Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:23]([S:42][CH2:43][C@@H:44]([C:46]([NH:48]CC(N)=O)=[O:47])[NH2:45])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:45][C@H:44]([C:46]([NH2:48])=[O:47])[CH2:43][S:42][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)CNC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 60 °C

Procedure:
1.00 g (3.36 mmol) of N-[(9H-Fluoren-9-ylmethoxy)carbonyl]glycine was dissolved in 30 ml dichloromethane. 1.41 g (3.36 mmol) S-Trityl-L-cysteinylglycinamide, 0.59 ml (3.36 mmol) N,N-diisopropylethylamine and 1.28 g (3.36 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 300 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 20/1, dichloromethane/methanol 10/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.63 g (2.06 mmol, 81% of theory) of the desired product.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]([F:53])([F:52])[O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][C:41]([F:40])([F:53])[F:52])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3OC(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-(trifluoromethoxy)phenyl)boronic acid gave 157. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.40 (dd, J=7.9, 2.3 Hz, 1H), 7.84 (s, 1H), 7.54-7.44 (m, 5H), 4.89-4.80 (m, 1H), 4.69-4.53 (m, 1H), 4.41-4.28 (m, 1H), 4.21-4.02 (m, 1H), 3.77 (s, 3H), 3.48-3.38 (m, 1H), 2.13-2.02 (m, 1H), 1.91-1.72 (m, 3H). LCMS (ES+) m/z 515 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:29](I)[CH3:30].CN(C)C=O>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:29][CH3:30])=[O:22])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
A mixture of 5-(1-benzyloxycarbonyl-4-piperidyl)valeric acid (54.8 g), sodium bicarbonate (29 g), ethyl iodide (21 ml) and N,N-dimethylformamide (150 ml) is stirred for 3 hours at 70°-80° C. After further addition of ethyl iodide (10 ml), the stirring is continued for further 3 hours at 90°-100° C. After cooling, the mixture is diluted with water and extracted with ethyl acetate (1 l). The extract is washed successively with water, 1N hydrochloric acid and sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)valerate (58 g) as a pale yellow oil.
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH:41]4[CH2:43][CH2:42]4)[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:46]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47]1>CC#N>[CH:41]1([N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:50]([CH:46]3[CH2:49][CH2:48][CH2:47]3)=[O:51])[CH2:20][NH:19][CH2:24]2)=[O:44])[CH2:43][CH2:42]1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1C
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)C3CCC3)C2)C2CC2)ccc1C

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{cyclopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzyl]-carbamoyl}piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 98A.) and cyclobutane-carbonyl chloride. MS: 458.7 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.88 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N=C2CCCCC2=O)=[CH:5][CH:4]=1.[OH2:18].S(=O)(=O)(O)O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:9][C:4]1[C:5](=[O:18])[CH2:6][CH2:7][CH2:8][C:3]2=1
Reactant: O
Reactant: COc1ccc(NN=C2CCCCC2=O)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CCCC3=O

Procedure:
232 g. (1 mole) of cyclohexanedione-mono-p-methoxyphenylhydrazone, 1200 ml. of water, 350 g. of sulfuric acid (65 Be) and 100 ml. of ethanol are allowed to boil under reflux for three hours. After cooling down, the mixture is filtered with suction and rendered free from acid by washing with water. The resultant 6-methoxy-1,2,3,4-tetrahydrocarbazol-1-one melts at 222° C. and gives a yield of 193 g. (=90% of the theoretical).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:43]3[CH2:44][CH2:45][N:40]([C:37](=[O:39])[CH3:38])[CH2:41][CH2:42]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. LC-MS: 635.2 [(M+H)+]
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.B(O)(O)[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[N:11][CH:10]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Br:15][C:12]1[N:11]=[CH:10][C:9]([NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Br)nc1
Reactant: Cn1ccc(N)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ccc(Nc2ccc(Br)nc2)n1
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-ylamine (0.23 g, 2.3 mmol, 1.0 equiv) and 2-bromopyridyl-5-boronic acid (0.70 g, 3.5 mmol, 1.5 equiv) in 10 Ml dichloromethane was added pyridine (0.43 Ml, 5.4 mmol, 2.4 equiv), copper (II) acetate (0.63 g, 3.5 mmol, 1.5 equiv) and 4 Å molecular sieves. The heterogeneous reaction mixture was allowed to stir vigorously open to air overnight. The reaction was then filtered through Celite, concentrated in vacuo, and purified by silica gel chromatography to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s, 3H) 5.84 (s, 1H) 7.45 (d, J=8.59 Hz, 1H) 7.60 (d, J=2.02 Hz, 1H) 7.86 (dd, J=8.59, 3.03 Hz, 1H) 8.41 (d, J=2.78 Hz, 1H) 8.92 (s, 1H); (M+H)+255.1.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[CH2:17]([O:19][C:20](=[O:34])[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:24](=[O:32])[C:23]1=[O:33])[CH3:18].O1C2C=CC(O)=CC=2OC1.[O:45]1[C:49]2[CH:50]=[C:51]([OH:54])[CH:52]=[CH:53][C:48]=2[CH2:47][CH2:46]1>>[CH2:17]([O:19][C:20](=[O:34])[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:24]([OH:32])([C:52]2[C:51]([OH:54])=[CH:50][C:49]3[O:45][CH2:46][CH2:47][C:48]=3[CH:53]=2)[C:23]1=[O:33])[CH3:18]
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl(4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compound was obtained (68%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.66 (br, 1H), 7.31-7.19 (m, 3H), 6.73 (dd, 1H), 6.49-6.45 (m, 1H), 5.09-4.36 (m, 4H), 4.20 (q, 2H), 3.14-2.90 (m, 2H), 1.23 (t, 3H); MS (ES+) m/z 432.2 (M−17).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([CH3:20])[CH3:19])=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].Cl[C:22]([O:24][CH3:25])=[O:23]>N1C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([CH3:20])[CH3:19])=[C:6]([CH2:7][NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])[CH:16]=1
Reactant: COC(=O)Cl
Reactant: CC(C)Oc1ccc(N)cc1CNC(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(OC(C)C)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 78.8 %

Procedure:
To 8F (24 mg, 0.09 mmol) in pyridine (15 mL) at 0° C. was added methyl chloroformate (18 μL, 0.24 mmol). After removing the ice bath and stirring at rt 7 h, the reaction was concentrated and purified via preparative HPLC (MeOH/water/TFA) to provide 8G (24 mg, 83%). LC-MS: 361.22 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][NH:4][S:5](Cl)(=[O:7])=[O:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]([NH2:33])([CH3:32])[CH3:31])[CH:27]=[CH:28][CH:29]=3)[CH:19]=2)=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]([NH:33][S:5]([NH:4][CH2:3][C:2]([F:10])([F:9])[F:1])(=[O:7])=[O:6])([CH3:31])[CH3:32])[CH:27]=[CH:28][CH:29]=3)[CH:19]=2)=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)NCC(F)(F)F
Reactant: Cn1nc(-c2cccc(C(C)(C)N)c2)cc1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(-c2cccc(C(C)(C)NS(=O)(=O)NCC(F)(F)F)c2)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
2,2,2-Trifluoroethylsulfamoyl chloride (53 mg, 0.3 mmol) was added dropwise to a stirred solution of the amine from Step 4 (50 mg, 0.2 mmol) and Et3N (37 μL, 0.3 mmol) in CH2Cl2 (2 m]L) at RT under N2. The mixture was stirred at RT overnight and then diluted with CH2Cl2 (25 mL), washed with NaHCO3 solution (20 m L), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica eluting with 20% EtOAc/iso-hexane to yield the title sulfamide (5 mg, 6%). 1H NMR (CDCl3, 500 MHz) δ 8.02 (1H, s), 7.69 (1H, d, J=6.6 Hz), 7.45-7.42 (4H, m), 7.18 (2H, t, J=8.6 Hz), 6.58 (1H, s), 4.70 (1H, s), 4.30-4.27 (1H, m), 3.90 (3H, s), 3.57-3.53 (2H, m), 1.80 (6H, s). MS (ES+) C21H22F4N4O2S requires: 470, found: 471 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([OH:7])[CH:3]=1.C(#N)C.CS(O[CH:16]1[CH2:19][N:18]([C:20]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[CH2:17]1)(=O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH:16]2[CH2:19][N:18]([C:20]3[N:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:21]=3[C:22]([O:24][CH3:25])=[O:23])[CH2:17]2)[CH:3]=1
Reactant: Cc1cc(O)no1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Solvent: CC#N
Product: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cc(C)on2)C1
Temperature: 180 °C
Yield: 16.5 %

Procedure:
To a solution of 5-methylisoxazol-3-ol (33.48 mg, 0.34 mmol) in acetonitrile (0.7 ml) potassium carbonate (60.85 mg, 0.44 mmol) was added followed by addition of methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (120 mg, 0.34 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 25 min. After solvent evaporation the residue was purified by Biotage SNAP-Si column (10 g) eluting with cycloexane/ethyl acetate from 95/05 to 70/30. Collected fractions were evaporated in vacuo tot afford the title compound (D88) (20 mg)
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:13]([C:14]([C:16]3[C:24]([Cl:25])=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=3[Cl:26])=[O:15])=[CH:12][NH:11][C:10]=12)(=[O:3])[CH3:2].[NH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:13]([C:14]([C:16]3[C:17]([Cl:26])=[CH:18][C:19]([C:20]([NH:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])=[O:22])=[CH:23][C:24]=3[Cl:25])=[O:15])=[CH:12][NH:11][C:10]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nccc2c(C(=O)c3c(Cl)cc(C(=O)O)cc3Cl)c[nH]c12
Reactant: NCCOCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nccc2c(C(=O)c3c(Cl)cc(C(=O)NCCOCCO)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichlorobenzoic acid (0.1 g, 0.25 mmol) was taken in a reaction vial. To it 2-(2-aminoethoxyl)ethanol (0.029 g, 2.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.073 g, 3.8 mmol), 1-hydroxybenzotriazole (0.051 g, 3.8 mmol) and dimethylformamide (2 mL) were added. The whole reaction mixture was stirred at room temperature for overnight. Water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude mass which was purified by flash column chromatography to get 4-{[7-(acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-[2-(2-hydroxyethoxyl)ethyl]benzamide (0.035 g, 29%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][CH:25]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:30][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: Cc1cccc(C=O)n1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(C=Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)n1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1 H-pyrazolo[3,4-d]pyrimidine and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 182 mg (1.5 mmol) of 6-methyl-pyridine-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(6-methyl-pyrid-2-yl)-methyleneamino)-1H-pyrazolo-[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in ethyl acetate yield 4-(3-chloro-phenylamino)-3-[(6-methyl-pyrid-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p: 231-233° C.; HPLC: tRet(grad20-100)=6.6; MS: (M)+=365.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1(=O)[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][NH:7]1>ClC1C=CC=CC=1>[Cl:3][C:6]1[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2cnccc12
Solvent: Clc1ccccc1
Product: Clc1nccc2cnccc12
Temperature: 100 °C

Procedure:
Under stirring, 184 ml (2.00 mol) phosphorus oxychloride was added slowly to a suspension of 146 g (1.00 mol) 2,6-naphthyridine-1(2H)-one in 1500 ml chlorobenzene at room temperature. The reaction mixture was heated to 100° C., stirred at this temperature for 16 hours and then cooled to room temperature. The solids were filtered off, washed with chlorobenzene and dried under vacuum. The residue was taken up in 1.5 l ice-cold water, 350 ml 50% aqueous sodium hydroxide solution to reach a pH value of 7-8. The precipitate thus formed was filtered off, washed with water and dried under vacuum yielding 1-chloro-[2,6]naphthyridine as brown crystals; HPLC/MS (A): 1.62 min, [M+H] 165.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:39])[C:11](=[O:38])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][C:31]=1[CH3:37])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].[O:40]=[C:41]1[NH:45][CH2:44][CH:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42]1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:39])[C:11](=[O:38])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([N:45]2[CH2:44][CH:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42][C:41]2=[O:40])=[CH:32][C:31]=1[CH3:37])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(I)cc1C)C(=O)OC(C)(C)C
Reactant: COC(=O)C1CNC(=O)C1
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(N2CC(C(=O)OC)CC2=O)cc1C)C(=O)OC(C)(C)C
Yield: 72.2 %

Procedure:
Using the compound (650 mg, 1.00 mmol) of Example 293, step A and methyl 5-oxopyrrolidine-3-carboxylate (215 mg, 1.50 mmol), and according to the method of Example 298, step A, the title compound (480 mg, yield 72%) was obtained as a brown oil (480 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[CH3:13]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CNCCC#Cc1ccccn1
Product: Cc1ccccc1C(=O)N(C)CCC#Cc1ccccn1
Yield: 37.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-methylbenzoyl chloride (58 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 32.5 mg of N,2-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 37%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.C1(C)C=CC=CC=1.[CH2:12]([O:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[CH:28]=2)[NH:23]C(=O)[C:21]1=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([O:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[CH:28]=2)[N:23]=[C:1]([Cl:4])[C:21]1=[O:36])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1[nH]c2ccc(-n3ccnc3)cc2n(OCc2ccccc2)c1=O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1c(Cl)nc2ccc(-n3ccnc3)cc2n1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 20% phosgene in toluene (57 ml; 118 mmol) was added to a stirred solution of 4-benzyloxy-6-(1H-imidazol-1-yl)-quinoxaline-2,3(1H,4H)-dione (9.2 g; 27.5 mmol) in 200 ml dry N,N-dimethylformamide at 0° C. The mixture was stirred at 25° C. overnight and then evaporated in vacuo. The residue was stirred with ice-cooled water and 4N sodium hydroxide was added until pH was about 6 which resulted in the title compound (9.5 g; 98%) as a precipitate. M.p. 140° C. (decomp.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[C:12]([Cl:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10](F)[C:9]=2[CH3:20])[CH2:4][CH2:3]1.[F-].[K+].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([CH3:20])=[C:10]([C:11]([N+:16]([O-:18])=[O:17])=[C:12]([Cl:15])[C:13]=2[F:14])[NH:26][CH:23]2[CH2:25][CH2:24]2)[CH2:4][CH2:3]1
Reactant: NC1CC1
Reactant: Cc1c(F)c([N+](=O)[O-])c(Cl)c(F)c1N1CCN(C)CC1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(NC2CC2)c([N+](=O)[O-])c(Cl)c(F)c1N1CCN(C)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To the thus obtained 2-(4-methyl-1-piperazinyl)-3,6-difluoro-4-chloro-5-nitrotoluene (0.13 g) are added anhydrous dimethylformamide (2 ml), potassium fluoride (37 mg) and cyclopropylamine (0.15 ml) and the mixture is stirred at 100° C. for 3 hours. After cooling, the reaction mixture is poured into ice-water, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and purified by silica-gel column-chromatography (eluent; dichloromethane: methanol=10:1) to give 3-(4-methyl-1-piperazinyl)-4-fluoro-5-chloro-2-methyl-6-nitro-N-cyclopropylaniline (0.14 g).
Reaction SMILES: N1N=C(C2C=CC=CC=2C([N:14]2[CH2:18][CH:17]3[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:16]3[CH2:15]2)=O)NC=1.[N:29]1[N:30]([C:34]2[C:35]([C:40]([OH:42])=O)=[N:36][CH:37]=[CH:38][CH:39]=2)[N:31]=[CH:32][CH:33]=1.N1N=C(C2C=CC=CC=2C(O)=O)NC=1>>[N:31]1[N:30]([C:34]2[C:35]([C:40]([N:14]3[CH2:18][CH:17]4[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:16]4[CH2:15]3)=[O:42])=[N:36][CH:37]=[CH:38][CH:39]=2)[N:29]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Reactant: O=C(O)c1ncccc1-n1nccn1
Agent: O=C(O)c1ccccc1-c1nnc[nH]1
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ncccc3-n3nccn3)CC2C1

Procedure:
tert-Butyl 5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was prepared in a manner analogous to Intermediate 59 substituting 3-[1,2,3]triazol-2-yl-pyridine-2-carboxylic acid (Intermediate 72) for 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calculated for C19H24N6O3, 384.19; m/z found, 385.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([N:19]3[CH2:23][CH2:22][C@@:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[C:25](=[O:32])[O:24]4)[CH2:20]3)=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(#N)C.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>>[CH3:43][S:44]([N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([N:19]4[CH2:23][CH2:22][C@@:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20]4)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[C:2](=[O:1])[CH2:7]1)(=[O:46])=[O:45]
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5=O)cc4)CC3)C2)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R)-1′-({1-[4-(2-oxopiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (36 mg, 0.000083 mol) in acetonitrile (0.5 mL, 0.01 mol) were added triethylamine (29 μL, 0.00021 mol) and methanesulfonyl chloride. After stirring at rt for 3 hours, the crude product was isolated and purified by prep-HPLC. LC/MS: 510.2 (M+H+).