Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[OH:11].B(F)(F)F.[CH3:16][C:17]1[S:18][C:19]([CH3:27])=[CH:20][C:21]=1[C:22](O)([CH:24]=[CH2:25])[CH3:23].C(O)=C>O1CCOCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[C:4]2[C:3]=1[O:11][C:22]([C:21]1[CH:20]=[C:19]([CH3:27])[S:18][C:17]=1[CH3:16])([CH3:23])[CH2:24][CH2:25]2
Reactant: C=CC(C)(O)c1cc(C)sc1C
Reactant: Cc1cc(O)c(Cl)c(C)c1O
Agent: C=CO
Agent: FB(F)F
Solvent: C1COCCO1
Product: Cc1cc(C2(C)CCc3c(C)c(O)c(C)c(Cl)c3O2)c(C)s1
Temperature: 120 °C
Reaction time: 3 h
Yield: 5.6 %

Procedure:
To a solution of 2-chloro-3,5-dimethyl-benzene-1,4-diol (520 mg) and BF3 etherate (1.28 g) in dioxane (10 mL) at 120° C. was added slowly a solution of the vinyl alcohol 2-(2,5-dimethyl-thiophen-3-yl)-but-3-en-2-ol (600 mg) in 2 mL of dioxane in 30 min. After completion, the solution was stirred at 120° C. for 3 h. Workup and purification by silica gel column chromatography eluting with 10% EtOAc in hexane gave 50 mg off-white solid 4-Chloro-6-(2,5-dimethyl-thiophen-3-yl)-1,3,6-trimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol. 1H NMR (300 MHz, CDCl3) δ: 6.52 (s, 1H), 4.29 (s, 1H, OH), 2.63-2.33 (3s+m, 12H), 2.06-2.01 (s+m, 4H), 1.62 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3 δ: 145.40, 143.98, 139.90, 134.97, 132.28, 125.68, 121.24, 120.34, 119.97, 119.57, 78.05, 32.85, 28.52, 21.74, 15.49, 14.96, 13.49, 11.77 ppm. MS m/z: 337 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](F)[C:6]([CH3:12])=[N:7]2.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:17][CH:14]1[CH2:16][CH2:15]1)[C:6]([CH3:12])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1F
Reactant: NC1CC1
Product: Cc1nc2cccc(Br)c2nc1NC1CC1
Yield: 82.8 %

Procedure:
This compound (1.06 g, 83% yield) as a light yellow crystalline solid was prepared similarly to that described in the preparation of Example 174a, using 5-bromo-3-fluoro-2-methylquinoxaline (Example 126f; 1.11 g, 4.60 mmol) and cyclopropanamine (Aldrich; 1.50 mL, 21.65 mmol) as starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (1H, dd, J=7.6, 1.2 Hz), 7.78 (1H, dd, J=8.2, 1.2 Hz), 7.19-7.26 (1H, m), 5.12 (1H, br. s.), 3.04-3.14 (1H, m), 2.47-2.55 (3H, m), 0.93-1.01 (2H, m), 0.60-0.68 (2H, m). m/z (ESI, +ve) 278/280 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=3)[N:9]=2)[N:8]=1
Reactant: Cc1ccc(C(=O)CBr)cc1[N+](=O)[O-]
Reactant: COc1ccc(N)nn1
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)cn2n1
Yield: 85.2 %

Procedure:
A stirred solution of 6-methoxypyridazin-3-amine (Apollo Scientific, 0.750 g, 5.99 mmol) and 2-bromo-1-(4-methyl-3-nitrophenyl)ethanone (1.54 g, 5.99 mmol) in acetonitrile (20 mL) is heated at 80° C. for 16 hours. The reaction mixture is concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford the title compound (1.45 g, 85%) as a light yellow solid: Rf 0.45 (1:1 EtOAc:hexanes); LCMS (m/z)=285.4 [M+H]+, tR=7.47 min. (10 min run)
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:28])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[F:29][C:30]1[CH:31]=[C:32]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[N:44][C:45]=3[NH2:47])[NH:40][N:39]=2)[CH:33]=[C:34]([O:36][CH3:37])[CH:35]=1>>[NH2:47][C:45]1[N:44]=[CH:43][N:42]=[C:41]2[N:40]([CH:2]([C:4]3[O:5][C:6](=[O:28])[C:7]4[C:12]([C:13]=3[C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:21]5[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]5)=[CH:18][CH:19]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:39]=[C:38]([C:32]3[CH:33]=[C:34]([O:36][CH3:37])[CH:35]=[C:30]([F:29])[CH:31]=3)[C:46]=12
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCN(C)CC2)cc1
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCN(C)CC4)cc3)c3ncnc(N)c23)c1
Yield: 8 %

Procedure:
The title compound was made in a similar way as that of example 134, step a, from 3-(1-hydroxyethyl)-4-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-isochromen-1-one (Intermediate B46, 750 mg, 1.982 mmol) and 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 565 mg, 2.18 mmol) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-isochromen-1-one (98 mg, 0.158 mmol, 7.98% yield) as a brown solid.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[Na:12].C1C(=O)[N:17](OC(ON2C(=O)CCC2=O)=O)[C:15](=[O:16])C1.C(OCC)(=O)C>CS(C)=O>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:15]([NH2:17])=[O:16])=[CH:7][CH:8]=1)([OH:11])(=[O:10])=[O:2].[Na:12]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)Nc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 115 %

Procedure:
A solution of sodium sulfanilic acid (195 mg; 1 mmol) in dry DMSO (3 ml) was added dropwise to a solution of N,N′-disuccinimidyl carbonate (530 mg; 2 mmol) in dry DMSO (4 ml) and the resulting brownish solution stirred at room temperature for 20 hours. A solution of PAMAM 4.0 (EDA) (75 mg; 0.011 mmol) in dry DMSO (1 ml) added and the solution stirred for a further 18 hours. The solution was then concentrated under high vacuum (10−5 mmHg; 35°) to give a yellowish semi-solid. The crude product was dissolved in DMSO (4 ml) and the solution added to 200 ml of well stirred ethyl acetate. The precipitated white solid was collected by filtration and washed with ethyl acetate (2×) and ether (2×), then dried to give a white powder (275 mg). This material was further purified by gel filtration (Sephadex LH20; water) to give PAMAM 4.0 (EDA) terminated with 32 sodium 4-sulfophenylurea groups (106 mg). 1H nmr (D2O): δ2.31; 2.55; 2.75; 3.19; 7.32 (d, J=9 Hz); 7.63 (d, J=9 Hz). 13C nmr (D2O): δ36.3; 40.7; 43.3; 43.8; 53.7; 55.7; 123.3; 130.9; 140.9; 146.0; 161.4; 178.2; 178.6.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]1=O)C.Cl.[NH2:25]N>CCO>[N:25]1[NH:2][CH:4]=[C:5]2[C:6]=1[CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10]2
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC(=CN(C)C)C1=O
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21
Reaction time: 18 h

Procedure:
A solution of enaminoketone 3b (327 mg, 1.00 mmol) in abs. EtOH (10 mL) was cooled to 0° C. and hydrazine monohydrogen chloride was added in one portion. The mixture was stirred for 18 h during which time the temperature reached rt after 2 h. The mixture was concentrated and the residue partitioned with deionized H2O and EtOAc. The organic layer was removed and the aqueous portion extracted with EtOAc (2×). The combined EtOAc portions were washed with brine, dried over MgSO4 and filtered through a SiO2 plug capped with a MgSO4 layer (EtOAc for elution). The solution was concentrated give the title compound 4b as a brittle white foam crushed to a white solid; 253 mg, 87%, MS m/z 240.0, 194.0 (ESI+, M−tBu, M−Boc).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.Cl.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1.C(N(CC)CC)C>C1COCC1>[OH:39][C@H:36]1[CH2:37][CH2:38][C@H:33]([NH:32][C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:30])[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=2)[CH2:34][CH2:35]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@H]2CC[C@H](O)CC2)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 48 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol), trans-4-aminocyclohexanol hydrochloride (151 mg, 1 mmol), and triethylamine (0.28 mL, 2 mmol) were combined in THF (10 mL) and stirred under Ar at 50° for 2 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography with 0-20% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a pale yellow crystalline solid. mp 148-151°, LC MS m/z=463 (MH+) Retention time=2.0 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.C(N(CC)CC)C.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a stirred solution of 1-bromo-3-(bromomethyl)benzene (677 mg, 2.71 mmol) in THF (10 ml) was added triethylamine (380 μL, 2.71 mmol), followed by tert-butyl piperazine-1-carboxylate (504 mg, 2.71 mmol). The mixture was allowed to stir at RT for one hour. The solvent was evaporated and the residue was purified with a silica gel column eluting with 1:10 EtOAc/hexanes to give the title compound as an oil (888 mg, 2.49 mmol, 92%). [M+H] calc'd for C16H24BrN2O2, 355; found, 355.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24]C(N)=O)([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][NH:10][C:11](=[O:28])[O:12][CH2:13][CH3:14])([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Solvent: CCO
Product: CCOC(=O)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide following a procedure analogous to that described in Example 612 using ethanol as solvent. LC-MS Method 1 tR=1.83 min, m/z=493, 495 (M+1); 1H NMR (CD3OD) 7.25-7.20 (m, 4H), 7.03 (t, J=8.8 Hz, 2H), 6.81 (d, J=8.2 Hz, 2H), 5.41 (q, J=7.3 Hz, 1H), 3.91 (q, J=7.2 Hz, 2H), 3.10-3.00 (m, 2H), 2.90-2.85 (m, 1H), 2.38-2.34 (m, 1H), 2.22-2.14 (m, 2H), 2.01 (t, J=7.6 Hz, 2H), 1.42 (d, J=7.3 Hz, 3H), 1.10 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C(O)(=O)C.[OH:15][C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:20][O:21][CH3:22])[CH2:17][CH:18]=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:18][CH2:17][C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:15])[CH2:20][O:21][CH3:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: COCC(O)(CC=O)c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCC(O)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-1-(4-Bromo-phenyl)-ethylamine (0.93 g), NaHB(O2CH3)3 (0.98 g), and acetic acid (0.27 mL) were added in the given order to a solution of 3-hydroxy-4-methoxy-3-phenyl-butyraldehyde (0.90 g) in tetrahydrofuran (20 mL) at ca. 10-15° C. The cooling bath was removed and the mixture was stirred at room temperature for 2 h. Then, water (50 mL) and 1 M aqueous NaOH solution (20 mL) were added and the resulting mixture was stirred for another 30 min. The mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine. After drying (MgSO4), the solvent was removed to give the title compound which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16](O)=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[SH:55][CH2:56][C:57]([OH:59])=[O:58]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([S:55][CH2:56][C:57]([OH:59])=[O:58])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: O=C(O)CS
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)SCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoic acid (0.25 g, 0.724 mmol) in dry DMF (7.5 ml), HATU (0.275 g, 0.724 mmol) and 4-methylmorpholine (0.080 ml, 0.724 mmol) were added, and the resulting solution was stirred under nitrogen at RT until complete conversion of starting acid into the activated ester intermediate (UPLC-MS check). Then 2-mercaptoacetic acid (0.042 ml, 0.603 mmol) was added drop wise, and the reaction was stirred at RT overnight. Additional 2-mercaptoacetic acid (0.008 ml, 0.120 mmol) was added, and the mixture was stirred at the same temperature for 5 days. The solvent was removed under vacuum and the residue was partitioned between EtOAc and HCl 1N; the organic phase was dried over Na2SO4 and the solvent was evaporated. The crude was purified by chromatography on silica gel column (DCM:MeOH=95:5) to afford 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetic acid (0.206 g, 0.491 mmol, 81% yield, MS/ESI+ 419.9 [MH]+). This intermediate was used as such without any further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[ClH:46].O1CCOCC1>CO>[ClH:46].[ClH:46].[ClH:46].[NH2:38][C:34]1([C:31]2[CH:30]=[CH:29][C:28]([C:27]3[N:13]4[C:14]5[CH:26]=[CH:25][CH:24]=[N:23][C:15]=5[NH:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[C:12]4=[N:11][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=3)=[CH:33][CH:32]=2)[CH2:35][CH2:36][CH2:37]1
Reactant: CC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 98 %

Procedure:
tert-Butyl (1-{4-[2-(4-acetylphenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (27 mg, 0.045 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 22.5 hours. The mixture was concentrated to afford the desired product (27 mg, 98%) as a pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.66-8.63 (m, 3H), 8.11 (dd, J=4.6 Hz and 1.7 Hz, 1H), 7.98 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.88 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H), 7.35-7.35 (m, 2H), 7.31 (d, J=7.4 Hz, 1H), 7.14 (t, J=7.2 Hz, 1H), 6.91 (dd, J=8.0 Hz and 1.7 Hz, 1H), 6.74 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.73-3.70 (m, 1H), 3.68-3.65 (m, 1H), 2.64-2.53 (m, 5H), 2.24-2.15 (m, 1H), 1.89-1.80 (m, 1H). LCMS: 498 [M+H].
Reaction SMILES: C(OC([N:11]1[CH2:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[NH:14][C:13](=[O:24])[CH2:12]1)=O)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:15]2[NH:14][C:13](=[O:24])[CH2:12][NH:11][CH2:17][C:16]=2[CH:18]=1
Reactant: COc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2c(c1)CNCC(=O)N2
Reaction time: 2 h
Yield: 98.4 %

Procedure:
A solution of 7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (1.26 g, 3.86 mmol) in ethyl acetate (25 mL) and ethanol (25 mL) was treated with 10% Pd—C (125 mg) and hydrogenated under 40 psi H2 on a Paar apparatus. After two hours LCMS indicated completion of the reaction. The mixture was filtered and concentrated to afford 7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (730 mg, 96%) as a white solid, used without further purification; NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.00 (d, J=8 Hz, 1H), 6.80 (d, J=8 Hz, 1H), 6.78 (s, 1H), 3.80 (s, 2H), 3.72 (s, 3H), 3.38 (s, 2H), 3.00 (br, 1H); MS (m/e) 193 (M+1); mp 148° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[OH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22](=[O:21])[CH:23]=[CH:24]2)[CH:7]=1
Reactant: Oc1ccnc2ccccc12
Reactant: COc1ccc(Br)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Br)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Temperature: 85 °C
Yield: 73.5 %

Procedure:
A mixture of 2-[2-(5-bromo-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (5.0 g, 14.2 mmol), 4-hydroxyquinoline (3.08 g, 21.2 mmol) and sodium ethoxide (21 wt. % solution in ethanol, 5.3 mL, 14.2 mmol) in ethanol (120 mL) was heated at 85° C. for 14 hours. The reaction was quenched with water and concentrated in vacuo to remove most of the ethanol. The residue was diluted with methylene chloride and washed with half saturated sodium bicarbonate (NaHCO3), dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was precipitated from diethyl ether-hexanes to afford 1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (5.2 g, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:21])[C:17](Br)([CH3:19])[CH3:18])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[C:11]([O:15][C:16](=[O:21])[C:17]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:19])[CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Temperature: 140 °C
Yield: 54.4 %

Procedure:
To a solution of 5-chlorosalicylaldehyde (5 g, 32 mmol) in N,N-dimethylformamide (100 mL) was added 2-bromo-2-methyl-propionic acid tert-butyl ester (10.7 g, 48 mmol), Cs2CO3 (3.1 g, 95 mmol). The reaction mixture was heated at 140° C. for 18 h. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over Na2SO4 and concentrated to give 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid tert-butyl ester as a pale yellow solid (Yield 5.2 g, 54%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].O.[NH2:21][C:22]1[CH:23]=[C:24]([C:32]([NH:34][NH2:35])=[O:33])[C:25](=[CH:30][CH:31]=1)[C:26](NN)=[O:27].C(=O)([O-])[O-].[Na+].[Na+].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.Cl>COCCO>[O:27]=[C:26]1[C:25]2[C:24](=[CH:23][C:22]([NH:21][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])=[CH:31][CH:30]=2)[C:32](=[O:33])[NH:34][NH:35]1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: NNC(=O)c1ccc(N)cc1C(=O)NN
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(=O)[nH][nH]c(=O)c4c3)c2cc1OCC
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 273 mg (1.54 mM) of 4-Aminophthalhydrazide Hydrate in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solution was made acetic by addition of concentrated HCl and the solid was collected, washed with water followed by ether and dried under vacuum at 80° C. The solid was taken up into 200 ml of methanol and 500 μl of 5 N sodium hydroxide and boiled for 20 minutes. To this heterogeneous mixture was added 100 ml of glacial acetic acid and the volume was reduced to a total of 100 ml by boiling. To the room temperature mixture, 500 ml of ice cold water was added and the solid was collected, washed with water followed by ether and dried under vacuum at 80° C. The solid was digested in 400 ml of ethanol until the volume had been reduced to 150 ml. The hot solution was filtered and the solid was washed with ethanol and to dried under vacuum at 80° C. yield 121 mg of the title compound as a white solid: mass spectrum (electrospray, m/e): M+H 418.0, mp=>270° C.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=O)[NH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([C:8]1[C:9]([SH:16])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cccc1Cc1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Sc1ncccc1Cc1ccccc1
Reaction time: 8 h
Yield: 16.7 %

Procedure:
3-Benzyl-2-pyridone (1.65g, 8.9 mmol) and P2S5 (1.98 g, 8.9 mmol) were heated at reflux for 22 hours under argon in pyridine (17ml), and then allowed to stand overnight at ambient temperature. The mixture was diluted with brine and extracted with ethyl acetate. The ethyl acetate extracts were dried (MgSO4) and purified by chromatography using 5% CH3OH--CH2Cl2 as eluant followed by recrystallization from CH2Cl2 --ether--hexane to yield 300 mg (15%) of 3-benzyl-2-mercaptopyridine: m.p. 129°-130° C. That the 3-benzyl isomer had been isolated was confirmed by use of proton NMR spectroscopy.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21]>CO>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 22 h
Yield: 101 %

Procedure:
A solution of amorphous ibandronic acid (5 g) in methanol (100 ml) was stirred at room temperature. Solid sodium hydroxide (0.63 g) was added. The obtained precipitate was stirred at room temperature for an additional 22 hours. The precipitate was isolated by vacuum filtration, washed with methanol (30 ml), and dried in a vacuum oven at 50° C. for 24 hours to obtain 5.4 g of ibandronate sodium crystal form Q5.