Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.N[CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[CH:19][CH:18]=2)[CH2:12]1.C([OH:32])C>Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:8][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:32])=[CH:4][CH:3]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: N#Cc1ccc(Cl)s1
Reactant: CCO
Agent: Cl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (5.7 g) in ethanol (70 ml) added potassium carbonate (7.1 g) and the mixture was stirred 2 h at 25 to 30° C. then filtered to obtain 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (free base). In another flask charged solution of 5-chlorothiophene-2-carbonitrile (2.9 g) under nitrogen in ethanolic HCl (12 ml) and stirred for 5 h at room temperature till white precipitate was obtained. Distilled under nitrogen to avoid from moisture and obtained residue added in solution of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one. The mixture was stirred for 16 to 18 h at reflux temperature. Added aq.ethanol (5 ml) and again heat the mixture at reflux temperature for 10 to 12 h to obtain 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (crud material) which further purified by column Chromatography.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:19]([O:21][CH3:22])=[O:20])[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCOC(C)=O>[CH2:23]([N:8]1[C:9]2[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=2[C:15]2[N:16]=[C:4]([Br:3])[CH:5]=[C:6]([C:19]([O:21][CH3:22])=[O:20])[C:7]1=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(OC)ccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)nc2c3ccc(OC)cc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
Sodium hydride (81 mg, 2 0 mmol) was added to a solution of methyl 2-bromo-7-methoxy-5H-pyrido[3,2-b]indole-4-carboxylate (450 mg, 1.34 mmol) in THF (6 mL) in an ice bath. After 20 min this was removed from the bath and left stirring at RT for 0.5 h. Benzyl bromide (276 mg, 1.61 mmol) was added. After stirring at RT for 3 days, this was diluted with EtOAc, washed with water, brine, and dried over Na2SO4 Removal of the solvent followed by radial chromatography (elution with DCM) afforded methyl 5-benzyl-2-bromo-7-methoxy-5H-pyrido[3,2-b]indole-4-carboxylate (130 mg, 0.31 mmol, 23% yield). MS (ESI) m/z 425.0 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.27 (1H, d, J=8.55 Hz), 7.59 (1H, s), 7.17-7.24 (3H, m), 6.97 (1H, dd, J=8.70, 1.98 Hz), 6.88-6.93 (2H, m), 6.84 (1H, d, J=1.83 Hz), 5.67 (2H, s), 3.86 (3H, s), 3.70 (3H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([CH2:8][OH:9])=[CH:6][N:7]=1.C(N(CC)CC)C.[C:24]([O:27]C(=O)C)(=[O:26])[CH3:25]>ClCCl>[CH3:25][C:24]([O-:27])=[O:26].[C:24]([O:1][CH2:2][C:3]1[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([CH2:8][OH:9])=[CH:6][N:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cnc(CO)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1ncc(CO)n1Cc1ccccc1
Product: CC(=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,5-bis-(hydroxymethyl)-N-benzylimidazole (436 mg, 2.0 mmol) in dichloromethane (10 mL) was added triethylamine (0.35 mL, 2.0 mmol) and acetic anhydride (0.19 mL, 2.0 mmol). The mixture was then stirred overnight (16 h) at room temperature. The reaction was then washed with aqueous ammonium chloride and the layers separated. The aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated. Purification by chromatography on silica gel (5% methanol in dichloromethane) gave the monoacetate, 2-acetoxymethyl-5-hydroxymethyl-N-benzylimidazole, as a white powder (300 mg, 58%). 1H NMR (CDCl3) δ 1.83 (s, 3H), 4.49 (s, 2H), 5.06 (s, 2H), 5.33 (s, 2H), 6.97 (m, 2H), 7.28 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[S:11])[NH:13][CH2:14][C:15]([NH2:17])=[O:16]
Reactant: NCC(N)=O
Reactant: Cc1cccc(C)c1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=S)NCC(N)=O
Yield: 77.2 %

Procedure:
A mixture of 2,6-dimethylphenyl-isothiocyanate (16.3 g), glycinamide hydrochloride (11.05 g), triethyl amine (12.0 g), and chloroform (250 mL) was heated at reflux for 3 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with 1N HCl (300 mL) then with water (300 mL). The organic phase was evaporated to dryness, then the residue was stirred with diethyl ether. The solid was collected by filtration and dried to afford 2-[3-(2,6-dimethylphenyl)-thioureido]-acetamide as a solid (18.3 g). Mass spectrum (EI, M.+) m/z 237. This compound was used without further purification in the preparation of the title compound.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH:6]([C:8]([CH2:10][CH3:11])=[O:9])=[CH2:7].C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1.[CH2:32]([O:39][C:40](=[O:46])[NH:41][CH:42]=[CH:43][CH:44]=[CH2:45])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C.CCOCC>[C:8]([C@H:10]1[C@@H:42]([NH:41][C:40](=[O:46])[O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:43]=[CH:44][CH2:45][CH2:11]1)(=[O:9])[CH2:6][CH3:7]
Reactant: C=CC(=O)CC
Reactant: C=CC=CNC(=O)OCc1ccccc1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Solvent: CCOCC
Product: CCC(=O)[C@@H]1CCC=C[C@@H]1NC(=O)OCc1ccccc1
Temperature: -30 °C
Reaction time: 84 h
Yield: 91 %

Procedure:
Concentrated (70% aqueous) perchloric acid (431 μL, 5.0 mmol) was added slowly to a stirring solution of ethyl vinyl ketone (2.49 mL, 25.0 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (1.35 g, 5.0 mmol) pre-chilled to −30° C. Then, buta-1,3-dienyl-carbamic acid benzyl ester (4.47g, 31.3 mmol) was added dropwise over 15 minutes as a solution in 12.5 mL of absolute ethanol. After stirring for 3.5 days, the reaction was diluted with ether (150 mL), washed successively with 1N HCl (50 mL), water (50 mL) and brine (25 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a pale brown oil. Purification by silica gel (8:1 hexanes:ethyl acetate) afforded the title compound as a single diastereomer (as judged by HPLC analysis) in 91% yield (5.17g, 22.7 mmol) and 98% ee. The combined aqueous extracts were treated with solid K2CO3, extracted with 3×50 mL portions of CHCl3, dried over anhydrous Na2SO4 and concentrated in vacuo to afford a 91% recovery of (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (1.23 g, 4.55 mmol) after silica gel chromatography. IR (film) 3411, 3329, 3064, 3031, 2974, 2938, 2879, 2836, 1956, 1872, 1711, 1523, 1455, 1409, 1376, 1331, 1278, 1236, 1164, 1120, 1060, 1028, 988.9, 973.1, 775.6, 736.0, 697.9 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.33 (m, 5H, ArH), 5.82 (m, 1H, CH═CH), 5.70 (m, 1H, CH═CH), 5.04 (m, 3H, CH2Ph and NH), 4.63 (m, 1H, CHNH), 2.86 (ddd, J=10.2, 3.9, 3.9 Hz, 1H, CHCO), 2.70 (dq, J=18.0, 7.2 Hz, 1H, one of CH2CO), 2.43 (dq, J=17.7, 7.2 Hz, 1H, one of CH2CO), 2.10-1.65 (m, 4H, CH2CH2), 1.00 (dd, J=6.9, 6.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 212.0, 155.9, 136.6, 130.1, 128.7, 128.2, 128.1, 126.9, 67.0, 50.4, 46.9, 34.8, 24.2, 20.7, 8.0; HRMS (CI) exact mass calc'd for (C17H21NO3) requires m/z 287.1521, found m/z 287.1519. [α]D=+122.0 (c=1.0, CHCl3). Product ratios were determined by HPLC analysis (OD-H column, 3% ethanol in hexanes, 1 mL/min, 254 nm); (1S, 6R) endo isomer tr=12.5 min, and (1R, 6S) endo isomer tr=11.3 min, exo isomers tr=8.6, 9.2 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]=[CH:17][CH2:18][CH3:19])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[C:21]([O:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:12]=1[CH:16]=[CH:17][CH2:18][CH3:19])([CH3:28])[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCC=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC=Cc1ccc(OCc2ccccc2)cc1OC(C)(C)C(=O)OCC
Temperature: 55 °C
Yield: 76 %

Procedure:
5-Benzyloxy-2-but-1-enylphenol (0.70 g, 2.75 mmol) (see Ex. 40, part A) was dissolved in anhydrous DMF (12 mL), followed by the addition of ethyl bromoisobutyrate (1.62 mL, 11.0 mmol), and cesium carbonate (3.58 g, 11.0 mmol). The mixture was then heated for 18 h (55° C.). The reaction mixture was then cooled and concentrated in vacuo. The crude residue was partitioned between ethyl acetate (70 mL) and water (40 mL). The organic layer was washed with brine, dried (Na2SO4), and removed in vacuo. The crude residue was purified using radial chromatography, eluting with 5% ethyl acetate/hexanes to give 0.77 g (76%) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.41-7.28 (m, 6H), 6.65-6.59 (m, 2H), 6.40 (d, J=2.4 Hz, 1H), 6.14-6.07 (m, 1H), 4.99 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 2.22 (quintet, J=7.6 Hz, 2H), 1.56 (s, 6H), 1.26 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.6 Hz, 3H), MS (ES) m/e 369 (M+1).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[F:28][C:2]([F:27])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C(F)(F)F
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
40% Methanolic Triton B (0.18 mL, 0.4 mM) was added to a solution of the 9-[(2-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (120 mg, 0.31 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (98.5 mg, 0.62 mM) was added and the resultant mixture stirred at room temperature for 4.5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate/THF) to afford 95 mg (67%) of the {9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ 7.7 (d, 1H, J=8 Hz), 7.5-7.2 (m, 6H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.45 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.7 (s, 2H), 4.9 (s, 2H), and 3.9 (s, 3H). IR (CHCl3, cm−1) 1763 and 1674. MS (ES) m/e 457.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[C:12]1([NH2:23])[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([NH2:21])[C:13]=1[F:22].[ClH:24].Cl.[N:26]1([CH2:32][CH:33]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([O-:41])=[O:40])=[CH:37][CH:36]=2)[CH3:34])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[CH2:44](N(CC)CC)[CH3:45]>C(Cl)Cl>[C:12]1([NH2:23])[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([NH2:21])[C:13]=1[F:22].[ClH:1].[ClH:24].[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][N:29]2[CH2:30][CH2:31][N:26]([CH2:32][CH:33]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([O:41][CH2:44][CH3:45])=[O:40])=[CH:37][CH:36]=3)[CH3:34])[CH2:27][CH2:28]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(CN1CCNCC1)c1ccc(C(=O)[O-])cc1
Reactant: ClCC=Cc1ccc(Cl)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C(C)CN2CCN(CC=Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
By the reaction of 4-chlorocinnamyl chloride with the dihydrochloride of 4-[1-(piperazin-1-yl)-prop-2-yl]-benzoate in methylene chloride in the presence of triethylamine (analogously to Example 25), there is obtained a yield of 81% of theory of the dihydrochloride of ethyl 4-{1-[1-(4-chlorocinnamyl)-piperazin-4-yl]-prop-2-yl}-benzoate; m.p. 249°-250° C. (recrystallised from ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4](N)[CH:3]=1.[C:10](O)(C(F)(F)F)=[O:11].N(OC(C)(C)C)=O>CO>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([O:11][CH3:10])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc(Cl)c(I)cn1
Agent: CC(C)(C)ON=O
Solvent: CO
Product: COc1cc(Cl)c(I)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a solution of 4-chloro-5-iodo-pyridin-2-ylamine (64.2 g, 0.25 mol) in methanol (1.1 L) and TFA (93.7 mL, 1.26 mol) was added tert-butyl nitrite (150 mL, 1.26 mol) so as to maintain temperature less than 3° C. The resultant mixture was stirred at RT for 1 h then allowed to warm to RT and stirred for 16 h. The reaction was quenched by the careful addition of water then concentrated in vacuo to ¼ volume. The resultant residue was treated with water (1 L) and the precipitate formed collected by filtration and dried in vacuo at 35° C. to give the title compound (62.3 g, 92%). Contains 16% impurity. 1H NMR 400 MHz (DMSO-d) δ: 8.56 (1H, s), 7.20 (1H, s), 3.86 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:5]([N:7]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:6].[H-].[Na+].[C:25]([O:29][C:30]([N:32]([C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)[CH2:33][CH2:34]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([O:29][C:30](=[O:31])[N:32]([CH2:33][CH2:34][O:22][C:20]1[CH:19]=[C:4]([C:5](=[O:6])[N:7]([CH2:8][CH2:9][CH3:10])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[CH:3]=[C:2]([Cl:1])[CH:21]=1)[C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCN(C(=O)c1cc(O)cc(Cl)c1)c1cc(F)cc(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C(=O)OC(C)(C)C)c2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1cc(F)cc(F)c1
Reaction time: 66 h
Yield: 34.7 %

Procedure:
To a solution of 3-chloro-N-(3,5-difluoro-phenyl)-5-hydroxy-N-propyl-benzamide (0.050 g) in DMF (0.5 ml) stirred at room temperature under nitrogen was added sodium hydride (60% dispersion in oil, 0.007 g) and after 10 min was added toluene-4-sulfonic acid 2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethyl ester (0.060 g). The reaction was stirred for 66 h, quenched with water and then concentrated in vacuo. and the residue subjected to preparative hplc. The title compound (0.029 g) was obtained as an colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18].[OH-].[Na+]>C1COCC1>[CH3:12][NH:11][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])(=[O:13])=[O:14]
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Temperature: 50 °C

Procedure:
To 2.3 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH and the mixture was heated at 50° C. for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 312.0 ([M−H]−, 100%)
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([CH:23]=[O:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=O)(C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18]([O:27][CH3:28])=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:22]=1)[CH:23]=[O:24]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Ex-61A: 2-(5-Formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester (Ex-36A, 2.0 g, 5.2 mmol) was dissolved in 100 ml of THF, and Bu4NF (6.86 g, 26 mmol) was added. The reaction mixture was stirred at room temperature overnight. No reaction occured at this condition. Then, Bu4NF (6.86 g, 26 mmol) was added to the mixture, and the mixture was stirred at reflux for 4 days. The reaction was about 50% completion (HPLC). The reaction mixture was poured into CH2Cl2, and washed with water and brine. The organic phase was dried over MgSO4, and concentrated. The residue was purified by column chromatography (EtOAc: Hex, 2:1) to give 0.45 g (30%) of 5-(1H-indol-2-yl)-2,4-dimethoxy-benzaldehyde. 1H-NMR (CDCl3) δ 10.37 (s, 1H), 9.25 (br, 1H), 8.28 (s, 1H), 7.63 (d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.08–7.20 (m, 2H), 6.92 (d, J=2 Hz, 1H), 6.56 (s, 1H) 4.11 (s, 3H), 4.00 (s, 3H). HMRS (EI) calcd. for C17H15NO3: 281.1052; found: 281.1049.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:26](O)=[O:27])=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:20]3[C:19]([Cl:18])=[CH:24][C:23]([Cl:25])=[CH:22][N:21]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 3,5-dichloro-pyridine-2-carboxylic acid (CAS 81719-53-1) following procedure I yielded the title compound as a crystalline white solid. MS (ISP): m/z=415.1 [M+H]+and 417.1 [M+2+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]([O:26]CC)=O)[O:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:29]1([CH2:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][CH2:34][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[CH2:42][CH2:41]3)=[O:26])[O:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: C1CCN(CCCN2CCNCC2)C1
Reactant: CCOC(=O)c1nc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2noc(C(=O)N3CCN(CCCN4CCCC4)CC3)n2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 3-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,2,4-oxadiazole-5-carboxylate (30 mg, 0.07 mmol), 1-[3-(pyrrolidin-1-yl)propyl]piperazine (31 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (3 mL). The crude product was purified using prep method C, then FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=1)=[O:4].[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:21])[F:22])=[CH:11][CH:10]=4)=[O:20])[CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc(NC(=O)C(F)(F)F)cc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(NC(=O)C(F)(F)F)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl {4-[(trifluoroacetyl)amino]phenyl}carbamate (200 mg, 0.527 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (130 mg, 0.527 mmol), diisopropylethylamine (0.184 ml, 1.05 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 12-hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product as a solid. The solid was recrystallized from a mixed solvent of ethyl acetate and hexane to give 43.0 mg (17.1%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH:41]1([C@H:44]([NH:51][CH3:52])[CH2:45][N:46]2[CH2:49][CH:48]([OH:50])[CH2:47]2)[CH2:43][CH2:42]1>CN(C=O)C.C(Cl)Cl>[CH:41]1([C@H:44]([N:51]([CH3:52])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=2)[CH2:45][N:46]2[CH2:49][CH:48]([OH:50])[CH2:47]2)[CH2:43][CH2:42]1
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: CN[C@H](CN1CC(O)C1)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N(C)[C@H](CN2CC(O)C2)C2CC2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
4-Fluoro-3-methylbenzoic acid (0.095 g, 0.62 mmol), TBTU (0.226 g, 0.70 mmol) and 4-methylmorpholine (0.194 mL, 1.76 mmol) was mixed in DMF (2 mL). After 30 min at rt was (S)-1-(2-cyclopropyl-2-(methylamino)ethyl)azetidin-3-ol (Compound J3) (0.1 g, 0.59 mmol) added. The resultant mixture was stirred at rt overnight. Analysis by LCMS indicated formation of both mono and diacylated product. Additional TBTU (0.189 g, 0.59 mmol), 4-fluoro-3-methylbenzoic acid (0.091 g, 0.59 mmol) and NMM (0.129 mL, 1.17 mmol) were added to drive the reaction towards the diacylated product. The resultant mixture was stirred at rt overnight. The mixture was diluted with DCM (5 mL) and the organic phase was washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was dissolved in a mixture of MeOH (3 mL) and NaOH (aq. 3 mL, 1M) and the resultant mixture stirred at rt for 30 min. The solvents were evaporated and the crude mixture purified by preparative HPLC to give the title compound (54 mg, 30%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ −0.13-1.25, 2.01-2.48, 2.60-2.65, 2.73-3.22, 3.39-4.02, 4.21-4.45, 6.96-7.45. Total no of protons: 22. HRMS (M+H)+: calculated 307.1822. found 307.1827.