Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]2[C:24](O)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].ClC1C=CC=C[NH+]=1.C(N(CC)CC)C.[NH2:42][CH2:43][CH:44]([OH:51])[CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48]>C(Cl)Cl>[CH2:47]([N:46]([CH2:45][CH:44]([OH:51])[CH2:43][NH:42][C:24]([C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[C:10]([C:9]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:25])[CH2:49][CH3:50])[CH3:48]
Reactant: CCN(CC)CC(O)CN
Reactant: O=C(O)c1c(OCc2ccccc2)c2ccccc2n1-c1ccccc1
Agent: Clc1cccc[nH+]1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CC(O)CNC(=O)c1c(OCc2ccccc2)c2ccccc2n1-c1ccccc1

Procedure:
10.5 g of N-phenyl-3-benzyloxyindole-2-carboxylic acid are reacted with 4.5 g of 2-chloro-N-pyridinium iodide, 4.2 ml of triethylamine and 2.5 g of 1-amino-2-hydroxy-3-diethylaminopropane in 45 ml of methylene chloride at room temperature, After 14 h, the reaction mixture is washed with a saturated solution of sodium chloride and with a 10% sodium carbonate solution, dried over sodium sulfate, filtered and evaporated. The residue is dissolved in dilute hydrochloric acid/ether and the ether phase separated. The aqueous phase is made alkaline and extracted with ether. The ether extract is washed with water, dried over sodium sulfate and evporated. The raw 2-[3-N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-benzyloxy-1-phenylindole is recrystallized from isopropanol/ether. Melting point: 80°-81° C.
Reaction SMILES: [CH2:1]([O:19][C:20]1[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[C:32]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH:31]=[CH:30][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[BH4-].[Na+].Cl>C(Cl)(Cl)Cl.CO>[CH2:1]([O:19][C:20]1[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[C:32]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH:31]=[CH:30][C:21]=1[CH:22]([OH:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(O)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 45 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
2,3,4-Tris(octadecyloxy)benzophenone (3.00 g, 3.04 mmol) was dissolved in a mixed solvent of chloroform (30 mL) and methanol (10 mL), sodium borohydride (360 mg, 9.51 mmol) was added, and the mixture was stirred at 45° C. for 2 hr. After completion of the reaction, 0.1 mol/L aqueous hydrochloric acid was added dropwise to decompose unreacted sodium borohydride and the mixture was washed with 1.0 mol/L aqueous hydrochloric acid. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Methanol was added to the concentrated solution, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (2.98 g, 99.0%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].O.[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14])[CH3:17]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: CCc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccccc1-c1ccc(C(=O)OC)cc1COC
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate, (Intermediate 28, step 2) (12 g, 0.0463 mol) in toluene (150 mL) and water (35 mL) under N2, was added 2-ethyl benzene boronic acid (9.02 g, 0.0601 mol) followed by potassium carbonate (19 g, 0.1389 mol) and Pd(PPh3)4 (2.67 g, 0.0023 mol). The reaction mixture was degassed with N2 for 10 min before heating. After 12 hours at 100° C., the reaction mixture was diluted with EtOAc. The organic layer was washed with sodium bicarbonate sat. solution (1×100 mL), water (2×100 mL) and finally with brine (1×100 mL). It was then dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 60-120 mesh, eluting with pet ether/EtOAc) to afford the title compound as a pale yellow liquid (12 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 8.24-8.26 (1H, s), 7.99-8.01 (1H, d), 7.32-7.38 (2H, m), 7.22-7.27 (2H, m), 7.07-7.09 (1H, d), 4.12-4.21 (2H, d), 3.93-3.95 (3H, s), 3.28-3.30 (3H, s), 2.28-2.43 (2H, m), 1.01-1.05 (3H, t).
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH2:5][S:6][C@@H:7]2[C@H:14]([NH:15][C:16](=[O:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:13](=[O:24])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11].Cl.[CH3:28][O:29][NH2:30]>O1CCCC1.O>[CH3:28][O:29][N:30]=[CH:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:14]([NH:15][C:16](=[O:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:13](=[O:24])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CON
Reactant: COC(OC)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CON=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 10 h
Yield: 83.8 %

Procedure:
To a solution of 3-dimethoxymethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (76 mg) in tetrahydrofuran (4 ml) is added a solution of O-methylhydroxylamine hydrochloride (23 mg) in water (1 ml), and the mixture is kept at room temperature for 10 hours. The reaction mixture is evaporated to remove tetrahydrofuran, and the separated solid material is collected by filtration. Recrystallization of the solid from a mixture of ethyl acetate and ether gives 3-methoxyiminomethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (61 mg). m.p. 186°-189° C. Yield: 80%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C@H:13]1[CH2:19][N:18]2[C:20]([CH2:23][CH2:24][OH:25])=[CH:21][N:22]=[C:17]2[C@H:16]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:15][CH2:14]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:25][CH2:24][CH2:23][C:20]1[N:18]2[CH2:19][C@H:13]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([F:12])[C:6]=3[F:5])[CH2:14][CH2:15][C@@H:16]([NH:26][C:27]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:33])[C:17]2=[N:22][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CCO)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
Acetyl chloride (24 μL, 0.344 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (70 mg, 0.172 mmol) and triethylamine (48 μL, 0.344 mmol) in dichloromethane (6 mL) at 0° C. After 1.5 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (64 mg). MS 450.2 (M+1).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1>[C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][C:44](=[O:46])[CH3:45])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
A mixture of 0.312 g of 3ξ-hydroxy-7β-phenylacetylamino-cepham-4ξ-carboxylic acid diphenylmethyl ester in 15 ml of pyridine and 7 ml of acetic anhydride is left to stand for 16 hours at 0° C. and after addition of 50 ml of toluene is evaporated under reduced pressure. The residue is taken up in ethyl acetate; the organic solution is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by means of preparative thin layer chromatography; a silica gel plate of 100 cm length is used and development is carried out with a 1:1 mixture of toluene and ethyl acetate. 3ξ-Acetoxy-7β-phenylacetylaminocepham-4α-carboxylic acid diphenylmethyl ester of Rf=0.47 is obtained, melting at 162-164° C. after crystallisation from a mixture of methylene chloride and pentane; [α]D20 =+55°±1° (c=0.492 in chloroform); ultraviolet absorption spectrum (in 95% strength ethanol): λmax =253 mμ (ε=700), 258 mμ (ε=820) and 265 mμ (ε=660): infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96μ, 5.66μ, 5.77μ, 5.97μ, 6.28μ and 6.71μ.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH2:14][C:15]1[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[C:18]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH2:37])[CH2:31][CH2:30]2)=[O:27])=[CH:17][C:16]=1[Cl:38].[O-2].[Ca+2]>CN(C)C(=O)C>[NH2:14][C:15]1[C:20]2[CH2:21][C:22]([CH3:24])([CH3:25])[O:23][C:19]=2[C:18]([C:26]([NH:28][CH:29]2[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][NH:37][C:2]3[N:11]=[C:10]([OH:12])[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=4)[N:3]=3)[CH2:33][CH2:34]2)=[O:27])=[CH:17][C:16]=1[Cl:38]
Reactant: Oc1nc(Cl)nc2ccc(Cl)cc12
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)NC3CCN(CCN)CC3)c2O1
Agent: [Ca+2]
Agent: [O-2]
Solvent: CC(=O)N(C)C
Product: CC1(C)Cc2c(N)c(Cl)cc(C(=O)NC3CCN(CCNc4nc(O)c5cc(Cl)ccc5n4)CC3)c2O1
Temperature: 140 °C
Reaction time: 3 h
Yield: 18.2 %

Procedure:
A mixture of 2.6 g of 2,6-dichloro-4-quinazolinol (described in J.Med.Chem., 1968, p.130), 3.7 g of 4-amino-N-[1-(2-aminoethyl)-4-piperidinyl]-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxamide (described in EP-0, 445, 862), 0.8 g of calcium oxide and 5.64 g of N,N-dimethylacetamide was stirred for 3 hours at 140° C. After cooling, the reaction mixture was evaporated and the residue was taken up in a mixture of dichloromethane and methanol. The whole was washed with water. The partly precipitated product was filtered off (first fraction). The organic layer was decanted, dried, filtered and evaporated (second fraction). The combined fractions were purified twice by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 95:5; CH2Cl2 /CH3OH 92:8). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile. At 0° C., the product was filtered off and dried in vacuo at 60° C., yielding 1 g (18.3%) of 4-amino-5-chloro-N-[1-[2-[(6-chloro-4-hydroxy-2-quinazolinyl)amino]ethyl]-4-piperidinyl]-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxamide; mp. 206.6° C. (comp. 21).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[O:37])[O:29][C:28]=1[CH2:38]O.[Br:40]C(Br)(Br)Br.C(Cl)Cl>CO>[Br:40][CH2:38][C:28]1[O:29][C:30](=[O:37])[C:31]2[C:36]([C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[F:20])=[CH:35][CH:34]=[CH:33][CH:32]=2
Reactant: O=c1oc(CO)c(-c2ccccc2F)c2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=c1oc(CBr)c(-c2ccccc2F)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Triphenylphosphine (0.127 g, 0.488 mmol)) was added to a solution of 4-(2-fluorophenyl)-3-(hydroxymethyl)-1H-isochromen-1-one (intermediate B4, 40 mg, 0.148 mmol) and perbromomethane (0.161 g, 0.488 mmol) in DCM (0.7 ml, 57.5 mmol), and the resulting mixture was stirred at RT for 24 hrs. The reaction was taken up with MeOH then concentrated under reduced pressure. The crude was purified over a Biotage Silica 10 g SNAP cartridge with a gradient of hexane and EtOAc to give the title compound (37 mg, 75%).
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[CH3:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([S:1][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH:11][C:10]2=[O:12]
Reactant: ClCc1ccncc1
Reactant: Cc1cccc2c(=O)[nH]c(S)nc12
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(SCc3ccncc3)nc12
Yield: 44 %

Procedure:
The title compound was prepared in a yield of 44.0%, using 2-mercapto-8-methyl-4(3H)-quinazolinone in place of 2-mercapto-3-phenyl-4(3H)-quinazolinone and 4-chloromethylpyridine hydrochloride in place of 2-chloromethyl4-methylpyridine hydrochloride.
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:38].C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:38].[C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 74 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 74% of theory, C29H32N6O3 (512.6); EKA mass spectrum: (M+H)+=513; (M+H+Na)++=268; (M+2H)++=257.
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH2:42][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49]C)=[O:48])=[CH:45][CH:44]=3)[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)=[CH:28][CH:27]=3)=[CH:9][CH:8]=2)[NH:3]1.[OH-].[Li+].Cl>C1COCC1.O>[O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][N:15]([CH2:42][C:43]3[CH:44]=[CH:45][C:46]([C:47]([OH:49])=[O:48])=[CH:51][CH:52]=3)[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)=[CH:28][CH:27]=3)=[CH:11][CH:12]=2)[NH:3]1
Reactant: COC(=O)c1ccc(CN(CCc2ccc(-c3noc(=O)[nH]3)cc2)CCc2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CN(CCc2ccc(-c3noc(=O)[nH]3)cc2)CCc2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
A solution of 32.7 mg (0.05 mmol) of methyl 4-[({2-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)phenyl]ethyl}-{2-[2-(4′-trifluoromethylbiphenyl-4-ylmethoxy)phenyl]ethyl}amino)methyl]-benzoate from Example 11A in 2 ml of THF and 2 ml of water is mixed with 2.2 mg (0.09 mmol) of lithium hydroxide and stirred at 50° C. for 12 h. After cooling, the THF is stripped off and the aqueous phase is adjusted to pH 4-5 with 1 M hydrochloric acid. It is then extracted three times with ethyl acetate, and the combined organic phases are dried over sodium sulfate. The residue obtained after filtration and concentration is purified by preparative HPLC. 7.4 mg (0.01 mmol, 23% yield) of a colorless oil are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[C:8](=[S:12])[NH:7][CH:6]=1)=[O:4].[N:13]([O-])=O.[Na+]>Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]2[N:11]=[N:13][S:12][C:8]2=[N:7][CH:6]=1)=[O:4]
Reactant: O=N[O-]
Reactant: COC(=O)c1c[nH]c(=S)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cnc2snnc2c1
Temperature: -3 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
The amine (i) (1.3 g) was suspended in 0.5 M hydrochloric acid (200 mL) and cooled to −3° C. A solution of sodium nitrite (487 mg) in water (3 mL) was added dropwise over 10 minutes and the mixture was stirred for 2 hours when the solid product was collected and chromatographed on silica gel (chloroform) to afford a solid (0.90 g)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH2:16]([Cl:19])OC>C(=S)=S.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[C:12]([CH2:16][Cl:19])[CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Reactant: COCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: S=C=S
Product: COC(=O)C1(c2ccc(OC)c(CCl)c2)CC1
Temperature: 30 °C
Yield: 102.2 %

Procedure:
To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) and MOMCl (29.1 g, 364 mmol) in CS2 (300 mL) was added TiCl4 (8.30 g, 43.5 mmol) at 5° C. The reaction mixture was heated at 30° C. for 1 d and poured into ice-water. The mixture was extracted with CH2Cl2 (150 mL×3). The combined organic extracts were evaporated under vacuum to give 1-(3-chloromethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (38.0 g), which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CN1CCOCC1.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[CH2:33]([O:32][C:30]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:31])[CH3:34]
Reactant: CCCCCCCCCCCCCCCC(=O)NCCO
Reactant: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)NCCOC(=O)OCC

Procedure:
3.0 g of N-(2-hydroxyethyl) hexadecanamide (10 mmoles) was dissolved in 75 ml of tetrahydrofuran (THF) at 45° C. with stirring. 1.11 g of N-methylmorpholine (11 moles) and 1.19 g of ethyl chloroformate (11 moles) were added and the resulting mixture was stirred for a further 3 hours at ambient temperature. The mixture was then evaporated to dryness under vacuum. The residue was taken up with 50 ml of water and extracted 3 times with 30 ml of ethyl acetate; the organic phases were washed twice with 20 ml of water, recombined and evaporated to dryness. The residue was crystallized from 30 ml of tert-butylmethyl ether. The crystallizate was separated by filtration, washed twice with 5 ml of cold tert-butylmethyl ether and finally dried under a high degree of vacuum. The yield of the reaction was 93%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[C:16]=2[CH:15]=[CH:14][N:13]=1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][S:22]([C:17]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:21]=3[CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: COc1ccc(N)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2cccc3cnccc23)cc1OC
Reaction time: 0.5 h
Yield: 82 %

Procedure:
3.06 g of 3,4-dimethoxyaniline was dissolved in 30 ml of pyridine, to the solution was added in small portions 5.28 g of 5-isoquinolinesulfonyl chloride.HCl with stirring under ice cooling, and the mixture was stirred for 30 minutes, and further stirred at a room temperature overnight. After evaporating off the pyridine under a reduced pressure and additing 20 ml of water, the mixture was extracted twice with 50 ml of chloroform/isopropanol (10:1). The extract was dried over magnesium sulfate and evaporated under a reduced pressure to remove the solvent. To the resulting residue was added 20 ml of benzene/chloroform (3:1), and the mixture was slightly warmed and collected to obtain 5.64 g of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.O[N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[C:13]1(=[O:18])[N:12]([O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:16](=[O:17])[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(ON1C(=O)CCC1=O)c1ccc(Br)cc1
Temperature: 23 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
To 4-bromobenzoic acid (5.00 g, 24.9 mmol, 1.00 equiv) and N-hydroxysuccinimide (3.66 g, 31.8 mmol, 1.28 equiv) in a round-bottom flask in dioxane (120 mL) was added an dioxane solution (30 mL) that contained 1,3-dicyclohexylcarbodiimide (DCC) (6.77 g, 32.8 mmol, 1.32 equiv) dropwise over 5 min at 23 ° C. The reaction mixture was stirring at 23 ° C. for 24 h. The reaction mixture was concentrated in vacuo and the crude product was obtained by recrystallization in a cold acetone. The crude product was further purified by chromatography on silica gel eluting with hexanes/EtOAc 2:1 (v/v) to afford 6.34 g of the title compound as a colorless solid (86%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1>>[OH:23][CH:20]1[CH2:21][CH2:22][N:18]([C:7]([C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:19]1
Reactant: OC1CCNC1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Yield: 50 %

Procedure:
Prepared in analogy to Example 1 from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and rac-3-pyrrolidinol. The crude material was purified by flash chromatography (methanol/dichloromethane) to yield the title compound as a light brown foam (yield 50%). MS (m/e): 328.1 (M+H+, 100%).