Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([C:10]1[N:11]([CH3:22])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)[N:14]=1)[CH3:9])=[O:6].C1COCC1.CC(C)([O-])C.[K+].CCOC(C)=O>O>[I:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]=[C:10]([C@H:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])[CH3:9])[N:11]([CH3:22])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: C[C@@H](NC(=O)CCCCl)c1nc(-c2ccc(I)cc2)cn1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](c1nc(-c2ccc(I)cc2)cn1C)N1CCCC1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a 20-dram vial was added (R)-4-chloro-N-(1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethyl)butanamide and THF (10 mL). The vial was cooled to 0° C. under a nitrogen atmosphere and potassium t-butoxide (214 mg, 1.91 mmol) was added. The reaction was stirred for 1.5 h. To the reaction mixture was added EtOAc (50 mL) and water (10 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was then dissolved in dichloromethane and purified by silica gel chromatography (5-50% CH3CN/CH2Cl2) to afford 593 mg (86%) of (R)-1-(1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethyl)pyrrolidin-2-one as a white solid (M+H (m/z)=396).
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([C:39]([N:41]([CH2:43][C:44]2[N:51]3[C:47]([S:48][CH:49]=[CH:50]3)=[CH:46][N:45]=2)[CH3:42])=[O:40])[CH2:37][C@H:36]([S:52][C:53]2[C@H:54]([CH3:77])[C@@H:55]3[C@@H:65]([C@H:66]([O:68][Si](C(C)(C)C)(C)C)[CH3:67])[C:64](=[O:76])[N:56]3[C:57]=2[C:58]([O:60][CH2:61][CH:62]=[CH2:63])=[O:59])[CH2:35]1)=[O:33])[CH:29]=[CH2:30].P([O-])([O-])([O-])=O>C1COCC1>[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([C:39]([N:41]([CH2:43][C:44]2[N:51]3[C:47]([S:48][CH:49]=[CH:50]3)=[CH:46][N:45]=2)[CH3:42])=[O:40])[CH2:37][C@H:36]([S:52][C:53]2[C@H:54]([CH3:77])[C@@H:55]3[C@@H:65]([C@H:66]([OH:68])[CH3:67])[C:64](=[O:76])[N:56]3[C:57]=2[C:58]([O:60][CH2:61][CH:62]=[CH2:63])=[O:59])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(=O)N(C)Cc3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(=O)N(C)Cc3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 81.1 %

Procedure:
Acetic acid (0.132 ml) and 0.77 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of 114 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[N-(imidazo[5,1-b]thiazol-5-yl)methyl-N-methylaminocarbonyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl)-1-methyl-carbapen-2-em-3-carboxylate in 2.3 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 22.5 hr. 1/15 M phosphate buffer (pH 7.0) (3 ml) is added thereto, and the mixture is extracted twice with 15 ml of ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and filtered, and the solvent is removed under reduced pressure and by filtrate to give a yellowish orange oil. This oil is purified by column chromatography on silica gel (ethyl acetate:methanol=9:1) to give 78.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[N-(imidazo[5,1-b]thiazol-5-yl)methyl-N-methylaminocarbonyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate as a colorless solid.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[CH3:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COC1CCCC1.C(OCC)(=O)C.[Cu]I>[CH3:8][N:9]1[CH2:13][CH2:12][N:11]([C:2]2[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=2)[C:10]1=[O:14]
Reactant: CN1CCNC1=O
Reactant: Cn1ccc(I)n1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COC1CCCC1
Product: CN1CCN(c2ccn(C)n2)C1=O
Yield: 74.5 %

Procedure:
A solution of 3-iodo-1-methyl-1H-pyrazole (250 mg), 1-methylimidazolidin-2-one (120 mg), copper(I) iodide (46 mg), N1,N2-dimethylethane-1,2-diamine (0.052 mL) and tripotassium phosphate (510 mg) in cyclopentyl methyl ether (5 mL) was stirred overnight at 120° C. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with saturated aqueous ammonium chloride solution, water and saturated brine. The extract was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (161 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](N)=[C:10]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[ClH:32].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>CC#N>[Cl:32][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[N:12]=[C:11]2[N:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:23]=[CH:24][C:10]=12
Reactant: Cl
Reactant: Nc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc2c1cnn2-c1ccccc1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1ccc(-c2c(-c3ccc(Cl)cc3Cl)nc3c(cnn3-c3ccccc3)c2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
To a solution of 5-(4-chloro-phenyl)-6-(2,4-dichlorophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamine (16 mg, 0.034 mmol) in CH3CN (0.4 mL) is added cone. HCl (0.8 mL). NaNO2 (20 mg, 0.29 mmol) is added into the mixture at 0° C. After the addition, the mixture is warmed up to room temperature and stirred for 24 h. The mixture is then neutralized to pH˜7 by adding saturated aqueous NaHCO3 and extracted with EtOAc (3×3 mL). The combined organic layers are concentrated and purified by preparative thin layer chromatography to provide the titled compound as a white solid (4 mg, 24%). 1H NMR (CDCl3) δ(ppm) 8.35(s, 1H), 8.28 (d, 2H), 7.50 (t, 2H), 7.27-7.37(m, 2H), 7.24-7.26 (m, 2H), 7.07-7.16 (m, 4H); HPLC-MS calculated for C24H13Cl4N3 (M+1+): 484.0. Found: 484.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:6][O:7][C:8]1[CH:34]=[CH:33][C:11]([C:12]([NH:14][C:15]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][C:16]=2[C:17]([O:19]CC)=[O:18])=[O:13])=[CH:10][C:9]=1[Cl:35]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:6][O:7][C:8]1[CH:34]=[CH:33][C:11]([C:12]([NH:14][C:15]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][C:16]=2[C:17]([OH:19])=[O:18])=[O:13])=[CH:10][C:9]=1[Cl:35]
Reactant: CCOC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(OCc2ccc(OC)c(OC)c2)c(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2ccc(C(=O)Nc3ccc(Oc4ccccc4)cc3C(=O)O)cc2Cl)cc1OC
Reaction time: 16 h

Procedure:
A solution of 1C (160 mg, 0.29 mmol) in THF (30 mL) and MeOH (10 mL) at 0° C. was treated with a solution of LiOH monohydrate (60 mg, 1.42 mmol) in water (10 mL). The resulting solution was stirred for 16 hours, and then concentrated to 10 mL. The resulting suspension was taken up in water (10 mL) and brought to pH 5 with 1 N HCl. The solution was extracted with EtOAc (4×25 mL), dried (Na2SO4), filtered and concentrated to afford the 1D as a white solid. (130 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:9][C:8]([NH2:10])=[N:7][N:6]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:9][C:8]([NH:10][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:7][N:6]=1
Reactant: Nc1nnc(Cc2ccccc2Cl)o1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1nnc(Cc2ccccc2Cl)o1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 15 %

Procedure:
5-(2-Chloro-benzyl)-[1,3,4]oxadiazol-2-ylamine (21 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (21 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (6.0 mg, 0.015 mmol, 15%). ESI-MS m/z calc. 397.1. found; 398.3 (M+1)+ Retention time 2.96 minutes.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]([NH:20][CH2:21][CH:22](OC)OC)=[N:13][C:12]=2[CH:27]=1)(C)(C)C.Cl>>[CH3:19][C:17]1([CH3:18])[CH2:16][CH2:15][C:14]2[N:13]([CH:22]=[CH:21][N:20]=2)[C:12]2[CH:27]=[C:8]([NH2:7])[CH:9]=[CH:10][C:11]1=2
Reactant: COC(CNC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2C(C)(C)CC1)OC
Agent: Cl
Product: CC1(C)CCc2nccn2-c2cc(N)ccc21
Reaction time: 16 h

Procedure:
To the above solution of [2-(2,2-Dimethoxy-ethylamino)-5,5-dimethyl-4,5-dihydro-3H benzo[b]azepin-8-yl]-carbamic acid tert-butyl ester was added conc HCl (25 ml) and heating was continued at 80° C. for 16 h. Product LCMS=228.20 (M+H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)=[CH:16][CH:15]=1>CN(C=O)C>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=3)=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)c1coc(-c2ccc(CCl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc(-c2ccc(Cn3cnc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.4 %

Procedure:
To a solution of benzimidazole (1.5 eq) in DMF was added portionwise sodium hydride (60% suspension in mineral oil, 1.5 eq) and the reaction mixture was allowed to stir for 45 min at room temperature. The reaction mixture was then added to a solution of ethyl 2-[4-(chloromethyl)phenyl]-1,3-oxazole-4-carboxylate (1 eq) in DMF and the reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was poured into ice/water, stirred for 30 min, and the resulting precipitate filtered through a coarse filter without vacuum suction (if the filtration is bad, it is possible to decant the aqueous/DMF layer from the organic precipitate), the precipitate dissolved in methylene chloride, washed with aq. ammonium chloride, water, dried over sodium sulphate, evaporated, triturated with MTBE, filtered, dried in the oven at 40° C. overnight. The product (92.4% yield) was obtained as off-white crystals; m.p. 150-152° C. 1H NMR (300 MHz, DMSO-D6, δ): 8.92 (s, 1H), 8.45 (d, 2H, J=8.5 Hz), 7.99 (d, 2H, J=8.5 Hz), 7.68 (m, 1H), 7.51 (m, 1H), 7.46 (d, 2H, J=8.5 Hz), 7.21 (m, 2H), 5.61 (s, 2H), 4.31 (m, 2H, J=7.2 Hz), 3.32 (s, 2H), 130 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CC(=O)c1cc2ccccc2cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
3-Acetyl-isoquinoline (1.53 g, 8.9 mmole) is dissolved in 42 ml methanol in a 100 ml one neck round bottom flask at 0° C. The solution is treated portionwise with sodium borohydride (388 mg, 10.3 mmole) and the reaction mixture is stirred 30 min at 0° C. The volatiles are removed in vacuo and the residue is partitioned between 1×100 ml 1N sodium hydroxide and 3×25 ml dichloromethane. The combined organics are dried over potassium carbonate and are concentrated in vacuo to a pale yellow solid. The crude material is chromatographed over 60 g silica gel (230-400 mesh), eluting with 40% acetone/hexane, while collecting 9 ml fractions. Fractions 26-45 are combined and concentrated to afford 1.23 g (80%) of 3-(1-hydroxyethyl)-isoquinoline.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:13]=[C:12]([C:14]([Cl:17])([Cl:16])[Cl:15])[CH:11]=[CH:10][N:9]=1.Cl>N1C=CC=CC=1>[C:1]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([Cl:15])([Cl:17])[Cl:16])[CH:11]=[CH:10][N:9]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1cc(C(Cl)(Cl)Cl)ccn1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1cc(C(Cl)(Cl)Cl)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
7.3 ml (0.07 mol) of butyryl chloride were added to 10.6 g (0.05 mol) of 2-amino -4-trichloromethylpyridine and 70 ml of pyridine at 0° C. while cooling with ice. After stirring for three hours at 25° C., the reaction mixture was added to 5% strength hydrochloric acid and this mixture was extracted with ether. 12.7 g (90%) of the product wre obtained from the organic phase. Mp.: 88°-90° C., Active ingredient Example 1.003
Reaction SMILES: C(O)C.[OH:4][C:5]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:6]=1[CH:7]=O.O.Cl.[NH2:16][C@H:17]([C:20]([OH:22])=[O:21])[CH2:18][SH:19].C([O-])(=O)C.[Na+]>O>[OH:4][C:5]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:6]=1[CH:7]1[NH:16][C@H:17]([C:20]([OH:22])=[O:21])[CH2:18][S:19]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=Cc1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CSC(c2ccc(O)cc2O)N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In a mixed solvent including ethanol (10 ml) and water (10 ml), a solution including 2,4-dihydroxybenzaldehyde (943 mg, 6.83 mmol), L-cysteine hydrochloride monohydrate (1.0 g, 5.69 mmol), and sodium acetate (495 mg, 6.03 mmol) was stirred at room temperature for 14 hours. The produced precipitate was filtered, and a filter cake was washed with water, and ethyl acetate to obtain the target product that is a solid white (1.316 g, 95.8%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([OH:11])[CH:5]=1.[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18](O)=O.ClCCl.[OH-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:18]([CH2:17][O:16][C:15]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:14]=3[Cl:13])[O:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(COc3ccc(Cl)cc3Cl)oc2c1
Temperature: 140 °C
Yield: 68.4 %

Procedure:
A mixture of 4-amino-3-hydroxy-benzoic acid methyl ester (210.7 mg, 1.26 mmol) and 2,4-dichlorophenoxy acetic acid (200.0 mg, 0.90 mmol) in PPSE (3 mL) was heated at 140° C. for 2 h. At the end of the reaction period, the mixture was taken to dichloromethane and neutralized with 1 N NaOH solution. The organic layer was separated and the aqueous solution extracted with dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (n-Hexanes:EtoAC:MeOH=6:3:1) to afford 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-6 carboxylic acid methyl ester as a colorless powder (216.7 mg, 68.6% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:20])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]1=2.[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([C:18]1[CH:17]=[CH:16][C:8]2[O:9][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:6]([CH3:20])([CH3:5])[C:7]=2[CH:19]=1)(=[O:23])[CH3:22]
Reactant: CC1(C)c2ccccc2Oc2ncccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc2c(c1)C(C)(C)c1cccnc1O2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.7 %

Procedure:
9.5 g of powdered aluminum chloride is added in small portions to a mixture of 5 g of 5,5-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine and 5.6 g of acetyl chloride, keeping the temperature at 20°-30°C. The mixture is allowed to stand at 80°C for 1.5 hours, and then poured into ice water. The mixture is extracted with benzene, and the extract is washed with water. The benzene is distilled off, and the crystalline residue is recrystallized from isopropyl ether containing a small amount of carbon tetrachloride to give 4 g of 7-acetyl-5,5-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine melting at 106°-108°C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.CC(C)=[O:24]>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([OH:24])=[O:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(CCCCO)cccc1C(=O)c1ccc(F)cc1
Reactant: CC(C)=O
Product: Cc1c(CCCC(=O)O)cccc1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
14 ml of a sulfochromic mixture titrating 26.5 g of chromic anhydride per 100 ml were added over 25 minutes at 10° C to a solution of 3.47 g of 4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butanol in 35 ml of acetone and after returning the mixture to room temperature, the mixture was stirred overnight. The mixture was poured into ice water and vacuum filtered, was washed with water until the wash water was neutral and the precipitate recovered was dried over phosphoric acid and crystallized from cycloxane to obtain 3.02 g of 4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butyric acid in the form of colorless crystals melting at 94° C.
Reaction SMILES: [C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[N:25]=[C:24]([N:26]3[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:11]1)=[O:9].[ClH:46]>C(OCC)(=O)C>[ClH:46].[ClH:46].[C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[N:25]=[C:24]([N:26]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:11]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccccc4-c4ccccc4)C3)nc3ccccc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1-c1ccccc1)N1CC[C@H](Nc2nc(N3CCCNCC3)c3ccccc3n2)C1
Reaction time: 8 h

Procedure:
t-Butyl 4-(2-((S)-1-(2-biphenyl-2-ylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)-[1,4]diazepane-1-carboxylate (0.53 g) synthesized in the same manner as in Example 1 was dissolved in ethyl acetate (3 mL), followed by addition of a solution (2.2 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred overnight. Precipitated solids were collected by filtration and then washed with hexane to obtain 2-biphenyl-2-yl-1-((S)-3-(4-[1,4]diazepan-1-ylquinazolin-2-ylamino)pyrrolidin-1-yl)ethanone dihydrochloride (0.15 g). (2) 2-Biphenyl-2-yl-1-((S)-3-(4-[1,4]diazepan-1-ylquinazolin-2-ylamino)pyrrolidin-1-yl)ethanone di hydrochloride (40 mg) was suspended in chloroform (3 mL), followed by addition of pyridine (12 mg) and acetic anhydride (8.5 mg), and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform/methanol=10:1) to obtain the title compound (compound 1-210) (46 mg). The resulting purification product was dissolved in ethyl acetate (1.0 mL), followed by addition of a solution (0.015 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred to obtain the title compound (compound 1-212) (12 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[N:5]2[CH:24]=1.[CH2:25]=O>C(O)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[N:5]3[C:6]([CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:19])=[O:18])[CH2:25][C:24]=13)=[CH:7][CH:8]=[CH:9]2
Reactant: C=O
Reactant: Cc1cn2c(CNCCCCNS(=O)(=O)C(F)(F)F)cccc2n1
Solvent: CC(=O)O
Product: Cc1nc2cccc3n2c1CN(CCCCNS(=O)(=O)C(F)(F)F)C3
Temperature: 100 °C
Yield: 72 %

Procedure:
In 6 ml of acetic acid was dissolved 2.02 g (5.54 mmol) of 2-methyl-5-[N-[4-(trifluoromethanesulfonamido) butan-1-yl]aminomethyl]imidazo(1,2-a]pyridine. To the solution was added 6.2 ml (83.15 mmol) of a 37% aqueous solution of formalin, and the mixture was heated for 30 minutes at 100° C. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized by the addition of 1N HCl under ice-cooling, which was extracted twice with 100 ml of chloroform. The extract was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to afford 1.45 g of the desired compound (72.0%, colorless liquid).
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C2C(=CC=CC=2)C=CC=1.Cl>N1C=CC=CC=1>[CH3:13][N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4]1
Reactant: Cn1nc(-c2ccccc2)c(Br)c1-c1ccccc1
Reactant: Sc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: Cn1nc(-c2ccccc2)c(Sc2ccccc2)c1-c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-1-methyl-3,5-diphenylpyrazole (21.84 g, 0.07 mole), copper(1)salt of benzenethiol (14.67 g, 0.085 mole), pyridine (10 ml) and quinoline (100 ml) is stirred and heated at 175° C to 185° C (reflux) for 8 hours. The reaction mixture is allowed to stand overnight at room temperature. The mixture is poured into dilute hydrochloride acid and extracted with benzene. The benzene layer is separated and stripped in vacuo to give a brown syrup. The syrup is extracted with a hot mixture of n-hexane and n-heptane and filtered. The cooled filtrate yields a gray colored solid m.p. 109° C to 110° C. Recrystallization from n-hexane affords white crystals 17.35 g (74.5%), m.p. 109° C to 110° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([C:26]([O:28][CH3:29])=[O:27])[C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[NH:11][C@@H:10]([CH:23]2[CH2:25][CH2:24]2)[CH2:9]1.[C:39](Cl)([Cl:41])=[O:40].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1)[CH2:6][N:7]([C:26]([O:28][CH3:29])=[O:27])[C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:11]([C:39]([Cl:41])=[O:40])[C@@H:10]([CH:23]2[CH2:24][CH2:25]2)[CH2:9]1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)Nc2c(Br)cc(C(F)(F)F)cc21
Solvent: Cc1ccccc1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)Cl)c2c(Br)cc(C(F)(F)F)cc21
Reaction time: 24 h

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Example 100C) (1.0 g) in 50 mL of a 20% phosgene in toluene solution was heated to reflux for 24 h. Additional phosgene/toluene (50 ml) was added and heating was continued for an additional 24 h. Excess phosgene was removed by purging with nitrogen. The resulting solution was concentrated to afford the crude title product which was used without further purification. MS m/z 681.5 (M+).