Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@H:9]([O:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH2:8][NH:7][C@@H:6]1[C:19]([OH:21])=O)=[O:4].[C:22]1([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:22]1([C:28]2[CH2:33][CH2:32][N:31]([C:19]([C@@H:6]3[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][C@H:9]([O:11][C:12]([N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[O:13])[CH2:8][NH:7]3)=[O:21])[CH2:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2S,3S,5S)-3-(methoxycarbonyl)-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-2-carboxylic acid (90.1 mg, 0.000300 mol) and 4-phenyl-1,2,3,6-tetrahydropyridine (64.6 mg, 0.000330 mol) HCl salt, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (146 mg, 0.000330 mol) in N,N-dimethylformamide (0.44 mL, 0.0057 mol) was added N,N-diisopropylethylamine (0.115 mL, 0.000660 mol) at rt. The mixture was stirred at rt overnight, then quenched with aq. sodium bicarbonate. After separation of the organic layers, the aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to dry. The crude material was used directly in next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:23])[C:5]([C:18]1[NH:22][N:21]=[N:20][N:19]=1)=[CH:6]3.[N:24]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][N:26]=[CH:25]1>CS(C)=O>[N:24]1([CH2:29][CH2:30][CH2:31][NH:32][C:10]2[C:9]3[O:14][CH2:15][C@H:16]([CH3:17])[N:7]4[C:8]=3[C:3]([C:4](=[O:23])[C:5]([C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:6]4)=[C:2]([NH2:1])[C:11]=2[F:12])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: NCCCn1ccnc1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(-c4nnn[nH]4)cn1c23
Solvent: CS(C)=O
Product: C[C@H]1COc2c(NCCCn3ccnc3)c(F)c(N)c3c(=O)c(-c4nnn[nH]4)cn1c23
Temperature: 120 °C

Procedure:
To a solution of 13 (250 mg, 0.78 mmol) in 5 ml of DMSO were added 132 μl (1.17 mmol) of 3-(1H-imidazol-1-yl)propan-1-amine. The reaction mixture was heated to 120° C. for 1 h. Upon completion of the reaction the DMSO was removed and the remaining solid was purified by preparative HPLC. To the combined HPLC fractions containing the product were added several drops of 1 N HCl before they were dried down to generate the HCl salt of the compound. The title compound was obtained as a yellow solid (118 mg, 37% yield).
Reaction SMILES: [CH2:1]([P:3]([O-:8])[O:4][CH2:5][CH2:6][OH:7])[CH3:2].[CH3:9][C:10](=[CH2:13])[CH:11]=[O:12].[O-]CC.[Na+]>>[CH2:1]([P:3]([CH2:9][CH:10]([CH3:13])[CH:11]=[O:12])(=[O:8])[O:4][CH2:5][CH2:6][OH:7])[CH3:2]
Reactant: C=C(C)C=O
Reactant: CCP([O-])OCCO
Agent: CC[O-]
Agent: [Na+]
Product: CCP(=O)(CC(C)C=O)OCCO
Yield: 87.7 %

Procedure:
A 500 ml five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel is initially charged with 63.5 g (0.46 mol) of 2-hydroxyethyl ethylphosponite (produced as in Example 4) and 32.2 g (0.46 mol) of 2-methyl-2-propenal. While stirring, 25 ml of sodium ethoxide (30% in ethanol) are added dropwise at such a rate that a reaction temperature of 60° C. becomes established. A slightly yellow-colored liquid is obtained. The crude product thus obtained is distilled in vacuo to obtain 84 g (88% of theory) of 2-hydroxyethyl ethyl(2-methyl-2-formylethyl)phosphinate as colorless liquid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([NH:28][C:29]([C:31]2[CH:32]=[C:33]([C:43]([CH3:46])=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][C:37]([C:40]([OH:42])=O)=[CH:36][CH:35]=2)=[O:30])[CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1.[NH2:57][CH2:58][C:59]([NH:61][CH3:62])=[O:60].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([NH:28][C:29]([C:31]2[CH:32]=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([NH:57][CH2:58][C:59]([NH:61][CH3:62])=[O:60])=[O:42])=[CH:36][CH:35]=3)[C:43]([CH3:46])=[CH:44][CH:45]=2)=[O:30])[CH2:27][CH2:26]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cc1
Reactant: CNC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CNC(=O)c1ccc(-c2cc(C(=O)NC3CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HATU (65 mg, 0.17 mmol) was added to a solution of {3′-[(cyclopropylamino)carbonyl}-6′-methyl-biphen-4-yl}carboxylic acid (50 mg, 0.17 mmol) in DMF (2 ml). After 5 minutes HOBT (23 mg, 0.17 mmol), 2-amino-N-methylacetamide (0.17 mmol) and DIPEA (0.087 ml, 0.51 mmol) were added and the reaction mixture stirred at room temperature under nitrogen for 18 hours. The DMF was removed in vacuo and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate solution (1M, 5 ml). The organic phase was purified by SPE cartridge (Si, 5 g) eluting in turn with DCM, chloroform, ether, ethyl acetate, acetonitrile, acetone, ethanol, DCM:ethanol:ammonia (40:8:1, 20:8:1 and 10:8:1). The product fractions were concentrated in vacuo to give N3-cyclopropyl-N4′{[(methylamino)carbonyl]methyl}-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:37]([NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: O=C=Nc1ccccc1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Nc3ccccc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
125 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 21 mg (0.18 mmol, 1.2 eq.) of phenyl isocyanate were reacted according to General Method 4. Yield: 58 mg (92% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:14]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[O:14])=[CH:5][CH:4]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: COc1ccc(C(C)O)cc1
Solvent: ClCCl
Product: COc1ccc(CC=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A solution of 4-methoxyphenyl ethanol (15.0 g, 98.2 mmol) in 150 mL of methylene chloride was stirred at 0° C. while Dess-Martin periodinane (50 g, 1.2 eq.) was added in small portions. The ice-bath was removed and the reaction was stirred at rt for 1 h. The reaction mixture was then diluted with methylene chloride (100 mL), washed with 10% sodium thiosulfate, saturated NaHCO3 solution, water, saturated NaCl solution, and dried over Na2SO4. The product was purified using silica gel chromatography (100% hexanes to 20% EtOAC/hexanes) to afford 5.3 g (34%) of 4-methoxyphenyl acetaldehyde.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15](O)([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Yield: 97.8 %

Procedure:
A suspension of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Intermediate 73-2, 300 mg, 0.864 mmol) in DCM (2 mL) was treated with triethylsilane (1.380 mL, 8.64 mmol) and then slowly with TFA (0.666 mL, 8.64 mmol) and the mixture was stirred at rt for 40 min. The resulting suspension was diluted with DCM and the resulting solution was washed with NaHCO3 (aq). The organic phase was washed with water and brine, and dried and concentrated to give 4-bromo-7-isopropyl-9H-carbazole-1-carboxamide as a white solid (280 mg, 98%). 1H NMR (400 MHz, chloroform-d) δ 10.50 (1H, br. s.), 8.63 (1H, d, J=8.1 Hz), 7.32-7.40 (3H, m), 7.22 (1H, dd, J=8.4, 1.3 Hz), 5.97 (2H, br. s.), 3.02-3.18 (1H, m), 1.35 (6H, d, J=6.8 Hz). Mass spectrum m/z 331, 333 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][N:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])#[N:2].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[CH3:22][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:5]=1[N:4]([CH2:3][C:1]#[N:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(N(CC#N)c2ccccc2)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)c1cc(OC)ccc1N(CC#N)c1ccccc1
Yield: 68.8 %

Procedure:
A mixture of 7.1 g (0.025 mole) of 2-[(cyanomethyl)phenylamino]-5-methoxybenzoic acid [P. C. Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1974)], 4.0 g (0.029 mole) of anhydrous potassium carbonate, and 3.0 ml (4.0 g; 0.032 mole) of dimethyl sulfate in 200 ml of acetonitrile was stirred at reflux for 24 hours. The mixture was cooled and filtered, and the filter cake was washed several times with fresh acetonitrile. The combined filtrates were evaporated to an oil, which crystallized upon standing at room temperature. Recrystallization from aqueous methanol yielded 5.1 g (68% yield) of the ester product. A sample recrystallized again as above was analytically pure, mp 107°-109° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[CH3:25][S:22]([O:1][CH2:2][CH2:3][C:4]1([NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])[CH2:5][CH2:6]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(CCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CCOS(C)(=O)=O)CC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 6.472 g (32.16 mmol) of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate in 61 ml of anhydrous dichloromethane was added 12.79 ml (91 mmol) of anhydrous triethylamine. The resulting mixture is cooled at −20° C. Then 3.54 ml (45.66 mmol) of mesyl chloride in 11 ml of anhydrous dichloromethane was added. The resulting mixture was stirred at room temperature for 2 h. The mixture was poured into ice-water and the organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The crude product was triturated with petroleum ether and filtered to give 7.82 g of pure product as an orange solid. Mp: 88-89° C.
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[CH3:14][N:13]([CH3:15])[C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([O:1][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:3]=[CH:4][CH:5]=2)=[CH:12][CH:11]=1
Reactant: CN(C)c1ccc(-c2ccnn2O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C)c1ccc(-c2ccnn2OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-5-(4-dimethylaminophenyl)-pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (27%, crystals).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:9]([O:11]C)Cl>>[SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]=[O:11])=[CH:4][CH:3]=1
Reactant: COC(Cl)Cl
Reactant: Sc1ccccc1
Product: O=Cc1ccc(S)cc1

Procedure:
The above reaction of Example 68(A) is repeated except that the starting materials are mercaptobenzene and dichloromethyl methylether. Using the same reaction conditions and techniques, there is obtained 4-mercaptobenzaldehyde.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].[SH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].FC(F)(F)C(O)=O>C(Cl)Cl>[C:34]([CH2:33][CH2:32][S:31][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C:4]([OH:6])=[O:5])([O:36][CH3:37])=[O:35]
Reactant: COC(=O)CCS
Reactant: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCSC(CC(=O)O)c1ccccc1CCCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of t-butyl 3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propanoate (4.0 gm, 9.7 mmole) in methylene chloride (40 ml) was stirred under an inert atmosphere at -10° C. To this cold solution was added methyl 3-mercaptopropionate (6.2 ml, 56 mmole) in one portion followed by dropwise addition of trifluoroacetic acid (80 ml). The reaction mixture was then stirred for 5 hours at 0° C. Solvent and excess trifluoroacetic acid were removed on a rotary evaporator. The residue was redissolved in methylene chloride and washed twice with water and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography on silica gel eluting with hexane-ethyl acetate formic acid (85/15/0.5) gave the title compound. Anal.: Calcd. for C27H36O4S: C, 71.17; H, 7.74. Found: C, 70.46; H, 7.72. 250 MHz NMR (CDCl3) δ 1.28-1.68 (12H,m) 2.48 (2H,t) 2.56-2.72 (6H,m) 2.93 (2H,d) 3.66 (3H,s) 4.60 (1H,t) 7.18-7.39 (9H,m).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:4].[O:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[O:13]=[C:11]([C:15]1[O:14][CH:18]=[CH:17][CH:16]=1)[CH2:10][CH2:9][C:8]#[C:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)CCC#CCCC(=O)O
Reactant: c1ccoc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)CCC#CCCC(=O)c1ccco1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
To a mixture of 6-methoxycarbonyl-1-carboxy-3-hexyne [VI-1] (27.6 g, 0.15 mole), furan (30 7 g, 0.45 mole) and dichloromethane (150 ml) is added trifluoroacetic anhydride (37.8 g, 0.18 mole) at room temperature, and the mixture is reacted at 30°-35° C. for 24 hours. After completion of the reaction, the reaction solution is poured into ice-water, and neutralized with 20% aqueous sodium hydroxide solution. The organic layer is separated and washed successively with 5% aqueous sodium hydrogen carbonate solution and water. The organic layer is concentrated under reduced pressure to give 1-oxo-1-furyl-7-methoxycarbonyl-4-heptyne [VII-1] (32.3 g, yield; 92%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[S:17][C:18]([CH3:23])=[CH:19][C:20]=1[C:21]#[N:22].Cl>C1COCC1>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([NH:15][C:16]2[S:17][C:18]([CH3:23])=[CH:19][C:20]=2[C:21]#[N:22])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1cc(C#N)c(N)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)c(Nc2ccc(C#N)cc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (60%, 0.58 g) in THF (2 mL), was added 4-fluoro-3-nitro-benzonitrile (1.33 g, 8.0 mmol) and 2-amino-5-methyl-thiophene-3-carbonitrile (1.10 g, 8.0 mmol) in THF (10 mL), dropwise. The mixture was stirred at room temperature overnight. Two more batches of sodium hydride (60%, 0.50 g and 0.4 g) were added over the next 6 hours. After stirring for 3 days, the mixture was poured into ice-water (20 mL) and acidified to pH 3 with 6N hydrochloric acid (7 mL). The precipitate was filtered and washed with water. The solid was extracted with dichloromethane (35 mL). The solution was concentrated to a solid, and used in the next step without additional purification. LC-MS: m/z 285 (M+1), 307 (M+23). 1H NMR (CDCl3, 400 MHz): δ (ppm) 9.76 (s, 1H), 8.59 (s, 1H), 7.70 (d, 1H), 7.14 (d, 1H), 6.87 (s, 1H), 2.52 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(F)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 4-fluoro-2-methylbenzoic acid (32.5 g) in conc. sulfuric acid (50 ml) was added dropwise conc. nitric acid (8.4 ml) at 0° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice-water (500 ml), and the mixture was extracted with diisopropyl ether (300 ml), and the organic layer was washed with water, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure to give the title compound (40.0 g).
Reaction SMILES: CCN([CH2:6][CH3:7])CC.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[PH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[C:9]1[P:17]([C:12]1[CH2:11][C:10]2[C:7]([CH:6]=1)=[CH:15][CH:16]=[CH:8][CH:9]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN(CC)CC
Reactant: C1=C(Pc2ccccc2)Cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C1=C(P(C2=Cc3ccccc3C2)c2ccccc2)Cc2ccccc21
Temperature: 25 °C

Procedure:
To 4.00 g (0.021 mol) of 2-bromo-1-indene and 0.46 g (0.40 mmol) of Pd(PPh3)4 in 20 ml of toluene, 3.2 ml (2.32 g, 0.023 mol) of Et3N and, then, 4.52 g (0.020 mol) of 17 were added. This mixture was refluxed for 13 hours, cooled to room temperature, and passed through short column with Silica Gel using 150 ml of toluene as eluent. The resulted solution was evaporated to dryness. The crude product was crystallized from ethanol. Yield 1.63 g (28%) of white crystals of 16.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[C:27]([C:29]1[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=1)#[CH:28]>>[CH3:34][N:33]1[C:29]([C:27]#[C:28][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=2)[CH2:5][O:6][NH:7][C:8](=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:30][N:31]=[CH:32]1
Reactant: C#Cc1cncn1C
Reactant: O=C(NOCc1cccc(I)c1)c1ccccc1NCc1ccncc1
Product: Cn1cncc1C#Cc1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1

Procedure:
Starring materials: N-(3-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (see Example 361) and 5-ethynyl-1-methyl-1-H-imidazole (Aldrich).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1.P(Cl)(Cl)([Cl:17])=O.CN(C)C1C=CC=CC=1>>[Cl:17][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)cc(-c2ccncc2)n1
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)cc(-c2ccncc2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
32 g (170.04 mmol) of the compound (from example XXVIII) are dissolved in 87.1 ml (0.93 mmol) of phosphoryl chloride. 2.80 ml (22.11 mmol) of N,N-dimethylaniline are slowly added dropwise, and the mixture is stirred at 100° C. for one hour. The reaction solution is then stirred at room temperature for another two hours. The phosphoryl chloride is removed under reduced pressure using a rotary evaporator. Water/dichloromethane 9:1 is added to the residue, which is then boiled for 5 minutes. The mixture is then neutralized using saturated sodium bicarbonate solution and the product is filtered off with suction and dried under high vacuum.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:31]([CH:36]3[CH2:38][CH2:37]3)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:31]2[C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:39])[NH:19][C:9]5[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:38][CH2:37]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C3CC3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3C3CC3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M201) (245 mg, 0.443 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (122 mg, 63%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([CH2:16]O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:16][C:14]1[S:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCc1ccc(-c2ccc(CO)s2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(-c2ccc(CCl)s2)cc1
Reaction time: 8 h

Procedure:
To a solution of 60.4 (40 mg, 0.16 mmol) in DCM (0.8 mL) were added triethylamine (23 μL, 0.16 mmol) and thionyl chloride (18 μL, 0.24 mmol) at room temperature. The mixture was stirred overnight and concentrated to afford 60.5. The crude product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C([O-])(=O)C.[Na+].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(OCC)(=O)C>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Br)cc1
Temperature: 180 °C
Yield: 22 %

Procedure:
A mixture made from 10 g (49.5 mmol) of 2-bromo nitrobenzene, 13 g (163 mmol) of sodium acetate and 10 g (59 mmol) of 4-bromo aniline was stirred with heating at the temperature of 180° C. under the atmosphere of nitrogen gas for 8 hours. The reacted solution was cooled down to room temperature, diluted with ethyl acetate and filtered. After concentrating the filtrate, and by washing the residue with methanol 3.8 g of (4-bromophenyl)-(2-nitrophenyl) amine was obtained as orange crystals (yield: 22%).