Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5]1([O:11][CH2:12][CH2:13][CH2:14]Br)[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)(C)(C)C.[OH:16][CH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1>CN(C=O)C>[S:20]1[CH:21]=[CH:22][C:18]([CH2:17][O:16][CH2:14][CH2:13][CH2:12][O:11][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)=[CH:19]1
Reactant: OCc1ccsc1
Reactant: CC(C)(C)C1(OCCCBr)CCCCO1
Solvent: CN(C)C=O
Product: c1cc(COCCCOC2CCCCO2)cs1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (RS)-2-(3-bromo-propoxy)-tetrahydro-pyran with 3-hydroxymethyl-thiophene in DMF there was obtained (RS)-2-[3-(thiophen-3-ylmethoxy)-propoxy]-tetrahydro-pyran, which after cleavage of the THP group analogously to Example 53 (c) yielded 3-(thiophen-3-ylmethoxy)-propan-1-ol. Subsequent conversion into the mesylate according to a procedure known from the literature and alkylation therewith effected analogously to Example 44 (e) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46 (b)] gave tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate. By alkylation with 2-chloromethyl-1,4-dimethoxy-naphthalene analogously to Example 1 (g) there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow solid; MS: 648 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].ClCCl.[F:10][C:11]1[CH:12]=[C:13]([C@H:18]2[NH:23][C@@H:22]([CH:24]([OH:26])[CH3:25])[CH2:21][O:20][CH2:19]2)[CH:14]=[CH:15][C:16]=1[F:17].N1C=CC=CC=1>O>[F:10][C:11]1[CH:12]=[C:13]([C@@H:18]2[CH2:19][O:20][CH2:21][C@@H:22]3[C@H:24]([CH3:25])[O:26][C:1](=[O:5])[C:2](=[O:3])[N:23]23)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(O)[C@H]1COC[C@@H](c2ccc(F)c(F)c2)N1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1OC(=O)C(=O)N2[C@@H]1COC[C@H]2c1ccc(F)c(F)c1
Reaction time: 0.5 h

Procedure:
Under ice-cooling, oxalyl chloride (417 μL) was added dropwise into a dichloromethane (8 mL) solution of 1-[(3R,5R)-5-(3,4-difluorophenyl)morpholin-3-yl]ethanol (424 mg) and pyridine (2 mL). Stirring was continued for 30 minutes at the same temperature. Water was added to the reaction solution, and the organic layer was partitioned, and the resultant was dried with magnesium sulfate, and the solvent was removed under a vacuum. The residue was purified with silica gel column chromatography (heptane/ethyl acetate 9/1→1/4), and the title compound (353 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:26]=[C:25]4[C:20]([N:21]=[CH:22][C:23]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[N:24]4)=[CH:19][CH:18]=3)[CH:14]=[N:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(#N)C>[N:27]1([C:23]2[CH:22]=[N:21][C:20]3[C:25]([N:24]=2)=[CH:26][C:17]([C:13]2[CH:12]=[C:11]([NH:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:16]=[N:15][CH:14]=2)=[CH:18][CH:19]=3)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cncc(-c2ccc3ncc(N4CCNCC4)nc3c2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(7-{5-[(phenylsulfonyl)amino]-3-pyridinyl}-2-quinoxalinyl)-1-piperazinecarboxylate (1.80 mmol) in acetonitrile (4 ml) was added concentrated trifluoroacetic acid (4 ml). The reaction stirred at ambient temperature for 18 hours and was then concentrated to an orange oil. The residue was neutralized with 10% sodium carbonate solution and purified on silica by column chromatography (15% methanol/ethyl acetate). The desired fractions were combined and concentrated to give the title compound (500 mg, 61%) as a tan solid. MS(ES)+ m/e 447.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1)#[N:2].[ClH:15]>CO.CCOCC.[Pd]>[ClH:15].[F:14][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:1][NH2:2]
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CS(=O)(=O)Nc1ccc(CN)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
4-cyano-2-fluoro-1-methanesulfonylaminobenzene (1.03 g) prepared in step 2 was dissolved in methanol (20 mL) and added a catalytic amount of 10 wt. % Pd/C and concentrated HCl (3 mL) to hydrogenate. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with ether, filtered through celite, concentrated under reduced pressure and washed with ethylacetate to yield the title compound (1.13 g, 92%).
Reaction SMILES: C(Cl)(Cl)Cl.C[OH:6].[C:7]([NH:9][C:10](=[NH:25])[CH2:11][CH2:12][S:13][CH:14]([NH:20][C:21]([NH2:24])=[N:22][CH3:23])[C:15]1[N:16]=[CH:17][S:18][CH:19]=1)#[N:8].Cl>C(O)C>[C:7]([NH:9][C:10](=[NH:25])[CH2:11][CH2:12][S:13][CH:14]([NH:20][C:21]([NH2:24])=[N:22][CH3:23])[C:15]1[N:16]=[CH:17][S:18][CH:19]=1)(=[O:6])[NH2:8]
Reactant: CN=C(N)NC(SCCC(=N)NC#N)c1cscn1
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN=C(N)NC(SCCC(=N)NC(N)=O)c1cscn1

Procedure:
In a mixture of 20 ml of ethanol, 30 ml of chloroform, and 10 ml of methanol was dissolved 1.0 g of N-cyano-3-(2-methylguanidinothiazol-4-ylmethylthio)propionamidine and after cooling the solution to 0°-5° C. and passing therethrough a hydrogen chloride gas for one hour, the solvents were distilled off under reduced pressure. Then, the residue formed was recrystallized from ethanol to provide 1.2 g of N-carbamoyl-3-(2-methylguanidinothiazol-4-ylmethylthio)-propionamidine.di-hydrochloride showing a melting point of 180°-182° C.
Reaction SMILES: CN(C)C=[C:4]([C:14](=[O:21])[C:15]1[S:19][CH:18]=[CH:17][C:16]=1[CH3:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12]>O1CCOCC1.O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:14]([C:15]1[S:19][CH:18]=[CH:17][C:16]=1[CH3:20])=[O:21])([O-:13])=[O:12]
Reactant: Cc1ccsc1C(=O)C(=CN(C)C)c1ccccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccsc1C(=O)Cc1ccccc1[N+](=O)[O-]
Yield: 66.8 %

Procedure:
A solution of 62.0 g of β-(dimethylamino)-α-(3-methyl-2-thenoyl)-2-nitrostyrene in 565 ml of 1,4-dioxane and 115 ml of water was refluxed for 48 hr and concentrated. The residue was extracted with dichloromethane, and the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue crystallized at room temperature. Recrystallization from 95% ethanol gave 34.2 g of product, mp 85°-86.5° C.
Reaction SMILES: [CH2:1]([NH2:5])[C@@H:2]([NH2:4])[CH3:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>ClCCl>[NH2:4][C@@H:2]([CH3:3])[CH2:1][NH:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: C[C@H](N)CN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC[C@H](C)N)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To 62.9 parts of (S)-1,2-propanediamine under a nitrogen atmosphere (temp. 0°-5° C.) was added dropwise over 7 hours a solution of 80.84 parts of 4-methylbenzenesulfonyl chloride in 1689 parts of dichloromethane. After stirring overnight at 20° C., the reaction mixture was washed with 250 parts of water (3x). The organic layer was separated dried, filtered and evaporated. About 1 gram of the thus obtained product was dissolved in 4-methyl-2-pentanol by heating just below the reflux temperature. The mixture was allowed to cool slowly and at about 30° C. was seeded with the previously obtained crystals. After further cooling to 0° C., the precipitate was filtered off and triturated with 2,2'-oxybispropane. The crystals were filtered off, dried in vacuo, yielding 50.75 parts (52.4%) of (S)-N-2-aminopropyl-4-methylbenzenesulfonamide; mp. 82°-86° C.; [α]D20 =-1.10° (c=1% in methanol) (interm.1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:18]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Clc1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(Cl)cc1)C1CCCCC1
Temperature: 25 °C

Procedure:
To a mixture of 80 ml (0.78 mol) of chlorobenzene and 30 g (0.22 mol) of aluminium chloride are added dropwise at 15-20° C. 24 ml (0.18 mol) of cyclohexanecarboxylic acid chloride. After one hour at ambient temperature the reaction mixture is heated for 5 hours to 50° C. After cooling, the mixture is then decomposed with ice water/conc. hydrochloric acid and the aqueous phase is extracted with methylene chloride. The combined organic extracts are dried and evaporated down. The residue is distilled under high vacuum (2 mm, 105-115° C.). The desired fraction is combined with water, the precipitate formed is suction filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[CH:13]([CH3:15])[CH3:14].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: CC(C)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)COC(=O)c1cc(I)ccc1O

Procedure:
2-hydroxy-5-iodobenzoic acid (477 g, 1.8 mol), isobutanol (225 g), conc sulfuric acid (20 ml) in toluene (2 1) was refluxed for 6 h using a water separator. The solution was cooled and washed with water. The solution was treated with decolorizing carbon and the toluene was evaporated. The residue was recrystallized from methanol. Yield 376 g.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.CO.[C:13](=O)([O-])[O-].[Na+].[Na+]>>[OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:13])=[O:9])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CO)s1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CO)s1
Temperature: 0 °C
Yield: 296.3 %

Procedure:
To a solution of 5-(hydroxymethyl)thiophene-2-carboxylic acid (1.430 g, 9.040 mmol) in anhydrous methanol (140 ml) concentrated sulfuric acid (88.7 mg, 0.904 mmol) was added, and the mixture was heated under reflux for 40 hrs. After cooling to 0° C., sodium carbonate (300 mg) was added, and the mixture was concentrated to about 50 ml under reduced pressure. Saturated brine was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give methyl 5-(hydroxymethyl)thiophene-2-carboxylate (1.444 g, yield 92.7%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:26]=[N:25][C:18]3[O:19][CH2:20][C:21](=[O:24])[N:22]([CH3:23])[C:17]=3[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:26]=[N:25][C:18]4[O:19][CH2:20][C:21](=[O:24])[N:22]([CH3:23])[C:17]=4[CH:16]=3)[C:10]([F:12])([F:11])[F:13])=[C:4]([Cl:28])[CH:3]=2)=[CH:31][C:30]=1[F:29])=[O:37]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1cnc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3cnc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 17, step 2, 7-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=553.4 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[OH:8].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[C:19]=1F>>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[O:8][C:19]1[C:20]([C:24]#[N:25])=[CH:21][CH:22]=[CH:23][C:18]=1[F:17]
Reactant: N#Cc1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Product: N#Cc1cccc(F)c1Oc1ccc(N)cc1F

Procedure:
The entitled compound was obtained in the same method as in Example 221 (step 1) or in accordance with the method or by combining it with an ordinary method but using tert-butyl (3-fluoro-4-hydroxy-phenyl)-carbamate obtained in Example 196 (step 1) and 1,2-difluoro-3-cyano-benzene.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[F:15]C1C=C(C=CC=1)CBr.COP(OC)OC>>[F:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:2]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Reactant: Fc1cccc(CBr)c1
Agent: COP(OC)OC
Product: COP(=O)(Cc1cccc(F)c1)OC

Procedure:
Following the procedure of Compound 11, 3-fluorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]([NH2:9])=[S:8])=[N:2]1.Cl[CH:11]([C:15](=O)[CH3:16])[C:12](=[O:14])[CH3:13]>C(O)C>[CH3:16][C:15]1[N:9]=[C:7]([NH:6][C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)[S:8][C:11]=1[C:12](=[O:14])[CH3:13]
Reactant: NC(=S)Nc1cc[nH]n1
Reactant: CC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CC(=O)c1sc(Nc2cc[nH]n2)nc1C
Temperature: 25 °C

Procedure:
To a solution of N-1H-pyrazol-3-ylthiourea (5 g, 0.0352 mol) in absolute ethanol (50 ml) is added 3-chloro-2,4-pentanedione (4.78 g, 0.0352 mol) and the mixture is refluxed for 20 h under nitrogen. The reaction mixture is cooled down to rt and the resulting precipitate is filtered, washed with ethanol (25 ml) and dried under suction to afford the desired product as hydrochloride salt. It is neutralized with 10% solution of sodium bicarbonate, filtered and dried to afford 1-[4-Methyl-2-(1H-pyrazol-3-ylamino)-1,3-thiazol-5-yl]ethanone as pale brown solid (5 g, 64%). 1H NMR (CD3OD, 300 MHz): δ 2.49 (s, 3H), 2.61 (s, 3H), 6.14 (br s, 1H), 7.62 (br s, 1H). HPLC (Method B), Rt: 4.31 min (purity: 98.07%). TLC—Chloroform/methanol (8/2): Rf 0.4. Mp: 224-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C.[F:34][C:35]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:39][C:36]=1[CH2:37]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:37][C:36]3[CH:39]=[C:40]([O:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:41]=[CH:42][C:35]=3[F:34])=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: Fc1ccc(Oc2ccccc2)cc1CBr
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)OCc1cc(Oc2ccccc2)ccc1F
Temperature: 25 °C

Procedure:
To a mixture of 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (2.77 mmol), potassium carbonate (3.25 mmol) and hexamethylphosphoric triamide (HMPT) (3 ml), with stirring and under nitrogen, at RT, is added 2-fluoro-5-phenoxybenzyl bromide (2.77 mmol) in THF. The reaction is stirred at RT for about 48 hours and then worked up by partition between water/ether. The organic phase is washed with water and brine, dried over potassium carbonate, filtered and the solvent is removed from the filtrate. The residue is plated on prep. TLC plates developing with 10% ether/hexane to yield 2-fluoro-5-phenoxybenzyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH3:1][Mg]Br.[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13](=[O:15])[CH3:14].[Cl-].[NH4+].O>C(OCC)C.O1CCCC1>[OH:15][C:13]([C:6]1[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=1[OH:4])([CH3:1])[CH3:14]
Reactant: COc1cccc(O)c1C(C)=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(O)c1C(C)(C)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl magnesium bromide (24 mL of a 3M solution in diethyl ether, 72.2 mmol) in anhydrous tetrahydrofuran (20 mL) at 0° C. was added a solution of 2′-hydroxy-6′-methoxyacetophenone (4 g, 24.1 mmol) in anhydrous tetrahydrofuran (40 mL), maintaining the temperature below 11° C. during the addition. After stirring for 1.5 hours at room temperature, a solution of 10% ammonium chloride (30 mL) was added slowly maintaining the temperature below 22° C. with the use of an ice bath. Water (300 mL) was slowly added and the reaction was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water, brine, dried using anhydrous sodium sulfate and concentrated to give 2-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-phenol (4.52 g) as pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25](O)=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]([CH2:33][CH2:34][CH2:35][NH2:36])[CH3:32]>>[CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([NH:36][CH2:35][CH2:34][CH2:33][N:31]([CH3:32])[CH3:30])=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F
Product: CN(C)CCCNC(=O)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-benzyloxycarbamoyl-phenylamino)methyl]-2-fluoro-benzoic acid (Example 498) and 3-(N,N-dimethylamino)-1-propylamine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:13])[CH2:11][NH2:12].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:17][CH:16]=1.C(N(CC)CC)C.O>CS(C)=O>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH:12][CH2:11][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[OH:13])=[CH:17][CH:16]=1
Reactant: NCC(O)c1cc2ccccc2o1
Reactant: Cc1ccc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(CCCNCC(O)c2cc3ccccc3o2)cc1

Procedure:
A mixture of 2-(2-benzofuranyl)-2-hydroxyethanamine (1.75 g), 3-(4-methylphenyl)-1-(4-methylphenylsulphonyloxy) propane (3.0 g) and triethylamine (1.5 g) was stirred in dimethylsulphoxide for 2 days at ambient temperature. The mixture was poured into water, extracted with ether and the ether layers dried. Removal of the solvent gave an oil which was crystallised and recrystallised from ether to give N-[3-(4-methylphenyl)propyl]-2-(2-benzofuranyl)-2-hydroxyethanamine m.p. 118°-119°.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][OH:16]>>[N:7]1([CH2:6][C:5]2[CH:13]=[CH:14][C:2]([NH:1][CH:2]3[CH2:3][CH2:4][O:16][CH2:15][CH2:14]3)=[CH:3][CH:4]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CO
Reactant: Nc1ccc(CN2CCOCC2)cc1
Product: c1cc(NC2CCOCC2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with methanol (5 mL) and a few dozen dry molecular sieves (3 Å). The mixture is treated with acetic acid (1 mL) and terahydro-4H-pyran-4-one (0.24 mL). After 1 hour, the mixture is carefully treated with sodium cyanoborohydride (0.6 g) and heated to reflux under an argon atmosphere. After 1 hour, the mixture is cooled to room temperature and filtered with methanol washes. The filtrate is diluted with diethyl ether and washed with aqueous sodium hydroxide (2N). The aqueous is back-extracted with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is flash column chromatographed on silica eluting with 2% to 5% methanol in dichloromethane. The product-containing fractions are combined and evaporated to afford 0.34 g of N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-pyran-4-amine as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])[CH2:13][CH2:12]1)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:7][CH2:8][CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCNC1CCN(c2ccccc2C#N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1N1CCC(NCCN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 12 (256 mg, 0.74 mmol) in ethyl acetate (50 mL) was cooled to 0° C. and treated with anhydrous HCl (1 min). The mixture was stirred at room temperature (1 h). The solvent was removed in vacuo and the residue disolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichioromethane. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (13). The crude product was used directly.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1OS(C)(=O)=O)=[O:6])[CH3:3].[N-:23]=[N+]=[N-].[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[NH2:23][C@@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:8]1[NH:7][C:5]([O:4][C:2]([CH3:22])([CH3:3])[CH3:1])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1N
Temperature: 90 °C
Reaction time: 24 h
Yield: 18.9 %

Procedure:
Cis-1-[(1,1-dimethylethoxy)carbonylamino]-2-methanesulphonyloxyindan (18.1 g, 55.3 mmol) was dissolved in dry dimethyl acetamide (100 ml). Sodium azide (5.4 g, 83.0 mmol) was added and the mixture heated to 90° C. for 6 hours. The reaction was cooled, diluted with ethyl acetate (150 ml), washed with water (6×200 ml) and dried over magnesium sulphate. 10% Palladium on activated carbon was added and the mixture stirred under a hydrogen atmosphere for 24 hours. Filtration through celite followed by evaporation gave the title compound (2.6 g, 98%) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[CH3:2].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:1]([N:3]([CH:4]1[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6][CH2:5]1)[C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNC1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: CCN(C(=O)OCc1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-ethyl-1,4-dioxaspiro[4.5]decan-8-amine (1.8 g, 9.9 mmol) from above step a in THF is treated with TEA (1.4, 9.9 mmol) and benzyloxycarbonyl chloride (1.4 mL, 9.9 mmol). The mixture was stirred for 18 h at room temperature. THF was removed under vacuum and the residue was taken EtOAc and washed with 10% citric acid, saturated NaHCO3, and saturated NaCl. The solution was dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica column chromatography to give the title compound.