Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[NH:7][C:8](=[O:16])[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:4].C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[NH:7][C:8](=[O:16])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:30]([O:29][CH3:28])[CH:31]=2)[CH2:12][CH2:11]1)=[O:4]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COC(=O)c1ccccc1NC(=O)CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)c(OC)c2)CC1
Reaction time: 1 h

Procedure:
6.5 Grams of o-methoxycarbonyl-α-(1-piperazinyl)acetanilide and 2.4 g of triethylamine were dissolved in 50 ml of methylene chloride, then a methylene chloride solution containing 5.4 g of 3,4-dimethoxybenzoyl chloride was added dropwise thereto under ice-cooled condition with stirring. The reaction was continued at the same temperature for 1 hour, then the reaction mixture was washed with water, 5%-sodium bicarbonate aqueous solution, next with potassium carbonate aqueous solution, and was dried. Methylene chloride was removed by distillation, the residue obtained was crystallized by adding ethyl acetate, the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 7.5 g of o-methoxycarbonyl-α-[4-(3,4-dimethoxy-benzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169° C.
Reaction SMILES: [F:1][C:2]([F:48])([P:44]([OH:47])([OH:46])=[O:45])[C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C:8]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([O:40]C)=[O:39])=[CH:34][CH:33]=2)([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:24])[CH2:9][C:10]2[CH:15]=[CH:14][C:13](OP(C(F)F)(=O)O)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-:49].[Na+]>C1COCC1.CO>[F:1][C:2]([F:48])([P:44]([OH:46])([OH:45])=[O:49])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([OH:40])=[O:39])=[CH:36][CH:37]=2)([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:48])[P:44]([OH:47])([OH:46])=[O:45])=[CH:43][CH:42]=2)[C:23]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:24])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(Cc2ccc(OP(=O)(O)C(F)F)cc2)(Cc2ccc(C(F)(F)P(=O)(O)O)cc2)C(=O)c2ccc(F)cc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(Cc2ccc(C(F)(F)P(=O)(O)O)cc2)(Cc2ccc(C(F)(F)P(=O)(O)O)cc2)C(=O)c2ccc(F)cc2)cc1
Reaction time: 18 h

Procedure:
The compound of Example 10 (0.080 g, 0.112 mmol) was treated with NaOH in THF/MeOH at 60° C. After a period of 18 h, Dowex H+ was added. After a few minutes, the resin was filtered and the solvent evaporated to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:17](I)[CH2:18][CH3:19].Cl>>[CH2:17]([N:12]1[CH2:11][CH2:10][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:14][CH2:13]1)[CH2:18][CH3:19]
Reactant: CCCI
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Agent: Cl
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(3-Trifluoromethyl-phenyl)-piperidine and n-Pr-I: m.p. 195° C. (HCl), MS m/z (rel. intensity, 70 eV) 271 (M+, 4), 243 (16), 242 (bp), 159 (13), 70 (49).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:11]([C:3]1[C:2]([NH:1][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:18]=2)=[O:23])=[CH:7][C:6]([Cl:8])=[C:5]([O:9][CH3:10])[CH:4]=1)(=[O:13])[CH3:12]
Reactant: COc1cc(C(C)=O)c(N)cc1Cl
Reactant: CC(C)c1csc(C(=O)Cl)n1
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1cc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)cc1Cl
Yield: 69 %

Procedure:
N-(6-Acetyl-3-chloro-4-methoxyphenyl)-4-isopropylthiazole-2-carboxamide 217g was synthesized from compounds 201g and 214 as a beige solid in 69% yield, according to the procedure as described for compound 217a. MS (ESI, EI+): m/z=354 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:9]([OH:11])=[O:10])=[CH:6][S:7][CH:8]=1)[CH3:2].S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)Cl>[Cl:15][C:8]1[S:7][CH:6]=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[O:3][CH2:1][CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOc1cscc1C(=O)O
Solvent: ClC(Cl)Cl
Product: CCOc1c(C(=O)O)csc1Cl
Reaction time: 0.5 h

Procedure:
A 15.45 g. portion of 4-ethoxy-3-thiophenecarboxylic acid is suspended in 30 ml. of chloroform. To this is added dropwise 8.1 ml. of sulfuryl chloride with stirring. The mixture is stirred for 30 minutes and the precipitate is collected, giving 5-chloro-4-ethoxy-3-thiophenecarboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:25][NH:26][O:27][CH3:28]>O1CCCC1>[CH3:28][O:27][N:26]([CH3:25])[C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)acetic acid (8.75 g, 0.05 mol) in tetrahydrofuran (150 mL) was added CDI (11.34 g, 0.07 mmol) at 0° C. The formed mixture was stirred for 1 h. Then N,O-dimethylhydroxylamine (6.8 g, 0.07 mol) and TEA (8 mL) were added to the above mixture. The mixture was stirred at rt overnight. When the reaction was over, the mixture was concentrated. The residue was washed with 1 N aq HCl and aq. NaHCO3 (3×). The combined organic phase was concentrated to give crude product, which was used for next step without purification. 1H NMR (400 MHz, CDCl3): δ=1.42 (s, 9H), 3.16 (s, 3H), 3.66 (s, 3H), 4.04 (s, 2H), 5.22 (s, 1H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:37]=[C:36]([CH3:38])[O:35][N:34]=1)[NH2:32]>>[CH3:38][C:36]1[O:35][N:34]=[C:33]([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH:37]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: Cc1cc(C(N)=NO)no1
Product: Cc1cc(-c2noc(C3CC(c4ccc(OC(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)no1

Procedure:
150 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 80 mg (0.56 mmol) of N′-hydroxy-5-methylisoxazole-3-carboximidamide were reacted according to the General Method 2. Yield: 101 mg (54% of theory).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>ClCCl>[C:21]1([CH:18]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9][N:10]4[CH2:20][CH2:19]2)[CH:15]=[C:14]([NH:17][C:30]([NH:29][CH2:27][CH3:28])=[O:31])[CH:13]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCN=C=O
Reactant: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Solvent: ClCCl
Product: CCNC(=O)Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4), (102 mg, 0.30 mmol) in dichloromethane (15 mL) was added ethyl isocyanate (0.026 mL, 0.33 mmol), mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The solvent was removed under reduced pressure and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 15 to 20% EtOAc:Hexane to get 1-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)-3-ethylurea (484) (120 mg 97%). 1H NMR (300 MHz, CDCl3) δ ppm 0.91 (t, J=7.18 Hz, 3H) 2.05-2.20 (m, 2H) 2.21-2.39 (m, 2H) 2.96-3.28 (m, 6H) 4.07-4.19 (m, 2H) 4.35 (br. s., 1H) 5.58 (s, 1H) 6.43 (s, 2H) 7.06-7.36 (m, 10H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]3[N:18]([N:28]=[C:29]([C:31]([NH2:33])=O)[CH:30]=3)[C:19](=[O:27])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:16][C:17]3[N:18]([N:28]=[C:29]([C:31]#[N:33])[CH:30]=3)[C:19](=[O:27])[C:20]=2[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#Cc1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Reaction time: 2.5 h
Yield: 14.1 %

Procedure:
To a mixture of 22 mg (0.05 mmol) of 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid amide in 1 mL of dichloromethane (DCM) was added 0.04 mL (0.3 mmol) of triethylamine (Et3N), and the resulting mixture was cooled in an ice bath. Then 0.021 mL (0.15 mmol) of trifluoroacetic anhydride ((CF3CO)2O) was added during which time the mixture became homogeneous, and was stirred for 2.5 h. The reaction mixture was quenched by the addition of water, and concentrated to a residue which was purified via reverse-phase chromatography to afford (after lyophilization) 3 mg (14% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carbonitrile as indicated by LC-MS calcd for C26H24N4O2 [M++H]+: 425.19, found: 425.2.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH3:14][C:15]([NH2:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].Cl>O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:22][C:15]([CH3:21])([CH3:14])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: CC(C)(C)CC(C)(C)N
Agent: Cl
Solvent: O
Product: CC(C)(C)CC(C)(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 30.4 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g, 1.95 mm0l) in 1,1,3,3-tetramethylbutylamine (5 ml, 31 mmol) was stirred for 44 h at 120° C. in a sealed flask. Water (25 ml) was added to the cooled solution and pH was adjusted to <2 by the addition of 4M hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water, and then redissolved in 1N sodium hydroxide (15 ml) at 50-60° C. followed by treatment with decolorising charcoal. After filtration, the clear solution was acidified to pH 2 by the addition of 4M hydrochloric acid and the precipitate was filtered off and recrystallised from methanol to give 207 mg (31%) of the pure title compound; mp 369-371° C. dec; 1H-NMR (DMSO-d6): δ0.98 (s, 9H), 1.42 (s, 6H), 1,86 (s, 2H), 6.75 (br s, 1H), 7,12 (s, 1H), 10.55 (s, 1H); MS: m/e 349/351 (M+); (C13H20N3Cl1O2S2) calc. C, 44.63; H, 5.76; N, 12.01; found C, 44.74; H, 5.78; N, 11.84.
Reaction SMILES: O=P(Cl)(Cl)Cl.C1(N(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([N:31]([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN([CH:51]=[O:52])C>>[CH:51]([C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]([N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:39][CH:40]=1)=[O:52]
Reactant: CN(C)C=O
Reactant: c1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Agent: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)c2ccccc12
Yield: 39.7 %

Procedure:
The method of Example 4, Stage 1, was followed except that there was used 4.7 g of POCl3, 13.6 g of DMF, and in place of triphenylamine there was used N,N-diphenyl-1-naphthylamine (MW 295, 0.031M, 9.2 g) to give 4 g (40% yield) of 1-formyl-4-(N,N-diphenylamino) naphthalene as a yellow solid, m.p. 107°-110° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][NH:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.Cl[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][N:9]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: CC(C)c1c[nH]c2nc(N)nc(Cl)c12
Reactant: COc1c(C)cnc(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2cc(C(C)C)c3c(Cl)nc(N)nc32)c1C
Temperature: 45 °C
Yield: 20 %

Procedure:
A suspension of 4-chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (105 mg, 0.5 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (93 mg, 0.5 mmol) and K2CO3 (85 mg, 0.6 mmol) in dry DMF (1 mL) was heated to 45° C. overnight, Work-up (EtOAc), evaporation, and purification by preparative TLC (MeOH/CH2Cl2 10:1) gave 4-chloro-5-isopropyl-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (36 mg). HPLC Rt: 5.867 min. 1H-NMR (DMSO-d6): δ 8.07 (s, 1H), 6.74(s, 1H), 6.51 (s, 2H), 5.22 (s, 2H), 3.70 0s, 3H), 3.23 (7, 1H), 2.21 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11](O)(=[O:16])[CH2:12][CH:13]=[CH:14][CH3:15]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:9][CH3:10])[C:11](=[O:16])[CH2:12][CH:13]2[CH2:14][CH3:15]
Reactant: CC=CCC(=O)O
Reactant: COc1ccccc1OC
Product: CCC1CC(=O)c2cc(OC)c(OC)cc21
Temperature: 60 °C

Procedure:
A mixture of 1,2-dimethoxy-benzene (Compound 47a) (21.9 mL, 0.170 mole) and pent-3-enoic acid (Compound 47b) (25.5 g, 0.255 mole) was stirred under argon in an ice bath. Polyphosphoric acid (230 g, 1.05 mole) was added slowly. After addition was complete, the ice bath was removed and the reaction heated for 16 hours at 60° C. The reaction was added to ice water and extracted with dichloromethane. The organic extracts were washed with 3N NaOH, water, brine and dried over Na2SO4. The solvent was then removed in vacuo to yield a red oil containing the crude title compound. The crude material was purified on a silica gel column using dichloromethane as eluent. The pure fractions were combined and concentrated to yield the racemic mixture of the title compound as an off-white solid. MS m/z 221 (M+H)+;
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)=[CH:28][CH:27]=1)([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:10][CH:9]=1)[CH3:7])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:28][CH:27]=2)([CH3:7])[CH2:5][CH2:4][OH:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(C)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a 0° C. solution in THF (40 mL) of 3,3-bis(4-(2-quinolylmethoxy)phenyl)butanoic acid ethyl ester (3.2 g, 5.5 mmol), prepared as in Example 13, was added slowly a solution of LiAlH4 (1.0M, 6 mL, 6.0 mmol). The mixture was stirred for 2 hours and water (15 mL) was added slowly followed by aqueous 1N NaOH. The reaction mixture was diluted with THF (20 mL) and the mixture was filtered through a celite pad. The filtrate was extracted with ether and the organic extract was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 3,3-bis(4-(2-quinolylmethoxy)phenyl)butan-1-ol (2.4 g) as a pale yellow foam.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:23])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([OH:22])=O)[N:19]=2)[C:7]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(=[O:3])[CH3:2].[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.ClCCl>O>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:23])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([NH:47][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:22])[N:19]=2)[C:7]=1[C:24]([O:26][CH:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C(=O)O)cs3)[C@H]2SC1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C(=O)NCc4ccccc4)cs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 176 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(4-carboxy-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 33.3 mg of benzylamine, 79 mg of 2-ethoxy-1(2H)-quinolinecarboxylic acid, ethyl ester and 3 ml of dichloromethane was stirred at room temperature for 1 hour, then added to water and extracted with dichloromethane. The dichloromethane extract was evaporated, giving the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O.C(OCC)(=O)C>CO.CCCCCC.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccncc1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: Cc1ccncc1Nc1ccccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
10% Pd/C (100 mg) was charged portion wise to a solution of (4-methyl-pyridin-3-yl)-(2-nitro-phenyl)-amine (I-171a: 600 mg, 2.62 mmol) in methanol (15 mL) under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction was monitored by TLC (80% ethyl acetate in hexane). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 525 mg of the product (98.91% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH:22](OC)OC)[CH3:21]>CCOC(C)=O>[CH3:19][N:20](/[CH:22]=[C:10]1\[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2](/[N:1]=[CH:19]\[N:20]([CH3:22])[CH3:21])=[CH:7][CH:6]=2)[C:17]2[C:12]([C:11]\1=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:21]
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc(C2CCC(=O)c3ccccc32)cc1
Solvent: CCOC(C)=O
Product: CN(C)/C=N\c1ccc(C2C/C(=C\N(C)C)C(=O)c3ccccc32)cc1
Yield: 98 %

Procedure:
A mixture of 4-(4-aminophenyl)-3,4-dihydronaphthalen-1(2H)-one (6.0 g, 25.3 mmol) and DMF-DMA (60 mls, 10 vols) was heated at 100 C for 12 h. The reaction mixture was stripped and residue stirred in EtOAc at rt for 1 h. The resulting solids were then filtered and rinsed on the filter with water. After drying, the product was afforded as a yellow solid (8.6 g, 98%). LCMS m/e 348 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([OH:26])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([Cl:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
That is, 2,4-dihydroxybenzaldehyde [IV] is benzylated with benzyl chloride to produce 2,4-dibenzyloxybenzaldehyde [V], then [V] is reduced with sodium borohydride to produce 2,4-dibenzyloxybenzyl alcohol [VI] and then, [VI] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxybenzyl chloride [VII]. Then, [VII] is allowed to react with sodium cyanide to obtain 2,4-dibenzyloxyphenyl acetonitrile [VIII], thereafter [VIII] is hydrolyzed with an alkali to produce 2,4-dibenzyloxyphenylacetic acid [IX], then this [IX] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxyphenylacetyl chloride [X] and further, this [X] is allowed to react with L-asparagine or glutamine p-nitrophenyl ester to obtain [IIa].
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].[Br:14]Br>>[CH:1]([C:4]1[NH:5][C:6]2[C:12]([Br:14])=[C:11]([NH2:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)c1nc2ccc(N)cc2[nH]1
Product: CC(C)c1nc2ccc(N)c(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 0.95 g (5.4 mmol) of 2-isopropyl-5-aminobenzimidazole in 50 ml of ACOH was added 0.19 ml (3.7 mmol) of Br2 dropwise and resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (5% MeOH/EtOAC) to yield 0.89 g (3.5 mmol, 95%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:41])[CH:5]=[C:6]([O:39][CH3:40])[C:7](=[O:38])[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:30](=[O:31])[C:29]([O:32][CH3:33])=[C:28]([CH3:34])[C:27](=[O:35])[C:26]=1[O:36][CH3:37].ClC1C=C(C=CC=1)C(O)=[O:47]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:41])[CH:5]=[C:6]([O:39][CH3:40])[C:7](=[O:38])[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[O:47][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:30](=[O:31])[C:29]([O:32][CH3:33])=[C:28]([CH3:34])[C:27](=[O:35])[C:26]=1[O:36][CH3:37]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COC1=CC(=O)C(OC)=C(CCCCCCC/C=C\CCCCCCCC2=C(OC)C(=O)C(C)=C(OC)C2=O)C1=O
Solvent: ClCCl
Product: COC1=CC(=O)C(OC)=C(CCCCCCCC2OC2CCCCCCCC2=C(OC)C(=O)C(C)=C(OC)C2=O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25 Milligrams of 1-(2,5-dimethoxy-1,4-benzoquinon-3-yl)-16-(2,5-dimethoxy-6-methyl-1,4-benzoquinon-3-yl)-Z-8-hexadecene was dissolved in 2 ml of methylene chloride, then to this solution was added 30 mg of m-chlorobenzoic acid and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed the solvent was removed by evaporation under reduced pressure, then the residue obtained was purified by means of a preparative thin layer chromatography [adsorbent: "Silica gel F254 " manufactured by E. Merck A. G., developing solvent: benzene-ethyl acetate (5:1 mixture by volume/volume)] to obtain 9 mg of 1-(2,5-dimethoxy-1,4-benzoquinon-3-yl)-16-(2,5-dimethoxy-6-methyl-1,4-benzoquinon-3-yl)-8,9-epoxyhexadecane. Yellow oily substance.