Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+:2].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH:20]=3)[N:15]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)[C:14]=2[C:38]([OH:40])=[O:39])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][O:24][CH2:25][CH:26]4[CH2:27][CH2:28]4)[CH:20]=3)[N:15]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)[C:14]=2[C:38]([O-:40])=[O:39])=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5].[Na+:2]
Reactant: COc1cccc(Cn2c(C(=O)O)c(-c3ccc(C(C)(C)C)cc3)c3cc(CCOCC4CC4)ccc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(Cn2c(C(=O)[O-])c(-c3ccc(C(C)(C)C)cc3)c3cc(CCOCC4CC4)ccc32)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium hydride (6.8 mg, 0.28 mmol) was added to a cooled (0° C.) and stirred solution of 3-(4-tert-butylphenyl)-5-[2-(cyclopropylmethoxy)ethyl]-1-(3-methoxybenzyl)-1H-indole-2-carboxylic acid (Example 275, 145 mg, 0.283 mmol) in tetrahydrofuran (10 mL). The cold bath was removed and the mixture was stirred 2 h. Concentration in vacuo left 148 mg (98%) of the desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.63 (d, 2 H), 7.47 (s, 1 H), 7.34 (d, 2 H), 7.18 (d, 1 H), 7.09(dd, 1 H), 6.96 (dd, 1 H), 6.91 (s, 1 H), 6.85 (d, 1 H), 6.69 (dd, 1 H), 5.75 (s, 2 H), 3.66 (s, 3 H), 3.56 (t, 2 H), 3.22 (d, 2 H), 2.84 (t, 2 H), 1.32 (s, 9 H), 0.89-1.05 (m, 1 H), 0.35-0.45 (m, 2 H), 0.07-0.17 (m, 2 H); mass spectroscopy gave M+2H+−Na=512.2 (calcd exact mass for C33H36NNaO4=533.25).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:21]#[C:22]Cl.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:22]#[N:21])=[CH:18][CH:19]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: N#CCl
Reactant: Oc1ccc(C2(c3ccc(O)cc3)CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#COc1ccc(C2(c3ccc(O)cc3)CCCCC2)cc1
Yield: 98.9 %

Procedure:
86.8 g (0.1 mol) of 1,1-bis-(4-hydroxyphenyl)-cyclo hexane are suspended in 500 ml of water and 300 ml of methylene chloride at about 0° to 3° C. 20 ml (0.4 mol) of cyanogen chloride are added to this suspension and a solution of 10.6 g (0.1 mol) of Na2CO3 in 50 ml of water is added dropwise over the course of 90 minutes at the same temperature, with vigorous stirring, in such a way that a pH value between 7.5 and 8.5 is maintained in the reaction mixture. Thereafter, 1 N NaOH is added at 0° C in such a way that the abovementioned pH value is maintained, and persists as the final value. Thereafter, the organic phase is separated off and washed with 50 ml of water and the solvent is stripped off at room temperature. 29 g (99% of theory) of 1-(4-hydroxyphenyl)-1-(4-cyanatophenyl)-cyclohexane are thus obtained.
Reaction SMILES: FC(F)(F)[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=1)C)=O.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:3][NH:5][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=1
Reactant: CN(C(=O)C(F)(F)F)c1ccc(C#CCCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNc1ccc(C#CCCCO)cc1

Procedure:
Intermediate 36 (0.221 g, 0.7752 mmol) was reacted with K2CO3 (0.7752 mmol, 0.107 g) in 12 mL of 2:1 MeOH:Water at room temperature overnight. The reaction was worked up quenching the reaction with 1× saturated NaHCO3, extracted 4×25 ml EtOAc then washed 1× water, 1× saturated NaCl, dried over Na2SO4, then concentrated. The product was purified 0-10% MeOH in DCM over 15 min on TEA silica 12 g. ES/MS calcd. for C12H15NO 189.1. Found m/z=190 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[CH:13]=O.[OH:15][C:16]1[C:17]([C:26]([NH:28][NH2:29])=[O:27])=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[CH:13]=[N:29][NH:28][C:26]([C:17]1[C:16]([OH:15])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)=[O:27]
Reactant: O=Cc1c(O)ccc2ccc(O)cc12
Reactant: NNC(=O)c1cc2ccccc2cc1O
Product: O=C(NN=Cc1c(O)ccc2ccc(O)cc12)c1cc2ccccc2cc1O

Procedure:
Following the general procedure of Example 1, condensation of 2, 7-dihydroxy-1-naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide yielded yellow crystals (83%) [recrystallized from DMSO/H2O (8:2, v/v)]: mp225° C. (dec); 1H NMR d 12.75 (s, 1 H), 12.24 (s, 1 H), 11.27 (s, 1 H), 9.93 (s, 1 H), 9.40 (s, 1H), 8.50 (s, 1 H), 7.95 (d, 1 H, J=8.1 Hz), 7.80 (d, 2 H, J=8.7 Hz), 7.73 (d, 1 H, J=8.7 Hz), 7.54 (t, 1 H, J=7.5 Hz), 7.39 (t, 1 H, J=7.5 Hz), 7.37 (s, 1 H), 6.98 (d, 2 H, J=8.7 Hz); HRMS Calcd for C22H16N2O4 :372.1110, found 372.1099; Anal. (C22H16N2O4 1.4 DMSO) C, H, N.
Reaction SMILES: [Cl-:1].C(OC([NH:12][C:13]([CH3:27])([CH3:26])[CH2:14][CH2:15][N+:16]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:18])[CH3:17])=O)C1C=CC=CC=1>CO>[Cl-:1].[NH2:12][C:13]([CH3:26])([CH3:27])[CH2:14][CH2:15][N+:16]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:18])[CH3:17]
Reactant: CCCCOCC[N+](C)(C)CCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Cl-]
Solvent: CO
Product: CCCCOCC[N+](C)(C)CCC(C)(C)N
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
Under a nitrogen atmosphere, 10% pd/C (100 mg) was added to a solution of 3-(((benzyloxy)carbonyl)amino)-N-(2-butoxyethyl)-N,N,3-trimethylbutan-1-aminium chloride (0.38 g, 0.95 mmol) in 4 mL of methanol. The flask was degassed and placed under a hydrogen atmosphere, stirring for 24 hours at room temperature. The suspension was filtered through a pad of celite washing with methanol, and the filtrate was concentrated under reduced pressure to give 252 mg of clear viscous oil (quantitative yield). 1H NMR (400 MHz, D2O) δ 0.78-0.82 (t, J=7.4 Hz, 3H), 1.08 (s, 6H), 1.22-1.30 (sext, J=7.4 Hz, 6H), 1.45-1.52 (m, 2H), 1.77-1.81 (m, 2H), 3.04 (s, 6H), 3.36-3.40 (m, 2H), 3.45-3.49 (t, J=6.5 Hz, 2H), 3.82-3.83 (br m, 2H); LRMS (ESI/APCI) m/z 231 [M]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])([O:11][CH2:12][CH2:13][O:14][CH3:15])[O:6][CH2:7][CH2:8][O:9][CH3:10].[N-:21]=[N+:22]=[N-:23].[Na+]>C(#N)C>[N:21]([CH2:2][CH2:3][CH2:4][Si:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])([O:11][CH2:12][CH2:13][O:14][CH3:15])[O:6][CH2:7][CH2:8][O:9][CH3:10])=[N+:22]=[N-:23]
Reactant: COCCO[Si](CCCCl)(OCCOC)OCCOC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: COCCO[Si](CCCN=[N+]=[N-])(OCCOC)OCCOC

Procedure:
1.0 mole of 3-chloropropyltris(methoxyethoxy)-silane and 1.1 moles of sodium azide in 500 ml of acetonitrile were heated in the presence of 5 mole percent of the catalyst described in Example 1 (a) for eight hours under reflux and stirring. After separation of the salt the subsequent distillation under reduced pressure gave the 3-azidopropyltris(methoxyethoxy)silane in a yield of 84 weight percent with the following characteristics:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:8][C:5]2[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ncc(Br)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-3-nitropyridin-2-ol (30.00 g, 0.137 mmol) and p-toluenesulfonyl chloride (30.03 g, 0.158 mmol) were suspended in CH2Cl2 under N2 and treated dropwise with triethylamine (38.2 mL, 0.274 mmol) prior to the addition of DMAP (3.35 g, 0.027 mmol). After stirring at rt for 16 h the mixture was diluted with CH2Cl2 (500 mL) then washed with 1M HCl(aq) (2×500 mL) and brine (500 mL). The aqueous layer was back-extracted with CH2Cl2 (200 mL) and the combined organic layers dried over Na2SO4, and concentrated in vacuo. The crude material thus isolated was chromatographed over silica gel eluting with 50% EtOAc/hexane to give, on evaporation, a solid which was crystallized from 50% EtOAc/hexane to afford 5-bromo-3-nitropyridin-2-yl 4-methylbenzenesulfonate. 1H NMR (400 MHz, CDCl3) δ 2.51 (s, 3H), 7.43 (dd, 2H, J=8.4, 0.4 Hz), 7.99 (dt, 2H, J=6.8, 2.0 Hz), 8.52 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)cc1

Procedure:
68.4 mg of solid beige-coloured 3-[4-(3-p-tolylureido)phenyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and p-tolyl isocyanate.
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[CH2:19][CH2:20]S(C)(=O)=O)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.I.[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[C:42]([CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43]>>[CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[CH2:19][CH2:20][N:47]1[CH2:48][CH2:49][CH:44]([C:42]([C:34]2[NH:33][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=2)=[O:43])[CH2:45][CH2:46]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Reactant: COc1cc(C(=O)N(C)CC(CCS(C)(=O)=O)c2ccc(Cl)cc2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4[nH]3)CC2)c2ccc(Cl)cc2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(4-chlorophenyl)-4-methanesulfonylbutyl)-3,4,5-trimethoxybenzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: [Na].[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([S:11]([O-:14])(=O)=[O:12])=[CH:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][S:11]([C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:2][CH:3]=1)(=[O:14])=[O:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])c1csc2ccccc12
Agent: [Na]
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1csc2ccccc12

Procedure:
180 g of sodium-benzothiophene-3-sulphonate are placed in 650 ml of phosphorus oxychloride and then combined with 156 g of phosphorus pentachloride. The reaction mixture is refluxed for 3.5 hours before the excess phosphorus oxychloride is eliminated by distillation in vacuo. The residue is taken up in 800 ml of chloroform and the precipitate formed is separated off by filtering. The filtrate is concentrated by evaporation and stirred into 800 ml of petroleum ether with heating. The crystalline substance thus precipitated is filtered off, washed with petroleum ether and dried at 35° C. Yield: 113 g. M.p.: 88-89° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[C:18]([Cl:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=3[Cl:21])[C:6]=2[O:5]1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH3:1][N:2]([CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[C:14]([Cl:21])=[CH:15][C:16]([Cl:20])=[CH:17][C:18]=3[Cl:19])[C:6]=2[O:5]1)[C:32](=[O:33])[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CNCC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1)C(=O)OCc1ccccc1
Yield: 94 %

Procedure:
Treatment of (±)-N-methyl-1-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.1 g, 3.57 mmol) with diisopropylethylamine (0.69 g, 5.35 mmol) and benzyl chloroformate (0.0.82 g, 4.28 mmol) generally according to the procedure described for Intermediate 12 provided 1.6 g (99%) of (±)-benzyl methyl{[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:23](I)=[C:11]3[CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:25]([C:23]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]=12)#[N:26]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(-c3cccc(F)c3)c(I)c2C1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2nc(-c3cccc(F)c3)c(C#N)c2C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of Intermediate 1H (6.0 g, 13.54 mmol) in DMF (10 mL) was added zinc cyanide (2.066 g, 17.60 mmol) and zinc (0.265 g, 4.06 mmol) to give a brown suspension. The reaction mixture was degassed under nitrogen for 15 min, added Pd2(dba)3 (0.620 g, 0.677 mmol), dppf (0.750 g, 1.354 mmol), and stirred at 90° C. for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with ethyl acetate (3×50 mL). Combined organic layer was washed with aqueous ammonia (2×50 mL), water, dried over Na2SO4, filtered and concentrated to afford crude Intermediate 1I as a brown gummy solid. The residue was purified by ISCO using 40 g REDISEP® silica gel column eluting with 3% MeOH in chloroform. The collected fractions were concentrated together to afford Intermediate 1I (3 g, 64%) as white solid. MS(ES): m/z=343 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.84-7.94 (m, 2H), 7.34-7.44 (m, 2H), 4.78 (s, 2H), 4.23 (t, J=5.36 Hz, 2H), 3.87 (t, J=5.45 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([C:21]1[CH:30]=[C:27]([O:28][CH3:29])[CH:26]=[C:23]([O:24][CH3:25])[CH:22]=1)([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([O:13]C)=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[OH-].[Na+].CC1C(C2(C3C(C)=CC(O)=C(C(C)C)C=3)OC(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1>O1CCOCC1.O>[NH:1]([C:15]([O:17][C:18]([C:21]1[CH:22]=[C:23]([O:24][CH3:25])[CH:26]=[C:27]([O:28][CH3:29])[CH:30]=1)([CH3:19])[CH3:20])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)OC(C)(C)c1cc(OC)cc(OC)c1)C(=O)OC
Agent: Cc1cc(O)c(C(C)C)cc1C1(c2cc(C(C)C)c(O)cc2C)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)CNC(=O)OC(C)(C)c1cc(OC)cc(OC)c1)C(=O)O

Procedure:
10 g (23.56 mmols) of Ddz-Gly-Ile-OMe were dissolved in a mixture of 24 ml of dioxane and 8 ml of water and titrated with 1 N NaOH against thymolphthalein as indicator. Over 23 ml were consumed depending on the acetic acid content. After neutralization with citric acid, the dioxane was distilled off. The residue was taken up in water and a pH of 3 was adjusted at 0° C. with 2 N citric acid. If necessary, the aqueous phase was again acidified to pH 3 and extracted with ethyl acetate. The combined ethyl acetate extracts were shaken once with water, dried over Na2SO4, concentrated and dried again in a high vacuum. An amorphous substance was obtained. Yield 8.9 g (92%), m.p. 80°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)c(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3c(C)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:28][C:29]3[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=3[C:31]([O:33]C)=O)=[O:27])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:39]([F:42])([F:41])[F:40])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([N:25]3[C:31](=[O:33])[C:30]4[C:29](=[CH:38][CH:37]=[CH:36][CH:35]=4)[NH:28][C:26]3=[O:27])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:39]([F:42])([F:41])[F:40])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1NC(=O)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(-n2c(=O)[nH]c3ccccc3c2=O)c1

Procedure:
The title compound was prepared from methyl 2-{[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino) carbonyl]amino}benzoate and LiOH according to the procedure of Example 1. MS (ES) m/z 535.8.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11])([CH3:6])[CH3:5].[OH-].[Na+].Cl.[Cl-].[Na+]>CO>[C:3]([C:4]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])([CH3:6])[CH3:5])([OH:17])=[O:2]
Reactant: COC(=O)c1cccc(C(C)(C)C(=O)OC)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate (54 mg, 0.229 mmol) in methanol (2 mL) was treated with 1 M NaOH (aq) (1 mL, 1.000 mmol), and the mixture was stirred overnight at room temperature. The mixture was treated with 1.0 N HCl (aq) (1.2 mL), and the methanol was removed in-vacuo. The remaining aqueous mixture was freeze dried to yield a mixture of the title compound and sodium chloride as colorless powder, which was used as-is in the next step.
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=O)[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].P(Cl)(Cl)[Cl:21]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:21][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: ClP(Cl)Cl
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C1=C(Cl)CC2CC(=O)N12
Reaction time: 5 h

Procedure:
Benzyl 1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (26 mg, 0.1 mmol) in anhydrous DMF (0.5 ml) containing PCl3 (27 mg, 0.2 mmol) is kept at 25° C. for 5 hrs. The mixture is diluted with toluene (5 ml), washed with H2O (5×1 ml), 5% HCl (2 ml), 5% NaHCO3 (2 ml) and brine, dried with MgSO4, and filtered. Evaporation of the solvent in vacuo provides crude benzyl 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8](COCC[Si](C)(C)C)[C:7]1=[O:23])[CH2:5]2.Cl.C(N)CN.[OH-].[Na+]>CO.O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:23])[CH2:5]2
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3ccc(N)cc3C2)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Reaction time: 0.5 h

Procedure:
A solution of (S)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step B (13.7 g, 35.9 mmol) in methanol (300 mL) was saturated with HCl (g). The mixture was resaturated with HCl (g) every 30 min until the starting material was consumed, and then concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and treated with ethylenediamine (2.4 mL, 35.9 mmol) and 10 N sodium hydroxide (7.2 mL, 72 mmol) to adjust the mixture to pH 10. After 30 min, the mixture was diluted with H2O (400 mL) and extracted with CHCl3 (2×1 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was triturated with MeOH (50 mL) to give the title compound. MS: m/z=252 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[F:7][C:8]([F:15])([F:14])[C:9](OCC)=[O:10]>O1CCCC1>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:9](=[O:10])[C:8]([F:15])([F:14])[F:7]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCC(O)CO
Solvent: C1CCOC1
Product: O=C(NCC(O)CO)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
15 g of 3-aminopropan-1,2-diol (164.6 mmol) were solubilized in 100 ml of tetrahydrofuran in a round-bottomed flask provided with a magnetic bar. The reaction mixture was then cooled to 0° C. on an ice bath and 21.5 ml of ethyl trifluoroacetate (181.1 mmol) were gradually added. The reaction mixture was stirred for 2 hours at room temperature. The crude reaction product was then evaporated to dryness. 29 g of a pure colorless oil were thus obtained (yield: 95%), that product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[C:19]([F:25])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])=[C:19]([F:25])[CH:18]=1
Reactant: CC(C)CNS(=O)(=O)c1ccccc1Cl
Reactant: Fc1cc(Br)ccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1ccc(Br)cc1F)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 10, step 3, 2-chloro-N-isobutyl-benzenesulfonamide was reacted with 4-bromo-2-fluorobenzyl bromide, cesium carbonate and 10 mol-% tetrabutylammonium iodide as a catalyst in N,N-dimethylacetamide to give N-(4-bromo-2-fluoro-benzyl)-2-chloro-N-isobutyl-benzenesulfonamide as a colorless oil. MS: 434.2 ([M+H]+)