Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[C:3]=1[C:4]([OH:6])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:61]1[CH2:64][CH:63]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:62]1>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[C:3]=1[C:4]([N:61]1[CH2:64][CH:63]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:70])([CH3:69])[CH3:71])[CH2:62]1)=[O:6]
Reactant: O=C(O)c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC1CN(C(=O)c2c(F)cc(F)cc2Nc2ccc(I)cc2F)C1
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
2,4-Difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 μL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [1-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (125 mg) as a colorless oil.
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:36]=[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](=[O:46])[N:38]1[CH2:47][CH2:48][CH2:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH:53]=O>C(Cl)Cl.C1COCC1>[CH3:2][C:3]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:4]=1/[CH:5]=[CH:53]\[C:52]1[CH:51]=[C:50]([CH2:49][CH2:48][CH2:47][N:38]2[C:39](=[O:46])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37]2=[O:36])[CH:57]=[CH:56][CH:55]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: Cc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(/C=C\c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 2,3-dimethylbenzyltriphenylphosphonium bromide (1.1197 g, 2.43 mmol) in CH2Cl2 (10 mL) was added a solution of potassium tert-butoxide (2.5 mL of a 1 M solution in THF, 2.5 mmol). The mixture was stirred for 5 min, then a solution of phthalimide 29 (0.3380 g, 1.15 mmol) in CH2Cl2 (10 mL) was added. The mixture was warmed to room temperature, stirred for 20 min then concentrated under reduced pressure. 10% EtOAc-heptane was added and the solids were removed by filtration. The filtrate was concentrated under reduced pressure. Purification by repeated flash chromatography (6 to 40% EtOAc-hexanes gradient then 10% EtOAc-hexanes) gave (Z)-2-(3-(3-(2,3-dimethylstyryl)phenyl)propyl)isoindoline-1,3-dione as an oil. Yield (0.1871 g, 41%), trans-/cis-isomer ratio 1:11.7. Cis-isomer: 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J=5.6, 2.8 Hz, 2H), 7.72 (dd, J=5.2, 3.2 Hz, 2H), 7.04 (t, J=7.6 Hz, 1H), 6.88-6.98 (m, 6H), 6.68 (d, J=12.0 Hz, 1H), 6.56 (d, J=12.0 Hz, 1H), 3.64 (t, J=7.2 Hz, 2H), 2.52 (t, J=7.6 Hz, 2H), 2.52 (s, 3H), 2.17 (s, 3H), 1.80-1.88 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][CH2:12]O.S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+]>>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCO
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)[C@H]1CC[C@@H](O)CC1
Temperature: 70 °C

Procedure:
To a solution of cis-4-hydroxycyclohexanecarboxylic acid (4.00 g, 27.7 mmol) in EtOH (20 mL, 300 mmol) was added sulfuric acid (0.1 mL, 2 mmol), and the solution was heated to 70° C. for 2 h. After cooling to rt, Na2CO3 solution was added slowly to bring to pH=8. The organic solvent was removed in vacuo, and the material was extracted with EtOAc and washed with water. The organic layer was concentrated in vacuo to afford the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ=1.17 (t, J=7.1 Hz, 3H), 1.42-1.56 (m, 6H), 1.73-1.86 (m, 2H), 2.26-2.39 (m, 1H), 3.60-3.71 (m, 1H), 4.04 (q, J=7.1 Hz, 2H), 4.38 (d, J=3.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=O)O[CH:14]=2)=[CH:5][CH:4]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:18])[CH:11]=[C:12]3[C:15](=[O:17])[NH:24][CH2:21][CH2:22][N:23]3[CH:14]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(COc2coc(C(=O)O)cc2=O)cc1
Reactant: NCCN
Solvent: O
Product: COc1ccc(COc2cn3c(cc2=O)C(=O)NCC3)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
The mixture of 5-((4-methoxybenzyl)oxy)-4-oxo-4H-pyran-2-carboxylic acid (Example 2b) (5.24 g, 18.21 mmol), ethane-1,2-diamine (1.830 mL, 27.3 mmol) in water (80 mL) was stirred at 60° C. for 1 h and then 80° C. for 20 h. Yellow solid precipitated from the reaction when heating. After cooling, white precipitate was filtered off, washed with 20 mL of cold water/acetone (v:v=1:1) and dried to give 7-((4-methoxybenzyl)oxy)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione (4.15 g, 13.82 mmol, 76% yield) as white solid, which was used in the next step without further purification. LCMS (M+H)+: 301.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li]C(CC)C.CN([CH:23]=[O:24])C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[C:7]=1[CH:23]=[O:24]
Reactant: Clc1cc(Cl)cc(N2CCOCC2)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of to a solution of 4-(3,5-dichlorophenyl)-morpholine (1.60 g, 6.93 mmol) in dry THF (20 mL) under N2 at −78° C. was added dropwise sec-BuLi (1.4M in cyclohexane, 5.44 mL). The solution was allow to stir for 30 min then DMF (2.68 mL, 34.7 mmol) was slowly added to the. Upon disappearance of the starting material by TLC, the reaction was warmed to 0° C. then was quench by addition of H2O (15 mL). The mixture was extracted with EtOAc (150 mL), the organic phase was dried over Na2SO4 and the solvent was evaporate under reduced pressure. The resulting solid was triturated with Et2O to yield 2,6-dichloro-4-morpholin-4-yl-benzaldehyde as an off white solid. 1H NMR (400 MHz, Acetonitrile-d3): δ 10.44 (s, 1H), 7.06 (s, 2H), 3.85-3.93 (m, 4H), 3.46-3.54 (m, 4H). MS (m/z) 260.0 (M+1).
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][C:13]([O:15]CC)=[O:14])[N:11]=2)[CH2:6][CH2:5]1>C1COCC1.O>[CH:4]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1coc(C2CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1coc(C2CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Lithium hydroxide monohydrate (7.83 g, 186.7 mmol) was added to ethyl (2-cyclopropyl-1,3-oxazol-4-yl)acetate (Preparation 154, 7.00 g, 35.9 mmol) in THF (200 mL) and water (100 mL). The mixture was stirred at room temperature for 2 hours then the reaction mixture volume was reduced to one third by evaporation in vacuo. The aqueous residue was acidified using aqueous HCl (1.0 M) then extracted with EtOAc (200 mL). The organic phase was evaporated in vacuo and the crude material was triturated with diethyl ether (100 mL) to afford the title compound as a white solid in 66% yield, 4.00 g.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:8]=[CH:9][CH:10]=1.[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][N:29]([CH3:34])[C:30]=1[C:31](O)=[O:32])=[O:25])[CH3:22].CCN(C(C)C)C(C)C>CCOC(C)=O>[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][N:29]([CH3:34])[C:30]=1[C:31](=[O:32])[NH:19][C:17]1[CH:16]=[CH:15][N:14]2[CH:20]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:6]=3)[N:12]=[C:13]2[N:18]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(3-(2-Fluoroethoxy)phenyl)imidazo[1,2-a]pyrimidin-7-amine (1 eq.) was combined with EtOAc (7.50 ml) to give a light yellow suspension. 4-(Ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (1 eq.) and DIPEA (6 eq.) were added. The reaction mixture was cooled down to 0° C. and n-propylphosphonic acid anhydride, cyclic trimer (1.17 g, 1.1 ml, 1.84 mmol, 2.50 eq.) was added dropwise. After stirring at 0° C. during 30 min, the reaction mixture was stirred and allowed to warm-up to RT overnight. The reaction mixture (yellow solution) was poured into 50 ml EtOAc and extracted with H2O (1×30 ml). The aqueous layer was back-extracted with DCM (3×20 ml). The organic layers were combined and washed with sat. NaCl-solution (1×30 ml), dried over MgSO4, filtrated and concentrated under vacuum to give a yellow solid (207 mg). The crude material was purified by flash chromatography (silica gel, 20 g, CH2Cl2 to 50% CH2Cl2/MeOH/NH3 aq. 140:10:1). Yellow solid (332 mg, 31%).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O>[N:27]1([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1COCCN1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Solvent: O
Product: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12

Procedure:
wherein R3 is C, N—CH3 or a direct C—C bond. The yield is modest (around 60% w/w yield). The patent discloses the reaction of 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17β-ol with morpholine in the presence of water to yield 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α,17β-diol. The step is conducted for a reaction time of three days after which the solvents are removed by evaporation and the final product is crystallized from acetone followed by further recrystallization from methanol.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]#[N:8])[CH:4]=[N:3][CH:2]=1.[NH2:9][OH:10]>CO>[OH:10][N:9]=[C:7]([C:5]1[CH:6]=[N:1][CH:2]=[N:3][CH:4]=1)[NH2:8]
Reactant: NO
Reactant: N#Cc1cncnc1
Solvent: CO
Product: NC(=NO)c1cncnc1

Procedure:
A solution of the product of Example 79B (5.47 g, 52 mmol) and aqueous hydroxylamine (Aldrich, 50%, 2.3 mL, 78 mmol) in methanol (50 mL) was stirred at 65° C. for 1 hour and then concentrated under reduced pressure to remove the volatiles. The residue was triturated with EtOAc (30 mL). The precipitates were collected by filtration and dried to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 6.14 (s, 2 H), 9.03 (s, 2 H), 9.18 (s, 1 H), 10.06 (s, 1 H) ppm; MS (DCI/NH3) m/z 139 (M+H)+, 156 (M+NH4)+.
Reaction SMILES: [C@@H:1]([OH:10])([C:7]([OH:9])=[O:8])[C@H:2](O)[C:3]([OH:5])=[O:4]>CO>[C:7]([OH:9])(=[O:8])[C@H:1]([CH2:2][C:3]([OH:5])=[O:4])[OH:10]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CO
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
One of the intermediates, (S)-1-methyl-3-pyrrolidinol, was synthetized with retention of optical purity as shown in Chart IX starting with (S)-malic acid. The (S)-1-methyl-3-pyrrolidinol was shown to be dextrorotatory. As an alternative method of obtaining the resolved isomers of 1-methyl-3-pyrrolidinol, the racemic mixture was treated with (2S,3S)-tartaric acid in methanol. The resulting crystals, after one recrystallization, were converted to the base. This base was the dextrorotatory (S)-1-methyl-3-pyrrolidinol identical to that produced from (S)-malic acid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:29]>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:29]
Reactant: Cc1cccc(C(C)Cl)n1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Product: Cc1cccc(C(C)Sc2c(Cl)ccc3c2CCNCC3)n1

Procedure:
Use a method similar to the Example 315, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and (±)-2-(1-chloroethyl)-6-methylpyridine hydrochloride to give, after deprotection by a method similar to the General Procedure 1-4, the title compound as a tan solid. MS (ES+) m/z: 333 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=3[F:21])=[O:25])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1cccc(F)c1F
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4cccc(F)c4F)CC3)cccc2n1
Yield: 74 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using 2,3-difluorobenzoyl chloride (65 mg; 0.37 mmol) via Method AA to yield 114 mg. (74% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.51 (q, J=8.8 Hz, 1H), 7.33 (m, 2H), 7.2 (m, 3H), 6.77 (d, J=8.4 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.54 (br d, J=12.8 Hz, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.44 (d, J=14.0 Hz, 1H), 3.14 (t, J=12.4 Hz, 1H), 2.88 (m, 1H), 2.23 (s, 1H), 1.9 (d, J=12.4 Hz, 1H), 1.75 (d, J=10.8 Hz, 1H), 1.26 (m, 2H). MS m/z (ESI) 414 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[I-].[Na+].[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[C:26]([NH2:32])[C:22]=3[C:23](=[O:25])[CH:24]=2)=[CH:15][C:14]=1[F:33])(=[O:11])[CH3:10].[H-].[Na+]>CN(C)C=O.O>[C:9]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[C:26]([NH2:32])[C:22]=3[C:23](=[O:25])[CH:24]=2)=[CH:15][C:14]=1[F:33])[CH2:2][CH2:3][CH2:4][O:5][CH3:6])(=[O:11])[CH3:10]
Reactant: COCCCCl
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
949 mg of 1-chloro-3-methoxypropane and 1.30 g of sodium iodide were dissolved in 20 ml of dimethylformamide under argon atmosphere and the mixture was stirred at 90° C. for 2 hours. The reaction solution was cooled on ice and 1.51 g (4.35mmol) of Compound 27 obtained in Example 27 and 89 mg of sodium hydride (60% oil dispersion) were added thereto. The mixture was stirred at room temperature for 1 hour, 943 mg of 1-chloro-3-methoxypropane and 191 mg of sodium hydride (60% oil dispersion) were added, the temperature was raised to 60° C. and the mixture was stirred for 2 days. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 1.18 g (65%) of 2-[4-[N-acetyl-N-(3-methoxypropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:10]=2[CH:9]=[C:8]([C:23]([O:25]C)=[O:24])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[OH-].[Na+]>CO.C1COCC1>[C:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:10]=2[CH:9]=[C:8]([C:23]([OH:25])=[O:24])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc2c(c1)C=C(C(=O)OC)CCN2C(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccc2c(c1)C=C(C(=O)O)CCN2C(=O)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 1-propionyl-7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g), and to the solution was added 1N sodium hydroxide solution (5 ml). The mixture was stirred at room temperature overnight, concentrated, and then neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-propionyl-7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2 g) as colorless crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH3:17]>ClCCl>[CH:5]1[C:4]2[C:9](=[CH:10][C:11]3[C:16]([C:3]=2[CH2:2][NH:17][CH2:2][C:3]2[C:16]4[C:11]([CH:10]=[C:9]5[C:4]=2[CH:5]=[CH:6][CH:7]=[CH:8]5)=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: N
Reactant: ClCc1c2ccccc2cc2ccccc12
Solvent: ClCCl
Product: c1ccc2c(CNCc3c4ccccc4cc4ccccc34)c3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
A solution of 9-chloromethyl anthracene (278 mgr, 1.22 mmoles) in dichloromethane (1.5 ml) was bubbled with gaseous ammonia for 10 minutes. More dichloromethane was added, the reaction vessel was tightly closed and the reaction mixture was stirred for two days, at room temperature. Concentration in vacuo and purification of the crude product by flash chromatography afforded 30 mgr (14%) of N,N-di-(9-anthrylmethyl)-amine as yellow solid. 1H NMR (250 MHz, CDCl3): δ 8.48 (2H, s), 8.25-8.10 (4H, m), 8.09-7.80 (4H, m), 7.55-7.25 (8H, m), 4.95 (4H, s), 1.98 (NH, broad) ppm; 13C NMR (62.5 MHz, CDCl3): δ 131.8, 131.3, 130.4, 129.3, 128.4, 126.2, 125.1, 124.2, 45.6 ppm; FTIR: 3317, 3052, 2919, 2846, 1938, 1726, 1620, 1448, 1096, 1030, 891, 738 cm−1. HRMS (MALDI) calcd for C30H23N [M+H+] 398.1903, found 398.1917.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CCC(=O)OCC)n1Cc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1ncc(CCC(=O)O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A solution of ethyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]propanoate (179 mg, 0.513 mmol) in ethanol (10 mL) was treated with sodium hydroxide (62 mg, 1.54 mmol) dissolved in water (2 mL). The solution was stirred for one hour at 25° C., cooled, acidified with 10% aqueous hydrochloric acid solution to pH 4.2 and concentrated to near dryness in vacuo. Water (3 mL) was added, and the resulting white solid was filtered, washed with water and dried to give 32 mg (20%) of 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]propanoic acid; mp 163.5°-164.5° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:28])[C@@H:7]([NH:15][C:16]([C:18]1[NH:27][C:21]2=[CH:22][N:23]=[C:24]([Cl:26])[CH:25]=[C:20]2[CH:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C>C1COCC1>[Cl:26][C:24]1[CH:25]=[C:20]2[CH:19]=[C:18]([C:16]([NH:15][C@@H:7]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([OH:28])=[O:5])=[O:17])[NH:27][C:21]2=[CH:22][N:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydroxide solution (2.5 ml, 2M, 5.1 mmol) was added to a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylpropionic acid ethyl ester (EXAMPLE 41, 940 mg, 2.5 mmol) in THF (30 mL) and the reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the solid partitioned between hydrochloric acid (2M, 40 mL) and ethyl acetate (3×40 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid. m/z (ES+)=344 [M+H]+; RT=3.29 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]2[N:25]([C:28](=[O:44])[CH:29]([NH:36]C(OC(C)(C)C)=O)[CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:27][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16](=[O:24])[NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:13]2[N:25]([C:28](=[O:44])[CH:29]([NH2:36])[CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:27][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of 39 (460 mg, 0.76 mmol) in DCM (10 mL) was cooled to 0° C. and treated with TFA (4 mL). After 2 h, the solution was concentrated, diluted with EtOAc and washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 40 (366 mg) as a pale yellow-colored foam that was used without further purification. Mass spectrum, m/z [505.5] (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][C:10]=1[C:34]1[N:38]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[N:37]=[N:36][N:35]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:29]([C:27]1[CH:26]=[CH:25][C:24]([O:32][CH3:33])=[C:23]([C:12]2[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:34]3[N:38]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[N:37]=[N:36][N:35]=3)[CH:11]=2)[CH:28]=1)([CH3:31])[CH3:30]
Reactant: [H][H]
Reactant: COCCCn1nnnc1-c1cc(-c2cc(C(C)C)ccc2OC)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCCn1nnnc1-c1cc(-c2cc(C(C)C)ccc2OC)c(O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
5% Pd/C was wetted carefully with methanol under N2, then a solution of 5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-1-(3-methoxy-propyl)-1H-tetrazole (100 mg, 0.17 mmol) in methanol (5 ml) was added. The reaction system was vacuumed and filled with hydrogen three times, and the reaction was stirred under hydrogen at r.t. overnight. After filtering the catalyst over celite, the filtrate was concentrated to give product 5′-isopropyl-2′-methoxy-5-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-2,4-diol (49 mg, 71%). M.p.: 174-176° C.; 400 MHz 1H NMR (CDCl3) δ: 10.58 (s, 1H), 7.60 (s, 1H), 7.28 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.81 (s, 1H), 6.62 (s, 1H), 4.73 (t, J=6.8 Hz, 2H), 3.90 (s, 3H), 3.38 (t, J=5.6 Hz, 2H), 3.10 (s, 3H), 2.99-2.87 (m, 1H), 2.28 (pent, J=6.4 Hz, 2H), 1.27 (d, J=7.2 Hz, 6H); LCMS: 399 [M+H].