Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:17])=O)=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]#[N:17])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(F)ccc1-2
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1cc(F)ccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
6.31 g (21 mmol) of (S)-7-fluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide were suspended in 20 ml of dioxan and 3.6 ml of pyridine and treated dropwise at 5° to 10° with 3.3 ml of trifluoroacetic anhydride. The reaction mixture was stirred at room temperature overnight and poured into 150 ml of water. The suspension obtained was filtered and the crystals were dried. There were obtained 5.36 g (90%) of (S)-7-fluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile of m.p. 254°-256°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c(F)c1
Solvent: ClCCl
Product: Cc1cc(F)c(O)c([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 93 %

Procedure:
2-Fluoro-4-methylphenol (2.6 g, 20.61 mmol) was dissolved in dichloromethane (DCM) and placed in a 100 mL RB flask. Nitric acid, 70% (1.576 mL, 24.74 mmol) was added dropwise (exotherm observed). The reaction mixture was left to stir for ˜1 hr, washed with water, the organic dried and evaporated to give a yellow solid, 2-fluoro-4-methyl-6-nitrophenol (3.276 g, 19.14 mmol, 93% yield).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([N:8]=[C:9]=[O:10])([CH3:7])([CH3:6])[CH3:5].[Cl-].[Na+]>C(O)C>[C:4]([NH:8][C:9](=[O:10])[NH:2][NH2:3])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)N=C=O
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NC(=O)NN
Reaction time: 1 h

Procedure:
To a solution of 30 g of hydrazine hydrate (80%) in 100 ml of ethanol was added dropwise 34 ml of t-butyl isocyanate under ice-cooling, followed by stirring for 1 hour. After stirring at room temperature for an additional 3 hours, a saturated aqueous solution of sodium chloride was added to the reaction solution. The mixture was extracted three ,times with ethyl acetate, and the organic layer was distilled under reduced pressure. To the residue was added 65 ml of a 10% hydrochloric acid aqueous solution. After washing with chloroform, 16 ml of a 50% aqueous solution of sodium hydroxide was added thereto, and sodium chloride was further added thereto The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. Recrystallization of the residue from n-hexane/ethyl acetate (9:1 by volume) to obtain 36 g of 4-t-butylsemicarbazide (melting point:109 -110 ° C.).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[S:5][C:6]([Br:9])=[CH:7][N:8]=1.CO.C[O-].[Na+].[CH:15](O)=[O:16]>C(OCC)=O>[Br:9][C:6]1[S:5][C:4]([CH2:3][NH:2][CH:15]=[O:16])=[N:8][CH:7]=1
Reactant: NCc1ncc(Br)s1
Reactant: O=CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC=O
Product: O=CNCc1ncc(Br)s1
Temperature: 48 °C
Reaction time: 5 h

Procedure:
2-Aminomethyl-5-bromothiazole hydrochloride (350 g) was dissolved in 7 L of ethyl formate. To this solution were added 296 ml of a 28% methanol solution of sodium methoxide and 173 ml of a formic acid solution. The mixture was then stirred at an internal temperature of 48° C. for 5 hr. The solvent was removed by evaporation under the reduced pressure. When precipitate occurred, ethanol was added to dissolve the precipitate. The solvent was again removed by evaporation under the reduced pressure until crystal was formed. The solution was stirred under ice cooling overnight. The precipitated crystal was then collected by filtration, was then washed with cold ethanol and hexane, and was dried under the reduced pressure to give 189 g of 5-bromo-2-formylaminomethylthiazole. Further, the filtrate was concentrated, and the concentrate was crystallized from ethanol to give 58 g of secondary crystal.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>C(O)CCC>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: C1CNCCNC1
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(N2CCCNCC2)cc1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
A solution of homopiperazine (11.4 g, 114 mmol) in 1-butanol (40 mL) was added to a refluxing solution of 1-chloro-4-nitrobenzene (6.0 g, 38 mmol) in 1-butanol (40 mL) over 15 minutes. The mixture was maintained at reflux for 24 hours then cooled to room temperature and extracted with 2N hydrochloric acid. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford 1-(4-nitro-phenyl)-[1,4]diazepane (3.5 g, 42%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]([CH2:7][F:8])([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:13]1([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C>CC(N(C)C)=O.CO.CCOCC.C(Cl)Cl>[C:13]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([NH:26][C:3](=[O:4])[C:2]([OH:1])([CH3:6])[CH2:7][F:8])=[CH:27][CH:28]=2)(=[O:20])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(O)(CF)C(=O)O
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: C
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(O)(CF)C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-fluoromethylpropionic acid (0.78 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto water, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with water, and brine. After drying (Na2SO4) the ethyl acetate was removed by evaporation to give an amber foam. Trituration with ether/methylene chloride yielded the title tertiary carbinol (0.75 g, 52%) as a light tan solid; mp=189°-192° C. 1H-NMR (300 MHz, d6 -DMSO): 1.31 (s, 3H, CH3), 4.38 (dd, J=72 and 9.4 Hz, 1H, CH2F), 4.58 (dd, J=72 and 9.3 Hz, 1H, CH2F), 6.29 (s, 1H, OH), 7.58-7.68 (m, 4H, ArH), 7.89-8.02 (m, 5H, ArH), 10.16 (S, 1H, NH). MS (CI, CH4): 338(M+1, 100).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:18]2[C:17](=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=2)=[CH:6][C:7]([CH2:10][CH3:11])=[CH:8][N:9]=1
Reactant: O=C1C=CCCC1
Reactant: CCc1cnc(Cl)c(C=O)c1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: CCc1cnc(Cl)c(C(O)C2=CCCCC2=O)c1
Yield: 95 %

Procedure:
The clear solution of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.43 g).
Reaction SMILES: [OH-].[K+].Cl.[CH:4]1([CH2:7][NH2:8])[CH2:6][CH2:5]1.Cl[CH2:10][C:11]1[N:15]2[C:16]3[CH:30]=[CH:29][CH:28]=[CH:27][C:17]=3[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][CH2:20][C:14]2=[N:13][N:12]=1.[I-].[K+]>O1CCCC1>[CH:4]1([CH2:7][NH:8][CH2:10][C:11]2[N:15]3[C:16]4[CH:30]=[CH:29][CH:28]=[CH:27][C:17]=4[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][CH2:20][C:14]3=[N:13][N:12]=2)[CH2:6][CH2:5]1
Reactant: NCC1CC1
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1)=NC2
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(C2=NCc3nnc(CNCC4CC4)n3-c3ccccc32)cc1

Procedure:
In the manner given in Example 3, a solution of potassium hydroxide and (cyclopropylmethyl)amine hydrochloride is treated with a solution of 1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and potassium iodide in tetrahydrofuran to give 1-[[(cyclopropylmethyl)-amino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccccc1N1CCNCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: COc1ccc([N+](=O)[O-])cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Potassium nitrate (6.06 g) was added portionwise during 2 h to a solution of 1-(2-methoxyphenyl)piperazine ( 10.0 g) in sulphuric acid (50 ml; 95%) at room temperature. The resulting brown solution was stirred at room temperature for 30 min and added cautiously to ice (300 ml). The solution was basified with aqueous sodium hydroxide (5N) and extracted with ethyl acetate (2×400 ml). The dried extract was evaporated and the residue was purified on a column of silica (190:10:1) to give the title compound as a yellow solid (9.4 g). m.p. 102°-104° C.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:7][CH2:6]1)=O.[C:28]([NH2:36])(=[S:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>CCO>[C:29]1([C:28]2[S:35][CH:2]=[C:3]([CH:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH:15]4[C:27]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[C:21]5[C:16]4=[CH:17][CH:18]=[CH:19][CH:20]=5)=[O:12])[CH2:9][CH2:10]3)[N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CBr)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: NC(=S)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2csc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
To a stirred solution of (9H-fluoren-9-yl)methyl 4-(bromoacetyl)piperidine-1-carboxylate (3 g, 7.03 mmol) in EtOH (20 mL) was added thiobenzamide (0.96 g, 7.03 mmol). This reaction mixture was stirred at RT for 24 h. NaHCO3 (3 g) was added and the reaction mixture was further stirred for 5 d. The reaction mixture was concentrated to afford the crude material which was chromatographed over silica gel eluting with a gradient (0-10% EtOAc:hexanes) to afford (9H-fluoren-9-yl)methyl 4-(2-phenylthiazol-4-yl)piperidine-1-carboxylate (2 g, 61%) as an off white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:33])[CH2:11][C@H:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C@H:22]3[C:30]4[C:25](=[C:26]([OH:32])[CH:27]=[CH:28][C:29]=4[F:31])[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:8][O:9][C:10](=[O:33])[CH2:11][C@H:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C@H:22]3[C:30]4[C:25](=[C:26]([O:32][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:27]=[CH:28][C:29]=4[F:31])[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triethylamine (0.4 mL) is added to a mixture of {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.15 g), phenylboronic acid (0.10 g), freshly activated molecular sieves 4A (1.0 g), copper(II) acetate (78 mg) and dichloromethane (8 mL) at room temperature. The flask is purged with O2 and sealed. The mixture is stirred under O2 atmosphere (1 bar) at room temperature for 16 h. The mixture is diluted with dichloromethane, filtered and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→80:20) to give the title compound. LC (method 3): tR=0.81 min; Mass spectrum (ESI+): m/z=435 [m+H]+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH3:11]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(O)(C)C>[CH:8]1[CH:7]=[C:5]2[N:6]=[C:2]([S:1][S:1][C:2]3[S:3][C:4]4[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:11]=3)[S:3][C:4]2=[CH:10][CH:9]=1
Reactant: N
Reactant: Sc1nc2ccccc2s1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Temperature: 70 °C

Procedure:
40 g (0.24 mol) of 2-mercaptobenzothiazole (MBT), 4 mg (0.02×10-3 mol) of copper (II) acetate, (Cu(OAc)2. H2O), 4.08 g (0.24 mol) of ammonia, and 120 g of isopropanol are placed in a glass autoclave equipped with a jacket for the circulation of a heating liquid, a thermometer, a pressure measuring device and a stirring device. The reaction mixture is heated to 70° C., stirred vigorously, and placed under an oxygen pressure of 4 bar. Absorption of oxygen is noted immediately and a precipitate, dibenzothiazyl disulfide (MBTS), is formed. After 6.5 hours the reaction is discontinued and the precipitate is filtered off, washed with isopropanol, and dried under a vacuum at 50° C. 37.8 g of a product are obtained in this manner. Upon elementary analysis, IR, NMR and MS, the product formed is found to correspond to dibenzothiazyl disulfide. The purity is found to be 100% upon chromatographic analysis (melting point 178° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[C:20]2[CH:26]=[CH:25][NH:24][C:21]2=[N:22][CH:23]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccc(F)cc3)cnc3[nH]ccc23)CC1
Temperature: 150 °C
Yield: 66.4 %

Procedure:
4-Fluorophenylboronic acid (44.0 mg, 0.315 mmol), PS-palladium tetrakis (119 mg, 0.0131 mmol) and 2N sodium carbonate (262 μL, 0.525 mmol) were added to tert-butyl 4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.262 mmol, see Example 1) in dioxane (1 mL, degassed with Ar). The reaction was heated to 150° C. for 1 hour under microwave irradiation. The reaction was then cooled down and filtered. The filtrate was diluted with DCM and dried with MgSO4. After concentration, the residue was purified by chromatography (SP4, 25+M, water/ACN 90/10→10/90, 20CV) to yield tert-butyl 4-(5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (69 mg, 66.4% yield) as a solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@@H:4]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1>C(O)C.[Ni](Cl)Cl>[CH3:3][C@@H:4]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:20])[CH3:21])[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][NH2:15])=[CH:12][CH:13]=1
Reactant: CC(C)=CCC[C@H](C)CCOc1ccc(C#N)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)=CCC[C@H](C)CCOc1ccc(CN)cc1
Yield: 71.1 %

Procedure:
Sodium borohydride (NaBH4, 29.4 mmol) was added to a mixture of 4-[(3S)-3,7-dimethyl-6-octenyloxy]cyanobenzene (2.52 g, 9.80 mmol) and anhydrous nickel chloride (NiCl2, 9.8 mmol) in dry ethanol (20 mL). After 2 hours the reaction mixture was filtered over Celite® and the Celite® bed was rinsed with ethanol (2×10 mL). The solution was diluted with water (150 mL) and extracted with ether (3×25 mL). The combined ethereal phase was washed with water, dried over MgSO4, and the solvent was evaporated to afford an oil which was purified by column chromatography (EtOAc-hexane) to give 4-[(3S)-3,7-dimethyl-6-octenyloxy]benzylamine as a colorless oil (1.82 g, 6.97 mmol, 71.1% yield).
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([OH:13])=[O:12].[CH3:14]O>>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CO
Reactant: O=C(O)c1cnccn1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnccn1
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To methanol (8.0 mL), thionyl chloride (2.08 mL) was added dropwise under a nitrogen atmosphere at −10° C. and the mixture was stirred at the same temperature for 30 minutes. To this, 2-pyrazinecarboxylic acid (1.00 g, 8.06 mmol) was added at the same temperature and the mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated, a saturated aqueous sodium bicarbonate solution was added to the residue, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol 19/1) to give methyl 2-pyrazinecarboxylate (969 mg, yield: 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH2:42][CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH2:42][CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K23) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (324 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].[CH2:27]([CH:30]([NH2:34])[CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:34][CH:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: CCCC(N)CCC
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Product: CCCC(CCC)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Yield: 67.8 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester(0.50 g, 1.21 mmol), prepared substantially as described in Part C of Example 19a, and 1-propyl-butylamine (0.28 g, 2.42 mmol) were treated in the same manner as in Part C of Example 19a to produce 0.31 g (69%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-propyl-butyl)-amine: MS (AP) m/z 377.9 [(M+H)+, 100].
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:21][C@H:20]([OH:19])[CH2:22][O:23][C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[CH:26]=[CH:27][NH:28]5)[CH2:15][CH2:14]3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Product: O=[N+]([O-])c1ccc2c(C3CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-nitro-3-(piperidin-4-yl)-1H-indole (0.49 g, 2.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.40 g, 2.1 mmol). The product was isolated as a yellow crystalline solid. Yield 0.34 g (37%). mp 212-214° C. FDMS m/e=434 (M+ of free base).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.S(Cl)([Cl:14])=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([Cl:14])=[O:9])=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncc(Br)cc1F
Solvent: ClCCl
Product: O=C(Cl)c1ncc(Br)cc1F
Reaction time: 3 h

Procedure:
5-Bromo-3-fluoropyridine-2-carboxylic acid (0.40 g, 1.8 mmol) was dissolved in dichloromethane (8 mL), treated with thionyl chloride (0.80 mL, 11 mmol, 6 equiv) and the mixture was placed into a preheated oil bath at 45° C. for 3 hours. The mixture was concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21]I>C(#N)C>[Cl:18][CH2:19][CH2:20][CH2:21][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])ccc1OCCCCl
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a stirred solution of 2-methyl-4-nitrophenol (1.0 g, 6.5 mmol) and potassium carbonate (1.8 g, 13.0 mmol) in acetonitrile was added 1-chloro-3-iodopropane (1.2 g, 5.9 mmol). The mixture was heated at reflux overnight then cooled to r.t. and filtered, the solids being further washed with acetonitrile. The combined filtrates were evaporated to dryness. The crude residue was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and brine solution. The organic phase was dried over sodium sulfate, filtered and concentrated to afford 1-(3-chloro-propoxy)-2-methyl-4-nitro-benzene (700 mg, 52%) as an oil.