Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=5)[CH2:22][CH2:21]4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: COc1cccc(I)c1
Product: COc1cccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:23]1([C:26]#[CH:27])[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>O1CCCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:27]#[C:26][CH:23]3[CH2:25][CH2:24]3)[CH:7]=2)[C:9]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[N:10]1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)n1cc(-c2ccnc(Br)c2)c(-c2ccc(Cl)s2)n1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)n1cc(-c2ccnc(C#CC3CC3)c2)c(-c2ccc(Cl)s2)n1
Temperature: 120 °C
Reaction time: 0.05 h
Yield: 50.9 %

Procedure:
To a solution of 2-bromo-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (0.18 mmol) in 2 mL of tetrahydrofurane was added cyclopropylacetylene (0.71 mmol), copper iodide (0.053 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.053 mmol) and N,N-diisopropylethlamine (0.88 mmol). The resulting mixture was stirred in the microwave at 120° C. for 3 min. The solvent was then evaporated and the residue was purified by chromatography on silica gel (hepthane:ethyl acetate 5:1 to 2:1) to afford 35 mg of 4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]-2-(cyclopropylethynyl)pyridine (51% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:31]([O:33]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:37][NH2:38]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:37][NH:38][C:31](=[O:33])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(C)C)cc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(CN(C)C)cc2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (210 mg) in 85% hydrazine monohydrate (1 mL) and methanol (10 mL) was stirred at 23° C. for overnight. Methanol was removed under reduced pressure. The crude was purified by flash chromatography to give the title compound (72 mg, yield 37%). LC-MS (ESI) m/z: 439 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.18 (d, 3H), 1.19 (d, 3H), 2.26 (s, 6H), 2.79-2.83 (m, 1H), 3.51 (d, 2H), 4.27 (d, J=8.0 Hz, 1H), 4.73 (d, J=8.0 Hz, 1H), 6.98-7.00 (m, 2H), 7.05-7.07 (m, 2H), 7.18-7.22 (m, 3H), 7.25-7.27 (m, 2H), 7.54-7.56 (m, 1H), 7.56-7.59 (m, 1H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)=[NH:4].N[C:19]1[CH:20]=[CH:21][C:22]([F:27])=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:20]=[CH:21][C:22]=1[F:27])#[N:25]
Reactant: CS(=O)(=O)NCCNc1nonc1C(=N)NO
Reactant: N#Cc1cc(N)ccc1F
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(C#N)c1

Procedure:
The title compound was prepared according to the procedure of Example 17, step E, using N-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-cyano-4-fluoroaniline [Aldrich, product #639877] as the starting materials. LCMS for C13H14FN7NaO4S (M+Na)+: m/z=406.0. 1H NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 9.08 (s, 1H), 7.35 (m, 1H), 7.18 (m, 3H), 6.56 (m, 1H), 6.23 (m, 1H), 6.24 (s, 2H), 3.32 (m, 2H), 3.14 (m, 2H), 2.89 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]=[CH2:20])=[CH:12][CH:11]=2)[CH:3]=1.[Zn](CC)[CH2:22]C.ICI>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]3[CH2:22][CH2:20]3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: C=COCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC[Zn]CC
Solvent: CCOCC
Solvent: ICI
Product: Clc1ccc(Br)cc1Cc1ccc(CCOC2CC2)cc1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-bromo-1-chloro-2-(4-(2-(vinyloxy)ethyl)benzyl)benzene (100 mg, 0.27 mmol) and Et2Zn (0.68 mL, 0.68 mmol, 1.0 M in hexane) in dry ethyl ether (2 mL) was added diiodomethane (0.06 mL, 0.68 mmol) dropwise during 20 min at room temperature under argon. After stirring overnight, the reaction mixture was poured slowly into ice cold dilute hydrochloride solution with stirring. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL) and then with brine (10 mL), and then dried over sodium sulfate. The residue was concentrated and purified by preparative TLC (eluent EA:PE=1:25) to obtain intermediate CR (86 mg) as a light yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 7.32˜7.24 (m, 3H), 7.18 (d, 2H), 7.12 (d, 2H), 4.05 (s, 2H), 3.73 (t, J=7.2 Hz, 2H), 3.32˜3.29 (m, 1H), 2.88 (t, J=7.2 Hz, 2H), 0.57˜0.44 (m, 4H).
Reaction SMILES: [P:1]([O-:10])([O:6][CH2:7][CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5].C(Cl)(Cl)(Cl)[Cl:12]>C(N(CC)CC)C>[P:1]([Cl:12])(=[O:10])([O:6][CH2:7][CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5]
Reactant: [O-]P(OCCCl)OCCCl
Reactant: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=P(Cl)(OCCCl)OCCCl
Yield: 100 %

Procedure:
The amount of 1.9 moles of bis(2-chloroethyl) phosphite was reacted with excess carbon tetrachloride in the presence of a small amount of triethylamine. The bis(2-chloroethyl) phosphorochloridate formed was reacted with 0.86 mole of 2-butene-1,4-diol in the presence of pyridine. The product was isolated in the manner described in the above examples to obtain a yield of 100%. Identified by IR as tetrakis(2-bromoethyl) 2,3-butene diphosphate, the product had a refractive index (nD22) of 1.4852 and contained 29.65% chlorine and 12.24% phosphorus (compared to calculated percentages in C12H22Cl4O8P2 of 28.51% chlorine and 12.45% phosphorus).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][OH:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS([C:21]1[N:22]([CH3:32])[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:24][N:25]=1)(=O)=O>>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][O:14][C:21]3[N:22]([CH3:32])[C:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[N:24][N:25]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Reactant: OCc1nnn(-c2cccc(I)c2)n1
Agent: [H-]
Agent: [Na+]
Product: Cn1c(OCc2nnn(-c3cccc(I)c3)n2)nnc1-c1ccncc1

Procedure:
The title compound is prepared from [2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27]O)=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.CS(Cl)(=O)=O.[CH2:34]([N:36](CC)[CH2:37][CH3:38])[CH3:35].N1CCCC1>C(Cl)Cl>[CH3:15][N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[N:25][C:24]([CH2:27][N:36]4[CH2:37][CH2:38][CH2:35][CH2:34]4)=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:5]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CN4CCCC4)nc3)n2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
To a solution of [5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-2-yl]methanol (Intermediate 125, 50 mg, 132 μmol) in DCM (10 mL) was added methanesulfonyl chloride (11 μL, 139 μmol) and triethylamine (20 μL, 145 μmol). The reaction mixture was stirred for 90 min at room temperature under an inert atmosphere and then evaporated to dryness. The resulting solid was dissolved in DCM (10 mL), pyrrolidine (24 μL, 333 μmol) and triethylamine (46 μL, 333 μmol) and stirred for a further 3 h at room temperature. Incomplete reaction was observed so the reaction was heated at 35 C for a further 16 h. The reaction mixture was then washed with water (3×25 mL) and combined organics were dried over magnesium sulfate and evaporated to dryness. The resulting crude product was purified by silica chromatography (5% MeOH in DCM) to afford the title compound as a beige solid (25 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Si:12]([C:16]#[CH:17])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>[Cu](I)I>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:17]#[C:16][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
2-amino-5-iodobenzoic acid (500 mg, 1.9 mmol, 1 eq.) was dissolved in nitrogen-degassed THF (10 mL) at room temperature. TMS-acetylene (0.34 mL, 2.5 mmol, 1.3 eq.), nitrogen-degassed triethylamine (0.8 mL, 5.7 mmol, 3 eq.), dichloro-bis(triphenylphosphine)palladium(II) (267 mg, 0.4 mmol, 0.2 eq.), and copper iodide (145 mg, 0.8 mmol, 0.4 eq.) were added, in order, to the reaction in the dark. The reaction was then stirred at room temperature for 20 minutes. The solvent was evaporated, and the residue was purified on silica column (DCM/MeOH, 39:1→19:1) to result in 315 mg (71%) of the title compound as a dark orange solid. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=1.7, 1H, Ar—H), 7.37 (dd, J=1.8, 8.6, 1H, Ar—H), 6.57 (d, J=8.6, 1H, Ar—H), 0.22 (s, 9H, SiC3H9). 13C NMR (126 MHz, CDCl3) δ 173.11 (COOH), 151.15 (C—Ar), 138.41 (C—Ar), 136.64 (C—Ar), 116.94 (C—Ar), 111.06 (C—Ar), 109.23 (C—Ar), 104.98 (CSi(CH3)3), 92.02 (CCSi(CH3)3), 0.29 (Si(CH3)3). Exact Mass, 233.09. 231.7418 [M−H]−, 233.7569 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27](B(O)O)=[CH:28][C:23]=2[CH2:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[N:10]=4)[CH:7]=3)=[CH:28][C:23]=2[CH2:22][CH2:21]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1
Product: O=C(Nc1nc2ccc(-c3ccc4c(c3)CCO4)cn2n1)c1ccccc1
Yield: 70 %

Procedure:
The title compound was prepared following procedure described for example 56 but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5), 150 mg; 0.47 mmol; 1.0 eq.) and 2,3-dihydro-1-benzofuran-5-ylboronic acid (155 mg; 0.95 mmol; 2.0 eq.). Purification by flash chromatography on silica (EtOAc/c-Hex, gradient from 40:60 to 100:0) gave the title compound as a white solid (117.2 mg, 69%). HPLC, Rt: 3.18 min. (purity 84.6%). LC/MS, M+(ESI): 357.1, M−(ESI): 355.1.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[S:5][C:4]([C:14]([O:16][CH3:17])=[O:15])=[C:3]([O:18][CH3:19])[C:2]=1[C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1sc(-c2ccccc2Cl)c(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OC
Reaction time: 8 h
Yield: 57.5 %

Procedure:
7.84 g of compound of step A, 4.10 g of 4-chlorophenylboronic acid and 21.68 ml of a 2M solution of sodium carbonate are added to 60 ml of toluene. Argon is bubbled through for 30 min, before adding 1.25 g of Tetrakis. Heating is carried out at 110° C. overnight. After a return to ambient temperature, 60 ml of distilled water are added and the mixture is extracted with 60 ml of ethyl acetate, and the organic phase is dried and evaporated. The product obtained is purified by silica chromatography (eluent: heptane/ethyl acetate (80/20; v/v)). 4.90 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[CH2:31][NH:30][CH2:29][CH2:28]2>O>[Cl:8][C:6]1[N:5]=[C:4]([N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:31]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: Nc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CN(c1nc(N)nc(Cl)n1)CC2
Reaction time: 1 h

Procedure:
2-amino-4,6-dichloro-1,3,5-triazine (9.7 g, 58.8 mM) was dispersed in water (50 mL), sodium carbonate solution (2N, 60 mL) and dioxane 15 mL) at 0° C. 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (13.9 g, 58.8 mM) was added and the mixture was stirred vigorously for 1 hr. The product was filtered, rinsed with water, dried and recrystallized from methanol; 14.3 g (75%), mp=196°-197° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[Br:23][C:24]1[C:25]([CH:34]=O)=[CH:26][C:27]2[O:32][CH2:31][CH2:30][O:29][C:28]=2[CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:23][C:24]1[C:25]([CH2:34][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:26][C:27]2[O:32][CH2:31][CH2:30][O:29][C:28]=2[CH:33]=1
Reactant: O=Cc1cc2c(cc1Br)OCCO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cc4Br)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To 10 mL of a chloroform solution containing 130 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 109 mg of 7-bromo-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde, 25 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 140 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=10:1] to give 113 mg of 1-(2-(4-((7-bromo-2,3-dihydro-1,4-benzodioxin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:14](=O)([O-])[O-:15].[Na+].[Na+]>C(OC)=O.CN(C=O)C>[OH:15][CH:14]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC=O
Product: COC(=O)C(=CO)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of methyl phenylacetate (16.03g) in methyl formate (132ml) and dry DMF (100 ml) was added dropwise over 40 minutes to a stirred suspension of sodium hydride (5.14g) in dry DMF (200ml) at between 0° and 5° C. (effervescence and foaming). The resulting mixture was stirred at about -5° C. for 30 minutes, diluted with dry DMF (250ml), then allowed to warm and stir at room temperature for 3 hours. Ice and sodium carbonate were added to the mixture and it was washed with ether (x2), then acidified with concentrated hydrochloric acid and extracted with ether (x4). The extracts were washed with water (x3), treated with magnesium sulphate and charcoal, filtered and concentrated to give methyl 3-hydroxy-2-phenylpropenoate (13.56g, 71%) as a solid, m.p. 33.5°-35.5° C., which was used for the subsequent steps without further purification.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:5]=2[O:4][C:3]1=[O:19].[OH-:20].[K+]>>[OH:4][C:5]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:2]([CH3:1])[C:3]([OH:19])=[O:20]
Reactant: [OH-]
Reactant: CC1C(=O)Oc2c(Sc3ccccc3Cl)cccc21
Agent: [K+]
Product: CC(C(=O)O)c1cccc(Sc2ccccc2Cl)c1O

Procedure:
3-Methyl-7-(2-chlorophenylthio)-2,3-dihydrobenzofuran-2-one was treated with potassium hydroxide in the same manner as Example 21-(10) to give crystalline 2-[2-hydroxy-3-(2-chlorophenylthio)phenyl]propionic acid, mp. 143°-145° C.
Reaction SMILES: [H][H].[NH:3]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[N:25]O)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C(O)C.O1CCCC1.[Ni]>[NH:3]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([NH2:25])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2c([nH]1)CCCC2
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4c([nH]3)CCCC4)cccc21
Yield: 97.3 %

Procedure:
The procedure used in Example 6 is followed. In a 25 ml autoclave, dissolve 43 mg of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 4 ml of ethanol and 4 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to a hydrogen pressure of 1 bar and heat the autoclave at 600 for 12 hours. After cooling, the volume of hydrogen absorbed is 12 ml. After filtration of the catalyst, concentration to dryness under reduced pressure and purification by formation of a paste with diisopropyl ether, in this way we obtain 40 mg of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a beige powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11](=[O:24])[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][CH2:20][CH2:21][CH:22]=[CH2:23])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:6]([O:10][C:11](=[O:24])[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[N:19]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:20][CH2:21][CH:22]=[CH2:23])([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CCCN[C@@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCN(C(=O)C=C)[C@@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
Acryloyl chloride (47 mg, 0.50 mmol) was added at 0° C. to a solution of trans-(2-but-3-enylamino-cyclohexyl)-carbamic acid tert-butyl ester (123 mg, 0.46 mmol) and triethylamine (51 mg, 0.51 mmol) in dichloromethane (3 ml), and the reaction mixture was allowed to reach room temperature over 3 h. After partitioning between dichloro-methane and 10% aq. citric acid solution, the organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (103 mg, 70%). Light yellow solid, MS (ISP) 323.3 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[Br:18][CH2:19][C:20]([N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:21]
Reactant: c1ccc(NC2CC2)cc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)N(c1ccccc1)C1CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a stirred solution of 908 mg (6.83 mmol) Cyclopropyl-phenyl-amine (Kang, Sung, Kim, J. Chem. Soc., Chem. Commun., 1987, 897-898) and 690 mg (6.83 mmol, 1 equiv) Et3N in 10 mL DCM is added 1.38 g (6.83 mmol, 1 equiv) Bromoacetyl bromide in 4 mL DCM dropwise over 15 minutes at 0° C. The reaction mixture is stirred 3 h at 0° C., diluted with 30 mL DCM, washed with 1N HCl (30 mL), dried (MgSO4), and concentrated in vacuo. The crude product is purified by flash chromatography on 30 g silica gel eluted successively with EtOAc/Hexanes (1:9, 100 mL), (3:17, 300 mL). Appropriate fractions were combined and concentrated in vacuo to give 948 mg (3.73 mmol) of 2-Bromo-N-cyclopropyl-N-phenyl-acetamide as an amber oil: 1H NMR (CDCl3, 300 MHz) δ7.39 (m, 3H), 7.15 (m, 2H), 3.62 (s, br, 2H), 3.24 (m, 1H), 0.83 (m, 2H), 0.52 (m, 2H); TLC Rf =0.18 (EtOAc/Hexanes, 3:17).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([NH:14][C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:11][C:12](=[O:13])[NH:14][C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[O:5]
Reactant: CCCNC(=O)NC(=O)CCl
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCCNC(=O)NC(=O)COC(=O)/C=C/C(=O)OC
Yield: 1.9 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with 1-(2-chloroacetyl)-3-propyl urea (0.82 g, 4.60 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to provide 0.02 g (2% yield) of the title compound (19) as a white solid. Addition of methanol (MeOH) afforded 0.49 g (48% yield) of white solid. 1H NMR (CDCl3, 400 MHz): δ 6.90-6.99 (m, 2H), 4.77 (s, 2H), 3.82 (s, 3H), 3.25-3.24 (q, 2H, J=5.6 Hz), 1.57-1.55 (q, 2H, J=7.2 Hz), 0.95-0.91 (t, 3H, J=7.6 Hz). MS (ESI): m/z 273.08 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:14][Zn]C.O>O1CCOCC1>[Cl:13][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:14])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)cncc1Br
Reactant: C[Zn]C
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)cncc1Cl
Temperature: 60 °C
Yield: 90 %

Procedure:
To the solution of ethyl 3-bromo-5-chloropyridine-4-carboxylate (28 g, 105 mmol) in dioxane (300 mL) in a 1 L round bottom flask was added dimethylzinc (105 mL, 1.0 M in hexane) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) dichloromethane complex (1.3 g, 1.6 mmol). The resulting mixture was heated at 60° C. for 20 hours. After cooling, the reaction mixture was poured into cold water (500 mL) and extracted with dichloromethane (3×200 mL). After evaporation of the solvent, the crude product was filtered through a silica pad (10 cm) with 20% ethyl acetate in hexane (400 mL), and the solvent was evaporated. The oily ethyl 3-chloro-5-methylpyridine-4-carboxylate (20 g, 90% yield) was used in the next step without further purification.