Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@H:10]2[O:19][C@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]3[C@H:11]2[CH2:20][CH2:21][N:22]2[C:27](=[O:28])[C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[N:24]=[N:23]2)=[CH:4][CH:3]=1.O1CCCC1>[Pd].CO>[CH3:17][C:15]1([CH3:18])[O:14][C@@H:13]2[O:19][C@H:10]([CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)[C@H:11]([CH2:20][CH2:21][N:22]3[C:27](=[O:28])[C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[N:24]=[N:23]3)[C@@H:12]2[O:16]1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(Br)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2O[C@H](CCc3ccccc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Reaction time: 4 h
Yield: 118.2 %

Procedure:
To the solution of the compound obtained from step j of Example 1 (0.3 g) in a solvent mixture of tetrahydrofuran:methanol (10 mL:10 mL) palladium/carbon (0.2 g, 10%) was added at room temperature, and the reaction mixture was hydrogenated at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (0.3 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1>C1C=CC=CC=1.C(NCC)C>[CH2:3]([N:4]([CH2:5][CH3:6])[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1)[CH3:2]
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Solvent: c1ccccc1
Solvent: CCNCC
Product: CCN(CC)c1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 20 ml of benzene, 20 ml of diethylamine was added, and the mixture was heated for 24 hours at 80°-90 ° C. in a sealed tube. The reaction mixture was evaporated. Water was added to the residue, and then the aqueous solutron was adjusted with dilute hydrochloric acid to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.75 g of the desired compound as yellow plates, m.p. 217°-218 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=S)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH3:26]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[NH:26])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: S=C(Nc1ccccc1)Nc1ncccc1OCc1ccc(Cl)cc1
Product: N=C(Nc1ccccc1)Nc1ncccc1OCc1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
A mixture of N-[3-(4-chlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea (3.00 g, 0.008 mol), yellow mercuric oxide (2.17g, 0.01 mol) and methanolic ammonia solution (40 ml) was stirred for 48 hours. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 1.8 g (63%), m.p. 173°-174 ° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:20][NH:21][NH2:22]>FC(F)(F)C(O)C(F)(F)F>[CH3:20][N:21]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:22]1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CNN
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)n(C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 4-(4-nitrophenyl)-2,4-dioxobutanoate (500 mg, 1.885 mmol) was dissolved in hexafluoroisopropanol (4 ml) and methylhydrazine (87 mg, 1.885 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, concentrated to dryness, triturated with ether; and filtered to provide the title compound.
Reaction SMILES: C([C:5]1[O:6][C:7]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(OC)=O.[OH-].[Na+]>O1CCOCC1>[Cl:15][C:14]1[C:7]2[O:6][CH2:5][C:9](=[O:10])[C:8]=2[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1oc2c(Cl)cccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1COc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
According to the procedure of D. C. Schroeder, et al., J Org. Chem., 27, 586 (1962) a mixture of 2-carbomethoxy-7-chloro-3-hydroxybenzofuran (16.9 g, 0.075 mol), dioxane 75 mL), and 1N NaOH (375 mL, 0.375 mol) was stirred at room temperature for 2 days. The dioxane was removed under reduced pressure and the mixture was left standing for another day. Acidification with 2N HCl (270 mL, slowly) and filtration of the resulting precipitate gave a yellow solid (12.6 g). NMR analysis showed this material to be a 3:1 mixture of product and starting material. Purification by preparative HPLC gave a yellow solid (5.8 g, 46%), m.p. 108°-111° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[OH-].[K+].Br[CH2:13][CH2:14][CH3:15]>CS(C)=O.O>[CH2:15]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH:14]=[CH2:13]
Reactant: Cc1cccc(C)c1O
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1c(C)cccc1C
Reaction time: 0.5 h

Procedure:
2,6-Dimethylphenol (1.22 g) is added to a mixture of powdered potassium hydroxide (2.24 g) in dimethylsulfoxide (20 ml). Then 3-bromopropane (2.42 g) is added at 20°-25° and stirred for 0.5 hr. The mixture is diluted with water (100 ml) and extracted with methylene chloride (3×). The organic extracts are washed with water (2×) and then with saline, dried over sodium sulfate and concentrated under reduced pressure to give 1-allyloxy-2,6-dimethylbenzene.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH3:17][CH:18]([CH3:22])[C:19](=[O:21])[CH3:20].Cl>C1COCC1>[OH:21][C:19]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)([CH3:20])[CH:18]([CH3:22])[CH3:17]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC(=O)C(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)C(C)C)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Isopropyl magnesium chloride (12.0 mL of a 2 M solution in THF, 24.0 mmol) was added to a solution of methyl 4-iodobenzoate (5.24 g, 20.0 mmol) in THF (50 mL) at −40° C. After 1 h, a second portion of isopropyl magnesium chloride (5.00 ml, of a 2 M solution in THF, 10.0 mmol) was added and the resulting mixture allowed to stir at −40° C. for 4 h. 3-Methyl-2-butanone (2.10 mL, 19.6 mmol) was then added and the resulting mixture allowed to warm to room temperature overnight. The reaction mixture was poured into 1 N HCl and extracted three times with EtOAc. The combined organic extracts were washed water, brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-20% EtOAc/hexanes as eluent) afforded the title compound i-2a. 1HNMR (500 MHz, CDCl3): δ 8.02 (d, 2H, J=8.5 Hz), 7.52 (d, 2H, J=8.5 Hz), 3.95 (s, 3H), 2.05 (p, 1H, J=6.6 Hz), 1.57 (s, 3H), 0.95 (d, 3H, J=6.6 Hz), 0.80 (d, 3H, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:11][C:12]([C@H:15]1[CH2:19][CH2:18][NH:17][C@H:16]1[CH3:20])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Li+].[Li+]>>[F:1][C:2]1[CH:9]=[C:8]([N:17]2[CH2:18][CH2:19][C@H:15]([C:12]([OH:11])([CH3:14])[CH3:13])[C@@H:16]2[CH3:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(F)c1

Procedure:
Using 2,4-difluorobenzonitrile (696 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (784 mg), the title compound was obtained as a colorless solid (yield: 838 mg) by an operation similar to that in Example 3.
Reaction SMILES: Br[CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[NH:4][C:3]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+]>CS(C)=O>[N:16]([CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[NH:4][C:3]1=[O:15])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ccccc2CCCCC1Br
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCCCc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (14.2 g) and sodium azide (7.1 g) in dimethylsulfoxide (400 ml) is maintained at 80° C. under an atmosphere of nitrogen for 3 hours. The reaction mixture is poured into ice/water (1200 ml) and the suspension is stirred for 30 minutes. The solid is filtered off, washed with water (300 ml) and dried to give 3-azido-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:18])[CH2:14][C:15](N)=[O:16])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][Mg]I.[Mg].CI.S(=O)(=O)(O)O>C(Cl)Cl.CCOCC>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[CH3:19])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CC(N)=O)c1ccc(C2CCCCC2)cc1
Reactant: C[Mg]I
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Solvent: ClCCl
Product: CC(=O)CC(C)c1ccc(C2CCCCC2)cc1
Temperature: 0 °C

Procedure:
A solution of 24.54 gm (0.1 mol) of 3-(4-cyclohexylphenyl)-butyramide in 750 ml of dry methylene chloride was added dropwise within one hour to a methyl magnesium iodide solution, prepared from 12.2 gm (0.5 mol) of magnesium and 71 gm (0.5 mol) of methyl iodide in a total of 400 ml of anhydrous ether, and, to complete the reaction, the resulting mixture was refluxed for 6 hours. The cooled mixture was then stirred into a mixture of 2 kg of ice and 100 ml of concentrated sulfuric acid. The organic phase was separated and washed twice with water, then with a saturated aqueous sodium bicarbonate solution and finally once more with water, then dried over anhydrous magnesium sulfate and concentrated by evaporation in vacuo. The residue was chroomatographically purified on 800 gm of silicagel, using benzene as the eluant, and the evaporated eluates were finally distilled in vacuo. 19.8 gm (81% of theory) of colorless oil, b.p. 104°-106°C at 0.05 mm Hg were obtained.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][C:14]1[C:15]([C:24]([O:26]C)=O)=[CH:16][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[N:18][CH:19]=1.O.NN>CCO>[CH3:22][CH:21]([O:20][C:17]1[CH:16]=[C:15]2[C:14]([CH2:13][CH2:12][NH:3][C:24]2=[O:26])=[CH:19][N:18]=1)[CH3:23]
Reactant: COC(=O)c1cc(OC(C)C)ncc1CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc2c(cn1)CCNC2=O
Temperature: 25 °C
Yield: 95.6 %

Procedure:
To methyl 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-2-(propan-2-yloxy)pyridine-4-carboxylate (112c, 0.630 g, 1.71 mmol) in EtOH (50 mL) was added hydrazine monohydrate (0.850 mL, 17.1 mmol). The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and the white solids collected by filtration and rinsed with EtOH. The mother liquor was concentrated and H2O (25 mL) was added, then the aqueous layer extracted with EtOAc (3×25 mL) The combined organic layers were concentrated under vacuum and purified by column chromatography (0-80% ethyl acetate/heptanes) to give 7-(propan-2-yloxy)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (112d, 337 mg, 96%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH2:12][OH:13])([CH2:10][OH:11])[CH:8]=[CH2:9])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl-].[NH4+]>ClCCl>[C:1]([O:5][C:6]([C:7]1([CH:8]=[CH2:9])[CH2:12][O:13][C:22](=[O:24])[O:11][CH2:10]1)=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CC(CO)(CO)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC1(C(=O)OC(C)(C)C)COC(=O)OC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 178.8 %

Procedure:
A solution of 2,2-bis-hydroxymethyl-but-3-enoic acid tert-butyl ester (202 mg, 1 mmol) and pyridine (0.5 mL, 6 mmol) in dichloromethane (5 mL) was stirred at −78° C. under nitrogen. A solution of triphosgene (150 mg, 0.5 mmol) in dichloromethane (2.5 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was warmed to room temperature and stirred at room temperature for 15 min and saturated ammonium chloride solution was added. The organic layer was separated, washed with hydrochloric acid (1 M), saturated sodium hydrogen carbonate solution and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 4:1 to 3:2 to afford the title compound (204 mg, 89%) as a clear gum. 1H NMR (300 MHz, CDCl3): δ 1.48 (s, 9H), 4.38 (d, J=10.7 Hz, 2H), 4.71 (d, J=10.7 Hz, 2H), 5.39 (d, J=17.4 Hz, 1H), 5.47 (d, J=10.7 Hz, 1H), 5.77 (dd, J=17.4, 10.7 Hz, 1H). LCMS (m/z) 229.1 [M+H], Tr=2.04 min.
Reaction SMILES: N[C:2]1[S:3][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:5][N:6]=1.N([O-])=O.[Na+].P(P(O)(O)=O)(O)(O)=O.[OH-].[NH4+]>P(=O)(O)(O)O.O>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:4]2[S:3][CH:2]=[N:6][CH:5]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: Nc1ncc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)s1
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: O=P(O)(O)P(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)c2cncs2)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a cooled (-5° C.), stirred solution of 2-amino-5-[(4-nitrophenyl)sulfonyl]thiazole (5.15 g, 18.1 mmol) in 85% phosphoric acid (200 mL) was added dropwise a solution of sodium nitrite (1.56 g, 22.6 mmol) in distilled water (10 mL) at such a rate to maintain the internal temperature between -5° and 5° C. When the addition was complete the reaction mixture was stirred for 1 hour at 0° C. then treated dropwise with 50% hypophosphoric acid (15 mL). After the addition, the ice bath was removed and reaction mixture stirred at room temperature for 3 hours during which time moderate frothing occurred. The brown solution was diluted with water (total volume=1 L), neutralized with 28% ammonium hydroxide and filtered. Flash chromatography of the resulting brown solid (eluted with 5% v/v ethyl acetate in methylene chloride) yielded the title thiazole (1.72 g, 35%) as a yellow solid; mp 168°-170° C. 1H-NMR (250 MHz, d6 -DMSO): 8.32 (d, 2H, J=12.6 Hz, aromatic), 8.45 (d, 2H, J=12.8 Hz, aromatic), 8.74 (s, 1H, aromatic), 9.578 (s, 1H, aromatic). MS (CI, CH4): 271(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([O:16]CC)=[O:15].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C#Cc1ccc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.65 g (1.175 mmol) of ethyl (2-chloro-4-trifluoromethylphenyl)propynoate is dissolved in 20 mL of ethanol, combined with 2 mL of 2M sodium hydroxide solution, and stirred for 3 hours at ambient temperature. The reaction mixture is evaporated down, the residue is taken up in water, and extracted with ethyl acetate. The aqueous phase is combined with 2 mL of 1M hydrochloric acid and stirred for 1 hour at ambient temperature. Then it is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate. Yield: 0.14 g (48% of theory); C10H4ClF3O2 (M=248.59); calc.: molecular ion peak (M−H)−: 247/249; found: molecular ion peak (M−H)−: 247/249; Rf value: 0.09 (silica gel, petroleum ether/ethyl acetate (4:1)).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([OH:31])[C:17]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([O:31][S:33]([CH3:32])(=[O:35])=[O:34])[C:17]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCC(O)(c1cccnc1)C(O)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(O)(c1cccnc1)C(OS(C)(=O)=O)c1ccc(Cl)cc1Cl
Yield: 50.6 %

Procedure:
23.6 ml (177 mmol) of triethylamine were added dropwise to a mixture of 8.5 g (23 mmol) of 1-(2,4-dichlorophenyl)-2-(pyrid-3-yl)-octane-1,2-diol, 2.5 ml (32 mmol) of methanesulfonyl chloride and 100 ml of methylene chloride at about 20° C. Thereafter, the mixture was washed with 30 ml of saturated sodium bicarbonate solution and 30 ml of water and was worked up in a conventional manner to obtain the product. The crude product was purified by chromatography. Yield: 50.6%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:15]2[CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:22].[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:22][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH2:11][N:12]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:13][CH2:14][C:15]=2[C:5]=1[O:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[F:23]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1F
Yield: 81.5 %

Procedure:
Dissolve 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 0.297 mmol) in DCM (5 mL). Add 2-fluorobenzoyl chloride (39 μL, 0.326 mmol), triethylamine (62 μL, 0.445 mmol) and stir at ambient temperature for 72 h under nitrogen atmosphere. Dilute with DCM, add 1M aqueous HCl and extract the aqueous phase with DCM. Dry the combined organic extracts over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:3 and 2:1) to give 7-chloro-6-[2-(2-fluorobenzoylamino)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (111 mg, 820%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[C:5]([F:13])[C:4]=1[F:14])#N.C([O-])(O)=[O:16].[Na+]>[Ni].C(O)=O>[F:13][C:5]1[C:4]([F:14])=[C:3]([CH:1]=[O:16])[CH:12]=[CH:11][C:6]=1[NH:7][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ccc(C#N)c(F)c1F
Reactant: O=C([O-])O
Agent: [Ni]
Agent: [Na+]
Solvent: O=CO
Product: CC(=O)Nc1ccc(C=O)c(F)c1F
Yield: 92.5 %

Procedure:
A mixture of 11 g of Raney nickel, 8.2 g of 4'-cyano-2',3'-difluoroacetanilide and 125 mL of 95% HCOOH is stirred and heated 30 minutes at 80°-85° C. The hot solution is filtered through diatomaceous earth and the cake washed with 3×100 mL of CH2CL2. The filtrate and wash are evaporated in vacuo to furnish a white solid. Excess saturated NaHCO3 is added to neutralize the residual HCOOH and the product is extracted with 3×400 mL of CH2Cl2. The CH2Cl2 extract is washed with saturated NaHCO3 and H2O (100 mL each), dried with Na2SO4 and evaporated to furnish 7.7 g (92.5% yield) of 2',3'-difluoro-4'-formylacetanilide, m.p. 154° C. The mass spectrum shows an ion at 200.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O>C1COCC1>[NH2:1][C:2]1[S:6][C:5]([Br:11])=[N:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncsc1N
Solvent: C1CCOC1
Product: COC(=O)c1nc(Br)sc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of methyl 5-amino-1,3-thiazole-4-carboxylate (J & W PharmLab, 10.0 g, 63.2 mmol) in THF (100 mL), N-bromosuccinimide (12.0 g, 67.4 mmol) was added portion-wise. After stirring at room temperature for 1 h, the mixture reaction was filtered to give a first crop of product as a pink solid (9.8 g). The filtrate was concentrated under reduced pressure. The resulting residue was triturated with EtOAc (15 mL) and filtered to give a second crop of product as a pink solid (5.0 g, total yield: 99%). LCMS calc. for C5H6BrN2O2S (M+H)+: m/z=236.9. found 237.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:25][C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([C:35]#[N:36])=[CH:30][CH:29]=4)[C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:39]I>CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH2:25][C:26]3[N:27]([CH3:39])[C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([C:35]#[N:36])=[CH:30][CH:29]=4)[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Cc1cc2cc(C#N)ccc2[nH]1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cc2cc(C#N)ccc2n1C)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 0.17 h

Procedure:
3.0 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-indolyl)propionate was dissolved in 30 ml of N,N-dimethyl-formamide, and then stirred under ice cooling. 270 mg of 60% sodium hydride was added to the above solution, and the stirring was continued for 10 minutes. The resulting reaction solution was mixed with 0.4 ml of methyl iodide, and the mixture was stirred at room temperature for 1 hour. The thus treated reaction solution was diluted with a toluene/ethyl acetate mixture, and then washed with an aqueous solution of ammonium chloride. After drying the resulting organic layer to distill off the solvent, the residue thus obtained was purified by subjecting it to silica gel column chromatography using a dichloromethane/acetone mixture as an elution solvent. In this way, 2.0 g of the title compound was obtained in a viscous and oily form.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[C:10](=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:13]=3[CH2:14]2)[CH2:9]1)C1C=CC=CC=1.[BH4-].[Na+].Cl>O.C(O)C.Cl[Pd]Cl>[CH3:21][C:19]1[CH:18]=[CH:17][C:13]2[CH2:14][CH:15]3[CH:10]([CH:11]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]=2[CH:20]=1)[CH2:9][NH:8][CH2:16]3
Reactant: Cc1ccc2c(c1)C(c1ccccc1)=C1CN(Cc3ccccc3)CC1C2
Agent: Cl[Pd]Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)C(c1ccccc1)C1CNCC1C2
Reaction time: 0.5 h

Procedure:
A solution of 0.55 g of palladium-II-chloride and 0.39 g of common salt in 50 cc of water is added at 25° to a solution of 35.2 g of (9aRS)-2-benzyl-9,9a-dihydro-6-methyl-4-phenyl-benz[f]isoindoline in 300 cc of ethanol. A solution of 2.0 g of sodium borohydride in 25 cc of water is added dropwise to the mixture at 0°, stirring is effected at 25° for 30 minutes, the pH of the solution is adjusted to 2 with aqueous concentrated hydrochloric acid, and hydrogenation is finally effected at 60° and a pressure of 4 atmospheres for 18 hours. The reaction mixture is filtered, the filtrate is concentrated, the residue is extracted with hot ethanol, and the clear solution is allowed to cool, whereby the hydrochloride salt form of the title compound, having a M.P. of 215°-220° (from methanol/ether), crystallizes.