Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1cnccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cnccc1-c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromonicotinonitrile (1.00 g, 5.46 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.90 g, 7.10 mmol) and potassium fluoride (1.05 g, 18.03-mmol) in tetrahydrofuran (50 ml) was degassed with nitrogen for 30 min then treated with tris(dibenzylideneacetone)dipalladium(0) (0.05 g, 0.05 mmol) followed by tri-tert-butylphosphine (0.60 ml of a 0.2 M solution in 1,4-dioxane, 0.11 mmol) and then the reaction was stirred at ambient temperature for 30 min before heating at 50° C. for 1 h to complete the coupling. The slurry-like reaction mixture was then diluted with water (100 ml) and stirred at ambient temperature for 90 min. The resulting solid was collected by filtration, washed with water then with isohexane, and finally dried under vacuum over phosphorus pentoxide, to afford 4-(2-fluoro-5-nitrophenyl)-nicotinonitrile as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.44-7.52 (2H, m), 8.38-8.47 (2H, m), 8.95 (1H, d, J 5 Hz), 9.06 (1H, s).
Reaction SMILES: CN(C)[CH:3]=[O:4].[C:6]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[CH3:7].O.O.O.C([O-])(=O)C.[Na+]>O>[C:22]([O:21][CH2:20][CH2:19][N:12]([CH2:11][CH2:10][O:9][C:6](=[O:8])[CH3:7])[C:13]1[CH:18]=[CH:17][C:16]([CH:3]=[O:4])=[CH:15][CH:14]=1)(=[O:24])[CH3:23]
Reactant: CN(C)C=O
Reactant: CC(=O)OCCN(CCOC(C)=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OCCN(CCOC(C)=O)c1ccc(C=O)cc1
Temperature: 60 °C

Procedure:
To 450 ml of dry dimethyl formamide were slowly added dropwise with stirring and at a temperature of 0°-10° C. 100 ml of freshly distilled phosphoroxytrichloride. This mixture was stirred for 2 hours at 20° C. To this mixture there was subsequently added dropwise with proper stirring and over a period of 60 minutes the crude reaction product of the previous step, viz. N,N-di(2-acetyloxyethyl)aniline, the reaction mixture being kept at a temperature of 20° C. Next, the reaction mixture was heated to 60° C. for 60 minutes and then poured, with vigorous stirring, into a mixture of 1 kg of ice and a solution of 525 g of sodium acetate trihydrate in 1 l of water. The organic layer was separated and the water layer was extracted four times, each time with 300 ml of dichloromethane. The combined organic layers were washed three times, each time with 200 ml of water, dried on magnesium sulphate, and concentrated by evaporation. The residue (about 280 g of dark brown oil), which consisted almost entirely of 4-di(2-acetyloxyethyl)aminobenzaldehyde, was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.CCOC(C)=O>[N:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:14]=[N-:15]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN=[N+]=[N-])c1
Reaction time: 3 h

Procedure:
To a solution of methyl 3-(bromomethyl)benzoate in DMF (55 ml) under N2 was added sodium azide (10.39 g, 160 mmol) and stirred for 3 h. The solution was diluted with EtOAc, washed (water twice, then brine), dried (MgSO4), filtered, and concentrated to give the title compound. This material was used without further purification. MS (EI+) (m/z)=101.1 [M++1]
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[N:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:14]=[N-:15]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(CN=[N+]=[N-])c1
Temperature: 50 °C
Yield: 99.9 %

Procedure:
To a solution of methyl 3-(bromomethyl)benzoate (1.0 g, 4.4 mmol) in anhydrous DMF (10 mL) was added sodium azide (285 mg, 4.4 mmol). The resulting mixture was heated at 50° C. for 2 h, cooled, diluted with CHCl3 (100 mL), washed with water (5×50 mL), dried over MgSO4 and concentrated under reduced pressure to yield methyl 3-(azidomethyl)benzoate (0.84 g, quant.), which was used without purification. 1H-NMR (CDCl3): δ 8.01 (2H, m), 7.44–7.54 (2H, m), 4.42 (2H, s), 3.94 (3H, s).
Reaction SMILES: C[O-].[Na+].C([O:6][CH2:7][CH3:8])=O.[CH2:9]([C:19]1[CH:28]=C2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=[O:29])=[CH:21][CH:20]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1(C)C=CC=CC=1>[OH:29][CH:26]=[C:25]1[CH2:24][CH2:23][C:22]2[C:8](=[CH:28][C:19]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=2)[C:7]1=[O:6]
Reactant: CCCCCCCCCCc1ccc2c(c1)C(=O)CCC2
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCc1ccc2c(c1)C(=O)C(=CO)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (5.4 gm, 40.5 moles), ethyl formate (7.4 gm, 100 mmoles) and 100 mL dry toluene was cooled in an ice bath under inert atomosphere nitrogen. A solution of the 7-decyl-tetralone (11.5 gm, 40 mmoles) in 100 mL dry toluene was added with rapid stirring. The ice bath was removed and the reaction was stirred at room temperature for 4 hours. The reaction mixture was treated with 100 mL water and 100 mL 6N HCl. The organic layer was separated and washed twice with 50 mL saturated sodium chloride, dried over anhydrous Na2SO4, filtered and evaporated to remove all the toluene. The oily residue was used for the next reaction without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:18])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].C(OCC)(=O)C>C(Cl)Cl>[NH2:18][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Yield: 54.2 %

Procedure:
To a stirred solution of 5-tert-butyl-2-(4-methoxyphenyl)-2H-pyrazol-3-ylamine (5.3 g, 21.6 mmol) in anhydrous DCM (43.2 mL) was added aluminum trichloride (14.4 g, 108.0 mmol, 5.0 eq) proportion wise, and the reaction was stirred at reflux for 18 h. The cooled reaction was poured into ethyl acetate, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. Crystallization from DCM/ether afforded the title compound (2.71 g, 54%) as a white solid. 1H-NMR (DMSO-d6) δ 9.47 (s, 1H), 7.21 (d, J=9.0 Hz, 2H), 6.75 (d, J=8.7 Hz, 2H), 5.25 (s, 1H), 4.91 (broad s, 2H), 1.13 (s, 9H); MS LC-MS [M+H]+=232, RT=1.13 min; TLC (35% EtOAc/hex), Rf=0.13.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][C:10](=[O:12])[O:9][C:7](=[O:8])[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[NH3:13]>>[C:7]([CH2:6][CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:11][C:10]([OH:9])=[O:12])(=[O:8])[NH2:13]
Reactant: CC(C)CC1CC(=O)OC(=O)C1
Reactant: N
Product: CC(C)CC(CC(N)=O)CC(=O)O

Procedure:
In another step of the method, 3-isobutylglutaric acid anhydride is reacted with ammonia to form (±)-3-(carbamoylmethyl)-5-methylhexanoic acid. In this step, the cyclic anhydride is opened and one of the carbonyl groups is converted to an amide. (±)-3-(carbamoyl methyl)-5-methylhexanoic acid can be recrystallized from a number of solvents including ethyl acetate, water, chloroform and 2-butanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:17][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1ccccc1Br
Product: CCOC(=O)c1ccccc1-c1cc(OC)c(OC)c(OC)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (7.1 g) and ethyl 2-bromobenzoate (7.0 g) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]#[C:6]/[CH:7]=[CH:8]/[CH2:9][N:10]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12)[CH3:11])([CH3:4])[CH3:3].Cl.N.[C:25]([OH:30])(=[O:29])[CH:26]([CH3:28])[OH:27]>>[CH3:4][C:2]([C:5]#[C:6]/[CH:7]=[CH:8]/[CH2:9][N:10]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12)[CH3:11])([CH3:1])[CH3:3].[C:25]([O-:30])(=[O:29])[CH:26]([CH3:28])[OH:27]
Reactant: CC(O)C(=O)O
Agent: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2ccccc12
Agent: Cl
Agent: N
Product: CC(O)C(=O)[O-]

Procedure:
The reaction was conducted in the same manner as Example 1 with the difference that 17.5 g terbinafine-hydrochloride obtained in Step B were converted into the base by adding aqueous ammonia. The obtained product was reacted with 5 g lactic acid. 18.5 g terbinafine-lactate were obtained.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].C(O)(=O)CC.[OH-].[Ca+2:13].[OH-]>>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Ca+2:13].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCC(=O)O
Product: CC(O)C(=O)[O-]

Procedure:
Feed grade (80%) lactic acid in the amount of 16.56 g is combined with 24.86 g propionic acid and divided into three equal fractions. Calcium hydroxide, 16.81 g, is divided into three equal fractions. The first fraction of lactic acid is added to 20 g of almond shell meal while stirring. Then, the first fraction of the combined base mixture is slowly added while stirring. The temperature of the mixture is observed to increase and water starts evaporating. When the product appeared to be dry, the same procedure was repeated for the remaining fractions, adding the acid while stirring, adding the base while stirring and drying. After the addition of the last fraction of the base, the evaporation of water from the mixture is closely observed. As soon as the rate of evaporation is observed to decrease, the fumaric acid is added while stirring. Because the produced salt is not yet dry, the fumaric acid agglomerates with the salt, yielding a granule comprising an organic salt and a free organic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:15][CH2:16][Cl:17])=[CH:9][CH:8]=1)[CH3:3].[C:30]([OH:35])(=[O:34])[CH:31]([CH3:33])[OH:32]>CO>[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)/[CH2:15][CH2:16][Cl:17])=[CH:11][CH:12]=1)[CH3:3].[C:30]([O-:35])(=[O:34])[CH:31]([CH3:33])[OH:32].[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)/[CH2:15][CH2:16][Cl:17])=[CH:11][CH:12]=1)[CH3:3]
Reactant: CC(O)C(=O)O
Agent: CN(C)CCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CC(O)C(=O)[O-]

Procedure:
To a solution of toremifene base (1.00 g, 0.0025 moles) and methanol (20 ml) was slowly added lactic acid (223 μl, 0.0025 moles). The mixture was stirred for a while and evaporated to dryness. The lactate of toremifene was obtained as sticky white solid. 1H-NMR (d6-DMSO) d 7.38 (tt, 2H), 7.35-7.27 (m, 3H), 7.27-7.12 (m, 5H), 6.76 (d, 2H), 6.61 (d, 2H), 3.99 (q, 1H), 3.92 (t, 2H), 3.43 (t, 2H), 2.85 (t, 2H), 2.62 (t, 2H), 2.22 (s, 6H), 1.22 (d, 3H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[Br:13]Br>CCOCC>[CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH:10]([Br:13])[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: CCOCC
Product: CCOC(=O)C1CCCC(Br)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 31 g. of ethyl cyclohexanone-2-carboxylate in 25 ml. of ether, cooled to -10° C., was added dropwise 35 g. of bromine. Stirring was continued one hour while the solution was allowed to come to room temperature. The solution was poured into ice water containing 20 g. sodium carbonate and was extracted with ether. The ether extract was washed with water, dried and evaporated to dryness to give 23 g. of the title compound; b.p. 88°-91°C. (0.2 mm).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].P(Br)(Br)[Br:15]>N1C=CC=CC=1>[Br-:15].[Br-:15].[CH2:11]([OH:12])[CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13]
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: OCCOCCOCCOCCO
Product: [Br-]
Temperature: 25 °C

Procedure:
300 g. of tetraethylene glycol and 100 g. of anhydrous pyridine are slowly added to 727 g. of phosphorus tribromide, while agitating and cooling the mixture. After cooling to room temperature, the mixture is poured on to ice and the organic phase is decanted, washed with water and dilute hydrochloric acid and dried over sodium sulphate. After distillation under vacuum (123°C-125°C and 0.4 mm. Hg) the title compound is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Methyl 4-t-butylphenylacetate (20 mmol) was dissolved in MeOH (160 mL) and treated with water (40 mL) and LiOH monohydrate (30 mmol). The reaction was allowed to stir at room temperature overnight. Volatiles were removed under reduced pressure; the remaining residue was diluted with water and neutralized to pH 4 with 1 N sulfuric acid. The resulting solids were filtered, washed with water and dried to leave 4-t-butylphenylacetic acid as an off-white solid (3.8 g, 99%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>CS(C)=O.O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 533.4 %

Procedure:
Piperidine (362 mg, 0.2 mmol) was added to a solution of 1-fluoro-4-nitro-benzene (200 mg, 1.4 mmol) in DMSO (10 mL) and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 220 mg (75%) of 1-(4-nitro-phenyl)-piperidine.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH3:3].[Cl-].[S:11](Cl)[Cl:12]>N1C=CC=CC=1>[Cl:12][S:11][N:4]([CH:2]([CH3:3])[CH3:1])[C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: ClSCl
Reactant: CCOC(=O)NC(C)C
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCOC(=O)N(SCl)C(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.2 %

Procedure:
To a solution of ethyl (1-methylethyl)carbamate (13.1 g, 0.1 mol) in 100 mlmethylene chloride cooled to 0° C. was added sulfur dichloride (11.3g, 0.11 mol) in one portion. While maintaining the temperature of the mixture at 0° C., pyridine (8.7 g, 0.11 mol) was added dropwise over eleven minutes. After complete addition of the pyridine the temperature was allowed to rise to room temperature and stirring was continued for additional 1.5 hours. The mixture was let stand overnight. Methylene chloride was evaporated under vacuum and 100 ml hexane was added. Filteration of the pyridine hydrochloride and evaporation of hexaneresulted in an orange oil which was distilled in a Kugelrohr apparatus to give 12.5 g of the title compound Bp: 64°-80° (bath temperature) at 1.4 mm Hg.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+]>O>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Brc1ccc2c(c1)C=NCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(c1)CNCC2
Temperature: 50 °C
Yield: 91.7 %

Procedure:
A total of 219 g (0.89 mol) of 7-bromo-3,4-dihydro-isoquinoline hydrochloride and 1.5 liters of water were combined and heated to 50° C. A total of 33.7 g (0.89 mol) of sodium borohydride was added in portions over 0.5 hours during which time the temperature rose to 62° C. The reaction was then cooled to ambient temperature and extracted three times with 1 liter of methylene chloride. The combined organic layers were washed with 1 liter of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to yield 173 g of an oil.
Reaction SMILES: [CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)(=O)C.[Fe]>[CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield by reducing trans-N-decyl-2-(4-nitrophenyl)cyclopropanecarboxamide with iron powder in glacial acetic acid, in a manner analogous to Preparation 34.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1)[O:8][C:7]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:6][C:5]2([CH3:20])[CH3:19].C(N(CC)CC)C.O1CCCC1.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>CCCCCC.[Cu]I.C(OCC)(=O)C>[CH2:15]([C:7]1([CH2:17][CH3:18])[CH2:6][C:5]([CH3:20])([CH3:19])[C:4]2[C:9](=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=[C:2]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[CH:3]=2)[O:8]1)[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: CCC1(CC)CC(C)(C)c2cc(Br)cc(C(C)C)c2O1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1(CC)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C(C)C)c2O1
Yield: 78.1 %

Procedure:
Following General Procedure D and using 6-bromo-2,2-diethyl-8-isopropyl-4,4-dimethyl chroman (Intermediate 27, 0.89 g, 2.62 mmol), triethyl amine (5 mL), tetrahydrofuran (10 mL), copper(I)iodide (0.050 g, 0.26 mmol), trimethylsilyl acetylene (2.5 mL, 17.6 mmol) and dichlorobis(triphenylphosphine)palladium(11) (0.184 g, 0.26 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using hexane to 2% ethyl acetate in hexane as the eluent, the title compound (0.73 g, 79%) was obtained as a brown oil.
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[K+].[F:16][CH:17]([F:21])[C:18](F)=[O:19]>C1(C)C=CC=CC=1>[F:16][CH:17]([F:21])[C:18](=[O:19])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C(F)C(F)F
Reactant: CCOC(=O)C=CN1CCCCC1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Ethyl 3-piperidin-1-ylacrylate (99%, 8.7 g, 50 mmol) and KF (spray dried) (4.44 g, 76.3 mmol) were initially charged in 100 ml of toluene and cooled to −30° C. At this temperature, difluoroacetyl fluoride (98%, 6.10 g, 61 mmol) was then introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 h, warmed to room temperature. The reaction mixture was washed with deionized water (50 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. This gave ethyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 13.0 g; purity according to GC: 91.2%; yield: 94%). 1H-NMR (CDCl3): δ=1.3 (t, 3H), 1.75 (m, 6H), 3.3 (m, 2H), 3.6 (m, 2H), 4.25 (q, 2H), 6.6 (t, 1H), 7.85 ppm (s, 1H).
Reaction SMILES: C1CCNCC1.[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[Cl:20][C:21]1[CH:39]=[CH:38][C:24]([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][NH:33][C:34](=[O:37])[CH2:35][NH2:36])[CH2:28][CH2:27]2)=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:39]=[CH:38][C:24]([CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([CH2:32][NH:33][C:34](=[O:37])[CH2:35][NH:36][S:16]([C:13]3[CH:14]=[CH:15][C:10]([CH:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=3)(=[O:18])=[O:17])[CH2:30][CH2:31]2)=[CH:23][CH:22]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(C)c1ccc(S(=O)(=O)NCC(=O)NCC2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g) and 4-isopropylbenzenesulfonyl chloride (1.5 equivalents) were added to a chloroform (2 mL) solution of 1-(4-chlorobenzyl)-4-[(glycylamino)methyl]piperidine (14.8 mg, 0.05 mmol). The resulting mixture was stirred at 25° C. for 16 hours, then filtered and concentrated to thereby afford 1-(4-chlorobenzyl)-4-[[N-(4-isopropylphenylsulfonyl)glycyl]aminomethyl]piperidine (Compd. No. 869) (22.1 mg, 92%). The purity was determined by RPLC/MS (86%). ESI/MS m/e 478 (M++H, C24H32N3O3S).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][C:11](=O)[NH:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2>O1CCCC1>[O:7]1[CH2:12][CH2:11][NH:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2
Reactant: O=C1COc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCO2
Reaction time: 0.25 h

Procedure:
Into a 250 mL 3-necked round bottom flask was placed a solution of lithium aluminum hydride (3.6 g, 94.74 mmol) in tetrahydrofuran (80 ml). The mixture was stirred for 15 minutes. This was followed by the addition of a solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (5.7 g, 38.22 mmol) in tetrahydrofuran (21 mL), which was added dropwise with stirring. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). The reaction mixture was then quenched by the adding 3.6 mL of H2O and 10.8 mL 15% NaOH. A filtration was performed. The filter cake was washed with 30 mL of tetrahydrofuran. The resulting solution was extracted two times with 100 mL of ethyl acetate and the organic layers combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 4.8 g (79%) of 3,4-dihydro-2H-benzo[b][1,4]oxazine as red oil.