Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5]1.C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>ClCCl>[Si:22]([O:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1cc(C)n(CCO)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C)n(CCO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl 1-(2-hydroxyethyl)-5-methylpyrazole-3-carboxylate (9.39 g, 47.4 mM) in dichloromethane (150 ml) was cooled to below 0° C. and treated with triethylamine (7.19 ml , 52 mM) followed by t-butyldimethylsilyl chloride (7.85 g, 52 mM). The mixture was stirred at room temperature for 3 days. The reaction mixture was washed with brine, dried (MgSO4) and evaporated. Purification on silica geleluting with 50% ethyl acetate in hexane gave the title compound as a pale yellow solid in quantitative yield; νmax (film) 1719, 1472 and 1388 cm−1; δH(CDCl3) −0.08 (6H, s), 0.81 (9H, s), 1.38 (3H, t, J7 Hz), 2.33 (3H, s), 3.98 (2H, t, J5 Hz), 4.21 (2H, t, J5 Hz), 4.39 (2H, q, J7 Hz), and 6.53 (1H, s); NH3DCI m/e 313 (100%).
Reaction SMILES: [I-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:19])[CH2:16][CH2:17][Cl:18])[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[S:5]1(=[O:25])=[O:24].[CH3:26][NH:27][CH3:28]>CC(C)=O>[ClH:18].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:19])[CH2:16][CH2:17][N:27]([CH3:28])[CH3:26])[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[S:5]1(=[O:25])=[O:24]
Reactant: CN1c2ccccc2N(C(=O)CCCl)c2ccccc2S1(=O)=O
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(C)CCC(=O)N1c2ccccc2N(C)S(=O)(=O)c2ccccc21
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.5 g (0.037 mol) of sodium iodide are added to 13 g (0.037 mol) of 6-methyl-6,11-dihydro-11-(3-chloropropionyl)-dibenzo[c,f][1,2,5]thiadiazepine 5,5-dioxide in 100 ml of acetone, and the mixture is heated under reflux for 30 minutes. After cooling, 7 ml of aqueous 33% dimethylamine are added, and the mixture is kept with stirring at ambient temperature for 16 hours. It is concentrated and the residue is treated with 5% HCl, the insoluble fraction is filtered off and the filtrate is alkalized with NaHCO3 ; a solid forms, which is filtered off, washed with water and dried.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]([NH2:12])([C:9]([OH:11])=[O:10])[CH2:7][OH:8].[CH3:13]O>>[ClH:3].[CH3:5][C@@:6]([C:9]([O:11][CH3:13])=[O:10])([CH2:7][OH:8])[NH2:12]
Reactant: O=S(Cl)Cl
Reactant: CC(N)(CO)C(=O)O
Reactant: CO
Product: COC(=O)[C@@](C)(N)CO
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (12.8 mL, 175 mmol) was added dropwise to a stirred suspension of DL-2-methylserine hydrate, (10.4 g, 88.0 mmol) in anhydrous methanol (67 mL) at 0° C. The solids gradually dissolved during the addition. Upon complete addition the bath was removed and the mixture stirred at room temperature overnight. The solvent was then removed in vacuo to give an oil which was azeotroped twice with ether and further dried under vacuum to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:13](O)=O)[C:3]=1[OH:16].Br[C:18]1[CH:23]=[CH:22][C:21](C)=[CH:20][CH:19]=1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:13][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]=1[O:16][CH3:26].[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:13][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:3]=1[OH:16]
Reactant: O=C(O)c1cc2cc(Br)ccc2c(Br)c1O
Reactant: Cc1ccc(Br)cc1
Reactant: Brc1ccccc1
Product: COc1c(Cc2ccccc2)cc2cc(Br)ccc2c1Br
Product: Oc1c(Cc2ccccc2)cc2cc(Br)ccc2c1Br

Procedure:
Using the Example 1 compound 4,7-dibromo-3-hydroxy-2-naphthoic acid as the starting material, and 4-bromotoluene to replace bromobenzene, the procedures of Examples 3-7 were repeated to obtain compounds 1,6-dibromo-2methoxy-3-benzylnaphthalene and 1,6-dibromo-3-benzyl-2-naphthol.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[Na+].[Br:19][CH2:20][CH2:21]Br>O.C(O)C.CC(C)=O>[Br:19][CH2:20][CH2:21][O:16][C:14]1[CH:13]=[CH:12][C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[C:2]([OH:1])[CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: O=C(c1ccccc1)c1ccc(OCCBr)cc1O
Reaction time: 16 h
Yield: 42.5 %

Procedure:
A 2000 mL, 1 neck round-bottomed flask containing a magnetic stir bar is charged with 2,4-dihydroxybenzophenone (85.6 g, 0.40 mol, Aldrich Chemical Co., Milwaukee, Wis.). To this is added a solution of sodium hydroxide (16.0 g) dissolved in 320 mL of water. Next, 1,2-dibromoethane (105.6 g, 0.56 mol) dissolved in 320 ml of ethanol is added. The reaction mixture is heated to reflux with stirring for 16 hours. The reaction vessel is then transferred to a rotary evaporator where the liquids are removed at aspirator pressure at 80° C. A brown solid is obtained which is suspended in 180 mL of acetone and stirred for 1 hour at 45° C. This mixture is filtered and the filtrate poured into 2 L of water containing 20 g of sodium carbonate yielding 65 grams of a tan precipitate. This material is recrystallized from approximately 100 mL of ethanol to give 55.3 g (0.17 mol, 43%) of a light tan solid m.p. 87°-89.5° C.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)amide hydrochloride and sodium hydroxide solution.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22](Cl)(=[O:24])[CH3:23]>>[C:22]([NH:21][S:18]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=2)[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=1)(=[O:19])=[O:20])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(C)=O)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and acetyl chloride, gave N-acetyl-3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)#[N:7].[N+:15]([O-])([OH:17])=[O:16]>>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]#[N:7])=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C#N)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C#N)cc1[N+](=O)[O-]

Procedure:
An amount of 240 parts by weight of concentrated sulfuric acid was cooled to -5° C. in a reaction vessel equipped with a drip funnel, agitator and thermometer. While stirring the mixture well, 40 parts by weight of 4-cyanotoluene were added portionwise and 25 volume parts of concentrated nitric acid were then added dropwise at a temperature between -5° C. and +5° C. To complete the nitration, the mixture was agitated at 0° C. for two hours and the reaction mixture was then poured onto 400 parts by weight of ice. The precipitate was recovered by filtration, thoroughly washed with water and dried in air. The result was 50.9 parts by weight of 1-methyl-4-cyano-2-nitrobenzene with a melting point of 105° to 106° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C=O)C.CCOC(C)=O.O>[CH3:28][C:26]1[O:25][N:24]=[C:23]([C:4]2[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:3]=2)[N:27]=1
Reactant: C1CNCCN1
Reactant: Cc1nc(-c2nc(Br)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)no1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(N3CCNCC3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)no1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of tert-butyl N-[5-bromo-3-(5-methyl-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (200 mg, 0.4383 mmol) in DMF (1.562 mL) was treated with piperazine (377.5 mg, 4.383 mmol) and the reaction mixture heated at 100° C. for 30 minutes. The reaction was allowed to cool to RT and diluted with EtOAc/Water and the layers separated. The organic layer was washed with water (3×), dried (MgSO4), filtered and concentrated in vacuo. The material was used crude in the next step (150 mg, 67% Yield). 1H NMR (400.0 MHz, CDCl3) d 1.37 (18H, s), 2.73 (3H, s), 3.14 (4H, m) ppm; MS (ES+) 462.14
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[C:23]([CH3:35])=[N:24][C:25]([N:28]4[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[CH3:34])=[CH:26][CH:27]=3)[S:21][C:14]=12>>[CH3:33][C:32]1[N:28]([C:25]2[N:24]=[C:23]([CH3:35])[C:22]([C:20]3[S:21][C:14]4[C:15](=[N:16][CH:17]=[CH:18][C:13]=4[NH:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)[CH:19]=3)=[CH:27][CH:26]=2)[C:29]([CH3:34])=[CH:30][CH:31]=1
Reactant: Cc1nc(-n2c(C)ccc2C)ccc1-c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(-n6c(C)ccc6C)nc5C)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-2-methyl-pyridin-3-yl]-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.08 (s, 1H), 7.82 (d, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 7.25 (d, 1H), 7.07 (d, 1H), 6.92 (dd, 1H), 6.58 (d, 1H), 6.07 (s, 1H), 5.80 (s, 2H), 2.60 (s, 3H), 2.36 (s, 3H), 2.05 (s, 6H); RP18-HPLC RT: 6.55 minutes; API MS: 464 (M+1).
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5]1.C([Li])CCC.O.Cl>O1CCCC1.CCCCCC>[C:3]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5]1)#[CH:2]
Reactant: CCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C#C[C@H]1CC[C@H](CCCC)CC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A solution of 162.1 g of trans-1-(2,2-dibromovinyl)-4-butylcyclohexane in 1.3 l of absolute tetrahydrofuran was cooled to -75° C. under nitrogen gasification and treated dropwise within 1 hour with 690 ml of a 1.6M solution of butyl lithium in hexane. The mixture was subsequently stirred at -70° C. for a further 2 hours, then poured into 1.5 l of water, neutralized with concentrated hydrochloric acid and extracted twice with 1 l of hexane each time. The combined organic phases were washed with 500 ml of water, dried over sodium sulphate and concentrated to dryness on a rotary evaporator. Distillation of the resulting light yellow crude product in a high vacuum gave in the main run 75.9 g (92.4%) of trans-1-ethynyl-4-butylcyclohexane as a colourless liquid; b.p. 41°-43° C./0.4 Torr.
Reaction SMILES: P(=O)(O)(O)O.CO[CH:8]([CH2:14][CH3:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11]>>[C:10]([O:12][CH3:13])(=[O:11])[CH2:9][CH:8]=[CH:14][CH3:15].[C:10]([O-:12])(=[O:11])/[CH:9]=[CH:8]/[CH2:14][CH3:15]
Reactant: CCC(CC(=O)OC)OC
Agent: O=P(O)(O)O
Product: CC/C=C/C(=O)[O-]
Product: CC=CCC(=O)OC
Temperature: 300 °C

Procedure:
A 1 l stirred flash was charged with 500 g of vacuum gas oil and 6 g of an 85% strength phosphoric acid, and the mixture was heated to 300° C. 40 g/hour of methyl 3-methoxyvalerate from a stock vessel were fed, together with 10 l/hour of nitrogen, below the surface of the stirred oil/catalyst mixture. The gaseous products leaving the reaction vessel were cooled, and the condensate was investigated by gas chromatography. In this manner, 11.0 g/hour of methyl 3-pentenoate and 10.7 g/hour of 2-trans-pentenoate were obtained, inter alia, in addition to 7.5 g/hour of unconverted methyl 3-methoxyvalerate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[CH3:25][O:24][C:22]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:23]
Reactant: COC(=O)Cl
Reactant: NCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCSc1cccc2nccn12
Yield: 66.9 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.93 g, 10 mmoles) and triethylamine (1.53 ml, 11 mmoles) in methylene chloride (30 ml ) was added methyl chloroformate (0.77 ml, 10 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was washed in turn with an aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to obtain 1.68 g of the desired product (66.9%, colorless crystals).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4](N)[CH2:3][CH2:2]1.[ClH:12].[NH:13]1[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[ClH:12].[CH2:3]1[N:4]2[C:5]3[C:10]([C:17]4[CH2:18][CH2:19][NH:13][CH2:14][CH2:15][C:16]=42)=[CH:9][CH:8]=[CH:7][C:6]=3[S:1][CH2:2]1
Reactant: NN1CCSc2ccccc21
Reactant: O=C1CCCNCC1
Agent: Cl
Product: c1cc2c3c(c1)c1c(n3CCS2)CCNCC1

Procedure:
1,2,8,9,10,11-Hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole hydrochloride was prepared from 2,3-dihydro-4H-1,4-benzothiazin-4-amine and hexahydro-4H-azepin-4-one hydrochloride following the procedure of example 471, step A to give the 1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole hydrochloride
Reaction SMILES: [Li+].[OH-:2].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[OH2:8]>>[O:3]=[CH:7][CH2:6][CH2:5][CH2:4][CH2:4][CH2:5][CH2:6][C:7]([OH:8])=[O:2]
Reactant: O
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Li+]
Product: O=CCCCCCCC(=O)O

Procedure:
A solution of the above methyl 8-(4-trans (2-tert-butoxycarbonylaminocyclopropyl)phenylamino)-8-oxooctanoate (0.53 mmol, 220 mg) and LiOH (1.05 mmol, 44 mg) in tetrahydrofuran/water (5 mL/5 mL) was stirred overnight at room temperature. The reaction was quenched by addition of 2 N HCl until pH=4, then the precipitate was filtered, washed with water (3×30 mL) and dried to obtain the pure 8-4-trans(2-tert-butoxycarbonylaminocyclopropyl)phenylamino)-8-oxooctanoic acid as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]2[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][CH:17]=1
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(N)cc1
Yield: 90.3 %

Procedure:
To a solution of 2-n-butyl-4-chloro-5-methoxymethyl-1-(4-nitrobenzyl)imidazole (11.22 g) in methanol (100 mL) under N2 was carefully added 1.0 g of 10% palladium on charcoal. Hydrogen gas was then bubbled through the solution for 4 hours. The solution was filtered through Celite® and the solvent removed in vacuo to yield 9.23 g of an amber oil. NMR (200 MHz, CDCl3) δ 7.99 (s, 1H); 6.78 (d of d, 4H, J=5,5 Hz); 5.05 (s, 2); 4.24 (s, 2H); 3.27 (s, 3H); 2.59 (t, 2H, J=7 Hz); 1.62 (t to t, 2H, J=7,7 Hz); 1.32 (t of q, 2H, J=7,7 Hz); 0.84 (t, 3H, J=7 Hz). Mass Calcd. for C16H23ClN3O; 307.1451. Found: 307.1460.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:31]([C:30]3[CH:29]=[CH:28][C:27]([N:17]([CH3:16])[C:18](=[O:26])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[CH:35][CH:34]=3)=[O:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A mixture of 0.291 g of 6,11-dihydro-5H-dibenz[b,e]azepine, 0.518 g of 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride and 0.182 g of triethylamine in 10 ml of tetrahydrofuran is stirred at room temperature for 2 hours. The solvent is removed, the residue diluted with water and extracted with dichloromethane. The extract is washed with 1 N HCl water, 1M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and chilled to give 0.52 g of crystals, m.p. 160°-170° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:15][CH2:16][CH3:17])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=1)=[O:5].C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:22]([C:12]1[CH:13]=[C:8]([CH2:7][CH2:6][P:4](=[O:5])([O:15][CH2:16][CH3:17])[O:3][CH2:2][CH3:1])[CH:9]=[CH:10][N:11]=1)#[N:23]
Reactant: C[Si](C)(C)C#N
Reactant: CCOP(=O)(CCc1cc[n+]([O-])cc1)OCC
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CCOP(=O)(CCc1ccnc(C#N)c1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.6 %

Procedure:
Diethyl 2-(4-pyridyl)ethylphosphonate N-oxide (9.9 g, 38 mmol) was dissolved in nitroethane (200 ml), and trimethylsilyl cyanide (7.5 g, 75 mmol) and N,N-dimethylcarbamoyl chloride (6.1 g, 56 mmol) were added thereto. The mixture was stirred at room temperature for 12 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (15:1) were collected and concentrated to give the titled compound (7.3 g, 71%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]([C:19]3[CH:28]=[C:27]4[C:22]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][C:26]4=[O:29])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[BH4-].[Na+].O>C1COCC1.CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[C:17]([C:19]3[CH:28]=[C:27]4[C:22]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][CH:26]4[OH:29])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:12]1
Reactant: CC1(C)CCC(=O)c2cc(-c3cccc(N4CCN(CCCCCO)CC4)n3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CCC(O)c2cc(-c3cccc(N4CCN(CCCCCO)CC4)n3)ccc21
Reaction time: 0.5 h

Procedure:
50 mg (0.12 mmol) of 7-{6-[4-(5-hydroxypentyl)piperazin-1-yl]pyridin-2-yl}-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one are dissolved in 0.5 ml of THF and 1 ml of methanol, cooled to 0° C., and 4.5 mg (0.12 mmol) of sodium borohydride are added. The reaction mixture is stirred for 30 min, water is added, and the mixture is extracted with ethyl acetate, dried and evaporated. The crude product is purified by means of prep HPLC and subsequently converted into the hydrochloride using methanolic HCl.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[N:7]([CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)[CH2:6]1)=[O:4].[B].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)N(CC2COc3ccccc3O2)C1
Agent: Cl
Agent: [B]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1CCN(CC2COc3ccccc3O2)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution containing 300 mg (1.03 mmol) of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in dry tetrahydrofuran (4 mL) was cooled to 0° C. under nitrogen. After adding 4 mL of 1M BH3-tetrahydrofuran solution (4.12 mmol), the reaction mixture was allowed to warm to room temperature and it was stirred for 5 h. Decomposition of the boron complexes was effected by addition of 3 mL of methanol and 3 mL of 6 M HCl-solution followed by stirring the mixture at 40° C. for ½ h. Tetrahydrofuran was evaporated off under vacuum. The residue was dissolved in 50 mL of water and the pH of the solution was adjusted to 10 using 1M Na2CO3 solution. The water phase was extracted with ethyl acetate (3×25 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (silica gel, heptane/ethyl acetate, 7:3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[OH:15][C:16]12[CH2:26][CH:20]3[CH2:21][C:22]([OH:25])([CH2:24][C:18]([NH2:27])([CH2:19]3)[CH2:17]1)[CH2:23]2.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:27][C:18]34[CH2:24][C:22]5([OH:25])[CH2:21][CH:20]([CH2:26][C:16]([OH:15])([CH2:23]5)[CH2:17]3)[CH2:19]4)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cnn2cc(Br)cc2c1NC12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 80 mg, 0.291 mmol), 3,5-dihydroxyadamantan-1-amine (53.4 mg, 0.291 mmol) and DIPEA (0.104 mL, 0.583 mmol) in DMF (1 mL) was heated in microwave oven at 130° C. for 1.5 h. The reaction mixture was cooled to rt, water added (4 volumes) and the resulting mixture was stirred rapidly overnight. The solids were filtered and rinsed with water to afford the title compound as a yellow solid (72 mg, 56% yield). HPLC (condition 0): retention time=2.16 min; LCMS: 423.00 (M+2); 1H NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.01 (d, J=1.8 Hz, 1H), 6.23 (s, 2H), 2.52 (m, 1H), 2.14 (app dd, J=7.1 Hz, 4H), 2.01 (m, 2H), 1.82 (m, 2H), 1.72 (s, 4H).