Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.P(Cl)(Cl)([Cl:12])=O>>[Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1c[nH]c(=O)c(Br)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cnc(Cl)c(Br)c1
Reaction time: 20 h

Procedure:
A mixture of 3-bromo-5-methyl-2(1H)-pyridinone (25 g, 0.13 mol) and phosphorus oxychloride (500 mL) was boiled with stirring for 20 h. Phosphorus oxychloride was removed by distillation and the residue was poured onto ice/water (800 mL). The mixture was adjusted to pH 8.5 with 2 N sodium hydroxide solution and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue, 23.4 g of the title compound as a greyish solid was introduced into the next step without purification, MS (EI) 204.9, 206.9 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:14][C@H:15]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH:14][C@H:15]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(=O)(=O)c3cc(Cl)cc(Cl)c3O)c3ccccc3)CC2)c1

Procedure:
Prepared Procedure Q1 and Scheme AC using 3,5-dichloro-2-hydroxybenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 605.4 (M+H)+.
Reaction SMILES: C1(N)CCCCCCC1.CCC(C(Cl)=O)=O.[CH:17]1([NH:25][C:26](=[O:32])[C:27]([O:29]CC)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Na]>C(Cl)(Cl)Cl.C(O)C>[CH:17]1([NH:25][C:26](=[O:32])[C:27]([OH:29])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C(=O)NC1CCCCCCC1
Agent: CCC(=O)C(=O)Cl
Agent: NC1CCCCCCC1
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C(O)C(=O)NC1CCCCCCC1
Temperature: 10 °C

Procedure:
To a solution of cyclooctylamine (12.7 g., 0.10 mole) in chloroform (50 ml.) at 10°-20° C. is added dropwise ethyloxalyl chloride (6.83 g., 0.05 mole) in chloroform (50 ml.) over a period of 30 minutes. After stirring for 2 additional hours at 10° C., the mixture is washed with H2O (4×50 ml.), and the organic layer dried over Na2SO4. After filtration and evaporation an oil is obtained (11.3 g.). To the crude ethyl N-cyclooctyloxamate dissolved in ethanol (27 ml.) is added sodium (1.15 g., 0.05 mole) dissolved in absolute ethanol (35 ml.) and the mixture is stirred overnight. Following evaporation, the residue is dissolved in H2O (41 ml.) with heating, and the solution filtered while hot. The filtrate is acidified with 6 N HCl, and the resulting slurry cooled at ice temperature. The solid obtained by filtration is recrystallized from boiling H2O (100 ml.) to give N-cyclooctyloxamic acid, m.p. 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]2[CH2:42][CH2:41][CH2:40][NH:39]2)[CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:39]4[CH2:40][CH2:41][CH2:42][CH:38]4[C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1cncc(C2CCCN2)c1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCCC1c1cccnc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(3-pyridinyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=577.97 (M+H+); retention time=0.63 minutes.
Reaction SMILES: [CH2:1]([CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:7]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:6]=2[NH:5][C:4]1=[O:24])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:7]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:6]=2[N:5]([CH3:25])[C:4]1=[O:24])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30 g (0.092 M) of rac-3-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 200 ml of absolute acetone, treated with 16 g of powdered potassium carbonate and 8 ml of methyl iodide and the mixture is stirred at room temperature. After 1 hour, a further 4 ml of methyl iodide are added and the mixture is stirred for a further 2.5 hours. The undissolved inorganic salts are filtered off under suction and the solution is concentrated. The residue is treated with water, the mixture is extracted with methylene chloride and the extract is dried with sodium sulphate, filtered and concentrated. After crystallisation from ethyl acetate/petroleum ether, there is obtained rac-3-ethyl-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 175°-176° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:28]([O:32][C:33]([N:35]1[CH2:39][CH2:38][C@H:37]([C:40](O)=[O:41])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.Cl.C(N(CC)CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1>ClCCl>[C:28]([O:32][C:33]([N:35]1[CH2:39][CH2:38][C@H:37]([C:40](=[O:41])[NH:27][CH2:26][CH2:25][CH2:24][NH:23][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:2][CH2:3]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: NCCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)NCCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)C1
Yield: 90.2 %

Procedure:
A stirred suspension of 2-[2-(3-aminopropylamino)-5-chloropyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (500 mg, 1.24 mmol) in dichloromethane (30 mL) is treated at room temperature with (S)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (333 mg, 1.55 mmol), N,N-diisopropylethylamine (0.220 mL, 1.26 mmol), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.25 mmol) and 1-hydroxybenzotriazole (171 mg, 1.21 mmol) for 24 hours. The mixture is then diluted with dichloromethane (30 mL), filtered, washed with water (30 mL) and diethyl ether (30 mL), and dried to provide (S)-3-{3-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propylcarbamoyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (670 mg, 90%). A stirred mixture of this intermediate (665 mg, 1.11 mmol) in dichloromethane (25 mL) is treated at room temperature with TFA (2.5 mL) for 72 hours. The mixture is then concentrated under reduced pressure and subjected to chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 16-40%, to provide the title compound (474 mg, 82% yield). ES+(m/z) 499 (35Cl) and 501 (37Cl) [M+H].
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3CC(C)(C)C([O-])=O)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CC[O:34]C(C)=O.CCCCCC>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([OH:34])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(Cc1cccc2nc(C#Cc3ccccc3)ccc12)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1cccc2nc(C#Cc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(Phenylethynyl)quinoline-5-ylpivalate (15.4 mg, 0.0468 mmol) was dissolved in THF (0.78 mL), followed by cooling down to 0° C. After LiAlH4 (0.06 mL, 0.117 mmol) was added thereto, the resulting mixture was warmed to room temperature and stirred for 1 hr. The completion of the reaction was confirmed by TLC (EtOAc/Hexane=1:1). When the reaction was completed, a saturated aqueous solution was added thereto, and the resulting mixture was extracted with diethylether, to thereby obtain an organic layer. The organic layer was dried over anhydrous MgSO4 and filtrated. The filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/Hexane=1:1, R.f: 0.7), to thereby obtain 2-(phenylethynyl)quinoline-5-ol (5.6 mg, 49%) as a yellow solid.
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14]CC)=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[OH-].[Na+]>O1CCCC1.CO>[N:1]1[N:2]([C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([OH:14])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CCOC(=O)c1cccnc1-n1cc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1-n1cc2ccccc2n1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of ethyl 2-(2H-indazol-2-yl)nicotinate (3.44 g, 12.87 mmol; prepared according to procedures of WO 2008/080969) in a mixture of tetrahydrofurane (THF) (50 ml) and methanol (100 ml) a 2 M aqueous solution of sodium hydroxide (20 ml) was added and stirred over night at room temperature. The mixture then was concentrated. Water (200 ml) and then a 2 N aqueous solution of hydrochloric acid (HCl) (40 ml) were added, and the immediately formed solid was filtered off under suction. Treatment of the solids with ethylacetate (50 ml) gave 2.95 g of the title compound as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[NH2:19][C:20]1[N:24]([CH2:25][CH3:26])[N:23]=[CH:22][CH:21]=1>O.[Cu]>[CH2:25]([N:24]1[C:20]([NH:19][C:8]2[C:9](=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[C:10]([OH:12])=[O:11])=[CH:21][CH:22]=[N:23]1)[CH3:26]
Reactant: COc1ccc(C(=O)O)c(I)c1
Reactant: CCn1nccc1N
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCn1nccc1Nc1cc(OC)ccc1C(=O)O
Temperature: 25 °C
Yield: 56.2 %

Procedure:
K2CO3 (13.94 g, 0.101 mol) was dissolved in water (67 ml) and then 2-iodo-4-methoxybenzoic acid (25.3 g, 0.091 mol) was added, followed by 5-amino-1-ethylpyrazole (11.2 g, 0.101 mol) and finally copper (2.7 g). The reaction mixture was refluxed for 20 hours, cooled to room temperature and then water (350 ml) was added and the mixture was refluxed for 0.75 hours. The reaction mixture was cooled, and the product was collected by filtration, recrystallized from ethanol, and dried in an oven at 40° C. to afford 13.37 g (56%) of N-(1-ethylpyrazol-5-yl)-4-methoxyanthranilic acid, m.p. 130°-135° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([C:29]([OH:34])([CH2:32][CH3:33])[CH:30]=[CH2:31])[CH3:28]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH:27][C:29]([CH2:32][CH3:33])([OH:34])[CH2:30][CH3:31])[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(O)(CC)CC
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Solvent: CO
Product: CCC(O)(C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1)CC

Procedure:
Obtained by a procedure similar to that described in Example 1, from 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 1) and 3-ethylpent-1-en-3-ol (Example 9(a)), as a foam. Rf 0.66 (SS 7). [α]D25 -27° (c=0.1, CH3OH). Found: C,75.33; H,+.29; N,5.65. C28H34N2O3 requires C,75.30; H,7.67; N,6.26%.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C1C(=O)N([Cl:18])C(=O)C1>>[Cl:18][C:9]1[CH:8]=[CH:7][C:6]([NH2:10])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(N)c1
Reactant: O=C1CCC(=O)N1Cl
Product: CC(C)c1cc(N)ccc1Cl

Procedure:
Prepared from 7.84 g of 3-iso-propyl-phenylamine and 7.75 g NCS. Yield: 4.6 g. LC-MSD, m/z for C9H12ClN [M+H]+=170.2, 172.0;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.OS(O)(=O)=O.[CH3:16]O>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:16])=[O:9])[CH:3]=1
Reactant: O=C(O)c1cc(O)ccn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)ccn1

Procedure:
A mixture of commercially available 4-hydroxypicolinic acid (3.000 g; 21.56 mmol) and concentrated H2SO4 (0.6 ml) in anh. MeOH (40 ml) was refluxed, under nitrogen, for 22 h. MeOH was removed under reduced pressure, and the residue was basified by addition of a solution of 10% aq. NaHCO3. The mixture was then extracted with DCM (3×), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording methyl 4-hydroxypicolinate as a beige solid. LC-MS (conditions A): tR=0.18 min.; [M+H]+: 154.11 g/mol.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1.O>ClC1C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:6]2[CH:11]=[CH:10][C:9]([Cl:1])=[CH:8][CH:7]=2)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1
Reactant: [Cl-]
Reactant: CNCC(O)c1ccc(Br)cc1
Agent: [Al+3]
Solvent: O
Solvent: Clc1ccccc1
Product: CNCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Aluminium chloride (278 mg, 2.087 mmol) was added portionwise to a stirred solution of 1-(4-Bromo-phenyl)-2-methylamino-ethanol (160 mg, 0.696 mmol) in chlorobenzene (3 ml) and the reaction mixture stirred at room temperature for 17 hours. Water (2 ml) was added dropwise and the reaction mixture was then partitioned between dichloromethane (100 ml) and saturated NaHCO3 (30 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was then purified by Phenomenex_Strata_SCX column chromatography eluting with methanol followed by 2N ammonia in methanol to afford the desired product. LC/MS: (PS-B3) Rt 3.58 [M+H]+ 324.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][N:9]=C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])[CH3:3].[CH:23]1(Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:2]([O:5][C:6](=[O:7])[CH:8]([NH2:9])[CH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: BrC1CCCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(N)C1CCCCCC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(diphenylmethylene)glycerine tert-butyl ester (6.83 mmol) and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphthol[7,6,1,2-cde]azepinium bromide (6.84 μmol) in 45 mL toluene were sequentially added cycloheptyl bromide (8.2 mmol) and CsOH H2O (34.2 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 10 min and then at RT for 4 days. Another portion of (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphthol[7,6,1,2-cde]azepinium bromide (6.84 μmol) was added and stirring was continued at RT for another 24 h. The reaction was quenched with water and extracted 3 times with DCM. The combined organic layers were combined, concentrated and the residue was redissolved in 100 mL THF. A solution of 100 mL aq. 0.5M citric acid solution was added and the mixture was stirred at RT for 4 h. The mixture was concentrated to half of its volume and extracted twice with Et2O. The aqueous layer was basified with solid NaHCO3 and extracted 3 times with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired product as yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[O-:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].O>C1COCC1>[C:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: [O-]c1ccccc1
Reactant: C=CCCC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)Oc1ccccc1
Reaction time: 24 h
Yield: 90 %

Procedure:
4-Pentenoyl chloride (8.16 g, 69.1 mmol) was added dropwise to sodium phenoxide (8.02 g, 69.1 mmol) in THF (160 ml) at 20° C. After 24 hours at 20° C. H2O (100 ml) was added and the aqueous phase was extracted with Et2O (3×200 ml). The organic phase was washed with NaHCO3 (2×200 ml), brine (2×200 ml) to neutrality, then dried (Na2SO4), filtered, concentrated and bulb-to-bulb distilled to afford the desired title ester in 90% yield. B.p.: 70° C./0.04 mbar.
Reaction SMILES: [CH2:1]([C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][OH:17])[O:5][CH2:4]1)[CH3:2].CC1(C)N([O])C(C)(C)CCC1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:31])C>C(Cl)Cl>[CH3:14][C:12]([O:11][C:9]([N:8]1[C@H:3]([CH2:1][CH3:2])[CH2:4][O:5][C@H:6]([C:16]([OH:31])=[O:17])[CH2:7]1)=[O:10])([CH3:13])[CH3:15]
Reactant: CC[C@@H]1CO[C@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Product: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a vigorously stirred solution of 1,1-dimethylethyl(2S,5R)-5-ethyl-2-(hydroxymethyl)-4-morpholinecarboxylate (2.52 g, 10.27 mmol) in CH2Cl2 (50 mL) that was cooled to 0° C. were added TEMPO (0.321 g, 2.054 mmol) and (diacetoxyiodo)benzene (7.28 g, 22.60 mmol). The ice bath was removed, and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with CH3OH and then concentrated to afford the title compound (0.711 g) as a yellow oil. LC-MS (ES) m/z=260 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[C:15]1[C:16](=[O:30])[NH:17][CH:18]([CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([O:28][CH3:29])[CH2:24][CH2:23]2)[C:19]=1[OH:20].CCN(CC)CC>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:5]([O:4][C:2](=[O:3])[O:20][C:19]1[CH:18]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([O:28][CH3:29])[CH2:26][CH2:27]2)[NH:17][C:16](=[O:30])[C:15]=1[C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[CH3:7])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CON1CCC(CC2NC(=O)C(c3cc(C)ccc3C)=C2O)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCN(OC)CC1
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (72 mg, 0.67 mmol) was added dropwise to a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-5-(1-methoxy-piperidin-4-ylmethyl)-1,5-dihydro-pyrrol-2-one (220 mg, 0.67 mmol), Et3N (94 mg, 0.9 mmol) and DMAP (30 mg, 0.25 mmol) in 10 ml of THF at room temperature. The mixture was stirred for 30 min and concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel. Yield: 150 mg of carbonic acid 4-(2,5-dimethyl-phenyl)-2-(1-methoxy-piperidin-4-ylmethyl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (title compound P1.1) as a gum.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.Cl.[NH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[NH:1]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:2]([C:15]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: COC(=O)CCN
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)[C@@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Yield: 69.8 %

Procedure:
Boc-D-Trp(CHO)-OH (10.0 g), HCl.H-βAla-OMe (4.41 g) HOBt (4.47 g), WSCD (5.14 g) and DMF (100 ml) were reacted in a similar manner to that of Preparation 1-1) to give Boc-D-Trp(CHO)-βAla-OMe (8.77 g). mp: 134°-135° C. Rf: 0.54 (CHCl3 :MeOH=9:1)
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:29][CH2:28]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:29][CH2:28]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCCO)CC1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Product: O=C(OCc1ccccc1)N1CCC(CCCCCBr)CC1

Procedure:
Prepared similarly to Intermediate 10 from phenylmethyl 4-(5-hydroxypentyl)-1-piperidinecarboxylate (for a preparation, see Chem. Pharm. Bull., 1986, 34(9), 3747-3761)
Reaction SMILES: [C:1]1(C)C=CC(S(N=[N+]=[N-])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].COP(CC(=O)C)(=O)OC.[C:30]([O:34][C:35](=[O:45])[NH:36][CH:37]1[CH2:42][CH2:41][CH:40]([CH:43]=O)[CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>CC#N.CO>[C:30]([O:34][C:35](=[O:45])[NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([C:43]#[CH:1])[CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: COP(=O)(CC(C)=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: C#C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of p-toluenesulfonyl azide (10.57 g, 53.1 mmol) in MeCN (660 ml) were added K2CO3 (18.6 g, 134.5 mmol) and (2-oxo-propyl)-phosphonic acid dimethyl ester (7.3 ml, 53.1 mmol). The slurry was stirred at rt for 2 hours and a solution of (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (8.5 g, 37.4 mmol) in MeOH (100 ml) was added and the reaction proceeded overnight. The solvent was removed in vacuo. The residue was partitioned between water (100 ml) and EA (150 ml). The aq. layer was further extracted twice with EA (2×150 ml). The combined extracts were washed with brine and concentrated to dryness. The residue was chromatographed (Hex-EA 3-1) to afford the title alkyne (4.6 g, 55% yield) as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([SH:33])[NH:31][CH:32]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([S:33][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:22])=[N:4][CH:3]=2)[NH:31][CH:32]=1)=[O:27])[CH3:24]
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCOCC1
Reactant: CCOC(=O)c1c[nH]c(S)n1
Product: CCOC(=O)c1c[nH]c(Sc2cnc(NC(=O)N(C3CCCCC3)C3CCOCC3)s2)n1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-pyran-4-yl)-urea (Example 189) and ethyl-2-mercapto-1H-imidazole-4-carboxylate.