Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]1([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]4[CH2:20][CH2:21][NH:22][CH2:23][C:13]([C:14]=34)=[CH:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C=O.Cl>C1COCC1>[ClH:1].[CH3:24][N:22]1[CH2:21][CH2:20][C:15]2[C:14]3[C:13](=[CH:12][N:11]([S:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)(=[O:10])=[O:9])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:23]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CCNC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCc2cccc3c2c(cn3S(=O)(=O)c2ccccc2)C1
Temperature: 70 °C
Yield: 12 %

Procedure:
1-(Phenylsulfonyl)-3,4,5,6-tetrahydro-1H-azepino[3,4,5-cd]indole hydrochloride, Example 12 (100 mg, 0.3 mmol) was dissolved in THF (4 mL) before sodium triacetoxyborohydride (203 mg, 1.0 mmol) and acetic acid (191 mg, 3.2 mmol) was added. Aqueous formaline (37%, 1 mL) was added and the reaction mixture was heated in MW at 70° C. for 300 s. The reaction mixture was evaporated and the crude product was purified by preparative HPLC using System B, 100 mM NH4HCO3/MeCN (36-66% MeCN). The product was isolated and transformed to the hydrochloride. 15.2 mg of the pure product was isolated as an yellow oil, yield 12%. MS m/z 327 [M+H]+.
Reaction SMILES: COC1C=CC(C[C:8]2[C:16]([O:17][C:18](=[O:34])[C@H:19]([CH:31]([CH3:33])[CH3:32])[NH:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O-:12])=[O:11])=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:24]([O:23][C:21]([NH:20][C@H:19]([C:18]([O:17][C:16]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:34])[CH:31]([CH3:33])[CH3:32])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(Cc2c(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)cccc2C(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methoxybenzyl-3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate (13.7 g, 27.8 mmole) in dichloromethane (150 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred for 2 hours at room temperature. The solution was evaporated under reduced pressure and the product crystallized from toluene. Yield: 10.1 g=87%. The compound can be activated and esterified to a drug or further modified as described below
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=1.N1C=CC=CC=1.Cl>ClCCl.CCCCCC>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=2)=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=C(Cl)c1cc(Cl)c(Cl)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)cc2F)cn1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A solution of 4,5-dichloro-2-fluoro-benzoyl chloride (4.35 g, 19.13 mmol) in dichloromethane (40 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (2.91 g, 19.13 mmol), pyridine (4.64 mL, 57.39 mmol) and dichloromethane (60 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 2 hours. The mixture was poured into 1N HCl (50 mL) and dichloromethane (50 mL). The two layers were separated. The aqueous layer was extracted with dichloromethane (3×200 mL). The combined organic layer was washed with water (1×150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexanes to remove impurities. The solid was isolated by filtration using hexane to yield methyl 5-[(4,5-dichloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate (5.33 g, 81%) as a cream color solid. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.94 (d, J=2.5 Hz, 1H), 8.36 (dd, J=8.6, 2.5 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.08 (d, J=6.6 Hz, 1H), 7.95 (d, J=9.6 Hz, 1H), 3.87 (s, 3H) ppm. ESI-MS m/z calc. 342.00. found 343.1 (M+1)+; Retention time: 1.72 minutes (3 minutes run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[O:12]1[CH2:24][C@H:13]1[CH2:14][O:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH:7][CH2:24][C@H:13]([OH:12])[CH2:14][O:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: COc1ccccc1CCN
Reactant: N#Cc1cccnc1OC[C@@H]1CO1
Product: COc1ccccc1CCNC[C@H](O)COc1ncccc1C#N
Temperature: 60 °C

Procedure:
A mixture of 2-methoxyphenethylamine (0.91 g, 6 mmole) and (S) -2-(2,3-epoxy-1-propoxy)-3-cyanopyridine (1.05 g, 6 mmole) was heated at 60° C. for 18 hr. Upon cooling, the material solidified. Recrystallization from toluene afforded (S)-2-[3-(2-methoxyphenethylamino)-2-hydroxy-1-propoxy]-3-cyanopyridine (m.p. 97°-99°).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][O:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].O>N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[N:14]1[C:13]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:12]=2[S:11][C:10]=1[NH:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:24](=[O:27])[CH2:25][CH3:26])[CH2:4][CH2:5]1
Reactant: CCC(=O)Cl
Reactant: NCC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NCC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a stirred solution of N2-[4-(aminomethyl)cyclohexyl]-4,5-dihydrobenzo[2,3]oxepino[4,5-d][1,3]thiazol-2-amine (0.600 g, 1.49 mmol) in anhydrous pyridine (3 ml) and diisopropylethylamine (3 ml) was added propionyl chloride (0.144 ml, 1.66 mmol) dropwise. The solution was stirred for 20 minutes at room temperature and then poured into water (50 ml) and extracted with EtOAc. The solvent was removed and the residue chromatographed on silica-gel eluting with EtOAc to yield 70% (402 mg) of the product as a light yellow solid: 1H-NMR (CDCl3) δ 1.12 (6H, m), 1.50 (1H, m), 1.65 (1H, m), 1.85 (2H, d, J=12.1 Hz), 2.22 (4H, m), 3.16 (4H, t, J=5.3 Hz), 3.32 (1H, m), 4.33 (2H, t, J=5.2 Hz), 4.81 (1H, m), 5.49 (1H, m), 7.00 (1H, d, J=8.5 Hz), 7.15 (2H, m), 8.25 (1H, d, J=8.1 Hz). m.p. 56-60° C. FAB+m/z=386 (MH+).
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:30]=[CH:29][C:11]2[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C4CCCCO4)=[CH:18][CH:17]=3)=[N:13][O:14][C:10]=2[CH:9]=1.C([O-])(O)=O.[Na+]>CO>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:11]3[CH:29]=[CH:30][C:8]([OH:7])=[CH:9][C:10]=3[O:14][N:13]=2)=[CH:17][CH:18]=1
Reactant: c1cc(OC2CCCCO2)ccc1Cc1noc2cc(OC3CCCCO3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(Cc2noc3cc(O)ccc23)cc1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
6-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)benzyl]-1,2-benzisoxazole (3.85 mmol) and paratoluenesulfonic acid (APTS, catalytic amount) were dissolved in methanol (20 ml). After reaction at 60-70° C. for 3 h, the reaction mixture was cooled to room temperature and poured into satured NaHCO3 and extracted with EtOAc. After washing (H2O) and drying (MgSO4), the extract was concentrated. The crude product was purified by flash chromatography (toluene/1,4-dioxane 8/2) and crystallised to give an off-white crystal (0.58 g, 31%). mp 178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6](/[N:7]=[C:8](/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)\[CH3:9])=[CH:5][CH:4]=1>CC([O-])=O.CC([O-])=O.[Pd+2].CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:16][CH:17]=1)[NH:7][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[CH:9]2
Reactant: COc1ccc(/N=C(\C)c2ccccc2)cc1
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Temperature: 40 °C
Reaction time: 48 h
Yield: 86.9 %

Procedure:
A 500 mL round-bottom flask equipped with a stirrer bar was charged with (E)-4-methoxy-N-(1-phenylethylidene)aniline (50 mmol, 11.3 g), Pd(OAc)2 (0.56 g, 2.5 mmol, 5 mol %) and Cu(OAc)2 (18.2 g, 100 mmol, 2 equiv). The flask was evacuated and refilled with N2 for three times, followed by addition of DMSO (250 mL). The flask was sealed with a glass stopper and then the reaction mixture was stirred at 40° C. for 48 h. Upon cooling to room temperature, the reaction mixture was diluted with 150 mL of ethyl acetate and filtered through a pad of silica gel using 100 mL of ethyl acetate as additional eluent. The filtrate was washed with water (3×250 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by recrystallization (EtOAc/hexane) to afford the title compound as an off-white solid (9.7 g, 87%). The product showed the same degree of analytical purity compared with that obtained by a small-scale reaction.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4]C.C[C:9]1([CH3:17])[O:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])O1>>[O:16]=[C:11]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:12][C:13]([O:14][CH2:9][CH3:17])=[O:15]
Reactant: CCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CCCCC(=O)CC(=O)OCC

Procedure:
The title compound was prepared in a manner analogous to Intermediate 123 from valeryl chloride and 2,2-dimethyl-1,3-dioxane-4,6-dione (both commercially available).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]3[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:21])([CH3:22])[C:15]=3[CH:23]=2)=[CH:30][CH:29]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCOS(C)(=O)=O)cc21
Product: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCSc3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-chloro-thiophenol.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[C:6]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])[CH:7]=[C:8]([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:9]=1.[C-:21]#[N:22].[K+].ClCCl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:17]([C:16]([C:6]1[CH:5]=[C:4]([CH2:3][C:21]#[N:22])[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:7]=1)([CH3:20])[CH3:19])#[N:18]
Reactant: [C-]#N
Reactant: CC(C)(C#N)c1cc(CCl)cc(Cn2cncn2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C#N)c1cc(CC#N)cc(Cn2cncn2)c1

Procedure:
A mixture of the product from Example 28 (0.73 g), tetrabutylammonium bromide (0.01 g), potassium cyanide (0.52 g), dichloromethane (2 ml) and water (2 ml) was heated under reflux for 3 h. It was then cooled, water (20 ml) was added, and the mixture was extracted three times with ethyl acetate. The extracts were combined, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash column chromatography, eluting with methanol:ethyl acetate (3:97 by volume), to give 3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenylacetonitrile. Nmr in deuteriochloroform: δ 8.18(1H,s), 8.0(1H,s), 7.42(1H,m), 7.38(1H,m), 7.18(1H,m), 5.4(2H,s), 3.78(2H,s), 1.72(6H,s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH3:10][NH2:11]>C1COCC1>[CH3:10][NH:11][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1
Reactant: CN
Reactant: N#Cc1cc(Cl)ncn1
Solvent: C1CCOC1
Product: CNc1cc(C#N)ncn1

Procedure:
To 6-chloro-pyrimidine-4-carbonitrile (1.37 g, 9.84 mmol) stirring in 10 ml THF under N2 was added a methylamine solution (2.0 M in THF, Aldrich) in aliquots, causing immediate precipitation. Reaction progress was monitored after addition of 5 ml methylamine solution, then 3 ml, then 2 ml. The mixture was concentrated and filtered through a pad of silica, eluting with 2%->5% MeOH in CH2Cl2 to obtain 6-methylamino-pyrimidine-4-carbonitrile as a pale yellow solid. MS: 135.0 (M+1); Calc'd. for C6H6N4—134.14.
Reaction SMILES: C[O:2][CH2:3][CH:4]1C[CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)[N:30]=1.N1CCC[C@@H]1C(N)=O>>[S:24]([CH2:23][C:19]1[CH:18]=[C:17]([NH:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([N:5]3[CH2:6][CH2:7][CH2:8][C@@H:4]3[C:3]([NH2:30])=[O:2])[N:11]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:25])(=[O:26])[NH2:27]
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Agent: NC(=O)[C@H]1CCCN1
Product: NC(=O)[C@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B23 was obtained as a white powder by following the procedure reported for B4 using A1 and (R)-proline amide; yield: 65 mg (19%). MS (ES) C15H19N7O3S requires: 377. found: 378 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:27]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:12][N:13]([C:21]2[S:22][C:23](Br)=[CH:24][N:25]=2)C(=O)OC(C)(C)C)=[CH:2]1.[O:40]=[C:41]1[NH:45][C:44]2[CH:46]=[CH:47][C:48](B(O)O)=[CH:49][C:43]=2[S:42]1>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>[NH2:27][C@@H:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:12][NH:13][C:21]1[S:22][C:23]([C:48]2[CH:47]=[CH:46][C:44]3[NH:45][C:41](=[O:40])[S:42][C:43]=3[CH:49]=2)=[CH:24][N:25]=1
Reactant: CC(C)(C)OC(=O)N(C[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ncc(Br)s1
Reactant: O=c1[nH]c2ccc(B(O)O)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: N[C@H](CNc1ncc(-c2ccc3[nH]c(=O)sc3c2)s1)Cc1c[nH]c2ccccc12

Procedure:
This compound was synthesized using a procedure similar to that shown in Scheme 1 with a coupling reaction between (S)-tert-butyl 3-(1H-indol-3-yl)-2-(4-nitrophenylsulfonamido)propyl(5-bromothiazol-2-yl)carbamate and commercially available 2-oxo-2,3-dihydrobenzo[d]thiazol-6-ylboronic acid using PdCl2(PPh3)2 as the catalyst instead of tetrakis-(triphenylphosphine)palladium. MS m/z: 422 (M+1). 1H NMR (400 MHz, CD3OD): δ ppm 3.11-3.20 (m, 2H), 3.57 (d, J=7.04 Hz, 2H), 3.66-3.72 (m, 1H), 3.76-3.86 (m, 1H), 7.05-7.18 (m, 3H), 7.25 (s, 1H), 7.33-7.42 (m, 3H), 7.52 (d, J=1.56 Hz, 1H), 7.60 (d, J=7.82 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:23])([F:22])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.FC1C(C(C2N3N=C(C(=O)C)C=CC3=NC=2)C)=C(F)C=C2C=1C=NN2C>O1CCOCC1.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>[F:22][C:11]([F:23])([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)[C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Solvent: C1COCCO1
Product: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 35.2 %

Procedure:
The title compound as a light yellow oil (180 mg, 30%, 80% pure) was synthesized from 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)quinoline (500 mg, 1.507 mmol), tributyl(1-ethoxyvinyl)stannane (2.55 ml, 7.54 mmol) and PdCl2(PPh3)2 (106 mg, 0.151 mmol) in 1,4-dioxane using the same procedure as described in the synthesis of compound 31.4. 1H-NMR (400 MHz, MeOH-d4) δ ppm 9.17 (s, 1H), 8.91 (d, 1H), 8.65 (s, 1H), 8.43 (d, 1H), 8.28 (q, 2H), 7.96 (d, 1H), 7.92 (m, 1H), 2.61 (s, 3H). LCMS (method B): [MH]+=340.1, tR=2.16 min.
Reaction SMILES: FC(F)(F)C1C=CC(OCC2C=CC(SC3C=CC(OCC(O)=O)=C(C)C=3)=CC=2)=CC=1.C([O:34][C:35](=[O:68])[CH2:36][O:37][C:38]1[C:47]2[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=2[C:41]([S:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][O:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=3)=[CH:51][C:50]=2[Cl:67])=[CH:40][CH:39]=1)C>>[Cl:67][C:50]1[CH:51]=[C:52]([CH2:55][O:56][C:57]2[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:64])[F:65])=[CH:59][CH:58]=2)[CH:53]=[CH:54][C:49]=1[S:48][C:41]1[C:42]2[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=2[C:38]([O:37][CH2:36][C:35]([OH:68])=[O:34])=[CH:39][CH:40]=1
Reactant: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)c2c1CCCC2
Agent: Cc1cc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O
Product: O=C(O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)c2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 7, using compound 23.2 as the starting material. MS APSI m/e: 521 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 13.04 (1H, brs); 7.66 (2H, d, J=8.8 Hz); 7.59 (1H, d, J=1.6 Hz); 7.37 (1H, d, J=8.5 Hz); 7.29 (1H, dd, J=1.6, 8.2 Hz); 7.17 (2H, d, J=8.6 Hz); 6.81 (1H, d, J=8.6 Hz); 6.51 (1H, d, J=8.2 Hz); 5.12 (2H, s); 4.77 (2H, s); 2.67-2.64 (4H, m); 1.67-1.66 (4H, m).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][NH:7][C@@H:8]([CH3:16])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[NH:21]([C:34]([O:36][CH2:37][CH:38]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[C@H:22]([C:31](O)=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH:40]1[C:39]2[CH:38]([CH2:37][O:36][C:34]([NH:21][C@H:22]([C:31]([N:7]([CH2:6][C:4]3[C:3]4[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=4[S:1][CH:5]=3)[C@@H:8]([CH3:16])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])=[O:32])[CH2:23][C:24]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:30])=[O:35])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(OCC)[C@H](C)NCc1csc2ccccc12
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)—N-(benzo[b]thiophen-3-ylmethyl)-1,1-diethoxypropan-2-amine (Compound IX-6) 13.2 g (45 mmol) and Fmoc-Asp(tBu)-OH 24.2 g (58.8 mmol) were dissolved in DMF (200 ml). HATU (25.6 g, 67.5 mmol) and DIEA (8.7 g, 67.5 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was poured into water (800 ml). The solution was extracted with EA (300 ml×3). The combined extracts were dried over Na2SO4 and then filtered. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=30:1 to 5:1 to give the title compound 20.4 g, (yield 66%).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:19]=[C:18]3[C:13]([NH:14][C:15](=[O:25])[C:16]([C:20]([O:22]CC)=[O:21])=[N:17]3)=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].S(=O)(=O)(O)O>>[N:1]1([CH:6]([C:10]2[CH:19]=[C:18]3[C:13]([NH:14][C:15](=[O:25])[C:16]([C:20]([OH:22])=[O:21])=[N:17]3)=[CH:12][CH:11]=2)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C(c1ccc2[nH]c(=O)c(C(=O)O)nc2c1)n1ccnc1
Yield: 24.6 %

Procedure:
A solution of 4.25 parts of ethyl 3,4-dihydro-7-[1-(1H-imidazol-1-yl)-2-methylpropyl]-3-oxo-2-quinoxalinecarboxylate in 20 parts of a sodium hydroxide solution 1N was stirred for 4 hours at room temperature. The reaction mixture was treated with a diluted sulfuric acid solution to pH 5.5. After concentration, the residue was crystallized from pyridine. The product was filtered off and dried, yielding 1 part (24.6%) of 3,4-dihydro-7-[1-(1H-imidazol-1-yl)-2-methylpropyl]-3-oxo-2-quinoxalinecarboxylic acid; mp. 237.5° C. (comp. 129).
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([C:13]([OH:15])=O)[O:11][C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:26]([NH2:29])([CH3:28])[CH3:27]>C1C=CC=CC=1>[CH:26]([NH:29][C:13]([CH:12]1[O:11][C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[O:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:15])([CH3:28])[CH3:27]
Reactant: CC(C)N
Reactant: O=C(O)C1Oc2ccccc2OC1c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)NC(=O)C1Oc2ccccc2OC1c1ccccc1
Reaction time: 2 h

Procedure:
To 22 g of (3-phenyl-1,4-benzodioxan-2-yl)-carboxylic acid in 300 cc of anhydrous benzene are added 18.1 g of PCl5 in portions with cooling. After 2 hours the reaction mixture is added to a cold solution of isopropylamine in anhydrous benzene. After stirring for 2 hours, the product is poured onto ice. The organic phase is separated, washed with H2O and finally dried over Na2SO4. The solvent is removed under vacuum. The residue is crystallised from isopropyl alcohol, m.p. = 196°-8°.
Reaction SMILES: Br[CH:2]([CH2:4][CH3:5])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24](=[O:25])[N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=2[CH3:44])=[CH:15][CH:14]=1>CN(C)C=O.C(OCC)(=O)C>[CH:2]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:24](=[O:25])[N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=2[CH3:44])=[CH:17][CH:18]=1)([CH2:4][CH3:5])[CH3:3]
Reactant: CCCc1nc(C)c(-c2ccc(O)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C)c(-c2ccc(OC(C)CC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of 2-bromobutane (0.19 mL), cesium carbonate (1.7 g) and 4′-{[5-(4-hydroxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g) in N,N-dimethylformamide (5 mL) was stirred for 2 hr at 80° C. The mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (0.5 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[O:33][C:34]([CH:37]=O)=[CH:35][CH:36]=2)=[CH:4][N:3]=1.[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][NH:44][CH3:45]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[O:33][C:34]([CH2:37][N:44]([CH2:43][CH2:42][CH2:41][N:40]([CH3:46])[CH3:39])[CH3:45])=[CH:35][CH:36]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CNCCCN(C)C
Product: COc1cc(-c2csc3c(-c4ccc(CN(C)CCCN(C)C)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-{4-[4-amino-7-(5-formyl-2-furyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide, N,N,N′-trimethylpropane-1,3-diamine and the procedure described in General Procedure B. 1H NMR (DMSO-d6, 400 MHz) δ 9.53 (s, 1H), 8.31 (s, 1H), 8.01 (d, 1H), 7.71 (d, 1H), 6.67 (s, 1H), 7.59 (d, 1H), 7.36 (s, 1H), 7.32 (m, 1H), 7.22 (s, 1H), 7.15 (m, 1H), 7.11 (m, 1H), 6.80 (m, 1H), 6.49 (m, 1H), 5.63 (br, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 3.66 (s, 2H), 2.43 (m, 2H), 2.35 (s, 6H), 2.26 (s, 3H), 2.19 (m, 2H), 1.96 (m, 2H); MS: (M−H)− 621.