Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][C:12]=2[C:13]=1[C:14]([NH:16][CH3:17])=[O:15].Cl[C:38]1[CH:47]=[CH:46][C:45]2[CH2:44][CH2:43][N:42]3[C:48]4[CH:49]=[CH:50][CH:51]=[C:52]([F:55])[C:53]=4[CH:54]=[C:41]3[C:40]=2[N:39]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19]([C:38]3[CH:47]=[CH:46][C:45]4[CH2:44][CH2:43][N:42]5[C:48]6[CH:49]=[CH:50][CH:51]=[C:52]([F:55])[C:53]=6[CH:54]=[C:41]5[C:40]=4[N:39]=3)=[CH:18][C:12]=2[C:13]=1[C:14]([NH:16][CH3:17])=[O:15]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2F)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2F)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 100 °C
Reaction time: 10 h
Yield: 41.9 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (500 mg, 0.96 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (240 mg, 0.87 mmol) and K2CO3. (241 mg, 1.75 mmol) in 1,4-dioxane (5 mL) and H2O (5 drop) were added X-Phos (10 mg) and Pd2(dba)3 (10 mg) under N2. The reaction mixture was stirred at 100° C. for 10 hours and concentrated in vacuo to remove 1,4-dioxane. The reaction mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the product (230 mg, yield: 42%). 1H-NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.7˜57.81 (m, 1H), 7.66˜7.69 (m, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.15˜7.18 (m, 2H), 6.98˜7.09 (m, 2H), 6.79 (t, J=8.4 Hz, 1H), 5.81 (br s, 1H), 4.35 (t, J=6.4 Hz, 2H), 3.39 (s, 3H), 3.32 (t, J=6.4 Hz, 2H), 2.96 (d, J=4.8 Hz, 3H), 2.68 (s, 3H). MS (M+H)+: 631.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N+:15]([O-:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CCCCCCCCCC>>[C:5]1([C:8]2([CH2:9][N:10]3[CH:14]=[N:13][CH:12]=[N:11]3)[CH2:18][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:17][N:15]2[CH3:16])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: C=CCCCCCCCCCCCCCCCC
Reactant: C[N+]([O-])=C(Cn1cncn1)c1ccc(Cl)cc1
Product: CCCCCCC1CC(Cn2cncn2)(c2ccccc2)N(C)O1

Procedure:
Derivative 3 (R=H, n=5) is prepared by a procedure similar to that described in Example 1 by reacting 1-phenyl-N-methyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide (1: R=H) with 1-octene (2: n=5). The resulting cis- and trans-diastereomeric mixture of compound 3 (R=H, n=5) is flash-chromatographed on neutral silica gel using as eluent a 98:2 by volume mixture of chloroform-methanol. Isomer A has a melting point of 93°-99° C. (ethyl acetate).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([C:16](=[O:19])[CH2:17][CH3:18])[CH:13]([CH3:14])[CH2:12][C:11]([CH3:15])=[CH:10][CH2:9]1.[H][H].Cl>C(OCC)C.O>[CH3:7][C:8]1([CH:16]([OH:19])[CH2:17][CH3:18])[CH:13]([CH3:14])[CH2:12][C:11]([CH3:15])=[CH:10][CH2:9]1
Reactant: CCC(=O)C1(C)CC=C(C)CC1C
Reactant: [H][H]
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCC(O)C1(C)CC=C(C)CC1C

Procedure:
A solution of 0.075 moles (2.85 g) lithium aluminum hydride in 150 ml absolute diethyl ether was put in a 250-ml 3-necked flask with a magnetic stirrer, high-power condenser, dropping funnel and internal thermometer. 0.2 moles (36 g) 1-(1,4,6-trimethylcyclohex-3-en-1-yl)propan-1-one (as per Example 4) was added dropwise to this solution with cooling. Then heating with refluxing was carried out for an hour, followed by cooling, and water was added to the reaction mixture until hydrogen evolution ended. Then enough 2N hydrochloric acid was added so that the precipitate formed could be dissolved. Lastly the phases were separated, the organic phase dried with sodium sulfate and the solvent drawn off. After fractional distillation via a 30-cm Vigreux column the desired end product was obtained in practically quantitative yield.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:19][CH:18]=2)[C:12](=[O:30])[C:11]1=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32]([O:38][CH2:39]Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)=[CH:19][CH:18]=2)[C:12](=[O:30])[C:11]1=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C(=O)N(Cc2ccc(Nc3ncccn3)cc2)CCN1Cc1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a mixture of 372 mg of sodium hydride (purity 50%) and 30 ml of N,N-dimethylformamide was added dropwise a solution of 3 g of 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine in 20 ml of N,N-dimethylformamide with stirring over 30 min., after which the resulting mixture was subjected to reaction at 60° to 70° C. for one hour. After the completion of the reaction, 1.3 g of pivaloyloxymethyl chloride was dropped thereinto over 10 min. at the same temperature. After the completion of the dropwise addition, the resulting mixture was subjected to reaction at 70° to 80° C. for 30 min. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was extracted with 100 ml of chloroform. The chloroform layer was washed with 30 ml of water and 40 ml of saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (Wakogel C-200, eluted with chloroform), and then recrystallized from ethyl acetate-diisopropyl ether, to obtain 2.5 g (64.3% yield) of 1-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 144° to 146° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:19]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][CH:33]2[CH2:35][O:34]2)=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[Na+].[Cl-]>CN(C=O)C>[C:3]([O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:35][CH:33]([OH:34])[CH2:32][O:31][C:30]1[CH:36]=[CH:37][C:27]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=1)[CH:14]=[CH:13]2)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C(=O)OC(C)(C)C)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.077 g (1.93 mmol) sodium hydride as a 60% dispersion in mineral oil is suspended in 15 ml absolute DMF, stirred at room temperature for 10 min, mixed with a solution of 0.400 g (1.84 mmol) tert-butylindole-5-carboxylate in 15 ml absolute DMF and stirred at room temperature for one hour. A solution of 0.483 g (1.84 mmol) 2-(4-octyl-phenoxymethyl)oxirane in 15 ml absolute DMF is added drop-wise. Following four hours of heating at 60° C. and subsequent cooling, hydrolysis is carried out in a semi-saturated NaCl solution. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the product as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([NH2:14])=[N:8][C:9]=2[NH2:13].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH2:13][C:9]1[N:8]=[C:7]([NH:14][CH2:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[N:6]=[C:5]2[C:10]=1[N:11]=[CH:12][N:4]2[CH2:3][CH2:2][Cl:1]
Reactant: Nc1nc(N)c2ncn(CCCl)c2n1
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(NCc2cccnc2)nc2c1ncn2CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
100 mg (0.47 mmol) of 9-(2-chloroethyl)-2,6-diamino-purine (example 12, step A) were dissolved in 10 ml MeOH and 3 g molecular sieves (4 Å), 0.044 ml (0.47 mmol) 3-pyridinecarboxaldehyde and 0.135 ml (2.35 mmol) acetic acid were added. The mixture was stirred for 2 hours at room temperature. 23.6 mg (0.38 mmol) sodium cyano-borohydride were added and stiffing was continued for 4 hours. Additional 0.044 ml (0.47 mmol) 3-pyridinecarboxaldehyde were added and 72 mg sodium cyano-borohydride were added in three portions over three days at room temperature. The solvent was evaporated and the residue was taken up in 50 ml ethyl acetate. The organic layer was washed with sat. aqueous sodium carbonate and brine, dried over Na2SO4 and the solvent was evaporated in vacuo to give 0.254 g of the crude product as yellow oil. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 99.5/0.5→80:20) to give 88 mg of the desired product as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[C:10]([NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO>[NH2:15][C:13]([C:11]1[C:10]([NH:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[CH:9][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Br:1])[CH:12]=1)=[O:14]
Reactant: CCOC(=O)c1cc(NCC(C)C)c(C(N)=O)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CNc1cc(C(=O)O)c(Br)cc1C(N)=O
Temperature: 45 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of ethyl 2-bromo-4-(aminocarbonyl)-5-[(2-methylpropyl)amino]benzoate (315 mg, 0.91 mmol) in methanol (20 mL) was added 1N aqueous sodium hydroxide (15 mL) and the mixture was stirred for 2 hr at 45° C. The mixture was then concentrated by rotary evaporation and diluted with water then adjusted to pH 2 by 1N aqueous hydrochloric acid addition and the mixture was allowed to stand for 1 hr at room temperature. The crystalline solid was collected by filtration and washed with water then dried to give 4-(aminocarbonyl)-2-bromo-5-[(2-methylpropyl)amino]benzoic acid (250 mg, 87.1%). MS (EI) for C12H15BrN2O3: 315.1 (MH+)
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[C:3]#[CH:4].Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: C#CC(O)c1cccn1C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccn3C)c21

Procedure:
Using Method D above, 3-hydroxy-3-(1-methyl-pyrrol-2-yl)-1-propyne (132 mg, 0.98 mmol) (from Example 27 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (112 mg, 0.35 mmol) (Starting Material 2) using (Ph3P)2PdCl2 (31 mg)(Aldrich) and CuI (17 mg)(Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 28 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(1-methyl-pyrrol-2-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 114 mg, 87%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:14](O)(=O)[CH:15]([CH3:17])[CH3:16]>>[CH:15]([C:17]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1)([CH3:16])[CH3:14]
Reactant: CC(C)C(=O)O
Reactant: NC(C(=O)O)C(O)c1ccccc1
Product: CC(C)c1nc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures Y, Z with isobutyric acid, Z1 and Z2. LC-MS-conditions 02: tR=0.90 min; [M+H]+=232.51.
Reaction SMILES: CN(OC)[C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:16][CH:15]=2)=[O:13])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C>ClCCl>[CH:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][C:12](=[O:13])[C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:30]=[C:29]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:18][CH:19]=2)[CH:5]=1)=[O:37]
Reactant: CON(C)C(=O)c1ccc(C)c(NC(=O)c2ccc(Nc3nc(-c4ccccc4)c4ccccc4n3)cc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C=O)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A stirred solution of N,4-dimethyl-N-(methyloxy)-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)amino]benzamide (1.16 g, 2.24 mmol) in dichloromethane (150 mL) was cooled to −78° C. under nitrogen and a 1 M solution of diisobutylaluminum hydride in dichloromethane (6.7 mL, 6.7 mmol) was added dropwise over 30 min. The cooled solution was stirred for additional 1 h, then excess ethyl acetate was added to quench the reaction. The cooling bath was removed and the mixture was warmed to 0° C. using an ice bath. Methanol (2 mL) and then water (2 mL) was added carefully to the reaction mixture with vigorous stifling. A solution of 1 N hydrochloric acid (20 mL) was then added and the precipitates that formed were collected. The filtrates were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated on a rotary evaporator to give yellow solid that was combined with the previously collected precipitate, washed with water and dried under reduced pressure to give N-(5-formyl-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (791 mg, 77%). 1H NMR (400 MHz, CD3OD): δ 9.98 (s, 1H), 8.23 (d, 1H), 8.06 (d, 2H), 7.98 (d, 2H), 7.95 (d, 1H), 7.85 (m, 3H), 7.78 (q, 3H), 7.03 (m, 1H), 7.76 (t, 3H), 7.46 (d, 1H), 2.43 (s, 3H). MS (EI) for C29H22N4O2: 459.0 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])(C)[C:4]([O:6][CH3:7])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[CH:18][CH:17]=1.[BH4-].[Na+]>ClCCl.C(N(CC)CC)C>[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][NH:2][CH:3]([CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[CH:18][CH:17]=1
Reactant: COC(=O)C(C)(C)N
Reactant: O=Cc1ccnc2ccccc12
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)NCc1ccnc2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 25.7 %

Procedure:
A mixture of 1.5 g of methyl α-aminoisobutyrate hydrochloride and 1.4 ml of triethylamine in 30 ml of dichloromethane is stirred at 0° C. for 20 minutes. Next, 1 g of magnesium sulfate and 1.5 g of quinoline-4-carbaldehyde are added. Stirring is continued for 15 hours at room temperature and the mixture is then concentrated under reduced pressure. The residue is taken up in 35 ml of methanol and the solution obtained is cooled to 0° C. 0.4 g of sodium borohydride is added portionwise and stirring is continued at room temperature for 15 hours. The precipitate formed is filtered and the filtrate is concentrated under reduced pressure. The residue obtained is purified by recrystallization from diisopropyl ether. 600 mg of the expected product are obtained in the form of a pink oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2.C(N(CC)CC)C.[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH:31]=[CH2:32].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][O:28][C:29](=[O:33])[CH2:30]/[CH:31]=[CH:32]/[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2
Reactant: C=CCC(=O)OC
Reactant: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C/C=C/c1cccc2nc(NCc3ccc(C)o3)ccc12
Temperature: 120 °C

Procedure:
(5-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (400 mg, 1.3 mmol) was dissolved in 4 mL N,N-dimethylformamide. Triethylamine (167 mg, 1.7 mmol), methyl-3-butenoate (173 mg, 1.7 mmol), tri-ortho-tolylphosphin (31 mg, 0.1 mmol) and palladium acetate (11 mg, 0.05 mmol) were added. The reaction mixture was heated at 120° C. for 1 hour and quenched by addition of 50 mL water. The mixture was extracted three times with ethyl acetate (100 mL each). The organic phases were pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->75:25 gradient). (E)-4-{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-but-3-enoic acid methyl ester was obtained as a yellow oil (294 mg, 69%), MS: m/e=337.4 (M+H+).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CCN(C(C)C)C(C)C.Br[CH2:19][C:20]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC#N>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][CH2:19][CH:20]1[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: Nc1ccccc1N
Reactant: COC(=O)c1cccc(C(=O)CBr)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C2CNc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,2-phenylenediamine (300 mg, 2.77 mmol) was dissolved in 2.7 mL MeCN. Hunig's Base (485 μl, 2.77 mmol) was added, followed by methyl 3-(2-bromoacetyl)benzoate (713 mg, 2.77 mmol). The resulting reaction mixture was stirred at room temperature for 30 minutes. Acetic acid (476 μl, 8.32 mmol) and sodium triacetoxyborohydride (1176 mg, 5.55 mmol) were added. The mixture was stirred at r.t. overnight. TLC indicated that the starting material was consumed, and the reaction was quenched with saturated ammonium chloride and extracted into DCM. The organic phase was dried with MgSO4, filtered, concentrated, and purified on a 100 g silica column with 0-30% EtOAc/hexanes gradient to give methyl 3-(1,2,3,4-tetrahydroquinoxalin-2-yl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4=[N:19][O:21][C:29]([C:26]5[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=5)=[C:17]4[CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(Cl)cc2)cc1
Reactant: N#CCc1ccc(F)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc23)cc1

Procedure:
The title compound, yellow solid (28 mg, 22%), MS (ISP) m/z=390.2 [(M+H)+], mp 154° C., was prepared in accordance with the general method of example 1 from 1-(4-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate H) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:11]([O:13]C)=[O:12])[C:7]([O:9][CH3:10])=[O:8].[OH-].[K+]>CO.O>[S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(C(=O)OC)=C1SC=CS1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C(C(=O)O)=C1SC=CS1
Temperature: 50 °C
Yield: 84.4 %

Procedure:
Dimethyl 2-(1,3-dithiol-2-ylidene)malonate (2) (116 g) was suspended in methanol (2 l), to which a solution of 33.5 g of 85% potassium hydroxide in water (250 ml) was added. The resulting mixture was heated under reflux for 8 hours. After the solvent was removed, water (2.5 l) was added and the resulting mixture was heated to 50° C. Insoluble matter was filtered off. Concentrated hydrochloric acid (50 ml) was added to the filtrate to acidify the same. The resultant precipitate was collected by filtration and after washing, was dried at 40° C. in air, whereby 2-(1,3-dithiol-2-ylidene)-3-methoxy-3-oxopropionic acid (3) (92 g, yield: 84%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH2:12])=[O:11].[C:13]([CH2:15][C:16](O)=[O:17])#[N:14].CS(Cl)(=O)=O.O.C(O)(C)C>CN(C)C=O>[C:13]([CH2:15][C:16]([NH:12][C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:11])=[O:17])#[N:14]
Reactant: NC(=O)Nc1ccc(I)cc1F
Reactant: N#CCC(=O)O
Agent: CS(=O)(=O)Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC(=O)NC(=O)Nc1ccc(I)cc1F
Temperature: 25 °C

Procedure:
To a mixture of (2-fluoro-4-iodophenyl)-urea 78 (21.7 g) and cyanoacetic acid 73 (7.88 g) in N,N-dimethylformamide (108 ml) was added, and methanesulfonyl chloride (7.17 ml) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 2 hrs, and water-isopropyl alcohol [1:2 (volume ratio), 210 ml] was added dropwise. The mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration and washed with water to give 1-(2-cyanoacetyl)-3-(2-fluoro-4-iodophenyl)-urea 79 (wet crystals), which was used for the next reaction in the form of wet crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[C:34]([O:38][C:39]([NH:41][C@H:42]([C:46]([O:48][CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:47])[CH2:43][CH2:44]O)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Br:1][CH2:44][CH2:43][C@H:42]([NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[C:46]([O:48][CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:47]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCBr)C(=O)OC1CCCC1
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a slurry of N-bromosuccinimide (1.86 g, 10.4 mmol) in DCM (16.2 ml) was added a solution of triphenylphosphine (2.56 g, 9.74 mmol) in DCM (7.2 ml). The solution was stirred for a further 5 minutes after addition. Pyridine (338 μl, 4.18 mmol) was added, followed by a solution of Stage 4 product (Scheme 7) (1.00 g, 3.48 mmol) in DCM (8.8 ml). The solution was stirred for 18 hours, concentrated under reduced pressure and the residual solvent azeotroped with toluene (3×16 ml). The residue was triturated with diethyl ether (10 ml) and ethyl acetate:heptane (1:9, 2×10 ml). The combined ether and heptane solutions was concentrated onto silica and purified by column chromatography using ethyl acetate/heptane (1:9 to 2:8) to provide 1.02 g (84% yield) of title compound. 1H NMR (300 MHz, CDCl3), δ: 5.30-5.05 (2H, m), 4.45-4.30 (1H, m), 3.45 (2H, t, J=7.3 Hz), 2.50-2.30 (1H, m), 2.25-2.10 (1H, m), 1.95-1.60 (8H, br m), 1.47 (9H, s).