Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)#[CH:9].C([O-])([O-])=O.[Cs+].[Cs+].O>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(S([O-])(=O)=O)=CC=2C(C)C)CCCCC1.[Na+].C(#N)C>[S:12]1[CH:13]=[CH:14][C:10]([C:8]#[C:9][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11]1
Reactant: Clc1cccnc1
Reactant: C#Cc1ccsc1
Agent: CC(C)c1cc(S(=O)(=O)[O-])cc(C(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: C(#Cc1ccsc1)c1cccnc1
Yield: 92.9 %

Procedure:
The general procedure described in Example 27 was used with 3-chloropyridine (0.050 mL, 0.50 mmol), 3-ethynylthiophene (0.074 mL, 0.75 mmol), PdCl2(CH3CN)2 (3.2 mg, 0.0125 mmol, 1.25 mol %), sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (20.0 mg, 0.0375 mmol, 3.75 mol %), Cs2CO3 (650 mg, 2.00 mmol), water (1.0 mL), acetonitrile (1.5 mL), 10 h, 100° C. The product was isolated as a white solid (86 mg, 93%). Mp=62° C. (lit. 65.5-64.0° C.). 1H NMR (400 MHz, CDCl3) δ: 8.75 (d, 1H, J=1.6 Hz), 8.54 (dd, 1H, J=2.0 Hz, 5.2 Hz), 7.79 (dt, 1H, J=8.0 Hz, 2.0 Hz), 7.57 (dd, 1H, J=2.8 Hz, 1.2 Hz), 7.32 (dd, 1H, J=5.2 Hz, 2.8 Hz), 7.27 (qd, 1H, J=0.8 Hz, 4.8 Hz, 3.2 Hz), 7.21 (dd, 1H, J=1.2 Hz, 5.2 Hz). 13C NMR (125 MHz, CDCl3) δ: 152.4, 148.7, 138.5, 129.9, 129.6, 125.9, 123.2, 121.8, 120.6, 87.9, 85.7.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:29])([F:28])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:12]([F:27])[CH:11]=1)=[O:8]>O>[F:29][C:6]([F:5])([F:28])[C:7]([NH:9][C:10]1[CH:11]=[C:12]([F:27])[C:13]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])=[CH:14][C:15]=1[N+:1]([O-:4])=[O:2])=[O:8]
Reactant: O=C(Nc1ccc(C2CCCN2C(=O)C(F)(F)F)c(F)c1)C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=C(Nc1cc(F)c(C2CCCN2C(=O)C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 ml of fuming nitric acid was added to 28 g of 2,2,2-trifluoro-N-(3-fluoro-4-(1-(trifluoroacetyl)pyrrolidin-2-yl)phenyl)acetamide with cooling with ice, and the reaction liquid was stirred at room temperature for 1 hour. Water with ice was added to the reaction liquid to dilute it, then extracted with ethyl acetate, washed with saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=10/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]([NH:6][S:7]([CH:10]=[CH2:11])(=[O:9])=[O:8])([CH3:5])[C:3]#[N:4].[Cl:12][C:13]([Cl:19])([S:17]Cl)[CH:14]([Cl:16])[Cl:15].O.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[Cl:12][C:13]([S:17][CH2:5][C:2]([CH3:1])([NH:6][S:7]([CH:10]=[CH2:11])(=[O:9])=[O:8])[C:3]#[N:4])([Cl:19])[CH:14]([Cl:16])[Cl:15]
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: C=CS(=O)(=O)NC(C)(C)C#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CS(=O)(=O)NC(C)(C#N)CSC(Cl)(Cl)C(Cl)Cl
Reaction time: 8 h
Yield: 44.3 %

Procedure:
To a stirred mixture of 3.9 g (0.02 mole) 2-methyl-2-(ethenylsulfonamido)propionitrile (the product of Example 22), 5.0 g (0.02 mole) 1,1,2,2-tetrachloroethylsulfenyl chloride and 0.5 g benzyltriethylammonium chloride in 150 ml methylene chloride, cooled by an ice bath, 10 ml water was added; then 1.6 g (0.02 moles) 50% sodium hydroxide was added dropwise. The reaction mixture was stirred and allowed to come to room temperature overnight. The reaction mixture was washed twice with equal amounts (about 150 ml) water, dried over magnesium sulfate, filtered and stripped. The solid residue was washed with petroleum ether and then dried to give 3.3 g of the above-identified product as a beige solid.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[F:14])[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17].[I:18]CI.N(OCCC(C)C)=O>CC#N.C(Cl)Cl>[F:14][C:8]1[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([I:18])=[C:3]([C:16]#[N:17])[C:4]([CH3:15])=[N:5]1
Reactant: ICI
Reactant: Cc1nn(-c2ccc(O)cc2F)c(N)c1C#N
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nn(-c2ccc(O)cc2F)c(I)c1C#N
Temperature: 50 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a stirred solution of 5-amino-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (114 mg, 0.49 mmol) in MeCN (2.5 mL) was added diiodomethane (0.293 mL, 3.63 mmol) followed by isoamyl nitrite (0.029 mL, 0.216 mmol). The reaction vessel was heated using a heating gun to initiate the reaction. After the rest of isoamyl nitrite (0.261 mL, 1.94 mmol) was added and the reaction was stirred for 1 hour at 50° C. The reaction was diluted with DCM and concentrated into silica and purified using silica gel (Heptane-EtOAc 1:0 to 0:1) to give 1-(2-fluoro-4-hydroxyphenyl)-5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (90.0 mg, 53%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C@H:18]1[NH:23][C@@H:22]([CH3:24])[CH2:21][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=O)[NH:30][CH:31]=2)=[O:26])[CH2:19]1>C(O)C.N1CCCCC1>[CH3:24][C@H:22]1[NH:23][C@@H:18]([CH3:17])[CH2:19][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:11][C:10]3=[O:16])[NH:30][CH:31]=2)=[O:26])[CH2:21]1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.5 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellow solid (21.5 mg, 20%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[C:11][C:12]3[CH:31]=[CH:30][C:15]4[NH:16][C:17]([NH:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[C:26]([F:29])([F:28])[F:27])=[N:18][C:14]=4[CH:13]=3)[CH:8]=2)[CH:3]=[N:2]1>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:31]=[CH:30][C:15]4[NH:16][C:17]([NH:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[C:26]([F:29])([F:27])[F:28])=[N:18][C:14]=4[CH:13]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: FC(F)(F)c1ccccc1Nc1nc2cc(C#Cc3ccc4cn[nH]c4c3)ccc2[nH]1
Solvent: CCO
Product: FC(F)(F)c1ccccc1Nc1nc2cc(CCc3ccc4cn[nH]c4c3)ccc2[nH]1

Procedure:
A solution of [5-(1H-Indazol-6-ylethynyl)-1H-benzoimidazol-2-yl]-(2-trifluoromethylphenyl)-amine (0.3 mmol; see Example 159) in ethanol (3 mL) was reduced under hydrogenation conditions at 50 psi as described in general procedure to yield {5-[2-(1H-indazol-6-yl)-ethyl]-1H-benzimidazol-2-yl}-(2-trifluoromethylphenyl)amine. MS: m/z 422 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][O:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:32]Cl)=[C:27]([O:34][CH3:35])[CH:26]=[CH:25]2.C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>CN(C=O)C.O>[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:32][N:3]1[C:2](=[O:1])[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][O:6][C:5]3[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=3)=[C:27]([O:34][CH3:35])[CH:26]=[CH:25]2
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Reactant: COc1ccc2cc(Br)ccc2c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccccc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 67.5 %

Procedure:
A mixture of (S)-tert-butyl 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.412 g, 5.07 mmol), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (1.59 g, 5.58 mmol), Cs2CO3 (1.98 g, 6.09 mmol), and NaI (913 mg, 6.09 mmol) in DMF (16.9 mL) was stirred at RT for 22 h, diluted with H2O and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and. The filtrate was concentrated to give a residue that was purified by silica gel chromatography to give (S)-tert-butyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.804 g, 67%) as an off-white solid. MS m/z 549/551 (MNa)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccccc1Cl
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccccc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-chloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(N(CC)CC)C>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
0.59 g (2.41 mmol) of 2,4-Dichloro-3-nitroquinoline and 0.42 g (2.41 mmol) of N-(tert-butoxycarbonyl)-1,3-propanediamine were heated at 70° C. in 10 ml of triethylamine and stirred for 1.5 hours. Triethylamine was distilled off under reduced pressure. The resulting residue was dissolved in methylene chloride, washed with water, and dried (Na2SO4). After the solvent was distilled off under reduced pressure, the residue was triturated with methanol and filtered to obtain 0.61 g (1.60 mmol) of 4-[3-(tert-butoxycarbonylamino)propylamino]-2-chloro-3-nitroquinoline shown below as yellow crystals (mp: 159-161° C.). ##STR34## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3310, 1680, 1580. 1H-NMR (CDCl3) δ (ppm) : 1.50 (9H, s), 1.77 (2H, m), 3.27 (2H, q, J=6.1 Hz), 3.36 (2H, q, J=6.0 Hz), 4.82 (1 H, br), 7.37 (1H, br), 7.55 (1H, t, J=7.8 Hz), 7.72 (1H, t, J=7.7 Hz), 7.89 (1H, d, J=8.2 Hz), 8.27 (1H, d, J=8.4 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6](OC)=[O:7].[CH3:11][NH:12][CH3:13].C(O)C>>[CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([N:12]([CH3:13])[CH3:11])=[O:7]
Reactant: COCC(=O)CC(=O)OC
Reactant: CNC
Solvent: CCO
Product: COCC(=O)CC(=O)N(C)C

Procedure:
0.17 mol (25 g) of methyl 4-methoxy-acetoacetate and 91 ml 33% dimethylamine in ethanol (about 0.51 mol dimethylamine) were stirred in a pressure reactor for 4 h at 110° C. The reaction mixture was then evaporated to dryness and 27 g of crude product chromatographed over 350 g silica gel with ethyl acetate/methanol 9/1. After drying, 12.4 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[S:19][C:18]([C:20]3([O:24][CH2:25][O:26][CH3:27])[CH2:23][CH2:22][CH2:21]3)=[N:17][CH:16]=2)=[C:4]2[CH:10]=[C:9](/[C:11](=[N:13]/[OH:14])/[NH2:12])[NH:8][C:5]2=[N:6][CH:7]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([C:41](O)=[O:42])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[NH2:12]/[C:11](=[N:13]\[O:14][C:41]([CH:37]1[CH2:38][CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36]1)=[O:42])/[C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([C:15]3[S:19][C:18]([C:20]4([O:24][CH2:25][O:26][CH3:27])[CH2:23][CH2:22][CH2:21]4)=[N:17][CH:16]=3)=[C:4]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(/C(N)=N/O)cc34)s2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(/C(N)=N/OC(=O)C5CCCN(C(=O)OC(C)(C)C)C5)cc34)s2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of Example 22B (0.09 g, 0.221 mmol), 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (0.056 g, 0.243 mmol), N-methylmorpholine (0.085 mL, 0.772 mmol), and 1-hydroxybenzotriazole hydrate (0.017 g, 0.110 mmol) in N,N-dimethylformamide (2.5 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.063 g, 0.331 mmol), and the reaction was stirred at ambient temperature for 3 hours. The reaction was treated with water (15 mL), and the resulting suspension was stirred for 10 minutes and filtered. The solid collected was washed with water and dried under vacuum. The crude material was purified by flash chromatography on silica gel, eluting with a gradient of from 0% to 40% ethyl acetate in hexane, to provide the title compound. MS ESI(+) m/z 619.2 [M+H]+.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[C:17]=3I)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1.BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[C:54]1(B(O)O)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[C:17]=3[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)c(I)c2c(=O)[nH]ncc21
Reactant: OB(O)c1ccccc1
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)c(-c2ccccc2)c2c(=O)[nH]ncc21
Yield: 55.1 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 299 mg (0.495 mmol) of 2-(3-cyclobutoxy-4-difluoromethoxyphenyl)-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Example 34-(a) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, and using 95 mg (0.779 mmol) of phenylboronic acid in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 1-(a), whereby 151 mg of the title compound was obtained as a pale beige solid. (Yield: 89%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14]1([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[PH4+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.[Pd]>[C:21]1([N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [PH4+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1

Procedure:
In another embodiment, there is provided a method for forming an arylamine, comprising adding 4-bromobiphenyl and diphenylamine in toluene into a continuous plug flow reactor, the continuous plug flow reactor further comprising continuously reacting the 4-bromobiphenyl and the diphenylamine in the toluene in a presence of a base and a palladium catalyst under Buchwald conditions in the continuous plug flow reactor, adding a phosphonium-based ionic liquid with tri-t-butylphospine to the 4-bromobiphenyl and the diphenylamine in the continuous plug flow reactor, continuously reacting the 4-bromobiphenyl and the diphenylamine in the toluene and the phosphonium-based ionic liquid with the tri-t-butylphospine in the presence of the base and the palladium catalyst under Buchwald conditions in the continuous plug flow reactor until N,N-diphenyl-4-biphenylamine is produced, and collecting the N,N-diphenyl-4-biphenylamine.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C4C(C)=CC=CC=4C)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:34]([CH2:37][CH:38]1[CH2:42][C:41]2[CH:43]=[CH:44][CH:45]=[C:46]([C:47]3[C:52]([CH3:53])=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:54])[C:40]=2[O:39]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[CH3:54][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]([CH3:53])[C:47]=1[C:46]1[C:40]2[O:39][CH:38]([CH2:37][NH2:34])[CH2:42][C:41]=2[CH:43]=[CH:44][CH:45]=1
Reactant: Cc1cccc(C)c1-c1cccc2c1OC(CN=[N+]=[N-])C2
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(C)cccc4C)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: Cc1cccc(C)c1-c1cccc2c1OC(CN)C2
Yield: 84 %

Procedure:
Treatment of (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.646 g, 1.58 mmol) with sodium azide (0.411 g, 6.33 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.057 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.383 g (84%) of (±)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C17H19NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 69.06; H, 7.01; N, 4.21.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13])=[O:4].CCN(C(C)C)C(C)C>C(#N)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][O:13][C:7]=2[CH:8]=1
Reactant: O=C(CCl)Nc1ccc(F)cc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1COc2cc(F)ccc2N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide (5.5 g, 27 mmol) in acetonitrile (40 mL) was added DIPEA (7 g, 54 mmol) and the reaction solution was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (50 mL) and water (50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 3.5 g (78%) of 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one as a brown solid. 1H NMR (400 MHz, CDCl3) δ 8.35 (br. s, 1H) 6.67-6.77 (m, 3H) 4.62 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH2:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][NH:11][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=2)[CH2:14][CH2:15]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Temperature: 140 °C

Procedure:
To a solution of 4-chloropicolinic acid (0.8 gm, 0.0051 mol) in DMSO (4 mL) was added benzyl 4-(aminomethyl)piperidine-1-carboxylate (2.5 gm, 0.010 mol) and the mixture warmed to 140° C. for 18 h. The reaction was cooled and diluted with 10% sodium bicarbonate (100 mL) and washed with ether (2×25 mL). The aqueous extract was washed with dichloromethane (3×50 mL), and the dichloromethane extract dried over sodium sulfate and concentrated to an oil (2.4 gm). The oil was chromatographed on silica using dichloromethane/methanol/acetic acid/water—90/10/1/1 to give 4-[(1-benzyloxycarbonyl-piperidin-4-ylmethyl)-amino]-pyridine-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[NH:9][S:10]([C:13]1[CH:36]=[CH:35][C:16]([CH2:17][CH2:18][C:19]2([NH:27]C(=O)OC(C)(C)C)[CH2:24][O:23]C(C)(C)[O:21][CH2:20]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(OC(=O)NC1(CCC2C=CC(S(N3C4C(=CC=C(OC)C=4)C(C(=O)C4C=C(OC)C(OC)=C(OC)C=4)=C3)(=O)=O)=CC=2)COC(C)(C)OC1)(C)(C)C>>[NH2:27][C:19]([CH2:20][OH:21])([CH2:24][OH:23])[CH2:18][CH2:17][C:16]1[CH:35]=[CH:36][C:13]([S:10]([NH:9][CH:6]2[CH2:5][CH2:4][CH:3]3[CH2:8][CH:7]2[C:2]3([CH3:37])[CH3:1])(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(S(=O)(=O)NC3CCC4CC3C4(C)C)cc2)COC(C)(C)OC1
Agent: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(CCC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Product: CC1(C)C2CCC(NS(=O)(=O)c3ccc(CCC(N)(CO)CO)cc3)C1C2
Yield: 80 %

Procedure:
When the product of Step C was substituted for tert-butyl-5-(4-(6-methoxy-3-(3,4,5-trimethoxybenzoyl)-1H-indol-1-ylsulfonyl)-phenethyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 13, Step F, the similar process afforded the title compound in 80% yield, as colourless solid. 1H-NMR (D2O) 0.67 (s, 3H); 0.94 (s, 3H); 1.14-1.17 (m, 2H); 1.71 (m, 6H); 1.88-2.01 (b, 4H); 2.17 (m, 1H); 2.67-2.78 (m, 4H); 3.68 (s, 4H); 7.42 (d, 2H, J=8.17 Hz); 7.70 (d, 2H, J=8.18 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7](CC2C=CC(OC)=CC=2OC)[CH2:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])[CH3:2].S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(O)c2ccc(OCc3ccccc3)cc2CN1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncc2cc(OCc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
Dichloromethane (100 mL) was cooled to 0° C. and 5.7 g (12 mmol) of 7-benzyloxy-2-(2,4-dimethoxy-benzyl)-4-hydroxy-1,2-dihydro-isoquinoline-3-carboxylic acid ethyl ester and 1.31 mL (18 mmol) of thionyl chloride were added. The reaction was stirred for one hour and then allowed to warm to room temperature and stirred for an additional 3 hours. 60 mL of hexanes was added to the resultant slurry and the white solid was collected by filtration through a medium glass fritted filter. The solid was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.7 g, white solid); MS (ESI+): 324.3 e/z (M+1)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]([OH:26])[CH2:13][N:14](CC2C=CC=CC=2)[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][C:3]=1[Cl:27].[H][H]>CO.Cl.[Pd]>[ClH:27].[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH:12]([OH:26])[CH2:13][NH:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:4][C:3]=1[Cl:27]
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)c1cc(Cl)c(N)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)NCC(O)c1cc(Cl)c(N)c(C(F)(F)F)c1

Procedure:
0.76 gm of 1-(4'-amino-3'-chloro-5'-trifluoromethyl-phenyl)-2-(N-benzyl-N-tert.butylamino)-ethanol were dissolved in 20 ml of methanol and 1.95 ml of 1N hydrochloric acid, and the solution was hydrogenated in a hydrogenation vessel in the presence of 80 mgm of palladium/coal-catalyst (10%) until 1 mol of hydrogen had been absorbed. Afterwards, the catalyst was removed by filtration, and the filtrate was evaporated to dryness in vacuo. The oily residue was purified by column chromatography (silicagel; chloroform:methanol:concentrated ammonia = 80:20:1 as eluant). The fractions containing the desired substance were combined, and the solvent was removed in vacuo. The remaining crystalline base of the desired compound was converted into its hydrochloride with the calculated quantity of 1.07 N hydrochloric acid in isopropanol, and recrystallized from ethyl acetate/ether. M.p. 205°-207° C. (decomp.).