Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[C:20]1([CH3:33])[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[C:29]([CH:31]=O)[N:30]=2)=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:31][C:29]3[N:30]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([CH3:33])=[CH:21][CH:22]=4)[S:27][CH:28]=3)[C:5](=[O:7])[CH:4]([CH3:9])[CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Reactant: Cc1ccc(-c2nc(C=O)cs2)cc1
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1csc(-c2ccc(C)cc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with commercially available 2-(p-tolyl)thiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 423.98 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([OH:18])=[CH:7][C:6]=1[N:5]2[CH3:19].Cl[C:21]1C=C2C(=CC=1)C(=O)C1C(O)=CC(O)=CC=1N2.C(=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([O:18][CH3:21])=[CH:7][C:6]=1[N:5]2[CH3:19]
Reactant: O=c1c2ccc(Cl)cc2[nH]c2cc(O)cc(O)c12
Reactant: Cn1c2cc(Cl)ccc2c(=O)c2c(O)cc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(O)c2c(=O)c3ccc(Cl)cc3n(C)c2c1
Yield: 65 %

Procedure:
A method analogous to Method E-6, applied to 6-chloro-1,3-dihydroxy-10-methyl-10H-acridin-9-one, 18 (52 g, 0.2 mol), dry acetone (1.75 L), potassium carbonate (80 g, 0.58 mol) and iodomethane (175 ml, 0.74 mol) added for 3 hrs reflux gave complete reaction, work-up and recrystallisation gave the title compound (37 g, 0.13 moles, 65%).
Reaction SMILES: C([O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7])(=O)C.S[C:13]1[CH:18]=CN=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:6]([Si:5]([O:4][Si:5]([CH2:6][CH3:7])([CH2:8][CH3:9])[CH2:10][CH3:11])([CH2:18][CH3:13])[CH2:8][CH3:9])[CH3:7]
Reactant: Sc1ccncc1
Reactant: CC[Si](CC)(CC)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC[Si](CC)(CC)O[Si](CC)(CC)CC
Yield: 71 %

Procedure:
This solution of chloride (4) is mixed with 4-mercaptopyridine (2.45 g; 1.3 equivalents) and sodium carbonate (1.8 g; 1 equivalents) and concentrated in vacuum. The residue is dissolved in toluene, filtered to remove solid, and extracted with toluene. This is extracted with 2N-hydrochloric acid, mixed with sodium hydrogen carbonate, reextracted with toluene, and worked up as usual to give 4-pyridylsulfide (7) (7.87 g). Yield: 71%. IR (CHCl3)ν: 3100-2900, 1735, 1707, 1610, 1430 cm-1.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>C1CCCCC1.C(OCC)(=O)C>[CH3:33][O:32][C:28](=[O:31])/[CH:29]=[CH:30]/[C:2]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1
Reactant: C=CC(=O)OC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C#N)cc2)CC1

Procedure:
Prepared in analogy to example 139 from 4-[4-(2-Iodo-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile (Example AG) and methyl acrylate. Chromatography (SiO2; cyclohexane/ethyl acetate 3:7) yields the title compound as a slightly yellow solid (M+H+: 454.3)
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:28]([NH:27][C:22]1[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=1)=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N=C1CCCN1Cc1ccccc1
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Agent: F[B-](F)(F)F
Product: O=C(N=C1CCCN1Cc1ccccc1)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g.; 0.025 mole) is converted to the free base (4.36 g.; 0.025 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 4.29 g. (0.025 mole) of 3-chloro-4-fluorophenyl-isocyanate is added. The reaction mixture is stirred at room temperature for 1 hour and then evaporated to dryness in vacuo to give a solid residue. Recrystallizations from acetone-ether yields the pure product, 1-(1-benzyl-2-pyrrolidylidene)- 3-(3-chloro-4-fluorophenyl)urea, m.p. = 131°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:25]2[NH:26][C:27]([CH2:30][C:31]([O-:33])=[O:32])=[N:28][N:29]=2)[CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7](=[O:8])[NH:22][C:21]1[CH:20]=[CH:19][C:18]([C:25]2[NH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[N:28][N:29]=2)=[CH:17][C:16]=1[O:15][CH3:14])=[O:5]
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Reactant: COc1cc(-c2nnc(CC(=O)[O-])[nH]2)ccc1[N+](=O)[O-]
Solvent: CC#N
Product: COc1cc(-c2nnc(CC(=O)O)[nH]2)ccc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of equivalent amounts of 2-chloro-4-fluorobenzoyl isocyanate in acetonitrile was added dropwise to the solution of 89 mg of [5-(3-methoxy-4-nitrophenyl)-4H-[1,2,4]triazol-3-yl]acetate in 5 ml of acetonitrile and the mixture was stirred at room temperature overnight. The solid formed was then filtered off with suction and dried under reduced pressure.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH2:2][NH:1][C:29]2[N:28]=[C:27]([O:26][CH3:25])[CH:32]=[CH:31][N:30]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: COc1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(NC[C@H]2[C@@H](C)CCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)n1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 4-methoxy-2-chloropyrimidine, and DIPEA in isopropanol was stirred at 110° C. for 18 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 456.02 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OO)(=[O:21])C>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([OH:21])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: COc1cc(O)ccc1OCc1ccccc1
Reaction time: 18 h

Procedure:
24.2 g of 4-benzyloxy-3-methoxy benzaldehyde (Beilst. Vol. 8, II p 283) were dissolved in 100 ml of acetic acid and a mixture of 25 ml of peracetic acid and 50 ml of acetic acid was added without exceeding 45° C. The mixture was stirred for 18 hours at +40° C. and after concentration to dryness, the residue was chromatographed on silica (eluant: hexane-ethyl acetate 8-2) to obtain 9.1 g of the expected product melting at 84° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:7][CH:6]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]([OH:13])[CH2:12][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][CH2:25][NH:24][C:23]3=[O:28])[CH2:18][CH2:17]2)=[CH:7][CH:6]=1
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: COCCc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: COCCc1ccc(OCC(O)CN2CCC(N3CCCNC3=O)CC2)cc1

Procedure:
A solution of 10.4 g of 1-[p-(2-methoxyethyl)-phenoxy]-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 7 ml of abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from ethyl acetate/petroleum ether to yield the 1-[3-(p-(2-methoxyethyl)-phenoxy)-2-hydroxypropyl]4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].[N+](=[CH2:21])=[N-]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([C:7]1[C:12]([C:13]([O:15][CH3:21])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(Cl)c1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccnc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Chlorobenzoyl)-3-carboxypyridine was dissolved in a solution of 10% methanol and methylene chloride. Diazomethane was added and the solution was stirred for 1 hour at room temperature. The solution was extracted with methylene chloride followed by methylene chloride +1% methanol The desired product was combined from recrystallization (ethyl ether/hexane) and from the filtrate to yield 1.23 g of 2-(3-chlorobenzoyl)-3-methoxycarbonyl-pyridine.
Reaction SMILES: COCCN[S](F)(F)([F:12])NCCOC.[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][C@H:31]([CH2:33][N:34]3[CH:38]=[C:37]([CH2:39]O)[N:36]=[N:35]3)[O:30][C:29]2=[O:41])[CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][C@H:31]([CH2:33][N:34]3[CH:38]=[C:37]([CH2:39][F:12])[N:36]=[N:35]3)[O:30][C:29]2=[O:41])[CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: Cc1cn(-c2ccc(N3C[C@H](Cn4cc(CO)nn4)OC3=O)cc2F)cn1
Reactant: COCCN[S](F)(F)(F)NCCOC
Solvent: ClCCl
Product: Cc1cn(-c2ccc(N3C[C@H](Cn4cc(CF)nn4)OC3=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 16 %

Procedure:
Bis[(2-methoxyethyl)amino]sulfur trifluoride (150 μl, 0.81 mmol) was added to a solution of (5R)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-5-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-ylmethyl]-1,3-oxazolidin-2-one (Example 48) (222 mg, 0.60 mmol) in dichloromethane (2 ml) at −78° C. The reaction mixture was allowed to gradually warm to room temperature. After 20 hours, the reaction mixture was heated to 40° C. for 3 hours before cooling to room temperature and quenching with methanol. Chromatography on silica gel with 7.5% methanol in dichloromethane gave 36 mg of product.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Na].[C:8](OCC)(=[O:17])[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=O.C(O)(=O)C>O>[CH2:15]([O:14][C:12]([C:10]1[C:6]2[CH:5]=[N:4][NH:3][C:2]=2[N:1]=[C:8]([OH:17])[CH:9]=1)=[O:13])[CH3:16]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(O)nc2[nH]ncc12
Temperature: 85 °C
Yield: 28.4 %

Procedure:
To a solution of 3-aminopyrazole (224 g, 2.7 mol) in water (1 L) were added a solution of diethyl oxalacetate sodium salt (567 g, 2.7 mol) in water (1.3 L) and then acetic acid in 4 portions (0.8 L). The reaction mixture was heated at 85° C. for 15 hours then cooled to room temperature and filtered. The precipitate was washed with water and then dried to afford the title compound as an orange solid (159 g, 28%). 1H NMR (250 MHz, DMSO): δ 1.35 (t, 3H), 4.36 (q, 2H), 6.69 (s, 1H), 8.16 (s, 1H).
Reaction SMILES: [NH3:1].[C:2]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19]C(=O)C)[CH:15]([C:23](Cl)=[O:24])[CH2:14][CH2:13]2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C=CC=CC=1>[C:2]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[OH:19])[CH:15]([C:23]([NH2:1])=[O:24])[CH2:14][CH2:13]2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: CC(=O)Oc1cc2c(cc1C(=O)c1ccccc1)CCC2C(=O)Cl
Solvent: c1ccccc1
Product: NC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
Dry ammonia is passed into a solution of 27 g of crude 5-benzoyl-6-acetoxy-indane-1-carboxylic acid chloride in 200 ml of anhydrous benzene at a temperature of 15°-20° C, with exclusion of moisture, until saturation is reached. The reaction solution is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 200 ml of water and 3 times 200 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Fractional crystallisation of the evaporation residue from hot dimethylformamide-water gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid amide of melting point 205°-207° C. The starting material can be obtained as follows. A solution of 20 g of 5-benzoyl-6-hydroxy-indane-1-carboxylic acid in 200 ml of acetic anhydride is heated to the reflux temperature for 4 hours. It is then evaporated to dryness in vacuo, 50 ml of toluene are added to the evaporation residue and the mixture is evaporated to dryness. This procedure is repeated twice more. The crude 5-benzoyl-6-acetoxy-indane-1-carboxylic acid thus obtained is used directly for further conversion.
Reaction SMILES: [OH:1][C:2]1([CH3:25])[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[ClH:26].[CH3:24][C@H:4]1[C:5]2[C:10]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[N:9][CH:8]=[N:7][C:6]=2[C:2]([CH3:25])([OH:1])[CH2:3]1
Reactant: C[C@@H]1CC(C)(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CC(C)(O)c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (28 mg, 0.080 mmol) in DCM (6 mL) was added to a 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol). The mixture was stirred at room temperature for 4 hours. A 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol) from a different bottle was added. The resulting mixture was stirred for 18 hours. The solvents were removed in vacuo to give (5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride. DIPEA (41.5 mg, 0.321 mmol) was added to a suspension of this (5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (25.8 mg, 0.0803 mmol), 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (32.9 mg, 0.0964 mmol), and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (36.6 mg, 0.0964 mmol) in CH2Cl2 (6 mL) at room temperature. The resulting mixture was stirred for 1 hour. The solvent was removed in vacuo. The residue was purified by a silica cartridge (5.0 g) eluted by EtOAc to give tert-butyl 2-(4-chlorophenyl)-3-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (46 mg, 100%) as a gel. LCMS (APCI+) [M−Boc+H] +472.2; Rt: 3.51 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[H-].[Na+].I[CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH2:31]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)[CH2:32][CH2:33][CH3:34]
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 28.2 %

Procedure:
In the manner of Example 25, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.98 g), 60% sodium hydride in oil (0.30 g), dimethylformamide (25 ml), and 1-iodobutane (0.60 g), the title compound (0.32 g) was obtained as a crystalline solid, m.p. 122-123° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([C:22]([OH:24])=[O:23])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:25][CH:26]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:27][C@H:28]([CH3:40])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:25][CH:26]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:27][C@H:28]([CH3:40])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([O:23][C:22]([C:12]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=2)=[O:24])=[CH:37][CH:38]=1
Reactant: CCCCC(Cl)C[C@H](C)CCCOc1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)Oc2ccc(OCCC[C@@H](C)CC(Cl)CCCC)cc2)c1

Procedure:
0.65 g of 4-n-octoxybiphenylcarboxylic acid, 0.60 g of (R)-4-(6'-chloro-4'-methyldecyloxy)phenol, 0.04 g of N,N'-dicyclohexyl carbodiimide and 20 ml of dichloromethane were stirred for 3 hours at room temperature.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[CH3:22].[OH-].[K+].Cl>CO.O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])/[CH:20]=[CH:1]/[C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])=[CH:15][C:14]=1[CH3:22]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)/C=C/c2cccc(C(=O)O)c2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
3-Formylbenzoic acid (15.0 g, 0.1 mol, Aldrich) and 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol, Indofine) was dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (28.0 g, 0.5 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, filtered, washed with water (200 mL), methanol (100 mL) and dried in the air. 19 g (67%) of a solid was obtained as the desired (E)-3-(3-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)phenoxy)acetic acid. 1H NMR (400 MHz, DMSO-d6): 13.18 (br, 1H), 10.39 (s, 1H), 8.38 (s, 1H), 8.15 (m, 1H), 7.95 (m, 4H), 7.75 (d, 1H), 7.60 (m, 1H), 6.95 (d, 1H), 2.20 (s, 3H). MS (EI) for C17H14O4: 283 (MH+).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[CH:11]2[CH:7]([CH2:8][NH:9][CH2:10]2)[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])([OH:12])[CH2:5][CH2:4]1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32](O)=[O:33])=[CH:23]1>>[CH3:2][C:3]1([CH3:21])[CH:11]2[CH:7]([CH2:8][N:9]([C:32](=[O:33])[CH2:31][C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][CH:23]=3)[CH2:10]2)[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])([OH:12])[CH2:5][CH2:4]1
Reactant: COc1ccccc1C1(O)CCC(C)(C)C2CNCC21
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: Cl
Product: COc1ccccc1C1(O)CCC(C)(C)C2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Yield: 20.4 %

Procedure:
By working according to the experimental procedure of Example 6, from 0.6 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol hydrochloride and 0.4 g of 3-indoleacetic acid, and after purification on a column of silica gel (particle size 0.04-0.06 mm, diameter 2.4 cm, height 15 cm), 0.17 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-(3-indolylacetyl)-4-perhydroisoindolol is obtained, in the form of a white foam.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:21]O>>[NH2:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=1)[CH2:3][C:4]([O:6][CH3:21])=[O:5]
Reactant: CO
Reactant: NC(CC(=O)O)c1ccc2c(c1)OCCO2
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Amino-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propionic acid [synthesis according to instructions known from the literature (e.g., L. Lázár, T. Martinek, G. Bernáth, F. Fülöp, Synth. Comm. 1998, 28, 219-224)]is introduced into a vessel in methanol (about 0.5 to 1.0 mol/l) and admixed dropwise at 0° C. with 1.2 eq of thionyl chloride. When the addition has been made the reaction mixture is stirred at room temperature overnight and subsequently concentrated. The residue is dissolved in a little methanol and the product is precipitated with diethyl ether. The solid is filtered off with suction, washed repeatedly with diethyl ether and dried under reduced pressure.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=O)[C:3](=[O:9])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[NH:19]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([CH3:31])[N:22]=1)[NH2:20].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:31][C:23]1[N:22]=[C:21]([NH:19][NH:20][C:16]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[C:2](=[O:1])[C:3](=[O:9])[C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)=[O:18])[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=1
Reactant: O=C(C(=O)N1CCCCC1C(=O)O)c1cccs1
Reactant: Cc1cc(C(F)(F)F)cc(NN)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)cc(NNC(=O)C2CCCCN2C(=O)C(=O)c2cccs2)n1

Procedure:
From Intermediate 3 (267 mg, 1 mmol), 2-hydrazino-6-methyl-4-trifluoromethylpyridine (191 mg, 1 mmol), PyBrop (466 mg, 1 mmol), DMAP (122 mg) and DIEA (2 mL) in THF (30 mL), using the same procedure for Compound 1, the title compound was obtained as a white solid; 110 mg (25%). MS (m/z) 441 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[C:11]([N+:31]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:31][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:23][CH2:24]1)=[O:18]
Reactant: COc1cc(C(=O)N2CCN(c3ccccn3)CC2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCN(c3ccccn3)CC2)c(N)cc1OCc1ccccc1
Yield: 139.9 %

Procedure:
[4-(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(2-pyridyl)piperazino]methanone (7b) (500 mg, 1.11 mmol) was dissolved in methanol (10 mL), SnCl2.2H2O (753 mg, 3.3 mmol) was added and refluxed until the TLC indicated the completion of the reaction. The methanol was evaporated by vacuum and the aqueous layer was then adjusted to pH 8 with 10% NaHCO3 solution and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude (450 mg, 95% yield), This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product 8b (650 mg, in 94% yield). 1H NMR (CDCl3) δ 3.15-3.30 (m, 4H), 3.70-3.80 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 6.20 (s, br,) 7.00-7.50 (m, 5H), 7.70 (s, 1H), 8.25-8.35 (d, J=9.05, 2H); FABMS: 418 (M+H)+.