Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[C@H:24]1[CH2:31][O:32]C(=O)C.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[C@H:24]1[CH2:31][OH:32]
Reactant: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1CO

Procedure:
Compound of example 130 (0.2 g, 0.04 mmol) in methanol (5 mL) was subjected to hydrolysis using a 10% NaOH solution (5 mL) according to the procedure in example 4 to get the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6](=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].O>CO.S(=O)(=O)(O)O>[C:1]([CH2:5][C:6](=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)CC(=O)CC#N
Temperature: 40 °C
Yield: 69.2 %

Procedure:
After 0.4 g of potassium cyanide was added at room temperature to a solution of 1 g of Methyl 4-chloro-3-oxobutanoate in 20 ml of methanol, the resulting mixture was warmed to 40° C. and maintained for further 8 hours. Thereafter, reaction solution was cooled and pH of the solution was adjusted to 3 by adding 10 ml of water and a few drops of concentrated sulfuric acid. After the mixture was extracted thrice with diethyl ether, total amount of which was 100 ml, the separated organic layers were combined and concentrated under reduced pressure to give 0.6 g of methyl 4-cyano-3-oxobutanoate (Purity: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH:9]2[CH:14]([OH:15])[C:13]([CH3:17])([CH3:16])[O:12][C:11]3[CH:18]=[CH:19][S:20][C:10]2=3)=[O:7])=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].[K+].[Br-]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]2[CH:14]([OH:15])[C:13]([CH3:17])([CH3:16])[O:12][C:11]3[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[S:20][C:10]2=3)=[O:7])=[CH:21][CH:22]=1
Reactant: CC1(C)Oc2ccsc2C(NC(=O)c2ccc(Cl)cc2)C1O
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(NC(=O)c2ccc(Cl)cc2)C1O

Procedure:
The title compound was prepared as described in Example 9 starting with 7-(4-chlorobenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.23 g, 3.64 mmol) and 90% nitric acid (1.5 mL) in acetic acid (20 mL) to give the product, 0.384 g (28%), as a yellow solid: mp 226°-229° C. dec; IR (KBr): 3315, 1655, 1535 and 1503 cm-1;MS: m/z 383 (MH+); 1H NMR (DMSO-d6): δ 1.25 (s, 3H), 1.44 (s, 3H), 3.90 (m, 1H, simplifies to d, J=8.9 Hz with D2O), 4.95 (m, 1H, simplifies to d, J=8.9 Hz, with D2O), 5.94 (d, J=6.0 Hz, 1H exchanges with D2O), 7.60 (d, J=8.6 Hz, 2H), 7.72 (s, 1H), 7.94 (d, J=8.6 Hz, 2H) and 9.11 (d, J=7.6 Hz, 1H, exchanges with D2O).
Reaction SMILES: N([C:3]1[N:8]=[C:7]([CH:9]([OH:11])[CH3:10])[CH:6]=[CH:5][N:4]=1)N.[CH2:12](O)C>CO.[Ni]>[NH2:8][C:3]1[CH:12]=[C:7]([CH:9]([OH:11])[CH3:10])[CH:6]=[CH:5][N:4]=1
Reactant: CCO
Reactant: CC(O)c1ccnc(NN)n1
Agent: [Ni]
Solvent: CO
Product: CC(O)c1ccnc(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-hydrazinopyrimidin-4-yl)ethanol (13a) was dissolved in ethanol (300 mL) and Raney-Ni (35 mL, 50% slurry in water) was added. The flask was flushed with argon, put under a hydrogen atmosphere (balloon) and stirred at room temperature overnight. The mixture was filtered and concentrated under vacuum to give a red oil that was dissolved in methanol and concentrated onto silica before being purified by silica flash chromatography (100% ethyl acetate to 20% methanol in ethyl acetate) to give the title compound (9.0 g) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][CH2:5][NH:6][CH2:7][CH:8](OC)OC.[F:19][C:20]([F:25])([F:24])[C:21](O)=[O:22]>O>[F:19][C:20]([F:25])([F:24])[C:21]([N:6]1[CH2:5][CH2:4][C:3]2[C:2]([F:1])=[CH:16][CH:15]=[C:14]([O:17][CH3:18])[C:13]=2[CH2:8][CH2:7]1)=[O:22]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(F)c(CCNCC(OC)OC)c1
Solvent: O
Product: COc1ccc(F)c2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
N-(2-Fluoro-5-methoxyphenethyl)-2,2-dimethoxyethanamine (3.0 g, 11.7 mmol, 1.0 eq.) was added dropwise to trifluoacetic anhydride (5.2 mL, 37.3 mmol, 3.2 eq.) at −15° C. The reaction mixture was allowed to warm to r.t. and stirred for 25 min. Then, trifluoroacetic acid (9.2 mL, 120.0 mmol, 10.3 eq.) was added and the resulting solution was heated to 40° C. for 18 hours. The reaction mixture was poured in cold water (100 mL). The mixture was extracted with DCM (3×50 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. To a solution under N2 of the residue in AcOEt/EtOH 1:1 (60 mL), palladium on activated carbon (10 wt. %, 400 mg) was added. The flask was evacuated and backfilled with H2 (3×). The black suspension was stirred at r.t. under an H2-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+50% AcOEt) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH2:24][CH3:25].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[C:23](=[O:26])[CH2:24][CH3:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@@H]1NCC[C@H]21
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(=O)N1CC[C@@H]2c3cccc(OC)c3CC[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
2.35 g (0.0116 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole were dissolved in 40 ml of CH2Cl2, 2.80 ml (0.0201 mol) of triethylamine were added thereto and a solution of 1.1 ml (0.0127 mol) of propionyl chloride in 10 ml of CH2Cl2 was added dropwise thereto at 25° under argon. The mixture was stirred at room temperature for 1 hour, then poured into water and extracted with CH2Cl2. The organic phase was dried with MgSO4, filtered and concentrated. By chromatography of the residue over silica gel with ether/ethyl acetate 1:1 there were obtained 3.0 g (99.7%) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-propionyl-1H-benzo[e]indole as a pale yellow, oily material which crystallized overnight; m.p. 81°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH:16]12[CH2:22][CH:20]([O:21]1)[CH2:19][NH:18][CH2:17]2>>[CH:20]12[CH2:22][CH:16]([O:21]1)[CH2:17][N:18]([C:13]([C:5]1[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=1)=[O:15])[CH2:19]2
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: C1NCC2CC1O2
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CC4CC(C3)O4)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 6-oxa-3-azabicyclo[3.1.1]heptane by following the similar procedure as described for intermediate-11a.
Reaction SMILES: NC(NC)NC(=O)CC1C(Cl)=CC=CC=1Cl.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[N:31]=[C:30]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])[N:29]=[C:28]([NH:41][C:42](NC(C)C)=O)[N:27]=2)=[CH:21][CH:20]=1)#[N:18]>CN(C=O)C>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][C:30]1[N:29]=[C:28]([NH:41][CH3:42])[N:27]=[C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=2)[N:31]=1
Reactant: CC(C)NC(=O)Nc1nc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Agent: CNC(N)NC(=O)Cc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Product: CNc1nc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 104 °C
Yield: 30.3 %

Procedure:
A mixture of N-[amino(methylamino)methyl]-2,6-dichloro-benzeneacetamide (4.15 g) and intermediate 6 (3.05 g) in DMF (25 ml) was stirred and refluxed for 20 hours. The solvent was evaporated, the residue dissolved in DMF (25 ml) and heated at 80° C. for 16 hours and at 100-108° C. for another 66 hours. The reaction mixture was cooled, quenched with water, extracted with diethyl ether, and washed with dilute NaOH, water, brine, and dried over K2CO3. The solvent was evaporated, and the residue was purified by flash column chromatography, and recrystallized from 2-propanol, and finally from methanol, yielding 0.78 g (12.6%) of 4-[[4-[(2,6-dichlorophenyl)methyl]-6-(methylamino)-1,3,5-triazin-2-yl]amino]benzonitrile (compound 7, mp. 229-230° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17](I)=[C:18](C)[N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.C(NC([C:31]1N=[CH:33][N:34]2[C:40]3[CH:41]=CC(F)=C[C:39]=3C(=O)N(C)[CH2:36][C:35]=12)=O)C#C.IN1C(=O)CCC1=O.C(NC(C)C)(C)C>C(O)(=O)C.C1COCC1>[CH:35]([N:34]([CH2:33][C:17]1[O:16][C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[C:7](=[O:23])[N:8]([CH3:22])[CH2:9][C:10]=23)=[N:19][CH:18]=1)[CH:40]([CH3:41])[CH3:39])([CH3:36])[CH3:31]
Reactant: Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)oc1I
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N(Cc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1)C(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 6 %

Procedure:
125 ml of a crude THF solution of 8-fluoro-3-(5-iodo-methyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one (prepared from 15.6 g (0.050 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid prop-2-ynylamide and 16.9 g (0.075 mol) of N-iodosuccinimide in 300 ml of acetic acid, subsequently completely freed from the solvents, dried azeotropically several times with toluene and dissolved in 500 ml of THF) were treated with 15.4 ml (0.109 mol) of diisopropylamine and stirred at room temperature for 42 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the brownish product was chromatographed over silica gel with dichloromethane/methanol 39:1 as the eluent. There was obtained 0.83 g (1 6%) of 3-(5-diisopropylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 176°-178°.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)[CH3:20])[CH2:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:37]I>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][O:28][CH3:37])=[CH:25][CH:26]=2)[CH3:20])[CH2:14][CH2:13]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](c1ccc(CO)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccccc2)OC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc([C@H](C)N2CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c3ccccc3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(hydroxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 0.02 mmol) in THF (5 mL) was added NaH (1.4 mg) at 0° C. After stirring for 1 h at rt, the mixture was cooled to 0° C., and CH3I (90 mg 0.78 mmol) was added. The mixture was stirred overnight at rt. The reaction was quenched with H2O, and the layers were separated. The aqueous layer was extracted with CH2Cl2 for two times. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(methoxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 71%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.[H-].[Na+].[C:14](O)(=O)[CH2:15][C:16](CC(O)=O)(C(O)=O)O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O.BrC(C)C.O1CCCC1>[CH:15]([O:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:7])[CH:9]=[CH:10][CH:11]=1)([CH3:16])[CH3:14]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COC(=O)c1cccc(O)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)Br
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 3-hydroxybenzoate (500 mg) in dimethylformamide (5 ml), 0.463 ml of 2-bromopropane and 197 mg of sodium hydride were added under ice-cooling, and the reaction solution was stirred at room temperature for 5 hours. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford a crude product as a yellow oil. To a solution of lithium aluminum hydride (250 mg) in tetrahydrofuran (3 ml), a solution of the crude product in tetrahydrofuran (2 ml) was added under ice-cooling, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution was added sodium sulfate decahydrate, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was Celite-filtered, and the filtrate was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-30:70)) to afford the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:24]2[CH:25]=[CH:26][NH:27][C:28]=2[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6,7-dichloro-3-(piperidin-4-yl)-1H-indole (0.80 g, 3.0 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.64 g, 3.1 mmol) and potassium carbonate (0.83 g, 6.0 mmol). The product was isolated as a tan foam. Yield 278 mg, 21%. mp 160°-165° C. FDMS m/e=441 (M+ of free base).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[C:15]([O:19][C:20]([NH:22][O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:15]([O:19][C:20]([N:22]([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12](=[O:14])[CH2:11][CH2:10][S:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: COc1ccc(SCCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(SCCC(=O)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of the compound prepared in Example 8(11) (106 mg) in DMF (5 ml), N-t-butoxycarbonyl-N-t-butoxycarbonyloxyamine (120 mg), EDC hydrochloride (106 mg) and 4-(dimethylamino)pyridine (6 mg) were added at 0° C. The mixture was stirred for 16 hours at room temperature. To the reaction solution, water was added and it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (211 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[NH2:10].[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.C1CCN2C(=NCCC2)CC1.[CH2:34]([O:36][C:37]([C:39]1([CH:42]=O)[CH2:41][CH2:40]1)=[O:38])[CH3:35]>C(O)C>[CH2:34]([O:36][C:37]([C:39]1([C:42]2[N:1]=[C:2]3[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]3[N:10]=2)[CH2:41][CH2:40]1)=[O:38])[CH3:35]
Reactant: CCOC(=O)C1(C=O)CC1
Reactant: COc1ccc[n+](N)c1N
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(c2nc3c(OC)cccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a stirred solution of diamino-3-methoxy-pyridinium salt of 4-nitrobenzoic acid (1 g, 7.14 mmol) in ethanol (10 mL) at 0° C., DBU (2.1 mL) was added followed by 1-formyl-cyclopropanecarboxylic acid ethyl ester (1.5 g, 10.71 mmol). After addition the reaction mixture was stirred at RT for 2 hours. The reaction mixture was concentrated, the obtained residue was diluted with EtOAc (100 mL), washed with water (20 mL×2), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (using 0 to 15% EtOAc in CH2Cl2 as eluent) to afford the title compound (800 mg, 53%, white solid). 1H NMR (400 MHz, CDCl3): δ=8.18-8.16 (d, J=6.4 Hz; 1H), 6.89 (t, J=7.2 Hz, 1H), 6.76 (d, J=8 Hz; 1H), 4.20-4.14 (m, 2H), 4.03 (s, 3H), 1.73-1.70 (m, 2H), 1.59-1.56 (m, 2H), 1.20 (t, J=6.8 Hz; 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([F:12])[C:6]=1[F:13])[CH3:2].[C:15]([O:19][C:20](=[O:27])[NH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([N:24]2[CH2:25][CH2:26][CH:22]([NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:27])[CH2:23]2)=[C:7]([F:12])[C:6]=1[F:13])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1ccc(F)c(F)c1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 70.1 %

Procedure:
A solution of 2,3,4-trifluorobenzoic acid ethyl ester (Example 1g, 3.70 g, 18.1 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.02 g, 21.6 mmol), and triethylamine (18.0 mL, 129 mmol) in acetonitrile (50 mL) is heated at 50° C. under nitrogen atmosphere for 4.5 hours. The solution is concentrated in vacuo and poured into a saturated NaHCO3 solution. The mixture is then extracted with chloroform, and the combined organic extracts are washed with brine, dried with Na2SO4, filtered, and the mixture concentrated in vacuo. The resulting residue is then purified by column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (4.70 g). 1H NMR (CDCl3): δ 7.59–7.49 (m, 1H), 6.35–6.26 (m, 1H), 4.88–4.84 (bd, 1H), 4.39–4.28 (m, 3H), 3.81–3.50 (m, 3H), 3.48–3.34 (m, 1H), 2.32–2.15 (m, 1H), 2.02–1.76 (m, 1H), 1.45 (s, 9H), 1.40 (t, 3H).
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[NH:6][NH3+:7].CO[CH:14](OC)[CH2:15][C:16](=O)[CH3:17]>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]([N:6]2[CH:14]=[CH:15][C:16]([CH3:17])=[N:7]2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: COC(CC(C)=O)OC
Reactant: [NH3+]Nc1ccc(F)c(Br)c1
Agent: [Cl-]
Solvent: CCO
Product: Cc1ccn(-c2ccc(F)c(Br)c2)n1
Yield: 20.7 %

Procedure:
To a solution of (3-bromo-4-fluoro-anilino)ammonium chloride [CAS: 1166990-89-1](5412 mg, 22.41 mmol) in ethanol (30 mL) was added 4,4-dimethoxybutan-2-one (3.12 mL, 23.53 mmol), and the reaction was heated to reflux for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was loaded onto silica (50 g, SNAP cartridge), eluting with EtOAc in isohexane from 0% to 25%. Fractions containing the faster running desired product were combined and concentrated in vacuo to give one of the isomers 1-(3-bromo-4-fluoro-phenyl)-3-methyl-pyrazole (D86) (1249 mg, 4.65 mmol, 20.8% yield) (1.26 g);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=1[Cl:26]>>[Cl:18][C:19]1[CH:24]=[C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: Clc1ccc(I)cc1Cl
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1,2-dichloro-4-iodobenzene according to the coupling protocol described in example 2. 1H NMR (DMSO-d6): δ 8.43 (s, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.13 (dd, J=8.6, 2.3 Hz, 1H), 7.06 (m, 2H), 6.93 (d, J=2.4 Hz, 1H), 6.89 (dd, J=8.8, 2.7 Hz, 1H), 3.27 (s, 3H), 1.98 (m, 4H), 0.82 (t, J=7.3 Hz, 6H); MS (ESI) m/z 379/381/383 ([M+H]+); MS (ESI) m/z 377/379/381 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10][C:11](=O)[CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.[OH-].[Na+]>COCCOC>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[NH:9][C:11]([CH:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc(Br)cc1NC(=O)C(c1ccccc1)N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=c1[nH]c(C(c2ccccc2)N2CCCC2)nc2cc(Br)sc12
Temperature: 150 °C
Yield: 95.5 %

Procedure:
A mixture of 5-bromo-3-{[phenyl(pyrrolidin-1-yl)acetyl]amino}thiophene-2-carboxamide (320 mg), 2M aqueous sodium hydroxide solution (3 mL) and 1,2-dimethoxyethane (1 mL) was stirred with heating in a microwave reactor at 150° C. for 30 min. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (292 mg) as a pale-yellow solid.