Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]1([S:7][C@@H:8]2[O:16][C@H:15]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:13]([O:14][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:11]([O:12][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:9]2[O:10][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H]1OC(=O)C(C)(C)C
Temperature: 95 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 1-deoxy-1-(phenylthio)-β-D-galactopyranose (0.38 g, 1.4 mmol) in 25 mL of pyridine, pivaloyl chloride (1.75 mL, 14.0 mmol) and DMAP (0.200 g, 1.40 mmol) are added. The reaction mixture is stirred at 90-100° C. for 8 h. Pyridine is removed under reduced pressure, and the residue is dissolved in 100 mL of CH2Cl2 and washed with dilute HCl (100 mL), H2O (100 mL), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (10% EtOAc/hexane) to give 0.65 g (76%) of 1-deoxy-1-(phenylthio)-2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranose 40: Rf 0.59 (15% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz) δ 7.97 (d, J=8.9 Hz, 2 H, ArH), 7.70 (t, J=7.3 Hz, 1 H, ArH), 7.60 (t, J=7.3 Hz, 2 H, ArH), 5.39 (t, J=9.9 Hz, 1 H, H-2), 5.30 (d, J=3.0 Hz, 1 H, H-4), 5.10 (dd, J=9.9, 3.0 Hz, 1 H, H-3), 4.57 (d, J=9.9 Hz, 1 H, H-1), 4.05-4.20 (m, 2 H, H-6), 3.79 (dd, J=10.6, 5.9 Hz, 1 H, H-5), 1.25-(s, 9 H), 1.18 (s, 9 H), 1.08 (s, 9H), 0.92 (s, 9 H). 13C NMR (CDCl3, 270 MHz) δ 177.7, 177.0, 176.7, 176.3, 134.4, 134.2, 131.0, 128.7, 89.4, 74.9, 71.7, 65.9, 63.9, 60.5, 38.4, 38.7, 38.6, 27.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:21]([O:23]C)=[O:22])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O.CO>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:21]([OH:23])=[O:22])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C)c(C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Adapting a literature known protocol (Dayal, et al., Steroids, 1990, 55(5), 233-237), a reaction mixture of methyl 3-[3-tert-butoxy-1-[(tert-butoxycarbonylamino)methyl]-3-oxo-propyl]-4-methyl-benzoate (8d) (4.08 g, 10.0 mmol) and commercial lithium hydroxide monohydrate (LiOH.H2O) in a mixture of water (20 mL) and methanol (MeOH) (5 mL) is stirred at room temperature. The reaction is monitored by TLC and/or LC/MS to completion. The solvent is partially removed under reduced pressure using a rotary evaporator. The pH of the residue is adjusted to ˜1-2 with a 10.0M hydrochloric acid (HCl). The aqueous phase is extracted with ethyl acetate (4×) and the combined organic extracts are washed with and brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents removed under reduced pressure using a rotary evaporator to yield the target compound 3-[3-tert-butoxy-1-[(tert-butoxycarbonylamino)methyl]-3-oxo-propyl]-4-methyl-benzoic acid (8e), which can be used directly in the next step.
Reaction SMILES: C([Li])CCC.[CH:6]1[C:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23]Br)[CH3:20].C(Cl)Cl>C(OCC)C>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][C:6]1[C:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH3:20]
Reactant: CCOC(CBr)OCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(Cc1cccc2c1Cc1ccccc1-2)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of n-butyllithium (100.0 mL, 1.6 M, 0.161 mol) in hexanes was added dropwise to a cooled (0° C.) solution of fluorene (26.75 g, 0.161 mol) in 200 mL of diethyl ether. The reaction solution turned orange and was warmed to 25° C. for 30 minutes. The orange solution was added dropwise to a cooled (0° C.) solution of bromoacetaldehyde diethylacetal (25.0 mL, 0.161 mol) in 50 mL of diethyl ether. The reaction solution was stirred for 12 hours and the solvent then removed in vacuo leaving purple oil. Methylene chloride (300 mL) was added to the residue to give a cloudy white mixture, which was extracted with deionized water (5×100 mL). The yellow organic layer was dried over Na2SO4 and the solids were then separated by filtration. Solvent was removed from the filtrate in vacuo to leave a pale yellow oil which solidified to a yellow waxy solid upon standing. Yield: 42.2 g, 0.149 mol (93%). 1H NMR (CDCl3, 600 MHz): δ 7.73 (d, 3JHH=7.8 Hz, 2H, flu-H4), 7.54 (d, 3JHH=7.8 Hz, 2H, flu-H1), 7.34 (t, 3JHH=7.2 Hz, 2H, flu-H3), 7.28 (t, 3JHH=7.2 Hz, 2H, flu-H2), 4.69 (t, 3JHH=6.0 Hz, 1H, CH), 4.08 (t, 3JHH=7.2 Hz, 1H, flu-CH), 3.52 (dm, 4H, OCH2CH3), 2.21 (dd, 2H, CH2), 1.13 (t, 3JHH=7.2 Hz, 6H, OCH2CH3). 13C{1H} NMR (CDCl3, 150.8 MHz): 147.25 (s, C1-a), 140.81 (s, C4a), 126.96 (s, C2), 126.82 (s, C3), 124.73 (s, C1), 119.78 (s, C4), 101.41 (s, CH), 61.45 (s, OCH2CH3), 43.93 (s, C9), 37.49 (s, CH2), 15.27 (s, OCH2CH3). MS (ES) m/z (assignment, relative intensity): 305.2 (C19H22O2Na, [M+Na]+, 100%). Anal. Calcd. for C19H22O2: C, 80.82; H, 7.85. Found: C, 80.89; H, 8.09.
Reaction SMILES: [CH:1]([CH:4]([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7](=[O:9])[CH3:8])([CH3:3])[CH3:2].C>C(OCC)(=O)C.[Pd]>[CH:1]([CH:4]([CH2:5][CH2:6][C:7](=[O:9])[CH3:8])[CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:3])[CH3:2]
Reactant: CC(=O)C=CC(CCC(C)=O)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCC(CCC(C)=O)C(C)C

Procedure:
1.96 G (10 mM) of 5-isopropyl-non-3-ene-2,8-dione, prepared according to the method described in paragraph a) of Example 2, in 20 ml of ethyl acetate were reduced by catalytic hydrogenation in the presence of 0.196 g of palladium at 10% over charcoal. After filtration and evaporation of the volatile portions, a residue was obtained which by fractional distillation gave 1.77 g (89%), of the desired dione;
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[Cl:9].[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>C(O)(C)C>[Cl:9][C:3]1[N:4]=[N:5][C:6]([Cl:8])=[CH:7][C:2]=1[N:11]([CH2:12][CH2:13][OH:14])[CH3:10]
Reactant: CNCCO
Reactant: Clc1cc(Br)c(Cl)nn1
Solvent: CC(C)O
Product: CN(CCO)c1cc(Cl)nnc1Cl
Yield: 90.1 %

Procedure:
A solution of 4-bromo-3,6-dichloro-pyridazine (1.11 g, 5 mmol). (J. Chem. Soc., Perkin Trans I, 1974, 696), and 2-(methylamino)ethanol (0. 75 g, 10 mmol) in isopropanol (10 ml) was heated at reflux for 30 minutes. The solvent was removed by evaporation, the residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH9 with solid potassium carbonate. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give 2-(N-(3,6-dichloropyridazin-4-yl)-N-methylamino)ethanol (1 g, 90%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1.C[C:29](C)([O-:31])C.[K+]>CO>[CH3:29][O:31][CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1
Reactant: CC(C)(C)[O-]
Reactant: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(CCl)o4)cc23)c1
Agent: [K+]
Solvent: CO
Product: COCc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A solution of 2-(chloromethyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (0.30 g, 0.76 mmol) and potassium tert-butoxide (85%, 0.12 g, 0.91 mmol) in methanol (5 mL) was stirred overnight at room temperature. Potassium tert-butoxide (85%, 0.03 g, 0.23 mmol) was added to the reaction mixture, and the resulting mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) and recrystallized from hexane/ethyl acetate to give the title compound (0.20 g, yield 67%) as colorless crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 4-methoxyphenol (5.0 g, 40 mmol) in N,N-dimethylformamide (50 mL) was added 60% sodium hydride (1.6 g, 40 mmol) under ice-cooling, and the mixture was stirred for 30 min. Ethyl bromoacetate (7.4 g, 44 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:1) to give the title compound (8.0 g, yield 94%). oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:3]([OH:19])[C:4]([N:6]1[CH2:17][C@@H:16]([Cl:18])[CH2:15][C@H:7]1[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5].[CH2:27]([O:34][C:35]([NH:37][C@@H:38]([CH2:42][CH2:43][S:44](=[O:47])(=[O:46])[NH2:45])[C:39](O)=[O:40])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]([NH:37][C@@H:38]([CH2:42][CH2:43][S:44](=[O:46])(=[O:47])[NH2:45])[C:39]([NH:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:3]([OH:19])[C:4]([N:6]1[CH2:17][C@@H:16]([Cl:18])[CH2:15][C@H:7]1[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])=[O:40])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: NS(=O)(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCS(N)(=O)=O)NC(=O)OCc1ccccc1
Yield: 77.6 %

Procedure:
Following a procedure similar to that described in Example 66, but using 122 mg (0.32 mmol) of (4S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide [prepared as described in Preparation 21(b)] and 100 mg (0.32 mmol) of (S)-2-benzyloxycarbonylamino-4-sulfamoylbutyric acid, 169 mg of the title compound were obtained as a colorless powder, melting at 115°-122° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[CH:18]=2)[C:13]([OH:15])=O)=[N:7][CH:8]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:13](=[O:15])[C:12]2[CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[CH:18]=[C:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:11]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cn3)cc(C(=O)O)c2)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Oc3ccc(C#N)cn3)cc(Oc3ccc(C#N)cn3)c2)CC1
Yield: 62.5 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoic acid 0.6 g (1.67 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.31 g, 1.67 mmol) were used to afford 0.55 g of the required product. 1HNMR (DMSO-d6): δ 1.42 (9H, s), 3.45 (6H, m), 3.56 (2H, m), 7.20 (2H, d), 7.27 (1H, t), 7.32 (2H, d), 8.37 (2H, dd), 8.70 (2H, d).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][N:27]([CH2:29][CH2:30][CH2:31][NH2:32])[CH3:28]>O1CCOCC1>[CH3:26][N:27]([CH3:28])[CH2:29][CH2:30][CH2:31][NH:32][C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc3ccccc23)CC1
Reactant: CN(C)CCCN
Solvent: C1COCCO1
Product: CN(C)CCCNc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1

Procedure:
tert-Butyl 4-(2-chloroquinazolin-4-ylamino)piperidine-1-carboxylate (3.34 g. 9.21 mmol) and 3-(N,N-dimethyl amino)propylamine (2.9 ml, 23.03 mmol) in dioxane (15 ml) in a sealed-tube were heated to 120° C. overnight. The solvent was removed and the crude product was purified by silica gel column chromatography using 10% NH3 ca. 7 N MeOH in CH2Cl2 and 90% CH2Cl2 solution as eluent to produce the title compound as a pure white solid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10]CC)=[O:9]>O.CCO>[Cl:3][C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]([CH3:14])([CH3:13])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of KOH (2.48 g, 44.2 mmol, 15 eq) in H2O (12 mL) was added a solution of ethyl 2-(2,4-dichlorophenoxy)-2-methylpropionate (compound 5; 0.80 g, 2.89 mmol) in EtOH (12 mL). The solution was stirred at room temperature for 4 hours, then excess EtOH was removed under vacuum. The remaining aqueous solution was washed with EtOAc (10 mL), then acidified with concentrated aqueous HCl. The aqueous mixture was then extracted with EtOAc (10 mL), and the organic extract dried over Na2SO4, filtered, and evaporated to yield a thick, colorless oil which was used without further purification: 1H NMR (CDCl3) δ 7.42-7.41 (d, 1H), 7.19-7.15 (dd, 1H), 7.04-7.01 (d, 1H), 1.64 (s, 6H).
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C(N(CCCC)CCCC)CCC.ClC(OCC(C)C)=O.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45]>CN(C)C=O>[OH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1
Reactant: NCCCCCCO
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCCO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
A mixture of 10.0 g (41 mmoles) biotin (1) and 800 ml N,N-dimethylformamide was stirred until all of the biotin had dissolved. Then 12.8 ml (53.8 mmoles) of tributylamine was added and the solution stirred for 10 minutes. To this solution was added 6.4 ml (49.4 mmoles) of isobutyl chloroformate followed by stirring for 30 minutes. This solution was then slowly added to a cold (-5° C.) solution of 5.80 g (49.4 mmoles) 6-amino-1-hexanol in 800 ml N,N-dimethylformamide. Addition took place over a 30-minute period, and the temperature of the reaction mixture was maintained at 0° C. during the addition. After addition was complete, the reaction mixture was stirred at 0° C. for 3 hours, then allowed to warm to 20° C. The solution was evaporated under high vacuum (2 Torr) and the residue was dissolved in 400 ml of anhydrous ethanol with heating. The solution was stored at -20° C. overnight, filtered, and the white crystalline precipitate washed with anhydrous ethanol. The washed precipitate was allowed to air dry to yield 13.4 g of white crystals, with an Mp of 170°-176° C. Recrystallization from anhydrous ethanol yielded material of MP 179°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=[CH:7][C:3]=1C(O)=O.[N-:18]=[N+]=[N-].[Na+]>OS(O)(=O)=O>[NH2:18][C:3]1[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=1[Cl:1])[CH2:11][NH:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cc(CNC(=O)C2CC2)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1cc(CNC(=O)C2CC2)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoic acid (5.0 g, 19 mmol) in conc. H2SO4 (30 mL) was added NaN3 (1.4 g, 21 mmol) lotwise at 50° C. The reaction mixture was stirred at 50° C. for 18 h. The reaction mass was quenched with ammonia and ice water. The solid obtained was filtered and suck dried to afford 3.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.66 (m, 4H), 1.56 (m, 1H), 4.12 (d, J=6.0 Hz, 2H), 5.27 (s, 2H), 6.41 (d, J=6.9 Hz, 1H), 6.61 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 8.48 (m, 1H); MS (m/z): 225.22 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.O.O.O.O.O.[OH-].C[N+](C)(C)C.[CH3:33][O:34][CH2:35][CH2:36]Br.Cl>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:36][CH2:35][O:34][CH3:33])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Reactant: COCCBr
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Temperature: 50 °C
Reaction time: 36 h
Yield: 110.5 %

Procedure:
To 4-(6-chloro-2,3-dihydro-indol-1-yl)-quinazolin-7-ol (125 mg, 0.42 mmol; from Example 65) in DMF (2 mL) was added H2O (50 μL), K2 CO3 (s) (116 mg, 0.84 mmol), and tetramethylammonium hydroxide pentahydrate (15 mg, 0.08 mmol) followed by 2-bromoethyl methyl ether (43 μL, 0.46 mmol). The mixture was stirred at 50° C. under N2(g) for 24 hours before another aliquot (43 μL) of 2-bromoethyl methyl ether was added. Stirring at 50° C. was continued for another 36 hours before extractive workup and chromatography analogous to that described in Example 1 followed by conversion to the HCl salt as outlined for Example 2 afforded 91 mg (61%) of product. (M.P. 213°-216° C. (dec); LC-MS: 356 (MH+); anal. RP18-HPLC RT: 4.73 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[OH:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)c(Cl)c3)nc3ccccc23)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)c(Cl)c3)nc3ccccc23)n[nH]1
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
To crude (3-chloro-4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (458 mg, 1.2 mmol) in 1:1 MeOH/THF (60 mL) at 0° C. was added sodium borohydride (0.048 g, 1.3 mmol), and the solution was stirred for 30 min. The reaction was quenched by addition of 6 N HCl and the mixture was concentrated to dryness. The residue was purified by silica gel chromatography eluting with 0-15% MeOH/DCM. The resulting solid was triturated with methanol to afford (3-chloro-4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanol (42 mg). 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H) 5.70 (s, 1H) 6.01 (s, 1H) 6.41 (s, 1H) 7.36 (t, 1H) 7.47-7.52 (m, 2H) 7.79-7.82 (m, 3H) 8.59 (d, 1H) 10.42 (bs, 1H) 12.16 (bs, 1H); LC-MS (ESI) m/z 384 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH2:24][OH:25])[N:9]=2)[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(Cl)Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH:24]=[O:25])[N:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(CO)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A mixture of N-(7-(5-fluoro-2-methylphenyl)-5-(hydroxymethyl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (80 mg, 0.2 mmol) and Dess-Martin periodinane (120 mg, 0.27 mmol) and methylene chloride (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid (65 mg, 80%), which was used in the next step without further purification.
Reaction SMILES: Cl.[C:2]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1>C(O)C>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]2[NH:20][C:2]3[C:10]4[C:5]([CH2:4][C:3]=3[C:16]=2[CH:15]=1)=[CH:6][CH:7]=[CH:8][CH:9]=4
Reactant: Cc1ccc(NN)cc1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: CCO
Product: Cc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Temperature: 25 °C
Yield: 91.9 %

Procedure:
In a 250 mL round bottom flask, 180 mL of ethanol, 10 mL of HCl, 16.3 grams of 1-indanone (0.124 mole) and 19.5 grams of p-methylphenylhydrazine hydrochloride (0.124 mole) are heated to reflux for six hours. After cooling to 25° C., the resulting precipitate is filtered, washed twice with 100 mL of 10% aqueous ethanol, twice with 50 mL of water, and then twice with 50 mL of hexane. After drying, 25 grams of 8-methyl-5, 10-dihydroindeno[1,2-b]indole is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[C:18]([F:19])=[CH:17][C:15]([NH2:16])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[C:18]([F:19])[C:12]([F:11])=[CH:13][C:14]=2[N+:20]([O-:22])=[O:21])=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1cc(F)c(F)cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4,5-difluoro-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.49 (bs, 1H), 9.04-8.97 (m, 2H), 8.25-8.19 (m, 2H), 7.56-7.53 (m, 1H).