Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[OH:27])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:35](I)[CH3:36]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[O:27][CH2:35][CH3:36])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(F)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
In a 4 mL screw cap vial fitted with a small egg-shaped stir bar, were combined 5-fluoro-2-(4-fluoro-2-hydroxybenzoylamino)-N-(5-chloropyridin-2-yl)benzamide (200 mg, 0.49 mmol) and powdered anhydrous K2CO3 (103 mg, 0.74 mmol, 1.5 eq) in 0.5 mL of dry dimethylformamide (DMF). Ethyl iodide (115 mg, 0.74 mmol) was then added, the vial was capped, and the slurry heated to 50° C. with vigorous stirring overnight. The slurry was diluted with 20 mL water and extracted into 15 mL of dichloromethane. The organic layer was then washed with 20 mL portions of saturated NaHCO3, water, and brine; then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in a few mL of dichloromethane and purified by radial chromatography, eluting using hexanes, then 4:1 hexanes:EtOAc, to provide 135 mg (63%) of the title compound as pinkish-white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=O.CN>O1CCCC1>[CH3:20][NH:22][C:17](=[O:19])[CH2:16][N:15]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C(O)Cn1c(-c2ccccn2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccccn2)nc2cccnc21
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of 2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.44 g, 0.0096 mole), 1,1'-carbonyldiimidazole (1.56 g, 0.0096 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 5 hours. A solution of 1M monomethylamine in tetrahydrofuran (15 ml) was added and the reaction stoppered and stirred overnight. The tetrahydrofuran was evaporated in vacuo and the residue triturated in water (30 ml) and filtered. The filter cake was again triturated in water (30 ml) and filtered, giving 1.94 g (76%) of solid, mp 228°-230° C. Recrystallization from tetrahydrofuran-methanol gave 1.49 g of a white solid, mp 228.5°-230° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=1
Reactant: CCCCCCC(O)(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC=C(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 27.6 %

Procedure:
To a solution of 3-{4-[1-hydroxy-1-(4′-trifluoromethyl-biphenyl-4-yl)-heptyl]-benzoylamino}-propionic acid methyl ester (150 mg, 0.277 mmol) in dichlorormethane (10 mL) is added TFA (160 mg, 1.4 mmol). 5 min later, triethylsilane (161 mg, 1.4 mmol) is added dropwise. 5 h later, the reaction mixture is diluted with ethyl acetate, washed with 1N NaOH, water, brine, dried over sodium sulfate, concentrated and purified by column chromatography to give the title compound (40 mg).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:5][CH:4]=1)#[N:2].C(O)(=[O:28])C.B(F)(F)F.[OH-].[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:5][CH:4]=1)(=[O:28])[NH2:2]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C#N)cc23)c(OC)c1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cccc3ccc(C(N)=O)cc23)c(OC)c1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A mixture of methyl 4-(7-cyanonaphth-1-ylmethyl)-3-methoxybenzoate (394 mg), acetic acid (0.68 ml) and BF3 -etherate (0.22 ml) was heated to 120° C. for 15 min. After cooling, to the reaction mixture was added methylene chloride (50 ml) and 6N sodium hydroxide (3.5 ml) and it was stirred for 10 min. The aqueous layer was extracted with methylene chloride. The combined organic extract was washed (brine) and dried (MgSO4). Evaporation and trituration with hot ethyl acetate afforded methyl 4-(7-carbamoylnaphth-1-ylmethyl)-3-methoxybenzoate (262 mg, 63%) as a white solid; mp 215.0°-216.5° C.; MS(CI), m/e=350(M+H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[C:4]2[C:19](=[O:23])[NH:20][C:21](=[O:22])[C:3]=12>COC(O)C>[OH:16][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:20]1[C:21](=[O:22])[C:3]2[C:4](=[C:5]([NH2:18])[C:6]3[C:7](=[O:17])[C:8]4[C:13]([C:14](=[O:16])[C:15]=3[C:2]=2[NH2:1])=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:19]1=[O:23]
Reactant: Nc1c2c(=O)[nH]c(=O)c2c(N)c2c(=O)c3ccccc3c(=O)c12
Agent: COC(C)O
Product: Nc1c2c(=O)c3ccccc3c(=O)c2c(N)c2c(=O)n(CCCCCCO)c(=O)c12
Temperature: 120 °C
Yield: 83 %

Procedure:
A suspension of 1,4-diaminoanthraquinone-2,3-dicarboximide (15.0 parts) and 6-aminopropanol (28.6 parts) in methoxyethanol (200.0 parts) was heated at 120° C. for 6 hours. The reaction mixture was cooled to room temperature, followed by cooling in ice for several hours. Thereafter the resulting mixture was filtered and washed with methanol (600 parts). The product obtained was dried in vacuo for 8 hours at 45° C. yielding N-(6'-hydroxyhexyl)1,4-diaminoanthraquinone-2,3-dicarboximide (17.1 parts, 83%); m.p.: 210°-211° C.
Reaction SMILES: C(OC(N[C@H](C(NCC(NC[C:28]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[C:38]2[C:29]=1[O:30][C:31]1[C:32]([CH2:48][C:49]([O:51]CC3C=CC=CC=3)=[O:50])=[C:33]([O:46][CH3:47])[CH:34]=[CH:35][C:36]=1[C:37]2([CH3:45])[CH3:44])=O)=O)[C@@H](C)OC(C)(C)C)=O)C1C=CC=CC=1>[Pd].CO>[CH3:47][O:46][C:33]1[CH:34]=[CH:35][C:36]2[C:37]([CH3:45])([CH3:44])[C:38]3[C:29]([O:30][C:31]=2[C:32]=1[CH2:48][C:49]([OH:51])=[O:50])=[CH:28][C:41]([O:42][CH3:43])=[CH:40][CH:39]=3
Reactant: COc1ccc2c(c1CNC(=O)CNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)Oc1c(ccc(OC)c1CC(=O)O)C2(C)C

Procedure:
A solution of 0.67 g (0.84 mmol) of benzyl 5-[(N-benzyloxycarbonyl-O-tert-butyl-L-threonyl-glycyl)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate in 100 ml of e methanol was treated with 140 mg of palladium/charcoal (10%) and stirred under hydrogen for 1. hour. Thereafter, the catalyst was filtered off and the filtrate was brought to dryness. 0.46 g of 5-[O-tert-butyl-L-threonyl-glycyl)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetic acid was obtained as the residue in the form of a colourless amorphous powder; IR 3400-2500, 1675, 1606, 1578, 1531, 1493 cm-1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].I[CH2:14][C:15]([CH3:17])=[CH2:16]>C1COCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)([OH:5])[CH2:16][C:15]([CH3:17])=[CH2:14]
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: C=C(C)CI
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCCl)c1ccc(F)cc1
Reaction time: 1 h
Yield: 76 %

Procedure:
The reaction mixture was mildly exothermic, and began to reflux spontaneously. After the refluxing had ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1-(4-fluorophenyl)propan-1-one not reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2×500 mL). The combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1, to give 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (17 g, yield 76%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: Cc1oc(=O)oc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1oc(=O)oc1CBr
Yield: 72.6 %

Procedure:
3.42 g of 4,5-dimethyl-1,3-dioxolen-2-one [compound of formula (III') in which R is methyl, prepared in accordance with the procedure described in Tetrahedron Letters, pages 1701-1704, (1972)] was dissolved in 150 ml of carbon tetrachloride. To the solution were added 5.34 g of N-bromosuccinimide and a catalytic amount of α,α'-azobisisobutyronitrile. The mixture was heated under reflux for 15 minutes. The reaction mixture was cooled with ice, and the insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give a syrupy residue. The residue was distilled under reduced pressure, and a fraction having a boiling point of 115° to 120° C./5 mmHg was recovered. Thus, 4.2 g (yield 73%) of the captioned compound having the following properties was obtained as a colorless liquid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C([Cl:8])=O.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([CH:40]([OH:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([CH3:11])[C:13]=1[C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([C:40](=[O:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1c(Cl)c2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
DMSO (0.06 mL, 0.9 mmol) was added to a solution of oxalyl chloride (0.14 mL, 2.0 M, 0.28 mmol, in 4 ml, of methylene chloride) and the solution was then stirred for 10 minutes under a nitrogen atmosphere at −78° C. A solution of N-[(1-methylindole-2-carbonyl) valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (85 mg, 0.18 mmol) in dry methylene chloride (1 mL), was added dropwise to the reaction mixture and the mixture was stirred for 15 minutes at −78° C. Triethylamine (0.15 ml, 1.08 mmol) was added dropwise to the reaction mixture and the mixture was stirred for 10 minutes at −78° C. and then was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous layer was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution and brine, dried over sodium sulfate, and concentrated to give a brown foam. The foam was triturated with ether to afford the title product as a light brown powder (64 mg). MS for C24H31ClFN3O5: (MH)−=494/496.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[O:21][C:20]=2[CH3:30])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[O:21][C:20]=2[CH3:30])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3ccccn3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccn2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of cyclohexyl[2-methyl-5-(pyridin-2-yl)furan-3-yl]methanol (271 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (183 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.5 mL) and 1,1′-(azodicarbonyl)dipiperidine (505 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give methyl 4-{cyclohexyl[2-methyl-5-(pyridin-2-yl)furan-3-yl]methoxy}benzoate as an amorphous compound. The obtained methyl 4-{cyclohexyl[2-methyl-5-(pyridin-2-yl)furan-3-yl]methoxy}benzoate was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (174 mg, 46%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([NH2:34])[CH:27]=1)=[O:4].C1COCC1.CO>O>[NH2:34][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[C:32]#[N:33])[CH2:25][N:6]1[C:7](=[O:24])[CH2:8][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:12])=[O:13])[CH2:10][CH:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CN2C(=O)CN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2C(=O)O)cc1N
Reaction time: 16 h
Yield: 39.6 %

Procedure:
Water (5 drops) is added to a solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (30 mg, 0.05 mmol), EXAMPLE 99, in a 1:1 mixture of THF/MeOH (2 mL). At ambient temperature, LiOH monohydrate (7 mg, 1.66 mmol) is then added. After 16 h, the reaction mixture is diluted with water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 10 mg (34%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.18 (dd, J=12.1, 3.5 Hz, 1H), 3.61 (d, J=16.0 Hz, 1H), 3.77 (d, J=16.0 Hz, 1H), 3.95 (d, J=16.0 Hz, 1H), 4.06 (d, J=12.1 Hz, 1H), 4.14 (m, 1H), 6.40 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.57 (dd, J=8.6, 1.9 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.18 (s, 1H), 8.33 (s, 1H) ppm; MS (ISP loop): m/z 505 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].N.C([O-])(=O)C1C(=CC=CC=1)C([NH2:21])=O.[NH4+]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:10]([NH2:21])=[O:11])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NC(=O)c1ccccc1C(=O)[O-]
Agent: N
Agent: [NH4+]
Product: NC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 300 °C
Reaction time: 0.5 h

Procedure:
3-Nitrophthalic anhydride (10.0 g, 50 mmol) was added in portions over 20 minutes to concentrated aqueous ammonia solution (15 ml), and the mixture was stirred at 300° C. for a further 30 minutes. The crystalline mass of ammonium phthalamate, deposited upon cooling the pale yellow solution, was collected and redissolved in a minimum amount of warm water. Concentrated hydrochloric acid (4.5 ml) was added dropwise, with stirring, and the resulting paste was washed with water, and dried in vacuo to give 3-nitrophthalamic acid as a fine white powder. (9.01 g, 83%), m.p. 217° C. Found: C, 45.76; H, 2.79; N, 13.21. C8H6N2O5 requires C, 45.71; H, 2.86; N, 13.33%; vmax /cm-1 3466.52, 3321.84, 1668.64, 1604.98, and 1525.89; δH (d6 -DMSO, 200 MHz) 7.75 (1H, br s, CONH), 7.8 (1H, t, Ar-5H), 8.16 (1H, brs, CONH), 8.2 (1H, d, Ar-6H), 8.3 (1H, d, Ar-4H); δC (d6 -DMSO) 127.32, 130.06, 132.28, 133.49, 134.78, 147.71, 166.25, and 166.60; m/z (EI) 192 (M+ -1), 177, 149, 103, 75.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[NH:30][C:29](=[O:31])[C@@H:28]([NH:32]C(OC(C)(C)C)=O)[CH2:27][C:26]2[CH:40]=[C:22]([CH:23]=[CH:24][C:25]=2[OH:41])[C:21]2=[CH:42][C:17](=[C:18]([OH:43])[CH:19]=[CH:20]2)[CH2:16][C@@H:15]([C:44]([NH:46][CH2:47][CH2:48][CH2:49][C@H:50]([NH2:58])[CH2:51][C:52]([NH:54][CH2:55][CH2:56][NH2:57])=[O:53])=[O:45])[N:14]([CH2:59][CH3:60])[C:13]1=[O:61])(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[NH2:32][C@H:28]1[CH2:27][C:26]2[CH:40]=[C:22]([CH:23]=[CH:24][C:25]=2[OH:41])[C:21]2=[CH:42][C:17](=[C:18]([OH:43])[CH:19]=[CH:20]2)[CH2:16][C@@H:15]([C:44]([NH:46][CH2:47][CH2:48][CH2:49][C@H:50]([NH2:58])[CH2:51][C:52]([NH:54][CH2:55][CH2:56][NH2:57])=[O:53])=[O:45])[N:14]([CH2:59][CH3:60])[C:13](=[O:61])[C@H:12]([CH2:11][CH2:10][CH2:9][NH2:8])[NH:30][C:29]1=[O:31]
Reactant: CCN1C(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H]1C(=O)NCCC[C@H](N)CC(=O)NCCN
Agent: Cl
Solvent: C1COCCO1
Product: CCN1C(=O)[C@H](CCCN)NC(=O)[C@@H](N)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H]1C(=O)NCCC[C@H](N)CC(=O)NCCN
Reaction time: 2 h

Procedure:
0.1 ml of 4M solution of hydrogen chloride in dioxane is added to a solution of 7.5 mg (0.009 mmol) of tert-butyl{3-[(8S,11S,14S)-8-[({(4S)-4-amino-6-[(2-aminoethyl)amino]-6-oxohexyl}amino)carbonyl]-14-[(tert-butoxycarbonyl)amino]-9-ethyl-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-11-yl]propyl}carbamate (Example 204A) in 0.1 ml of dioxane at 0° C. After 2 h at RT, the reaction solution is concentrated in vacuo, coevaporated with dichloromethane several times and dried under high vacuum. The residue is mixed with diethyl ether and concentrated.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([NH:20][C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: COc1ccc(N)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccnc1Nc1ccc(OC)nc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 90.4 %

Procedure:
5.0 g (29 mmol) of methyl 2-chloronicotinate and 4.3 g (35 mmol) of 6-methoxypyridine-3-amine were dissolved in toluene (80 mL), and 16.1 g (50 mmol) of cesium carbonate, 1.3 g (1.5 mmol) of tris(dibenzylideneacetone)dipalladium(0), and 1.8 g (3.1 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were added to the solution. The resulting mixture was heated and stirred for 72 hours at 90° C. The solvent was distilled off from the reaction mixture, water and ethyl acetate were added to the residue, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic phase was dried and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 1:1), and thus 6.8 g of the title compound was obtained as a pale yellow viscous product (yield: 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: Fc1ccccc1N1CCNCC1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 85%). 1H NMR (200 MHz, CDCl3): δ 3.17-3.20 (m, 4H), 3.77-3.80 (m, 4H), 4.13 (s, 3H), 6.97-7.09 (m, 4H), 7.24-7.41 (m, 3H), 7.81-7.82 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][CH3:14])[N:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][CH3:14])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: CCn1nc([N+](=O)[O-])cc1C(=O)OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCn1nc(N)cc1C(=O)OC
Reaction time: 8 h

Procedure:
To 2-ethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (526, 1.30 g, 6.53 mmol) in methanol (60.0 mL) was added 20% Pd(OH)2/C (0.1 g). The reaction was stirred under an atmosphere of hydrogen overnight. The reaction was filtered and concentrated to give a light yellow solid (527, 1.0 g, 90.6%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]2=[O:23])[CH3:10])[CH2:4][CH2:3]1.[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([N:14]=[CH:13][C:12](=[O:23])[N:11]2[CH:9]([CH3:10])[CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:35][C:33]3[CH:32]=[CH:31][C:28]4[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)[CH2:3][CH2:4]2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(=O)n(C(C)CN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(C(C)CN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 43 %

Procedure:
1-[2-(4-aminopiperidin-1-yl)-1-methylethyl]-7-methoxyquinoxalin-2(1H)-one (Intermediate 221) (160 mg crude, 0.51 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (91 mg, 0.51 mmol), and sodium triacetoxy borohydride (320 mg, 1.5 mmol) were reacted as described according to Example 69. Chromatography on silica gel eluting with 5% methanol/dichloromethane containing 0.25% ammonium hydroxide gave 105 mg (63%) of the title compound as an off-white solid.
Reaction SMILES: COC([C:5]1[S:6](=[O:21])(=[O:20])[N:7]([CH2:16][CH:17]([F:19])[F:18])[C:8]2[C:13]([C:14]=1[OH:15])=[N:12][CH:11]=[CH:10][N:9]=2)=O.Cl>C(O)C>[F:19][CH:17]([F:18])[CH2:16][N:7]1[C:8]2[C:13](=[N:12][CH:11]=[CH:10][N:9]=2)[C:14](=[O:15])[CH2:5][S:6]1(=[O:20])=[O:21]
Reactant: COC(=O)C1=C(O)c2nccnc2N(CC(F)F)S1(=O)=O
Agent: Cl
Solvent: CCO
Product: O=C1CS(=O)(=O)N(CC(F)F)c2nccnc21
Temperature: 150 °C
Yield: 47.6 %

Procedure:
To a solution of 1-(2,2-difluoro-ethyl)-4-hydroxy-2,2-dioxo-1,2-dihydro-2-λ-6-thia-1,5,8-triaza-naphthalene-3-carboxylic acid methyl ester (0.520 g) (Example 9.3) in ethanol (3 ml) was added aqueous hydrochloric acid (2M) (1 ml). The mixture was heated in a microwave for 20 minutes at 150° C. twice. The reaction mixture was concentrated to give 1-(2,2-difluoro-ethyl)-2,2-dioxo-2,3-dihydro-1H-2-λ-6-thia-1,5,8-triaza-naphthalen-4-one (0.203 g). 1H-NMR (400 MHz, CDCl3): 8.66 (d, 1H), 8.61 (d, 1H), 6.03-6.33 (m, 1H), 4.61 (s, 2H), 4.54-4.61 (m, 2H) ppm.