Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)[CH3:11].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH:46]=[C:45](Br)[CH:44]=[N:43]2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH:46]=[C:45]([C:17]3[CH:16]=[N:15][C:14]([NH2:28])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[CH:18]=3)[CH:44]=[N:43]2)[CH2:40][CH2:41]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 87 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
To a stirred solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (15.22 g, 35.64 mmol) and 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (14.12 g, 42.77 mmol) in DME (143 mL) was added a solution of Na2CO3 (11.33 g, 10692 mmol) in water (36 mL). The solution was degassed and charged with nitrogen three times. To the solution was added Pd(PPh3)2Cl2 (1.25 g, 1.782 mmol). The reaction solution was degassed and charged with nitrogen again three times. The reaction solution was stirred at 87° C. oil bath for about 16 hours (or until consumption of the borane pinacol ester), cooled to ambient temperature and diluted with EtOAc (600 mL). The reaction mixture was filtered through a pad of celite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified on a silica gel column eluting with EtOAc/Hexane system (Biotage 90+ Column: equilibrium 600 mL 100% Hexanes, segment 1:2250 mL 50% EtOAc/Hexanes Linear, segment 2: 4500 mL 75% EtOAc/Hexanes Linear, segment 3: 4500 mL 100% EtOAc) to afford 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (11.8 g, 60% yield, ˜95% purity) with a Rf of 0.15 (50% EtOAc/Hexanes). MS m/e 550 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[N:15]1([CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[C:27](=[O:30])[O:28][CH2:29][C:25]=3[CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[OH:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:18]1[CH2:19][CH2:20][N:15]([CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[C:27](=[O:30])[O:28][CH2:29][C:25]=3[CH:24]=2)[CH2:16][CH2:17]1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Product: Cc1c(C(O)CN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc2c1COC2=O

Procedure:
5-(1-Hydroxy-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one and 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: COCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CCOC)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 61.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (22 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (14 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[N+:15]([C:18]1[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]([OH:28])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C=O)C.O>[CH2:2]([O:28][C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)c2cccnc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c2cccnc12
Temperature: 90 °C
Yield: 68.5 %

Procedure:
Bromomethyl-benzene (424 μl, 3.57 mmol) and K2CO3 (493 mg, 3.57 mmol) were added to a solution of 8-nitro-quinolin-5-ol 563 (566 mg, 2.98 mmol) in DMF (5 ml) and the mixture was heated at 90° C. for 6 h. After cooling, the mixture was diluted with water (25 ml) and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine (25 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound (572 mg, 69%) which was used in the next step without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH3:7][C:8]1[CH:9]=[C:10]([S:15]C#N)[CH:11]=[CH:12][C:13]=1[OH:14].O>O1CCCC1>[CH3:7][C:8]1[CH:9]=[C:10]([SH:15])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: Cc1cc(SC#N)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(S)ccc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 250 ml three-necked flask, to a stirred mixture of lithium aluminum tetrahydride (LiAlH4, 0.8 g, 21 mmol) and tetrahydrofuran (30 ml) was added dropwise a solution of 3-methyl-4-hydroxy-phenyl thiocyanic acid (1.1 g, 6.6 mmol) in tetrahydrofuran (THF 30 ml) at 0° C. (cooled with chilled water). After 30 min of stirring at 0° C. and another 2 hours of stirring at room temperature, the reaction was quenched by addition of broken ice in an ice water bath. The value of pH of the mixture was adjusted to 3-4 by adding 6 N hydrochloric acid, and then the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with a saturated solution of sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtrated, and evaporated in vacuo to yield a crude product of 3-methyl-4-hydroxy-mercaptobenzene (yellow liquid).
Reaction SMILES: O.[F:2][C:3]1[C:4]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:5][C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:7]([N+:9]([O-])=O)[CH:8]=1>C(O)(=O)C.[Fe]>[F:2][C:3]1[C:4]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:5][C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:7]([CH:8]=1)[NH2:9]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a solution of 19 g of iron powder, 60 ml of acetic acid and 6 ml of water, a solution of 19.12 g of 5-fluoro-2-{2-(methoxycarbonyl)methoxyphenoxy}-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene [Compound 4-19 of the present invention] in 60 ml of acetic acid was added dropwise under ice cooling. After the addition, the temperature of the reaction mixture was raised to room temperature and the mixture was stirred for 4 hours. The reaction mixture was filtered with sellaite and diluted with ethyl acetate. The dilution was washed with water, saturated aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 15.16 g of 5-fluoro-2-{2-(methoxycarbonyl)methoxyphenoxy}-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CN(C)C=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)[nH]cnc2cc1O
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Palladium on carbon (3.3 g of a 10% mixture) was added to a solution of 7-(benzyloxy)-6-methoxyquinazolin-4-(3H)-one (20 g, 71 mmol) (prepared according to J. Med. Chem. 1999, 42, 5369-5389) was suspended in dimethylformamide (530 ml). Ammonium formate (45 g, 710 mmol) was then added portion wise over 1.25 hours. The reaction mixture was stirred for an additional 0.5 hours and the catalyst was removed by filtration. The solvent was removed in vacuo to yield 7-hydroxy-6-methoxyquinazolin-4-(3H)-one (8.65 g, 64% yield):
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C:6]2=O>C1COCC1>[Br:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:8][OH:12])=[C:5]([CH2:6][OH:7])[CH:4]=1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: [Li]
Solvent: C1CCOC1
Product: OCc1ccc(Br)cc1CO
Temperature: -30 °C
Yield: 125.6 %

Procedure:
Lithium aluminumhydride (320 mg, 8.81 mmol) was added to a solution of 5-bromoisobenzofuran-1,3-dione (1 g, 4.4 mmol) in THF at room temperature. The mixture was heated at reflux for 3 h, cooled to −30° C., and then quenched with water. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to afford the title compound (1.2 g). 1HNMR (400 MHz, DMSO-d6): δ 7.54 (d, 1H), 7.42 (dd, 1H), 7.33-7.31 (m, 1H), 5.23 (t, 1H), 5.15 (t, 1H), 4.51 (d, 2H), 4.45 (d, 2H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[C:38]1[N:43]=[C:42]([C:44](O)=[O:45])[CH:41]=[CH:40][C:39]=1[F:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:44]([C:42]3[CH:41]=[CH:40][C:39]([F:47])=[C:38]([C:32]4[C:31]([F:30])=[CH:36][CH:35]=[CH:34][C:33]=4[F:37])[N:43]=3)=[O:45])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (12.0 mg, 0.030 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (9.0 mg, 0.036 mmol), HATU (28.2 mg, 0.074 mmol) in DMF (0.07 mL) and DIPEA (11.5 mg, 0.089 mmol) was stirred at room temperature for 2 h. The reaction mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to afford the sub-title compound (11 mg, 58%). LCMS calc. for C33H37F3N5O5 (M+H)+: m/z=640.3. Found: 640.1.
Reaction SMILES: [CH2:1]1[O:18][CH:4]([C:5]2[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]([O:14][CH3:15])[C:6]=2[O:16][CH3:17])[O:3][CH2:2]1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.[Pt]=O>[CH2:2]1[O:3][CH:4]([C:5]2[C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[NH2:11])[O:18][CH2:1]1
Reactant: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1OC
Agent: O=[Pt]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(C2OCCO2)c1OC
Reaction time: 24 h

Procedure:
A solution of 2,3-dimethoxy-6-nitrobenzaldehyde-ethyleneketal (12.1 g, 62.7 mM) in ethyl acetate (350 ml) containing sodium acetate (0.5 g) is treated with platinum oxide (1.0 g) and the mixture hydrogenated for 24 hours at ~50 psi. The solvent is removed in vacuo after filtering off the catalyst to give a pale brown oil. After crystallization from n-hexane, the product is obtained as a tan solid; yield 12.8 g (85.1%); m.p. 78°-80° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[NH:11].C[O:14][C:15](=O)/[C:16](/[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:17](\O)/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(OC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=C(Cl)C=2Cl)N=1)=O)(C)(C)C>>[C:21]([O:20][C:18]([C:17]1[C:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:15]([OH:14])[N:12]=[C:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Br:2])[N:11]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Reactant: N=C(N)Cc1ccccc1Br
Agent: CC(C)(C)OC(=O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(Cc2ccccc2Br)nc(O)c1OCc1ccccc1
Yield: 83.3 %

Procedure:
5-Benzyloxy-2-(2-bromobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (148) (28 g, crude) as a brown solid was synthesized from 2-(2-bromophenyl)-acetamidine hydrochloride salt (147) (17.76 g, 71.32 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (32.95 g, 106.98 mmol) following the procedure as described for 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (130). The product was used without purification for further synthesis.
Reaction SMILES: [OH:1][C:2]1([C:12]#[N:13])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH2:3]1.[CH:14](Br)([CH3:16])[CH3:15].[H-].[Na+].O>CN(C)C=O>[CH:14]([O:1][C:2]1([C:12]#[N:13])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH2:3]1)([CH3:16])[CH3:15]
Reactant: CC(C)Br
Reactant: N#CC1(O)CC=CC2=C1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC1(C#N)CC=CC2=C1CCCC2

Procedure:
4-Hydroxy-5,6,7,8-tetrahydro-4-naphthonitrile (1.73 g, 10 mm), isopropyl bromide (0.78 g, 10 mM), and sodium hydride (0.24 g, 10 mM) in dimethyl formamide were stirred for 3 hours. Water was added and the mixture was extracted with ether. The ether was dried and evaporated to give the isopropyl ether (7).
Reaction SMILES: [Na].CCCCCC.Cl[C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[CH2:18]([OH:21])[CH2:19][CH3:20]>>[CH2:18]([O:21][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[CH2:19][CH3:20]
Reactant: CCCO
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na]
Solvent: CCCCCC
Product: CCCOc1ncccc1C(=O)O
Reaction time: 0.5 h

Procedure:
Sodium metal (9.2 g, 0.4 mol), washed free of oil (with hexane), was added in small pieces, over 2 h, to anhydrous n-propanol (350 mL) whilst maintaining a temperature between 50° C. and 100° C. To the resultant clear, yellow solution was added a slurry of 2-chloronicotinic acid (31.5 g, 0.2 mol) in anhydrous propanol (100 mL), and the suspension heated to reflux for 6 h. The bulk of the solvent was distilled off, and replaced, after cooling, with diethyl ether (200 mL) to afford a thick white solid which was removed by filtration and washed with diethyl ether (500 mL). The solid was taken up in water (300 mL), washed with dichloromethane (200 mL), and the aqueous phase acidified with concentrated hydrochloric acid to pH 4.5 and extracted with dichloromethane (3×200 mL). The combined extracts were washed with brine, dried over MgSO4, and concentrated to an oil (40 g). The oil was taken up in pentane (150 mL) and stood in ice for 30 mins to deliver a white crystalline solid which was collected by filtration, washed with fresh pentane (3×200 mL) and dried under vacuum to afford 2-propoxynicotinic acid (26.5 g, 146 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([O:7][CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[O:7][C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1
Reactant: CCOC(=O)N1CCN(C(=O)C(Oc2ccc(OC)cc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)N1CCN(c2c(-c3ccccc3)oc3ccc(OC)cc23)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
The mixture of 4,070 g of 1-[α-(4-methoxyphenoxy)-phenylacetyl]-4-ethoxycarbonyl piperazine, 20,000 ml of toluene and 2,850 ml of phosphorus oxychloride is stirred under nitrogen at 98° for 24 hours. It is poured hot onto 100 kg of crushed ice, followed by 10,000 ml of 50% aqueous sodium hydroxide. After stirring for 30 minutes the organic phase is separated and the aqueous layer extracted with 10,000 ml of toluene. The combined toluene solutions are washed with 10,000 ml of 2 N aqueous sodium hydroxide and 4 times with 10,000 ml of water, dried, filtered and evaporated at about 60°, to yield the 1-(5-methoxy-2-phenyl-3-benzofuryl)-4-ethoxycarbonylpiperazine showing in the NMR-spectrum peaks centered at 8.09, 3.72 and 3.12 ppm.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([SH:22])=[N:19][N:18]=3)=[CH:13][C:12]=12.Br[CH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29]>>[N:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([S:22][CH2:24][C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=4)[C:28]#[N:29])=[N:19][N:18]=3)=[CH:13][C:12]=12
Reactant: Sc1nnc(-c2ccn3ncnc3c2)o1
Reactant: N#Cc1cccc(CBr)c1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CSc2nnc(-c3ccn4ncnc4c3)o2)c1
Yield: 20 %

Procedure:
In the same manner as in Example 1 and using 5-(1,2,4-triazolo[1,5-a]pyridin-7-yl)-1,3,4-oxadiazole-2-thiol triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 20%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1([CH3:33])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]4[CH2:30][CH2:31][CH2:32][C:27]([CH3:33])([CH3:26])[CH2:28]4)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CC1(C)CCCNC1
Solvent: CN(C)C=O
Product: CC1(C)CCCN(Cc2nc(-c3ncn4c3[C@@H]3CCN3C(=O)c3c(Cl)cccc3-4)no2)C1
Yield: 98.6 %

Procedure:
1.13 g (3 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 2 g (17.7 mmol) of 3,3-dimethylpiperidine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.34 g (98%) of (S)-8-chloro-1-[5-(3,3-dimethyl-piperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: C(C1N(CC2C=CC=CC=2Cl)C([C:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])=CN=1)CCC.[OH-].[K+]>C(O)C.O>[CH2:21]([CH:10]([C:11]([OH:13])=[O:12])[C:16]([OH:18])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCc1ncc(C(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethyl [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl -malonate [Example 8(iii)] (5.54 g, 0.0108 mol) in ethanol (75 mL) was treated all at once with a solution of potassium hydroxide (3.65 g, 0.065 mol) in water (50 mL). The resulting mixture was stirred at room temperature for 24 hours, then refluxed for 3 hours. The ethanol was evaporated, water was added to the aqueous product, and the basic solution was extracted with diethyl ether. The aqueous layer was acidified to pH 4 with hydrochloric acid and the product was extracted into ethyl acetate. The dried, concentrated product was crystallized twice-from ethyl acetate to give 0.6 g of 2-n-butyl-1-{(2chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-malonic acid; mp 165°-166° C.(d). The filtrates from the crystallizations (4.9 g) consisted of additional malonic acid, the propanoic acid derivative and the mono ethyl ester malonate derivative. These are converted to [ 2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid by the method described previously.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([C:19]([CH2:24][CH3:25])([CH2:22]O)[CH2:20]O)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([C:19]1([CH2:24][CH3:25])[CH2:22][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:20]1)[CH2:16][CH2:17][CH3:18]
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: CCCCC(CC)(CO)CO
Product: CCCCC1(CC)COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
4-Nitrobenzylphosphonic acid and 2-butyl-2-ethyl-1,3-propanediol were treated in the same manner as in Reference Example 20 to yield 5-butyl-5-ethyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinan-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 111°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[C:5]2[O:11][CH2:10][CH2:9][N:8]=[CH:7][C:6]=2[C:12]=1[CH3:13].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([OH:16])[CH3:15])[C:5]2[O:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[C:12]=1[CH3:13]
Reactant: CC(=O)c1cc(Cl)c(C)c2c1OCCN=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Cl)cc(C(C)O)c2c1CNCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
1-(7-Chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-9-yl)ethanone (630 mg, 2.6 mmol) was stirred in methanol (20 mL) and cooled to 0° C. Sodium tetrahydroborate (150 mg, 4.0 mmol) was added. The mixture was stirred for 1 hour at room temperature and evaporated. The mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated gave the desired compound (580 mg, 90%). LCMS calculated for C12H17ClNO2 (M+H)+: m/z=242.1; found: 242.0.