Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([NH:23][OH:24])=[O:22])=[C:14]([O:30]C)[CH:13]=2)=[CH:8][CH:7]=1>ClCCl.O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([CH3:29])([S:25]([CH3:28])(=[O:26])=[O:27])[C:21]([NH:23][OH:24])=[O:22])=[C:14]([OH:30])[CH:13]=2)=[CH:8][CH:7]=1
Reactant: COc1cc(-c2ccc(F)cc2)ccc1CCC(C)(C(=O)NO)S(C)(=O)=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(CCc1ccc(-c2ccc(F)cc2)cc1O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Yield: 17.1 %

Procedure:
Boron tribromide (750 ul, 0.75 mmol, 1.0 M in dichloromethane) was added to a solution of (+/−)-4-(4′-fluoro-3-methoxybiphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide prepared as in Example 18 (154 mg, 0.389 mmol) in dichloromethane (10 mL) at 0° C. The reaction was allowed to warm to rt and stirred until complete, then was diluted with water (60 mL) and extracted with ethyl acetate (3×60 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The solid was dissolved in 1N aqueous NaOH (60 mL), washed with ethyl acetate (3×80 mL), acidified using 1N aqueous HCl, and extracted with ethyl acetate (3×100 mL). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound as an off-white solid (25.4 mg, 17.1%). LC-MS m/z 382.5 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.68 (s, 3H) 2.12-2.23 (m, 1H) 2.41-2.55 (m, 2H) 2.74-2.90 (m, 1H) 3.07 (s, 3H) 6.97-7.03 (m, 2H) 7.10-7.20 (m, 3H) 7.53-7.60 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1>CC(O)=O.O=[Pt]=O>[CH2:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: Oc1cccc2cnccc12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Oc1cccc2c1CCNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
A mixture of isoquinolin-5-ol (4 g, 27.6 mmol) and PtO2 (1.3 g) in HOAc (50 mL) was stirred under H2 (45 Psi) at room temperature overnight. The mixture was filtered and the filtrate was concentrated under vacuum to give the crude product (3.2 g, 80%) which was used in the next step without purification. LCMS (m/z): 150.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: Nc1ccccc1
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCCN(CC(=O)Nc1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and aniline: MS (APCI) m/z 360 ([M]−).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[C:35]([CH3:39])=[CH:36][CH:37]=[CH:38][C:33]=4[Cl:32])(=[O:41])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)cccc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-chloro-6-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=610.1)=70%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:26])[CH2:8][C@@H:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.[ClH:27]>ClCCl.CCOCC>[ClH:27].[N:4]1([C:7](=[O:26])[CH2:8][C@@H:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][NH:10]2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CC(=O)N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(C[C@@H]1Cc2ccccc2CN1)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2.88 g (7.18 mmol) of the compound obtained in Step A in 16 mL of dichloromethane, there are added dropwise 80 mL (80 mmol) of 1M solution of HCl in ether. The batch is stirred at ambient temperature for 15 hours, and then the suspension is filtered and the precipitate washed with ether. After drying, the title product is obtained in the form of a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2.C(N(CC)CC)C.[C:23]([O:27][C:28](ON=C(C1C=CC=CC=1)C#N)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:28]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2)([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCc1cccc2ccc(C(=O)O)cc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Part D--A solution of 8-aminomethyl-2-naphthoic acid (0.50 g, 0.00025 mol) and triethylamine (0.038 mL, 0.028 g, 0.000275 mol) in aqueous tetrahydrofuran (50%, 5 mL) was added, portionwise as a solid, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.068 g, 0.000275 mol). All was stirred at ambient temperature over 5 hours. The solution was concentrated to half volume and extracted with diethylether. The aqueous layer was then acidified to a pH of 1.0 using hydrochloric acid (1N) and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give the title compound, N-(BOC)-8-aminomethyl-2-naphthoic acid (0.050 g, 0.00017 mol) as a white solid. mp=190°-191° C.; 1H NMR (DMSO) d 13.1 (bs, 1H), 8.8 (s, 1H), 8.0 (q, 2H, J=7.9 Hz), 7.9 (d, 1H, J=8.1 Hz), 7.6 (t, 1H, J=7.5 Hz), 7.65-7.55 (m, 2H), 4.6 (d, 2H, J=5.5 Hz), 1.4 (s, 9H).
Reaction SMILES: [C:1]1(Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[Cl:19])[NH:15][C:14](=[O:20])[CH:13]=[N+:12]2[O-:21].CO>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[Cl:19])[NH:15][C:14](=[O:20])[C:13]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N+:12]2[O-:21]
Reactant: O=c1c[n+]([O-])c2cc(Cl)c(Cl)cc2[nH]1
Reactant: Brc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[n+]([O-])c1-c1ccccc1
Reaction time: 2 h
Yield: 39 %

Procedure:
To a stirred solution of Grignard reagent prepared from Mg (240 mg, 10 mmol) and phenyl bromide (10 mmol) in THF (50 mL) solid powdered nitrone 124 (2 mmol) was added in small portions. The mixture was stirred for 2 h, then decomposed with MeOH (50 mL) and evaporated. The crude hydroxylamine derivative 139 was washed with hexane (3×10 mL), suspended in CHCl3 (100 mL) and stirred with MnO2 for 16 h. Solid inorganic material was filtered off, washed with CHCl3 (10×10 mL), and MeOH (10×10 mL). Combined organic filtrate was evaporated. Solid residue was chromatographed on prep. TLC plate, eluent--mixture CHCl3 --MeOH (15:1), to yield of 3-aryl nitrone 126. Yield: 39%; the compound was identical to that prepared in Example 6.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([C:25]([O:29][N:30]1N=NC2C=CC=C[C:31]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>C(Cl)Cl>[C:1]([NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=1)[C:19]([N:30]([O:29][CH3:25])[CH3:31])=[O:21])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2 g of (N-Boc)-4-cyanophenylalanine, 2.32 g of TBTU, 2.40 ml of DIPEA and 806 mg of N,O-dimethylhydroxylamine hydrochloride are mixed together in 30 ml of DCM. After stirring for 24 hours at RT, the reaction mixture is concentrated to dryness and the residue is then extracted with EtOAc. The organic phase is washed with a pH 2 buffer solution, a saturated NaHCO3 solution and then a saturated NaCl solution. The expected compound crystallizes from a mixture of isopropyl ether and pentane (1.89 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=2)[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
(3-(4-(Trifluoromethyl)phenoxy)phenyl)methanol from Step 1 (1.3 g, 4.85 mmol), in dichloromethane (10 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (0.39 mL, 5.33 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 h. The reaction was concentrated by evaporation and the residue was purified by silica gel chromatography (0-20%, EtOAc:heptane) to afford the title compound (1.34 g) as a thick oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[CH3:16][NH:17][O:18][CH3:19].FC1C=CC(C(Cl)=O)=CC=1>C(Cl)Cl.C(N(CC)CC)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:17]([O:18][CH3:19])[CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A suspension of 4-fluorobenzoic acid (20 g, 143 mmol) in thionyl chloride (130 g; 1.1 mol) was stirred under reflux for 6 h: vigorous evolution of gas, clear solution after about 10 min, deepening of the color from yellow to orange. Excess thionyl chloride was removed by distillation (initially atmospheric pressure/40° C., then membrane pump vacuum/400° C.). From the distillation residue, 4-fluorobenzoyl chloride was distilled off under membrane pump vacuum at 90° C. over a short column. The reaction product crystallized on storing in a fridge (n20D 1.5315; m.p. 9° C., yield 20 g/89%). Freshly distilled triethylamine (29 ml) was added to a suspension of N,O-dimethylhydroxylamine hydrochloride (9.0 g; 92 mmol) in CH2Cl2 (75 ml). The reaction mixture was stirred at room temperature for 2 h and then cooled to −10° C. With cooling, 4-fluorobenzoyl chloride (13.5 g; 85 mmol) was, over a period of 6 min, added dropwise to the initial charge. After the addition had ended, cooling was removed and the reaction mixture was stirred at room temperature for 1.5 h. The light-brown suspension was poured into H2O (100 ml). The organic phase was removed and the aqueous phase was extracted with diethyl ether (2×). The combined extract was washed with saturated NaCl solution, dried over Na2SO4 and concentrated. The oily brown residue crystallized on cooling and scratching. The crude product was dried using an oil pump (residual triethylamine!) and reacted without further purification.
Reaction SMILES: [C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][C:8]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].I[C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[NH2:33])=[CH:9][C:8]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(B(O)O)ccc1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Nc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2ccccc2N)ccc1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
A solution of 17.89 g (44.0 mmol) 4-(tert-butyl-diphenyl-silanyloxy)-3-methoxy-phenyl-boronic acid, 6.89 g (31.45 mmol) 2-iodoaniline, 17.4 g (125.8 mmol) K2CO3 and 425 mg (6 mol %) Pd(OAc)2 in 140 ml THF and 80 ml H2O is heated to reflux for 20 hours. After cooling the mixture is filtrated over cellite and concentrated. The residue is dissolved in ethyl acetate and washed with water. After drying (MgSO4) and evaporating the solvent, the residue is subjected to flash-chromatography (ethyl acetate/hexane 1:9). Yield: 4′-(tert-Butyl-diphenyl-silanyloxy)-3′-methoxy-biphenyl-2-ylamine is isolated as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(C(F)(F)F)c4)C3)CC2)cc1
Yield: 8.7 %

Procedure:
The title compound (D149) (20 mg) was prepared according to the experimental procedure described in Description 148 starting from 5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)azetidin-1-yl)nicotinic acid (D105) (160 mg, 0.423 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (115.45 mg, 0.507 mmol). The residue obtained from SPE-Si cartridge purification (38 mg) dissolved in a mixture of chloroform/ethanol/n-hexane (70/15/15) (1 ml) was separated by chiral HPLC [Phenomenex Lux1 column (250×20 mm, 5 μm particle size). Mobile phase: isocratic premixed mixture of (hexane 75%, ethanol 25%) containing 0.1% of diethylamine. Flow rate=10 ml/min. UV detection: 235 nm]. Collected fractions, after solvent evaporation afforded the title compound (D149) (20 mg)
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Al+3].[Cl-].[Cl-].[Cl-].[C:16](Cl)(=[O:18])[CH3:17]>[N+](C1C=CC=CC=1)([O-])=O>[OH:11][C:3]1[C:2]([CH3:1])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:5][C:4]=1[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc([N+](=O)[O-])c(C)c1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
To a solution of 2-methyl-3-nitrophenol (2.0 g, 13 mmol) in nitrobenzene (16 mL) at RT under Ar gas is added AlCl3 (3.9 g, 29 mmol). The reddish mixture is heated to 50° C. To the reddish mixture is added dropwise via addition funnel a solution of acetyl chloride (1.2 mL, 17 mmol) in nitrobenzene (10 mL). The reaction is heated to 120° C. After 2 h at 120° C., the reaction mixture is cooled to RT and quenched slowly into a 1N HCl/ice mixture. The resulting mixture is stirred for 30 min and extracted with EtOAc (3×). The organic layers are combined and concentrated. Water is used to azeotrope off the nitrobenzene. The resulting residue is purified by flash column chromatography using 20% EtOAc/hexane. Obtained is the title compound as reddish oil (1.2 g). The title compound is 60% pure by LC-MS. Compound is used as is in the next step. LC-MS (m/e): 194 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=[CH:26][C:27](O)=O)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1>>[O:15]1[C:20]2[CH:21]=[CH:22][C:23](/[CH:25]=[CH:26]/[C:27]3[NH:1][C:2]4[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=4[N:8]=3)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCCO2
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCCO4)nc2n(CC)c1=O
Yield: 50.8 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.85 g (14.4 mmol) of 5,6-diamino-1,3-diethyluracil and 2.70 g (13.1 mmol) of 3-(1,4-benzodioxan-6-yl)acrylic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.45 g (yield 51%) of Compound 89 as a pale yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[CH:16][C:17]([CH:20]([F:22])[F:21])=[N:18][CH:19]=1>>[F:21][CH:20]([F:22])[C:17]1[N:18]=[CH:19][C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: FC(F)c1ccc(Br)cn1
Product: O=C(O)c1ccc(-c2ccc(C(F)F)nc2)cc1

Procedure:
Operations similar to those of Production Example 14 were conducted using 4-carboxyphenylboronic acid and 5-bromo-2-(difluoromethyl)pyridine, to provide the title compound as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][Br:18])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c1ncn2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Yield: 60 %

Procedure:
To a stirred solution of 4-methyl-benzimidazole-1-carboxylic acid tert-butyl ester (800 mg, 3.4 mmol) in CCl4 (7 mL) was added N-bromosuccinimide (730 mg, 4.1 mmol) and 2,2′-azobis(2-methylpropionitrile) (84 mg, 0.51 mmol). The resultant mixture was heated at reflux for 18 h after which it was filtered and concentrated to a yellow/orange syrup and crystals (1.4 g). Purification by column chromatography on silica gel (200:15—Hexanes:EtOAc) gave the desired title compound as a yellow syrup (635 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 7.95 (dd, 1H, J=7.8, 1.5 Hz), 7.42-7.34 (m, 2H), 4.96 (s, 2H), 1.71 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=3)[CH:12]=[CH:11]2)=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CSc1ccc(Br)cc1
Product: COC(=O)c1ccc2ccn(-c3ccc(SC)cc3)c2c1
Yield: 47 %

Procedure:
In the same manner as in Reference Example 89 and using 1-bromo-4-(methylthio)benzene instead of methyl 2-chloroisonicotinate and methyl 1H-indole-6-carboxylate instead of 2-aminopyridine, the title compound (yield 47%) was obtained as colorless crystals.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:35]=[CH:36][CH:37]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cccc(COCCCCBr)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cccc(COCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3-methoxybenzyloxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(4-(3-methoxybenzyloxy)butyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.O.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccc(C)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 89.8 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 24.7 mg of palladium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.9 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][C:14]([O:19][CH3:20])([CH2:16][O:17][CH3:18])[CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].[CH:21]([NH2:23])=O.C([O-])=O.[NH4+]>>[CH3:20][O:19][C:14]1([CH2:16][O:17][CH3:18])[CH2:13][CH2:12][C:5]2[C:6]3[C:7]([OH:8])=[N:23][CH:21]=[N:1][C:2]=3[S:3][C:4]=2[CH2:15]1
Reactant: CCOC(=O)c1c(N)sc2c1CCC(COC)(OC)C2
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: COCC1(OC)CCc2c(sc3ncnc(O)c23)C1
Yield: 84 %

Procedure:
A mixture comprising 21.46 g (71.7 mmol) (RS)-ethyl 2-amino-6-methoxy-6-(methoxymethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (prepared according to intermediate example 16c), 114 mL methanamide and 7.23 g ammonium formate was stirred at 150° C. overnight. The reaction mixture was cooled in an ice bath, the precipitate was filtered off, washed with water and ethanol and dried to give 16.95 g (84%) of the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[O:16]1[CH2:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[O:16]1[CH2:17][CH:18]=[C:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[O:4][C:3]=2[CH:13]([OH:15])[CH3:14])[CH2:20][CH2:21]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
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: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1C1=CCOCC1
Yield: 25.7 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A2, 0.50 g, 1.86 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.51 g, 2.42 mmol), Pd(PPh3)4 (0.11 g, 0.093 mmol) and Cs2CO3 (0.30 mg, 0.93 mmol) to afford the title compound (0.13 g, 26%) as a orange oil.