Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.[Cl:48][C:49]1[CH:50]=[C:51]([CH:54]=[C:55]([Cl:57])[CH:56]=1)CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:48][C:49]1[CH:50]=[C:51]([CH:54]=[C:55]([Cl:57])[CH:56]=1)[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:13]=1)=[O:7]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: NCc1cc(Cl)cc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.19 cm3 of 3,5-dichlorobenzylamine and 0.19 cm3 of triethylamine, 0.025 g of N-(3,5-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a white solid melting above 260° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH2:14]([C@H:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]1[OH:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][S:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:23][C@H:22]1[OH:27])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Reactant: O[C@@H]1CNCC[C@@H]1Cc1ccccc1
Product: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Yield: 66 %

Procedure:
The title compound was prepared from 4-(2-chloro-ethanesulfonyl)-phenol and (3S,4S)-4-benzyl-piperidine-3-ol in 66% yield as a white solid.
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].[SH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][SH:8])=[O:4]
Reactant: OCCCCCCCCCCCS
Reactant: CC(C)(Br)C(=O)Br
Product: CC(C)(Br)C(=O)OCCCCCCCCCCCS

Procedure:
Mercaptoundecyl bromoisobutyrate was synthesized through the reaction of bromoisobutyryl bromide and 11-mercapto-1-undecanol using a method published previously. 1H NMR (300 MHz, CDCl3): 4.15 (t, J=6.9 Hz, 2H, OCH2), 2.51 (q, J=7.5 Hz, 2H, SCH2), 1.92 (s, 6H, CH3), 1.57-1.72 (m, 4H, CH2), and 1.24-1.40 (m, 16H, CH2).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([CH:24]2[CH2:29][CH2:28][NH:27][C:26](=[O:30])[CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:27]2[CH2:28][CH2:29][CH:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:25][C:26]2=[O:30])[CH:11]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)CCN1
Reactant: O=C(NCc1ccccc1)c1ccnc(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)c1ccnc(N2CCC(c3ccccc3)CC2=O)c1
Temperature: 90 °C
Yield: 77.8 %

Procedure:
A degassed mixture of N-benzyl-2-chloroisonicotinamide (0.05 g, 0.20 mmol), 4-phenylpiperidin-2-one (0.04 g, 0.22 mmol), cesium carbonate (0.20 g, 0.61 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.005 g, 0.008 mmol), tris(dibenzylideneacetone)dipalladium (0.004 g, 0.004 mmol) in N,N-dimethylformamide (3.0 mL) was heated at 90° C. for 18 hours and cooled to ambient temperature. The resulting solution was diluted with ethyl acetate (30 mL), washed with water (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 2-oxo-4-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid benzylamide as a colorless solid (0.06 g, 77%): mp 55-60° C.; 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J=5.1 Hz, 1H), 8.09 (s, 1H), 7.50 (d, J=5.1 Hz, 1H), 7.40-7.16 (m, 11H), 4.59-4.46 (m, 2H), 4.09-3.84 (m, 2H), 3.24-3.09 (m, 1H), 2.79 (dd, J=17.5, 5.3 Hz, 1H), 2.61 (dd, J=17.5, 11.2 Hz, 1H), 2.26-2.22 (m, 1H), 2.13-1.95 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 170.6, 165.1, 154.8, 148.7, 143.2, 142.9, 137.8, 128.9, 128.7, 128.1, 127.6, 127.0, 126.5, 119.0, 117.8, 47.4, 44.1, 40.8, 38.6, 30.3; MS (ES+) m/z 386.5 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[CH3:12][S:13]([O-:15])=[O:14].[Na+]>C(O)C>[CH3:12][S:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1)(=[O:15])=[O:14]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of 1-bromomethyl-3-nitro-benzene (5.0 g, 23 mmol) in ethanol (50 mL) was added solution of sodium methanesulfinate (3.06 g, 30 mmol) in ethanol (30 mL) and the mixture was stirred for 4 h at room temperature, then was concentrated in vacuo to volume about 20 mL and diluted with water (200 mL). Formed precipitate was filtered out, washed with water (2×100 mL) and dried to give 1-methanesulfonylmethyl-3-nitro-benzene (4.3 g; 87%) as yellowish crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:15].[NH2:16][C@@H:17]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:18](NC1C=C(C2C=CN=CC=2)C=CC=1OCC1C=CC=CC=1)=[O:19]>>[NH2:16][C@@H:17]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:18]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:15])=[O:19]
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)ccc1OCc1ccccc1
Reactant: Cc1cc(-c2ccc(O)c(N)c2)ccn1
Product: Cc1cc(-c2ccc(O)c(NC(=O)[C@@H](N)Cc3ccccc3)c2)ccn1

Procedure:
64.0 was prepared from 64.B analogous to the preparation of 13.F. LC-MS (+esi, M+H+=348.1).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[C:23]([CH3:29])=[N:24][C:25](Cl)=[CH:26][CH:27]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[SH:36][CH2:37][CH2:38][OH:39]>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[C:23]([CH3:29])=[N:24][C:25]([S:36][CH2:37][CH2:38][OH:39])=[CH:26][CH:27]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: OCCS
Reactant: Cc1nc(Cl)ccc1Oc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(SCCO)ccc1Oc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Temperature: 80 °C
Reaction time: 17 h
Yield: 2 %

Procedure:
A mixture of 4-[6-(6-chloro-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (835 mg, 1.98 mmol) and potassium carbonate (305 mg, 2.2 mmol) in 3 mL of 2-mercapto-ethanol was stirred in microwave at 80° C. After 17 hours, mixture was continued to be stirred at 100° C. for 30 minutes and then 120° C. for 30 minutes. Mixture was purified by HPLC and column chromatography (hexane/AcOEt) to give Compound C12 as a white solid (16.4 mg, 2%). 1H NMR (CDCl3, 400 MHz) δ 1.07-1.09 (d, J=6.3 Hz, 6H), 1.68-1.78 (m, 2H), 1.90-1.99 (m, 2H), 2.12 (s, 3H), 2.29 (s, 3H), 3.23-3.25 (t, J=5.1 Hz, 2H), 3.32-3.38 (m, 2H), 3.68-3.71 (m, 2H), 3.91-3.94 (t, J=4.9 Hz, 2H), 4.84-4.90 (m, 1H), 5.24-5.30 (m, 1H), 7.12-7.21 (m, 2H), 8.12 (s, 1H). Exact mass calculated for C22H30N4O5S 462.19, found 463.3 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH2:27])[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH:27][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:23][CH:24]1[CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: COC(=O)[C@@H](N)CC1CC1
Agent: Cl
Product: COC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (αS)-α-amino-cyclopropanepropanoic acid methyl ester hydrochloride (1:1) (CAN 206438-31-5) as starting materials, LC-MS (UV peak area/ESI) 100%, 359.153 (M+H)+.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(=O)([O-])[O-].[K+].[K+].Cl.[N+:23]([C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH2:30])=[NH:29])([O-:25])=[O:24]>C(O)C>[O:13]=[C:11]1[NH:30][C:28]([C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[N+:23]([O-:25])=[O:24])=[N:29][CH:4]=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2[N+](=O)[O-])[nH]c1=O
Yield: 20.1 %

Procedure:
Diethyl ethoxymethylenemalonate (0.73 g., 3.44 mmoles), potassium carbonate (0.95 g., 6.88 mmoles), and ethanol (11 ml.) were added to 2-nitrobenzamidine hydrochloride (0.69 g., 3.44 mmoles)(prepared according to general method disclosed in U.S. Pat. No. 2,450,386). The mixture was heated under reflux for 3.5 hours. The cooled mixture was filtered. The filtrate was poured into ice-water (150 ml.) and the pH adjusted to 6.0 with acetic acid. The precipitate was collected and dried to give the title compound (0.20 g., 20.2%), m.p. 171°-175°. Recrystallization from acetonitrile gave analytical material, m.p. 175°-177°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1(CN)CC1.C([N:34]([CH:37]([CH3:39])[CH3:38])[CH2:35]C)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH:37]1[CH2:38][CH2:39]1)[CH3:35])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(C(C)C)C(C)C
Agent: ClCl
Agent: NCC1CC1
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N(C)C2CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, N-cyclopropylmethylamine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.33 minutes; C21H20Cl2N4O2 (431.32); mass spectrum: (M−H)−=430/432/434 (chlorine isotope).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:16]([O-:18])=[O:17])[CH:7]=1.[K+].C(=O)([O-])[O-].[Na+].[Na+].[CH2:26](O)[CH3:27]>>[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:16]([O:18][CH2:26][CH3:27])=[O:17])[CH:7]=1
Reactant: CCO
Reactant: O=C([O-])c1cnc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cnc2ccccc2c1
Temperature: 85 °C

Procedure:
In a sealable tube, concentrated sulfuric acid (32 □L) was added to a solution of potassium quinoline-3-carboxylate in ethanol (1 mL). The flask was sealed and heated at 85° C. for 24 h. The mixture was cooled to ambient temperature, basified with 1 M sodium carbonate (10 mL), and the product was extracted with dichloromethane (3×15 mL). The organic fractions were dried over sodium sulfate and concentrated. Purification of the product by flash column chromatography (10% to 20% EtOAc/hexane) afforded the title compound (292 mg, 1.45 mmol). MS m/z: 202 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:30]([C:31](=[O:34])[NH:32][CH3:33])=[C:29]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)[O:28][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][C:18]([CH3:27])([CH3:26])[C:19]([O:21]CC(C)C)=[O:20])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:30]([C:31](=[O:34])[NH:32][CH3:33])=[C:29]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)[O:28][C:7]3=[N:8][C:9]=2[N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[CH2:15][CH2:16][CH2:17][C:18]([CH3:27])([CH3:26])[C:19]([OH:21])=[O:20])[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCC(C)(C)C(=O)OCC(C)C)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCC(C)(C)C(=O)O)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Yield: 66.1 %

Procedure:
To isobutyl 5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)-2,2-dimethylpentanoate 3 (50 mg, 0.086 mmol) in MeOH (2 mL) is added NaOH (3 mL, 2M, 6.00 mmol) and the reaction is heated at 60° C. overnight. The MeOH is removed by evaporation, and the solution is acidified to pH 5. The solid is collected by filtration then purified by HPLC to give 30 mg (64% yield) of 5-[(5-Cyclopropyl-3-methylcarbamoyl-2-p-tolyl-furo[2,3-b]pyridin-6-yl)-methanesulfonyl-amino]-2,2-dimethyl-pentanoic acid 1H-NMR (DMSO-d6, 400 MHz) δ 12.05 (m, 1H), 8.49 (m, 1H), 7.74 (d, 2H, J=8 Hz), 7.55 (s, 1H), 7.36 (d, 2H, J=8 Hz), 3.65 (m, 2H), 3.16 (s, 3H), 2.83 (d, 3H, J=8 Hz), 2.43 (m, 1H), 2.38 (s, 3H), 1.48 (s, 2H), 1.38 (s, 2H), 1.04 (m, 2H), 1.00 (s, 6H), 0.7 (bm, 2H). MS-ES [M+H]+=528.21.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]#[C:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[C:6]=1[CH3:13].[NH2:16][C:17]1[C:18](=[O:30])[N:19]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:20]([CH3:23])[C:21]=1[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:24]1([N:19]2[C:18](=[O:30])[C:17]([NH:16][C:10]([C:7]3[C:6]([CH3:13])=[C:5]([C:4]#[C:3][C:2]([CH3:1])([CH3:15])[CH3:14])[O:9][N:8]=3)=[O:12])=[C:21]([CH3:22])[N:20]2[CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)noc1C#CC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C#CC(C)(C)C
Reaction time: 16 h

Procedure:
5-(3,3-Dimethylbut-1-yn-1-yl)-4-methylisoxazole-3-carboxylic acid (85 mg, 0.410 mmol) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (86 mg, 0.410 mmol) in DMF (2 mL) were treated with DIPEA (0.287 mL, 1.641 mmol) and HATU (172 mg, 0.451 mmol) at room temperature and stirred for 16 hours. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with a 0.5 M Lithium Chloride (aq) solution, dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].[Br-].[Li+].[N+:9]([C:12]1[CH:24]=[CH:23][C:15]2[CH2:16][CH2:17][CH2:18][CH:19](Br)[C:20](=[O:21])[C:14]=2[CH:13]=1)([O-:11])=[O:10].O>CN(C)C=O.CCOCC>[N+:9]([C:12]1[CH:24]=[CH:23][C:15]2[CH2:16][CH2:17][CH:18]=[CH:19][C:20](=[O:21])[C:14]=2[CH:13]=1)([O-:11])=[O:10]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CCCC1Br
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
A mixture of 548 g of lithium carbonate and 548 of lithium bromide in 5.480 liters of dimethylformamide was heated to 100° C. and 548 g of 3-nitro-6-bromo-6,7,8,9-tetrahydro [5H] benzocycloheptene-5-one were added thereto over 5 minutes. The mixture was held at 100° C. for 45 minutes and was then poured into 25 liters of a mixture of water and ice. The mixture was vacuum filterd and the insolubles were extracted 8 times with 1 liter of methylene chloride. The organic phase was washed with water, dried over sodium sulfate and was evaporated to dryness under reduced pressure to obtain a red crystalline mass. The latter was empasted successively 3 times with 400 ml of ether, once with 400 ml of ethanol and once with 400 ml of ether and was dried at 40° C. to obtain 286.7 g of 3-nitro-8,9-dihydro [5H] benzocycloheptene-5-one in the form of orange-red crystals melting at 128° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:32])[C:12]2[O:18][C:17]3[C:19]([Cl:28])=[CH:20][C:21]([NH:23][C:24](=[O:27])[CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:29])[C:13]=2[CH:31]=1)=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:32])[C:12]2[O:18][C:17]3[C:19]([Cl:28])=[CH:20][C:21]([NH:23][C:24](=[O:27])[CH2:25][NH:4][CH:1]([CH3:3])[CH3:2])=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:29])[C:13]=2[CH:31]=1)=[O:8]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC(C)C)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Isopropyl amine (0.77 ml, 9 mmol) was added to a solution of Example 133 (0.4 g, 0.9 mmol) in DMF (10 mL). The reaction mixture was stirred at 80° C. for 2 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.172 g, (40%); 1H NMR (CDCl3): δ 1.22 (d, 6H, 2CH3), 2.7 (s, 3H, CH3), 2.87 (septet, 1H, CH), 3.38 (s, 2H, CH2), 3.92 (s, 3H, OCH3), 4.71 (s, 2H, CH2), 7.57 (s, 1H, Ar), 7.82 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.45 (s, 1H, Ar), 9.68 (s, 1H, NH); MS: m/e (ES+) 467 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].[NH2:10][CH:11]1[C:16](=[O:17])[N:15]2[CH:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH2:21][CH:14]2[N:13]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[Cl:44])(=[O:36])=[O:35])[CH2:12]1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:18]2[N:15]3[C:16](=[O:17])[CH:11]([NH:10][C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:8])[CH2:12][N:13]([S:34]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])(=[O:36])=[O:35])[CH:14]3[CH2:21][N:20]([CH:22]([CH3:24])[CH3:23])[C:19]2=[O:25])=[CH:28][CH:29]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: O=C(Cl)c1cnccn1
Product: CC(C)N1CC2N(C(=O)C(NC(=O)c3cnccn3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 22 using pyrazine-2-carbonyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=664.08 (calculated, monoisotopic); measured value (M+H)+: 665.05
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C(O)C.[C:20]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([N:23]1[CH2:28][CH2:27][C:26]2([C:16]3=[C:15]4[C:10](=[N:9][C:8]3=[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH2:4]3)[NH:1]2)[CH:11]=[CH:12][CH:13]=[CH:14]4)[CH2:25][CH2:24]1)(=[O:22])[CH3:21]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N1CCC2(CC1)NC1=CC=CCC1=C1N=c3ccccc3=C12

Procedure:
To a solution prepared from 5 g of 2-(2-aminophenyl)indole, 100 ml of ethanol and 2 ml of glacial acetic acid was added dropwise 3 ml of 1-acetyl-4-piperidone. The resultant solution was refluxed for 6 hours and thereafter cooled, whereupon a solid precipitated. Filtration and washing with ether and hexane gave 3.95 g of yellow solid, m.p. 285°-287° dec.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[C:28]1([CH2:34][S:35](Cl)(=[O:37])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:35]([CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:37])=[O:36])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Product: Cc1ccc(Sc2ccc(OS(=O)(=O)Cc3ccccc3)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 5 (120 mg, 0.294 mmol) was reacted with phenyl-methanesulfonyl chloride (55 mg, 0.294 mmol) for 22 h following the procedure from Example 58 giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (15 mg, 9%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.31 (d, 1H) 7.73 (d, 1H) 7.11 (d, 1H) 6.85 (d, 1H) 6.74 (s, 2H) 6.64 (d, 2H) 6.53 (d, 2H) 5.75 (d, 1H) 2.81 (q, 2H) 2.42 (q, 2H) 1.78 (s, 3H) 0.76 (m, 6H); MS (ESI+) m/z 484 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19]>C(#N)C.O1CCOCC1.[Cu]I>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:3][C:2]=1[C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(NC2CCN(C)CC2)cc1I
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1ccc(NC2CCN(C)CC2)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Into a flask maintained under argon atmosphere N-(3-iodo-4-methoxyphenyl)-1-methylpiperidin-4-amine (180 mg, 0.52 mmol), CuI (9.9 mg, 0.052 mmol) and Pd(Ph3P)Cl2 (36.5 mg, 0.052 mmol) were added and dissolved in acetonitrile (5 mL) and dioxane (5 mL). The solution was degassed and backfilled with argon for three times. TEA (0.725 mL, 526 mg, 5.2 mmol) and (ethynyl)trimethylsilane (0.147 mL, 0.102 mg, 1.04 mmol) were added with a syringe and the solution was stirred at room temperature for 75 min. The volatiles were evaporated and the residue was taken up with EtOAc (30 mL), washed with water (3×5 mL), dried over sodium sulfate and the solvent was removed under vacuum.