Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11](Cl)[CH:10]=1.[Cl:19]N1N=C(OC)C=C(OC)N1>C(OCC)(=O)C>[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[Cl:19]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: COC1=CC(OC)=NN(Cl)N1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)O)cc1Cl

Procedure:
Separately, 23.5 g of N-Methylmorpholine is added to a mixture of 33.1 g of 4-Amino-chloro-benzoic acid 34.4 g of 2-Chloro-4,6-dimethoxytriazine (DMT-Cl) in 300 ml of ethyl acetate over 20-30 minutes at ambient temperature for 2-3 hours at 23-27° C. to obtain the DMT active ester of 4-Amino-3-chlorobenzoic acid. The mixture is cooled to 0° to +5° C. and 300 ml of purified water are added to the solution keeping temperature in the same range. The solution of the deprotected t-leucine product as the citrate salt is added at 0° C. to +5° C. over 30-60 minutes, the reaction mixture is then brought to pH 6.5-7.5 by adding 30% sodium hydroxide (approx. amount: 71 ml), and stirred 6-7 hrs at 20° to 25° C. After completion of the reaction, the phases are separated and the organic layer added to sodium bisulfate solution (15 g of sodium bisulfate in 235 ml of water) and stirred for 3 hrs at 20° C. to 25° C. The phases are separated and the organic layer is washed four times with water (150 ml each), twice with sodium bicarbonate solution (total: 20 g of sodium bicarbonate in 400 ml of water), and once with 150 ml of water. To the solution is added 10 g of activated charcoal and 10 g of Dicalite and filtered and the solids washed with 100 ml of ethyl acetate. The filtrate was distilled under vacuum to a volume of 200 ml at <40° C. when the resultant mixture crystallizes. Ethyl acetate (150 ml) was added to a total volume of 350 ml. N-heptane (300 ml) was added over 2 hrs and after stirring the slurry for 3 hrs at 200 to 250, the solid was filtered, washed with ethyl acetate/N-Heptane (100 ml, 1:1) and dried at 60° C. under vacuum.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:12]1[CH:17]=[C:16]([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>CCCCCC.CN(C)C=O>[CH2:9]([S:10][C:12]1[CH:17]=[C:16]([C:18]2[S:22][C:21]([C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[N:20][C:19]=2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH:15]=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCc1ccccc1
Reactant: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(F)c2)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(SCc3ccccc3)c2)c1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
After sodium hydride (60% paraffin dispersion, 0.13 g, 3.2 mmol) was washed with hexane twice, it was suspended in N,N-dimethylformamide (15 mL). Phenylmethanethiol (0.35 mL, 3.0 mmol) was added to this suspension and stirred for 10 minutes. A solution of 5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole (0.49 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) was added to this mixture and stirred for 1 hour. An 8N aqueous solution of sodium hydroxide was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the extract was washed with water. This extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 2:1) to obtain 0.48 g (yield 79%).
Reaction SMILES: [NH:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[N:3]1[CH2:13][CH:14]=[CH2:15].[Br:16]N1C(=O)CCC1=O>O1CCCC1>[Br:16][CH2:15][CH:14]1[CH2:13][N:3]2[C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:1]1
Reactant: C=CCn1c(=O)[nH]c2ccccc2c1=N
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C2=NC(CBr)CN12
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 79.8 %

Procedure:
To a solution of 3,4-dihydro-4-imino-3-allyl-2(1H) -quinazolinone (10 g, 50 mmol) in tetrahydrofuran (70 mL) was added N-bromosuccinimide (9.0 g, 50 mmol). The mixture was then stirred at room temperature for 25 minutes. The solid was collected by filtration and recrystallized from THF to afford 2-bromomethyl-2,3-dihydro-imidazo[1,2-c]quinazolin-5(6H)-one (11.18 g, 95%), mp 213°-214° C. 1H NMR (300 MHz, DMSO-d6): δ3.67(m, 2H, CH2), 3.74 (q, 1H, CH), 3.94 (t, 1H, CH), 4.57 (m, 1H, =CH), 7.07 (q, 2H, Ar--H), 7.51 (t, 1H, Ar--H), 7.78 (d, 1H, Ar--H), 10.65 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): d 47.80, 64.16, 110.27, 115.13, 122.23, 125.80, 133.59, 139.97, 147.47, 153.98, 206.07. Anal. Calcd for C11H10N3OBr: C, 47.16; H, 3.59; N, 15.00. Found: C, 47.09; H, 3.41; N, 14.90.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[F:9][CH:10]([F:18])[C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CO>O>[F:9][CH:10]([F:18])[C:11]1[CH:12]=[C:13]([NH:14][C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(C(F)F)c1
Reactant: O=C1CCCC(=O)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: O
Product: O=C1C=C(Nc2cccc(C(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of cyclohexane-1,3-dione (2.00 g, 17.84 mmol), 3-(difluoromethyl)aniline (2.55 g, 17.82 mmol) and Ytterbium(III) trifluormethanesulfonate (111 mg, 178 μmol, 1.0 mol %) is stirred at room temperature for 2 h. Methanol and water are added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate). Yield: 2.76 g; ESI mass spectrum [M+H]+=237, Retention time HPLC: 0.40 min (X012_S01).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]2[N:14]=[CH:15][CH:16]=[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:21]([F:33])[CH:20]=3)[C:11]2=[N:10][CH:9]=1>>[F:33][C:21]1[CH:20]=[C:19]([O:18][C:17]2[C:11]3[C:12](=[N:13][C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][N:10]=3)[N:14]=[CH:15][CH:16]=2)[CH:24]=[CH:23][C:22]=1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3nc(Cl)cnc23)cc1F
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3nc(N4CCOCC4)cnc23)cc1F

Procedure:
Method D6 was used with morpholine and tert-butyl 4-(3-chloropyrido[2,3-b]pyrazin-8-yloxy)-2-fluorophenylcarbamate to give the title compound as a white solid. Yield: 117 mg (89%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17].C([O-])(=O)C.[Na+]>ClCCCl>[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH:14]=[O:15])=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN(C=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1C=O
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
Phosphorus oxychloride (2.0 mL) was added to N-methylformanilide (2.9 g), and after the mixture was stirred for 15 minutes, 1,2-dichloroethane (50 mL) and 5-chloroindole-2-carboxylic acid ethyl ester (4.0 g) were added thereto, followed by heating under reflux for 1 hour. The reaction mixture was poured into an aqueous solution (28 mL) of sodium acetate (14 g) under ice cooling, and the thus-obtained mixture was stirred for 18 hours. Insoluble matter was collected by filtration, and was sequentially washed with water and diethyl ether, to thereby give the title compound (3.56 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C@H:10]([C:14]([N:16]2[CH2:23][CH2:22][CH2:21][C@H:17]2[C:18](O)=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])=[CH:5][CH:4]=1.[NH2:26][CH:27]([CH:34]([CH3:36])[CH3:35])[CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@@H:10]([CH:11]([CH3:12])[CH3:13])[C:14]([N:16]2[CH2:23][CH2:22][CH2:21][C@H:17]2[C:18]([NH:26][CH:27]([CH:28]([OH:33])[C:29]([F:30])([F:31])[F:32])[CH:34]([CH3:35])[CH3:36])=[O:19])=[O:15])=[O:8])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)O)C(C)C)cc1
Reactant: CC(C)C(N)C(O)C(F)(F)F
Product: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)NC(C(C)C)C(O)C(F)(F)F)C(C)C)cc1

Procedure:
reaction of N-(4-methoxybenzoyl)-L-valyl-L-proline with 3-amino-4methyl-1,1,1-trifluoro-2-pentanol to give (S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro 1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide; followed by
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]1[C:16]([O:17][C:18](=O)[O:19]C2C(F)=C(F)C(F)=C(F)C=2F)=[C:15]([F:32])[C:14]([F:33])=[C:13]([F:34])[C:12]=1[F:35]>C1COCC1>[F:10][C:11]1[C:16]([O:17][C:18](=[O:19])[NH:8][C:6]2[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([CH3:1])[CH:7]=2)=[C:15]([F:32])[C:14]([F:33])=[C:13]([F:34])[C:12]=1[F:35]
Reactant: Cc1cc(N)cc(C)n1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc(C)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2,6-dimethyl-pyridin-4-ylamine (Example C1.2., 1.23 g, 10 mmol) in THF (30 mL) is slowly added to a cooled (−10° C.) solution of bis(pentafluorophenyl)carbonate (3.94 g, 10 mmol) in THF (10 mL). The mixture is stirred at r.t. for 48 h and the solution of title compound is used as stock solution for subsequent coupling reactions.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH:18]=[C:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:31]CCl>C(O)C>[ClH:31].[C:22]1([C:17]2[C:16](=[N:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[CH2:21][CH2:20][CH2:19][CH:18]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=C2CCCC=C2c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCON=C2CCCC=C2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above ester (0.4 g, 1.1 mmol) was dissolved in ethanol (10 ml) and 4N sodium hydroxide (1 ml) was added. The mixture was stirred at ambient temperature for 3 h and excess concentrated hydrochloric acid was added followed by dichloromethane (400 ml). The suspension was dried (MgSO4) and the solvent evaporated in vacuo. The residue was re-evaporated with acetone, dissolved in acetone (10 ml) and left for crystallisation. This afforded 0.17 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:16]([N:18]([CH2:23][CH3:24])[C:19](=[O:22])[CH2:20]Cl)[CH3:17].[I-].[Na+]>C(C(C)=O)C>[CH2:16]([N:18]([CH2:23][CH3:24])[C:19](=[O:22])[CH2:20][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3][C:2]1=[NH:1])[CH3:17]
Reactant: CCN(CC)C(=O)CCl
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CC)C(=O)Cn1c(=N)sc2cc(OC(F)(F)F)ccc21
Temperature: 20 °C
Yield: 30.1 %

Procedure:
The procedure is as in Example 21, starting with 2-amino-6-trifluoromethoxybenzothiazole (9.4 g), N,N-diethylchloroacetamide (12 g) and sodium iodide (13.5 g) in methyl ethyl ketone (30 cc). The mixture is heated for 16 hours to boiling and then cooled to a temperature in the region of 20° C. The reaction medium is added to distilled water (100 cc), treated with IN sodium hydroxide (50 cc) and then extracted with ethyl acetate (150 cc). After drying over magnesium sulphate and then concentrating to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa), the residue is purified by chromatography on a silica column with ethyl acetate as eluent. N,N-Diethyl-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)acetamide (4.2 g) is obtained, which product is converted to a hydrochloride, m.p. 223° C.
Reaction SMILES: [C:1](Br)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Br:45])=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32](=[O:39])(=[O:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:22][C:21]=3[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]2)[CH:12]=1>>[Br:45][C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])=[CH:12][C:11]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:38])(=[O:39])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:22][C:21]=2[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]1
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 77 %

Procedure:
Propionyl bromide was reacted with 2-(5-amino-2-bromophenyl)-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D) according to the procedure of Example 26 to give a 77% yield of the title compound as a stiff, off-white foam, mp 119°-121° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 686,688 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:6]([O:8]C)=[O:7].[OH-].[K+].Cl>CO.O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]([N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:6]([OH:8])=[O:7]
Reactant: COCCC(C(=O)OC)n1cccn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCC(C(=O)O)n1cccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of 0.045 g (0.23 mmol) of methyl 4-methoxy-2-(1H-pyrazol-1-yl)butanoate from step A in 2 mL of methanol was added a solution of 0.032 g (0.57 mmol) of potassium hydroxide in 0.5 mL of water. The mixture was stirred at ambient temperature for 1.5 h then acidified with a 2 N hydrochloric acid solution until a pH of 4 was achieved. The mixture was evaporated to remove all volatiles then extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the title compound (0.040 g, 95%). LC-MS: m/z (ES) 185 (MH)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([I:15])=[CH:9][CH:8]=3.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[I:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([I:1])=[CH:3][CH:4]=3
Reactant: Ic1ccc2[nH]c3ccc(I)cc3c2c1
Reactant: OCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCCCCCCCn1c2ccc(I)cc2c2cc(I)ccc21
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of 3,6-diiodocarbazole (10.0 g, 23.87 mmol) and 11-bromo-1-undecanol (7.0 g, 27.87 mmol) in DMF (100.0 ml) was added K2CO3 (32.0 g, 231.33 mmol). The reaction was carried out at room temperature for 24 h. Water (300 ml) was added. The precipitate was filtered. The crude product was purified by silica gel column using Hexane/ethyl acetate (7:3) as solvent. 12.4 g (87.9%) of pure product as white solid was obtained. 1H-NMR (CDCl3, TMS, 500 MHZ): δ=8.32 (d, 2Harom, J=1.5 Hz), 7.71 (dd, 2Harom, J1=1.5 Hz, J2=8.5 Hz), 7.16 (dd, 2Harom, J1=1.5 Hz, J2=8.5 Hz), 4.21 (t, 2H, NCH2), 3.64 (m, 2H, OCH2), 3.41 (t, 1H, OH), 1.81 (m, 4H, 2×CH2), 1.54 (m, 4H, 2×CH2), 1.30 (m, 10H, 5×CH2) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH:6]1[CH2:18][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)[CH3:5].C(N(CC)CC)C.[O:36](C(OC(C)(C)C)=O)[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:40]([O:39][C:37]([N:10]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][C:16]=2[C:8]2[CH2:7][CH:6]([C:4]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:21])=[O:20])([C:3]([O:2][CH3:1])=[O:28])[CH3:5])[CH2:18][C:9]1=2)=[O:36])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)C(C)(C1Cc2[nH]c3ccc(Cl)cc3c2C1)S(=O)(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C1Cc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 94.7 %

Procedure:
130 mg (0.31 mmol) (RS,SR)-2-benzenesulfonyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester were dissolved in 7 mL CH2Cl2 at RT. 90 μL (0.62 mmol, 2 eq) triethylamine, 4 mg (0.031 mmol, 0.1 eq) DMAP and 81 mg (0.37 mmol, 1.2 eq) BOC2O were added. The reaction mixture was stirred for 2 hours. The reaction was quenched with 10 mL of an aqueous 1M solution of HCl. The organic layer was separated and the aquous layer was washed with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to yield to 152 mg (94%) (RS,SR)-2-(1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester as a white powder, M: 535 (MNH4+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([O:20]CC)=[O:19])[CH2:13][C:12]([F:15])([F:14])[C:11]2([F:17])[F:16])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([OH:20])=[O:19])[CH2:13][C:12]([F:15])([F:14])[C:11]2([F:16])[F:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(OCC)cc2)CC(F)(F)C1(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C2(C(=O)O)CC(F)(F)C2(F)F)cc1
Temperature: 0 °C

Procedure:
Ethyl 1-(4-ethoxyphenyl)-2,2,3,3-tetrafluorocyclobutane carboxylate (14.5 g) was dissolved in ethanol (100 ml) and a 10% w/w solution of sodium hydroxide in water (100 ml) was added and the mixture refluxed for 2.5 hours. The mixture was cooled, added to ice water and extracted with diethyl ether. The aqueous layer was acidified and the precipitate was filtered off, washed with water, dried and crystallised from 60°-80° petroleum ether to give the acid mp 112°-3° C. Yield 11.2 g (85%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][C:6]=1[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])=[O:4].[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH3:29])[N:22]=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][C:6]=1[S:14]([NH:17][C:18]([NH:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH3:29])[N:22]=1)=[O:19])(=[O:15])=[O:16])=[O:4]
Reactant: COC(=O)c1ccc(N=C=O)cc1S(=O)(=O)N=C=O
Reactant: COc1nc(C)nc(N)n1
Solvent: CC#N
Product: COC(=O)c1ccc(N=C=O)cc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 27 g of 2-methoxycarbonyl-5-isocyanatobenzenesulfonylisocyanate in 250 ml of anhydrous acetonitrile is added in small portions at ambient temperatures, 14 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine, the mixture is then stirred at ambient temperature for 16 hours. The resultant product, a white precipitate is removed by filtration and dried in vacuo.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-trifluoromethylbenzoyl chloride (14 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH2:12]>S(=O)(=O)(O)O.CO>[CH3:11][NH:12][C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CN
Agent: O=S(=O)(O)O
Solvent: CO
Product: CNC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Phenylacetic acid (10 g, 73.5 mmol) and methanol (60 ml) were added to a 250 ml three-necked flask, followed by addition of 10 drops concentrated sulphuric acid. The resulting solution was heated to reflux for 2 hours. Then, the solution was cooled to room temperature, followed by adding 25-30% aqueous solution of methylamine (50 ml, approximately 403 mmol), and heated to reflux for another 3 hours. After the reaction was completed, it was cooled to room temperature. Most of the solvent was removed by rotary vacuum evaporation, 30 ml of water was added thereinto, and then the mixture was extracted with ethyl acetate (3×80 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to yield 10.1 g of N-methyl phenylacetamide (white solid, yield: 91.8%).
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+].CO>O>[Cl:15][C:10]1[CH:9]=[C:8]([C:4]2([CH:1]([NH2:22])[CH3:2])[CH2:7][CH2:6][CH2:5]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane (2.2 g) prepared as described in Example 1, ammonium acetate (7 g), sodium cyanoborohydride (0.4 g) and methanol (28 ml) was stirred at room temperature for four days. The reaction mixture was poured into a mixture of ice and water and the resulting mixture extracted with ether. The ether extract was washed with water, dried and the ether removed to leave 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine as an oil which was identified by standard analytical techniques as the compound of Example 1 in the form of its free base.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[BH4-].[Na+]>C(O)C.ClCCl>[OH:1][CH:2]1[CH2:3][CH:4]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reaction time: 3 h
Yield: 93.6 %

Procedure:
3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester (8 g, 35.5 mmol) was dissolved in 100 mL of ethanol. Sodium borohydride (2 g, 53.5 mmol) was added to the solution portionwise at room temperature. After stirring for 3 hours, the reaction was evaporated in vacuo to give clear viscous oil. The oil was dissolved in dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford 7.55 g of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester as a white crystalline solid; 1H NMR (300 MHz, DMSO-d6): 4.23 (dd, J=2.7, 4.6 Hz, 1 H), 4.18-4.06 (m, 2 H), 2.17-2.06 (m, 1 H), 1.99-1.91 (m, 3 H), 1.72-1.50 (m, 5H), 1.47 (s, 9H).