CH:9]=[CH2:10])=[CH:7][N:6]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1cnc(C)nc1
Temperature: 120 °C

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-methyl-pyrimidine (1.7 g, 9.87 mmol) was dissolved in DMF:THF (3:1 24 mL). Tributylvinyltin (3.2 mL, 10.8 mmol) and Pd(PPh3)4 (0.148 g, 0.128 mmol) was added to this solution at RT under nitrogen and was heated at 120° C. for 30 min. The reaction mixture was cooled to RT and diluted with water (60 mL) and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (20% Ethyl acetate-Hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-methyl-5-vinylpyrimidine a as light yellow liquid (1.1 g, 91% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:19]([C:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][C:26]=2[CH:25]=[C:24]([CH:35]([CH3:37])[CH3:36])[C:23]=1[NH2:38])([CH3:21])[CH3:20]>C1(C)C=CC=C(C)C=1>[CH:19]([C:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][C:26]=2[CH:25]=[C:24]([CH:35]([CH3:37])[CH3:36])[C:23]=1[N:38]1[CH2:2][CH2:3][N:4]=[C:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:21])[CH3:20]
Reactant: O=C(NCCCl)c1ccccc1
Reactant: CC(C)c1cc2oc3ccccc3c2c(C(C)C)c1N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1cccc(C)c1
Product: CC(C)c1cc2oc3ccccc3c2c(C(C)C)c1N1CCN=C1c1ccccc1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
N-(2-chloroethyl)benzamide (4.09 g, 22.27 mmol) and 90 mL m-xylene were added to a 250 ml, round-bottom flask. Next, phosphorus pentachloride (6.96 g, 33.4 mmol) was added carefully. The reaction mixture was heated to reflux under nitrogen for 2 h. The reaction mixture was cooled down to room temperature and 1,3-diisopropyldibenzo[b,d]furan-2-amine (6.55 g, 24.50 mmol) in 30 mL m-xylene was added. The reaction mixture was refluxed overnight under nitrogen. The reaction mixture was cooled in an ice bath. White solid was collected by filtration. The solid was washed with hexanes, dissolved in ethyl acetate, and washed twice with 10% sodium hydroxide solution. The organic layer was dried over magnesium sulfate, filtered, evaporated to a white solid which was dried under vacuum. 4.78 g (54% yield) of product was obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH:13]3[CH2:15][CH2:14]3)(O)[CH3:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:31]3[C:30]4[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=4)[NH:33][CH:32]=3)([CH:13]3[CH2:15][CH2:14]3)[CH3:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(O)(c1ccc2sccc2c1)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc4sccc4c3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (2.75 mmol) of the compound from Example 141A and 0.25 ml (3.30 mmol) of trifluoroacetic acid were added to 487 mg (2.75 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). 404 mg (39% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=3)[N:10]([C:23](=[O:31])[NH:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][N:29]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[NH:33]1[CH2:36][CH2:35][CH2:34]1>>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][C:20]([N:33]4[CH2:36][CH2:35][CH2:34]4)=[O:22])[CH:15]=3)[N:10]([C:23]([NH:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][N:29]=3)=[O:31])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CNC1
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCCC(=O)O)cc12
Agent: Cl
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCCC(=O)N3CCC3)cc12

Procedure:
4-(1′-Acetyl-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)butanoic acid and azetidine hydrochloride
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[C:16](=[O:19])([O-])[O-].[K+].[K+].[CH3:22][N:23](C)[CH:24]=[O:25].Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:9][CH2:10][CH2:11][CH2:22][N:23]1[C:24](=[O:25])[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=[C:2]2[C:16]1=[O:19]
Reactant: CN(C)C=O
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
A mixture of 9.1 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 8.9 g of N-(4-bromoethyl)phthalimide, 4.4 g of potassium carbonate and 100 ml of N,N-dimethylformamide was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and made weak acidic by the addition of 10% hydrochloric acid, after which 200 ml of ethyl acetate was added for extraction. The ethyl acetate layer was successively washed with 10% hydrochloric acid and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated to give crude crystals. The crude crystals were washed with n-hexane and then dried under reduced pressure, which afforded 14.5 g of 3,5-dichloro-4-(4-phthalimidobutyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (94% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.Cl[C:27]([O:29][C:30]([CH3:32])=[CH2:31])=[O:28].O.C(Cl)Cl>N1C=CC=CC=1>[CH3:15][C:14]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:27](=[O:28])[O:29][C:30]([CH3:32])=[CH2:31])[CH:7]=2)=[CH:10][CH:11]=[C:12]([NH:16][C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:24])[CH3:23])=[O:18])[N:13]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(N)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2C)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A solution of N-((5-((2-aminopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide (0.280 g, 0.815 mmol) in pyridine (6 mL) was treated with isopropenyl chloroformate (0.100 mL, 0.913 mmol) and stirred at RT overnight. The mixture was treated with water and DCM, stirred for 0.5 h, the layers separated and the aqueous layer extracted with additional DCM (3×). The combined organics were dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl (4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (328 mg, 94%). MS (ESI) m/z: 428.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[C-:25]#[N:26].[Na+].Cl>CN(C)C=O>[CH3:23][C:20]([C:7]1[CH:8]=[C:9]([C:11]2[S:12][C:13]([C:25]#[N:26])=[N:14][N:15]=2)[CH:10]=[C:5]([C:2]([CH3:3])([CH3:4])[CH3:1])[C:6]=1[OH:24])([CH3:21])[CH3:22]
Reactant: [C-]#N
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nnc(C#N)s2)cc(C(C)(C)C)c1O
Temperature: 85 °C
Yield: 45 %

Procedure:
A solution of 0.52 g (1.41 mmol) of methyl sulfone (Example 36) and 0.15 g (3.06 mmol, 2.17 equiv. ) of NaCN in 4 ml dimethylformamide is warmed at 65° C. for 25 hours. An additional portion of NaCN is added and the reaction is warmed at 75° C. for 16 hours and 85° C. for one hour. The reaction is poured onto 3N aqueous HCl and extracted with ethyl acetate (three times). The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography (SiO2, 230-400 mesh, 15×4.5 cm, 15% ethyl acetate-hexane) gives 0.20 g of the nitrile. Recrystallization from cyclohexane gives 0.14 g (0.44 g theor., 31%) of the pure nitrile, mp 140°-140.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.C[CH:11]([NH2:15])[CH2:12][O:13][CH3:14].[C:16](=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:15]([CH2:11][CH2:12][O:13][CH3:14])[CH3:16])=[CH:6][CH:7]=1
Reactant: COCC(C)N
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN(C)Cc1ccc(Cl)nc1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (384 mg, 2.37 mmole) in 4 mL of dry acetonitrile is 0.51 mL (4.74 mmol) of 1-methyl-2-methoxyethylamine followed by 328 mg (2.37 mmol) of potassium carbonate. The reaction is heated at 80° C. for 3 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 395 mg (78% yield) of (6-Chloro-pyridin-3-ylmethyl)-(2-methoxy-ethyl)-methyl-amine. Diagnostic 1H NMR (400 MHz, CDCl3) 2.25 (s, 3H), 2.59 (t, 2H, J=5.6 Hz), 3.32 (s, 3H), 3.49 (t, 2H, J=5.6 hz), 7.26 (d, 1H, J=8.5 Hz), 7.68 (dd, 1H, J=8.3 and 2.5 Hz), 8.27 9d, 1H, J=1.6 Hz); MS 215.2 (M+H).