Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc(C)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C)nc1

Procedure:
Ethyl 3-(6-methyl-3-pyridyl)acrylate (60.36 g) was hydrogenated in ethanol at 35° and 355 kPa using palladiumon charcoal catalyst (10%, 1.0 g). The mixture was filtered and the filtrate was evaporated to give ethyl 3-(6-methyl-3-pyridyl)propionate as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F-:11].[K+]>S1(CCCC1)(=O)=O.[Cl-].C([N+]1C=CC(N(CCCC)CCCC)=CC=1)C(C)(C)C>[F:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: [F-]
Agent: CCCCN(CCCC)c1cc[n+](CC(C)(C)C)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)cc1
Reaction time: 9 h
Yield: 96.3 %

Procedure:
A reaction mixture of 85.3 g of 4-chloronitrobenzene (CNB), 45.3 g of potassium fluoride, 1.4 g of the N-neopentyl-4-(N',-N'-di-n-butylamino)pyridinium chloride (NPDBAPC) obtained in Example lII in 109.6 g of sulfolane was heated with stirring for 9 hours at 205°-215° C. At the end of this period, HPLC assay of a sample of the reaction mixture indicated less than 1% residual CNB. Simple distillation of the reaction mixture under vacuum gave 73.6 g of 4-fluoronitrobenzene (FNB) for a 96.3% yield.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C)C1C=CN=CC=1>[Si:14]([O:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(CO)N1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC1CCC(=O)N1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of 5-hydroxymethylpyrrolidin-2-one (5 grams, 43.4 mmol) in dichloromethane (174 mL) was added imidazole (6.5 grams, 95.5 mmol), 4-dimethylaminopyridine (530 mg, 4.3 mmol) followed by tert-butyldiphenylsilyl chloride (12.53 grams, 45.57 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane, washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain title compound of 15.37 grams, as gummy liquid, which was taken up for the next reaction without further purification.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[NH:23][N:24]=[C:25]([CH3:26])[C:15]=3[N:14]=2)[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[CH3:26][C:25]1[C:15]2[N:14]=[C:13]([C:9]3[CH:8]=[C:7]([OH:6])[CH:12]=[CH:11][CH:10]=3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]=2[NH:23][N:24]=1
Reactant: COc1cccc(-c2nc3c(C)n[nH]c3c3ccccc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1n[nH]c2c1nc(-c1cccc(O)c1)c1ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
380 μl of 1M boron tribromide solution in methylene chloride were added dropwise, at −78° C., to a solution of 55 mg of 5-(3-methoxyphenyl)-3-methyl-1H-pyrazolo[4,3-c]isoquinoline (3) in 3 ml of methylene chloride. The reaction solution was stirred at RT for 12 h, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 5. C17H13N3O (275.31); MS (ESI 276 (M+H)
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Br>>[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Reactant: COC(=O)CCCBr
Agent: Cl
Product: COC(=O)CCCN1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 33.2 %

Procedure:
The title compound (106 mg, 32.6%) was prepared from the compound from step 2, Example 8 (165 mg, 0.9 mmol) and 4-bromo-butyric acid methyl ester (165 mg, 90 mmol) by the procedure described in step 3 of Example 4: MS (ESI) m/z 355 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.84 (m, 2H), 2.36-2.44 (m, 4H), 2.60 (t, J=4.8 Hz, 4H), 3.14 (t, J=4.8 Hz, 4H), 3.68 (s, 3H), 6.89-7.04 (m, 7H), 7.26-7.29 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]([NH:25][NH2:26])=O)=[CH:22][C:17]=2[NH:16][CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O=P(Cl)(Cl)Cl>>[C:1]1([S:7]([CH2:10][C:11]2[S:36][C:23]([C:21]3[CH:20]=[CH:19][C:18]4[NH:14][CH:15]=[N:16][C:17]=4[CH:22]=3)=[N:25][N:26]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cc1nnc(-c2ccc3[nH]cnc3c2)s1)c1ccccc1

Procedure:
The compound was synthesized starting from phenylsulfonylacetic acid (201 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described in method 3; yield: 0.051 G (14.3%); MS m/z: 357.1 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 5.51 (s, 2H); 7.63-7.67 (m, 2H); 7.75-7.77 (m, 1H); 7.84-7.87 (m, 3H); 7.98 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 8.30 (d, 1H, 4J=1.7 Hz); 8.95 (s, 1H); HPLC (METHOD [A]): rt 10.49 min (98.3%)
Reaction SMILES: [OH:1][CH2:2][P:3]([OH:5])[OH:4].Cl.[CH2:7]([NH:14][CH2:15][C:16]([OH:18])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:19]=O>Cl>[CH2:7]([NH:14][CH2:15][C:16]([CH2:19][P:3]([CH2:2][OH:1])(=[O:5])[OH:4])=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCP(O)O
Reactant: O=C(O)CNCc1ccccc1
Reactant: C=O
Agent: Cl
Product: O=C(CNCc1ccccc1)CP(=O)(O)CO
Yield: 88 %

Procedure:
The procedure of Example 1 is carried out starting from 9.6 g (0.1 mole) of hydroxymethylphosphonous acid ##STR8## 20.2 g (0.1 mole) of N-benzylglycine hydrochloride, 100 ml of conc. hydrochloric acid and 31.6 g of 38% formaldehyde solution. The reaction mixture is concentrated by rotary evaporation, yielding 22.7 g (88%) of (N-benzylglycylmethyl)hydroxymethylphosphinic acid of the formula ##STR9## as a glassy substance which sinters at 92° C., becomes liquid at 118° C., and decomposes at 135° C.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.N[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH2:17]1.[OH-].[Na+].C[N:25](C=O)C>>[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[NH:25][C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Reactant: NN1C=CN=CC1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: c1cnc(Nc2ncnc3[se]c4c(c23)CCCC4)cn1
Yield: 65 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (600 mg, 2.20 mmol, from step b of example 1) in DMF (10 mL) was added sequentially 4-aminopyrazine (310 mg, 3.30 mmol) and powdered NaOH (260 mg, 6.60 mmol) at rt. Work-up as described in example 2, gave the product as a pale yellow color solid (470 mg, 65%), mp 192-194° C. 1H NMR (400 MHz, CDCl3): δ 9.94 (1H, s), 8.56 (1H, s), 8.29 (1H, s), 8.23 (1H, s), 7.93 (1H, s, exchangeable with D2O), 3.14 (2H, s), 2.96 (2H, s), 2.01 (2H, s), 1.95 (2H, s); 13C NMR (100 MHz, CDCl3): δ 171.9, 153.4, 151.5, 149.1, 141.9, 138.8, 137.7, 126.7, 120.1, 28.2, 28.1, 22.7, 22.5; LC-MS (negative ion mode): m/z 328, 330 (M−H)−.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]([NH:15][CH:16]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]2[CH2:33][C@H:34]([C:36](OC)=[O:37])[N:35]=[C:17]12)=[O:14].CO.O>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]([NH:15][CH:16]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]2[CH2:33][C@H:34]([CH2:36][OH:37])[N:35]=[C:17]12)=[O:14]
Reactant: COC(=O)[C@H]1CN2C(=N1)C(NC(=O)CCc1ccc(Cl)cc1Cl)N=C(c1ccccc1)c1ccccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCc1ccc(Cl)cc1Cl)NC1N=C(c2ccccc2)c2ccccc2N2C[C@H](CO)N=C12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Lithium borohydride (6.5 mg, 0.3 mmol) was added to a solution of (2R)-3-(2,4-dichlorophenyl)-N-{1,2-dihydro-2-methoxycarbonyl-6-phenyl-4H-imidazo [1,2-a][1,4]benzodiazepin-4-yl}propanamide (160 mg, 0.3 mmol) in THF (20 mL) and the mixture was stirred at room temperature for 18 h. The mixture was cooled to 0° C. and methanol then water were added. The solvent was evaporated under reduced pressure, ethyl acetate was added and the mixture was washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (97.5:2.5) to give (2R)-3-(2,4-dichlorophenyl)-N-{1,2-dihydro-2-hydroxymethyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl}propanamide as a foam.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3C=O)[CH:8]=2)[N:3]=1.Cl.[NH2:32][CH2:33][C:34]([NH2:36])=[O:35].[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:37][NH:32][CH2:33][C:34]([NH2:36])=[O:35])[CH:8]=2)[N:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Reactant: NCC(N)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: NC(=O)CNCc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 39 mg of aminoacetamide hydrochloride are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 113 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@H:12]3[CH2:14][C@@H:13]3[CH2:15][NH2:16])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@H:12]3[CH2:14][C@@H:13]3[CH2:15][NH:16][C:25](=[O:27])[CH3:26])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: Cc1cc2c([C@H]3C[C@@H]3CN)cccn2n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1C[C@@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.5 %

Procedure:
To a suspension of 1-[(1S,2S)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine dihydrochloride (750 mg, 2.74 mmol) and triethylamine (1.52 mL, 10.9 mmol) in tetrahydrofuran (27 mL) was added acetic anhydride (388 μL, 4.10 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (623 mg, yield 93%).
Reaction SMILES: C([N:8]([C@H](C1C=CC=CC=1)C)[C@@H:9]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19][CH2:18]2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])C1C=CC=CC=1.C(O)(=O)C.O>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19][CH2:18]2)[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C[C@H](c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COC(=O)CC(N)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A solution of methyl 3-{R}-[benzyl-({S}-1-phenyl-ethyl)-amino]-3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate (6.5 g, Reference Example 15) in ethanol (100 ml) was treated with 20% palladium hydroxide on charcoal (1.0 g), acetic acid (3.6 ml) and water (10 ml) and the mixture was hydrogenated at room temperature overnight. The spent catalyst was removed by filtration through Celite and the filtrate was evaporated to low bulk. The residue was taken up in ether and this solution was washed with aqueous sodium bicarbonate solution, and the layers separated. The aqueous layer was extracted twice with fresh ether and the combined ether extracts were washed with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (1:9, v/v) to give the title compound (1.7 g) as a clear oil which slowly crystallised on standing. MS (ES+) 335 (MH+), 357 (MNa+), 669 (2MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[C:10]([CH3:29])=[N:11][C:12]3[C:17]([N:18]=2)=[C:16]([C:19]2[NH:23][C:22]4[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=4[CH:20]=2)[CH:15]=[CH:14][CH:13]=3)[CH2:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:29][C:10]1[C:9]([NH:8][C@H:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:30](=[O:32])[CH3:31])[CH2:3]2)=[N:18][C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]1[NH:23][C:22]2[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=2[CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](N)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1CCC[C@H](Nc2nc3c(-c4cc5c([nH]4)[C@@H](C)NC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A mixture of (R)-2-(3-(((1S,3R)-3-aminocyclohexyl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (483) (29 mg, 0.074 mmol), acetic anhydride (35.0 μL, 0.37 mmol), and N-ethyl-N-isopropylpropan-2-amine (91 μL, 0.52 mmol) in DCM (743 μL) was stirred at RT for 30 min when mostly product was observed via LCMS. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aqueous sodium bicarbonate (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product in DCM was loaded onto the column and was purified via automated flash chromatography (silica gel) with 100% DCM to 8% 2 M ammonia in MeOH/DCM to give N-((1R,3S)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinoxalin-2-yl)amino)cyclohexyl)acetamide (486, 19 mg, 0.044 mmol, 59% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 1H) 1.20-1.32 (m, 1H) 1.42 (d, J=6.65 Hz, 3H) 1.44-1.52 (m, 2H) 1.78 (s, 3H) 1.80-1.90 (m, 2H) 2.11 (br. s., 2H) 2.53 (s, 3H) 3.58-3.71 (m, 1H) 4.04-4.17 (m, 1H) 4.54 (q, J=6.59 Hz, 1H) 6.87 (d, J=7.63 Hz, 1H) 6.95 (d, J=1.57 Hz, 1H) 7.33 (t, J=7.82 Hz, 1H) 7.59 (dd, J=8.02, 1.37 Hz, 1H) 7.62 (s, 1H) 7.81-7.88 (m, 2H) 11.99 (s, 1H). MS (ESI, pos. ion) m/z: 433.1 (M+1).
Reaction SMILES: C(C1C=C(C=CC=1)C=O)C.[C:11]1([C:17]2[N:21]=[CH:20][N:19]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:41]([C:43]1[CH:44]=[CH:45][C:46]([F:51])=[C:47]([CH:50]=1)[CH:48]=[O:49])[CH3:42]>>[CH2:41]([C:43]1[CH:44]=[CH:45][C:46]([F:51])=[C:47]([CH:48]([C:20]2[N:19]([C:22]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:18]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:21]=2)[OH:49])[CH:50]=1)[CH3:42]
Reactant: c1ccc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: CCc1ccc(F)c(C=O)c1
Agent: CCc1cccc(C=O)c1
Product: CCc1ccc(F)c(C(O)c2nc(-c3ccccc3)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 82.5 %

Procedure:
According to the procedure for Intermediate 370.1, 3-phenyl-1-trityl-1H-1,2,4-triazole (250 mg, 0.66 mmol) and 5-ethyl-2-fluorobenzaldehyde (100 mg, 0.66 mmol) afforded 294 mg of Intermediate 384.1 as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.06 (t, J=7.70 Hz, 3H) 2.41 (q, J=7.58 Hz, 2H) 2.89 (d, J=9.05 Hz, 1H) 5.41 (d, J=9.29 Hz, 1H) 6.60 (dd, J=9.90, 8.44 Hz, 1H) 6.82-6.93 (m, 1H) 6.96 (dd, J=7.34, 2.20 Hz, 1H) 7.02-7.09 (m, 6H) 7.09-7.16 (m, 9H) 7.24-7.39 (m, 4H) 7.98-8.10 (m, 2H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6]([C:9]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1)(=[O:8])=[O:7]>C(OCC)(=O)C>[CH3:5][S:6]([C:9]1[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=1)(=[O:8])=[O:7]
Reactant: O=C(Cl)Cl
Reactant: CS(=O)(=O)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methylsulfonyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methylsulfonyl-1,3,4-thiadiazol-2yl isocyanate dimer.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][C:35]([N:37]=[C:38]=[O:39])=[O:36]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH3:26])=[O:39])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1CC(=O)N=C=O
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 308 (370 mg, 1.05 mmol) and (2-methoxy-phenyl)-acetyl isocyanate (240 mg, 1.25 mmoL) [A. J. Hill et al. JACS, 62; 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and eluted with EtOAc, to afford the title compound 309c in 42% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 10.98 (s, 1H), 10.69 (s, 1H), 8.41(d, 1H, J=5.3 Hz), 7.94(d, 1H, J=1.2 Hz), 7.81(dd, 1H, J1=13.1 Hz, J2=2.4 Hz), 7.77(d, 1H, J=0.9 Hz), 7.65 (s, 1H), 7.45-7.40 (m, 2H), 7.26-7.19 (m, 2H), 6.97(d, 1H, J=8.0 Hz), 6.89(dt, 1H, J1=0.8 Hz, J2=8.2 Hz), 6.54(d, 1H, J=5.5 Hz), 4.04(q, 2H), 3.75 (s, 3H), 3.70 (s, 2H), 1.38(t, 3H). MS (m/z): 546.1 (M+H) (found).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1.[Br:17][CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>COCCOC.C(OCC)C>[BrH:17].[CH3:15][C:10]1([CH3:16])[C:11]([CH3:14])([CH3:13])[O:12][B:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:1]=3)[CH:4]=2)[O:9]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Solvent: COCCOC
Solvent: CCOCC
Product: Br
Product: CCOC(=O)c1cn2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Temperature: 20 °C
Reaction time: 40 h
Yield: 52.4 %

Procedure:
To a solution of 4 g of 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in 40 mL of 1,2-dimethoxyethane are added 4.26 g of ethyl 3-bromo-2-oxopropionate. The reaction mixture is stirred for 40 hours at 20° C. The precipitate is filtered off by suction, washed with a small amount of 1,2-dimethoxyethane and pentane and then taken up in 50 mL of ethanol and refluxed for 1 hour. The reaction mixture is concentrated to dryness under reduced pressure. The oil obtained is redissolved in ethyl ether and the solution is concentrated under reduced pressure. The solid is filtered off by suction and washed with a small amount of ethyl ether to give 3.78 g of ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxylate hydrobromide (1:1) in the form of a white solid.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([NH:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=O)C.N1CCCC1.Cl>CO>[SH:4][CH2:5][CH:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([NH:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CC(=O)SCC(CC(C)C)C(=O)Nc1cccc(C(=O)O)c1C
Agent: Cl
Solvent: CO
Solvent: C1CCNC1
Product: Cc1c(NC(=O)C(CS)CC(C)C)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
3-[(2-Acetylthiomethyl-4-methylpentanoyl)amino]-2-methylbenzoic acid (compound of Example 175) (3 g), 70% aqueous methanol (30 ml) and pyrrolidine (2.2 g) are mixed, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is adjusted to pH 3.0 with 10% hydrochloric acid, and methanol is distilled off under reduced pressure. The precipitated crystals are separated by filtration and dissolved in 50% aqueous acetonitrile and purified by a column chromatography using Diaion HP-20 (eluant, water-acetonitrile). The fractions containing the desired compound are collected and acetonitrile is distilled off under reduced pressure, and the precipitated crystals are separated by filtration to give the title compound (2 g). m.p.: 166°-168° C. (colorless needles) IR (KBr; cm-1): 1690, 1660