Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O-:7][N+:8]1[C:13]2[CH:14]=[C:15]3[CH2:20][CH2:19][O:18][C:16]3=[CH:17][C:12]=2[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=O)[N:9]=1.[BH3-]C#N.[Na+].CC(O)=O>CO.CN(C=O)C>[N:1]1([CH2:23][CH2:22][CH2:21][C:10]2[N:9]=[N+:8]([O-:7])[C:13]3[CH:14]=[C:15]4[CH2:20][CH2:19][O:18][C:16]4=[CH:17][C:12]=3[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CCO3
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Morpholine (0.22 mL, 2.52 mmol) was added to a solution of aldehyde 214 (220 mg, 0.90 mmol) in MeOH (10 mL) and DMF (10 ml), and the solution stirred for 30 min. NaCNBH3 (176 mg, 2.80 mmol) was added, followed by HOAc (0.12 mL) and the mixture stirred at 20° C. for 30 min. The solvent was evaporated and the residue partitioned between DCM (40 mL) and water (40 mL). The aqueous phase was extracted with DCM (2×40 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 215 (210 mg, 74%) as a pale brown solid, mp 96-99° C.; 1H NMR δ 8.27 (t, J=1.6 Hz, 1H, H-9), 7.11 (s, 1H, H-5), 4.80 (t, J=8.4 Hz, 2H, H-8), 3.59 (t, J=4.6 Hz, 4H, 2×CH2O), 3.43 (dt, J=8.4, 1.6 Hz, 2H, H-7), 2.97-3.01 (m, 2H, CH2), 2.44-2.48 (m, 2H, CH2), 2.41 (t, J=4.5 Hz, 4H, 2×CH2N), 2.03-2.11 (m, 2H, CH2); 13C NMR δ 167.1, 166.4, 150.5, 134.8, 128.9, 116.2, 103.9, 73.0, 67.0 (2), 58.3, 53.5 (2), 53.4, 27.0, 24.9. Anal. calcd for C16H20N4O3: C, 60.8; H, 6.4; N, 17.7. Found: C, 60.7; H, 6.5; N, 17.7%.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 53.2 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (80 mg, 0.26 mmol) was reacted with tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (170 mg, 0.44 mmol) to afford the desired product (68 mg, 32%) as a yellow solid: ESI MS m/z 492 [C27H29N3O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:34]=[C:35]([C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)[CH3:36])[C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: COc1ccc(C(C)=CBr)cc1
Reactant: CC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=Cn2c3c(c4cc(Cl)ccc42)CCN(C)C3C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.1 %

Procedure:
6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (85 mg, 0.36 mmol) was dissolved in DMF (6 mL). To this solution was added CuI (7 mg, 0.036 mmol), L-proline (8 mg, 0.073 mmol), K3PO4 (156 mg, 0.734 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 1-(1-bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44 mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 18 mg of 6-chloro-9-(2-(4-methoxyphenyl)prop-1-enyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.60 (m, 3H), 7.18 (s, 2H), 7.05 (s, 1H), 7.0 (d, 2H), 3.80 (s, 3H), 3.50 (m, 2H), 2.85 (m, 4H), 2.70 (m, 2H), 1.80 (s, 3H), 1.20 (d, 3H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[CH:1]1([NH:7][C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: S=C(Nc1ccc(Cl)cc1)NC1CCCCC1
Reaction time: 3 h

Procedure:
To a solution of cyclohexylamine (1.75 g.) in chloroform (15 ml.) was added dropwise with stirring a solution of p-chlorophenylisothiocyanate (3.0 g.) in chloroform (15 ml.) at room temperature. After stirring 3 hours, the white solid was filtered off, washed with a little CHCl3 and recrystallised from toluene to give 1-cyclohexyl-3-(p-chlorophenyl)thiourea, m.p. 179°-180°.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:22][OH:23])[C@@H:15]([C:18]([F:19])([F:20])[F:21])[O:16][CH2:17]1
Reactant: N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl isothiocyanate (19.0 mL) was added to a solution containing ((2S,3R,45)-4-amino-4-(2-fluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (28.72 g) in DCM (150 mL), and the mixture was stirred at RT for 18 h. Sodium bicarbonate (sat., aq., 200 mL) was then added, the mixture extracted with EtOAc (3×300 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% to 30% EtOAc in hexanes) to obtain the title compound (37.07 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.22 (dd, J=8.1, 4.5 Hz, 1 H), 3.31 (td, J=8.0, 3.0 Hz, 1 H), 3.94-4.07 (m, 1 H), 4.31-4.46 (m, 1 H), 4.53 (d, J=9.9 Hz, 1 H), 4.83 (d, J=9.9 Hz, 1 H), 6.97-7.14 (m, 1 H), 7.22 (td, J=7.7, 1.3 Hz, 1 H), 7.31-7.45 (m, 1 H), 7.49-7.61 (m, 2 H), 7.61-7.70 (m, 1 H), 7.75 (td, J=8.1, 1.5 Hz, 1 H), 7.79-7.93 (m, 2 H), 8.90 (s, 1 H), 11.85 (s, 1 H)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34]I.[H-].[Na+].Cl>CN(C=O)C>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([O:23][CH3:34])[CH2:20][N:19]3[C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1C[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of benzyl (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (400 mg) and CH3I (0.57 mL) in DMF (5 mL) was added NaH (60% oil suspension, 48 mg) at 5° C. The mixture was stirred at the same temperature for 10 minutes, then stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted HCl, and extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogen carbonate, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography (hexane-EtOAc, 1:1 elution) to give benzyl (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-methoxypyrrolidine-1-carboxylate (402.9 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2N)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (R)-3-(2-nitrophenylamino)piperidine-1-carboxylic acid tertbutyl ester (2.48 g, 7.72 mmol) and 10% Pd/C (250 mg) in EtOAc (50 mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 20 h. The suspension was then filtered through a PTFE frit and the filtrate was concentrated in vacuo affording (R)-3-(2-Aminophenylamino)piperidine-1-carboxylic acid tertbutyl ester as a clear glass (2.25 g, quantitative). LCMS: RT 2.64 min [M+H-Boc]+ 192.1.
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C:26]4[CH:27]=[CH:28][C:29]5[S:34][CH2:33][C:32](=[O:35])[NH:31][C:30]=5[CH:36]=4)[CH2:20][CH2:19]3)=[N:12]2)=[CH:7][CH:6]=1.[C:37](O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([N:24]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]5[S:34][CH2:33][C:32](=[O:35])[NH:31][C:30]=5[CH:36]=4)[CH3:37])[CH2:20][CH2:19]3)=[N:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2ncc(OCCN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COc1ccc2ncc(OCCN3CCC(N(C)Cc4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 22.3 %

Procedure:
Paraformaldehyde (29 mg, 0.10 mmol, 1.0 eq) is added at room temperature to a stirred solution of 6-({1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one (50 mg, 0.10 mmol, 1.0 eq) in 1,2-dichloroethane (2 mL) and methanol (0.5 mL), followed by acetic acid (7 μL, 0.12 mmol, 1.3 eq) and sodium cyanoborohydride (9 mg, 0.12 mmol, 1.3 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×5 mL) and a saturated sodium hydrogen carbonate aqueous solution (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-[({1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-methyl-amino)-methyl]-4H-benzo[1,4]thiazin-3-one as a light brown viscous oil (11 mg, 21% yield).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:13]3)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:24])([F:23])[F:25])(=[O:21])=[O:20])=[CH:13]4)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1
Reactant: O=S(=O)(Nc1ccc2c(OCc3ccc(Br)cc3)cccc2c1)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=S(=O)(Nc1ccc2c(OCc3ccc(-c4ccc(Cl)cc4)cc3)cccc2c1)C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 1 and 4-chlorophenyl boronic acid according to the procedure of Example 2, m.p. 131-133.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@H:19]1[CH2:24][CH2:23][C@H:22](/[CH:25]=[C:26](\[CH3:29])/[CH2:27][OH:28])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:18][C@H:19]1[CH2:20][CH2:21][C@H:22](/[CH:25]=[C:26](\[CH3:29])/[CH:27]=[O:28])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C/C(=C\[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C(C=O)=C\[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a -78° C. solution of oxalyl chloride (105 μL, 1.2 mmol) in 1.0 mL of methylene chloride was added dimethylsulfoxide (170 μL, 2.4 mmol). The resulting solution was stirred for 5 min and then 170 mg (0.6 mmol) of the alcohol 135 was added in 1.0 mL of methylene chloride. The reaction mixture was stirred at -78° C. for 45 min at which time 500 μL (3.6 mmol) of triethylamine was added and the solution was allowed to warm to ambient temperature, The reaction was quenched with 1.0N HCl and the aqueous layer was extracted with three portions of methylene chloride. The combined organic extracts were dried over MgSO4 and evaporated to dryness to give the crude aldehyde 136 which was used directly in the next reaction. 1H NMR consistent with structure,
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O1C=CC(=O)C=C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnnn1Cc1ccccc1
Reactant: C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=c1ccocc1
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(Cn2nncc2NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
To a solution of 1-benzyl-1H-1,2,3-triazol-5-amine (835 mg) and tetrahydropyran-4H-pyran-4-one (481 mg) in acetic acid (10 mL) was added sodium triacetoxyborohydride (1.53 g), and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=35/65→0/100 (volume ratio)], and crystallized from diisopropyl ether to give the title compound as pale-beige crystals (573 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][OH:20])[N:10]=1.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][O:20][C:41](=[O:43])[CH3:42])[N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCn1nc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)cc(C(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A solution of 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.43 mmol), N,N-diisopropylethylamine (0.23 mL, 1.29 mmol) and 4-N,N-dimethylaminopyridine (25.8 mg, 0.21 mmol) in methylene chloride (3.0 mL) cooled to 0° C. was treated with acetyl chloride (33.5 μL, 0.47 mmol). The reaction mixture was warmed to 25° C. over 3.5 h. The reaction mixture was then warmed to 40° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and then partitioned between methylene chloride (100 mL) and water (100 mL). The organics were then washed with a 1N aqueous hydrochloric acid solution (3×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. ISCO CombiFlash chromatography (40 g, 0.5-4.0% methanol/methylene chloride) afforded acetic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (45.9 mg, 21%) as a yellow solid. ES+-HRMS m/e calcd for C20H16N6O6Cl2 (M+H+) 507.0581, found 507.0582.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].C1(C(N)C2CCCCC2)CCCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:16]=[CH:15]/[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:13]
Reactant: CCOC(=O)Cc1ccccc1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccccc1/C=C/C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
To a mixture of ethyl 2-(2-bromophenyl)acetate (0.97 g, 4 mmol), t-butyl acrylate (0.51 g, 4 mmol), tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.1 mmol), dicyclohexylmethylamine (0.98 g, 5 mmol) in dioxane (5 mL) was added tri-tert-butylphosphine (0.2 mL, 1 N in toluene, 0.2 mmol). The mixture was heated at 70° C. for 30 minutes under N2. Ethyl acetate was added, and the mixture was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography eluting with hexanes and ethyl acetate (10:1) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.79 (m, 1H), 7.72 (d, J=15.6 Hz, 1H), 7.34 (m, 3H), 6.40 (d, J=15.7 Hz, 1H), 4.06 (q, J=7.2 Hz, 2H), 3.84 (s, 2H), 1.48 (s, 9H), and 1.17 (t, J=2 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][N:36]=[C:35](Cl)[N:34]=4)=[CH:29][CH:28]=3)[CH:21]=2)[NH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[N:34]=4)=[CH:29][CH:28]=3)[CH:21]=2)[NH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCCCCCN1CCCC1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCCCN5CCCC5)n4)cc3)cc12

Procedure:
Using 5-(pyrrolidin-1-yl)-pentylamine (reference example 93d) and and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 522 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][Cl:25])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: N#Cc1cc(CCl)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To the solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-(hydroxymethyl)benzonitrile (500 mg, 1.526 mmol) in DCM (30 mL), was added thionyl chloride (1.671 mL, 22.89 mmol) dropwise. The mixture was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice, dried over Na2SO4, concentrated and purified via flash chromatography to afford the title compound (479 mg, 89% yield) as a white solid. LCMS: rt=3.45 min
Reaction SMILES: [OH:1][C@@H:2]([C@H:7]([OH:15])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C@@H:7]([OH:15])[C@H:2]([O:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)c1ccc(F)cc1
Reaction time: 44 h
Yield: 83.2 %

Procedure:
Under argon atmosphere, a solution of methyl (2S,3R)-2,3-dihydroxy-3-(4-fluorophenyl)propionate (3.95 g, 18.4 mmol) dissolved in dichloromethane (100 ml) was cooled to -3° to -5° C., and triethylamine (3.86 ml, 27.7 mmol) and p-toluenesulfonyl chloride (3.62 g, 19.0 mmol) were added to the solution. After the mixture was stirred at -3° to -5° C. for 44 hours, the reaction mixture was washed with water and brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the residue obtained was purified by silica gel flash column chromatography (ethyl acetate/hexane=1/2) to obtain methyl (2S,3R)-3-(4-fluorophenyl)-3-hydroxy-2-p-toluenesulfonyloxypropionate (5.64 g, yield: 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:15]2[N:19]=[N:18][CH:17]=[N:16]2)[CH2:10][CH2:11][N:12](C)[CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C(OC(Cl)=O)C.C([O-])(O)=O.[Na+].[OH-].[K+]>C(Cl)(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:15]2[N:19]=[N:18][CH:17]=[N:16]2)[CH2:10][CH2:11][NH:12][CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)CCC(c1ccc(Cl)c(Cl)c1)n1ncnn1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CNCCC(c1ccc(Cl)c(Cl)c1)n1ncnn1
Yield: 80 %

Procedure:
To a solution of [3-(3,4-Dichloro-phenyl)-3-tetrazol-2-yl-propyl]-dimethyl-amine (2 mmol) in chloroform was added ethylchloroformate (>10 equiv.) and NaHCO3 (>20 equiv.) and this solution was refluxed for 3 h. After that, chloroform was evaporated and ethyl acetate was added and then this organic layer was washed with water 3 times. It was dried over MgSO4, filtered, evaporated and the filtrate was concentrated at reduced pressure. The residue was dissolved in ethanol and potassium hydroxide (>20 equiv.) dissolved in water was added and refluxed for 3 days. After that, ethyl acetate and sat. NaHCO3 were added and the organic layer was extracted. It was dried over MgSO4, filtered, evaporated and the filtrate was concentrated at reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate and methanol: Yield 80%
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=1[CH3:30].O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([F:20])=[C:22]([CH3:30])[CH:23]=4)=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(F)c(C)c3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 4-fluoro-3-methyl-benzoic acid, the title compound was prepared in the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as light brown powder. MS: m/e=417(M+H+).