Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][Cl:24])=[C:14]([NH:25][C:26]([C:28]2[NH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:37][CH3:38])=[CH:32][CH:31]=3)=[O:27])[CH:13]=1)=O)C1C=CC=CC=1>C1COCC1.[Pd]>[Cl:24][CH2:23][CH2:22][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:11])=[CH:13][C:14]=1[NH:25][C:26]([C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([O:37][CH3:38])=[CH:32][CH:31]=2)=[O:27]
Reactant: COc1ccc2[nH]c(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCCl)cc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C(=O)Nc3cc(N)c4ccccc4c3CCCl)cc2c1
Reaction time: 8 h
Yield: 78.1 %

Procedure:
A solution of 2-[4-(N-benzyloxycarbonylamino)-2-(5-methoxyindole-2-carboxamido)naphthalen-1-yl]ethyl chloride (68 mg, 0.13 mmol) in THF (10 mL) was added to a suspension of 10% Pd/C (100 mg) in chilled THF (10 mL) and the suspension was hydrogenated under H2 atmosphere at room temperature overnight. The suspension was filtered over Celite and the filtrate was concentrated in reduced pressure. The residue was crystallized with diethylether to yield 4-(2-Chloroethyl)-3-(5-methoxyindole-2-carboxamido)-1-naphthylamine (40 mg, 78%) as a white solid: mp 228° C. (decomp.); 1H NMR (DMSO-d6, 500 MHz) δ 9.95 (s, 1H), 8.11 (d, 8.5, 1H), 7.96 (d, 8.0, 1H), 7.52 (t, 7.0, 1H), 7.41 (t, 7.0, 1H), 7.35 (d, 9.0, 1H), 7.28 (s, 1H), 7.13 (s, 1H), 6.89 (d, 9.0, 1H), 6.67 (s, 1H) 5.83 (s, 2H), ), 3.77 (s, 3H), 3.73 (t, 8.0, 2H), 3.37 (t, 8.0, 2H); ); FABMS (NBA) m/z 394 (M+H+); IR (nujol) νmax 3296, 1652, 1592, 1533, 1462, 1260, 1094, 1020, 800 cm−1.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].CS(C)=O.[CH3:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]2=[CH:26][S:27][CH:28]=[C:17]2[C:16]1=[O:29]>Cl.CCOCC>[CH3:4][N:5]([CH3:6])[CH2:7][CH2:8][N:19]1[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:15]([CH3:14])[C:16](=[O:29])[C:17]2=[CH:28][S:27][CH:26]=[C:18]12
Reactant: CN(C)CCCl
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CN(C)CCN1c2cscc2C(=O)N(C)c2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 0.72 g. of 55% sodium hydride-mineral oil dispersion and 0.60 g. of dimethylaminoethylchloride hydrochloride in 25 ml. of dimethylsulfoxide is stirred at room temperature for 0.5 hours. To the mixture is added 0.46 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and stirring is continued for 3 hours. The reaction mixture is quenched by dropwise addition of water, diluted with about 200 ml. of water, acidified, filtered, made alkaline with 5N sodium hydroxide and extracted several times with chloroform. The chloroform extracts are dried over magnesium sulfate and concentrated under reduced pressure to give an amber oil. The oil is dissolved in a minimal volume of ethanolic hydrogen chloride solution and diluted with ether to give an oily semi-solid which slowly crystallizes. Recrystallization from ethanol-ether gives tan crystals, m.p. 245°-248° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1.[CH3:15][C:16]([CH2:20]O)([CH2:18]O)[CH3:17]>>[CH3:15][C:16]1([CH3:20])[CH2:18][O:12][B:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:13])[F:14])[CH:5]=2)[O:11][CH2:17]1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CC(C)(CO)CO
Product: CC1(C)COB(c2cccc(OC(F)(F)F)c2)OC1
Yield: 64 %

Procedure:
The title compound (64%, oil) was prepared from 3-trifluoromethoxyphenylboronic acid and neopentylglycol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23].[NH2:24][C:25]1[CH:36]=[CH:35][C:28]2[N:29]([CH3:34])[C:30](=[O:33])[CH2:31][S:32][C:27]=2[CH:26]=1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:24][C:25]3[CH:36]=[CH:35][C:28]4[N:29]([CH3:34])[C:30](=[O:33])[CH2:31][S:32][C:27]=4[CH:26]=3)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23]
Reactant: CN1C(=O)N(c2ccccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CN1C(=O)CSc2cc(N)ccc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CN1C(=O)CSc2cc(Nc3ncc4c(n3)N(C)C(=O)N(c3ccccc3Br)C4)ccc21
Temperature: 140 °C

Procedure:
320 mg 3-(2-bromo-phenyl)-3,4-dihydro-7-methanesulphonyl-1-methylpyrimido-[4,5-d]pyrimidin-2(1H)-one and 626 mg 7-amino-4-methyl-4H-benzo[1,4]thiazin-3-one (starting material k)) in 4 ml NMP were treated with 92 mg TFA and heated to 140° C. for 12 hrs. The mixture was diluted with aqueous HCl and the precipitated product collected by filtration.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28])(=[O:23])=[O:22]>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:25]=1
Reactant: COC(=O)CNc1cnccc1-c1ccccc1Cl
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-chloro-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 6 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light red foam (25%). MS (ESI): m/z=527.066 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:18][C:17]=2[CH2:26][NH:27][CH3:28])[CH2:12][CH2:11]1)C)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[OH:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([NH:8][CH3:6])[CH2:11][CH2:12]2)=[C:17]([CH2:26][NH:27][CH3:28])[CH:18]=1
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](NC)CC1
Reaction time: 2 h

Procedure:
7.1 g of trans-N-tert.butoxycarbonyl-N-methyl-4-[4-(3-hydroxypropyl)methylaminomethylphenyl]cyclohexylamine are combined with 20 ml of trifluoroacetic acid in 150 ml of methylene chloride at ambient temperature. After 2 hours, ice and 6N sodium hydroxide solution are added, the organic phase is separated off, washed, dried and evaporated down. After the residue has been recrystallised from ether, 3.1 g of the title compound are obtained, melting point 144°-146° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[S:8][CH2:7][CH2:6][C:5]2=[O:14].[CH3:16][O:17][CH2:18]Cl.[H-].[Na+]>C1COCC1>[CH3:16][O:17][CH2:18][O:1][C:2]1[C:3]([CH3:15])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[S:8][CH2:7][CH2:6][C:5]2=[O:14]
Reactant: COCCl
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CCS2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(C)c(C)c2c(c1C)C(=O)CCS2
Reaction time: 2 h

Procedure:
6-Hydroxy-5,7,8-trimethyl-2,3-dihydro-4H-thiochromen-4-one (2.24 g) was dissolved in anhydrous THF (100 mL) and treated with chloromethyl methyl ether (0.918 mL) and NaH (60% in mineral oil, 483 mg). The resulting reaction mixture was stirred for 2 h turning bright yellow as NaH was added and then gradually becoming pale yellow. The reaction mixture was quenched with a small amount of H2O followed by solvent evaporation and preloading the residue onto SiO2. Column chromatography (SiO2: hexane:EtOAc, 95:5 v/v) yielded 6-methoxymethoxy-5,7,8-trimethyl-2,3-dihydro-4H-thiochromen4-one as a white solid (2.37 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:10])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:10][C:17]2[CH:16]=[CH:15][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13][C:12]=2[Cl:11])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(Cl)c(S)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 2 h
Yield: 66 %

Procedure:
5.00 Grams of 5-chloro-2-fluoro-4-mercaptoaniline, 12.2 g of 3,4-dichlorobenzotrifluoride and 4.31 g of potassium carbonate were dissolved in 30 ml of dimethylformamide, and the resulting solution was stirred for 2 hours at a temperature of from 100° to 110° C. in an oil bath. Thereafter, the reaction solution was poured into water and extracted with three 200-ml portions of diethyl ether. The extract obtained was washed with water, dried, filtered and concentrated. The residue obtained was subjected to chromatography on silica gel to obtain 6.57 g of 5-chloro-2-fluoro-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2F)[CH2:5][CH2:4]1.[F:27][C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:25])([F:26])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2[N:30]2[CH2:31][CH2:32][C@@H:28]([F:27])[CH2:29]2)[CH2:7][CH2:8]1
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(F)c1F
Reactant: F[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC[C@@H](F)C2)c1F

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2,3-difluoro-4-methylamino-5-nitro-benzoic acid amide (200 mg, 0.52 mmol), (R)-3-fluoropyrrolidine×HCl (72 mg, 0.57 mmol), DIPEA (0.76 mL, 4.4 mmol) and MeCN (5 mL). Yield: 230 mg. HPLC Rt=1.52 min (method A). MS m/z: 451 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[N+:17]([C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1F)([O-:19])=[O:18]>O>[N+:17]([C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([O-:19])=[O:18]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 92.3 %

Procedure:
At a bath temperature of 40° C., 1.37 g (10 mmol) of 2-aminobenzoic acid and 2 g (18.7 mmol) of sodium carbonate in 40 ml of water are combined under vigorous stirring with 1.86 g (10 mmol) of 2,4-dinitrofluorobenzene and agitated for 2 hours. The batch is diluted with about 400 ml of water and precipitated with 4N HCl. The product is suctioned off, washed with water, and dried, thus obtaining 2.8 g of 2-(2,4-dinitrophenyl)aminobenzoic acid, mp: 266-270° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([N:15]=[S:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: N=S(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N=S(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.2 g (0.19 mol) of triethylamine in 50 ml of methylene chloride is added dropwise at room temperature, whilst stirring to a solution of 19 g (0.095 mol) of S,S-diphenylsulphilimine [compare Furukawa et al., Univ. Osaka: Tetrahedron Letters 1972, 1619-1622; Tamura et al., Univ. Osaka: Tetrahedron Letters 1972, 4137-4140] in 120 ml of methylene chloride and subsequently, whilst cooling slightly, a solution of 12.3 g (0.11 mol) of chloroacetyl chloride in 80 ml of methylene chloride is added dropwise. The mixture is stirred overnight at room temperature, the solvent is stripped off in vacuo, the residue is taken up in methylene chloride and the organic phase is washed with water until neutral. The product is then dried over sodium sulphate and the solution is evaporated in vacuo. N-(Chloroacetyl)-S,S-diphenylsulphilimine is obtained as an oily residue and is further processed as the crude product.
Reaction SMILES: [Br-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[C:4]=1[CH2:18][CH3:19].[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.CCOCC>C(O)(=O)C>[Br-:1].[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][N:5]2[CH:6]=[CH:7][N+:3]([N:2]=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([N:21]([CH3:30])[CH3:20])=[CH:23][CH:24]=3)=[C:4]2[CH2:18][CH3:19])=[CH:12][CH:13]=1
Reactant: CCc1n(CC(=O)c2ccc(Cl)cc2)cc[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCc1n(CC(=O)c2ccc(Cl)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension consisting of 1.72 g (5 mmol) of 1-amino-3-(p-chlorophenacyl)-2-ethylimidazolium bromide and 0.74 g (5 mmol) of 4-dimethylaminobenzaldehyde in 15 ml of glacial acetic acid is stirred at room temperature for 48 hours, treated with ether and filtered. The filtered-off crude product is chromatographed on 30 g of silica gel (particle size 0.063-0.200 mm) while eluting with methylene chloride/methanol (9:1 v/v) and then recrystallized from methylene chloride/methanol/ether. There is obtained 3-(p-chlorophenacyl)-1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium bromide of melting point 252°-253°.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:21]([O:23]C)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20].Cl>CO.O>[Br:3][C:4]1[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
Sodium hydroxide (4.35 mL, 8.69 mmol) was added to a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (1.6 g, 4.35 mmol) dissolved in MeOH (30 mL). The resulting suspension was stirred at 23° C. for 16 hrs. The mixture was diluted with water and the pH adjusted to 3 with HCl 2N. The precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide overnight to give 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (1.30 g, 84%) as a beige solid. Mass Spectrum: M+H+ 356
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[Na].[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2CBr)[CH:15]=1.[OH-].[K+]>O>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:8][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])[CH:15]=1
Reactant: BrCc1ccccc1-c1cnc2ccccc2c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(Cc1ccccc1-c1cnc2ccccc2c1)C(=O)O
Temperature: 130 °C

Procedure:
104 g (0.6 mol) of diethyl methylmalonate were added dropwise at room temperature to 13.8 g (0.6 mol) of sodium in 300 cm3 of H2 O-free EtOH. Subsequently, 178 g (0.6 mol) of 2-(3-quinolyl)benzyl bromide were added dropwise and the mixture was heated under reflux for 3 hours. At room temperature, 100 g (1.8 mol) of KOH dissolved in 400 cm3 of H2O were added and the mixture was heated under reflux for a further 4 hours. The EtOH was distilled off and the residue was admixed with H2O until completely dissolved and subsequently acidified with concentrated aqueous HCl to a pH of 1. The precipitate formed was filtered off with suction, dried and heated for 1 hour at 130° C. This gave 145 g (83%) of 2-(2-(3-quinolyl)benzyl)propionic acid as solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22]([O:11][C:10](=[O:12])[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[F:2])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:21]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.4 %

Procedure:
To a solution of (2-fluoro-phenyl)-phenylamino-acetic acid hydrochloride (I261) (217 mg, 0.77 mmol), (R)-quinuclidin-3-ol (338 mg, 2.66 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (180 mg, 1.332 mmol) in dry THF (15 mL), is added PS-DCC (1.0 g, 1.33 mmol). The mixture is shaken at RT for 15 hours. Then (R)-quinuclidin-3-ol (49.0 mg, 0.38 mmol) and PS-DCC (290 mg, 0.38 mmol) are added again and the reaction is shaken for additional 3 hours at RT. The resin is removed by filtration and washed several time with EtOAc. The solvent is evaporated, the residue is taken up with EtOAc and washed with NaHCO3, water and brine. The organic phase is dried (Na2SO4), filtered and evaporated to afford the title compound as a brown oil (225 mg, 82% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=1)[CH3:11]>ClCCl.CCCCCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Oc1ccccc1C
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1ccccc1OC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
The title compound, mp 142°-3° C. (dichloromethane-hexane), was prepared from ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methylphenoxy)propanoate by a method analogous to that described for Example 2.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][NH2:32])[CH3:22]>C(#N)C>[CH3:22][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][NH:32][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH3:20]
Reactant: CN(C)CC1CCCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: CN(C)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 53 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(dimethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 53% of theory. Colourless crystals, m.p. 189-190 (acetonitrile).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[N+:16]([O-:19])([OH:18])=[O:17].CC1C=C(C)[N:23]([C:27](N)=[NH:28])N=1>C(O)C>[N+:16]([O-:19])([OH:18])=[O:17].[N+:16]([O-:19])([OH:18])=[O:17].[CH3:15][N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH2:28])=[NH:23])[CH3:14]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: CN(C)Cc1cccc(OCCCNC(=N)N)c1
Yield: 50.9 %

Procedure:
3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine (2 g) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (2.1 g) were heated at reflux in ethanol for 16 hr. The solvent was removed and the residue was washed with boiling ethyl acetate before it was crystallised from ethanol to give the title compound as a white solid (1 g) m.p. 123°-4°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[O:34]1[CH2:35][CH2:36][N:31]([C:2]2[N:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH:9]3[C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:14]=3)[N:5]=[C:4]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[CH:3]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Reactant: C1COCCN1
Product: Cc1cc(Nc2cc(N3CCOCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1

Procedure:
Staring materials: 6-chloro-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 17) and morpholine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([N:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCCO
Reactant: O=C=NCCOCc1ccccc1
Solvent: ClCCl
Product: O=C(NCCOCc1ccccc1)N(CCO)CCO
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To 3-benzyloxypropionic acid (129.6 g) in ether (310 ml) and N,N-dimethylformamide (4ml) was added thionyl chloride (155 ml). The solution was refluxed for 2 hours, and solvents and excess thionyl chloride were removed by evaporation in vacuo. Yield 132 g of 3-Benzyloxypropionic acid chloride as an oil. To an ice cooled solution of the thus prepared acid chloride (132 g) in acetone (450 ml) was added a cold solution of sodium azide (48.5 g) in water (200 ml) at 5° C. After additional stirring at 5° C. for 30 minutes, the mixture was poured into water and toluene, and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine. After drying (magnesium sulfate) the solution was heated slowly to 85° C. on a steam bath until evolution of nitrogen ceased. The solvent was removed in vacuo leaving 108.4 g of 2-benzyloxyethylisocyanate as an oil. A mixture of 2-benzyloxy-ethylisocyanate (10 g) and diethanolamine (5.72 g) in dichloromethane (60 ml) was refluxed for 2.5 hours. After cooling to room temperature, the solution was washed with brine. Drying (magnesium sulfate) and evaporation of the solvent yielded 11.4 g of N-(2-benzyloxyethyl)-N',N'-di-(2-hydroxyethyl)-urea as an oil. A solution of the urea derivative (11.4 g) in dichloromethane (55 ml) was cooled to 5° C., and thionyl chloride (8.3 ml) was added at a temperature below 10° C. After the addition the mixture was refluxed for 1 hour and then left over night at room temperature. The solution was washed with cold sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 1,1,1-trichloroethane and refluxed for 3 hours. After cooling the solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo, yilding 6.6 g of the title compound 22a as an oil.