Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH:11]=[O:12])=[C:5]1[C:13]([O:15][CH3:16])=[O:14].N12CCCN=C1CCCCC2>O1CCCC1>[CH:11]([C:6]1[C:7]([CH3:10])=[C:8]([CH3:9])[N:4]([CH:3]=[CH2:2])[C:5]=1[C:13]([O:15][CH3:16])=[O:14])=[O:12]
Reactant: COC(=O)c1c(C=O)c(C)c(C)n1CCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=Cn1c(C)c(C)c(C=O)c1C(=O)OC
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A solution of 0.15 g (0.00052 mole) of methyl 1-(2-bromoethyl)-3-formyl-4,5-dimethylpyrrole-2-carboxylate and 0.08 g (0.00052 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene dissolved in 2 ml of tetrahydrofuran was heated under reflux for 6 hours. The reaction mixture was allowed to cool at room temperature and purified by column chromatography through silica gel using a 9:1 mixture of toluene and ethyl acetate as an eluent to give 0.080 g (74% yield) of methyl 3-formyl-4,5-dimethyl-1-vinylpyrrole-2-carboxylate as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].Cl>CC(O)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:10]([Cl:9])[CH:11]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CC(C)O
Product: Clc1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 84 °C
Yield: 61 %

Procedure:
250 mg of 4,6-dichloropyrimidine and 165 mg of m-chloroaniline were dissolved in 2.5 mL of i-PrOH and 0.25 mL of 37% HCl were added. The mixture obtained was refluxed (84° C.) for 2.5 hours under nitrogen atmosphere. A colorless precipitate was formed which was collected by filtration. 6-Chloro-N-(3-chlorophenyl)pyrimidin-4-amine hydrochloride in the form of colorless crystals was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH3:22]>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([C:18]1[C:17]([CH3:20])=[CH:16][C:15]([O:21][CH3:22])=[C:14]([O:13][CH3:12])[CH:19]=1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: COc1ccc(C)cc1OC
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC

Procedure:
Reaction of 9.5 g (0.05 mol) of 2,6-dichlorobenzoic acid and 7.5 g (0.05 mol) of 1,2-dimethoxy-4-methylbenzene, in a manner analogous to that of Example 3(a), yields (2,6-dichlorophenyl)-(3,4-dimethoxy-6-methyl-phenyl)-methanone as colourless crystals, m.p. 101°-103° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[CH2:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32](O)=[O:33])=[C:24]1[CH3:35])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([N:1]2[CH2:6][CH2:5][C:4]3([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[O:7]3)[CH2:3][CH2:2]2)=[O:33])=[C:24]1[CH3:35])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: Cc1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Product: Cc1c(C(=O)N2CCC3(CC2)OC(=O)c2ccccc23)c2ccccc2n1Cc1ccccc1

Procedure:
Following the general procedure I as described above, the acylation of 3H-spiro[2-benzofuran-1,4′-piperidin]-3-one prepared as described in example 16 above with 1-benzyl-2-methyl-1H-indole-3-carboxylic acid (preparation described in example 1), gave the title compound. ES-MS m/e (%): 451.6 (M+H+).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([OH:12])[CH:10]=[CH:9][CH2:8][O:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[OH:3][CH2:4][C@H:6]1[C@H:11]([OH:12])[CH:10]=[CH:9][CH2:8][O:7]1
Reactant: CCOC(=O)[C@@H]1OCC=C[C@H]1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC[C@@H]1OCC=C[C@H]1O
Reaction time: 0.5 h

Procedure:
To a stirred solution of trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (0.480 g, 2.79 mmol) in THF (20 ml) at RT, was added in portions LiAlH4 (0.126 g, 3.384 mmol) and the resulting mixture was stirred for 30 min. EtOAc (10 ml) was added, the mixture was stirred for 10 min and extracted with water (10 ml×2). The organic layer was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product purified by flash chromatography (25-30% EtOAc in hexane).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][C:11]3[CH:15]=[C:14]([C:16]([OH:18])=O)[S:13][C:12]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[NH:22][CH3:23]>>[Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][C:11]3[CH:15]=[C:14]([C:16]([N:22]([C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[Cl:19])[CH3:23])=[O:18])[S:13][C:12]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(s1)-c1cccc(Br)c1OCC2
Reactant: CNc1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1cccc(Br)c1OCC2)c1ccccc1Cl

Procedure:
Following Example 70 and General Procedure B, 114 was prepared from 7-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid and 2-chloro-N-methylaniline. MS: (ESI+) 450.0
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=O)[CH2:10][CH3:11].[OH-].[K+]>>[CH2:1](/[N:8]=[CH:9]/[CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC=O
Reactant: NCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CC/C=N/Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of benzylamine (20.0 g, 184 mmol) was added propionaldehyde (10.8 g, 184 mmol) over 1 hour. Potassium hydroxide (5.2 g, 92.7 mmol) was added, and the reaction was allowed to stand for 1 hour, during which time the solution separated into two layers. The organic layer was isolated and stored over potassium hydroxide pellets overnight in the refrigerator to give the product as a cloudy liquid, which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[CH2:15]([O:17][C:18]1[C:19](F)=[C:20]2[C:26]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])=[CH:25][NH:24][C:21]2=[N:22][CH:23]=1)[CH3:16]>C(O)CCC>[CH:30]1([C:28]([NH:27][C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([O:17][CH2:15][CH3:16])[C:19]=3[N:1]3[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]3)[NH:24][CH:25]=2)=[O:29])[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1F
Solvent: CCCCO
Product: CCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 160 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (205 mg, 1.0 mmol) was added to N-(5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (90 mg, 0.34 mmol) in n-butanol (2 mL). The reaction was stirred at 160° C. for 24 hours in a sealed tube. After cooling down and concentration, the residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, water/ACN 90/10→10/90, 30CV) to yield (R)-tert-butyl 1-(3-(cyclopropanecarboxamido)-5-ethoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (39 mg) as a solid.
Reaction SMILES: [CH2:1]1[O:4][C@H:2]1[CH3:3].[Cl:5][C:6]1[CH:15]=[C:14]([SH:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>>[Cl:5][C:6]1[CH:15]=[C:14]([S:16][CH2:1][C@@H:2]([OH:4])[CH3:3])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(S)cc1Cl
Reactant: C[C@H]1CO1
Product: COC(=O)c1ccc(SC[C@H](C)O)cc1Cl

Procedure:
86 mg of (S)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 275 mg of (S)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 220 mg of (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.0 (M)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][CH2:8]Cl)=[CH:5][CH:6]=1.Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)([OH:20])[CH3:19])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][N:24]2[CH2:25][CH2:26][CH:21]([C:18]([C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)([OH:20])[CH3:19])[CH2:22][CH2:23]2)=[CH:5][CH:6]=1
Reactant: ClCCc1ccc(Cl)s1
Reactant: CC(O)(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(O)(c1ccc(F)cc1)C1CCN(CCc2ccc(Cl)s2)CC1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A solution of 0.88 g of 2-chloro-5-(2-chloro-ethyl)thiophene in 10 ml of acetonitrile is treated with 1.3 g of 1-(4-fluorophenyl)-1-piperidin-4-yl-ethanol, hydrochloride and 0.82 g of NaHCO3 and stirred at 80° for 8 hours. After customary working-up, 1.3 g of 1-{1-[2-(5-chlorothiophen-2-yl)ethyl]piperidin-4-yl}-1-(4-fluorophenyl)ethanol are obtained. The residue is dissolved in acetone, treated with ether/HCl and the hydrochloride, m.p. 210-211°, is obtained after crystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCc1ccc(Cl)cc1
Product: CS(=O)(=O)OCCOCCc1ccc(Cl)cc1
Yield: 92 %

Procedure:
The 2-[2-(4-chlorophenyl)ethoxy]ethanol obtained according to the preceding paragraph was sulfonylated with methanesulfonyl chloride in a manner analogous to that described in Example 1(c) to give 1.5 g (92%) of 2-[2-(4-chlorophenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][C:14]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:13][CH:12]=1>>[CH2:18]([N:15]([CH2:16][CH3:17])[C:14]1[CH:20]=[CH:21][C:11]([NH:10][C:2]2[CH:3]=[C:4]([NH:8][CH3:9])[N:5]=[CH:6][N:7]=2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CNc1cc(Cl)ncn1
Reactant: CCN(CC)c1ccc(N)cc1
Product: CCN(CC)c1ccc(Nc2cc(NC)ncn2)cc1

Procedure:
The title compound is prepared analogously as described in Example 105A from (6-chloro-pyrimidin-4-yl)-methyl-amine and 4-amino-N,N-diethylaniline. The ethyl acetate layer is dried over Na2SO4 and evaporated in vacuo. The residue is suspended in CH2Cl2, filtered off and dried to afford the title compound.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][CH:27]=1>ClCCl.N1C=CC=CC=1>[F:31][C:28]([F:29])([F:30])[C:24]1[CH:23]=[C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)=[O:13])[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 15.1 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3-aminobenzotrifluoride (1.87 g, 11.6 mmol) in 15 mL of pyridine. The crude product was recrystallized from ethanol, then ethyl ether to yield 0.519 g of the title compound, mp 167°-168° C.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(O)C.[BH4-].[Na+]>O>[I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)/C=C/I
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)/C=C/I
Reaction time: 2 h

Procedure:
A solution of 78.2 g (0.310 moles) of 1-iodo-trans-1-octen-3-one (Example 724) in 150 ml. of absolute ethanol is added dropwise over 2 hours to a slurry of 6.49 g. (0.172 moles) of sodium borohydride in 50 ml. of absolute ethanol cooled in an ice bath. After the addition is complete, the mixture is stirred for 2 hours with ice cooling and is then poured into 1 1. of water. The mixture is extracted into benzene and the organic phase is washed with saturated brine, dried (Na2SO4) and evaporated. The resulting oil is dissolved into 400 ml. of absolute ethanol and treated with 5 mole percent of p-carboxyphenylhydrazine at 70° C. for 1.5 hours to remove residual ketone. The mixture is cooled and evaporated and the residue is dissolved into 400 ml. of ether and is filtered. The filtrate is washed with dilute sodium bicarbonate solution and saturated brine, dried (Na2SO4), and evaporated to an oil. This oil is chromatographyed upon 2 Kg. of Florisil® packed in hexane and the product is obtained upon elution with benzene Distillation of the product yields a colorless oil, b.p. 74°-76° C. (0.005 tor.).
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[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[S:21][C:14]=12>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:13]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[S:21][C:14]=13)=[CH:6][CH:5]=2
Reactant: Cc1cccc(-c2cc3nccc(Cl)c3s2)n1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cccc(-c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)n1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-(6-methyl-pyridin-2-yl)-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.51 (d, 1H), 7.83 (s, 1H), 7.68 (m, 2H), 7.34 (m, 1H), 7.27 (d, 1H), 7.16 (d, 1H), 6.97 (dd, 1H), 6.57 (d, 1H), 6.10 (s, 1H), 2.52 (s, 3H), 2.40 (s, 3H); RP18-HPLC RT: 5.70 minutes; API MS: 371 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1.[CH:15]1([NH:18][CH2:19][CH2:20][OH:21])[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH:15]1([N:18]([CH2:19][CH2:20][OH:21])[S:10]([C:6]2[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:14])(=[O:12])=[O:11])[CH2:17][CH2:16]1
Reactant: OCCNC1CC1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N(CCO)C2CC2)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 20 %

Procedure:
A solution of 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (7 mmol) in dichloromethane (12 ml) was slowly added dropwise to a solution of 2-(cyclopropylamino)ethanol (8 mmol) in dichloromethane (24 ml) and triethylamine (2.5 eq), cooled to 0° C. On completion of the addition the mixture was stirred for 90 min at 25° C. until the reaction was complete. The mixture was diluted with dichloromethane (200 ml) and washed with water and saturated NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated completely to obtain the desired product. Yield: 20%
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][CH:5]([F:29])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:19][C:20]1[N:25]=[C:24](Cl)[N:23]=[C:22]([O:27][CH3:28])[N:21]=1)=[O:18])(=[O:15])=[O:14]>O1CCOCC1.Cl>[F:4][CH:5]([F:29])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:19][C:20]1[N:25]=[C:24]([N:2]([CH3:3])[CH3:1])[N:23]=[C:22]([O:27][CH3:28])[N:21]=1)=[O:18])(=[O:15])=[O:14]
Reactant: CNC
Reactant: COc1nc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Agent: Cl
Solvent: C1COCCO1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(N(C)C)n1
Reaction time: 0.5 h

Procedure:
3.0 g of dimethylamine are introduced at 20°-30° C., with cooling, into a solution of 8.2 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-chloro-6-methoxy-1,3,5-triazin-2-yl)-urea in 80 ml of dioxane. After the formed suspension has been stirred for a further 30 minutes, it is taken up in 500 ml of 0.1N hydrochloric acid, and the product which has precipitated is separated by filtration; yield: 7.7 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-dimethylamino-6-methoxy-1,3,5-triazin-2-yl)-urea, m.p. 171°-172° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1COCC1>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
To a mixture of 1-bromomethyl-4-nitro-benzene (5.0 g, 29.1 mmol) and potassium carbonate (12.0 g, 87 mmol) in THF (100 mL) was added morpholine (6.35 mL, 73 mmol) in a slow stream. The reaction was stirred 24 h at room temperature, was filtered through Celite and evaporated. Purification by flash chromatography (SiO2) provided 4-(4-nitro-benzyl)-morpholine (5.27 g, 81% yield) as a pale yellow solid. 1H-NMR (DMSO-d6, 500 MHz) 8.20 (d, 2H), 7.60 (d, 2H), 3.61 (m, 6H), 2.38 (m, 4H) ppm; MS (FIA) 223.1 (M+H); HPLC (Method A) 1.577 min.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NCC1CN(c2ccc(Cl)cn2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCC1CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A mixture of 5-(azidomethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (139 mg, INTERMEDIATE 2) and triphenylphosphine (226 mg) was heated to 65° C. for 8 h in 66 ml of tetrahydrofuran and 9 ml of water. The sample was then cooled to room temperature, and concentrated in vacuo. The residue was purified via column chromatography on a Biotage Horizon 40M column eluting with 100% ethyl acetate (5 column volumes) to remove excess triphenylphosphine and triphenylphosphine oxide, followed by 100% methanol (5 column volumes), to provide the title compound (122 mg, 94%). Mass spectrum (ESI) 228.0 (M+1).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]#[N:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:24].[NH4+]>>[C:1]1([NH:7][C:8]2([C:22]([NH2:23])=[O:24])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: [OH-]
Agent: [NH4+]
Product: NC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To 4500 parts of sulfonic acid are added portionwise 710 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarbonitrile, while keeping the temperature below 25° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto a mixture of 10.000 parts of crushed ice and 3600 parts of ammonium hydroxide. The product is extracted with trichloromethane (7500 parts). The extract is dried, filtered and evaporated. The residue is stirred in 140 parts of 2,2'-oxybispropane. The product is filtered off and dried, yielding 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxamide; mp. 182.5° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of ethyl 3-(4-phenoxyphenyl)propanoate (S29, 500 mg, 1.95 mmol) in THF/MeOH (1/1, 8 mL) was treated with aqueous 4 N NaOH (0.5 mL) and was stirred for 20 h at 25° C. The reaction mixture was concentrated, diluted with aqueous 1 N HCl and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated to afford S30 (390 mg, 1.61 mmol, 82%) as a white solid: 1H NMR (CDCl3, 500 MHz) 7.34 (dd, 2H, J=8.4, 7.4 Hz), 7.18 (d, 2H, J=8.4 Hz), 7.10 (dt, 1H, J=7.7, 1.1 Hz), 7.00 (dd, 2H, J=8.8, 1.1 Hz), 6.95 (d, 2H, J=8.4 Hz), 2.96 (t, 2H, J=7.7 Hz), 2.70 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 125 MHz) 179.2, 157.3, 155.6, 135.0, 129.7, 129.5, 123.1, 119.0, 118.7, 35.7, 29.8.
Reaction SMILES: Cl[CH2:2][C:3]([O:5]C)=[O:4].[Br:7][C:8]1[C:9]([OH:17])=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>O1CCCC1.O>[Br:7][C:8]1[C:9]2[O:17][C:2]([C:3]([OH:5])=[O:4])=[CH:11][C:10]=2[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: O=Cc1cc(F)cc(Br)c1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(F)cc(Br)c2o1
Temperature: 130 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Methyl chloroacetate (7.6 mL, 86.8 mmol) was added to a mixture of 3-bromo-5-fluoro-2-hydroxy-benzaldehyde (9.5 g, 43.4 mmol), tetra-N-butyl-ammonium iodide (1.6 g, 4.34 mmol) and anhydrous potassium carbonate (24 g, 174 mmol). The reaction mixture was heated at 130° C. for 4 h, cooled to 0° C., diluted with tetrahydrofuran (100 mL) and then potassium hydroxide (17 g, 303 mmol) in water (100 mL). The mixture was stirred at rt for 18 h and then, concentrated under reduced pressure. The residue was acidified with HCl and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2; toluene/EtOAc, 40/1) to give 7.0 g (63%) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([CH2:30][CH2:31]Cl)=[CH:25][C:24]=1[Cl:33]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:31][CH2:30][C:26]3[CH:27]=[C:28]([Cl:29])[C:23]([NH2:22])=[C:24]([Cl:33])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: Nc1c(Cl)cc(CCCl)cc1Cl
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
This compound was prepared analogous to Example 12 from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-(4-amino-3,5-dichlorophenyl)-ethyl chloride.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[Cl:16][C:17]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:18]=1[CH2:19][CH:20]([C:22]([OH:24])=[O:23])[NH2:21]>>[C:22]([CH:20]([NH:21][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:18]1[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:17]=1[Cl:16])([OH:24])=[O:23]
Reactant: COc1ccc(Cl)c(CC(N)C(=O)O)c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: COc1ccc(Cl)c(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-chloro-5-methoxy-DL-phenylalanine to provide the title compound in good yield.