Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:21]([CH3:37])([CH3:36])[CH2:20]2)[N:11]=[C:10]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:45]([CH3:61])([CH3:60])[CH2:44]2)[N:9]=1>>[CH2:28]([O:27][N:22]1[C:23]([CH3:26])([CH3:25])[CH2:24][CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]2[N:11]=[C:10]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]3[CH2:44][C:45]([CH3:60])([CH3:61])[N:46]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:47]([CH3:49])([CH3:50])[CH2:48]3)[N:9]=[C:8]([N:7]=[C:2]=[O:3])[N:13]=2)[CH2:20][C:21]1([CH3:36])[CH3:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: O=C(Cl)C(=O)Cl
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(N=C=O)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of oxalyl chloride with the compound prepared in Example 21.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@:6]2(C)[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][C@H:10]3[CH3:22].OC[C@@H]1CC[C@@H]2[C@H]3[C@H](CC[C@]12C)[C@@H]1C(=CC(=O)CC1)C[C@H]3C>O1CCOCC1>[OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C@@H:17]1[C:12](=[CH:13][C@@H:14]([OH:21])[CH2:15][CH2:16]1)[CH2:11][C@H:10]3[CH3:22]
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)CC[C@]3(C)[C@@H]21
Agent: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)CC[C@@H]3[C@@H]21
Solvent: C1COCCO1
Product: C[C@@H]1CC2=C[C@@H](O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)CC[C@@H]3[C@@H]21

Procedure:
Following a procedure analogous to that described under ix of Example 6, the title compound was prepared from (7α,14β,17α)-17-(hydroxymethyl)-7-methylestr-4-en-3-one (Example 4). [α]D20=+28.2° (c=0.49, dioxane).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[N:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](OCC)=[O:26])=[CH:19][CH:18]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>C(OCC)C.O1CCCC1>[N:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:19][CH:18]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CCOC(=O)/C=C/c1ccc(Cn2ccnc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC/C=C/c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
In 36 ml of anhydrous diethyl ether was dissolved 1.6 g of anhydrous aluminum chloride, and to the resulting solution was added 1.3 g of lithium aluminum hydride in small portions with ice-cooling over 10 minutes. The resulting mixture was stirred at room temperature for 30 minutes, and to the solution thus obtained was added dropwise a solution of 5.9 g of ethyl (E)-3-[4-(imidazol-1-ylmethyl)phenyl]acrylate in 48 ml of anhydrous tetrahydrofuran with ice-cooling over 30 minutes, after which the resulting mixture was subjected to reaction at room temperature for one hour. Subsequently, 50 ml of hydrous tetrahydrofuran (water content: 10% by volume) was added thereto with ice-cooling, and insolubles were removed by filtration and then washed with five 20-ml portions of methanol. The washings were combined with the filtrate, and the solvent was removed by distillation under reduced pressure. To the resulting oily product were added 100 ml of chloroform and 50 ml of water to form a solution. The organic layer was separated, washed successively with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution, and thereafter dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform:ethanol (20:1 by volume)] to obtain 4.0 g (yield 81.3%) of colorless, oily (E)-3-[4-(imidazol-1-ylmethyl)phenyl]allyl alcohol. This was crystallized from a mixed solvent of methylene chloride and diisopropyl ether to obtain colorless needle crystals having a melting point of 97°-99° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[CH2:9][C:10]([OH:12])=[O:11].Cl.[Cl-].[Na+]>O1CCCC1>[CH3:1][S:2][CH2:3][CH2:4][O:5][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CSCCO
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCCOCC(=O)O
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
A solution of 2-methylthioethanol (10.0 g, 0.108 mol) in dry tetrahydrofuran (25 ml) was added dropwise, over 30 min, to a suspension of sodium hydride (9.54 g of a 60% dispersion in mineral oil, 0.238 mol, washed twice with hexane) in dry tetrahydrofuran (250 ml) at 22° C. After 30 min, a solution of chloroacetic acid (10.25 g, 0.108 mol) in dry tetrahydrofuran (20 ml) was added dropwise, over 30 min at 22° C., and the resulting mixture was then heated under reflux for 5 h. The cooled mixture was treated with 250 ml of 1 N hydrochloric acid and sodium chloride added to the aqueous phase until saturation. The organic phase was separated and the aqueous phase washed with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Distillation of the resulting residue in vacuo gave 11.27 g (69% yield) of the title acid as a clear oil; bp 85-95° C./0.3 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ ppm: 2.18 (3H, s, SCH3), 2.76 (2H, t, J=6.6 Hz, CH2), 3.77 (2H, t, J=6.6 Hz, CH2), 4.20 (2H, s, OCH2).
Reaction SMILES: [NH2:1][C:2]1[N:15]=[C:5]2[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]([C:10]([NH:12][NH2:13])=[O:11])[N:4]2[N:3]=1.[CH2:16]=[C:17]1[O:21][C:19](=O)[CH2:18]1.C1COCC1>C(Cl)Cl>[NH2:1][C:2]1[N:15]=[C:5]2[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]([C:10]3[O:11][C:19]([CH2:18][C:17](=[O:21])[CH3:16])=[N:13][N:12]=3)[N:4]2[N:3]=1
Reactant: C=C1CC(=O)O1
Reactant: NNC(=O)c1cc(Br)cc2nc(N)nn12
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Cc1nnc(-c2cc(Br)cc3nc(N)nn23)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product of Step 1, 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid hydrazide (1.0 g, 3.7 mmol), diketene (0.28 mL, 3.7 mmol) and THF (˜25 mL) were placed in a flask. The mixture was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and a solution of 9:1 CH2Cl2/MeOH. The organics were dried with MgSO4 and concentrated to give an oily yellow solid. The solid was dissolved in a small amount of CH2Cl2 and filtered through a plug of silica, eluting with CH2Cl2. The filtrate was concentrated to give 1-[5-(2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-[1,3,4]oxadiazol-2-yl]-propan-2-one, which was used without further purification, in Step 3. MS (APCI+): m/z 337.0, 339.0.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[CH3:40][O:41][C:42](=[O:52])[CH:43]([NH2:51])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[I:50]>C1COCC1>[CH3:40][O:41][C:42](=[O:52])[CH:43]([NH:51][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[I:1])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[I:50]
Reactant: COC(=O)C(N)c1ccccc1I
Reactant: O=C(O)c1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)c1ccccc1I)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-iodobenzoic acid (6.4 g, 25.8 mmol) in THF (90 mL) is added HOBt (3.5 g, 25.8 mmol). After the mixture is stirred at RT for 10 min, EDCl (4.93 g, 25.8 mmol) is added followed by triethylamine (4.9 mL, 34.4 mmol). The mixture is stirred at RT for 40 min then amino-(2-iodophenyl)-acetic acid methyl ester (5.0 g, 17.2 mmol) is added and stirring is continued for 18 h. The solvent is removed under reduced pressure and water is added to the residue. The mixture is extracted with EtOAc and the organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-60% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:17])[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9](=[O:12])[C:10]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[CH3:20][OH:21].Cl>C(Cl)Cl>[C:1]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:20]2[CH2:10][CH2:5][CH2:1][CH2:2][O:21]2)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=C(C(C)(C)C)C(=O)C(C(C)(C)C)=CC1=O
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(OC2CCCCO2)cc(C(C)(C)C)c(O)c1C(C)(C)C
Reaction time: 3 h
Yield: 81 %

Procedure:
2,6-di-tert-butyl-3-methyl-1,4-benzoquinone (49 g) was dissolved in methylene chloride (300 ml) and sodium borohydride (15 g) was added to the solution under a nitrogen atmosphere. After adding methanol (30 ml) dropwise, the mixture was stirred for 3 h, poured into 5% HCl under ice cooling, and subjected to extraction with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was dissolved in methylene chloride (200 ml) and, after adding 3,4-2H-dihydropyran (26 ml) and a catalytic amount of paratoluenesulfonic acid, the mixture was stirred overnight at room temperature. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 2,6-di-tert-butyl-3-methyl-4-tetrahydropyranyloxyphenol [54.4 g (yield, 81%)] as a colorless oil. Mass 320(M+)
Reaction SMILES: [OH:1][C:2]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:4]([O:5][C:6]3=[O:13])[CH2:3]1)[CH2:10]2.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:14]([O:1][C:2]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:4]([O:5][C:6]3=[O:13])[CH2:3]1)[CH2:10]2)(=[O:17])[CH:15]=[CH2:16].[OH:1][C:2]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:4]([O:5][C:6]3=[O:13])[CH2:3]1)[CH2:10]2
Reactant: C=CC(=O)Cl
Agent: O=C1OC2CC3CC1CC(O)(C3)C2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC12CC3CC(C1)OC(=O)C(C3)C2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 50 mmol of 1-hydroxy-4-oxatricyclo[4.3.1.13,8]undecan-5-one, 150 mmol of acryloyl chloride, 150 mmol of triethylamine, and 250 ml of toluene was stirred at 60° C. for 4 hours. The resulting reaction mixture was concentrated and was then subjected to column chromatography on a silica gel to yield 1-acryloyloxy-4-oxatricyclo[4.3.1.13,8]undecan-5-one of the following formula in a yield of 50% with a conversion rate from 1-hydroxy-4-oxatricyclo[4.3.1.13,8]undecan-5-one of 73%.
Reaction SMILES: [CH3:1][C:2](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].C(O)C>[CH3:1][CH:2]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccccc1N=C(C)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccccc1NC(C)c1ccccc1
Yield: 91.6 %

Procedure:
N-(α-methyl benzylidene)-o-carbethoxyaniline (13 g) prepared by the procedure described in example XXVA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. N-(α-methyl benzyl)-o-carbethoxyaniline (XVI) (12 g) was obtained by fractional distillation. XVI had a boiling point of 168° C. at 1.4 millimeter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.OO.S(=O)(=O)(O)[OH:16]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:16])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: ClCCCSc1ccc(Cl)cc1
Agent: OO
Solvent: CC(C)=O
Product: O=S(CCCCl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 206.76 g (0.44 mol) of 1-chloro-4-[(3-chloropropyl)thio]benzene (J.A.C.S. 82, 2505, 1960) and 111.50 g of 30% H2O2 (0.98 mol) in 1 L of acetone chilled in a dry ice acetone bath was added 90 mL of concentrated sulfuric acid. The ice bath was removed and the mixture stirred at ambient temperature for 16 hr. The mixture was diluted with 1 L of water and extracted with two 500 mL portions of CH2Cl2. The extracts were dried (MgSO4) and concentrated separately and the residual material from both extractions shown to be a mixture of product and starting material. The impure product was chromatographed on Florisil (4×75 cm) using petroleum ether-chloroform for elution. The yield was 50.36 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.Cl.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([CH:28]=[CH:29][N:30]=[C:31]3[Cl:34])=[CH:26][CH:25]=2)[C:19]1=[O:35]>N1C=CC=CC=1>[Cl:34][C:31]1[C:32]2[C:27](=[CH:26][CH:25]=[C:24]([CH2:23][N:20]3[CH2:21][CH2:22][C@H:18]([NH:17][S:12]([C:10]4[S:11][C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)=[CH:8][CH:9]=4)(=[O:14])=[O:13])[C:19]3=[O:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccncc2)s1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3ccncc3)s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Reaction time: 8 h

Procedure:
5-Pyridin-4-yl-thiophene-2-sulfonyl chloride is added to a solution of 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (0.12 g, 0.38 mmol) in pyridine (2 mL). The resulting mixture is stirred overnight then concentrated to dryness. The residue is diluted with methylene chloride and washed with saturated NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered and concentrated to give 105 mg of a crude solid. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to afford the title product (0.026 g, 0.052 mmol) as a white solid.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13]C)=O)[CH2:6]1)(=[O:3])[CH3:2].[NH3:15]>>[C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([NH2:15])=[O:13])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1CCC[C@H](NC(C)=O)C1
Reactant: N
Product: CC(=O)N[C@H]1CCC[C@H](C(N)=O)C1
Temperature: 70 °C
Yield: 57.1 %

Procedure:
Methanolic ammonia (20 ml) was added to trans-methyl 3-acetamidocyclohexanecarboxylate (350 mg, 1.75 mmol), taken in a steel bomb and heated at 70° C. for 18 h. The reaction mixture was concentrated, washed with n-pentane and dried under reduced pressure to afford 200 mg (57.1%) of trans-3-acetamidocyclohexanecarboxamide as white color solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([F:25])[CH:17]=1.[OH-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:14][CH2:13]2)=[O:21])=[C:18]([F:25])[CH:17]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
1-(3,5-Dimethylpyridin-2-yl)piperazine (2.42 g) described in Preparation Example 47 was dissolve in tetrahydrofuran (32 mL), 4-bromo-2-fluorobenzoyl chloride (3.0 g) and 1N aqueous sodium hydroxide solution (15 mL) were added, and the mixture was stirred at room temperature. The reaction mixture poured into water under cooling, 4N aqueous sodium hydroxide solution and ethyl acetate were added and the mixture was extracted with ethyl acetate. The organic layer was washed with 4N aqueous sodium hydroxide solution and saturated brine, then washed with saturated brine, sodium sulfate was added and dried. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (4.39 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:6].ClC1C=C(Cl)C=C(Cl)C=1[O:24][C:25](=O)[CH:26]([CH3:39])[C:27](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:28]>BrC1C=CC=CC=1>[CH:8]1([N:7]2[C:25](=[O:24])[C:26]([CH3:39])=[C:27]([OH:28])[C:4]([C:3]([O:2][CH3:1])=[O:14])=[C:5]2[CH3:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)C=C(C)NC1CCCCC1
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Brc1ccccc1
Product: COC(=O)c1c(O)c(C)c(=O)n(C2CCCCC2)c1C
Temperature: 170 °C
Yield: 21.3 %

Procedure:
To a solution of 3-cyclohexylaminobut-2-enoic acid methyl ester (1.12 g, 5.72 mmol) in bromobenzene (20 mL) was added 2-methylmalonic acid bis-(2,4,6-trichloro-phenyl)ester (2.71 g, 5.72 mmol)and the reaction mixture was heated at 170° C. for 3 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 94:6 methylene chloride/MeOH) and recrystallization from hot MeOH provided methyl 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate as pale yellow crystals (0.34 g, 21%): 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 4.00-3.90 (m, 1H), 3.76 (s, 3H), 2.75-2.60 (m, 2H), 2.31 (s, 3H), 1.81 (s, 3H), 1.80-1.70 (m, 2H), 1.65-1.50 (m, 3H), 1.40-1.20 (m, 2H), 1.15-1.05 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([N:11]([CH2:33][CH3:34])[CH:12]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:23]([CH3:24])=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=3)[NH:21][N:20]=2)=[O:18])[CH2:13]1)[CH3:10]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:32]#[C:31][C:27]2[CH:26]=[C:25]([C:22]3[NH:21][N:20]=[C:19]([C:17]([N:14]4[CH2:15][CH2:16][CH:12]([N:11]([CH2:33][CH3:34])[CH2:9][CH3:10])[CH2:13]4)=[O:18])[C:23]=3[CH3:24])[CH:30]=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Reactant: Clc1ccc(I)cc1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#Cc4ccc(Cl)cc4)c3)c2C)C1
Yield: 74 %

Procedure:
In analogy to the procedure described in Example 31F], 1-chloro-4-iodobenzene and (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone (Example 31E]) gave the title compound in 74% yield light yellow powder. MS: 461.1 (MH+, 1 Cl).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:14][C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(-c2ccc(CCl)s2)cc1
Reaction time: 8 h

Procedure:
To a solution of 61.3 (45 mg, 0.18 mmol) in DCM (0.9 mL) were added triethylamine (24 μL, 0.18 mmol) and thionyl chloride (19 μL, 0.26 mmol) at room temperature. The mixture was stirred overnight and concentrated to afford 61.4. The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([N:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].O>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([N:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH2:10][CH2:11][CH2:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)CCCC(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(O)CCCC(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 16 h

Procedure:
A solution of the product of Example 53 (2 g) in propan-2-ol (50 ml) and sodium borohydride (1 g) were heated under reflux for 2 hours. The mixture was allowed to stand for 16 hours at ambient temperature and was poured into water (500 ml). The resulting mixture was extracted with ether and the ether extracts were dried and evaporated to give 6-[1-(3,4-dichlorophenyl)cyclobutyl]-6-dimethylaminohexan-2-ol as an oil the boiling point of which was not determined.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:27]=[CH:26][C:10]3[NH:11][C:12](=[O:25])[C@H:13]([OH:24])[C@H:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[S:15][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH3:31][N:32]([CH2:34][CH2:35]Cl)[CH3:33]>>[CH3:31][N:32]([CH3:33])[CH2:34][CH2:35][N:11]1[C:10]2[CH:26]=[CH:27][C:7]([O:6][C:5]3[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][C:9]=2[S:15][C@@H:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@@H:13]([OH:24])[C:12]1=[O:25]
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccc(F)cc4)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccc(F)cc4)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1

Procedure:
Following a procedure similar to that described in Example 11(d), 3,4 g of (2S, 3S)-2,3-dihydro-8-(4- fluorophenoxy)-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one [prepared as described in step (c) above] were alkylated with dimethylaminoethyl chloride hydrochloride to give 3.63 g of the title compound as a syrup.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:36](Cl)(=[O:38])[CH3:37].Cl>>[F:1][C:2]([F:30])([F:31])[C:3]([N:5]([CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:36](=[O:38])[CH3:37])=[CH:22][CH:21]=1)[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:4]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc(N(CCOc2cccc3ccccc23)C(=O)C(F)(F)F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)c1ccc(N(CCOc2ccc(C(C)=O)c3ccccc23)C(=O)C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a solution of 5.4 g. of ethyl 4-[N-trifluoroacetyl-2-(1-naphthyloxy)ethylamino]benzoate and 5.7 g. of anhydrous aluminum chloride at 0° C. is added 1.1 g. of acetyl chloride with stirring. After 1 hour at 0° C., the solution is poured over 200 g. of ice plus 20 ml. concentrated hydrochloric acid. The organic phase is separated and the aqueous phase re-extracted. After washing with dilute acid, the methylene chloride extract is evaporated to dryness. The residue is crystallized from acetonitrile, m.p. 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[C:4]2[CH2:15][CH:16]([C:18]([O:20]CC)=[O:19])[O:17][C:3]=12>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[C:4]2[CH2:15][CH:16]([C:18]([OH:20])=[O:19])[O:17][C:3]=12
Reactant: CCOC(=O)C1Cc2cc3c(CC(C)C)noc3c(Cl)c2O1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)Cc1noc2c(Cl)c3c(cc12)CC(C(=O)O)O3

Procedure:
The above was obtained by analogous treatment of 7c and recrystallization from ethyl acetate/hexane; m.p. 181°-183° C. Anal. (C14H14ClNO4) C,H,N,Cl.