Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]([N:18]([C:20]2[C:21]([Cl:41])=[C:22]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:23][O:24][C:25]2[C:33]3[N:32]=[C:31]([O:34][CH3:35])[N:30]([CH3:36])[C:29]=3[CH:28]=[CH:27][CH:26]=2)[CH3:19])=[O:17])=[O:13])=[CH:6][CH:5]=1)([OH:3])=O.[NH2:42][C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:41][C:21]1[C:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]2[CH:8]=[N:9][C:4]([C:1](=[O:3])[NH:42][C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)=[CH:5][CH:6]=2)=[CH:39][CH:38]=[C:37]([Cl:40])[C:22]=1[CH2:23][O:24][C:25]1[C:33]2[N:32]=[C:31]([O:34][CH3:35])[N:30]([CH3:36])[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccncc1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)cccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)Nc5ccncc5)nc4)c3Cl)cccc2n1C
Temperature: 50 °C
Reaction time: 24 h
Yield: 7.7 %

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (90 mg) and 4-aminopyridine (14.3 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.7 mg) and 1-hydroxybenzotriazole (26.4 mg) at ambient temperature, and after standing for 1 day, the mixture was stirred for 8 hours at 50° C. To the mixture was added water, and extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 12:1, v/v) to give 4-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(4-pyridylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]-benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (7.8 mg).
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:3]1.O.NN>C(O)C.[Ni]>[F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(OCCCN2CCC(F)C2)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCCCN2CCC(F)C2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of crude 3-Fluoro-1-[3-(4-nitro-phenoxy)-propyl]-pyrrolidine (6.316 g, ˜24 mmol) was dissolved in absolute ethanol (180 mL) and to this solution was added hydrazine monohydrate (˜7.9 mL) followed by the addition of a small portion of Raney nickel (˜1 mL). The reaction mixture was heated to 50° C. with stirring for ˜2 h at which point all gas evolution had ceased. The reaction mixture was filtered through celite to remove the Raney nickel. The filtrate was concentrated in vacuo to give 4-[3-(3-Fluoro-pyrrolidin-1-yl)-propoxy]-phenylamine as a brown oil which was subjected to flash silica gel chromatography (CHCl3 to CHCl3:MeOH, 1:40 gradient eluant). Pure 4-[3-(3-Fluoro-pyrrolidin-1-yl)-propoxy]-phenylamine was isolated as a reddish oil (4.033 g, 79%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCCCO
Product: O=S(=O)(NCCCCCO)c1ccccc1

Procedure:
The preparation is carried out as in Example 1(a) from 353 g (2 mol) of benzenesulphonyl chloride and 216.6 g (2.1 mol) of 5-amino-1-pentanol.
Reaction SMILES: [C:1]([C:3]1([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH:4]1[C:6]([CH3:8])=[CH2:7])#[N:2]>C1(C)C=CC=CC=1>[C:1]([C:3]1([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH:4]=[C:6]([CH3:7])[CH2:8]1)#[N:2]
Reactant: C=C(C)C1CC1(C#N)C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C1(C#N)CC=C(C)C1
Yield: 79.3 %

Procedure:
A solution of 41.0 g of methyl 1-cyano-2-(1-methylethenyl)cyclopropane-1-carboxylate in 300 ml of toluene was passed through a pyrolysis column packed with glass helices and held at 425° C. A nitrogen flow rate was chosen which resulted in a contact time of 1-2 sec and the pyrolysate was collected in a dry ice-isopropyl alcohol cooled flask. The toluene solution was washed with 300 ml of saturated aqueous sodium bicarbonate and 300 ml of saturated sodium chloride solution, dried (MgSO4), and concentrated in vacuo to leave 32.5 g of brown oil. Distillation of the oil gave 30.4 g of the desired product as a yellow oil: b.p. 75°-100° (0.05 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH2:15]([O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Br:25])[C:22](O)=[N:21][C:20]=1[CH3:27])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Br:25])[C:22]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:21][C:20]=1[CH3:27])[CH3:16]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: CCOC(=O)c1cc(Br)c(O)nc1C
Product: CCOC(=O)c1cc(Br)c(OCc2c(-c3ccccc3)noc2C)nc1C
Yield: 76 %

Procedure:
As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (402 mg, 2.12 mmol) was converted using 5-bromo-6-hydroxy-2-methyl-nicotinic acid ethyl ester instead of 2-hydroxy-5-trifluoromethylpyridine to the title compound (SiO2, heptane:ethyl acetate=100:0 to 50:50, 700 mg, 76%) which was obtained as a colourless oil. MS: m/e=431.1/433.2 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH2:5][CH2:6][CH:7]1[CH2:9][O:8]1.C(O)(=O)C.[Li+].[Br-:17]>C1COCC1>[Br:17][CH2:9][CH:7]([OH:8])[CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:11])([CH3:10])[CH3:1]
Reactant: [Br-]
Reactant: C[Si](C)(C)C#CCCC1CO1
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCC(O)CBr
Reaction time: 8 h
Yield: 37.2 %

Procedure:
To a stirred solution of trimethyl(4-(oxiran-2-yl)but-1-ynyl)silane (4.5 g, 27 mmol) in THF (90 mL) containing acetic acid (4.81 g, 80.21 mmol), was added at 0° C. ahydrous LiBr (3.71 g, 42.78 mmol). The reaction mixture was left stiffing overnight at room temperature. The reaction was quenched with saturated NaCl and extracted with Et2O. The organic phase was washed once with a solution of 1M K2CO3 saturated with NaCl, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, from Cyclohxane 100% to DCM 100% as eluent) to afford 2.5 g of 1-bromo-6-(trimethylsilyl)hex-5-yn-2-ol (Yield: 38%) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:27]([NH:1][CH2:2][CH2:3][C@@H:4]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])[C:5]([O:7][C:8]([CH3:10])([CH3:11])[CH3:9])=[O:6])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CCN)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)O)[C@H](CCNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A solution of 1.0 g of 2(R)-[3-amino-1(S)-(tert-butoxycarbonyl)propyl]-4-methylvaleric acid in 20 ml of dichloromethane was cooled to 5° C. under nitrogen and treated with 1.3 ml of triethylamine and a solution of 0.54 g of benzoyl chloride in 10 ml of dichloromethane. The mixture was stirred overnight at room temperature and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with 2M aqueous hydrogen chloride and water. Drying over anhydrous magnesium sulfate, filtration and evaporation of the solvent gave a pale yellow oil which was purified by flash column chromatography on silica gel, using ethyl acetate/hexane (3:1), to give 0.78 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-4-methylvaleric acid in the form of a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:16])([CH3:15])[C:8](=[O:17])[CH2:7][CH2:6]2)#[CH:2].C1COCC1>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:16])([CH3:15])[C:8](=[O:17])[CH2:7][CH2:6]2)[CH3:2]
Reactant: C#Cc1cc2c(cc1OC)C(C)(C)C(=O)CC2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc2c(cc1OC)C(C)(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
6-Ethynyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (346 mg) was dissolved in ethanol:THF (=2:1 mixture solvent, 20 ml), added with 10% Pd/C (170 mg), and then the mixture was stirred at room temperature for 1 hr under hydrogen atmosphere. The catalyst was removed by filtration and the organic layer was concentrated under reduced pressure to obtain the title compound (322 mg, yield 91%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].CCN(C(C)C)C(C)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:7][N:6]=1)=[O:4]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
To a solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (Preparation 41, 85 g, 492 mmol) in DMF (365 mL) was added DIPEA (129 mL, 738 mmol) and piperidine (58.4 mL, 591 mmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was poured onto water (4 L) and the resulting precipitate was collected by filtration to give the title compound as a white solid (85.12 g) in a 78% yield.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].C(O)(=O)C.[F:10][C:11]([F:27])([F:26])[C@@H:12]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:27][C:11]([F:10])([F:26])[C@@H:12]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])=[CH:17][CH:18]=1
Reactant: C[C@@H](O)CN
Reactant: CS(=O)(=O)N[C@@H](c1ccc(C=O)cc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H](O)CNCc1ccc([C@H](NS(C)(=O)=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Dissolve (2R)-1-aminopropan-2-ol (0.4 g, 5.33 mmol) in DCM (10.6 mL); then acetic acid (366.2 uL, 6.39 mmol) and N-[(1S)-2,2,2-trifluoro-1-(4-formylphenyl)-ethyl]-methanesulfonamide (1.65 g, 5.86 mmol). Stir the resulting mixture at ambient temperature for 2 hours; then add sodium triacetoxyborohydride (2.82 g, 13.31 mmol); and stir at ambient temperature overnight. Add MeOH (1 mL) and evaporate a portion of the solvent under reduced pressure. Purify via SCX chromatography eluting with 2M NH3/MeOH. Concentrate the appropriate fractions under reduced pressure to give the title compound (1.7 g, 93.8%). MS (m/z): 341 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.[H-].[Na+].[C:16]([O:20][C:21]([N:23]1C(C2C=CC(C#N)=CC=2)O1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:22])[NH:23][N:3]1[C:4]([CH3:13])=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=[C:2]1[CH3:1])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Reactant: Cc1nc(-c2cccnc2)c(C)[nH]1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(-c2cccnc2)c(C)n1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(2,5-Dimethyl-1H-imidazol-4-yl)-pyridine (0.035 g, 0.220 mmol) was weighed into an oven dried, nitrogen swept 10 mL round bottomed flask. Tetrahydrofuran (THF, 1 mL) was added via syringe and the resulting slurry cooled on an ice bath under nitrogen and treated with sodium hydride (0.0097 g, 0.242 mmol 60% dispersion in oil) with stirring. After 10 minutes, 3-(4-cyano-phenyl)-oxaziridine-2-carboxylic acid tert-butyl ester (0.052 g, 0.212 mmol) was added as a solid and the thick yellow slurry allowed to warm to room temperature and stir for 2 hours. The crude reaction mixture was loaded directly onto a flash silica gel column and eluted with CH2Cl2:MeOH/10:1 giving (2,5-dimethyl-4-pyridin-3-yl-imidazol-1-yl)-carbamic acid tert-butyl ester as a light yellow oil as a 5:1 mixture with its regioisomer (0.027 g, 46%): IR (film) 3389, 2978, 2930, 1730, 1478, 1275, 1252, 1156, 1017, 951, 711, 573 cm−1; 1H NMR (300 MHz, DMSO, Major isomer) δ 10.41 (s, 1H), 8.81 (s, 1H), 8.39 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.44-7.28 (m, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.46 (s, 9H); ESIMS m/z 289 [(M+H)]+ and 287 [(M−H)]−.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Li].[CH2:16]([Si:20]([CH2:23][CH2:24][CH2:25][CH3:26])(Cl)Cl)[CH2:17][CH2:18][CH3:19].[Cl-].[NH4+]>C(OCC)C>[CH2:16]([Si:20]([CH2:12][CH2:11][CH2:10][CH3:9])([CH:23]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:24]1=[CH:25][CH:26]=[CH:8][CH:7]=2)[CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC[Si](Cl)(Cl)CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC[Si](CCCC)(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Fluorene (23.27 g, 140 mmol) was dissolved in 100 mL diethyl ether and the solution was cooled to −78° C. Methyllithium (1.4M in diethyl ether, 140 mL) was added dropwise to the stirred solution while maintaining the temperature at −78° C. After the addition was complete, the solution was allowed to warm to room temperature. Stirring was continued overnight. In a separate flask, di-n-butyldichlorosilane (14.9 g, 70 mmol) was dissolved in 50 mL diethyl ether. The temperature was reduced to −78° C., and the solution (prepared above) containing the fluorene anion was added to this stirred solution, dropwise. After the addition was complete, the reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was then treated with a saturated solution of ammonium chloride, the organic layer was collected and dried over magnesium sulfate, and dried in vacuo. The material was further purified by washing with methanol and drying in vacuo. Yield: 23.39 g (70.7%, 97% purity by GCMS).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH2:16][NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:10]2)C.Cl>[OH-].[Na+]>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([NH:17][CH2:16][CH:11]2[CH2:10][C:9]3[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][CH2:5][C:4]([OH:28])=[O:3])[CH:8]=3)[CH2:12]2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 70 °C
Yield: 76 %

Procedure:
195 mg (0.50 mmol) of ethyl-3-[2-[(4chlorophenyl)sulfonylaminomethyl]indan-5-yl]propionate was suspended in 3 ml of 2N sodium hydroxide and heated at 70° C. for 2 hours. After cooling, the system was made acidic with conc. HCl in an ice bath. The precipitated crystals were collected, recrystallized from a solvent mixture of ethyl acetate and hexane to obtain 137 mg of colorless flakes. Yield: 76%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)=[CH:4][CH:3]=1.[N:25]([Sn](CCCC)(CCCC)CCCC)=[N+:26]=[N-:27].O1CCOCC1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[N:18]=[N:25][NH:26][N:27]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)c(-c1ccc(Cl)cc1)nn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)cc1
Yield: 35 %

Procedure:
The title compound was prepared from 3-(4-chlorophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.351 g, 1.04 mmol), azidotributyl tin (0.351 g, 0.627 mL, 2.29 mmol) in toluene (10 mL) as described for the preparation of compound 167. Deprotection was effected by treating a dioxane solution (5 mL) with 5 mL of 6.0N aqueous solution of hydrogen chloride. Half of the solid obtained upon completion of the reaction was purified by preparatory HPLC (0.054 g, 0.18 mmol, 35% yield over 2 steps) 1H NMR (DMSO-d6) 13.7 (s, 1H), 8.8 (s, 1H), 8.1 (t, 3H), 7.8 (d, 1H), 7.6 (t, 2H); ES-MS (m/z) 297 [M+1]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17].Cl>O>[Cl:13][CH2:14][CH2:15][C:16]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=1[F:12])=[O:17]
Reactant: O=C(Cl)CCCl
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(CCCl)c1ccc(F)cc1F
Temperature: 50 °C
Yield: 75.2 %

Procedure:
Aluminum chloride (0.3 mol) was added carefully to 1,3-difluorobenzene (0.26 mol) and the mixture was heated with vigorous stirring till 50° C. 3-Chloropropionyl chloride (0.26 mol) was added dropwise over a 15 min. period at 40° C. (cooled on ice) and the mixture was stirred at 50° C. The mixture was poured into water (250 ml), ice (250 g) and HCl (25 ml) and it was stirred for 20 min. The formed precipitate was filtered off and extracted with CH2Cl2 and water, yielding 40 g (75%) of 3-chloro-1-(2,4-di-fluorophenyl)-1-propanone (interm. 1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:21]=O)=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2].[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][P:28](=[O:31])([OH:30])[OH:29].[BH3-]C#N.[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:21][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][P:28](=[O:29])([OH:31])[OH:30])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NCCCCP(=O)(O)O
Reactant: CCc1ccc(-c2ccc(C=O)nc2-c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(-c2ccc(CNCCCCP(=O)(O)O)nc2-c2ccccc2)cc1

Procedure:
Following General Procedure M, 5-(4-ethyl-phenyl)-6-phenyl-pyridine-2-carbaldehyde (Compound 56, 58 mg, 0.18 mmol), 4-aminobutylphosphonic acid (21 mg, 0.18 mmol), Bu4NOH (0.18 ml, 0.18 mmol, 1 M in MeOH) and NaCNBH3 (9 mg, 0.18 mmol) in MeOH (2 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)([N:15]1C=CN=C1)=O.[OH-].[NH4+]>CN(C)C=O>[CH:7]1[C:6]([C:10]([NH2:15])=[O:12])=[CH:5][C:4]2[CH:3]=[CH:2][NH:1][C:9]=2[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8.06 gm (50 mMol) indole-5-carboxylic acid in 150 mL dimethylformamide were added 8.11 gm (50 mMol) carbonyldiimidazole and the reaction mixture stirred at ambient temperature for 3 hours. The reaction mixture was then added dropwise to 150 mL concentrated ammonium hydroxide and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure to give a viscous oil which was subjected to silica gel chromatograpy, eluting with a gradient of dichloromethane containing 0-10% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give the title compound as an oil which crystallizes upon standing.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CC(C)=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCCCCCCBr
Solvent: CC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCCCCBr)cc2)cc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
0.2 mol (39 g) of 4-hydroxy-4′-cyanobiphenyl, 2 mol (487.5 g) of 1,6-dibromohexane, 1.45 mol (200 g) of potassium carbonate anhydride and 800 ml of acetone were placed in a 2 l three-neck flask equipped with a mechanical stirrer and the mixture was reacted under reflux for 20 hours by using a water bath. The reaction mixture was cooled to ambient temperature and then undissolved salts were removed by filtration. The resulting reaction solution was concentrated to a volume of about ½ by using a rotary evaporator, to which was then added 500 ml of hexane, followed by heating with stirring. Then, the resulting solution was cooled gradually to ambient temperature and then allowed to stand in a freezing chamber to crystallize. After the crystallized product was subjected to vacuum filtration, it was washed with n-hexane and dried under reduced pressure to obtain a crude target product (yield: 85% (61.3 g)), which was then recrystallized from ethanol to obtain a purified target product 4-(6-bromohexyloxy)-4′-cyanobiphenyl (yield: 58% (41.8 g)).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[N:13]1(C(OC(C)(C)C)=O)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CN(C=O)C>[C:7]1([N:6]2[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:3][N:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nnnn1-c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-n2nnnc2N2CCNCC2)cc1

Procedure:
Preparation took place by reacting 5-chloro-1-phenyl-1H-tetrazole with tert-butyl piperazine-1-carboxylate in DMF at 40° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.C([O-])(=O)C.[NH4+:17].O.[OH-].[Na+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH2:17])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(Br)ccc21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: NC1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
6-Bromo-3,4-dihydro-2H-naphthalen-1-one (9.5 g, 42.2 mmol) was suspended in 2-propanol (250 ml); then, NaBH3 CN (13.3 g, 211 mmol) was added, followed by ammonium acetate (65.1 g, 844 mmol). The reaction mixture was then stirred at RT for 4 hours. It was subsequently heated up to reflux and stirring was continued for 22 hours. The reaction mixture was then cooled down to RT and poured into cold H2O (500 ml); the pH was adjusted to >10 with sodium hydroxide solution and the mixture was extracted with CH2Cl2 (2×25 ml). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (9.842 g) which was purified by flash chromatography (silica gel, 100 g, 2% to 10% MeOH in CH2Cl2) to yield the title compound (8.08 g, 85%) as light red oil. MS: 226.0 (MH+, 1Br).