Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[F:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[C:41]2[CH:47]=O>>[F:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[C:41]2[CH:47]=[C:15]1[C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=2[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[O:28])[C:16]1=[O:17]
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccc(F)cc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 65.4 %

Procedure:
Following the procedure described for Example 1(A), Step A, N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (120 mg, 0.207 mmol) was condensed with 5-fluoro-1H-indole-3-carbaldehyde (48 mg, 0.248 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (1% MeOH in CH2Cl2 to 7% MeOH in CH2Cl2) yielded 85 mg of 2-[4-(5-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. MS 628.8 (M+1), 626.4 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:29]4[CH:28]=[C:27]([CH3:26])[CH:32]=[CH:31][CH:30]=4)=[O:35])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: Cc1cccc(N=C=O)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C)c4)cc3)cc2C1=O

Procedure:
The compound of example 21 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3-methyl phenyl isocyanate. The compound of example 21 was used directly without isolation for the preparation of compound of example 22.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.C(N(CC)CC)C.C([O:44][C:45]([C:48](Cl)=[O:49])([CH3:47])[CH3:46])(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:48](=[O:49])[C:45]([OH:44])([CH3:47])[CH3:46])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg) and triethylamine (0.40 mL) in tetrahydrofuran (5.0 mL) was added 1-chlorocarbonyl-1-methylethyl acetate (0.12 mL) at room temperature. After stirring at room temperature for 3 days, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in ethanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (1.5 mL) at room temperature. After stirring at room temperature for 24 hrs, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=9:1) to give the title compound (133 mg) as colorless crystals.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([CH3:25])[NH:9][C:8]=1[CH3:26])=[O:6])[CH3:3].[CH2:27]([O:29][C:30](=[O:35])[C:31](Br)([CH3:33])[CH3:32])[CH3:28]>O>[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:31]([C:30]([O:29][CH2:27][CH3:28])=[O:35])([CH3:33])[CH3:32])=[CH:17][CH:18]=2)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([CH3:25])[NH:9][C:8]=1[CH3:26])=[O:6])[CH3:3]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(O)cc1
Agent: [Na]
Solvent: O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(OC(C)(C)C(=O)OCC)cc1
Reaction time: 8 h

Procedure:
A solution of 2.3 g of sodium in 120 ml of alcohol is treated with 34.5 g of 2,6-dimethyl-4-(4-hydroxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and with 21.5 g of α-bromo-isobutyric acid ethyl ester added from a dropping funnel. The mixture is boiled overnight, added to water and extracted with ether. White crystals of melting point 215°C (benzene) are obtained from the evaporation residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccncc2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccncc2)cc1N

Procedure:
Prepared from (2-nitro-4-pyridin-4-yl-phenyl)-carbamic acid tert.-butyl ester (Example C11) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a light grey powder (305 mg).
Reaction SMILES: B1C2CCCC1CCC2.C1COCC1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=[CH2:22])[CH2:18][CH2:17]1.C[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([CH3:33])[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:33][C:26]1[C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=[C:24]([CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[N:25]=1
Reactant: C=C1CCN(C)CC1
Reactant: Cc1ccc([N+](=O)[O-])c(C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(CC2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
To a solution of 9-BBN in THF (0.5 M, 4.93 mL, 2.46 mmol) was added 1-methyl-4-methylenepiperidine (274 mg, 2.46 mmol). The reaction mixture was allowed to stir at 75° C. for 1 h and was then allowed to cool to rt. The resulting solution was transferred into a solution of 2-methyl-5-nitro-6-methylpyridine (486 mg, 2.24 mmol) in DMF (11 mL). To the mixture were added [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1:1 complex with DCM, 54.9 mg, 0.0672 mmol) and potassium carbonate (402 mg, 2.91 mmol). The reaction mixture was allowed to stir for 3 h at rt. The mixture was quenched by the addition of water (10 mL). The aqueous solution was extracted with DCM. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-methyl-6-[(1-methylpiperidin-4-yl)-methyl]-3-nitropyridine (64 mg, 10%) as a white solid. LCMS (FAL): Rt=3.38 min, m/z=250.2 (M+H).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])C.O=CCCCNC(C1CCCCC1)=O>>[O:3]=[CH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: CCOC(CCCNC(=O)N1CCN(c2ccccc2)CC1)OCC
Agent: O=CCCCNC(=O)C1CCCCC1
Product: O=CCCCNC(=O)N1CCN(c2ccccc2)CC1

Procedure:
4-Phenylpiperazine-1-carboxylic acid (4-oxobutyl)amide (61C) is prepared from 61B as described for 20B. The product is obtained in almost quantitative yield.
Reaction SMILES: B(Br)(Br)Br.C([O:7][C:8]1[CH:25]=[CH:24][C:11]2[S:12][C:13]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])=[C:14]([CH3:15])[C:10]=2[C:9]=1[C:26]#[N:27])C.C[OH:29]>ClCCl>[OH:7][C:8]1[C:25]([OH:29])=[CH:24][C:11]2[S:12][C:13]([C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[O:17])=[C:14]([CH3:15])[C:10]=2[C:9]=1[C:26]#[N:27]
Reactant: CCOc1ccc2sc(C(=O)N3CCOCC3)c(C)c2c1C#N
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCOCC2)sc2cc(O)c(O)c(C#N)c12
Reaction time: 48 h

Procedure:
A solution of 1 N boron tribromide in dichloromethane (3.4 ml) was added to a solution of 5,6-di(ethoxy-3-methyl-2-(morpholine-4-carbonyl)-benzo[b]thiophene-4-carbonitrile (0.19 g) in dichloromethane (40 ml) at 0° C. The mixture was allowed to stay at 6° C. for two days. Methanol was added and the mixture was evaporated to dryness. To the residue 0.1 N HCl was added and the product was extracted into ethyl acetate. Ethyl acetate was dried and evaporated to dryness. The compound was recrystallized from isopropanol.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([OH:22])=O)[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]([F:39])([F:38])[C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:37][C:34]2[S:35][CH:36]=[C:32]([C:31]([F:39])([F:38])[F:30])[N:33]=2)=[O:22])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (270 mg, 0.639 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (116 mg, 0.703 mmol) in the presence of EDCI hydrochloride (245 mg, 1.278 mmol) and DMAP (72 mg, 0.639 mmol) in a mixture of THF and DMF (1:1, 6 mL) to give 127 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.02 (s, 9H), 3.56 (s, 2H), 7.17 (t, J=74.1 Hz, 1H), 7.20-7.31 (m, 2H), 7.42-7.45 (m, 1H), 7.52 (d, J=15.9 Hz, 1H), 7.67-7.69 (m, 1H), 7.81 (d, J=16.2 Hz, 1H), 8.06-8.10 (m, 2H), 13.01 (br s, 1H); APCI-MS (m/z) 573.26 (MH)+.
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:31]([F:43])=[CH:32][C:33]([F:42])=[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:35]=2)[CH2:26][CH2:25]1>>[F:42][C:33]1[CH:32]=[C:31]([F:43])[C:30]([CH:27]2[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][CH2:21][NH:20][C:3](=[O:4])[C:2]([OH:1])([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:6]3[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=3)[CH2:29][CH2:28]2)=[CH:35][C:34]=1[NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40]
Reactant: Cc1ccc(C(O)(C(=O)O)c2ccc(C)cc2)cc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)c(F)cc1F
Product: Cc1ccc(C(O)(C(=O)NCCCN2CCC(c3cc(NC(=O)C(C)C)c(F)cc3F)CC2)c2ccc(C)cc2)cc1

Procedure:
Example 159 was prepared from hydroxy[bis(4-methylphenyl)]acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 8.78–8.62 (s, br, 1 H), 8.37 (t, 1 H, J=9.6 Hz), 7.40 (d, 4 H, J=8.4 Hz), 7.28 (s, 1 H), 7.09 (d, 4 H, J=8.0 Hz), 6.84–6.74 (m, 1 H), 5.14–4.82 (br, 1 H), 3.55–3.40 (m, 2 H), 3.11–2.94 (m, 2 H), 2.94–2.78 (m, 1 H), 2.59–2.46 (m, 2 H), 2.46–2.36 (m, 1 H), 2.31 (s, 6 H), 2.11–1.91 (m, 4 H), 1.77–1.61 (m, 4 H), 1.04 (d, 6 H, J=7.2 Hz); ESMS m/e: 578.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (0.22 g) was dissolved in methanol (10 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (1 mL). The reaction was stirred at room temperature 16 hours and stripped to give a solid that was suspended in water (2 mL) before sufficient methanol was added until a solution was obtained. 2N Sodium hydroxide solution was added to bring to pH 7, and the solution concentrated until a suspension formed. The white solid was filtered and washed with water (2 mL, twice to complete transfer and wash). This was dried under suction and then under vacuum at 50° C. to give the title compound as a white solid (0.189 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([CH2:10][OH:11])=[CH:4][N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:12](=[O:14])[CH3:13])[C:5]([CH2:10][OH:11])=[CH:4][N:3]=1
Reactant: Cc1cc(CO)c(CO)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(C)ncc1CO

Procedure:
2-Methyl-4,5-di(hydroxymethyl)pyridine (0.1 mole) is stirred in pyridine (50 ml.) with acetic anhydride (0.1 mole) at room temperature overnight. The pyridine is evaporated and the residue is dissolved in 10 ml. water and extracted with 2×30 ml. of chloroform. After drying over magnesium sulfate, the chloroform is evaporated and the residue is chromatographed on a silica gel column using benzene-ethanol as eluate. By this procedure is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.O.[NH2:24][NH2:25]>O1CCCC1.CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:24][NH2:25])=[O:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 4'-methylbiphenyl-2-carboxylic acid (6.4 g) in tetrahydrofuran (50 ml) were added N,N-dimethylformamide (two drops) and oxalyl chloride (4.4 g). The mixture was stirred for 16 hours at room temperature. The solvent was evaporated to dryness under reduced pressure to give an oil, which was added dropwise to a solution of hydrazine monohydrate (7.5 g) in tetrahydrofuran (50 ml) with stirring, followed by stirring for further 6 hours. The reaction mixture was diluted with water, which was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel to give crude crystals. Recrystallization from chloroform-isopropyl ether afforded the title compound as colorless needles (4.3 g, 63%), m.p.98°-99° C.
Reaction SMILES: CCOCC.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]#[N:15])[CH2:10][CH2:9]1.[OH:16][NH:17][C:18](=N)[CH:19]([CH3:21])[CH3:20]>CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[CH3:20][CH:19]([C:18]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][OH:6])[CH2:9][CH2:10]2)[O:16][N:17]=1)[CH3:21]
Reactant: N#CN1CCC(CO)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)c1noc(N2CCC(CO)CC2)n1
Reaction time: 0.5 h
Yield: 438 %

Procedure:
A solution of 1N ZnCl2 in Et2O (182 mL, 182 mmol) was added to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (21.3 g, 152 mmol) and N-hydroxy-2-methylpropanimidamide (18.6 g, 182 mmol) in EtOAc (50 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 30 min, decanted, and was treated with concentrated HCl (45 mL) and ethanol 20 mL). The mixture was heated at reflux for 2 h. The mixture was evaporated to dryness, and the resulting residue was charged with water and the pH was adjusted to basic with K2CO3. The mixture was extracted with EtOAc and the material obtained was combined with 9 other batches prepared similarly and purified by silica gel chromatography to give 150 g of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:23])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=2)[C:5]([CH3:14])=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][O:11][CH2:10]1.O[C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:1][C:2]1[C:3]([CH3:23])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:25]3[CH:38]=[CH:37][C:28]4[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=4[CH:26]=3)[CH:16]=2)[C:5]([CH3:14])=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(O[C@H]2CCOC2)c(F)c(C)c1-c1cccc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCOC5)c(F)c4C)c3)ccc21
Reaction time: 2 h
Yield: 72.2 %

Procedure:
(S)-(3′-Fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 19c (130 mg, 0.41 mmol), methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (85 mg, 0.41 mmol) and triphenylphosphine (161 mg, 0.62 mmol) were dissolved in 10 mL of dichloromethane, followed by addition of diisopropyl azodicarboxylate (125 mg, 0.62 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl 2-((S)-6-((3′-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 19d (150 mg, yield 72.5%) as a colorless oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.Br[C:14]([CH3:19])([CH3:18])[C:15](Br)=[O:16]>C(Cl)Cl>[CH3:18][CH:14]1[CH2:19][C:9]2[C:10](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:15]1=[O:16]
Reactant: Cc1cccc(C)c1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)CC(C)C2=O
Yield: 93 %

Procedure:
107 g (810 mmol) of AlCl3 were slowly added to a solution of 34.4 g (324 mmol) of m-xylene (99% pure) and 74 g (324 mmol) of 2-bromoisobutyryl bromide (98% pure) in 600 ml of analytical grade methylene chloride via a solids metering funnel at room temperature, while stirring vigorously, whereupon vigorous evolution of gases started. The mixture was stirred at room temperature 15 hours, poured onto ice-water, which was acidified with 25 ml of concentrated HC1, and extracted several times with ether. The combined organic phases were washed first with a saturated NaHCO3 solution and then with a saturated NaC1 solution, and dried with magnesium sulfate. The oil which remained after the solvent had been stripped off under reduced pressure was distilled over a short distillation bridge. 52.4 g of the indanone 1 passed over at 81°-90° C./0.1-0.2 mbar in the form of a colorless oil, which crystallized at room temperature. The yield was 93%.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]=[CH:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[CH3:1][N:2]([CH3:9])[CH:3]=[C:4]([C:20](=[O:21])[C:19]1[CH:23]=[C:24]([F:28])[C:25]([Cl:27])=[CH:26][C:18]=1[Cl:17])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C=CN(C)C
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 89.1 %

Procedure:
First a solution of 12.9 g of methyl 3-dimethylaminoacrylate in 25 ml of dioxane is added dropwise, and then 10.5 g of triethylamine are added to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 80 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for 3 hours, heated at 50°-60° C. for 1 hour, and the solvent is removed by distillation in vacuo and the residue is taken up in methylene chloride/H2O. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. The crystalline residue is recrystallized from methanol/water. 28.5 g of methyl 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 107°-109° C. are obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.[Br:24][CH2:25][CH2:26]Br.O>CN(C=O)C>[Br:24][CH2:25][CH2:26][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][C:4]([Cl:3])=[CH:5][C:6]=1[N+:21]([O-:23])=[O:22]
Reactant: BrCCBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CCBr)c2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.20 g (5.00 mmol)) in DMF (7.0 ml), 4′-chloro-2′-nitro-p-toluenesulfonanilide (1.20 g (3.67 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, 1,2-dibromoethane (2.00 ml (23.2 mmol)) was added and the mixture was heated at 130° C. for one hour with stirring. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether. The extract was washed with 1% aqueous sodium hydroxide solution, a saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to make the residue crystalline. Hexane was added to the crystals and the crystals were collected while washing to give 1.12 g (70%) of the title compound as pale yellow crystals.