Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:22])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (490 mg, 1.67 mmol, procedure from WO 2000/63173) in DMF (6 mL) was added K2CO3 (577 mg, 4.2 mmol) followed by methyl iodide (0.52 mL, 8.4 mmol) at rt. The mixture was stirred at rt for 18 h. It was then diluted with 50 mL ethyl acetate and the solids were removed by filtration. The solvent was then evaporated under vacuum and the residue was purified via silica gel chromatography (hexanes-100% EtOAc) to yield (3R,4R)-tert-butyl 3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (450 mg, 88% yield). LCMS (method T) RT 3.068 min, m/z 306.3 (M−H)−; 1H NMR (500 MHz, chloroform-d) δ 7.15 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.40-4.30 (m, 1H), 4.25-4.05 (m, 1H), 3.78 (s, 3H), 3.64-3.52 (m, 1H), 2.77-2.66 (m, 1H), 2.65-2.51 (m, 1H), 2.45 (br. s., 1H), 2.26-2.10 (m, 1H), 1.76 (d, J=2.7 Hz, 1H), 1.71-1.60 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16](=[O:18])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:10]=[C:11]([C:16](=[O:18])[CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=CN(c2ccc(F)cc2)C(c2ccc(Cl)cc2)CC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COC(=O)c1cn(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2)cc1=O
Yield: 85.5 %

Procedure:
In 20 ml of benzene was dissolved 1.0 g of methyl 6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinate, and to the resulting solution was added a mixed solution of 0.7 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone and 5 ml of benzene at 80° C., after which they were reacted at the same temperature for 30 minutes. After completion of the reaction, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the residue was suspended in 30 ml of chloroform and 30 ml of water This suspension was adjusted to a pH of 7.5 with sodium hydrogencarbonate, and the organic layer was then separated and washed successively with 30 ml of water and 30 ml of a saturated aqueous solution of sodium chloride, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 0.85 g of methyl 6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate having a melting point of 250°-254° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]2[C:13]([CH:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.O>[CH3:22][N:7]1[C:8]2[C:13](=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2c(N3CCN(C)CC3)cccc2n1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2cccc3c2cc(C(=O)O)n3C)CC1
Yield: 87.2 %

Procedure:
A solution of 1-(2-(ethoxycarbonyl)-1-methylindol-4-yl)-4-methylpiperazine (0.117 g, 0.39 mmol), lithium hydroxide hydrate (0.035 g, 0.83 mmol, 2 equivalents) in tetrahydrofuran (2 mL) and water (0.5 mL) was heated at reflux under nitrogen for 16 hours. The resulting reaction solution was evaporated under reduced pressure, and the residue was directly chromatographed using silica gel (approximately 10 g) and elution with methylene chloride/methanol/ammonium hydroxide [5:1:0.1] afforded the title compound (0.097 g, 0.34 mmol, 91%) as a yellow solid: 1H NMR (CD3OD) δ7.20-7.12 (m, 2H), 7.08 (s, 1H), 6.58 (dd, J=1.1 and 7.1 Hz, 1H), 4.90 (s, exchangeable H), 4.03 (s, 3H), 3.38 (br t, 4H), 3.34 (s, 3H), 3.28 (br t, 4H); LRMS (m/z, relative intensity) 274 (18), 273 (M+, 100), 258 (11), 229 (11), 203 (39), 202 (46), 71 (32), 70 (23); HRMS calculated for C15H19N3O2 273.1479, found 273.1479.
Reaction SMILES: C(N(/[CH:6]=[C:7]1/[C:8](=O)[C:9]2[CH:21]=[CH:20][CH:19]=[N:18][C:10]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]/1=2)CC)C.[Cl-].[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[CH2:28][NH:29][C:30]([NH2:32])=[NH2+:31].[O-]CC.[Na+]>C(O)C.ClCCl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[CH2:28][NH:29][C:30]1[N:32]=[CH:6][C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]=3[C:8]=2[N:31]=1
Reactant: NC(=[NH2+])NCc1cccc(Cl)c1
Reactant: CCN(/C=C1/C(=O)c2cccnc2Nc2ccccc21)CC
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Clc1cccc(CNc2ncc3c(n2)-c2cccnc2Nc2ccccc2-3)c1
Temperature: 80 °C

Procedure:
A mixture of (E)-6-((diethylamino)methylene)-6,11-dihydro-5H-benzo[f]pyrido[2,3-b]azepin-5-one (0.1 g, 0.38 mmol), 1-(3-chlorobenzyl)guanidinium chloride (2 equivalents), and sodium ethoxide (21% solution in ethanol) (1.9 equivalents) in absolute ethanol (3 mL) was heated at 80° C. overnight. The reaction mixture was cooled and diluted with dichloromethane (10 mL), washed with water (2×5 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 50% ethyl acetate in hexane) to give the pure desired product as solid. 400 MHz 1H NMR (DMSO-d6) δ 8.34 (s, 1H), 8.23 (s, 1H), 8.15 (s, 2H), 8.00 (t, J=6.0 Hz, 1H), 7.42 (s, 1H), 7.37-7.27 (m, 4H), 7.21-7.14 (m, 2H), 7.08-7.04 (m, 2H), 4.57 (d, J=5.2 Hz, 2H); LCMS (M+H)=386.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:15][C:16]1[N:21]=[C:20]([C:22]2[S:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26](=[O:28])[N:27]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:13][CH3:14]>C(OCC)(=O)C>[CH2:12]([S:15]([C:16]1[N:21]=[C:20]([C:22]2[S:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26](=[O:28])[N:27]=2)[CH:19]=[CH:18][CH:17]=1)=[O:9])[CH2:13][CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CCOC(C)=O
Product: CCCS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 75.7 %

Procedure:
A solution of 3-chloroperbenzoic acid (ca. 50%, 0.17 g, 0.49 mmol) in ethyl acetate (20 ml) was added dropwise to a solution of 2-(6-propylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.15 g, 0.48 mmol), which was obtained in Example 59, in ethyl acetate (50 ml) with stirring. The reaction mixture was stirred at room temperature for 18 hrs, washed with saturated aqueous sodium hydrogen carbonate solution (50 ml×2) and saturated brine, dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the titled compound (0.12 g, 76%) as crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:23]1([C:29]2[N:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(CCCN=C=NCC)C>CN(C)C=O.C(OCC)(=O)C>[C:23]1([C:29]2[N:34]=[CH:33][C:32]([C:35]([NH:1][CH2:2][C:3]3[CH:4]=[C:5]([S:9]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=3)=[O:36])=[CH:31][N:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
To a mixture consisting of tert-butyl 2-(3-(aminomethyl)phenylsulfonamido)ethylcarbamate (Compound 16, 278 mg), 2-phenylpyrimidine-5-carboxylic acid (Compound 17; synthesis described in Example 1, Steps 1-3 of WO 2007/041634 to Aldous et al., entitled “Pyrimidine Amide Compounds as PGDS Inhibitors”; 182 mg), HOBt (123 mg), and N-methyl-morpholine (0.11 mL) in N,N-dimethylformamide (11 mL) was added 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (287 mg) and the mixture was stirred for 2.5 hours. The crude reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (5:95 methanol-dichloromethane) to afford the title intermediate (363 mg, 87%); MS (ESI−) m/z 510 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C@@H:22]([CH2:25][CH3:26])[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:23])[CH2:25][CH3:26])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[C@H](C)CO
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A 0° C. solution of (R)-Methyl 2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetate (2.8 g, 10 mmol), (S)-2-methyl-1-butanol (1.1 mL, 10 mmol), triphenylphosphine (2.6 g, 10 mmol), and tetrahydrofuran (100 mL) was treated dropwise with diisopropylazodicarboxylate (1.9 mL, 10 mmol) via syringe. The resulting reaction mixture was allowed to warm to room temperature and maintained overnight. The reaction was concentrated and the residue was purified by column chromatography on silica gel (5%-10% ethyl acetate in hexanes) to afford (2R)-Methyl 2-(tert-butoxycarbonylamino)-(4-((S)-2-methyl-butoxy)-phenyl)acetate (2.8 g, 80% yield) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J=7.3 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 5.49 (d, J=6.6 Hz, 1H), 5.26 (d, J=7.3 Hz, 1H), 3.81 (dd, J=9.1, 6.1 Hz, 1H), 3.73 (s, 3H), 3.69-3.76 (m, 1H), 1.86 (dq, J=13.1, 6.5 Hz, 1H), 1.52-1.61 (m, 1H), 1.45 (s, 9H), 1.22-1.33 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 352.2 [(M+H)+, calcd for C19H30NO5 352.5].
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][C:30]([CH3:37])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:52][C:53](=[O:56])[CH2:54]Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:54][C:53]([O:52][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:56])[C:33]3[C:28](=[CH:29][C:30]([CH3:37])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 26.4 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (prepared analogously as in example 1) in 150 ml of DMF, 18 g of cesium carbonate and 12.7 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×300 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 23.6 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[CH2:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[CH:23]=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1c(OCc2ccccc2)cccc1OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1c(OCc2ccccc2)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2,6-bis-benzyloxyphenyl)-methanol (3.0 g) in methylene chloride (40 mL) is added Dess-Martin reagent (1.5 equivalents, 15% by weight in methylene chloride) and the mixture is stirred at RT for 30 min. Saturated NaHCO3 is added and the organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (7:1) as eluent to give the title compound as a reddish liquid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]([CH3:36])=[C:13]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:22][CH:23]=4)[CH2:18][CH:17]3[CH3:35])[N:14]=2)[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:32][C:30]([F:31])([F:33])[C:25]([C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:16]([CH2:15][C:13]1[N:14]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=3)[O:11][C:12]=1[CH3:36])[CH:17]([CH3:35])[CH2:18]2)([OH:34])[C:26]([F:29])([F:28])[F:27]
Reactant: COC(=O)c1cccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1oc(-c2cccc(CO)c2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A solution of 1.25 g (2.37 mmol) of 3-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-benzoic acid methyl ester (example 90) in 15 ml of THF was treated at 0° C. with 180 mg (4.73 mmol) of lithium aluminium hydride and allowed to reach RT within 3 hrs. Distribution of the crude between a saturated aqueous solution of NH4Cl and EtOAc, drying of the combined organic phases over Na2SO4 and evaporation of the solvent gave 1.1 g (93%) of 1,1,1,3,3,3-hexafluoro-2-{1-[2-(3-hydroxymethyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-2,3-dihydro-1H-indol-5-yl}-propan-2-ol, off-white foam, MS: 499 (M−H)−.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1>>[Br:1][C:5]1[C:4]([Cl:3])=[CH:9][C:8]([F:10])=[CH:7][C:6]=1[Cl:11]
Reactant: Fc1cc(Cl)cc(Cl)c1
Reactant: BrBr
Product: Fc1cc(Cl)c(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
Bromine (0.6 mol) is added to a mixture of 1,3-dichloro-5-fluorobenzene (0.6 mol) and ferrous powder within 2 hours. The brown reaction mixture is stirred 16 hours at room temperature and subsequently washed with dichloromethane and water. The organic layer is separated, washed with sodium hydrogen carbonate solution and dried with anhydrous sodium sulphate. The solvent is evaporated under reduced pressure. The raw product is recrystallized in ethanol to yield 61 g of the product as a white powder having a melting point of 83° C.
Reaction SMILES: BrC1C(F)=CC2C3CC(C3)N3C(CC4N(C)N=CC=4)=C(C(OC)=O)N=C3C=2C=1.[Br:29][C:30]1[C:31]([F:56])=[CH:32][C:33]2[O:39][CH2:38][CH2:37][N:36]3[C:40]([CH:47](O)[C:48]4[N:52]([CH3:53])[N:51]=[CH:50][CH:49]=4)=[C:41]([C:43]([O:45][CH3:46])=[O:44])[N:42]=[C:35]3[C:34]=2[CH:55]=1.CS(Cl)(=O)=O.[H][H]>[Pd]>[Br:29][C:30]1[C:31]([F:56])=[CH:32][C:33]2[O:39][CH2:38][CH2:37][N:36]3[C:40]([CH2:47][C:48]4[N:52]([CH3:53])[N:51]=[CH:50][CH:49]=4)=[C:41]([C:43]([O:45][CH3:46])=[O:44])[N:42]=[C:35]3[C:34]=2[CH:55]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C)CCOc1cc(F)c(Br)cc1-2
Reactant: [H][H]
Agent: [Pd]
Agent: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: CS(=O)(=O)Cl
Product: COC(=O)c1nc2n(c1Cc1ccnn1C)CCOc1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-3-((1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was prepared similarly to methyl 10-bromo-9-fluoro-3-((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. Methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with methanesulfonyl chloride followed by palladium on carbon and hydrogen to afford 105 mg (85% crude yield) of the titled crude product which was carried forward without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]([NH:41][CH3:42])([CH3:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]([CH:38]([CH3:40])[CH3:39])[CH3:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CNC(C)C
Product: CC(C)N(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-isopropylmethylamine according to conditions described in general procedure C. Mp: 102-104° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.94 (bs, 6 H), 1.58 (s, 6 H), 2.70 (bs, 1 H), 3.26-3.31 (m, 7 H), 6.19 (d, J=6.0 Hz, 1 H), 6.96 (d, J=12.4 Hz, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.51-7.62 (m, 3 H), 7.82 (d, J=7.6 Hz, 1 H), 7.97 (d, J=8.0 Hz, 1H), 8.22-8.24 (m, 1 H), 10.43 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1OCCCCCCC1C=CC=C(OCC2C=CC=CC=2)C=1OCC1C=CC=CC=1)[C:5]([OH:7])=[O:6].[H][H]>[Pd].O1CCCC1>[C:5]([OH:7])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1

Procedure:
A mixture of 0.6 g of 3-chloro-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid and 60 mg of 10% palladium on carbon in 20 ml of tetrahydrofuran was stirred in a hydrogen atmosphere for 6 hours. Workup as in Example 36 and recrystallization from ethyl acetate-hexane gave 0.24 g, mp benzoic acid.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[NH4+:14].[OH-]>C(O)(C)C>[NH2:14][CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1ccc(OC[C@H]2CO2)cc1
Agent: [OH-]
Solvent: CC(C)O
Product: N#Cc1ccc(OC[C@H](O)CN)cc1
Reaction time: 18 h
Yield: 91 %

Procedure:
4-[(2R)-Oxiranylmethoxy]benzonitrile (14.65 g, 83.6 mmol; prepared as described in international patent application WO 99/31100) was mixed with conc. NH4OH (64 mL) and 87 mL of isopropanol. The mixture was stirred at r.t for 18 h. The reaction mixture was filtered and the filtrate evaporated to give 14.6 g (91%) of the sub-title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O[C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:36])[C:23]3[C:24](=[C:26]([CH2:33][CH2:34][CH3:35])[N:27]([CH2:29][CH2:30][O:31][CH3:32])[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:37]([N:40]2[CH2:45][CH2:44][N:43]([CH2:46][CH3:47])[CH2:42][CH2:41]2)(=[O:39])=[O:38])=[CH:16][N:15]=1)C.[CH3:48][CH:49]([CH3:52])[CH2:50][OH:51]>>[CH2:50]([O:51][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:36])[C:23]3[C:24](=[C:26]([CH2:33][CH2:34][CH3:35])[N:27]([CH2:29][CH2:30][O:31][CH3:32])[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:37]([N:40]2[CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH2:45]2)(=[O:38])=[O:39])=[CH:16][N:15]=1)[CH:49]([CH3:52])[CH3:48]
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1CCOC
Reactant: CC(C)CO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC(C)C)[nH]c(=O)c2nn1CCOC
Temperature: 120 °C
Reaction time: 18 h

Procedure:
Potassium bis(trimethylsilyl)amide (149.7 mg, 0.75 mmol) was added to a solution of the title compound of example 3 (80 mg, 0.15 mmol) in 2-methyl-n-propanol (5 ml) and the reaction stirred at 120° C. for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in water (10 ml), and extracted with ethyl acetate (3×10 ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (100:0 to 95:5) to afford the title compound, 67 mg, as a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33]C1C=CC(CCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:7]1[CH:6]=[CH:5][C:4]([CH2:8][CH2:9][CH2:10][N:11]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:3][CH:2]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-methoxy-phenyl)-propionic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.