Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:6]([CH:20](OCC)OCC)([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:7]#[N:8])(OCC)=O.[OH-].[K+].[NH2:29][C:30]([NH2:32])=[NH:31]>C(O)C>[NH2:32][C:30]1[N:31]=[C:7]([NH2:8])[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[CH:20][N:29]=1
Reactant: CCOC(=O)C(C#N)(Cc1ccc(OC)c(OC)c1)C(OCC)OCC
Reactant: N=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OC
Yield: 52.4 %

Procedure:
A solution of α-carbethoxy-α-diethoxymethyl-β-(3,4-dimethoxyphenyl)propionitrile (3.75 g) and an equivalent amount of potassium hydroxide in ethanol (70 ml) was heated at reflux for one hour. A solution of guanidine (0.035 mol) in ethanol (50 ml) was added and reflux was resumed. Ethanol was boiled off until the reaction temperature reached 85° C. After 17 hours at reflux the mixture was allowed to cool and the product was filtered and washed with ethanol giving a white solid which was purified as described in Example 5 to yield 1.4 g (54%) of the title compound, m.p. 231°-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[N:13](C(OC(C)(C)C)=O)[CH:12]=3)=[CH:10][C:3]=12>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:32])=[O:33])[C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[NH:13][CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2nc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.8 %

Procedure:
Dissolve bisazaindole 27 (0.28 g, 0.48 mmol) in TFA at 50%/CH2Cl2 (8.0 mL) and stir at room temperature for 5 h. The reaction medium is concentrated under vacuum, and the residue is dissolved in EtOAc (100 mL), washed with saturated NaHCO3 (3×), dried (MgSO4) and concentrated, to give 28 (0.222 g, 96%) as an amorphous solid: TLC (EtOAc at 40%/heptane) Rf=0.05.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:21][CH2:22]2)=[CH:4][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:30]
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC3CC3)c2)CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC3CC3)c2)CCCC1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NBS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to yield ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (920 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])(=[O:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26]Br>C(O)(=O)C>[C:1]([O:5][C:6](=[O:25])[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][S:15]([C:18]2[CH:23]=[C:22]([Br:26])[CH:21]=[CH:20][C:19]=2[NH2:24])(=[O:17])=[O:16])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2ccccc2N)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2cc(Br)ccc2N)cc1
Yield: 38.7 %

Procedure:
4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester (12.16 g, 33.5 mmol) was dissolved in 150 mL of acetic acid at 10° C. A solution of bromine (2.06 mL, 40.2 mmol) in 50 mL acetic acid was added dropwise. After complete addition, a thick yellow precipitate was observed. The reaction was filtered, and the solid washed with water. Chromatography of the solid (20% ethyl acetate/hexanes, SiO2) gave 5.72 g (39%) of 4-[(2-Amino-5-bromo-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester as a white solid. 1H-NMR (CDCl3); 7.86 (d, 2H), 7.74 (d, 1H), 7.37 (dd, 1H), 7.23 (m, 2H), 6.65 (d, 1H), 5.19 (bt, 1H), 4.14 (d, 2H), and 1.58 (s, 9H). MS: M+=441.0 Da Step (4): Synthesis of 4-(7-Bromo-1,1,3-trioxo-3,4-dihydro-1H-1λ6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C)(=O)=O.[Si](O[C@@H]1[C@@](COS(C)(=O)=O)(CO)O[C@@H]([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])C1)(C(C)(C)C)(C)C>C(Cl)Cl>[NH:34]1[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]1=[O:36]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@](CO)(COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c[nH]c(=O)[nH]c1=O
Temperature: 24 °C

Procedure:
To a solution of 3'-O-β-butyldimethylsilyl-4'-hydroxymethyl-β-D-erythro-pentofuranosylthymine (1.2 g, 3.1 mM), prepared, e.g., as described in Preparation 4, in CH2Cl2 (20 ml), triethylamine (0.6 g. 6 mM) was added followed by the dropwise addition of mesyl chloride (0.340 g, 3 mM), while the solution was stirred at 24° C. The solution was concentrated by the removal of the solvent by evaporation. The residue was flash chromatographed on silica gel eluting by CH2Cl2 with 5% methanol, to give a mixture of the 4'-α and 4'-β isomers of 3'-O-t-butyldimethylsilyl-4'-methanesulfonyloxymethylthymidine (1.1 g, 2.4 mM). Calcd. for C18H32N2O8Si: C, 46.53; H, 6.94; N, 6.05. Found: C, 46.90; H, 7.02; N, 5.78.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Yield: 48.8 %

Procedure:
2,6-di-t-butyl-4-nitrophenol (6.3 g, 25 mmoles) is dissolved in methanol (100 ml). 0.6 g of palladium on carbon (10%) is added and the whole is placed under a hydrogen atmosphere under 2 bars of pressure. The catalyst is filtered out and the solvent is evaporated off under reduced pressure. The residue is taken up in heptane and filtered. In this way 2,6-di-t-butyl-4-aminophenol (2.7 g, 48%) is obtained which will be used without other purification in the following stages. Pink powder. Melting point: 123-124° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[NH:20][C:19](=O)[N:18]=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:19]1[N:20]=[C:15]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:27])([F:26])[F:1])[CH:6]=2)[CH:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)c(OCC(F)(F)F)c2)[nH]1
Product: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 6-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-4-trifluoromethyl-1H-pyrimidin-2-one (3.74 g, 9.21 mmol) and phosphoroxychloride (30 mL) according to the general procedure I. Obtained as a brown solid (3.75 g, 96%). MS (EI) 424.0 [(M)+]; mp 44° C.
Reaction SMILES: CCN=C=NCCCN(C)C.C(OC([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([C:32]([OH:34])=O)[N:29]([CH3:31])[CH:30]=2)=[CH:22][CH:21]=1)=O)(C)(C)C.[NH2:35][C:36]1[CH:37]=[C:38]([C:42]([O:44][CH3:45])=[O:43])[N:39]([CH3:41])[CH:40]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[C:28]([C:32]([NH:35][C:36]3[CH:37]=[C:38]([C:42]([O:44][CH3:45])=[O:43])[N:39]([CH3:41])[CH:40]=3)=[O:34])[N:29]([CH3:31])[CH:30]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(N)cn1C
Reactant: Cn1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2cc(-c3ccc(N)cc3)cn2C)cn1C
Reaction time: 6 h

Procedure:
Two eq of EDCI and 2.5 eq of DMAP were added to a stirred solution of 6 (0.45 gm, 1.2 eq) in DMF (8 mL) and the mixture was allowed to stir for 30 minutes after which commercially available methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (0.18 g, 1.18 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for a further 6 hour at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed with citric acid (100 mL), saturated aqueous NaHCO3 (100 mL), water (100 mL), brine (100 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product 9a (0.58 gm, yield 90.6%) was used for the boc deprotection step to afford 9 without further purification. For boc deprotection, 0.29 gm of 9a was dissolved in a small volume of MeOH and 4M HCl in dioxane (15 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 6 hours at which point TLC showed completion of reaction. Excess solvent was evaporated under vacuum to obtain a brown coloured solid (9). The solid product was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give pure 9. Yield 0.21 gm, 95%.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27](=[O:38])[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(OC(C)C)(C)C>>[CH3:25][O:26][C:27](=[O:38])[CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:2]2[C:3]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=4)=[C:9]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:35][CH:36]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(=O)CCCc1ccc(N)cc1
Solvent: CC(C)OC(C)C
Product: COC(=O)CCCc1ccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)cc1

Procedure:
Heat 200.8 mg (0.596 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 149.8 mg (0.775 mmol) of 4-(4-aminophenyl)butanoic acid methyl ester to 150° C. for 1.5 h. After cooling, concentrate under reduced pressure, add dichloromethane to the residue and purify the crude product by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 20:1). The product thus obtained is stirred with diisopropyl ether and the solid obtained is filtered off with suction and washed with a little diisopropyl ether. 236.7 mg (80.4% of theory) of the target product are obtained as a pale pink solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][NH:29][C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:28][N:29]([C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:26]
Reactant: CN[C@@H]1CCNC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)[C@@H]3CCNC3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added (R)—N-methylpyrrolidin-3-amine (50 mg, 0.50 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][N:15]=[N+:16]=[N-:17]>C1C=CC=CC=1.C1CCCCC1>[CH3:1][O:2][C:3]([C:5]1[N:17]=[N:16][N:15]([CH2:14][C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[Cl:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: [N-]=[N+]=NCc1ccccc1Cl
Reactant: COC(=O)C#CC(=O)OC
Solvent: c1ccccc1
Solvent: C1CCCCC1
Product: COC(=O)c1nnn(Cc2ccccc2Cl)c1C(=O)OC

Procedure:
A solution of 8 g (0.054 mol) of acetylene-dicarboxylic acid dimethyl ester in 25 ml of benzene is added dropwise to a solution of 8.4 g (0.05 mol) of o-chlorobenzyl azide in 50 ml of benzene that is boiling under reflux. After a further hour under reflux, the whole is diluted with 75 ml of cyclohexane and, after cooling, the substance that has crystallised out is filtered off with suction. After washing with a mixture of diethyl ether and hexane (1:1), there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester having a melting point of 88°-91°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:21])([CH3:20])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O)[C:4]=2[O:3][CH2:2]1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][C:27]2=[O:32]>C(O)(=O)C>[OH:19][C:12]1([C:15]([F:16])([F:17])[F:18])[CH2:11][C:10]([CH3:20])([CH3:21])[C:9]2[C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=[CH:7][C:8]=2[CH:13]1[NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][C:27]2=[O:32]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cccc2c1OCO2
Reactant: Nc1cccc2c1CNC2=O
Solvent: CC(=O)O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c2CNC3=O)c2ccc3c(c21)OCO3
Yield: 63.5 %

Procedure:
800 mg (2.63 mmol) of 4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is stirred in 5.2 ml of glacial acetic acid with 389 mg (2.63 mmol) of 4-amino-2,3-dihydroisoindol-1-one overnight at room temperature. The reaction mixture is spun in until a dry state is reached, and the residue is chromatographed on a Flashmaster. 725 mg (62.8%) of the desired compound is isolated as a racemate. Racemate cleavage (Chiralpak AD 20μ; mobile solvent: hexane/ethanol/diethylamine) yields 279.2 mg of the (+)-enantiomer {[α]D=+20.7 (c=1.03, methanol)}and 297.5 mg of the (−)-enantiomer {[α]D=−23.4 (c=1.02, methanol)}
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:22]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:31]=O)[C:25]=2[CH:24]=[CH:23]1>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:25]=2[CH2:24][CH2:23][NH:22]3)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2cccc3c2CCN3)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.6 %

Procedure:
1.38 g of 1-methylpiperazine and 2.92 g of sodium triacetoxyborohydride are successively added to a solution of 1 g of indole-4-carboxaldehyde in 40 ml of tetrahydrofuran under argon. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. The residue is taken up in 40 ml of acetic acid, cooled to 15° C., and then 1.30 g of sodium cyanoborohydride are added in portions. The reaction medium is stirred for 2 hours while allowing it to rise to ambient temperature, poured into a water/ice mixture, treated with 28% aqueous ammonia until the pH is neutral, and extracted with dichloromethane (4×50 ml). The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 95/05 dichloromethane/7N ammoniacal methanol, so as to give 1.22 g of 4-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-1H-indole in the form of a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][OH:45].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22]([N:39]3[CH2:43][CH2:42][CH2:41][C@H:40]3[CH2:44][OH:45])=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: OC[C@@H]1CCCN1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@H]3CO)c2C1)Cc1cc(F)c(F)cc1F
Yield: 116.9 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), (S)-pyrrolidin-2-ylmethanol (54.62 mg, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of dichloromethane under stirring, and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.14 g, 0.54 mmol) was then added to the solution. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 30a (0.2 g) as a white solid.
Reaction SMILES: Br[CH:2]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:22]=[CH:21][C:3]1([NH2:37])[NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[CH2:40]([C:56]1[CH:61]=[CH:60][C:59]([OH:62])=[CH:58][CH:57]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>>[NH2:37][C:3]1([CH:2]=[CH:24][C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:22][CH:21]1[O:62][C:59]1[CH:58]=[CH:57][C:56]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:61][CH:60]=1)[NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCCCCCc1ccc(O)cc1
Reactant: CCCCCCCCCCCCC1=CC(Br)C(N)(Nc2cccc3c2C(=O)c2ccccc2C3=O)C=C1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCc1ccc(OC2C=C(CCCCCCCCCCCC)C=CC2(N)Nc2cccc3c2C(=O)c2ccccc2C3=O)cc1

Procedure:
A mixture of 56 g of 2-bromo-1-amino-p-dodecyl-anilino-anthraquinone, 10 g of caustic soda powder and 700 g of p-n-hexadecylphenol was heated at 170°-175° C. for 4 hours. Then, 2000 g of a 5% aqueous solution of caustic soda were added thereto, and the resulting blue precipitate was recovered by filtration, washed sufficiently and dried to yield 1-amino-2-p-n-hexadecylphenoxy-4-dodecylanilinoanthroquinone. The reaction is expressed by the following formula: ##STR11##
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:11])[CH2:8][CH2:9]Cl)=[CH:4][CH:3]=1.[CH3:12][C:13]([O-:15])=[O:14].[Na+]>C(O)(=O)C>[C:13]([O:15][CH2:9][CH2:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:11])(=[O:14])[CH3:12]
Reactant: O=C(CCCl)c1ccc(Br)s1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCCC(=O)c1ccc(Br)s1
Temperature: 130 °C
Reaction time: 8 h
Yield: 541.3 %

Procedure:
To the mixture of 1-(5-bromothiophen-2-yl)-3-chloropropan-1-one (2.8 g, 1.6 mmol, 1.0 eq), NaOAc (4.5 g, 55.3 mmol, 5 eq) and KI (200 mg) in acetic acid (16 mL) was stirred at 130° C. for overnight. The mixture was extracted with CH2Cl2 (3×40 ml). The combined organic layers were washed (brine), dried (Na2SO4), filtered and concentrated to give yellow oil 3-(5-bromothiophen-2-yl)-3-oxopropyl acetate (2.4 g, 76.2%). LC-MS (m/z)=278.1 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1.[NH:13]1[CH:17]=[C:16]([CH:18]=O)[N:15]=[CH:14]1.[OH-].[Na+]>OS(O)(=O)=O>[NH:13]1[CH:17]=[C:16]([CH:18]=[C:6]2[C:5](=[O:12])[C:4]3[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[CH2:8][CH2:7]2)[N:15]=[CH:14]1
Reactant: O=Cc1c[nH]cn1
Reactant: Cc1ccc2c(n1)C(=O)CCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c(n1)C(=O)C(=Cc1c[nH]cn1)CC2
Temperature: 110 °C

Procedure:
A mixture of 2-methyl-6,7-dihydro-5H-quinolin-8-one (Intermediate 200A3) (15.1 g, 93.8 mmol) and imidazole-4-carbaldehyde (15 g, 156 mmol) in 40% H2SO4 (65 mL) was heated at 110° C. for 12 h. The reaction mixture was cooled to room temperature, poured onto crushed ice and basified with 2M NaOH until pH>8. The solids were collected on a glass frit, washed with water, dichloromethane and dried under vacuum to give unpurified 7-(1H-imidazol-4-yl-methylene)-2-methyl-6,7-dihydro-5H-quinolin-8-one (Intermediate 200A4) as a yellow solid, 22 g (98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:12][Mg]Br>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])([CH3:12])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)c1cc(F)cc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)cc(F)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 1-(3,5-difluorophenyl)ethanone (2.00 g, 12.8 mmol) in THF (20 mL) at 0-5° C., methylmagnesium bromide in THF (3.0 M; 5.12 mL, 15.4 mmol) was added dropwise. The mixture was stirred at 0-5° C. for 1 h, then quenched with brine, extracted with EtOAc (2 times). The combined organic phases were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give the sub-title compound as a colorless oil (2.12 g, 96.1%).
Reaction SMILES: [Cl-].[NH4+:2].[F:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7]>CO.O.[Fe]>[NH2:2][C:14]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[C:4]([F:3])[CH:15]=1
Reactant: CON(C)C(=O)c1ccccc1F
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CON(C)C(=O)c1ccc(N)cc1F

Procedure:
15.2 g of ammonium chloride and 8 g of iron powder were added to a suspension of 10.84 g of 2-fluoro-N-methoxy-N-methylbenzamide in 60 ml of methanol and 30 ml of water, and the reaction liquid was heated under reflux for 3 hours. The reaction liquid was filtered through Celite, and the solvent was evaporated away under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 1/2 to obtain the entitled compound as a brown oily substance.