Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][C@@H:10]([CH3:14])[C@H:9]2[CH3:15])[N:5]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:26][CH:25]([F:27])[C:17]1[N:16]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][C@@H:10]([CH3:14])[C@H:9]3[CH3:15])[CH:7]=[C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:3]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: C[C@@H]1OCCN(c2cc(Cl)nc(-n3c(C(F)F)nc4ccccc43)n2)[C@@H]1C
Reactant: C1COCCN1
Product: C[C@@H]1OCCN(c2cc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)[C@@H]1C
Temperature: 70 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
0.84 g (5 mmol) of 2-difluoromethylbenzimidazole dissolved in DMF (25 ml) was added and reacted with 60% sodium hydride (0.24 g, 6 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 2,4,6-trichloropyrimidine (0.92 g, 5 mmol) dissolved in DMF (25 ml) and stirred at room temperature for 1.5 hours. The reaction solution was poured into water and the resulting precipitates were recrystallized from methanol to obtain 0.98 g (yield: 62%) of 4,6-dichloro-2-(2-difluoromethylbenzimidazol-1-yl)pyrimidine. (2) 0.32 g (1.0 mmol) of 4,6-dichloro-2-(2-difluoro-methylbenzimidazol-1-yl)pyrimidine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate were added to DMF (10 ml) and stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.33 g (yield: 84%) of 4-chloro-2-(2-difluoro-methylbenzimidazol-1-yl)-6-(cis-2,3-dimethylmorpholino)-pyrimidine. (3) 0.33 g (0.8 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-(cis-2,3-dimethyl-morpholino)pyrimidine dissolved in morpholine (0.70 g, 8.0 mmol) was stirred at 70° C. for 1 hour. The solvent was removed under the reduced pressure from the reaction mixture and the residue was purified by silica gel column chromatography to obtain 0.326 g (yield: 90%) of the titled compound as colorless crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:33])=[CH:30][C:29]=1[C:37]([F:38])([F:39])[F:40])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc2c(c1)NCS2
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCc2ccccc2)c(C(F)(F)F)c1)N1CSc2ccccc21
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (282 mg) and 37% formalin (0.19 mL) in the same manner as in Example 1 was dissolved in chloroform (6 mL), and triethylamine (0.62 mL) and 4-benzyloxy-3-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at mom temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (356 mg) as a pale yellow oily substance.
Reaction SMILES: [CH:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[C:7]3([CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)[O:6][C:5]=2[N:4]=[CH:3][CH:2]=1.CC(O)=O>CO.[Pd]>[CH:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[C:7]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ncccc1-n1cccc12
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: c1cnc2c(c1)-n1cccc1C1(CCNCC1)O2

Procedure:
A solution of benzyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (220 mg, 0.586 mmol), AcOH (33 μL, 0.59 mmol) and Pd/C (22 mg, 0.21 mmol) in MeOH (2 mL) was stirred under a balloon on H2 for 6 hours. The mixture was filtered through celite and the fitrate was evaporated to give spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine] (ESI-MS m/z calc. 241.1. found 242.5 (M+1)+; Retention time: 0.46 minutes (3 min run)). The residue was then taken up in THF (3 mL) before Na2CO3 (1.2 mL of 2.0 M, 2.4 mmol) was added. Boc2O (156 mg, 0.70 mmol) was added and the mixture was stirred at room temperature for 12 hours. N,N-dimethylethylenediamine (0.5 mL) was added and the mixture was stirred at room temperature for 30 min. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with 0.1N HCl (3×), brine, dried (Na2SO4) and filtered through a plug of silica to give tert-butyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (134 mg, 67%). 1H NMR (400 MHz, DMSO) δ 8.18-8.13 (m, 1H), 8.12-8.00 (m, 1H), 7.69-7.56 (m, 1H), 7.32-7.12 (m, 1H), 6.39 (dd, J=5.8, 3.0 Hz, 1H), 6.33-6.20 (m, 1H), 3.94 (d, J=11.9 Hz, 2H), 3.26 (s, 2H), 2.02 (s br, 4H), 1.48 (d, J=2.3 Hz, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:16](COCC[Si](C)(C)C)[C:15]([O:25][C@H:26]3[C@H:30]4[O:31][CH2:32][C@@H:33]([OH:34])[C@H:29]4[O:28][CH2:27]3)=[N:14][C:5]2=[N:6][C:7]=1[C:8]1[CH2:9][CH2:10][S:11][CH2:12][CH:13]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:16][C:15]([O:25][C@H:26]3[C@H:30]4[O:31][CH2:32][C@@H:33]([OH:34])[C@H:29]4[O:28][CH2:27]3)=[N:14][C:5]2=[N:6][C:7]=1[C:8]1[CH2:13][CH2:12][S:11][CH2:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(C3=CCSCC3)c(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(C3=CCSCC3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To (3R,3aR,6R,6aR)-6-((6-chloro-5-(3,6-dihydro-2H-thiopyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (74 mg, 0.141 mmol) in anhydrous DCM (0.45 mL) was added TFA (0.45 mL, 5.84 mmol). The solution stirred at RT for 18 h. The reaction solution was added to saturated NaHCO3 (35 mL) and extracted with EtOAc (2×45 mL). The organic layers combined, dried over Na2SO4, filtered, and the filtrate evaporated under reduced pressure. Flash chromatography utilizing a 12 g silica RediSep Rf® Gold column and employing a 0-10% MeOH/DCM gradient afforded the title compound. LC-MS: calculated for C17H18ClN3O4S 395.07 observed m/e: 395.90 (M+H)+ (Rt 0.84/2.0 min)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1)=[O:27]
Reactant: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
A solution of 10.0 g (0.0383 mole) of 1-(methylthio)-4-(4-nitrophenoxy)benzene and 7.76 g (0.0383 mole) of 85% 3-chloroperbenzoic acid dissolved in 500 ml of CH2Cl2 was stirred at ambient temperature for 3 days. The reaction mixture was extracted with aqueous K2CO3, water and dried (Na2SO4). Removal of solvent in vacuo afforded 10.3 g (97.2% yield) of product. Recrystallization from 2-propanol yielded purified 1-(methylsulfinyl)-4-(4-nitrophenoxy)benzene, mp 76°-78° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][N:25]1[CH:29]=[C:28]([CH:30]([NH2:32])[CH3:31])[CH:27]=[N:26]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][CH:30]([C:28]4[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=4)[CH3:31])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: CC(N)c1cnn(C)c1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(NC(C)c3cnn(C)c3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 25 °C
Yield: 83 %

Procedure:
4-(4-Chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (200 mg, 0.599 mmol, for preparation see Intermediate 8) and [1-(1-methyl-1H-pyrazol-4-yl)ethyl]amine (113 mg, 0.9 mmol) were heated in a mixture of DIPEA (0.324 ml, 1.858 mmol) and NMP (15 ml) at 120° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with water (300 ml) and extracted with EtOAc (2×200 ml). The combined organic phase was washed with water (300 ml) and brine (200 ml), dried with sodium sulphate and evaporated. The resulting gum was dissolved in DCM (3 ml) loaded onto a 100 g silica cartridge and eluted with 2M methanolic ammonia/DCM (0-12%). The product-containing fractions were evaporated in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-3-nitroquinolin-4-amine (0.21 g, 0.497 mmol, 83% yield) which was used in the subsequent step without further purification. LCMS (formate) Rt 0.87 min, MH+ 423.
Reaction SMILES: C(O[C:6](=[O:36])[NH:7][C@H:8]([C:12](=[O:35])[NH:13][C@H:14]([B:22]1[O:30][C@H:29]2[C@:24]([CH3:34])([C@H:25]3[CH2:31][C@@H:27]([CH2:28]2)[C:26]3([CH3:33])[CH3:32])[O:23]1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.[C:37]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C@@H:44]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)C(O)=O)[CH:38]=1>>[C:37]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C@@H:44]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:6]([NH:7][C@@H:8]([CH:9]([CH3:11])[CH3:10])[C:12]([NH:13][C@H:14]([B:22]2[O:30][C@H:29]3[C@:24]([CH3:34])([C@H:25]4[CH2:31][C@@H:27]([CH2:28]3)[C:26]4([CH3:33])[CH3:32])[O:23]2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:35])=[O:36])[CH:38]=1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)C(C)C)cc1

Procedure:
The title compound is prepared as described in example 1 but using {(S)-2-Methyl-1-[(R)-2-phenyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-propyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionic acid.
Reaction SMILES: C(O[C:4](=[O:19])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.P(Cl)(Cl)(Cl)=O>>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[N:12][C:13]2[C:14]([C:4]=1[OH:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccccc1)C(=O)OCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccccc2c1O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A 1 L three-necked flask fitted with a mechanical stirrer was charged with 2-phenylaminomethylene-malonic acid diethyl ester (26.3 g, 0.1 mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g). The mixture was heated to about 70° C. and stirred for 4 h. The mixture was cooled to room temperature, and filtered. The residue was treated with aqueous Na2CO3 solution, filtered, washed with water and dried. 4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as a pale brown solid (15.2 g, 70%). The crude product was used in next step without further purification.
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCCC)(=O)C1C=CC=CC=1.[CH2:26]([O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([N+:52]([O-])=O)[C:42]=1[C:43](=[O:51])[C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=1)[C:37]([OH:39])=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:52][C:41]1[C:42]([C:43](=[O:51])[C:44]2[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=2)=[C:34]([O:33][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38]
Reactant: Cc1ccc(C(=O)c2c(OCc3ccccc3)cc(C(=O)O)cc2[N+](=O)[O-])cc1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: Cc1ccc(C(=O)c2c(N)cc(C(=O)O)cc2OCc2ccccc2)cc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 3-benzyloxy-4-(4'-methylbenzoyl)-5-nitrobenzoic acid and following the procedure described, 5-amino-3-benzyloxy-4-(4'-methylbenzoyl)benzoic acid is obtained with a melting point of 182.5°-184° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O.ClCCl>[NH2:1][C:2]1[S:3][C:4]([C:8]([NH:48][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(N)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
To a solution of 2-amino-4-methylthiazole-5-carboxylic acid (0.86 g, 5.44 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1-hydroxy-benzotriazole (0.96 g, 7.07 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (1.36 g, 7.07 mmol), N,N-diisopropylethylamine (2.46 mL, 14.14 mmol) and benzylamine (0.71 mL, 6.53 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate (15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (20-35% ethyl acetate in hexanes) to afford the title compound as a white solid (1.02 g, 76%): 1H NMR (300 MHz, DMSO-d6) δ 8.01 (t, J=6.0 Hz, 1H), 7.36-71.9 (m, 7H), 4.34 (d, J=6.0 Hz, 2H), 2.34 (s, 3H); MS (ES+) m/z 248.2 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([N:9]2[CH2:30][CH2:29][C:12]3([C:17]4=[CH:18][CH:19]=[CH:20][N:16]4[C:15]4[CH:21]=[CH:22][C:23]([C:25]([O:27]C)=[O:26])=[CH:24][C:14]=4[O:13]3)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:33][CH3:34])[CH3:2].[Li+].[OH-]>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([N:9]2[CH2:10][CH2:11][C:12]3([O:13][C:14]4[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[CH:21][C:15]=4[N:16]4[CH:20]=[CH:19][CH:18]=[C:17]34)[CH2:29][CH2:30]2)=[O:8])=[CH:5][C:4]=1[O:33][CH3:34])[CH3:2]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)OC)ccc2-n2cccc23)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)O)ccc2-n2cccc23)cc1OC

Procedure:
A solution of methyl 1-(4-ethyl-3-methoxy-benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylate (1.1 g, 2.5 mmol) in LiOH (2.5 mL of 4.0 M, 9.9 mmol) and dioxane (5 mL) was stirred at 50° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous was acidified with 1N HCl and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to yield a crude product that was used in the next step without further purification (0.60 g, 53%). ESI-MS m/z calc. 446.5, found 447.5 (M+1)+; Retention time: 1.84 minutes (3 min run).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([N:14]([CH3:16])[CH3:15])[CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[NH2:10])([CH3:3])[CH3:2].C=O.Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O.[C:28]1([B-:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Na+]>C(O)C.CO>[C:47]1([B-:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1.[CH3:15][N:14]([CH3:16])[C:6]1[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:9]([N:10]2[CH:26]=[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N+:20]3=[CH:28]2)=[C:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=1
Reactant: O=Cc1ccccn1
Reactant: CC(C)c1cc(N(C)C)cc(C(C)C)c1N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)c1cc(N(C)C)cc(C(C)C)c1-n1cc2cccc[n+]2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 142.5 %

Procedure:
was prepared according to general procedure (A); 77 μg 3,5-diisopropyl-N,N-dimethylbenzene-1,4-diamine (0.35 mmol, 1 equiv), 39 μl formalin (0.53 mmol, 1.5 equiv), 0.23 mL 3.05 M hydrochloric acid in ethanol (0.70 mmol, 2 equiv) and 34 μl picolinaldehyde (0.35 mmol, 1 equiv) were combined in 1.8 mL ethanol and maintained at room temperature for 12 hours. The reaction was concentrated in vacuo and dried under high vacuum at 0.2 Torr. The crude material was then dissolved in 2.5 mL ethanol and stirred with 0.8 g sodium bicarbonate for 30 minutes at room temperature. The resulting suspension was then filtered through a 0.2 um nylon syringe tip filter. The solid sodium bicarbonate was washed with ethanol three times using 0.5 mL of ethanol for each wash and filtered. The combined filtrate was concentrated. The resulting crude oil was dissolved in 3.0 mL methanol and 0.12 g sodium tetraphenylborate (0.35 mmol, 1 equiv) in 1.0 mL methanol was added drop wise while stirring vigorously. The mixture was cooled to 4° C. in a refrigerator. The methanol was then decanted, and the solid was rinsed with methanol three times using 0.25 mL of methanol for each rinse and dried under high vacuum at 0.2 Torr to obtain 0.16 g 2-(4-(dimethylamino)-2,6-diisopropylphenyl)-2H-imidazo[1,5-a]pyridin-4-ium tetraphenylborate (0.26 mmol, a 73% yield) as a dark brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCc1ccccn1
Agent: Cl
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4ccccn4)cc13)Sc1ccc(Br)cc1-2
Yield: 6.6 %

Procedure:
According to Example 34, the compound (150 mg) produced in Example 37 was reacted with 2-chloromethylpyridine hydrochloride (84 mg) to obtain the title compound (12 mg; 67%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]2[CH2:38][CH2:37][CH2:36]2)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]2[CH2:38][CH2:37][CH2:36]2)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1)=[O:16]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(OCC2CCC2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(OCC2CCC2)cc1

Procedure:
A solution of [(1S,2S)-1-({(4-cyclobutylmethoxy-phenyl)-[(1R,2R)-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid tert-butyl ester (53 mg) in DCM (1 mL) was treated with TFA/DCM (1/1 mL) for 1 h. The mixture was concentrated to give the titled compound as di-TFA salts (60.7 mg). 1H NMR (400 MHz, MeOD) δ ppm 8.2 (d, J=3.0 Hz, 1H), 7.5 (td, J=8.5, 2.9 Hz, 1H), 7.3 (dd, J=8.8, 4.3 Hz, 1H), 7.3 (d, J=8.1 Hz, 2H), 6.9 (d, J=8.3 Hz, 2H), 4.3 (dd, J=14.9, 8.8 Hz, 1H), 3.9 (dd, J=6.6, 2.3 Hz, 2H), 3.6 (dd, J=14.9, 2.8 Hz, 1H), 3.3-3.4 (m, 1H), 2.8 (dt, J=14.6, 7.2 Hz, 1H), 2.6 (dd, J=6.3, 2.5 Hz, 1H), 2.1 (td, J=8.5, 5.6 Hz, 2H), 1.8-2.1 (m, 5H), 1.8 (ddd, J=7.7, 5.9, 1.5 Hz, 1H), 1.7 (ddd, J=9.0, 5.4, 3.8 Hz, 1H), 1.4 (ddd, J=8.5, 6.0, 3.9 Hz, 1H), 1.4 (dd, J=7.5, 5.7 Hz, 1H), 1.2 (dd, J=15.5, 5.4 Hz, 1H), 1.0 (d, J=6.8 Hz, 3H), 0.9 (t, 3H). LRMS (ESI)=440.3, [(M+H)+, Calcd for C26H35FN3O2 439.6].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[N:17][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[N:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(CCCC(=O)O)nc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=C(O)CCCc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cn1
Reaction time: 8 h
Yield: 35.6 %

Procedure:
4-Chlorobenzenesulphonyl chloride (1.17 g) was added portionwise to a solution of 4-(5-aminopyrid-2-yl)butanoic acid (1 g) in pyridine (15 ml). The resulting solution was allowed to stand at room temperature overnight when the solvent was removed under reduced pressure. The residue was dissolved in dilute sodium hydroxide solution (50 ml) and extracted with chloroform (4×50 ml) and the chloroform extracts were discarded. The aqueous layer was adjusted to pH=4 and was extracted with chloroform (3×100 ml). The chloroform extracts were dried over magnesium sulphate, the solvent was removed and residue was recrystallised from acetonitrile/water 1:1 to give the title compound (0.7 g) as white plates. m.p. 178°-180° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[N:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[S:35])=[CH:29][CH:28]=1>C1COCC1.CCOC(C)=O>[Cl:26][C:20]1[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]2[N:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]4[N:36]=[C:34]([NH:33][C:30]5[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=5)[S:35][CH:2]=4)[CH:6]=3)[CH2:17][C:16](=[O:18])[NH:15][C:14]=2[CH:19]=1
Reactant: NC(=S)Nc1ccncc1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3csc(Nc4ccncc4)n3)c1)=N2
Temperature: 60 °C
Yield: 37.6 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (130 mg) (Example 193a) and 1-(4-pyridyl)-2-thiourea (46 mg) in THF (3 mL) was heated at 60° C. for 45 min. The mixture was diluted with AcOEt and washed with sat. NaHCO3 solution and with brine. The organic layer was dried and evaporated and the residue was triturated with Et2O to give the title compound (55 mg) as yellow solid.