Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31]([O:33]C)=[O:32])=[N:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1.O>[C:13]([O:12][C:11]([NH:10][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31]([OH:33])=[O:32])=[N:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@@H](CCCCNC(=O)[C@@H](CCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of methyl ester 15 (2.15 g, 2.94 mmol) in MeOH/THF/H2O (30 mL/30 mL/15 mL) was charged with NaOH (589 mg, 14.7 mmol) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH was adjusted to 5 with 1 N HCl. The suspension was partitioned between CH2Cl2 (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to afford compound 16 (1.80 g, 86%) as a white solid, which was used directly in the next step: 1H NMR (400 MHz, CD3OD) δ 4.07-4.00 (m, 1H), 4.00-3.91 (m, 1H), 3.35 (t, J=7.2 Hz, 2H), 3.25-3.10 (m, 2H), 1.89-1.23 (m, 12H), 1.52 (s, 9H), 1.46 (s, 9H), 1.438 (s, 9H), 1.436 (s, 9H).
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][C@@H:38]([CH3:42])[CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:62][CH3:63])[N:32]2[CH2:43][CH2:44][CH2:45][CH:46]1[CH2:51][CH2:50][CH2:49][N:48](C(OCC2C=CC=CC=2)=O)[CH2:47]1>>[CH3:42][C@H:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:62][CH3:63])[N:32]2[CH2:43][CH2:44][CH2:45][CH:46]2[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 3-{3-[6-amino-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-9-yl]propyl}-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3][C:2]([CH3:28])([CH3:1])[CH2:7]3)[N:14]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CCCC#N)cc3)n2)CC(C)(C)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCCCN)cc3)n2)CC(C)(C)N1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-butyronitrile (Example 192) (37 mg, 0.10 mmol) in 2 ml THF was added LAH (1 M in THF, 294 μl, 0.294 mmol). The reaction mixture was stirred at 60° C. for 2 hours. The mixture was quenched with 0.5 ml aqueous sodium sulfate, followed by 2N-NaOH (pH 11). Extraction with EtOAc and purification using preparative HPLC gave the title compound. Yield: 16 mg (43%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18](OC)=[O:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O.[OH-].[Na+]>O1CCCC1>[OH:19][CH2:18][CH:16]1[CH2:17][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Reaction time: 1 h
Yield: 95.4 %

Procedure:
Lithium aluminum hydride (128 mg) was placed in a round-bottomed flask and suspended in tetrahydrofuran (30 ml). This was cooled in an ice bath, and a solution of methyl 1-tert-butoxycarbonylazetidine-3-carboxylate (970 mg) in tetrahydrofuran (10 ml) was gradually added thereto, followed by stirring under a nitrogen atmosphere at the same temperature for 1 hr. To the reaction mixture were added water (0.13 ml) and a 5N aqueous solution of sodium hydroxide (0.13 ml) and water (0.39 ml) while cooling in an ice bath, followed by stirring at the same temperature for 1 hr. Insoluble matter in the reaction mixture was removed by filtration. The filtrate was concentrated to provide the titled compound as a colorless oil (805 mg, 95.3%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]([CH2:10][C:11]1[CH:19]=[CH:18]C(C(O)=O)=[CH:13][CH:12]=1)[CH3:9].NCC1C=CC(C(OC)=O)=CC=1.C=O.[OH-].[Na+]>>[CH3:7][N:8]([CH2:10][C:11]1[CH:19]=[CH:18][C:1]([C:2]([Cl:4])=[O:3])=[CH:13][CH:12]=1)[CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)Cc1ccc(C(=O)O)cc1
Agent: C=O
Agent: COC(=O)c1ccc(CN)cc1
Agent: [Na+]
Product: CN(C)Cc1ccc(C(=O)Cl)cc1

Procedure:
The 4-(N,N-dimethylaminomethyl) benzoyl chloride was prepared by reacting the acid with excess oxalyl chloride for 1 hr at 25° C. The 4-(N,N-dimethylaminomethyl) benzoic acid was in turn prepared from methyl 4-aminomethylbenzoate via reductive alkylation (CH2O, Na(OAc)3 BH as in J. Org. Chem., 1972, 37, 1673) followed by hydrolysis using 10% aqueous NaOH.
Reaction SMILES: [F:1][C:2]([N+:29]([O-:31])=[O:30])([N+:26]([O-:28])=[O:27])[CH2:3][O:4][CH:5](OCC([N+]([O-])=O)([N+]([O-])=O)F)[O:6][CH2:7][C:8]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[F:9].[Cl-].[Al+3].[Cl-].[Cl-].C([Cl:39])(=O)C>>[Cl:39][CH:5]([O:6][CH2:7][C:8]([F:9])([N+:13]([O-:15])=[O:14])[N+:10]([O-:12])=[O:11])[O:4][CH2:3][C:2]([N+:29]([O-:31])=[O:30])([N+:26]([O-:28])=[O:27])[F:1]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])C(F)(COC(OCC(F)([N+](=O)[O-])[N+](=O)[O-])OCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Product: O=[N+]([O-])C(F)(COC(Cl)OCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]

Procedure:
Next the tris(2-fluoro-2,2-dinitroethoxy)methane is refluxed with aluminum chloride and acetyl chloride to produce chloro bis(2-fluoro-2,2-dinitroethoxy)methane as illustated by example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[CH3:18][O:19][C:20]([C:22]1(OC)[CH2:26][CH2:25][CH:24](OC)O1)=[O:21]>>[CH3:18][O:19][C:20]([C:22]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]3)[CH:24]=[CH:25][CH:26]=1)=[O:21]
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F
Reactant: COC(=O)C1(OC)CCC(OC)O1
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F

Procedure:
51 mmol of 6-amino-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione were reacted with 51 mmol of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:21])[CH:5]([NH:13]CC1C=CC=CC=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.C([O-])=O.[NH4+]>C(O)(C)C.[Pd]>[CH3:2][O:3][C:4](=[O:21])[CH:5]([NH2:13])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C(NCc1ccccc1)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CC(C)O
Product: COC(=O)C(N)c1ccc(F)cc1
Temperature: 50 °C
Yield: 80.2 %

Procedure:
4-Fluoro-α-[(phenylmethyl)amino]benzeneacetic acid methyl ester hydrochloride (12.2 kg, 39.4 moles) was added to a slurry of 10% palladium-on-carbon (1.2 kg) in isopropanol (50 L). Ammonium formate (5.0 kg, 79.4 moles) was added and the batch was heated to 50° C. Progress of the reaction was monitored by HPLC. The batch was filtered through Hyflo Supercel and the filter cake was washed with isopropanol (25 L). The filtrate was evaporated to low volume and flushed with isopropyl acetate (50 L). The residue was dissolved in isopropyl acetate (30 L) and washed with 5% aqueous potassium phosphate (40 L), followed by saturated aqueous sodium chloride (10 L). The solution was evaporated under vacuum to give 5.79 kg (87% yield) of racemic α-amino-4-fluorobenzeneacetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17]([O:19]C)=O)=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1.[NH2:23][C:24]1[S:25][C:26]([CH3:29])=[CH:27][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17]([NH:23][C:24]4[S:25][C:26]([CH3:29])=[CH:27][N:28]=4)=[O:19])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1
Reactant: Cc1cnc(N)s1
Reactant: COC(=O)C1=C(O)c2sc3cc(Cl)ccc3c2S(=O)(=O)N1C
Product: Cc1cnc(NC(=O)C2=C(O)c3sc4cc(Cl)ccc4c3S(=O)(=O)N2C)s1
Yield: 42 %

Procedure:
Prepared analogous to Example 1 from methyl 7-chloro-4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-5-methyl-thiazole with a yield of 42% of theory.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8]OS(C)(=O)=O)[CH2:5][CH:4]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:2].[N-:21]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1COCC1.O>[NH2:21][CH2:8][CH:6]1[CH2:5][CH:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:3]([CH2:1][CH3:2])[CH2:7]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCC1CC(COS(C)(=O)=O)CC1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCC1CC(CN)CC1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 15 h
Yield: 46.5 %

Procedure:
To a solution of tert-butyl 2-ethyl-4-((methylsulfonyloxy)methyl)cyclopentanecarboxylate (0.295 g, 0.964 mmol) in DMF (5 mL) was added sodium azide (0.313 g, 4.82 mmol). The reaction was heated at about 50° C. for about 16 h and then cooled to about 15-20° C. Water (40 mL) was added to the reaction mixture. The aqueous solution was extracted with DCM (3×30 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a dark brown oil. The brown oil was dissolved in THF (6.5 mL) and water (3.5 mL). Triphenylphosphine (0.316 g, 1.205 mmol) was added. The reaction mixture was stirred at about 25° C. for about 15 h. The organic solvent was removed under reduced pressure and the residue partitioned between saturated aqueous NaHCO3 (20 mL) and DCM (20 mL). The organic phase was concd under reduced pressure. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-20% (20% (7 N ammonium in MeOH) in MeOH)) in DCM to give tert-butyl 4-(aminomethyl)-2-ethylcyclopentanecarboxylate (0.102 g, 46%) as a brown oil: LC/MS (Table 1, Method b) Rt=1.72 min; MS m/z: 228 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([F:13])([F:12])[CH2:10]O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:14]1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N>C(#N)C.[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([C:9]([F:13])([F:12])[CH2:10][NH2:14])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OCC(F)(F)c1ncc(Cl)cc1Cl
Reactant: c1ccncc1
Agent: N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: NCC(F)(F)c1ncc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of 1.3 g (5.7 mmol) of 2-(3,5-dichloropyridin-2-yl)-2,2-difluoroethanol (Int-9) in dry acetonitrile under argon, were added 0.744 mL (9.12 mmol) of dry pyridine. The reaction mixture was cooled to 0° C. and 1.06 mL (6.27 mmol) of triflic anhydride were added dropwise in 15 min while maintaining the temperature below 8° C. The reaction mixture was stirred at 0° C. for additional 30 min 9.9 mL of a 28% w/w aqueous solution of ammonia (144 mmol) were added and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with 50 mL of brine and the product extracted three times with 25 mL of ethyl acetate. The organic phases were collected, washed three times with 40 mL of brine and dried over magnesium sulfate. Afater evaporation of the solvent under vacuum 1.09 g of brown oil were obtained. After purification by column chromatography on silica gel (heptane/ethyl acetate gradient) 0.65 g (50%) of 2-(3,5-dichloropyridin-2-yl)-2,2-difluoroethanamine (IIa-15) were obtained as a yellow oil, (M+1)=227, 19F-NMR (235 MHz, CDCl3) δ (ppm): −104.80 (CF2).
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21]
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Reaction time: 0.75 h

Procedure:
Fmoc-protected tripeptide 74 (546 mg, 0.98 mmol) was treated with a 5% v/v solution of piperidine in DMF (5 mL). After stirring for 45 min, the reaction mixture was concentrated to dryness. The crude material was used for the next step without purification.
Reaction SMILES: O=[C:2]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:10][CH:9]=1)[C:4]([O:6]C)=O.[NH2:32][NH2:33].O>C(O)C>[N:29]1[CH:30]=[CH:31][C:26]([C:2]2[NH:33][NH:32][C:4](=[O:6])[C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][CH:9]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)C(C(=O)c1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 37 %

Procedure:
To a stirred solution of methyl 3-oxo-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)propanoate (0.2 g, 0.48 mmol) in ethanol (5 mL), NH2NH2.H2O (0.12 g, 2.42 mmol) and TEA (0.146 g, 1.45 mmol) were added dropwise at RT. The reaction mixture was then refluxed for 16 h and then concentrated in vacuo to obtain crude product. The crude material was washed with water (5 mL) and ether (5 mL) to afford 5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one (70 mg, 37%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 9.12 (bs, 1H), 8.38 (d, J=7.2 Hz, 2H), 8.02-7.96 (m, 3H), 7.76 (t, J=7.6 Hz, 2H), 7.64-7.56 (m, 3H), 7.16 (d, J=7.2 Hz, 2H), 6.96 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.21 (s, 1H). MS: M+H: m/z=395.1 and HPLC: 80%, (Condition-C).
Reaction SMILES: [NH2:1][C:2]([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>O1CCOCC1>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([CH2:10][N:9]2[C:5]([CH2:4][C:2]([NH2:1])=[S:28])=[CH:6][N:7]=[CH:8]2)=[CH:12][CH:13]=1)#[N:16]
Reactant: N#Cc1ccc(Cn2cncc2CC(N)=O)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(Cn2cncc2CC(N)=S)cc1
Temperature: 80 °C

Procedure:
To a 50 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 4-[5-(aminocarbonylmethyl) imidazol-1-ylmethyl]benzonitrile (0.36 g, 1.49 mmol), Lawesson's reagent (0.73 g, 1.8 mmol) and 1,4-dioxane (10 mL). This well stirred mixture was heated at 80° C. for 24 hours. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed (silica gel, 10% 2-propanol in ammonia saturated CHCl3). The title compound was obtained as a yellow, crystalline solid.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)([Cl:19])=O>ClC=C(Cl)Cl>[C:1]([Cl:19])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCC(=O)O
Solvent: ClC=C(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)Cl

Procedure:
Myristoyl chloride was synthesized by refluxing myristic acid (7.0 g) and thionyl chloride (9 ml) in trichloroethylene (100 ml) for 3 h. The solvent was then evaporated.
Reaction SMILES: [N:1]1([CH:10]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:11](O)=[O:12])C2C=CC=CC=2N=N1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:33]=1[C:39](=O)[CH3:40].CN1CCOCC1.C([O-])(=O)C.[NH4+].[OH-].[Na+]>C(Cl)Cl.O1CCCC1.O.CN(C)C=O>[Br:38][C:36]1[CH:35]=[CH:34][C:33]2[C:39]([CH3:40])=[N:1][CH:10]([NH:14][C:15](=[O:16])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11](=[O:12])[NH:31][C:32]=2[CH:37]=1
Reactant: O=C(NC(C(=O)O)n1nnc2ccccc21)OCc1ccccc1
Reactant: CC(=O)c1ccc(Br)cc1N
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
Under an argon atmosphere 1H-1,2,3-benzotriazol-1-yl{[(benzyloxy)carbonyl]amino}acetic acid (6.71 g, 20.6 mmol) was suspended in anhydrous methylene chloride (92 ml) and cooled to 0° C. in an ice bath. Oxalyl chloride (2.61 g, 20.6 mmol) was added dropwise to the suspension, followed by N,N-dimethylformamide (38 ml) added dropwise. After the addition the reaction was stirred at 0° C. in an ice bath for 30 minutes, until no more gas evolved. Then 1-(2-amino-4-bromophenyl)ethanone (4.0 g, 18.7 mmol) and 4-methylmorpholine (2.84 g, 28.0 mmol) were added dropwise in anhydrous methylene chloride (60 ml) under stirring in an ice bath. The reaction mixture was then allowed to warm to room temperature and stirred over night. Reaction was quenched with water (200 ml), then extracted with ethyl acetate (3×250 ml). The organic layers were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give a residue. This residue was dissolved in tetrahydrofuran (120 ml) and methyl-alcohol (35 ml) and then ammonia gas was bubbled through for 2.5 hours. The reaction was then concentrated to a very viscous light brown oil. The oil was dissolved in acetic acid (120 ml) and ammonium acetate (4.3 g, 56.1 mmol) was added in one portion and stirred for 12 hours. The reaction was diluted with water (100 ml) and then basified to pH=10 with 25% sodium hydroxide under stirring in an ice bath. The aqueous solution was then extracted with ethyl acetate (3×500 ml) and the organic layers combined, dried over magnesium sulfate, filtered and the filtrate concentrated to give a residue. The residue was purified to silica gel column chromatography eluting with 40% ethyl acetate in hexanes to give the title compound 162b (4 g, 53%). 1H NMR (CDCl3, 300 MHz): δ 9.90 (s-br, 1H), 7.42-7.31 (m, 6H), 7.12 (d, 1H, 1.5 Hz), 7.06-7.03 (m, 1H), 5.18-5.08 (m, 3H), 2.50 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=2)[C:17]([O:19]C)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)#[N:2].Cl>CO.C1COCC1.[OH-].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=2)[C:17]([OH:19])=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(-n3cccc3)c(C#N)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(-c2cc(C(=O)O)ccn2)ccc1-n1cccc1
Yield: 99.6 %

Procedure:
131 mg of methyl 2-(4-amino-3-cyanophenyl)isonicotinate and 67 μl of 2,5-dimethoxytetrahydrofuran were dissolved in 1.3 ml of acetic acid solution, followed by heating and stirring at 100° C. for 4 hours. The solution was poured into water, followed by extraction with ethyl acetate. The solvent of the organic layer was evaporated under reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate=10:1 to 1:1) to obtain 100 mg of methyl 2-[3-cyano-4-(1H-pyrrol-1-yl)phenyl]isonicotinate. (2) 100 mg of methyl 2-[3-cyano-4-(1H-pyrrol-1-yl)phenyl]isonicotinate was dissolved in a mixture of 2 ml of methanol and 3 ml of THF, and 66 μl of aqueous 1 M sodium hydroxide solution was added, followed by heating under reflux for 3 hours. The reaction mixture was cooled, then neutralized with 66 μl of 1 M hydrochloric acid, followed by extraction with a mixture of 2-propanol and chloroform (1:4). The organic layer was washed with brine. The solvent of the organic layer was evaporated under reduced pressure, and the resulting residue was recrystallized from a mixture of 2-propanol and chloroform (1:4) to obtain 95 mg of 2-[3-cyano-4-(1H-pyrrol-1-yl)phenyl]isonicotinic acid.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[CH:68]=[C:67]([C:69]([F:72])([F:71])[F:70])[CH:66]=[CH:65][C:61]=1[C:62](Cl)=[O:63]>>[F:59][C:60]1[CH:68]=[C:67]([C:69]([F:70])([F:71])[F:72])[CH:66]=[CH:65][C:61]=1[C:62]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:63]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)cc3)cc2C1=O
Yield: 73 %

Procedure:
The compound of example 191 was prepared was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-fluoro-4-trifluoromethyl benzoyl chloride.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[N:16]([CH2:17][C@H:18]2[CH2:20][C@@H:19]2[CH3:21])[C:10]2[C:11](=O)[NH:12][N:13]=[CH:14][C:9]=2[C:8]=1[CH3:22].[OH-].[Na+]>O>[Cl:3][C:11]1[N:12]=[N:13][CH:14]=[C:9]2[C:8]([CH3:22])=[C:7]([CH3:6])[N:16]([CH2:17][C@H:18]3[CH2:20][C@@H:19]3[CH3:21])[C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(=O)[nH]ncc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(Cl)nncc12
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 91.8 %

Procedure:
Phosphorus oxychloride (55 ml, 590 mmol) was added to 2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]-6,7-dihydropyrrolo[2,3-d]pyridazin-7-one (6.95 g, 30.1 mmol) and the mixture was stirred at 90° C. for 3.5 hours. After this time the reaction mixture was cooled to room temperature and poured dropwise into iced water. The aqueous solution was neutralized with 5N aqueous sodium hydroxide solution and extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated in vacuo. Hexane was added to the residue and the precipitate was collected by filtration to afford the desired compound (6.90 g, 92.0%) as a pale yellow powder.
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:11][C:9]([C:6]1[N:5]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:4]2[CH:3]=[CH:2][S:1][C:8]=2[CH:7]=1)=[O:10]
Reactant: COC(=O)c1cc2sccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: COC(=O)c1cc2sccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, methyl 4H-thieno[3,2-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-naphthalene to give 4-naphthalen-1-ylmethyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 306.3 ([M−H]−).