Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][CH3:12])=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][CH3:12])=[N:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: CNc1ncc(Br)n2ccnc12
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ncc(-c2ccc(F)cc2)n2ccnc12
Temperature: 170 °C

Procedure:
To a solution of (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (intermediate O) (68 mg, 0.3 mmol) in DMF (4 ml) and water (2 ml) was added 4-fluorobenzene boronic acid (84 mg, 0.6 mmol), K2CO3 (165 mg 1.2 mmol), and Pd(PPh3)4 (35 mg, 0.1 eq). The mixture was heated at 170° C. in microwave for 6 min. The mixture was purified on a silica gel column to give the title compound.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=O)=[CH:26][CH:25]=1.O>C1COCC1>[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:9][C:10]#[N:11])=[CH:26][CH:25]=1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(C(=CC#N)c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (1.4 mL, 8.9 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 8.9 mL, 8.9 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of bis-(4-dimethylamino-phenyl)-methanone (1.19 g, 4.4 mmol) in THF (20 mL) and refluxed overnight. The reaction mixture was poured into water (20 mL), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc/Hexane) to give 3,3-bis-(4-dimethylamino-phenyl)-acrylonitrile as a light yellow needle-like solid (0.75 g, 58% yield): mp, 181-183° C.; 1H NMR (DMSO-d6) δ 2.96 and 2.98 (2s, 6H, 2N(CH3)2), 5.70 (s, 1H, CH), 6.67-6.80 (m, 4H, Ar), 7.15-7.23 (m, 4H, Ar); 13C NMR (DMSO-d6) δ 39.7, 39.8, 87.0, 111.3, 111.4, 120.0, 124.2, 125.6, 129.8, 130.7, 151.0, 151.5, 162.2. Anal. Calcd for C19H21N3: C, 78.32; H, 7.26; N, 14.42. Found: C, 78.33; H, 7.29; N, 14.38.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH:15]=2)C.C1C2N(CC3C=CC(C([NH:53][OH:54])=O)=CC=3)C3C(=CC=CC=3)C=2C=CC=1>>[OH:54][NH:53][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH:15]=2
Reactant: O=C(NO)c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Reactant: CCOC(=O)CCCCCn1c2c(c3cc(-c4ccc(N(C)C)cc4)ccc31)CCCC2
Product: CN(C)c1ccc(-c2ccc3c(c2)c2c(n3CCCCCC(=O)NO)CCCC2)cc1

Procedure:
Compound 33 was prepared from 6-(6-bromo-1,2,3,4-tetrahydro-carbazol-9-yl)-hexanoic acid ethyl ester (compound 32) using the procedure described above for compound 29 as a white solid (85%). 1H NMR (400 MHz, MeOD): 87.86 (d, 2H), 7.65 (m, 3H), 7.33 (s, 2H), 4.09 (t, 2H), 2.76 (m, 4H), 2.16 (s, 1H), 2.08 (t, 2H), 1.98 (m, 2H), 1.90 (m, 2H), 1.77 (m, 2H), 1.66 (m, 2H), 1.38 (m, 2H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Br[C:16]1[CH:24]=CC=C2[C:17]=1C(CCN)=CN2.[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.C(O)CCC>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3[CH2:12][CH2:13][NH:14][C:16]([CH3:24])([CH3:17])[C:8]=3[NH:9]2)=[CH:5][CH:4]=1
Reactant: NCCc1c[nH]c2cc(Br)ccc12
Reactant: NCCc1c[nH]c2cccc(Br)c12
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCO
Product: CC1(C)NCCc2c1[nH]c1cc(Br)ccc21
Temperature: 60 °C
Reaction time: 96 h
Yield: 15 %

Procedure:
Concentrated HCl (10 mL) was added to a suspension of a 2:1 mixture of 2-(6-bromo-1H-indol-3-yl)ethanamine and 2-(4-bromo-1H-indol-3-yl)ethanamine (9.90 g, 41.4 mmol) and Na2SO4 (30 g) in 1:1 acetone/n-butanol (100 mL). The resulting suspension was heated at 60° C. with stirring for 4 d. The suspension was cooled and concentrated under reduced pressure. The residue was diluted with EtOAc, and the suspension was filtered. The filtrate was washed with saturate NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH) 100:0 to 0:100) yielded the title compound (1.68 g, 15%) as a red foam: 1H NMR (500 MHz, CDCl3) δ 7.66 (br s, 1H), 7.45 (d, J=1.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 1.5 Hz, 1H), 3.20 (t, J=5.5 Hz, 2H), 2.68 (t, J=5.5 Hz, 2H), 1.47 (s, 6H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:28])([F:27])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][CH3:25])=[CH:19][CH:18]=3)=[N:13]2)=[CH:8][CH:7]=1.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>O.[Pd]>[F:28][C:4]([F:3])([F:27])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH2:24][CH3:25])[CH2:30][C:29]([O:32][CH2:33][CH3:34])=[O:31])=[CH:19][CH:18]=3)=[N:13]2)=[CH:8][CH:7]=1
Reactant: CCC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(CC)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reaction time: 2 h
Yield: 90 %

Procedure:
Sodium hydride (60% immersion in oil, 0.32 g, 7.9 mmol) was weighed into an oven-dried three neck round bottomed flask. The flask was placed under nitrogen and tetrahydrofuran (44 mL) was added. The stirring mixture was placed in an ice bath. Triethylphosphonoacetate (1.4 mL, 6.9 mmol) was added and the mixture was stirred for 2 hours. Added 1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-one (CA7) (2.4 g, 6.5 mmol) as a solid and warmed to room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate/hexanes (1:1, 2×). The organic layers were dried over sodium sulfate, filtered, and concentrated. To the crude residue was added palladium on carbon (10 wt %, 0.70 g, 0.66 mmol) and dissolved in ethyl acetate (20 mL). The reaction was stirred under hydrogen by balloon overnight. The reaction mixture was filtered through Celite® and concentrated to give the title compound as a brown liquid (2.7 g, 90%): 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=0.6 Hz, 1H), 8.11 (dd, J=8.1, 6.0 Hz, 2H), 7.83-7.76 (m, 2H), 7.38 (dq, J=7.9, 1.0 Hz, 2H), 7.35-7.27 (m, 2H), 4.24-4.14 (m, 1H), 4.04 (qd, J=7.1, 1.6 Hz, 1H), 3.13-2.99 (m, 1H), 2.74-2.55 (m, 2H), 1.79-1.61 (m, 2H), 1.38-1.24 (m, 3H), 1.06 (dt, J=72.0, 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 434 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[S:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>ClC1C=CC=CC=1>[ClH:16].[S:17]1[CH2:21][CH2:20][N:19]([C:4]2[N:3]=[C:2]([NH2:1])[C:11]3[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[CH2:18]1
Reactant: COc1ccc2c(N)nc(Cl)nc2c1OC
Reactant: C1CSCN1
Solvent: Clc1ccccc1
Product: COc1ccc2c(N)nc(N3CCSC3)nc2c1OC
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 4.8 g. (0.02 mole) of 4-amino-2-chloro-7,8-dimethoxyquinazoline and 4.5 g. (0.05 mole) of thiazolidine in 50 ml. of chlorobenzene is heated at reflux for 18 hours, cooled to room temperature and the precipitate collected by filtration to give the title compound which was purified by recrystallization.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:12]C)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:14][Al:15](C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[O:11][CH3:14])[O-:12])([CH3:4])([CH3:3])[CH3:2].[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[O:11][CH3:14])[O-:12])([CH3:4])([CH3:3])[CH3:2].[CH3:14][Al+2:15]
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Reactant: C[Al](C)C
Solvent: ClCCl
Product: COc1ccc([O-])cc1C(C)(C)C
Product: C[Al+2]
Yield: 300 %

Procedure:
In a sufficiently dried egg-plant type flask provided with a stirrer was sufficiently dried 0.361 g (2 mmol) of 3-tert-butyl-4-hydroxyanisole recrystallized from hexane. After completion of the drying, 3.3 ml of methylene chloride was added thereto. Then, under nitrogen atmosphere, 0.9 ml (1 mmol) of trimethylaluminum was slowly added dropwise with ice-cooling and stirring, and the mixture was mixed in the dark at room temperature for 1 hour to obtain a methylene chloride solution of methylaluminum bis(3-tert-butyl-4-methoxyphenoxide) (1 mmol/3.3 ml).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH3:29][CH2:30][CH2:31][C:32](=O)[CH2:33][CH2:34][CH3:35].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C.C(N(CC)CC)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([CH:32]([CH2:33][CH2:34][CH3:35])[CH2:31][CH2:30][CH3:29])[CH2:27][CH2:28]2)=[O:22])=[CH:19][CH:20]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)N1CCNCC1
Reactant: CCCC(=O)CCC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: CCCC(CCC)N1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
The compound (57.7 mg) obtained in Example 32-2 was dissolved in methanol (1.73 ml) and then added with 4-heptanone (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (30.7 μl), sodium cyanoborohydride (13.8 mg), and triethylamine (76.5 μl). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 7 days. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then the whole was separated and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (27.7 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Br:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[CH:16]=[N+:17]([CH3:19])[CH3:18].BrC1C=C(C=CC=1)C=O.CNC>>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]([N:17]([CH3:19])[CH3:18])[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: C[N+](C)=Cc1cccc(Br)c1
Reactant: Cn1ccc2ccccc21
Agent: CNC
Agent: O=Cc1cccc(Br)c1
Agent: [Cl-]
Product: CN(C)C(c1cccc(Br)c1)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (3-bromo-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 3-bromo-benzaldehyde and dimethylamine.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][C@@H:4]2[CH2:8][N:9](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:11][N:3]12.C(O)=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:5]1[C@@H:4]2[CH2:8][NH:9][CH2:10][CH2:11][N:3]2[C:2](=[O:1])[CH2:7][O:6]1
Reactant: O=C(OCc1ccccc1)N1CCN2C(=O)COC[C@@H]2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O=CO
Product: O=C1COC[C@@H]2CNCCN12
Temperature: 120 °C

Procedure:
Benzyl (9aS)-4-oxohexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (0.19 g, 0.65 mmol was dissolved in ethanol (20 mL). The solution was transferred to a 25 mL vial, which contained 10% palladium on carbon (0.1 g), formic acid (0.1 g, 2.2 mmol) and ammonium formate (0.2 g, 3.17 mmol). The mixture was heated for 5 min at 120° C. using microwave single node heating. The catalyst was filtered off and the solution of crude (9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one was used in the next step without purification and quantification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CC(C)=O.CS(C)=O>[F:29][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=1)[C:16]([NH:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]2)=[CH:6][CH:7]=1)=[O:30]
Reactant: OC1CCNCC1
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OCCN2CCC(O)CC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Temperature: 25 °C
Yield: 14.8 %

Procedure:
N-[4-(2-Chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide (100 mg, 234 mmol) and 4-hydroxypiperidine (118 mg, 1.17 mmol) in acetone (3 ml) and dimethylsulfoxide (1 ml) are heated to 180° C. with microwave irradiation for 20 min. After cooling to room temperature the mixture is poured into ethyl acetate (100 ml) and washed with water (100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with ethyl acetate followed by 10% methanol in dichloromethane to give 3-fluoro-N-{4-[2-(4-hydroxypiperidin-1-yl)-ethoxy]-naphthalen-1-yl}-5-piperidin-1-yl-benzamide as a colorless foam (85 mg). 1H NMR 300 MHz (CDCl3) 8.31(dd, 1H, J=1.8 and 8.4 Hz), 7.9(s, 1H), 7.83(d, 1H, J=7.2 Hz), 7.71(d, 1H, J=8.4 Hz), 7.53(m, 2H), 7.31(s, 1H), 6.98(d, 1H, J=9 Hz), 6.83(d, 1H, J=8.4 Hz), 6.76(d, 1H, J=12.3 Hz), 4.23(t, 2H, J=5.7 Hz), 3.74(m, 1H), 3.01(s, 4H), 2.98(m, 4H), 2.42(t, 2H, J=9.5 Hz), 1.95(m, 2H), 1.57-1.71(m, 8H).
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.[Cl:10][C:11]1[N:12]=[C:13]([CH:16]([C:22]2[NH:23][C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)=[C:25]3[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[N:27]([CH3:34])[C:26]=23)[CH:17]([CH2:20]O)[CH2:18]O)[S:14][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:9][S:6]([O:5][CH2:20][C:17]([CH:16]([C:13]1[S:14][CH:15]=[C:11]([Cl:10])[N:12]=1)[C:22]1[NH:23][C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[C:25]2[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[N:27]([CH3:34])[C:26]=12)=[CH2:18])(=[O:7])=[O:8]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(c3nc(Cl)cs3)C(CO)CO)c2n(C)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(COS(C)(=O)=O)C(c1nc(Cl)cs1)c1[nH]c(-c2cccc(F)c2)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonic anhydride (1699 mg, 9.75 mmol) was added to a solution of 7-(1-(4-chlorothiazol-2-yl)-3-hydroxy-2-(hydroxymethyl)propyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (934 mg, 1.950 mmol) and triethylamine (1.631 mL, 11.70 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 16 hours. Further portions of triethylamine (1.631 mL, 11.70 mmol) and methanesulfonic anhydride (1699 mg, 9.75 mmol) were added as necessary to allow the reaction to run to completion. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH:18]([S:26](Cl)(=[O:28])=[O:27])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH:18]([S:26]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:28])=[O:27])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: On1nnc2ccccc21
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C=Cc1ccccc1)On1nnc2ccccc21
Temperature: 25 °C
Yield: 75.7 %

Procedure:
In dichloromethane (100 ml) are dissolved 1-hydroxy-1,2,3-benzotriazole (5.4 g) and triethylamine (5.6 ml). To the solution is added β-styrenesulfonyl chloride (8.0 g) with stirring at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is washed twice with water (30 ml) and dried over anhydrous magnesium sulfate-charcoal. After drying, the solvent is distilled off. The residue is dissolved in ethyl acetate (20 ml) and thereto is added n-hexane (50 ml) to give needles of 1-(β-styrenesulfonyloxy)-1,2,3-benzotriazole (9.0 g). A part of the product is recrystallized from ethyl acetate-n-hexane to give a pure product, melting point: 102°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[CH2:18][O:19][CH3:20].CO.O.O.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[CH2:18][O:19][CH3:20]
Reactant: COCc1cc(C(=O)OC)ccc1-c1ccccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc(C(=O)O)ccc1-c1ccccc1Cl
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To a solution of methyl 2′-chloro-2-(methoxymethyl)biphenyl-4-carboxylate (11 g, 37.8 mmol) in a mixture of THF (50 ml), MeOH (50 ml) and water (25 ml) was added lithium hydroxide monohydrate (4.76 g, 113.5 mmol) in portions. After 12 hours at RT, the reaction mixture was concentrated and the aqueous residual layer was acidified with a concentrated aqueous solution of HCl, and then extracted with EtOAc (2×100 mL). The organic layers were washed with water and brine, combined, dried (Na2SO4) and concentrated under reduced pressure to afford of the title compound as a white solid (7.5 g, 72%). LC/MS, M−(ESI): 275.0. 1H NMR (DMSO-d6, 400 MHz) δ 13.0 (1H, brs), 8.08 (1H, s), 7.92 (1H, d), 7.58 (1H, d), 7.44 (2H, m), 7.29 (2H, m), 4.21 (1H, dd), 4.13 (1H, dd), 3.16 (3H, s).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:16][CH2:17][CH2:18][Cl:19])[C:6]([O:8]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH:5]([CH2:16][CH2:17][CH2:18][Cl:19])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CCCCl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC(CCCCl)C(=O)O
Yield: 94.7 %

Procedure:
Benzyl 2-acetoxy-5-chloropentanoate (52.6 g, 0.19 mol) was dissolved in ethyl acetate (350 ml) and acetic acid (25 ml) and hydrogenated at 10 psi in a Parr apparatus in the presence of a Pd/C catalyst (5%, 2.5 g). After completion, the catalyst was filtered off and the volatiles were evaporated. The residue was dried in vacuo ( 1 mm Hg, 100° C.), and 35 g (98%) of the crude product was isolated and used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH:5]=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COCCOC
Product: O=C(Nc1cncc(-c2ccc(C(F)(F)F)cc2)c1)c1ccccc1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 11.35 g (40.96 mmol) of N-(5-bromopyridin-3-yl)benzamide, 11.67 g (61.43 mmol) of [4-(trifluoromethyl)phenyl]boronic acid and 8.68 g (81.91 mmol) of sodium carbonate were dissolved in 68 ml of 1,2-dimethoxyethane, 21 ml of water and 151 ml of DMF. The mixture was flushed with argon, 237 mg (0.21 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography (cyclohexane/ethyl acetate 1:1). Yield: 10.6 g (76% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)=[C:4]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[Br:25])[CH:3]=1.[Cl:26][C:27]1[CH:35]=[C:34]2[C:30]([CH2:31][CH2:32][NH:33]2)=[CH:29][CH:28]=1.Cl.CN([CH:40]=[O:41])C>>[NH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:17]=[CH:18][C:2]([NH:1][C:40]([N:33]2[C:34]3[C:30](=[CH:29][CH:28]=[C:27]([Cl:26])[CH:35]=3)[CH2:31][CH2:32]2)=[O:41])=[CH:3][C:4]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][C:20]=1[Br:25]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Reactant: Clc1ccc2c(c1)NCC2
Reactant: CN(C)C=O
Agent: Cl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)N2CCc3ccc(Cl)cc32)ccc1OCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
A mixture of tert-butyl 2-(4-amino-2-(4-bromo-1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (30 mg, 54 μmol) and 6-chloroindoline (8.3 mg, 54 μmol) in 1 mL of DMF was stirred at room temperature overnight. Then to the mixture was added 1 mL of 2M HCl. The mixture was stirred at room temperature overnight. The mixture was concentrated and the crude product was subjected to purification on HPLC. The proper fractions were collected and lyophilized to afford yellow oil in 20.1% yield. LCMS m/z (%)=492 (M+H 35Cl 79Br, 100). 1H NMR (400 MHz, MeOD) δ ppm 3.1 (m, 4 H), 3.7 (s, 3 H), 4.1 (m, 3 H), 4.2 (m, 1 H), 6.8 (dd, J=7.6, 2.0 Hz, 1 H), 7.1 (d, J=7.6 Hz, 1 H), 7.1 (d, J=9.1 Hz, 1 H), 7.3 (d, J=3.0 Hz, 1 H), 7.5 (s, 1 H), 7.6 (dd, J=9.1, 2.5 Hz, 1 H), 7.8 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].C1(OC2C=CC=CC=2)C=CC=CC=1.[K].[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:30]=1[N+:36]([O-:38])=[O:37]>CN1CCCC1=O>[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[C:33]([O:35][C:9]2[C:8]([F:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[Cl:1])[CH:32]=[CH:31][C:30]=1[N+:36]([O-:38])=[O:37]
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: N#Cc1cc(F)c(F)c(Cl)c1
Agent: [K]
Solvent: CN1CCCC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(Oc2c(F)cc(C#N)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
The product 3-chloro-4,5-difluorobenzonitrile, prepared for example as set forth in Example 3, above, is a useful intermediate for the preparation of various end products especially for the preparation of diphenyl ether herbicides. Thus, for example, this compound may be further reacted with the potassium salt of methyl-5-hydroxy-2-nitrobenzoate in a solvent, such as N-methyl-2-pyrrolidone at a temperature of about 120° to 180° Celsius to form methyl-5-(2-chloro-4-cyano-6-fluoro-phenoxy)-2-nitro-benzoate. The ester may be hydrolyzed in a conventional manner to the corresponding carboxylic acid.