Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[F:13])[C:7](O)=[O:8])[CH2:3][CH2:2]1.[NH3:14].C1COCC1>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[F:13])[C:7]([NH2:14])=[O:8])[CH2:3][CH2:2]1
Reactant: N
Reactant: O=C(O)c1ccc(F)c(C2CC2)c1
Solvent: C1CCOC1
Product: NC(=O)c1ccc(F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of compound 3-cyclopropyl-4-fluoro-benzoic acid (Preparation 56, 74 g, 0.41 mol, 1 eq) in THF (800 mL) was added N,N′-carbonyldiimidazole (88 g, 0.53 mol, 1.29 eq) at room temperature. The suspension was stirred at room temperature for 3 h, and turned into a brown solution. Ammonia/THF (1 L) was added to the mixture and the resulting mixture was stirred at room temperature overnight. THF was removed in vacuum and the residue was taken up with water (300 mL). The mixture was filtrated and the solid was washed with water (100 mL) and ether (200 mL). The solid was dissolved in DCM (500 mL), dried over sodium sulfate and concentrated in vacuum to title compound as a white solid (66 g, 0.368 mol, 89.7%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Cu][C:14]#[N:15]>CN(C=O)C.C(OCC)(=O)C>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:14]#[N:15])[CH:11]=[CH:10]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-bromo-2-naphthol (25.0 g, 112 mmol) and copper(I) cyanide (11 g, 123 mmol) in DMF (30 mL) was heated to 135° C., stirred for 18 hours, cooled to room temperature, diluted with ethyl acetate (50 mL), triturated with 10% sodium hydroxide, and filtered through diatomaceous earth (Celite®). The filtrate was adjusted to pH 2 and extracted with ethyl acetate. The combined extracts were concentrated, dissolved in ethanol (150 mL), triturated with water, and filtered to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Cc1ccnc(Nc2nc(Cl)ncc2F)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 2-amino-4-methylpyridine gave 2-chloro-5-fluoro-N4-(4-methylpyridin-2-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.22 (s, 1H), 8.16 (d, 1H, J=8.4 Hz), 8.13 (d, 1H, J=2.4 Hz), 6.91 (d, 1H, J=5.4 Hz), 2.42 (s, 3H); LCMS: purity: 87%; MS (m/e): 239 (MH+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1([C:14]([F:17])([F:16])[F:15])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[O:4]1.C([O-])(=O)C.[K+].[Br:25]Br>C(O)(=O)C.[Cl-].[Na+].O>[Br:25][C:10]1[CH:11]=[CH:12][C:7]2[NH:6][C:5](=[O:13])[O:4][C:3]([C:14]([F:17])([F:16])[F:15])([C:2]([F:1])([F:18])[F:19])[C:8]=2[CH:9]=1
Reactant: O=C1Nc2ccccc2C(C(F)(F)F)(C(F)(F)F)O1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C(C(F)(F)F)(C(F)(F)F)O1
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a stirred solution of 4,4-bis(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.50 g, 1.75 mmol) in glacial acetic acid (6 mL) buffered with potassium acetate (0.52 g, 5.25 mmol) was added bromine (0.28 g, 1.75 mmol). The reaction was stirred 30 minutes and poured into brine (30 mL), and extracted with ethyl acetate several times. The organic layer was dried over magnesium sulfate and concentrated. Flash column separation using 10% ethyl acetate/hexane gave 0.36 g of 6-bromo-4,4-bis(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid(57%). 1H NMR (DMSO-d6): δ 11.57 (s, 1H), 7.85 (dd, J=8.7, 2.2 Hz, 1H), 7.60 (s, 1H), 7.08 (d, J=8.7 Hz, 1H). MS (ESI) m/z 362/364 ([M+H]+); HRMS: calcd for C10H4BrF6NO2, 362.9330; found (ESI_FT), 363.93994.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[C:10]([Cu])#[N:11]>CN(C=O)C.CCOC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]#[N:11])=[N:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)nc1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)cn1
Temperature: 120 °C
Yield: 57.4 %

Procedure:
A mixture of 6-bromonicotinaldehyde (11.2 g, 60 mmol) and CuCN (8.06 g, 90 mmol) in DMF (100 mL) was heated at 120° C. for 3 h under N2. The mixture was cooled to rt and diluted with EtOAc and filtered through a pad of celite. The organic layer was washed with water and brine and then dried (MgSO4) and concentrated. The product 5-formylpicolinonitrile (4.55 g) was obtained by silica gel chromatography (elution with 0-20% EtOAc/Hex).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][C@@H:38]([CH3:41])[CH2:39][OH:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][C@@H:38]([CH3:41])[CH2:39][OH:40])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-2-amino-1-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.53 Hz, 3 H), 1.47-1.58 (m, 4 H), 1.61-1.74 (m, 4 H), 2.41 (d, J=11.58 Hz, 2 H), 3.38 (t, J=6.95 Hz, 4 H), 3.48 (t, J=5.05 Hz, 2 H), 3.97-4.12 (m, 1 H), 4.15-4.27 (m, 4 H), 4.98-5.02 (m, 1 H), 7.14 (t, J=8.95 Hz, 2 H), 7.41 (dd, J=8.84, 5.69 Hz, 2 H), 7.99 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.37 (d, J=8.00 Hz, 1 H), 17.24 (s, 1 H); ES+ MS: 525 (M+H+).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].CNC.C(O)(=O)CC.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH:17]=O)[CH3:14]>O>[CH3:3][C:2](=[CH:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])[CH:1]=[O:4]
Reactant: CCC=O
Reactant: CCOC(C=O)OCC
Agent: CNC
Solvent: O
Solvent: CCC(=O)O
Product: CCOC(C=C(C)C=O)OCC
Yield: 68.9 %

Procedure:
504 g of a solution of 240 g of propionaldehyde in 264 g of diethoxyacetaldehyde (glyoxal(mono)diethylacetal) are run into a mixture of 48 g of dimethylamine in 72 g of water and 80 g of propionic acid at 40° C. in the course of 30 minutes, while stirring. The reaction mixture is then stirred for a further 3 hours. After the lower aqueous phase has been separated off, fractional distillation of the organic phase gives 237 g (68.9% of theory) of 2-methyl-4,4-diethoxybut-2-enal of boiling point 67°-69° C./8 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH2:13][C:8]3(OCC[O:9]3)[CH2:7][CH2:6][C:5]2=1.C>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH2:13][C:8](=[O:9])[CH2:7][CH2:6][C:5]2=1
Reactant: Fc1ccc2[nH]c3c(c2c1)CCC1(C3)OCCO1
Solvent: CO
Product: O=C1CCc2c([nH]c3ccc(F)cc23)C1
Yield: 26.1 %

Procedure:
The title compound was prepared according to the procedure of Example 43 step C by replacing the 1,3,4,9-tetrahydrospiro[carbazole-2,2′-[1,3]dioxolane] with 6-fluoro-1,3,4,9-tetrahydrospiro[carbazole-2,2′-[1,3]dioxolane] (6.058 g, 0.0245 mol). The crude product was dissolved in warm methanol, treated with charcoal, filtered over Celite and the filtrate evaporated to dryness. The residue was slurried in a small amount of methanol, the off white solid collected and dried to provide the title compound (1.297 g), m.p. 165-167° C. MS (ES): [M−H]− @m/z 202.0.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:9]1[C:28]([O:30]CC)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH:18]=[CH:19][CH:20]=[CH:21]3)=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:9]1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.9 %

Procedure:
To a stirred solution of ethyl 1-benzyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylate (0.80 g, 1.9 mmol) in 20 mL of 2:1:1 THF/MeOH/water was added lithium hydroxide monohydrate (0.80 g, 19.0 mmol). The reaction was stirred at room temperature for 1 day. Most of the organic solvents was removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0:0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min). The product was collected based on UV absorption and concentrated to give the title compound as a white solid (0.70 g, 94%): 1H NMR (DMSO-d6+CDC3) δ 5.88 (s, 2 H), 6.23 (t, J=2.1 Hz, 2 H), 7.02 (t, J=2.1 Hz, 2 H), 7.10-7.50 (m, 13 H); MS (ESI) m/z 393 (MH+); MS (ESI) m/z 391 ([M−H]−); HRMS calcd for C26H21N2O2: 393.1604; found (ESI+): 393.1590; Anal. calcd for C26H20N2O2: C, 79.57; H, 5.14; N, 7.14. Found: C, 79.25; H, 5.04; N, 7.12.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CCN(C(C)C)C(C)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol) in dry THF (5 mL) was added DIPEA (3 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0° C. and pivaloyl chloride (0.025 g, 0.283 mmol) was added and stirred for 3 h at RT. The reaction mass was quenched in water, extracted with DCM:MeOH and concentrated to afford of the crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.030 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.28-4.30 (d, J=6 Hz, 2H), 7.39-7.42 (d, J=8. Hz, 1H), 7.59-7.61 (d, J=6.4 Hz, 2H), 7.84-7.86 (d, J=8.8 Hz, 2H), 8.14-8.19 (m, 3H), 12.59 (br s, 1H); MS (m/z): 451.29 (M−H−).
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5])[OH:2].[OH-].[K+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:1]([C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O:6][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[OH:2]
Reactant: CC(CO)(CO)C(=O)O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(CO)(CO)C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
A mixture of 2,2-bis(methylol)propionic acid (bisMPA) (18.0 g, 0.134 mol), KOH (85% assay; 8.9 g, 0.135 mol), and DMF (100 mL) was heated to 100° C. for 1 hour (the reaction mixture became a homogenous solution after 0.5 hour reaction). Benzyl bromide (27.6 g, 0.162 mol) was added to the warm solution under stirring, and the reaction was continued at 100° C. for 16 hours. The reaction mixture was cooled down and the solvent was removed under vacuum. Ethyl acetate (120 mL), hexanes (120 mL), and water (80 mL) were added to the residue. The organic layer was retained, washed with water (80 mL), dried over MgSO4 and evaporated. The resulting solid was recrystallized from toluene (30 mL) to give pure benzyl 2,2-bis(methylol)propionate (BnMPA) (19.5 g, 65%). 1H NMR (400 MHz, CDCl3, 22° C.): delta 7.38 (m, 5H, PhH), 5.19 (s, 2H, —OCH2Ph), 3.94 (d, 2H, —CH2OH), 3.73 (d, 2H, —CH2OH), 1.12 (s, 3H, —CH3).
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][C@@H:9]1[O:14][C:13]2[CH:15]=[C:16]3[C:21](=[CH:22][C:12]=2[NH:11][C:10]1=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]3)(C)(=O)=O.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:6][CH2:7][CH2:8][C@@H:9]3[O:14][C:13]4[CH:15]=[C:16]5[C:21](=[CH:22][C:12]=4[NH:11][C:10]3=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]5)[CH2:33][CH2:32]2)=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)OCCC[C@@H]1Oc2cc3c(cc2NC1=O)CCCC3
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cc3c(cc2O[C@H]1CCCN1CCN(c2ccc(F)cc2)CC1)CCCC3
Yield: 59.7 %

Procedure:
A mixture of (S)-6,7,8,9-tetrahydro-2-(3-mesyloxypropyl)-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one (1.02g), 1-(4-fluorophenylpiperazine (0.83g), triethylamine (0.43 ml) and dimethylformamide (15 ml) was stirred at 70° C. for 2 hours. The solvent was distilled off and the residue was purified by column chromatography on silica gel (60 g) with ethyl acetate-hexane (3:1, v/v) to yield crystals of (S)-(-)-2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one (0.76 g, 59.6%). Repeated recrystallization from MeOH gave colorless crystals, m.p. 155.5°-156.6° C. [α]D26 -19.9° (c=1.2, CHCl3).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[F:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[F:12][C:3]1[C:4]([F:11])=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.6 %

Procedure:
A mixture of 1,2,3-trifluoro-4-nitrobenzene (4.0 mL, 35 mmol), morpholine (3.1 mL, 35 mmol), and K2CO3 (4.8 g, 35 mmol) in DMSO (35 mL) was stirred at room temperature overnight. The mixture was diluted with AcOEt and washed with water and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (11.5 g, 67% yield) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.09-3.51 (4H, m), 3.58-4.08 (4H, m), 6.98 (1H, ddd, J=9.8, 8.1, 2.1 Hz), 7.94 (1H, ddd, J=9.9, 8.0, 2.1 Hz). LC-MS (ESI) m/z 245 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:46][C:47]1([CH3:55])[O:52][CH2:51][CH:50]([CH2:53]O)[CH2:49][O:48]1>C(Cl)Cl>[CH3:46][C:47]1([CH3:55])[O:52][CH2:51][CH:50]([CH2:53][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5]3)[CH2:49][O:48]1
Reactant: CC1(C)OCC(CO)CO1
Reactant: COC(=O)c1cc2cc(O)ccc2[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2cc(OCC3COC(C)(C)OC3)ccc2[nH]1
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Methyl 5-Hydroxy-1H-indole-2-carboxylate (0.10 g, 0.5 mmol), triphenylphosphine (0.28 g, 1.0 mmol), diethyl azodicarboxylate (0.18 g, 1.0 mmol) and (2,2-dimethyl-1,3-dioxan-5-yl)methanol (0.15 g, 1.0 mmol) were dissolved in CH2Cl2 (5 mL) and the mixture was stirred overnight. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized with saturated NaHCO3 and extracted with EtOAc. The organic extracts were combined dried over Na2SO4, filtered and evaporated to afford the title compound (0.15 g, 90%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.74 (br. s., 1H), 7.29 (d, 1H), 7.09 (d, 1H), 7.01 (d, 1H), 6.88 (dd, 1H), 3.92-4.01 (m, 4H), 3.81 (s, 3H), 3.72 (dd, 2H), 1.97-2.08 (m, 1H), 1.31 (s, 3H), 1.28 (s, 3H). MS: m/z 342.2 (M+23).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].I([O-])(=O)(=O)=[O:13].[Na+].C(Cl)(Cl)(Cl)Cl.C(#N)C>[Ru](Cl)(Cl)Cl.O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:13])=[O:11]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: OCCCCCCCCCBr
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: O=C(O)CCCCCCCCBr

Procedure:
9-Bromononyl alcohol (f) (3.347 g) was reacted with sodium metaperiodate and ruthenium chloride in the mixture of carbon tetrachloride, acetonitrile and water to give 9-bromo nonanoic acid (g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH2:38]([O:40][C:41](Cl)=[O:42])[CH3:39]>O1CCCC1>[CH2:38]([O:40][C:41]([N:19]1[CH2:20][CH2:21][C:15]2[N:14]=[C:13]([C:11]3[S:12][C:8]4[C:7]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)[NH:22][C:16]=2[CH2:17][CH2:18]1)=[O:42])[CH3:39]
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCc2nc(-c3nc4c(OC)ccc(N5CCOCC5)c4s3)[nH]c2CC1
Yield: 64.6 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.011 g ethylchloroformate. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.028 g (62%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid ethyl ester as yellow solid; MS (ISP): m/e=458 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([NH:42][CH:43]1[CH2:45][CH2:44]1)[C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([NH:42][CH:43]1[CH2:44][CH2:45]1)[C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCNCC(NC2CC2)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC(=O)C(CNCCOc2ccc(C(=O)O)cc2OC)NC2CC2)ccc1NC(=O)Nc1ccccc1C
Yield: 32.2 %

Procedure:
A mixture of ethyl 3-methoxy-4-[[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-N-[2-cyclopropylamino]ethylamino]ethoxy]benzoate (195 mg, 0.30 mmol)) in THF:MeOH(4:1, v/v) (5 mL) and 1 N NaOH (0.756 mL) was stirred at 50° C. for 15 hr. The pH of the mixture was adjusted to 7.4 by the addition of 1 N HCl, and extracted with CHCl3:MeOH(9:1, v/v). The extract was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was crystallized with Et2O to give 57 mg (38%) 3-methoxy-4-[[2-[3-methoxy-4-[N′-(2-methyl phenyl)ureido]phenylacetyl]-[2-cyclopropylamino]ethylamino]ethoxy]benzoic acid 264 as a white crystalline material. mp 135–140° C.; IR (KBr), 3324, 2937, 1535, 1032, 754 cm−1; 1H-NMR (CD3OD, 400 MHz) δ 0.50–0.73 (m, 4H), 2.29 (s, 3H), 2.53 (m, 1H), 2.98 (m, 1H), 3.21 (m, 1H), 3.58–3.88 (m, 11H), 3.91 (s, 1H), 4.09 (m, 1H), 4.25 (m, 1H), 6.76–6.92 (m, 3H), 7.01 (m, 1H), 7.18 (m, 2H), 7.60 (m, 3H), 8.00 (d, J=8.3 Hz, 1H); MS (FAB) m/z 591(M+H)+; Anal. Calcd. for C32H38N4O7.3.0H2O, C, 59.62; H, 6.88; N, 8.69. Found, C, 59.25; H, 6.29; N, 8.29.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)=O.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]([NH:29][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:5][CH:4]=2)[CH3:28])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: C[C@H](N)c1ccc(C(F)(F)F)cc1
Product: C[C@H](NCc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc(C(F)(F)F)cc1
Yield: 83 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using benzyl 4-formylbenzoate and (1S)-1-[4-(trifluoromethyl)phenyl]ethylamine gave the title compound as a pale yellow oil (83%). M+(LC/MS(ESI)): 414.3. HPLC (Condition A), Rt: 3.77 min (HPLC purity: 99.1%).
Reaction SMILES: OC1C=CC(C2C=CC(O)=CC=2)=CC=1.[OH-].[K+].[CH3:17][CH:18]([CH2:39][CH3:40])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33]CC(C)CC)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.Cl>C(O)C>[CH3:17][CH:18]([CH2:39][CH3:40])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: CCC(C)COc1ccc(-c2ccc(OCC(C)CC)cc2)cc1
Agent: Cl
Agent: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Solvent: CCO
Product: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1

Procedure:
A mixture of 4,4'-dihydroxybiphenyl (500 g), ethanol (7.5 l) and KOH (302 g) was heated under reflux with stirring, followed by dropwise adding (+) brominated 2-methylbutyl (prepared from (-) 2-methylbutanol with phosphorus bromide) (530 g), reacting the mixture for 4 hours, distilling off ethanol, adding water (2 l), filtering, collecting insolubles, and treating the insolubles with toluene to remove solubles. This soluble part was recrystallized from ethanol to obtain scaly crystals having a melting point of 80.5° C.; thus it was confirmed to be di-(2-methylbutyloxy)biphenyl. On the other hand, the insoluble part was heated with hydrochloric acid with stirring, followed by cooling, collecting solids and recrystallizing from toluene and further from ethanol to obtain 4'-(2-methylbutyloxy)-4-hydroxybiphenyl having a m.p. of 137.5° C. (125 g).