Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1C(OC)=CC2N(CC)C(=O)C(CC3C=CC=CC=3N)N=C(C3C=CC=CC=3)C=2[CH:30]=1.[CH3:33][O:34][C:35]1[C:36]([O:64][CH3:65])=[CH:37][C:38]2[N:44](CC)[C:43](=[O:47])[CH:42]([CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[CH2:55][NH2:56])[N:41]=[C:40]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:39]=2[CH:63]=1>>[CH3:33][O:34][C:35]1[C:36]([O:64][CH3:65])=[CH:37][C:38]2[NH:44][C:43](=[O:47])[CH:42]([C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[CH2:50][CH2:55][NH:56][C:3](=[O:2])[CH3:30])[N:41]=[C:40]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:39]=2[CH:63]=1
Reactant: CCN1C(=O)C(Cc2ccccc2N)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Reactant: CCN1C(=O)C(Cc2ccccc2CN)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Product: COc1cc2c(cc1OC)C(c1ccccc1)=NC(c1ccccc1CCNC(C)=O)C(=O)N2
Yield: 55 %

Procedure:
By replacing 7,8-dimethoxy-1-ethyl-3-(2-aminobenzyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIca) in example IIcf by 7,8-dimethoxy-1-ethyl-3-(2-aminomethylbenzyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIcg) and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. M: 122–124° C. 1H-NMR (CDCl3, 200 MHz): d 1.07–1.14 (m, 3H, CH3), 1.49 (s, 1H, COCH3), 3.41–3.80 (m, 6H, CHCH2+1HNCH2+OCH3), 3.89–3.98 (m, 4H, CHCH2+OCH3), 4.34–4.45 (m, 1HNCH2), 6.60 (s, 1H Ar), 4.55–4.57 (m, 2H, CH2NHAc), 6.52 (s, 6.85 (s, 1H Ar), 7.18–8.45 (m, 9H Ar), 8.45 (m, 1H, NHAc).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[C:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:6]2[O:5][C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])=[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]2=[O:1])=[CH:21]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2C)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 14.4 %

Procedure:
To a solution of ethyl 4-oxo-2-(o-tolylamino)-4,5-dihydrofuran-3-carboxylate (0.098 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.050 g, 0.34 mmol) in ethanol (2.0 mL), piperidine (0.0034 mL, 0.034 mmol) was added at ambient temperature. The mixture was refluxed for 32 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.019 g, y. 27%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[O:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Reactant: OB(O)c1ccncc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccncc2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 12 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-4-boronic acid. The title compound (701 mg) was obtained as a pale solid, m/z 326 (MH+).
Reaction SMILES: C(Cl)(Cl)=O.C1(C)C=CC=CC=1.N1CCCC1.CCOP(O)N(C(C)C)C(C)C.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[C:37]1[NH:38][C:39]2[CH:45]=[C:44]([C:46]([NH:48][NH2:49])=[O:47])[CH:43]=[CH:42][C:40]=2[N:41]=1.[CH3:50][CH2:51][N+:52](S(N=C(OC)[O-])(=O)=O)([CH2:55][CH3:56])[CH2:53]C>C1COCC1.CN1C(=O)CCC1>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[C:37]1[NH:38][C:39]2[CH:45]=[C:44]([C:46]3[O:47][C:53]([N:52]4[CH2:55][CH2:56][CH2:50][CH2:51]4)=[N:49][N:48]=3)[CH:43]=[CH:42][C:40]=2[N:41]=1
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: O=C(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(N4CCCC4)o3)cc2[nH]1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 20% solution of phosgene in toluene (163 uL, 0.310 mmol) was added dropwise to a solution of pyrrolidine (51 uL, 0.620 mmol) in THF (2 mL) and EDIPA (216 uL, 1.24 mmol) at 0° C. under N2. The reaction was stirred for 20 min before the addition of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (100 mg, 0.310 mmol) and NMP (1 mL). The ice bath was removed after 2 hr and the reaction allowed to stir overnight. The reaction was heated to 60° C. for 1.5 hr before being concentrated. The concentrate was added to a microwave vial charged with Burgess reagent (220 mg, 0.930 mmol) and the mixture heated to 150° C. for 15 min by microwave irradiation. The reaction was partitioned between EtOAc and H2O. The organic phase was concentrated and purified by reverse phase HPLC (25-50% ACN/H2O+5 mM NH4OH) to afford the title compound: 1H NMR (400 MHz, MeOD) δ ppm 2.05-2.14 (m, 4H) 3.58-3.67 (m, 4H) 7.55-7.64 (m, 3H) 7.79 (br. s., 1H) 7.94 (d, J=8.34 Hz, 1H) 8.19 (br. s., 1H); MS m/z=400.1 (M+1).
Reaction SMILES: BrC1C=CC(OCOCC[Si](C)(C)C)=CC=1C.CO[C:20]1[C:21]([O:30][CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH:22][C:23]([CH3:29])=[C:24]([B:26]([OH:28])[OH:27])[CH:25]=1>>[CH3:29][C:23]1[CH:22]=[C:21]([O:30][CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[CH:20]=[CH:25][C:24]=1[B:26]([OH:28])[OH:27]
Reactant: COc1cc(B(O)O)c(C)cc1OCOCC[Si](C)(C)C
Agent: Cc1cc(OCOCC[Si](C)(C)C)ccc1Br
Product: Cc1cc(OCOCC[Si](C)(C)C)ccc1B(O)O
Yield: 52 %

Procedure:
2-Methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid was prepared in 52% yield from [2-(4-bromo-3-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane according to the procedure for 5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid above. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, 1H, J=8.1 Hz), 6.98-6.92 (m, 2H), 5.29 (s, 2H), 3.78 (t, 2H, J=8.4 Hz), 2.78 (s, 3H), 0.98 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C13H23BO4Si—H2O) C, H. Calculated: C, 59.10; H, 8.01. Found: C, 59.07; H, 8.08.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1>Cl.CO>[ClH:1].[NH:10]1[CH2:11][CH:8]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Agent: Cl
Solvent: CO
Product: Clc1nccnc1C1CNC1
Yield: 199 %

Procedure:
A solution of compound (7) (540 mg, 2.0 mmol) in 2N HCl/MeOH (20 mL) was stirred at RT for 30 min according to Preparation 2. The reaction mixture was concentrated to give compound (8) (440 mg, 1.99 mmol, yield 99.7%).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5]C(=O)OC(C)(C)C.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:40].[N:41]12[CH2:48][CH2:47][CH:44]([CH2:45][CH2:46]1)[C@H:43]([NH:49][C:50]([C:52]1[O:53][C:54]3[C:60](Br)=[CH:59][CH:58]=[CH:57][C:55]=3[CH:56]=1)=[O:51])[CH2:42]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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.Cl[Pd]Cl.[Fe+2]>[ClH:40].[ClH:40].[NH2:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[C:60]1[C:54]2[O:53][C:52]([C:50]([NH:49][C@H:43]3[CH:44]4[CH2:45][CH2:46][N:41]([CH2:48][CH2:47]4)[CH2:42]3)=[O:51])=[CH:56][C:55]=2[CH:57]=[CH:58][CH:59]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: NCc1ccccc1-c1cccc2cc(C(=O)N[C@@H]3CN4CCC3CC4)oc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
500 mg (1.75 mmol) of tert-butyl 2-bromobenzylcarbamate, 512 mg (2.02 mmol) of bis(pinacolato)diboron, 428.7 mg (4.37 mmol) of potassium acetate, 49.2 mg (0.07 mmol) of PdCl2(dppf), 518.4 mg (1.34 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (free base: Example 31A), 3.36 ml of 2 M sodium carbonate solution and a further 49.2 mg (0.07 mmol) of PdCl2(dppf) in 5 ml of DMF are reacted by general method D. The crude product which has been dried under high vacuum is stirred in 4 ml of a 1:1 mixture of methanol and 4 M hydrogen chloride in dioxane at room temperature for 2 h. The reaction solution is concentrated, and the resulting crude product is purified by preparative HPLC. The product fractions are concentrated and, after addition of a 3:1 mixture of methanol and 1N hydrochloric acid, again concentrated and dried under high vacuum. 121.6 mg (22.4% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](=[O:13])(=[O:12])[NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:6][CH:5]=1
Reactant: Nc1cccnc1
Reactant: COC(=O)c1ccc(CS(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CS(=O)(=O)Nc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 4-chlorosulfonylmethylbenzoic acid methyl ester (435 mg, 1.75 mmol) and 3-aminopyridine (170 mg, 1.81 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (488 μL, 3.50 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with CHCl3, and the mixture was washed with water and brine. The organic layer was dried (Na2SO4) and evaporated under reduced pressure to give the crude product which was purified by MPLC on silica gel (3% MeOH in EtOAc) to afford the titled compound (434 mg, 81%) as a white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:11][CH2:10][CH2:9][C:8]([F:13])([F:12])[S:7]1(=[O:15])=[O:14].FC(F)(F)C(O)=O>C(Cl)Cl>[F:12][C:8]1([F:13])[S:7](=[O:15])(=[O:14])[NH:6][CH2:11][CH2:10][CH2:9]1
Reactant: COc1ccc(CN2CCCC(F)(F)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)NCCCC1(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a solution of 2-(2,4-dimethoxybenzyl)-6,6-difluoro-1,2-thiazinane-1,1-dioxide (0.090 g, 0.3 mmol) in methylene chloride (7 mL) was added trifluoroacetic acid (4 mL), and the resultant red solution stirred for 3 hrs at room temperature. The mixture was concentrated in vacuo to afford the crude residue. The crude product was purified by silica gel chromatography (10-60% ethyl acetate/hexanes) to give a clear oil (0.034 g). 1H NMR (CDCl3, 300 MHz) δ 4.85 (br s, 1H), 3.46-3.40 (m, 2H), 2.60-2.47 (m, 2H), 2.01-1.93 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:16]=[C:15]([O:17][CH2:18][C:19](O)=[O:20])[O:14][N:13]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>C1COCC1>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:19](=[O:20])[CH2:18][O:17][C:15]1[O:14][N:13]=[C:12]([C:11]([F:23])([F:10])[F:22])[CH:16]=1)[CH3:2]
Reactant: CCNc1ccccc1
Reactant: O=C(O)COc1cc(C(F)(F)F)no1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(C(=O)COc1cc(C(F)(F)F)no1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
1.30 ml (2.37 mmole) of N-ethylaniline and 0.50 g (2.37 mmole) of 2-(3-trifluoromethyl-5-isoxazolyloxy)acetic acid were dissolved in 2.4 ml of dry THF and to the solution was added 0.60 g (2.61 mmole) of dicyclohexylcarbodiimide. After being stirred at room temperature for one hour, the reaction mixture was allowed to stand overnight at room temperature. After the addition of glacial acetic acid (0.2 ml), the mixture was stirred at room temperature for 30 minutes and the precipitated crystals were filtered off. The filtrate was evaporated under reduced pressure and the residue was purified by chromatography on silica gel to give 638 mg of the titled compound as a pale red viscous liquid, yield 85.7%.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=O)[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1C=CC=CC=1>[CH3:2][C:1]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[CH2:6][CH2:5][N:4]=1
Reactant: CC(=O)NCCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC1=NCCc2sccc21
Temperature: 0 °C

Procedure:
To 5.70 g (0.0337 mol) of 2-acetylaminoethylthiophene (f-l) was added 157 ml of dry benzene; and while being refluxed, a mixture of 13.80 g (0.09 mol) of phosphorus oxychloride and 63 ml of dry benzene was added dropwise to the solution. After being refluxed for 2 hr., the mixture was cooled with ice, and the reaction solution was poured into 315 g of ice. Under ice-cooling, the mixture was adjusted to pH 10 or more with 48% aqueous NaOH, and the solution was extracted with ether. After being washed with saturated brine, the ether layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give 4.45 g (Yield : 87.3%) of the objective product, 4-methyl-6, 7-dihydrothieno[3, 2-c]pyridine (g-l) as dark red liquid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH3:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH2:16][S:17][CH2:18][CH2:19]/[N:20]=[C:21](/[NH:24][C:25]#[N:26])\[NH:22][CH3:23]>ClCCl>[CH3:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH2:16][S:17][CH2:18][CH2:19]/[N:20]=[C:21](/[NH:24][C:25]#[N:26])\[NH:22][CH3:23].[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: CN/C(=N\CCSCc1nc[nH]c1C)NC#N
Solvent: ClCCl
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.66 g (0.5 cmole) of aspartic acid and 1.26 g (0.5 cmole) of cimetidine was suspended in 15 ml of dichloromethane. It was stirred for 3 hours at room temperature, filtered, washed with dichloromethane and dried. Weight 1.87 g (yield 97.5%). A stereoscopically homogenous microcrystalline white solid. M.p.: 141°-142° C. In the infra red spectrum the lines at 3200, 3130, 2160, 1620 and 1585 cm-1 are characteristic.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])=[C:7]([C:13]#[N:14])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[NH4+]=[S:17]>CN(C)C=O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])=[C:7]([C:13](=[S:17])[NH2:14])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C#N)c(=O)oc2cc(O)ccc12
Solvent: CN(C)C=O
Product: Cc1c(C(N)=S)c(=O)oc2cc(O)ccc12
Temperature: 25 °C
Yield: 36.5 %

Procedure:
To a solution of 7-Hydroxy-4-methyl-2-oxo-2H-chromene-3-carbonitrile (7.50 g, 37.31 mmol) in N,N-dimethylformamide (150 mL), ammonium sulfide (40-48 wt. % solution in water; 38 mL, 560 mmol) was added, and the resulted mixture was stirred at room temperature for a week. An additional portion of ammonium sulfide (38 mL) was added on every second day. The solution was evaporated and the solid residue was triturated with water, filtered and dried. The obtained crude product was purified by column chromatography (Kieselgel 60), with chloroform-methanol (1:1) as eluent. The title compound (3.20 g, 13.6 mmol, 36%) was isolated as a yellow powder,
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[N:2]1([O:1][C:13](=[O:14])[N:12]([CH3:11])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1nnc2ccccc21
Product: CN(C(=O)On1nnc2ccccc21)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxybenzotriazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (98%, crystallizes slowly).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][C:7](=[O:30])[C:6]=2[CH:31]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([OH:30])[C:6]=2[CH:31]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 7-chloro-5-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in methanol (5 ml) is added with stirring sodium borohydride (0.05 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the reaction solution is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, and dried over magnesium sulfate. The resultant is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography to give 7-chloro-5-hydroxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.2 g) as colorless amorphous.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:17](Cl)(=[O:19])=[O:18].[OH-].[Na+]>O>[C:12]([C:11]1[CH:15]=[CH:16][C:8]([F:7])=[C:9]([S:17]([OH:19])=[O:18])[CH:10]=1)([OH:14])=[O:13]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(F)c(S(=O)O)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
15.6 g (0.124 mol) of sodium sulfite are dissolved in 120 ml of water at 70° C. While maintaining the temperature, 23.8 g (0.1 mol) of 4-fluoro-3-chlorosulfonylbenzoic acid and 10N NaOH are added simultaneously and in portions such that the pH is kept between 9 and 10 (exothermic reaction). The mixture is stirred for a further 3 hours at 70° C., stirred for a further 15 minutes with active carbon and then filtered. The filtrate is adjusted to pH 0-1 using concentrated hydrochloric acid with external cooling and the crystalline 5-carboxy-2-fluorobenzenesulfinic acid is filtered off.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3[O:17][C:18](Br)=[CH:19][CH:20]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3[O:17][C:18]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=4)=[CH:19][CH:20]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1
Reactant: O=C(Nc1cccc(Cc2nnn[nH]2)c1)c1ccc(Br)o1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(Nc1cccc(Cc2nnn[nH]2)c1)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
The bromo-derivative (84) (100 mg, 0.29 mmol) was coupled to 4-chloro-phenylboronic acid (49 mg, 0.32 mmol) using Method E. After reaction, the solvents were removed under a stream of N2, and the residue was dissolved in saturated NaHCO3 solution (5 ml) and washed with EtOAc (5 ml). The aqueous layer was acidified to pH 1 with 2M HCl until a white precipitate formed and extracted with EtOAc (2×5 ml). The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo. The residue was triturated with MeCN (4 ml) and further purified by preparative HPLC to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:24]2([CH3:25])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:26])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@@H:14]([CH3:19])[CH2:15][C:16]([OH:18])=[O:17])[CH2:5][C@@H:4]([OH:27])[CH2:3]1.CO.[N+](=[CH2:32])=[N-]>C(O)(=O)C>[CH3:32][O:17][C:16]([CH2:15][C@H:14]([CH3:19])[C@@H:13]1[C@:20]2([CH3:26])[C@H:10]([C@H:9]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:25])[C:6]([CH2:5][C@@H:4]([OH:27])[CH2:3][C@@H:2]2[OH:1])=[CH:7][CH2:8]3)[CH2:11][CH2:12]1)=[O:18]
Reactant: C=[N+]=[N-]
Reactant: C[C@@H](CC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C[C@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
A solution of 1.0 g of (20S)-1α,3β-dihydroxy-20-methyl-pregn-5-ene-21-carboxylic acid in 50 ml. of methanol was treated with an ethereal solution containing 4 mmol of diazomethane and stored at room temperature for 30 minutes. After addition of glacial acetic acid, the mixture was concentrated in vacuo. The crystalline residue, which was uniform according to thin-layer chromatography, was recrystallised from concentrated methanolic solution to give 0.79 g of (20S)-1α,3β-dihydroxy-20-methyl-pregn-5-ene-21-carboxylic acid methyl ester in the form of colourless prisms of melting point 144°-146° C.; [α]D =-56° (c=0.5 in chloroform). Each mol of this ester contained 1 mol of methanol of crystallisation. EXAMPLE 16
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[NH2:12][NH2:13].O=C(CC)CC(OC)=O>C(O)(=O)C>[NH2:5][C:4]1[CH:3]=[C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:13][N:12]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NN
Agent: CCC(=O)CC(=O)OC
Solvent: CC(=O)O
Product: Nc1cc(-c2ccccc2)[nH]n1

Procedure:
4.9 g (30.8 mmol) 3-amino-5-phenylpyrazole, which was prepared from 3-oxo-3-phenylpropionitrile and hydrazine (M. H. Elnagall, M. R. H. Elmoghayar, G. E. H. Elgemeie, Synthesis 1984, 1), and 4.0 g (30.7 mmol) methyl 3-oxovalerate were heated for 70 min in 10 ml acetic acid. The title compound precipitated in colorless needles from the mixture upon cooling, which were filtered by suction, washed with water, and recrystallized from ethanol,
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl[C:31]([O:33][CH3:34])=[O:32].[OH-].[Na+]>ClCCl.CCCC[N+](CCCC)(CCCC)CCCC.OS([O-])(=O)=O>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:31]([O:33][CH3:34])=[O:32])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: COC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)n1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Boc-DTrp-OBzl (12.19 g) in dichloromethane (60 ml) were added methyl chloroformate (4.8 ml), pulverized sodium hydroxide (4.1 g) and TBAHS (9.2 g), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water, dried over MgSO4 and evaporated in vacuo. The residue was crystallized from dichloromethane and hexane to give Boc-DTrp(COOMe)-OBzl (12.57 g). Boc-DTrp(COOMe)-OBzl (4.52 g) was dissolved in 4N-hydrogen chloride/1,4-dioxane (50 ml) and the mixture was stirred at room temperature for 45 min. Ethyl ether (50 ml) was added to the mixture to complete the precipitation. The precipitate was collected by filtration and dried in vacuo to give H-DTrp(COOMe)-OBzl·HCl (3.71 g). To a suspension of H-DTrp(COOMe)-OBzl·HCl (1.94 g) in dichloromethane (50 ml) were added NMM (0.55 ml), 2,6-dimethylpiperidinocarbonyl-γMeLeu-OH (1.42 g), HOBT·H2O (0.84 g) and EDCI·HCl (1.05 g) under ice cooling. The mixture was stirred at the same temperature for 2 h and at room temperature over night. The reaction mixture was washed with sat. aq NaHCO3 (50 ml), 10% aq. citric acid (50 ml) and brine (50 ml) successively, dried over MgSO4 and evaporated. The residue was purified by MPLC (Merck, LiChroprep Si 60) with hexane/ethyl acetate=2/1 for elution to give 2,6-dimethylpiperidinocarbonyl-γMeLeu-DTrp(COOMe)-OBzl (1.17 g). A solution of 2,6-dimethylpiperidinocarbonyl-γMeLeu-DTrp(COOMe)-OBzl (1.10 g) in methanol (30 ml) was hydrogenated over 10% Pd/C (50 mg) at an atmospheric pressure of hydrogen for 1.5 h. After removal of the catalyst by filtration, the filtrate was evaporated in vacuo to give the product (0.93 g).