Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[C:5]([Cl:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:35]([CH3:36])[C:34](=[O:37])[CH2:33][CH2:32][CH2:31][C:30]=2[CH:38]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[N:7][C:2]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[N:35]([CH3:36])[C:34](=[O:37])[CH2:33][CH2:32][CH2:31][C:30]=3[CH:38]=2)=[N:3][CH:4]=1
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4C(N)=O)n3)ccc21
Temperature: 120 °C
Yield: 69.7 %

Procedure:
A microwave vessel was charged with 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-benzamide (50.0 mg, 0.136 mmol), 7-amino-1-methyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (31.6 mg, 0.166 mmol), 10-camphorsulfonic acid (3.5 mg, 0.015 mmol) and isopropyl alcohol (2 mL). This mixture was heated at 120° C. for 20 minutes in a microwave reactor (sealed vessel). After quenching with saturated aqueous NaHCO3 solution (2 mL), the resulting precipitate was collected by filtration, successively washed water (5×2 mL) and ether (2×1 mL) to afford product as a yellow powder (49.5 mg, 70%) that had the following properties: mp: 288-290° C.; LC/MS (ESI+): 522 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 11.29 (s, 1H), 9.45 (s, 1H), 8.46 (d, J=8.0, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.52 (d, J=8.9, 1H), 7.32 (s, 1H), 7.20 (d, J=8.6, 1H), 7.09 (d, J=9.4, 1H), 3.77 (m, 4H), 3.25 (s, 3H), 3.15 (m, 4H), 2.60 (m, 2H), 2.20-2.10 (m, 2H), 2.10-2.00 (m, 2H).
Reaction SMILES: COC1C=C(C[N:12]2[C:16](=[O:17])[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[C:14]([CH3:28])[C:13]2=[O:29])C=CC=1OC.C(O)(C(F)(F)F)=O.OS(O)(=O)=O>C1(OC)C=CC=CC=1>[CH3:28][C:14]1[C:13](=[O:29])[NH:12][C:16](=[O:17])[C:15]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=1
Reactant: COc1ccc(CN2C(=O)C(C)=C(c3ccc(C(F)(F)F)cc3)C2=O)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1=C(c2ccc(C(F)(F)F)cc2)C(=O)NC1=O
Yield: 79.4 %

Procedure:
A solution of 1-{[3,4-bis(methyloxy)phenyl]methyl}-3-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (P3, 100 mg), anisole (107 μL), TFA (4 mL) and H2SO4 (catalytic amount) was heated at 90° C. overnight. The solution was then concentrated in vacuo, dichloromethane was added and the organic phase was washed with NaHCO3 (aqueous saturated solution), dried on sodium sulphate and evaporated in vacuo. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate 8/2 to give the title compound (50 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:7][CH2:8][CH3:9].CS[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][N:19]=1>>[CH2:7]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][N:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:8][CH3:9]
Reactant: CCCN(CCCCN)c1ccccn1
Reactant: CSc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Product: CCCN(CCCCNc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(4-aminobutyl)-N-propylamino]pyridine (1.24 g) and 2-methylthio-5-(4-fluorobenzyl)pyrimid-4-one (1.25 g) were fused together on an oil bath at 160° C. for 2.5 hr. On cooling the residue was crystallised twice from ethanol/water to give 2-[4-(N-propyl-N-pyrid-2-ylamino)butylamino]5-(4-fluorobenzyl)pyrimid-4-one 1.25H2O, 0.56 g (26.%) mp indeterminate.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]1([C:27]2[S:28][C:29]3[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[N:36]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C1COCC1>[C:21]1([C:27]2[S:28][C:29]3[N:30]([C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[N:36]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: c1ccc(-c2nc3c(s2)NCCCC3)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)N1CCCCc2nc(-c3ccccc3)sc21
Yield: 76 %

Procedure:
Stearoyl chloride (4.65 ml) was added dropwise to a mixture of 2-phenyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]-azepine (2.65 g), triethylamine (2.26 ml) and THF (30 ml) under ice-cooling and stirring. After completing addtion dropwise, the mixture was stirred for 1.5 hrs. at room temperature and distilled under reduced pressure to remove the solvent. The residue was extracted with chloroform, and the extract was washed with water, dried and distilled to remove the solvent. The residue was purified by a column chromatography on silica gel to give the title compound (4.31 g, 76%).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][N:5]=1.N>CO>[N+:10]([C:9]1[C:4]([NH:1][NH2:2])=[N:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=1)([O-:12])=[O:11]
Reactant: NN
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: N
Solvent: CO
Product: NNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Hydrazine (anhydrous, 0.75 ml, 23.9 mmol) was added to a solution of 2-chloro-3,5-dinitro-pyridine (3.42 g, 16.8 mmol) in methanol (25 mL). The resultant mixture was stirred at room temperature overnight. Solvent was evaporated, and the residue was washed with water and methanol several times to remove the impurities. A dark solid powder was obtained (3.0 g). MS (DCI/NH3) m/e: 200 (M+1). 1H NMR (DMSO-d6, 300MHz) d: 9.25 (m, 1H), 9.06 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:4]=[CH:5][N:6]=1.[ClH:18].Cl.[NH2:20][CH2:21][CH2:22][O:23][NH2:24]>C(O)C>[ClH:18].[ClH:18].[NH2:20][CH2:21][CH2:22][O:23][N:24]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH2:8][CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1nccn1CCCC(=O)c1ccccc1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Product: Cc1nccn1CCCC(=NOCCN)c1ccccc1
Reaction time: 4 h
Yield: 109.4 %

Procedure:
A mixture of 4-(2-methyl-1-(1H)-imidazolyl)-1-phenyl-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.35 g), 3 equivalents of pyddine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for four hrs. The solvent was evaporated toluene was added and evaporated The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol/ether to give 3.1 g (66%) of product, mp 153°-155° C.
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].[N:20]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][NH2:35])[CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.N>ClCCl.CO>[N:20]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][NH:35][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCN1CCCC(CN2CCCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CN3CCCCC3)C2)c2ccccc21
Yield: 38 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(piperidin-1-yl)methyl]-piperidin-1-yl]ethanamine in a yield of 38% of theory. Colourless amorphous substance, RF 0.16 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/methanol/conc. ammonia 90/10/1 v/v).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: OCCC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCOCC1
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a stirring solution of 2-(4-oxanyl)ethanol (9.63 g, 74.0 mmol) in dry dichloromethane (350 mL) was added distilled triethylamine (20.62 mL, 96.2 mmol) at 0° C., followed by drop-wise addition of methanesulfonyl chloride (7.44 mL, 96.2 mmol) over 15 min. The reaction was stirred for 16 h under N2 and slowly allowed to come to ambient temperature. The reaction was washed with saturated NaHCO3 (100 mL) and the aqueous phase was extracted with dichloromethane (1×50 mL). The combined organic extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to yield 11.9 g of a colorless oil (77.0% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C@H:24]([NH:34][CH3:35])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C@H:24]([N:34]([CH3:35])[C:10](=[O:11])[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)([CH3:14])[CH3:13])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C(=O)Cl)c1cc(Cl)cc(Cl)c1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2005002577) (0.146 g, 0.58 mmol) in CH2Cl2 (4 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (the preparation of which is described herein above) (0.15 g, 0.52 mmol) and ethyl-diisopropyl-amine (0.13 ml, 0.79 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 2 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 0.18 g (68%) of the title product as light brown oil.
Reaction SMILES: C([O:3][C:4](=[O:8])[CH2:5][NH:6][CH3:7])C.[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[CH:13]=[CH:14][C:15]=1[Cl:16]>>[CH3:7][N:6]([C:18](=[O:20])[CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1)[CH2:5][C:4]([OH:8])=[O:3]
Reactant: CCOC(=O)CNC
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: CN(CC(=O)O)C(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from commercially available sarcosine ethyl ester and 3,4-dichlorophenylacetic acid according to the procedure of Intermediate 1.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:21][C:22]1[C:23]([N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[CH2:43][CH2:42]2)=[CH:24][C:25]([F:40])=[C:26]([CH:39]=1)[C:27]([NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=[O:38])=[O:28].[Cl-].[Li+]>CN(C=O)C>[F:40][C:25]1[C:26]([C:27](=[O:28])[NH:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])=[CH:39][C:22]([NH:21][C:9]([C:7]2[N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[O:5][CH:6]=2)=[O:11])=[C:23]([N:41]2[CH2:42][CH2:43][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[CH2:45][CH2:46]2)[CH:24]=1
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: Cc1ccccc1N1CCN(c2cc(F)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(c2cc(F)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Reaction time: 0.05 h

Procedure:
To a solution of 2-cyclopropyl-oxazole-4-carboxylic acid 1h (22.8 mg, 0.149 mmol) in DMF (5.0 mL) HATU (75.4 mg, 0.198 mmol) was added and stirred for 3 min. N, N-diisopropylethylamine (0.086 mL, 0.496 mmol) was added to this followed by 5-amino-2-fluoro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 3d (45.0 mg, 0.099 mmol) in DMF (2.0 mL) and the reaction was stirred at room temperature for 16 h. Saturated solution of lithium chloride was added to this and the contents were extracted with ethyl acetate dried on anhydrous sodium sulfate, concentrated and the crude 3e was dissolved in methanol and purified on preparative HPLC using water/methanol as eluent.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][NH:28][CH2:29][CH2:30][CH3:31].Cl>C(#N)C>[CH3:27][N:28]([CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1)[CH2:29][CH2:30][CH3:31]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNC
Agent: Cl
Solvent: CC#N
Product: CCCN(C)CC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 14 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.175 g, 0.44 mmol), N-methylpropan-1-amine (0.35 ml) and ACN (2 ml). Yield: 0.11 g, 84%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 222° C. MS m/z (rel. intensity, 70 eV) 299 (M+, 1) 86 (100), 58 (8), 84 (6), 87 (6).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:41])([F:40])[CH2:37][C@H:36]3[C:42]([OH:44])=[O:43])=[O:34])[N:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:40])([F:41])[CH2:37][C@H:36]3[C:42]([OH:44])=[O:43])=[O:34])[N:28]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 100 mg 4-[(S)-4-tert-Butoxycarbonyl-2-({5-[2-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 2 ml dichloromethane were added 300 μl TFA. After stirring for 12 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 63 mg MS (ES+): m/e=665.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][CH:17]([F:20])[CH2:18]O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:18][CH:17]([F:20])[F:16])(=[O:8])=[O:9]
Reactant: OCC(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCC(F)F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
With cooling with ice, 2.7 ml of trifluoromethanesulfonic acid anhydride was added to a chloroform (100 mL) solution of 1 mL of 2,2-difluoroethanol and 2.2 mL of triethylamine, and stirred for 30 minutes. The reaction liquid was diluted with chloroform, and washed with aqueous saturated sodium bicarbonate solution and saturated saline water in that order. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17](=[NH:22])[NH:18][N+:19]([O-:21])=[O:20]>>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:18][N+:19]([O-:21])=[O:20])=[NH:22])[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: CN(C)Cc1nc(CSCCNC(=N)N[N+](=O)[O-])cs1

Procedure:
Following the above procedure, 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine was reacted with S-methyl N-nitroisothiourea to yield N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-nitroguanidine. The compound was purified by chromatography (silica-ethyl acetate/methanol), and melted at 104°-105.5° C. after recrystallization from ethyl acetate.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:20]=2[C:21]([NH:23][C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][C:30](=[O:35])[N:31]3[CH3:34])=[CH:26][CH:25]=2)=[O:22])[CH2:14][CH2:13]1)C1C=CC=CC=1>[C].[Pd].CO>[CH3:34][N:31]1[C:32]2[C:27](=[CH:26][CH:25]=[C:24]([NH:23][C:21](=[O:22])[C:20]3[CH:36]=[CH:37][C:38]([C:40]([F:42])([F:43])[F:41])=[CH:39][C:19]=3[NH:18][CH:15]3[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]3)[CH:33]=2)[CH2:28][CH2:29][C:30]1=[O:35]
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCN(Cc4ccccc4)CC3)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCNCC3)cc21

Procedure:
Palladium-carbon and ammonium formate were added to a methanol solution of 2-[(1-benzylpiperidin-4-yl)amino]-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide, followed by heating under reflux for 2 hours. After spontaneous cooling, Celite filtration was carried out and then the filtrate was concentrated under a reduced pressure. By purifying the residue by silica gel column chromatography, N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-(piperidin-4-ylamino)-4-(trifluoromethyl)benzamide was obtained.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][NH:6][C:7]([C:9]1[C:10]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:11]=2[S:12][C:13]=1[CH3:14])=[O:8]>C(Cl)Cl>[CH3:5][NH:6][C:7]([C:9]1[C:10]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:11]=2[S:12][C:13]=1[CH3:14])=[O:8]
Reactant: CNC(=O)c1c(C)sc2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNC(=O)c1c(C)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.1 %

Procedure:
A 1.0 M solution of BBr3 in CH2Cl2 (6 ml, 6 mmole) was added to a solution of 6-methoxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide 1c (683 mg, 2.9 mmole) in CH2Cl2 (60 ml) at 0°. The reaction was left stirring for 14 hours, gradually warming to ambient temperature, then poured onto crushed ice (˜70 g). The layers were separated and the aqueous phase was extracted with EtOAc (2×50 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 623 mg (97%) of a beige solid which was employed without further purification. 1H NMR (DMSO-d6) δ 9.56 (1H, s), 8.11 (1H, q, J=4.4 Hz), 7.53 (1H, d, J=8.7 Hz), 7.18 (1H, d, J=2.3 Hz), 6.83 (1H, dd, J=2.3, 8.7 Hz), 2.79 (3H, d, J=4.4 Hz), 2.50 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]([C:11]2([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[O:17])[CH2:14][CH:13](O)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[C:30]1(=[O:53])[N:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][C:49](O)=[O:50])[C:33](=[O:52])[CH:32]=[CH:31]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:16]([C:11]2([C:9]([O:8][CH2:7][C:6]3[CH:28]=[CH:29][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:10])[CH2:12][CH:13]([C:49](=[O:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][N:34]3[C:30](=[O:53])[CH:31]=[CH:32][C:33]3=[O:52])[CH2:14]2)=[O:17])=[CH:21][CH:22]=1
Reactant: COc1ccc(COC(=O)C2(C(=O)OCc3ccc(OC)cc3)CC(O)C2)cc1
Reactant: O=C(O)CCOCCOCCOCCOCCN1C(=O)C=CC1=O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)C2(C(=O)OCc3ccc(OC)cc3)CC(C(=O)CCOCCOCCOCCOCCN3C(=O)C=CC3=O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of PMB-CB-OH (1.154 g, 2.881 mmol), 15-maleinimido-4,7,10,13-tetroxapentadecanoic acid (1.49 g, 4.32 mmol) and triethylamine (1.20 ml, 8.64 mmol) in 20 ml anhydrous dichloromethane is admixed with 2-chloro-1-methylpyridinium iodide (1.10 g, 4.32 mmol) and stirred for three hours at room temperature. It is diluted with 80 ml dichloromethane, washed each time twice with 50 ml 1 n hydrochloric acid, 50 ml water and once with 50 ml sodium chloride solution (saturated) and dried over magnesium sulfate. Subsequently the solvent is removed in a vacuum and the residue is purified by column chromatography (silica gel, ethyl acetate). 1.93 g PMB-CB-4-Mal (92% of theory) is obtained as a colourless oil.
Reaction SMILES: C1(C)C=CC(S(O[N:11]=[C:12]([NH:14][C:15]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][NH:17][N:16]=2)[CH3:13])(=O)=O)=CC=1.N1C=CC=CC=1>C(O)C>[CH3:13][C:12]1[NH:14][C:15]2[N:16]([N:17]=[CH:18][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]=1
Reactant: CCOC(=O)c1c[nH]nc1NC(C)=NOS(=O)(=O)c1ccc(C)cc1
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1cnn2nc(C)[nH]c12
Yield: 45.3 %

Procedure:
A solution of ethyl 3-[1-(p-toluenesulfonyloxyimino)-ethyl]amino-1H-pyrazole-4-carboxylate (1.00 g) and pyridine (240 mg) in ethanol (20 ml) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with water. The solution was adjusted to pH 4 with 1N hydrochloric acid. The formed precipitate was collected by vacuum filtration to give ethyl 2-methyl-1H-pyrazolo[1,5-b][1,2,4]triazole-7-carboxylate (240 mg).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:2][CH2:3][N:4]([C:31](=[O:32])[CH2:30][O:29][C:28]3[CH:34]=[CH:35][C:25]([Cl:24])=[CH:26][CH:27]=3)[CH2:5][CH2:6]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[S:14][C:9]=2[N:10]=1
Reactant: Cc1ccc(-c2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Reactant: O=C(O)COc1ccc(Cl)cc1
Product: Cc1ccc(-c2nc3c(N4CCN(C(=O)COc5ccc(Cl)cc5)CC4)nc(N)nc3s2)cc1
Yield: 32 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-p-tolylthiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 32%, according to the procedure for the synthesis of example 50.