Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:10][C:11]([NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=[O:12].[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>O1CCOCC1.O>[CH3:38][C:37]1[CH:39]=[CH:40][C:34]([S:31]([NH:7][CH2:8][CH:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:10][C:11]([NH:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])(=[O:33])=[O:32])=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1ccc(NC(=O)CC(CN)c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)CC(CNS(=O)(=O)c2ccc(C)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Potassium carbonate (0.325 g, 2.35 mmol) was added to a solution of 51 (0.128 g, 0.392 mmol) in 1,4-dioxane/H2O 1:1 (5 mL) and followed by tosyl chloride (0.074 g, 0.392 mmol) at room temperature. After stirring for 2 h at room temperature, the resulting mixture was evaporated in vacuo to dryness. Water (10 ml) was added and the resulting white solid was separated by filtration and dried in vacuo. Pure 55 was obtained as an off-white solid (0.122 g, 0.254 mmol, 65%) without further purification, mp 135-137° C. 1H NMR (400 MHz, CD3OD) 1.36 (3H, t, J 7.2 Hz), 2.39 (3H, s), 2.63 (1H, dd, J 8.6, 14.6 Hz), 2.85 (1H, dd, J 6.2, 15.0 Hz), 3.05 (1H, dd, J 7.4, 13.0 Hz), 3.12 (1H, dd, J 6.8, 11.8 Hz), 4.32 (2H, q, J 7.2 Hz), 7.17-7.19 (3H, m), 7.23-7.27 (2H, m), 7.31 (2H, d, J 8.0 Hz), 7.54 (2H, d, J 8.4 Hz), 7.65 (2H, d, J 8.4 Hz), 7.90 (2H, d, J 8.8 Hz). 13C NMR (100 MHz, CDCl3) 14.57, 21.73, 40.65, 42.04, 47.77, 61.07, 119.15, 127.14, 127.75, 127.77, 129.29, 130.07, 130.94, 136.79, 140.74, 142.12, 143.97, 166.36, 170.24. νmax (solid)/(cm−1) 3324, 3191, 1707, 1675, 1597, 1534, 1270, 1157, 1105. MS (API-ES): m/z 481 [M+H]+ (100%), HRMS (API-ES) m/z found 481.1801 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[C:6](=[O:12])[NH:7]2.C1CCC(N=C=NC2CCCCC2)CC1.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][NH:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:13][C:14]([N:42]([CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:16])[C:6](=[O:12])[NH:7]2
Reactant: Cc1ccnc2[nH]c(=O)c(CC(=O)O)cc12
Reactant: COC(=O)CNCCNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Cc1cc2c(C)ccnc2[nH]c1=O
Reaction time: 0.67 h
Yield: 31.6 %

Procedure:
To a precooled (0° C.) solution of (5-methyl-1,8-naphthyridin-2(1H)-on-3-yl)acetic acid (1.20 g, 5.50 mmol) and DhbtOH (0.987 g, 6.10 mmol) in DMF (25 mL) was added DCC (1.25 g, 6.10 mmol) and the resulting mixture was stirred for 40 min. prior to the addition of methyl N-(2-(tert-butyloxycarbonyl)aminoethyl)glycinate (1.32 g, 6.10 mmol). The mixture was stirred at rt. overnight, evaporated in vacuo, redissolved in ethyl acetate (75 mL) and the DCU filtered off. The organic phase was washed with NaHCO3 (3×25 mL) and with brine (2×25 mL), dried (MgSO4) and evaporated in vacuo. The crude product was purified on silica using MeOH/dichloromethane (95:5 to 90:10 v/v) as the eluent. Fractions containing the product were pooled and evaporated in vacuo. to yield the desired product (752 mg, 33%) (mp 175-77° C.). 1H NMR (DMSO-d6; this compound exists as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 12.10 (12.08), (s br, 1H), 8.33 (8.33) (d, J=4.8 Hz, 1H), 7.96 (7.90) (s, 1H), 7.09 (d, J=4.8 Hz, 1H), 6.92 (6.70) (m, 1H), 4.07 (4.37) (s, 2H), 3.67 (s, 2H), 3.64 (s, 3H), 3.46 (m, 2H), 3.17 (m, 2H), 2.54 (2.53) (s, 3H), 1.37 (1.35) (s, 9H). 13C NMR (DMSO-d6): δ 170.30 (170.50), 170.04, 162.30, 155.73, 149.47, 149.25, 145.16, 132.92 (133.56), 129.12 (129.28), 119.87, 113.35, 77.97, 52.13, 51.76 (50.12), 47.47 (48.16), 38.98 (38.39), 33.81 (33.99), 28.24, 17.66. FAB+MS (m/z): 433.2087 (M+H+, calc. for C21H28N4O6+H+ 433.2086).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[CH:53][C:52]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[CH:53][C:52]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:60]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c(OC)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,4′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.019 g of product in 70% yield: LCMS (ESI) m/z 418 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][C:3]=1[NH:15][C:16](=[O:32])[C@@H:17]([NH:25][CH2:26][C:27]1[N:28]=[CH:29][S:30][CH:31]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:3]([NH:15][C:16](=[O:32])[C@@H:17]([NH:25][CH2:26][C:27]3[N:28]=[CH:29][S:30][CH:31]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:4]=2)[CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc(-c2ccc(O)c(NC(=O)[C@H](Cc3ccccc3)NCc3cscn3)c2)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccnc(C)c2)cc1NC(=O)[C@H](Cc1ccccc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
Phenol 64.D (248 mg, 0.56 mmol), methyl 2-bromoacetate (85 mg, 0.56 mmol), and Cs2CO3 (182 mg, 0.56 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 1 h. The reaction mixture was partitioned with EtOAc/H2O and the aqueous layer was exctracted with EtOAc (3×). The organic layers were combined, dried with sodium sulfate, filtered, and concentrated. The crude product was first purified on a silica gel column (12 g, 0-10% MeOH:DCM) and then by prepHPLC(C18, ACN:H2O:0.1% TFA, gradient). The desired fractions were combined, partially concentrated on a rotavap, neutralized with NaHCO3 (sat), and extracted with DCM (2×). The organic layers were combined, dried with sodium sulfate, filtered, and concentrated to yield 64 (190 mg, 66%). LC-MS (+esi, M+H+=517.2). 1H NMR (400 MHz, MeOH) δ ppm 8.86 (d, J=1.96 Hz, 1H) 8.59 (d, J=2.35 Hz, 1H) 8.42 (d, J=5.09 Hz, 1H) 7.56 (s, 1H) 7.46-7.51 (m, 2H) 7.34 (d, J=1.96 Hz, 1H) 7.19-7.30 (m, 5H) 7.09 (d, J=8.61 Hz, 1H) 4.84 (s, 2H) 3.85-4.02 (m, 2H) 3.78 (s, 3H) 3.59 (dd, J=8.41, 4.89 Hz, 1H) 3.19 (dd, J=13.69, 5.09 Hz, 1H) 2.92 (dd, J=13.69, 8.61 Hz, 1H) 2.60 (s, 3H).
Reaction SMILES: BrCC(O)C.Br[CH:7]([CH3:10])[CH2:8][OH:9].[F:11][C:12]1[CH:13]=[C:14]([OH:22])[CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([S:18]([CH3:21])(=[O:19])=[O:20])[CH:17]=1)[O:22][CH:7]([CH3:10])[CH2:8][OH:9]
Reactant: CC(Br)CO
Reactant: CS(=O)(=O)c1cc(O)cc(F)c1
Agent: CC(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CO)Oc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 120 °C

Procedure:
A mixture of 1-bromo-2-propanol (70%) and 2-bromo-1-propanol (30%) (5.81 g, 41.8 mmol) was added to a solution of 3-fluoro-5-methylsulfonyl-phenol (1.59 g, 8.36 mmol) and potassium carbonate (2.37 g, 16.71 mmol) in dry dimethyl formamide (10 ml), the mixture was heated to 120° C. for 20 hours, the mixture was allowed to cool to ambient temperature and water (100 ml) was added. The aqueous phase was extracted with ethyl acetate (3×100 ml), the combined organic phase was washed with LiCl (5% aqueous solution, 4×50 ml), brine (50 ml) and dried with Na2SO4 and evaporated. Purification flash chromatography (isooctane:ethyl acetate 1:0 to 3:2). 0.65 g (mixture of 1-(3-fluoro-5-methylsulfonyl-phenoxy)propan-2-ol and 2-(3-fluoro-5-methylsulfonyl-phenoxy)propan-1-ol), 31%. MS m/z (relative intensity, 70 eV) 248 (M+, 14), 204 (54), 203 (bp), 191 (37), 190 (44).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([OH:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][C:3]([O:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromoacetylchloride (52.11 grams) is added dropwise into a stirred solution of 89.27 grams of octadecanol and 50 ml of triethylamine in 400 ml of methylene chloride at 25°-30° C. After stirring the reaction mixture at room temperature overnight under N2, the mixture is filtered and the filtrate is concentrated under reduced pressure. Purification by liquid chromatography affords octadecyl bromoacetate as a white solid, mp 37°-40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.O>CS(C)=O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH:16]=[O:17])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CO)CC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ncccc1CN1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
16.1 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinemethanol and 38 ml of triethylamine were suspended in 60 ml of dimethyl sulfoxide, a mixed solution of 21.7 g of a sulfur trioxide-pyridine complex and 100 ml of dimethyl sulfoxide was added dropwise thereto, and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 10.9 g of the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:26])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH:23]([CH3:25])[CH3:24])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35]>CN1C(=O)CCC1.CC#N>[F:26][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:32]4[CH2:33][CH2:34][NH:29][C:30](=[O:35])[CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH:23]([CH3:25])[CH3:24]
Reactant: O=C1CNCCN1
Reactant: CC(c1c(F)cc2c(cnn2C(C)C)c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: CC(c1c(F)cc2c(cnn2C(C)C)c1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 180 °C
Reaction time: 3 h

Procedure:
(rac)-6-chloro-3-(1-(4,6-difluoro-1-isopropyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine (Intermediate U, 56.4 mg, 0.15 mmol), KF (44.5 mg, 0.75 mmol) and piperazin-2-one (46.4 mg, 0.45 mmol) were suspended in NMP (0.5 mL). The RM was stirred at 180° C. for 3 h. The mixture was diluted with CH3CN and purified by reverse phase chromatography (Büchi MPLC: 5-28% CH3CN, 0.1% HCOOH). The fractions was combined, concentrated and neutralized with NaHCO3, extracted with EtOAc. The combined organics layers were tried over Na2SO4, filtered, concentrated, crystallized in EtOAc to afford the title compound as a white solid (tR 3.98 min (conditions 5), MH+=440.3, 1H-NMR in DMSO-d6: 8.09 (s, 1H); 7.80 (d, 1H); 7.53 (s, 1H); 7.41 (d, 1H); 7.05 (d, 1H), 4.86 (m, 2H); 4.03 (d, 1H); 3.74 (d, 1H); 3.54 (d, 2H); 3.17 (m, 2H); 1.79 (d, 3H); 1.41 (m, 6H)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[C@H:24]1[CH2:31][OH:32].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[C@H:24]1[CH2:31][OH:32]
Reactant: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1CO

Procedure:
Following the procedure in example 17, compound of example 131 (0.155 g, 0.33 mmol) was demethylated using pyridine hydrochloride (2.0 g, 17.3 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[H-].[Na+].Cl[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1>CN(C=O)C>[CH3:47][S:44]([C:41]1[CH:42]=[CH:43][C:38]([CH2:37][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][C:3]=2[O:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:39][CH:40]=1)(=[O:45])=[O:46]
Reactant: O=C(NC1=Nc2c(ccc(OCCCN3CCOCC3)c2O)C2=NCCN12)c1cccnc1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(COc2c(OCCCN3CCOCC3)ccc3c2N=C(NC(=O)c2cccnc2)N2CCN=C32)cc1
Reaction time: 16 h
Yield: 70.3 %

Procedure:
N-[7-Hydroxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (Intermediate H, 0.09 g, 0.20 mmol) was suspended in DMF (2.0 mL) and NaH (0.02 g, 0.30 mmol, 60%) were added. After 20 min at rt 1-(chloromethyl)-4-(methylsulfonyl)benzene (0.06 g, 0.30 mmol) was added and the mixture was stirred at it for 16 h. The DMF was evaporated under reduced pressure and the residue triturated with a mixture of −10% MeOH in CH2Cl2 (4 mL). The mixture was vacuum filtered and the solids were washed well with CH2Cl2. The filtrate was concentrated under reduced pressure, and the residue purified via silica gel chromatography (0-6% MeOH/CH2Cl2). The fractions were combined, and the solvent was evaporated under reduced pressure. Drying under high vacuum gave the title compound (0.087 g, 70%): TLC (5% MeOH/CH2Cl2): Rf=0.47; HPLC MS RT=0.55 min, [M+Na]+=641; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.21-2.35 (2H, m), 3.05-3.17 (2H, m), 3.22 (3H, s), 3.31 (2H, m), 3.42-3.52 (2H, m), 3.60-3.72 (2H, m), 3.94-4.04 (2H, m), 4.29 (2H, m), 4.39 (2H, t), 4.56 (2H, m), 5.37 (2H, s), 7.52 (1H, d), 7.72 (1H, dd), 7.85 (2H, d), 8.01 (2H, d), 8.10 (1H, d), 8.66 (1H, d), 8.89 (1H, dd), 9.43 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[C:3]1[CH:42]=[CH:41][C:6]([C:7]([NH:9][C:10]2[C:11]([F:40])=[C:12]([C:16]3[C:28]4[C:27]5[C:22](=[CH:23][C:24]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[CH:25][CH:26]=5)[NH:21][C:20]=4[C:19]([C:35]([O:37]CC)=[O:36])=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][N:2]([CH3:43])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([F:40])=[C:12]([C:16]3[C:28]4[C:27]5[C:22](=[CH:23][C:24]([N:29]6[CH2:30][CH2:31][O:32][CH2:33][CH2:34]6)=[CH:25][CH:26]=5)[NH:21][C:20]=4[C:19]([C:35]([OH:37])=[O:36])=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:41][CH:42]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)c3ccc(N(C)C)cc3)c2F)c2c1[nH]c1cc(N3CCOCC3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccc(C(=O)Nc2cccc(-c3cnc(C(=O)O)c4[nH]c5cc(N6CCOCC6)ccc5c34)c2F)cc1
Yield: 84 %

Procedure:
To a suspension of ethyl 4-(3-(4-(dimethylamino)benzamido)-2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate (0.138 g, 0.237 mmol) in methanol (4 mL) at room temperature was added sodium hydroxide (1.068 mL, 1.068 mmol). The mixture was heated at reflux for 45 min. The methanol was removed under vacuum. To the residue was added water (5 mL), and the mixture was acidified with 1 N HCl to pH 5. The insoluble product (0.110 g, 0.199 mmol, 84% yield) was collected as a tan solid with suction filtration and dried at 50° C. under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH3:18]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a cooled solution of 4-methoxy-2-nitroaniline (25 g; 0.15 mol) in pyridine (370 ml), ethyl chloroformate (17.8 ml; 0.18 mol) was added dropwise. The mixture was refluxed for 10 hours, then cooled and poured into ice-water. The precipitated solid was collected and purified by flash chromatography (silica gel, eluent: hexane/diethyl ether 85:15) to yield the title compound as a yellow solid. 7.3 g; m.p. 56-57° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[C:14]([O:24][CH3:25])=[C:15]([CH:21]=[CH:22][CH:23]=3)[O:16][CH2:17][C:18](O)=[O:19])[N:10]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:68][CH:69]([CH3:72])[CH2:70][OH:71]>CN(C=O)C.CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[C:14]([O:24][CH3:25])=[C:15]([CH:21]=[CH:22][CH:23]=3)[O:16][CH2:17][C:18]([NH:68][CH:69]([CH3:72])[CH2:70][OH:71])=[O:19])[N:10]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1c(OCC(=O)O)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1ccccc1O
Reactant: CC(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCC(=O)NC(C)CO)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1ccccc1O
Reaction time: 16 h

Procedure:
To {3-[5-(4-Fluoro-phenyl)-3-(2-hydroxy-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetic acid (0.27 mmol) in dry DMF (0.5 mL) is added HATU (1.35 mmol), DIEA (0.45 mL, 2.7 mmol) and 2-amino-propan-1-ol. The mixture is kept at ambient temperature for 16 hours. The residue is diluted with EtOH (1 mL). Purification of the mixture by preparative LC/MS (30-100% MeCN/H2O) gives 2-{3-[5-(4-fluoro-phenyl)-3-(2-hydroxy-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-N-(2-hydroxy-1-methyl-ethyl)-acetamide. 1H NMR (400 MHz, CDCl3) δ 11.2 (s, 1H), 8.53 (m, 1H), 7.73 (m, 2H), 7.6 (s, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.15 (t, J=8 Hz, 2H), 6.9-7.1 (m, 5H), 4.58 (s, 2H), 4.14 (m, 1H), 4.06 (s, 3H), 3.69 (m, 1H), 3.59 (m, 1H), 2.1 (bs, 2H), 1.23 (m, 3H); LC/MS (ES+): 540.1 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([O:20][CH3:21])=[O:19])=[C:9]1[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:27])=[CH:14][CH:15]=2)[C:10]([C:18]([O:20][CH3:21])=[O:19])=[C:9]1[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(O)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 1-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylate (Compound 32, 560 mg, 1.73 mmol) in DMF (6.0 ml) was added methyl iodide (0.32 ml, 5.20 mmol) and K2CO3 (718 mg, 5.20 mmol). The mixture was stirred at room temperature for 16 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc-hexanes to yield methyl 1-benzyl-2-isopropyl-5-methoxy-1H-indole-3-carboxylate (Compound 33) as a yellow solid.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=2C)=[O:18])[CH:12]=1>O1CCCC1>[CH:1]1([O:7][C:11]2[N:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[O:18])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1)c1cc(OC2CCCCC2)ncn1
Reaction time: 0.17 h

Procedure:
Cyclohexanol (Fluka, 4.00 mL; 37.8 mmol) was treated with sodium hydride (35.0 mg; 0.80 mmol) and stirred during 10 minutes. Tetrahydrofuran (3 mL) was added, followed by 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide. Intermediate 7 (50.0 mg; 0.20 mmol). After 2 hours the solvents were removed in vacuo, the crude was redissolved in EtOAc. The organic phase was washed with sat. ammonium chloride and brine, dried over magnesium sulfate, filtered and evaporated in vacuo to give a residue, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH:18]=[CH2:19])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2]C=C>C1(C)C=CC=CC=1>[N:5]1([C:6]([O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:15])[CH2:1][CH2:2][CH:19]=[CH:18][CH2:17][CH2:16]1
Reactant: C=CCCN(CCC=C)C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC=CCC1
Temperature: 50 °C
Yield: 92.5 %

Procedure:
0.15 g Grubb's 2 catalyst was added to a solution of 8 g benzyl dibut-3-enylcarbamate in 680 mL toluene and heated at 50° C. for 5 h. The solvent was removed and the residue was purified by chromatographie on silica gel (ethyl acetate/hexane 1:5) to yield 6.6 g of the desired product. (M+H)+: 232
Reaction SMILES: [CH2:1]([CH:4]([CH2:25][CH2:26][CH3:27])[C:5]([O:7][CH2:8][CH2:9][C:10](=[O:24])[O:11][CH:12]1[CH2:17][O:16]C(C2C=CC=CC=2)[O:14][CH2:13]1)=[O:6])[CH2:2][CH3:3]>C(O)C.[Pd]>[CH2:25]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([O:7][CH2:8][CH2:9][C:10]([O:11][CH:12]([CH2:13][OH:14])[CH2:17][OH:16])=[O:24])=[O:6])[CH2:26][CH3:27]
Reactant: CCCC(CCC)C(=O)OCCC(=O)OC1COC(c2ccccc2)OC1
Agent: [Pd]
Solvent: CCO
Product: CCCC(CCC)C(=O)OCCC(=O)OC(CO)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
3-oxo-3-(2-phenyl-1,3-dioxan-5-yloxy)propyl 2-propylpentanoate (2.99 g, 7.9 mmol) was dissolved in ethanol (90 ml) under argon. Palladium catalyst (10 wt % Pd/C) (300 mg) was added, the flask was evacuated and allowed to stir 1 atm of hydrogen gas at room temperature for 16 hours. The crude reaction mixture was passed through a glass microfiber on a sintered funnel. The volatiles were removed under reduced pressure yielding 2.01 g (6.95 mmol, 88%) of a clear oil. The product was used without any further purification