Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)N(N([C:11](=[O:22])[CH2:12][S:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)CC([O-])=O)C(=O)CC1.[NH2:25][C@@H:26]([C:28]([NH:30][CH2:31][C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])=[O:29])[CH3:27].C(OCC)C>C(O)C.O>[C:14]([S:13][CH2:12][C:11]([NH:25][C@@H:26]([C:28]([NH:30][CH2:31][C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])=[O:29])[CH3:27])=[O:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C([O-])CN(C(=O)CSC(=O)c1ccccc1)N1C(=O)CCC1=O
Reactant: C[C@@H](N)C(=O)NCC(=O)NCC(=O)O
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: C[C@@H](NC(=O)CSC(=O)c1ccccc1)C(=O)NCC(=O)NCC(=O)O
Yield: 44.6 %

Procedure:
To a solution of 1 g of succinimidyl-N-(S-benzoylmercaptoacetyl)glycinate in 25 ml of anhydrous ethanol at 70° C. is added in one portion a solution of 203 mg of D-alanylglycylglycine in 10 ml of water at 70° C. The reaction mixture is refluxed for 1 hour and the solvents are evaporated under reduced pressure. The residue is agitated with 5 portions of 25 ml acetone, which is isolated by filtration. The combined filtrates are treated with diethylether until precipitation is complete. The precipitate is filtered off, washed with diethylether and dried over P2O5 under vacuum to obtain 170 mg (47,7%) of S-benzoylmercaptoacetyl-d-alanylglycylglycine as a white powder, m.p. 167°-170° C. [α]D20 +22 (c=1 in methanol); nmr (DMSO-d6): δ 1.24 (3H, d, CH3), 3.88 (2H, s, CH2 --S), 3.74 (4H, d, 2×CH2 --N), 4.31 (1H, q, CH), 8.08 and 8.24 (each 1H, t, α-- and β--NH), 8.51 (1H, d, δ--NH), 7.5-8.04 (5H, complex, aromatic).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Se:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.[Cl:32]CCl>>[ClH:32].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Se:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:13]
Reactant: O=C(O)c1ccccc1[Se]Cc1ccccn1
Reactant: ClCCl
Reactant: Nc1cccnc1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(Nc1cccnc1)c1ccccc1[Se]Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3 g (0.0103 mol) 2-(2-picolylseleno)benzoic acid (from Example 1) in 20 ml dichloromethane that has been cooled to -10° C. is added with stirring 1.32 g (0.0103 mol) chloromethylenedimethyliminium chloride, the mixture is then stirred at room temperature for 2 hours then a solution of 0.97 g (0.0103 mol) 3-aminopyridine and 2.32 g (0.023 mol) triethylamine in 20 ml dichloromethane are added dropwise with in 10 minutes and stirring is continued at room temperature for 14 hours, the reaction mixture is extracted with 50 ml water and the separated dichloromethane phase is dried and the solvent removed. The oily residue is treated with 50 ml 1 N HCl and filtered, it is then basified with NaOH (5%) and extracted twice with 50 ml portions of dichloromethane. The organic phase is dried over sodium sulfate and the solvent removed, the residue is dissolved in 40 ml 2-propanol and treated slowly with stirring with 15 ml 2-propanol/10% HCl when the hydrochloride crystallizes out. This is washed with 50 ml diethyl ether.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:16](OC(=O)C2C=CC=CC=2)[C@@H:15]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:14]([CH3:35])[O:13][C:11]1=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCN(CC)CC.C(Cl)(Cl)Cl>[C:1]([O:9][C:10]1[C:11]([O:13][C@@H:14]([CH3:35])[C@H:15]([O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:16]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1OC(=O)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@@H]1OC(=O)C(OC(=O)c2ccccc2)=C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
The compound (VII) (13.2 g, 27.8 mmol) is dissolved in Et3N:CHCl3 (1:4, 500 ml) under N2 current and stirred for 16 hours at a room temperature. After the reaction is finished, it is washed by water. An organic layer is dried using anhydrous MgSO4. The solution is vacuum concentrated and then the compound (VIII) (6.37 g, 65%) is isolated using flash column chromatography (toluene/EtOAc, 10:1, v/v).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].C1N=CN([C:21](N2C=NC=C2)=[S:22])C=1>O1CCCC1>[CH3:10][O:9][C:6]1[C:7]2[NH:8][C:21](=[S:22])[NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CCN(C)C)c(N)c1N
Solvent: C1CCOC1
Product: COc1ccc(CCN(C)C)c2[nH]c(=S)[nH]c12
Yield: 78.3 %

Procedure:
500 mg of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dimethylamine is heated for 3 hours under reflux with 50 ml of tetrahydrofuran and 430 mg of N,N'-thiocarbonyldiimidazole. After concentration, the residue is combined with water. The precipitate is recrystallized from ethanol, thus obtaining 470 mg of 7-methoxy-4-[2-(N,N-dimethylamino)ethyl]-2,3-dihydro-2-benzimidazolethione, mp 213°-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][C:14](C(OC)=O)=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1
Reactant: COC(=O)c1[nH]c(=O)n2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]cc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A mixture of 0.386 g (1 mmole) of 8-chloro-1,2-dihydro-6-(2-fluorophenyl)-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester, 10 ml of methanol, 1 ml of water and 0.225 g (4 mmole) of potassium hydroxide was heated to reflux for 31/2 hours under an atmosphere of nitrogen. The solvent was evaporated and the residue was acidified with acetic acid and extracted with methylene chloride. The extracts were dried and evaporated and the residue was heated in mineral oil up to 230° for 5 min. The reaction mixture was partitioned between 1N hydrochloric acid and methylene chloride/hexane. The acid extract was made alkaline with sodium carbonate solution and extracted with methylene chloride. The residue obtained after evaporation of the dried extracts was chromatographed over 10 g of silica gel using methylene chloride/ethyl acetate 1:2. Crystallization of the combined clean fractions from ethyl acetate/hexane yielded colorless crystals with mp 247°-250°. Uv λ max 212 mμ (ε=42250) sh 262 (10000) ir (KBr) 1695 cm-1 (CO) 3150 (NH). Nmr (CDCl3) 4.18 ppm (d, 1) and 4.88 (d, 1) (AB-system, J=12.5 Hz, C4 -H) 6.28 (d, 1, J=2 Hz, C3 -H) 6.9-7.7 (m, 5, aromatic H) 8.13 (d, 1, J=8.5 Hz, C10 -H) 10.46 (broad s, 1, NH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:6][C:5]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[NH:20][C:19]2=[O:29])=[C:4]([F:30])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:37](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:37][N:20]1[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][C:23](=[O:24])[N:18]([C:5]2[CH:6]=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-:17])=[O:16])[C:2]([Cl:1])=[CH:3][C:4]=2[F:30])[C:19]1=[O:29]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3[N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 43.5 %

Procedure:
A suspension of 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4,-dione (1.0 g), potassium carbonate (0.37 g), and 2,4-dinitrophenoxyamine (0.54 g) in anhydrous N,N-dimethylformamide (20 ml) was stirred at room temperature for 20 hours. The solution was processed and the resulting oil was chromatographed on silica gel eluting with methylene chloride:hexane:ethyl acetate, 2:3:0.5. The product was crystallized from methylene chloride:hexane:ethyl acetate to give a white solid (0.45 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14](=[O:18])[O:15][CH2:16][CH3:17].[CH2:19]([N:26]1[CH:31]2[C:32]([F:35])([F:34])[CH2:33][CH:27]1[CH2:28][C:29](=[O:36])[CH2:30]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CN1C(=O)CCC1.C1COCC1>[CH2:19]([N:26]1[CH:31]2[C:32]([F:35])([F:34])[CH2:33][CH:27]1[CH2:28][C:29]([CH2:13][C:14]([O:15][CH2:16][CH3:17])=[O:18])([OH:36])[CH2:30]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(C)=O
Reactant: O=C1CC2CC(F)(F)C(C1)N2Cc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CC2CC(F)(F)C(C1)N2Cc1ccccc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of diisopropylamine (1.02 g, 10 mmol, 5.0 eq) in THF (10 mL) was added n-BuLi (5 mL, 2.0 M, 5.0 eq) dropwise at −50° C. After 30 min, dry EA (880 mg, 10 mmol, 5.0 eq) in NMP/THF (11 mL, 1:10) was added dropwise. After 1 h at −50° C., a solution of compound 116h (500 mg, 2 mmol, 1.0 eq) in THF (5 mL) was added slowly, and the resulting mixture was warmed from −50° C. to room temperature for 2 h. The reaction mixture was quenched with water (50 mL), extracted with EA (100 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel (EA/PE=1:3) to give ethyl 2-(8-benzyl-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)acetate 116i as a colorless oil. 490 mg, yield: 72%. 1H NMR (400 MHz, DMSO-d6) ppm 7.37-7.19 (m, 5H), 4.45 (s, 1H), 4.09 (q, J=7.0 Hz, 2H), 3.84-3.70 (m, 2H), 3.27 (d, J=5.0 Hz, 1H), 3.08 (d, J=11.3 Hz, 1H), 2.70 (q, J=13.6 Hz, 1H), 2.43 (s, 2H), 2.37-2.26 (m, 1H), 2.13-2.00 (m, 2H), 1.84-1.72 (m, 1H), 1.52 (d, J=14.3 Hz, 1H), 1.22 (t, J=7.0 Hz, 3H); MS: calc'd (MH+) 340, measured (MH+) 340.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]([CH3:21])([CH2:19]O)[CH2:17][OH:18].O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[OH:18][CH2:17][C:16]1([CH3:21])[CH2:19][O:14][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:15]1
Reactant: CC(N)(CO)CO
Reactant: CCCCCCCCCCCC(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC1=NC(C)(CO)CO1
Yield: 84.6 %

Procedure:
A mixture of 20.03 g (100 mmoles) of dodecanoic acid and 11.57 g (110) mmoles) of 2-amino-2-methyl-1,3propanediol in 10 ml of xylene was heated for 30 hours at 185°-190°C. with azeotropic removal of water. The reaction mixture was taken up in ethyl acetate and was washed with water to remove excess amino alcohol. The organic layer was dried, concentrated and the residue was distilled at 152°-155° C./ 1 mmHg to give 22.8 g (84.6%) of 4-hydroxymethyl-4-methyl-2-undecyl-2oxazoline.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=[C:31]=[N:32][CH2:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37].CN1CCCNCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:37][N:36]1[CH2:35][CH2:34][CH2:33][N:32]([C:12]([C:11]2[CH:10]=[C:9]([C:7]3[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)[CH:17]=[CH:16][CH:15]=2)=[O:14])[CH2:31][CH2:38]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(=O)c1ccc(-c2cccc(C(=O)O)c2)o1
Agent: CN1CCCNCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(-c2cccc(C(=O)N3CCCN(C)CC3)c2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 109 %

Procedure:
To a solution of 3-(5-acetylfuran-2-yl)benzoic acid (1.10 g, 4.78 mmol) and HOBt (1.29 g, 9.56 mmol) in DMF (10 mL) was added EDCI (1.83 g, 9.56 mmol). The reaction was stirred at rt for 10 min and then added 1-methylhomopiperazine (2.38 mL, 19.12 mmol) followed by DIEA (3.35 mL, 19.12 mmol). The reaction mixture was stirred at rt for 1 h and diluted with H2O (50 mL). The mixture was extracted with DCM (3×50 mL), dried over Na2SO4 and concentrated to give brown oil (1.70 g). LCMS (ES): m/z 442 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CC#N>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: NCc1ccccn1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Solvent: CC#N
Product: COc1cc2c(NCc3ccccn3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 110 °C
Reaction time: 4 h

Procedure:
The mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide (for a preparation see Intermediate 40, 6 g, 18 mmol) was reacted with 2-aminomethylpyridine (2.5 eq, 4.23 g, 45 mmol) in CH3CN (100 ml) was stirred at 110° C. for 4 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over Na2SO4 and concentrated to dryness to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-4-[(2-pyridinylmethyl)amino]-3-quinoline carboxamide (5.84 g) which was used in the next step without purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.Cl.Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][C:26]([OH:28])=O)[CH2:19][CH2:18]1.C([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])C>ClCCl.CN(C)C=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][C:26]([N:37]2[CH2:38][CH2:39][CH2:2][CH2:1][CH2:41][CH2:40]2)=[O:28])[CH2:21][CH2:22]1
Reactant: COc1ccccc1N1CCN(CC(=CC(=O)O)c2ccccc2)CC1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CC(=CC(=O)N2CCCCCC2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (3.50 ml) was added to a suspension of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-3-phenylbut-2-enoic acid dihydrochloride (4.17 g, 9.81 mmol) in dichloromethane (50 ml) and a few drops of dry N,N-dimethyl formamide added. After stirring at room temperature for 3 h, the solid formed was filtered off and a solution of triethylamine (3.07 g, 30.4 mmol) and hexamethyleneimine (1.07 g, 10.8 mmol) in dichloromethane (25 ml) was added dropwise to an ice-cooled suspension of the filtered solid in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The crude product was chromatographed on silica gel, eluting with ethyl acetate: pentane (1:1 to 2:1) to afford the title compound as two isomers. The Z-isomer was obtained as an oil and this was dissolved in diethyl ether and acidified with ethereal hydrogen chloride to afford a colourless hygroscopic powder which was recrystallised from dichloromethane-diisopropylether to give the dihydrochloride as a colourless powder (0.36 g), m.p. 149.4° to 152.9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=2)=[CH:12][CH:11]=1.[H][H]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[NH:20][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H]1CCC(c2ccc(NCc3ccccc3F)cc2)=N1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(NCc3ccccc3F)cc2)N1
Yield: 92.1 %

Procedure:
A solution of methyl (2S)-5-(4-{[(2-fluorophenyl)methyl]amino}phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (D67, 39 mg, 0.119 mmol) and Pt 5% on carbon in ethyl acetate (10 ml) was stirred under 1 atm of hydrogen for 4.5 h, filtrated over celite and evaporated to afford the title compound (36 mg, 92%). MS: (ES/+) m/z: 329 [MH]+, —C19H21FN2O2 requires 328.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+]>O>[C:4]([CH2:3][CH2:2][S:9]([O-:12])(=[O:11])=[O:10])([O:6][CH2:7][CH3:8])=[O:5].[Na+:13]
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)CCBr
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCS(=O)(=O)[O-]
Yield: 152.8 %

Procedure:
A mixture of 52 g (0.29 moles) ethyl 3-bromopropionate and 36.1 g (0.29 moles) anhydrous sodium sulfite in 150 ml water was refluxed for about 16 hours. The reaction mixture was stripped. The residue was washed with acetone and ethyl ether, stripped, and dried in a vacuum oven to give 90.5 g of the above-identified product.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH2:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1>[Pd].CCO.CCOC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:9]=1[OH:8])[CH3:16]
Reactant: C=C(c1ccccn1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(c1ccccn1)c1cccc(-c2ccccc2)c1O
Reaction time: 2.75 h

Procedure:
A solution of 5 (0.50 g, 1.377 mmol, 1.0 equiv) and 20% Pd—C (55% H2O) (0.05 g) in 1:1 EtOH/EtOAc (30 mL) was hydrogenated at 30 psi H2 for 4.25 hr. LCMS showed some 5 remained along with A and a small amount of over-reduction products. The mixture was hydrogenated at 20 psi H2 for 2.75 hr (LCMS showed ˜2% 5 remained). The mixture was filtered through Celite, and the Celite layer was washed with 1:1 EtOH/EtOAc (30 mL). The filtrate was concentrated under reduced pressure to give a brown oil. The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (10 g) packed in hexanes. The column was eluted with hexanes (100 mL), 5% EtOAc/hexanes (100 mL) and 10% EtOAc/heptanes (200 mL). Product fractions were concentrated under reduced pressure to give 0.40 g (105%—residual solvent present) of A as a colorless, viscous oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][S:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:11][S:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(C=O)CC1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A solution of dimethylsulfoxide (39 ml, 0.55 mole) in dichloromethane (300 ml) was added slowly to a solution of oxalyl chloride (22.7 ml, 0.264 mole) in dichloromethane (700 ml) at −60° C. After 10 minutes a solution of 1-methanesulfonylpiperidine-4-methanol (46 grams. 0.238 mole) in dichloromethane (500 ml) was added slowly. After 30 minutes at −60° C., triethylamine (167 ml) was added. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (1.2 liters) and water (200 ml). The organic phase was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give 1-methanesulfonylpiperidine-4-carboxaldehyde (34 grams), m.p. 97° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C@@H:20]([NH2:24])[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C@@H:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Oc1ccc(Oc2ccc(CC[C@@H](N)C(C)C)cc2)cn1
Product: CC(=O)N[C@H](CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1)C(C)C

Procedure:
(R)-1-{2-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]ethyl}-2-methylpropylamine (48.7 mg, 0.148 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 42 mg (77%), M+H+: 371.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:12])=[CH:9][N:10]=1.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O>ClCCl>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[S:7][C:8]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][N:10]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1C(=O)c1cnc(NCCCN)s1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCCCNc2ncc(C(=O)c3ccccc3C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone was dissolved in dichloromethane and triethylamine and toluene-4-sulfonyl chloride added. The mixture was stirred overnight at room temperature, poured into 1 M pH4 phosphate buffer (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic phases were dried over magnesium sulfate and evaporated. The oily residue was purified by column chromatography on silica gel (13:7 hexane/acetone eluant), using a small amount of dichloromethane to apply the mixture to the column. The title compound was isolated as an off-white solid. MS (m/e): 428.3 (M−H, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([Cl:33])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:33])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 50 °C
Reaction time: 14 h
Yield: 65.3 %

Procedure:
To methyl 4-[(2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]-2-chlorobenzoate (0.465 mmol, 224.8 mg), methanol (20 mL) was added, and 1 M aqueous sodium hydroxide (2.3 mmol, 2.3 mL) was added. After 5 hours of stirring at 50° C., 14 hours of stirring at room temperature and 4 hours of stirring at 50° C., 1 M hydrochloric acid (2.3 mmol, 2.3 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the crude desired product as a yellow solid (193.3 mg). Further, 169 mg of the crude desired product was is dissolved in THF (35 mL) and stirred at room temperature for 2 days. The insolubles were filtered off, and the filtrate was concentrated and dried by means of a vacuum pump. After addition of chloroform, the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (142.3 mg, yield 75%).