Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:23]=2[S:24][C:25]=1[CH2:26][CH3:27])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([O:32][C:13]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:8]=[C:7]([C:5]([N:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[S:15][C:14]=34)=[CH:28][C:23]=2[S:24][C:25]=1[CH2:26][CH3:27])=[O:20]
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)ccc2c1C(=O)NC
Yield: 66.4 %

Procedure:
This material was prepared by reacting 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a (97 mg, 0.40 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (113 mg, 0.48 mmole) and Cs2CO3 (391 mg, 1.2 mmole) in a manner similar to that previously described for example 1 to give a yellow solid (120 mg, 52%). 1H NMR (DMSO-d6, 300 MHz) δ 8.59 (1H, d, J=5.67 Hz), 8.31 (1H, m), 7.98 (1H, d, J=2.27 Hz), 7.89 (1H, s), 7.81 (1H, d, J=8.69 Hz), 7.33 (1H, dd, J=1.51, 8.69 Hz), 6.76 (1H, d, J=5.29 Hz), 4.62 (2H, t, J=7.37 Hz), 4.11 (2H, t, J=7.37 Hz), 3.00 (2H, q, J=7.55 Hz), 2.83 (3H, d, J=4.53 Hz), 2.35 (2H, m), 1.28 (3H, t, J=7.55 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH3:13]>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:13]
Reactant: CCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1cc([N+](=O)[O-])cn1
Temperature: -25 °C
Yield: 80.2 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in anhydrous DMF (100 mL) was NaH (60% in oil) (1.94 g, 48.6 mmol) while being stirred at −25° C. under nitrogen. The mixture was stirred for 30 min before bromoethane (5.30 g, 48.6 mmol) was added. The mixture was continued to stir under nitrogen at −25° C. for 6 h. The solution was diluted with ethyl acetate (100 mL), washed with water (2×50 mL) and brine solution (50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford crude 123a (5.0 g, 80%), which was used in next step without further purification. MS-ESI: [M+H]+ 142.0
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:19]=[C:20]=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:20](=[O:21])[NH:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CCCCCCCN=C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Oc1ccc2ncccc2c1
Temperature: 21 °C
Reaction time: 40 h

Procedure:
A mixture of quinolin-6-ol (0.29 g., 2 mmol), heptyl isocyanate (0.39 ml, 2.4 mmol) and pyridine (2 ml) in dry tetrahydrofuran (10 ml) was stirred at room temperature (21° C.) for 40 hours, the reaction mixture was concentrated under vaccum and the residue was washed with water (2×5 ml) and crystallized with ether to give 1b; yield: 0.30 g. (52.4%).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2=[O:34])=[CH:4][CH:3]=1.[CH3:37][Mg]Br.CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2([OH:34])[CH3:37])=[CH:35][CH:36]=1
Reactant: C[Mg]Br
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, a solution of 13 (90 mg, 0.18 mmol) was dissolved in 0.885 mL of dry THF. A solution of 3 M of methylmagnesium bromide in ether (71 μL, 0.213 mmol) was added. The solution was allowed to stir at ambient temperature for 2 hours when TLC indicated complete consumption of starting materials. The reaction mixture was diluted with EtOAc and washed with water and saturated aqueous NH4Cl. The organic layer was reduced in vacuo to 1 mL and cooled to get the product 16 to crystallize from the solvent (92 mg, 99%). 1H NMR (300 MHz, CDCl3) δ 1.16 (d, 18H, J=8 Hz), 1.55 (septet, 3H, J=8 Hz), 1.78 (s, 3H), 2.29 (s, 1H), 4.04 (s, 3H), 4.72 (ABqt, 2H, J=13 Hz), 6.99 (t, 2H, J=9 Hz), 7.38 (dd, 2H, J=6,9 Hz), 7.52 (dd, 1H, J=4, 9 Hz), 8.42 (dd, 1H, J=2, 8 Hz), 8.87 (dd, 1H, J=2, 4 Hz); 19F NMR (282.6 MHz, CDCl3) δ 60.8.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([C:28](=[O:54])[CH2:29][CH2:30][C@H:31]([NH:38][CH2:39][C:40]2[C:45]([NH2:46])=[CH:44][N:43]=[C:42]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:41]=2)[CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:56]#[N:57]>CCO>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:12][CH2:13][C@@H:14]([N:17]([C:28](=[O:54])[CH2:29][CH2:30][C@H:31]([N:38]2[CH2:39][C:40]3[CH:41]=[C:42]([O:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[N:43]=[CH:44][C:45]=3[N:46]=[C:56]2[NH2:57])[CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc(Oc2ccccc2)cc1CN[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1
Reactant: N#CBr
Solvent: CCO
Product: NC1=Nc2cnc(Oc3ccccc3)cc2CN1[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1
Reaction time: 0.5 h

Procedure:
A solution of 4-[[4-[(5-amino-2-phenoxy-pyridin-4-ylmethyl)-amino]-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-(2-benzyloxy-ethyl)-amino]-cis-cyclohexanecarboxylic acid benzyl ester (0.5 g, 0.7 mmol) and BrCN (3M in CH2Cl2, 0.25 mL) in EtOH (20 mL) was stirred at room temperature overnight. The EtOH was evaporated. The resulting oil was stirred in diethyl ether (50 mL) for 30 min. 4-[[4-(2-Amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-(2-benzyloxy-ethyl)-amino]-cis-cyclohexanecarboxylic acid benzyl ester was collected as a solid as its corresponding HBr salt.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][C:6]=2[N:7]=1.NN.O>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To a solution of 2-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)isoindoline-1,3-dione 31 (100 mg, 0.24 mmol) in MeOH (7 mL) was added H2NNH2.H2O (24 μL, 0.48 mmol). The reaction was heated at reflux for 1 h. After cooling to room temperature the reaction was quenched with water (10 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo to afford (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 (0.05 g, 73%). MS (Q1) 285 (M)+
Reaction SMILES: [OH:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4](=[O:13])[C:3]=1[CH:14]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CCOCC>[C:17]1([NH:16][CH:14]=[C:3]2[C:2](=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][CH2:5][C:4]2=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CC1=C(O)c2ccccc2OCC1=O
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: O=C1COc2ccccc2C(=O)C1=CNc1ccccc1
Reaction time: 0.08 h
Yield: 58 %

Procedure:
A quantity of 10.0g (0.049 mole) of 2,3-dihydro-5-hydroxy-3-oxo-1-benzoxepin-4-carboxaldehyde was added to 15g of aniline. The temperature rose to 45° as most solid went into solution. The dark mixture was heated at 105°-110° for 10 minutes and cooled. Ether (500ml) and 300ml of cold 2N hydrochloric acid were added, and the mixture was stirred for 5 minutes. The entire mixture was filtered to remove the dark, suspended insolubles. The ether phase of the filtrate was washed well with water, dried (Na2SO4) and concentrated to give 8.0g (58%) of crude product; m.p. 94°-96°. Recrystallization from ethyl acetate gave pure, orange-tan crystals; m.p. 98°-100°.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.FC1C=CC(C2C(COC3N=[N:42][C:41]([C:44](O)=[O:45])=CC=3)=C(C)ON=2)=NC=1.C(CN)O>>[OH:45][CH2:44][CH2:41][NH:42][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:23]
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)nn1
Solvent: NCCO
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)NCCO)nn1
Yield: 42 %

Procedure:
As described for example 112b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (38 mg, 0.12 mmol) was converted, instead of 6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid, using ethanolamine instead of 2-amino-2-methyl-1-propanol, to the title compound (18 mg, 42%) which was obtained as a light yellow foam. MS: m/e=357.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]1[CH3:22].[OH:23][C:24]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]1/[CH:22]=[CH:26]/[C:25]1[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:24]=1[OH:23]
Reactant: COc1cccc(OC)c1-n1c(C)nc2ccccc2c1=O
Reactant: COc1cccc(C=O)c1O
Solvent: CC(=O)O
Product: COc1cccc(/C=C/c2nc3ccccc3c(=O)n2-c2c(OC)cccc2OC)c1O
Yield: 39.9 %

Procedure:
A mixture of 80 (170 mg, 0.57 mmol) and 2-hydroxy-3-methoxybenzaldehyde (9, 87 mg, 0.57 mmol) in AcOH (˜5 mL) was refluxed under N2 for 4 days and the reaction was monitored by MS and TLC. Additional 2-hydroxy-3-methoxybenzaldehyde (87 mg, 0.57 mmol) was added and the reaction mixture was refluxed for another 2 days. The solution was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give the pure 81 as a yellow solid (98 mg, 40%). MS (APCI): m/z 431 (100%, [M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]([OH:11])=O.[Cl:12][C:13]1[CH:14]=[C:15]([NH2:27])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:27][C:9](=[O:11])/[CH:8]=[CH:7]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)/C=C/c1ccccn1
Product: CCN(CC)CCOc1ccc(NC(=O)/C=C/c2ccccn2)cc1Cl

Procedure:
Prepared analogously to Example 172 starting from (E)-3-pyridin-2-yl-acrylic acid and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z2b) at RT (72 h). The crude product was purified by column chromatography (silica gel, dichloromethane/MeOH/conc. aqueous ammonia 90:10:0.1) and recrystallisation from petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].Cl.[CH:16]([NH:19][OH:20])([CH3:18])[CH3:17].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([N:19]([OH:20])[CH:16]([CH3:18])[CH3:17])=[O:5]
Reactant: CC(C)NO
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)N(O)C(=O)c1c(Cl)cccc1[Si](C)(C)C

Procedure:
The title compound was prepared by reaction of the compound of Example b and the i-propylhydroxylamine hydrochloride in dioxane in the presence of two equivalents of triethylamine using the amination methods described above. m.p. 175-179° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:26][C:24](=[NH:25])[CH2:23][O:22][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])=[O:6]
Reactant: N=C(N)COCCc1ccccc1Cl
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1ccccc1Cl)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(2-chloro-phenyl)-ethoxy]-acetamidine hydrochloride (example 105.2) in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{2-[2-(2-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as orange oil. MS: m/e=388.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH2:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:32][CH2:30][CH3:31])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCN
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Product: CCNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and ethylamine gave 206. MS: (ESI+) 441.0
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](OC)=[O:11]>C(Cl)(Cl)(Cl)Cl>[S:7]1[C:6]2[C:10](=[O:11])[NH:1][C:2]3[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=3[NH:4][C:5]=2[CH:9]=[CH:8]1
Reactant: COC(=O)c1sccc1Nc1ccccc1N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1Nc2ccccc2Nc2ccsc21

Procedure:
Methyl 3-(2-aminoanilino)-thiophene-2-carboxylate, m.p. 226° C. (CCl4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH2:34][CH3:35])=[CH:6]2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH2:34][CH3:35])=[CH:6]2
Reactant: CCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)OCC)cc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 89.7 %

Procedure:
Ethyl ester (99) (0.70 g, 1.50 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.59 g (90%) of the title compound (100) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J=7.3 Hz, 3H), 1.45-1.55 (m, 2H), 2.53 (t, J=7.7 Hz, 2H), 3.93 (s, 3H), 6.22 (d, J=16.0 Hz, 1H), 6.57 (d, J=8.6 Hz, 2H), 7.04 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.08-7.14 (m, 2H), 7.16 (d, J=2.4 Hz, 1H), 7.19-7.30 (m, 5H), 7.57 (s, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H). LCMS (APCI): m/z 439 (M+H)+, m/z 437 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-:18])(=[S:17])[CH3:16].[K+].[Na+].[I-]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:17][C:15](=[O:18])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 173821.91 %

Procedure:
To a solution of 6.9 g (0.02 mol) of 4-bromo-piperidine-1-carboxylic acid tert-butyl ester in DMF (18 mL) are added 5.25 g (0.012 mmol) potassium thioacetate, followed by a catalytic amount of NaI (0.35 g, 10 mol %) at room temperature. After complete addition, the reaction is heated to 50° C. for 20 h. The reaction mixture is partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer is dried over Na2SO4, filtered and the solvent is removed under reduced pressure to afford 5.41 g of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester as a brown oil. Yield: 81%; ES-MS: m/z 245 [M+H—CH3], 160 [M+H—C5H9O2]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.37-1.64 (11H, m), 1.78-1.99 (2H, m), 2.25-2.35 (3H, m), 3.06 (2H, ddd, J=13.63, 10.43, 3.05 Hz), 3.61 (1H, tt, J=10.28, 4.04 Hz), 3.76-3.96 (2H, m)
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([NH2:9])=[O:8])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Reaction time: 24 h

Procedure:
The above polymer-bound D-Leu-NH2 (20 g) was treated with CH2Cl2 (150 mL), pyridine (100 mL) and 4-chlorophenylsulfonyl chloride (20.0 g, 94.8 mmol). The mixture was shaken for 24 h, drained, washed with DMF (4×200 mL), CH2Cl2 (4×200 mL) and concentrated to give polymer-bound (R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide as a yellow resin (22 g). The completion of the reaction and the loading of the resin (0.57 mmol/g) were determined by the treatment of 50 mg of the resin with 10% (v/v) TFA/CH2Cl2 (2 mL) to give 8.7 mg of (R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].[OH-].[Na+]>C(O)C.O>[CH:1](=[N:10]/[OH:11])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C\c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a suspension of benzaldehyde (5.30 g, 55 mmol) and hydroxylamine hydrochloride (3.82 g, 55 mmol) in ethanol (4 mL) and water (12 mL) was added ice (23 g). Then a solution of sodium hydroxide (5.0 g, 125 mmol) in water (6 mL) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (5.31 g, 88%) which was obtained as a colourless liquid. MS m/e (EI): 121.0 [M].
Reaction SMILES: [NH2:1][C:2]1[N:6](C(OC(C)(C)C)=O)[N:5]=[C:4]([CH2:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.FC(F)(F)C(O)=O>N1C=CC=CC=1>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([CH2:15][CH2:14][C:4]3[CH:3]=[C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:40][CH:39]=4)[NH:6][N:5]=3)=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)n1nc(CCc2ccc3c(c2)OCO3)cc1N
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3cc(CCc4ccc5c(c4)OCO5)n[nH]3)cc2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 5-amino-3-(2-benzo[1,3]dioxol-5-ylethyl)pyrazole-1-carboxylate (229 mg, 0.69 mmol, 1.0 eq) in pyridine (5 ml) at 5° C. was added 4-(4-methylpiperazin-1-yl)benzoyl chloride (181 mg, 0.76 mmol, 1.1 eq). The reaction mixture was stirred to 60° C. for 24 h. After this time, the mixture was concentrated and redissolved in DCM (10 ml). Trifluoroacetic acid (464 μl, 6.25 mmol, 8.25 eq) was added and the reaction mixture stirred for 2 h at 25° C. The reaction mixture was then concentrated. The crude product was purified by reverse-phase prep. HPLC (basic) using a 30-50% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were combined and evaporated to afford the title compound as a white solid. (12 mg, 4%); 1H NMR (300.132 MHz, DMSO) δ 2.28 (s, 3H), 2.49 (t, 2H), 2.89 (s, 2H), 3.31-3.37 (m, 8H), 6.01 (s, 2H), 6.43 (s, 1H), 6.74 (d, 1H), 6.86 (d, 2H), 7.01 (d, 2H), 7.94 (d, 2H), 10.36 (s, 1H), 12.11 (s, 1H); MS: m/z 434 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([C:26](=[O:28])[NH2:27])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10][C:11](OCC1C=CC=CC=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10][C:11](=[O:12])[NH:27][C:26]1=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@](CC(=O)OCc1ccccc1)(NC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)CC(=O)NC1=O
Reaction time: 5 h
Yield: 89.7 %

Procedure:
(R)-1-Benzyl ethyl 3-t-butyloxycarbonylamino-3-carbamoylsuccinate (550 mg) obtained in Example 20 was dissolved in acetone (11 mL) and water (6 mL), the solution was added with potassium carbonate (231 mg), the mixture was stirred for 5 hours, and poured with 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (358 mg, yield: 90%) as colorless crystals. Optical rotation [α]D25 was −29.5° (c 0.50, ethanol).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.Cl.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28]1[N:29]=[C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[S:31][CH:32]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28]1[N:29]=[C:30]([N:33]2[CH2:34][CH2:35][N:36]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:37][CH2:38]2)[S:31][CH:32]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc(-c2csc(N3CCNCC3)n2)c(Cl)c1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(-c3ccc(Cl)cc3Cl)cs2)CC1
Yield: 17 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[4-(2,4-dichloro-phenyl)-thiazol-2-yl]-piperazine dihydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) (yield 17%). MS (m/e): 558.1 ({37Cl}M+H+, 19%), 555.9 ({37Cl35Cl}M+H+, 58%), 554.1 ({35Cl}M+H+, 100%).