Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([OH:12])[CH2:10]Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([OH:12])[CH2:10][NH:25][CH2:21][CH:22]([CH3:24])[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
The mixture of [(1S,2S)-3-chloro-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid tert-butyl ester (5, 100 g), isobutyl amine (294 g), sodium carbonate (31.3 g) and water was heated to 60-65° C. and maintained for 3 hours. After completion of reaction water (200 mL) was added and distilled out excess isobutyl amine under vacuum at below 75° C. Water (800 mL) was added to the distillate, cooled to 25-35° C. and stirred for 2 hours. The obtained solid was filtered and washed with water to get title compound 4 (yield 105 g).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: C1CCNCC1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCCCC2)cc1)c1ccc2oc(Cl)cc2c1
Yield: 82 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with piperidine (1 mL) in MeOH (3 mL) under reflux to give the desired product (63 mg, 82%, Z/E=1/1) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.24 & 7.22 (s, 1H), 7.21 (d, J=9.2 Hz, 1H), 7.09 & 7.06 (d, J=8.6 Hz, 2H), 7.01 & 6.99 (d, J=8.8 Hz, 1H), 6.78 & 6.69 (d, J=8.2 Hz, 2H), 6.68 & 6.66 (d, J=8.6 Hz, 2H), 6.47 & 6.45 (s, 1H), 6.42 & 6.25 (d, J=8.6 Hz, 2H), 4.10 & 3.90 (t, J=6.0 Hz, 2H), 2.81 & 2.70 (t, J=6.0 Hz, 2H), 2.48-2.57 (m, 6H), 1.47-1.68 (m, 6H), 0.89-0.93 (m, 3H); m/z=502[M+1]+.
Reaction SMILES: C1N(COCCO)[C:4]2NC(N)=[N:13][C:14](=O)[C:3]=2N=1.[CH:17]1[C:30]2C=CC3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[C:19](C(=NO)C)[CH:18]=1>>[CH:25]1[C:24]2[CH:23]=[CH:22][C:21]3[C:30](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:3]=[C:14]([NH2:13])[CH:26]=1
Reactant: Nc1nc(=O)c2ncn(COCCO)c2[nH]1
Reactant: CC(=NO)c1ccc2ccc3ccccc3c2c1
Product: Nc1ccc2ccc3ccccc3c2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To 385 g of polyphosphoric acic at 100° C. was added 32 g (0.14 mol) of 1-(3-phenanthryl)ethanone oxime from Step 1 over 30 minutes. The mixture was stirred at 100° C. for 2 hrs, cooled down to room temperature followed by the addition of water/ice. Stirred 30 minutes, filtered and washed with water. This white solid was then placed in 500 mL of methanol and 40 mL of concentrated HCl. The reaction was refluxed overnight, cooled down to room temperature and concentrated down. A mixture of ethyl acetate/water was added to the residue and the resulting solution was made basic with 10 N KOH. The aqueous layer was extracted with ethyl acetate and combined organic layers were washed with water, brine, dried over sodium sulphate and volatiles were removed under reduced pressure to afford 25 g of 3-phenanthrylamine as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:15][C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[CH3:17].[C:26]([O:30][C:31]([NH:33][CH:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:36]3[CH2:37][CH2:38][CH:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:35]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:15][C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[CH3:17]
Reactant: C[C@@H](Nc1cc(N2CCC(=O)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@@H](Nc1cc(N2CCC(N3CCC(NC(=O)OC(C)(C)C)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Yield: 50 %

Procedure:
To a stirred solution of (R)-1-(4-chloro-3-(1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidin-4-one (0.13 g, 0.32 mmol) and 3-(t-butoxycarbonylamino)pyrrolidine (0.24 g, 1.3 mmol) in dichloroethane (DCE) (2 mL) was added NaBH(OAc)3 (0.094 g, 0.44 mmol). The reaction mixture was heated at 80° C. for 4 h. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude was purified by flash chromatography (SiO2, 1-7% methanol in dichloromethane) to give t-butyl 1-(1-(4-chloro-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidin-4-yl)pyrrolidin-3-ylcarbamate (0.092 g, 0.16 mmol, 31%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:34]1[CH2:39][CH2:38][S:37](=[O:40])[CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:34]5[CH2:39][CH2:38][S:37](=[O:40])[CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: O=S1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=S1CCN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (5 mL) was added thiomorpholine 1-oxide (155 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (280 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (87 mg, yield 36%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 568 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([C:16](=[N:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[C:17](=[N:20][C:21]([O:23]C)=O)SC)[C:9]=1[F:34].[N:36]1[CH:41]=[CH:40][CH:39]=[N:38][C:37]=1[NH:42][NH2:43].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:35])[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([C:16](=[N:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=2)[C:17]2[NH:20][C:21](=[O:23])[N:42]([C:37]3[N:38]=[CH:39][CH:40]=[CH:41][N:36]=3)[N:43]=2)[C:9]=1[F:34]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCOC(=O)OC)c1F
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)OCCOc1cc(OC)cc(C(=Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1F
Temperature: 50 °C
Yield: 61 %

Procedure:
A mixture of the crude product containing carbonic acid {3-[1-(4-cyanophenylimino)-2-methoxycarbonylimino-2-methylsulfanylethyl]-2-fluoro-5-methoxyphenoxy}ethyl ester methyl ester (37 g, 73.4 mmol), toluene (740 mL), pyrimidin-2-yl-hydrazine (8.08 g, 73.4 mmol), and triethylamine (12.3 mL, 88.2 mmol) was heated at 50° C. for 10 minutes under stirring, gradually heated to 110° C., and heated at 110° C. for 4 hours under stirring. The mixture was gradually cooled to room temperature, and then the precipitate was filtered and dried to obtain the captioned compound (23.89 g) as a pale yellow powder.
Reaction SMILES: [Cl:1]CCC[N:5](C)C(=O)C(C1C=CC(Cl)=CC=1CC1C=CC=CC=1)=O.[I-].[Na+].N1CCOCC1.Cl.[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][N:43]([CH3:63])[C:44](=[O:62])[C:45]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][C:48]=2[C:54](=O)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=O)[CH2:36][CH2:35]1>CC(CC)=O>[ClH:1].[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][N:43]([CH3:63])[C:44]([C:45]2[NH:5][C:54]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[C:48]3[C:47]=2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49]3)=[O:62])[CH2:36][CH2:35]1
Reactant: CN(CCCCl)C(=O)C(=O)c1ccc(Cl)cc1Cc1ccccc1
Reactant: CN(CCCN1CCOCC1)C(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: C1COCCN1
Product: CN(CCCN1CCOCC1)C(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
A solution of 7.6 g. of o-benzyl-p-chlorophenylglyoxylic acid (3-chloropropyl)methylamide in 40 ml. of ethyl methyl ketone is treated with 3.0 g. of sodium iodide and 3.5 g. of morpholine and the mixture is boiled at reflux for 30 hours. After concentration under reduced pressure, the residue is partitioned between water and methylene chloride, the organic phase washed with water, dried over sodium sulfate and concentrated to dryness. The residual oily base is purified on 500 g. of aluminum oxide using methylene chloride/ethyl acetate (4:1) for the elution, dissolved in diethyl ether and treated with excess ethereal hydrochloric acid. The hydrochloride which crystallizes out is recrystallized from isopropanol/diethyl ether, and there is obtained 4.9 g. of o-benzoyl-p-chlorophenylglyoxylic acid [3-(morpholino)propyl]methylamide hydrochloride in the form of light yellow crystals having a melting point of 169°-172° C. (decomposition).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:31]([O:34][CH2:35]Cl)[CH2:32][CH3:33].O>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:35][O:34][CH2:31][CH2:32][CH3:33])[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCOCCl
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)c2ncn(Cc3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(-c2ccccc2)c1=O
Reaction time: 1 h

Procedure:
0.45 g (3.26 mmol) of potassium carbonate was added at 60° C. to a suspension of 0.65 g (2.04 mmol) of 7-benzyl-3-phenylxanthine from stage a) in 20 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 0.29 ml (2.65 mmol) of propoxymethyl chloride was then added dropwise and the mixture was stirred at 80° C. for 1.5 hours. 20 ml of water were then added, the mixture was extracted three times using 24 ml of methyl tert-butyl ether each time, and the combined organic phases were washed twice with 12 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column heptane/ethyl acetate (5/7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[S:27][C:16]2[C:17]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1.[CH3:28][N:29]=[C:30]=[O:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[S:27][C:16]2[C:17]3[CH:25]=[CH:24][C:23]([NH:26][C:30]([NH:29][CH3:28])=[O:31])=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1
Reactant: Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Reactant: CN=C=O
Product: CNC(=O)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures of Example 76, 2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-amine was reacted with methyl isocyanate to give 112. MS: (ESI+) 452.1
Reaction SMILES: C[O:2][C:3](=[O:20])[C@H:4]([CH2:9][C:10]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11]1)[CH2:5][C:6]([OH:8])=O.C(NC(C)C)(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:13]([C:10]1([CH2:9][C@H:4]([CH2:5][C:6]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:8])[C:3]([OH:2])=[O:20])[CH2:12][CH2:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H](CC(=O)O)CC1(Cc2ccccc2)CC1
Reactant: C1COCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-2-(1-Benzyl-cyclopropylmethyl)-succinic acid 1-methyl ester (2.453 g, 8.88 mmol), di-isopropyl amine (1.1 eq, 9.76 mmol, 1.26 g) and morpholine (1.5 eq., 13.3 mmol, 1.16 g) in dry dichloromethane under N2 was added PyBOP (1.1 eq., 9.76 mmol, 5.08 g). The mixture was stirred at room temperature for 5 hr, and concentrated in vacuum. The residue was dissolved in ethyl acetate (150 mL) and washed with water (100 mL), NH4Cl (100 mL), NaHCO3 (2×100 mL), then water (100 mL). The organic layer was dried (MgSO4) and concentrated in vacuum. The residue was purified over 120 g silica gel, eluted with ethyl acetate:heptane (1:1.5, 1:1, to 2:1) to afford the desired compound contaminated with PyBOP residues. A solution of the mixture in ether containing ethyl acetate (250 mL total) was washed with dilute HCl (150 mL), water (150 mL) dilute NaOH (150 mL) then water (150 mL). The organic layer was dried (MgSO4) and concentrated in vacuum to afford (R)-2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid methyl ester as a white solid (2.292 g, 74.7% yield).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7](=[O:29])[C@H:8]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH2:17])[CH:11]=1.[N:30]([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.O>[CH3:5][O:6][C:7](=[O:29])[C@H:8]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][N:30]=[N:17][C:12]=2[CH:11]=1
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(N)c1)NC(=O)OCc1ccccc1
Reactant: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1ccc2[nH]nnc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To a solution of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propionic acid methyl ester mono acetate (2.68 g, 6.65 mmol) in acetic acid (30 mL) and water (40 mL), at room temperature was added a solution of sodium nitrite (0.46 g, 6.65 mmol) in water (8 mL), dropwise over several minutes. The resulting mixture was stirred at room temperature for 20 min, then cooled to 0° C., concentrated ammonium hydroxide was added to adjust pH to 11. The mixture was extracted with ethyl acetate twice in the presence of solid sodium chloride, and the organic layers were dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate/hexanes (6:4) as eluent to afford the title compound as a tan solid (94% yield). 1H-NMR (CD3OD, 500 MHz) δ 7.75 (d, J=8.5 Hz, 1H), 7.58 (s, 1H), 7.31-7.25 (m, 5H), 7.18 (d, J=8.5 Hz, 1H), 5.39 (d, J=8.0 Hz, 1H), 5.10 (d, J=12.0 Hz, 1H), 5.05 (d, J=12.0 Hz, 1H), 4.74 (dd, J=13.5, 6.0 Hz, 1H), 3.73 (s, 3H), 3.34 (dd, J=14.0, 5.5 Hz, 1H), 3.22 (dd, J=13.5, 6.0 Hz, 1H). 13C NMR (CD3OD, 125 MHz) δ 172.1, 156.0, 136.1, 128.6, 128.3, 128.1, 67.2, 55.2, 52.7, 38.5. Mass spec. 355.18 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:23][C:24]1[CH:29]=[C:28]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])[CH:16]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2cccc(Cl)c2)c1
Yield: 66.6 %

Procedure:
3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.048 g (66%) of 3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[CH2:10](O)[CH2:11][CH:12]=[CH2:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([O:8][CH2:13][CH2:12][CH:11]=[CH2:10])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: Oc1ccc(Br)nc1Br
Reactant: C=CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc(Br)nc1Br
Yield: 84.9 %

Procedure:
To a stirred mixture of 2,6-dibromopyridin-3-ol (47.3 g, 0.188 mol) and but-3-en-1-ol (13.8 g, 0.191 mol) in anhydrous THF (200 mL) at 0° C. was added PPh3 (59.4 g, 0.226 mol), followed by diisopropylazo dicarboxylate (DIAD, 41.77 g, 0.207 mol). The mixture was heated at reflux for 1 hour and then concentrated in vacuo to give a dark brown oil. The oil was dissolved in Ethyl acetate, washed with saturated NaHCO3 solution and brine, dried with Na2SO4, and concentrated in vacuo. Petroleum (300 mL) was added to the crude product mixture. The white solid was removed by filtration, and the filtrate was purified by silica gel chromatography (petroleum/Ethyl acetate, 30/1) to afford compound the title compound as oil (49 g, 85%). 1H NMR (400 Mz, DMSO-d6): δ: 2.62-2.59 (m, 2H); 4.07-4.03 (t, J=6, 2H); 5.22-5.11 (m, 1H); 5.96-5.83 (m, 1H); 7.01 (d, J=7.2); 7.33 (d, J=9.3, 1 H).
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7](=[O:17])[NH:6][C:5]1=[O:18].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>CN(C)C=O>[CH3:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32]/[CH:3]=[C:4]3\[C:5](=[O:18])[NH:6][C:7](=[O:17])[C:8]4[C:13]\3=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=4)=[CH:28][CH:27]=2)[CH2:24][CH2:25]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(=O)O)cc21
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(C(=O)O)cc43)cc2)CC1
Temperature: 100 °C
Yield: 64.9 %

Procedure:
A mixture of 4-methoxymethylene-1,3-dioxo-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid (90 mg, 0.364 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (69.6 mg, 0.364 mmol) in 1 mL of N,N-dimethylformamide is heated at 100° C. for 1 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 96 mg (65%) of yellow solid mp 278-280° C.; HRMS (ESI) m/z calcd for C22H22N4O4 407.17139. found 407.17128 (M+H)+1, Analysis for C22H22N4O4, Calcd: C, 63.60; H, 5.58; N, 13.49. Found: C, 63.67; H, 5.98; N, 13.20.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:7]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:7]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: Nc1ccc(C(=O)c2ccncc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2ccncc2)cc1N

Procedure:
A suspension of 20 g. (0.082 mol) of 4-(3-nitro-4-aminobenzoyl)pyridine in 1 liter of tetrahydrofuran containing 5 g. of 5% palladium on carbon was reduced with hydrogen under a pressure of 3 atmospheres. The resulting mixture was filtered and concentrated in vacuo to reddish oil which was dissolved in a minimum amount of methylene chloride and diluted with petroleum ether to yield 4-(3,4-diaminobenzoyl)pyridine as an unstable orange solid, mp. 210° -214° C. (water-Norite).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N+:5]([O-])=[C:4]([CH3:10])[CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]([O:15]C(=O)C(F)(F)F)=[O:14]>C(Cl)Cl>[F:11][C:12]([F:23])([F:22])[C:13]([O:15][CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([CH3:10])[N:5]=1)=[O:14]
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Br)cc(COC(=O)C(F)(F)F)n1
Reaction time: 20 h

Procedure:
To a stirring solution of 2.14 g 4-bromo-2,6-dimethylpyridine 1-oxide in 10 mL of CH2Cl2 was added 7.4 mL of trifluoroacetic anhydride. After 20 h, the solution was concentrated, and the crude product was purified by flash silica gel chromatography (5% MeOH/CHCl3) to give 1.93 g of (4-bromo-6-methylpyridin-2-yl)methyl 2,2,2-trifluoroacetate with some impurity.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:21])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[N+:18]([O-])=O)=[O:8])[CH2:2][CH2:3][CH3:4]>[Pd].CO>[NH2:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:21]
Reactant: CCCCNC(=O)C(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)C(=O)Nc1ccc(OC)cc1N
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A mixture of 27.0 g (91 mmol) of N-butyl-N′-(4-methoxy-2-nitrophenyl)-oxalamide, 1200 ml of methanol and 7.3 g of 10% Pd/C catalyst is hydogenated for 3 h. The catalyst is filtered off, washed with aceton, the filtrate is concentrated and the residue is treated with 100 ml of diethyl ether. The obtained product is filtered, washed with diethyl ether and dried to yield 21.8 g (90%) of the title compound. Mp.: 180-181° C. (diethyl ether).