Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21](=[O:27])[C:22]([O:24]CC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:28]>CO>[NH2:28][C:22](=[O:24])[C:21]([NH:20][C:10]1[CH:11]=[C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:27]
Reactant: N
Reactant: CCOC(=O)C(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)C(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.4 %

Procedure:
To a solution of ethyl 2-((2-((tert-butoxycarbonyl)amino)-5-(thiophen-2-yl)phenyl)amino)-2-oxoacetate (0.2 g, 0.512 mmol) in MeOH (2 mL) was added methanolic ammonia (5 mL, 0.512 mmol, 1 equiv.) in a sealed tube. The reaction was stirred at room temperature for five h. The obtained white solid was filtered and dried to afford tert-butyl (2-(2-amino-2-oxoacetamido)-4-(thiophen-2-yl)phenyl)carbamate (0.11 g, 59% yield).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>>[Cl:14][C:15]1[CH:16]=[C:17]([C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2Cl)CC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
Tert-Butyl piperazine-1-carboxylate (0.931 g, 5 mmol) and 3-chloro-4-fluorobenzonitrile (0.785 g, 5.00 mmol) were combined, K2CO3 (0.898 g, 6.50 mmol) was added and the reaction mixture was stirred at 90° C. for 1 d. The mixture was triturated with ethyl acetate (3×5 mL) and the combined organic extracts were filtered. This was concentrated down to about 5-10 mL and subjected to flash column chromatograhy on silica gel (120 g SiO2, hexanes:ethyl acetate 1:0 to 4:1) to afford tert-butyl 4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate (1.264 g, 3.93 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.42 (s, 9H) 3.00-3.09 (m, 4H) 3.42-3.53 (m, 4H) 7.25 (d, J=8.59 Hz, 1H) 7.77 (dd, J=8.34, 2.02 Hz, 1H) 7.97 (d, J=2.02 Hz, 1H); [M+H] calc'd for C16H20ClN3O2, 322. found, 322.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:17]C)[CH:12]=2)[C:7]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.CO>C(Cl)Cl>[Br:5][C:6]1[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[CH:12]=[C:11]([OH:17])[CH:10]=[CH:9]2
Reactant: COc1ccc2c(-c3ccc(Cl)cc3)c(Br)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2cc(O)ccc2c(-c2ccc(Cl)cc2)c1Br
Temperature: -78 °C
Yield: 4664.2 %

Procedure:
A vessel was charged with boron tribromide (1 M in DCM, 0.7 mL, 0.7 mmol) and cooled to −78° C. 2-bromo-1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalene (0.1 g, 0.28 mmol) was added as a solution in DCM (0.5 mL). The reaction was allowed to slowly warm to room temperature over 3.5 h. This procedure was repeated twice on a scale of 1 g and 4.1 g of 2-bromo-1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalene with appropriate adjustments in the scale of other reagents. The three lots were combined, cooled to 0° C. and the volume of the reaction was slowly doubled with MeOH. After warming to room temperature, the mixture was concentrated in vacuo and the residue was taken up in EtOAc (150 mL), treated with saturated NaHCO3 (150 mL) and then small portions of solid NaHCO3 until the solution was pH ˜7. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (5-25% EtOAc/Hex) to afford 4.54 g (91%) of the title compound as a colorless syrup. LCMS-ESI+ (m/z): [M+H]+ calcd for C17H13BrClO: 348.64; found: 348.79.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:8]([CH2:12][O:13][CH2:14][CH:15]([OH:18])CO)[NH:9][C:10]=1[CH3:11])=[O:4].I([O-])(=O)(=O)=O.[Na+].[Cl-].[NH4+]>CO.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:8]([CH2:12][O:13][CH2:14][CH:15]=[O:18])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: CCOC(=O)C1=C(COCC(O)CO)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1=C(COCC=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
To an ice-cooled solution of 4-(2-chlorophenyl)-2-(2,3-dihydroxypropoxymethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester (IC, 13.0 g) in methanol (150 mL) was added a solution of sodium periodate (7.6 g) dissolved in water (100 mL) dropwise over 15 min. After stirring for 10 min, a saturated solution of ammonium chloride (25 mL) was added. Volatile materials were removed under reduced pressure, then ethyl acetate (200 mL) and water (100 mL) were added. The organic layer was separated and the aqueous layer was twice extracted with ethyl acetate (50 mL). The combined organic fractions was washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo to afford the title compound (11.8 g). Thin layer chromatography and proton NMR spectrum showed the crude title compound (ID) was sufficiently pure.
Reaction SMILES: FC1C=CC2C(C3CCNCC3)=NOC=2C=1.C([O-])([O-])=O.[K+].[K+].BrCCCO[C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][C:29]=1[O:37][CH3:38]>C(#N)C>[CH3:38][O:37][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:28]=1)[C:32]([NH2:34])=[O:33]
Reactant: COc1cc(C(N)=O)ccc1OCCCBr
Agent: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C(N)=O)c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10.0 mmol), K2CO3 (2.0 g) and 4-(3bromopropoxy)-3-methoxybenzamide (2.32 g, 8.0 mmol) in acetonitrile (80 ml) was heated at reflux for 5 hours. At the end of the reaction the solvent was evaporated. The residue was extracted into dichloromethane. The inorganic insolubles were filtered off. The dichloromethane was concentrated again. The crude residue was purified by flash chromatography over a silica gel column (55 g, SiO2; eluted with 1% methanol in dichloromethane, 1 l; 2% methanol in dichloromethane, 1 l). The material thus obtained weighed 2.93 g (84%) as white crystals. Recrystallization from hot ethanol (60 ml) gave 2.2 g of 4-[3-4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide as white crystals, m.p.=163-164° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([Cl:19])[CH:21]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Reactant: ClCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Yield: 87.6 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 3, from 5.08 g (23.4 mmol) of 4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester, 1.12 g (28.1 mmol) of 60% sodium hydride, 4.52 g (28.1 mmol) of 3-chlorobenzyl chloride in 60 mL DMF at 60° C. to give 7.01 g of the product as an off-white solid.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:8]=[C:9]([CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[CH2:10][NH:11][C:12](=[O:33])/[C:13](=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]2)=[C:21]([O:31][CH3:32])[CH:20]=1)/[CH2:14][CH2:15][CH2:16]Cl.[H-].[Na+].O>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[C:9]([CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14]/[C:13](=[CH:18]\[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)/[C:12]1=[O:33]
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NCc2ccc(N3CCOCC3)c(F)c2)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCN(Cc3ccc(N4CCOCC4)c(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
To a DMF (4 mL) solution of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl]benzylidene)valeric acid [3-fluoro-4-(morpholin-4-yl)benzyl]amide (135 mg), sodium hydride was added at 0° C. (40% mineral oil content, 35.6 mg) was added, and the reaction solution was allowed to be warmed to room temperature and agitated for 45 minutes. The reaction solution was cooled to 0° C. after confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After washed with a saturated saline solution the organic layer, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 113 mg of the title compound was obtained by purifying the obtained residue by silica gel chromatography (elution solvent; ethyl acetate->ethyl acetate:ethanol 90:10). The physical properties of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[F:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cccc(F)c3o2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cccc(F)c3O2)CC1
Yield: 87.3 %

Procedure:
To a degassed solution of tert-butyl 4-(7-fluorobenzofuran-2-yl)piperidine-1-carboxylate (3.4 g, 8.41 mmol) in EtOH (54.3 mL) was added 10% Pd—C (2.69 g, 2.52 mmol). Upon completion of addition, the reaction mixture was charged with 55 psi of H2 overnight. At the conclusion of this period, the Pd—C was filtered off through a pad of CELITE®, and the filter cake was rinsed with EtOH. The filtrate was concentrated under reduced pressure to afford Compound 3C as a colorless oil (2.36 g, 87% yield), which was used in next step without further purification. LC/MS (m/z)=344 (M+Na)+.
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[NH:17]2.BrCCC1CC1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[N:17]2[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2cccc(Br)c2C1=O
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 4-bromoisatin and (2-bromoethyl)cyclopropane with ethyl bromoacetate, the title compound was obtained as a yellow solid (68%): 1H NMR (300 MHz, CDCl3) δ 7.39 (t, 1H), 7.27(dd, 1H), 6.71 (dd, 1H), 4.47 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES+) m/z 312 (M+1), 314 (M+1), 334 (M+23) 336 (M+23).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:18]([N:29]3[C:33](=[O:34])[CH:32]=[CH:31][C:30]3=[O:35])=[CH:17][N:16]=2)[CH:8]=[CH:7][C:6]=1[N+:36]([O-:38])=[O:37]>>[NH2:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:18]([N:29]3[C:33](=[O:34])[CH2:32][CH:31]([N:2]([CH3:3])[CH3:1])[C:30]3=[O:35])=[CH:17][N:16]=2)[CH:8]=[CH:7][C:6]=1[N+:36]([O-:38])=[O:37]
Reactant: Nc1nc(NCCNc2ncc(N3C(=O)C=CC3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CNC
Product: CN(C)C1CC(=O)N(c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)C1=O

Procedure:
A large excess of dimethylamine was added to clean fractions of 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]-3-pyrroline-2,5-dione concentrated in vacuo.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:68][C:69]1[CH:83]=[CH:82][C:81]([F:84])=[CH:80][C:70]=1[CH2:71][C:72]1[O:76][N:75]=[C:74]([C:77](O)=[O:78])[CH:73]=1>CO.O1CCOCC1.ClCCl>[F:68][C:69]1[CH:83]=[CH:82][C:81]([F:84])=[CH:80][C:70]=1[CH2:71][C:72]1[O:76][N:75]=[C:74]([C:77]([NH:1][CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:78])[CH:73]=1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: CC[Si](C#CCCN=[N+]=[N-])(CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[Si](C#CCCNC(=O)c1cc(Cc2cc(F)ccc2F)on1)(CC)CC
Temperature: 60 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A mixture of (4-azidobut-1-ynyl)triethylsilane (1.00; 4.78 mmol) and triphenylphosphine (1.88 g; 7.16 mmol) in methanol (10 mL) was stirred at 60° C. for two hours. HCl (4N in dioxane was added to resulting solution and the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane. HATU (2.18 g; 5.73 mmol), N,N-diisopropylethylamine (2.06 mL; 4.78 mmol) and 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (1.26 g; 5.25 mmol) were added and the resulting mixture was stirred at room temperature overnight and diluted in dichloromethane, washed with sodium hydrogen sulphate, sodium carbonate and brine and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 1 to 60% ethyl acetate in heptane) to yield 0.901 g (47%) of 5-(2,5-difluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)isoxazole-3-carboxamide as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[CH3:25]O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([O:18][CH3:25])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
2-(2',4'-Difluoro-4-biphenylyl)propionic acid (2 g.), methanol (20 ml.) and concentrated sulphuric acid (0.6 ml.) were refluxed for 16 hours. Excess methanol was distilled in vacuo, the residue was diluted with water and the oil isolated in ether. Distillation gave methyl 2-(2',4'-difluoro-4-biphenylyl)propionate, b.p. 118°-120°C./0.2 mm.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[CH2:7]OS(=O)(=O)[O:4]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:13][CH:12]=1.C(N(CC)CC)C.CS(O)(=O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C@H:3]([OH:4])[CH2:7][NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:15][CH:16]=1
Reactant: O=S1(=O)OC[C@H](CCl)O1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C1COCCN1c1ccc(NC[C@@H](O)CCl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.6 %

Procedure:
Under an atmosphere of nitrogen to a solution of a 14.22 g of (R)-4-chloromethyl-[1,3,2]dioxathiolane 2,2-dioxide (MW=156.59; 1.37 eq.) in 190 mL of methylenechloride were added 12.68 g of 4-(4-amino-phenyl)-morpholin-3-one (APMO) (MW=192.22; 1 eq.) and 9.2 g (MW=101.12; 1.37 eq.) of triethylamine. The reaction mixture was stirred for 24 h at room temperature. Then the resulting suspension was concentrated in vacuo and the concentrate was dissolved in 400 mL of acetonitrile. 38 g of methane sulfonic acid (MW=96.11; 6.0 eq.). and 7.9 g of water (MW=18.02; 9.0 eq.) were added and the solution were stirred at ambient temperature. After stirring for 5 h, the reaction mixture was neutralized by addition of 50 g of sodium hydrogencarbonate (MW=84.01; 9.0 eq.). The resulting suspension was filtered and the cake washed with 200 mL of acetonitrile. The combined acetonitrile layers were concentrated in vacuo. To the concentrate were added 260 mL of 2-propanol and the mixture was stirred for 1 h at ambient temperature. The resulting slurry was cooled to 0° C. After stirring for at least 2 h at this temperature, the product was isolated by filtration and the filter cake was washed with 50 mL of 2-propanol. After drying in vacuo at 30° C., 11.75 g of the crystalline title compound (MW=284.75) were isolated. Yield=62.6%.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[N:13]([CH3:21])[C:12]2[CH:22]=[C:23]([CH2:26][NH2:27])[CH:24]=[CH:25][C:11]1=2)[CH3:9].[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38])([O-:30])=[O:29].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([N:10]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[N:13]([CH3:21])[C:12]2[CH:22]=[C:23]([CH2:26][NH:27][S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N+:28]([O-:30])=[O:29])(=[O:38])=[O:39])[CH:24]=[CH:25][C:11]1=2)[CH3:9]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN)ccc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine(0.6 ml) was added to a dichloromethane solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-aminomethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(1.0 g). The mixture was cooled with ice. 2-Nitrobenzenesulphonyl chloride(0.80 g) was added, and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=O)[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]([CH2:20][C:21]#[N:22])=[C:15]([C:18]#[N:19])[C:16]#[N:17].C(O)(=O)C.C([SiH](CC)CC)C>C(O)C>[NH2:17][C:16]1[N:22]=[C:21]2[O:12][C:7]3[C:8]([CH2:9][C:20]2=[C:14]([NH2:13])[C:15]=1[C:18]#[N:19])=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3
Reactant: N#CCC(N)=C(C#N)C#N
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: CC[SiH](CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1c(N)nc2c(c1N)Cc1cc([N+](=O)[O-])ccc1O2
Temperature: 66 °C
Yield: 60.1 %

Procedure:
5-nitrosalicylaldehyde (132 mmol, 22.00 g), 2-amino-1-propene-1,1,3-tricarbonitrile (132 mmol, 17.39 g), acetic acid (31 mL), and ethanol (500 mL) were combined and heated to reflux overnight. The resulting slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (350 mL) at 0° C. Triethylsilane (1.40 mol, 162 g, 225 mL) was added. The mixture was heated overnight at 66° C. The mixture was cooled and concentrated in vacuo. Triturating with methanol gave 2,4-diamino-7-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile as a yellow solid (22.48 g, 60% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.13 (d, J=9.0 Hz, 1H), 8.00 (s, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.70 (br s, 2H), 6.50 (bs, 2H), 3.82 (s, 2H); m/z 284 (M+H); Anal. Calcd for C13H9N5O3-0.5H2O: C, 53.43; H, 3.45; N, 23.96, found: C, 53.41; H, 3.17; N, 23.71.
Reaction SMILES: O.C(O)(C(F)(F)F)=O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:25][C:26](=[O:40])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=2[Cl:39])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18](OCC)[O:19]CC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([NH:25][C:26](=[O:40])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][C:30]=2[Cl:39])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]=[O:19]
Reactant: CCOC(COc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 0 °C
Reaction time: 48 h

Procedure:
40 mL water and 130 mL TFA was added to a solution of 11.40 g (0.023 mol) of N-[3-chloro-4-(2,2-diethoxy-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide in 130 mL chloroform at 0° C. and the mixture was stirred for 3.5 hours at 0° C. and for 48 hours at RT. The reaction mixture was neutralised with sat. aqueous sodium carbonate solution and exhaustively extracted with dichloromethane. The combined org. extracts were washed with water, dried over magnesium sulphate and evaporated down i. vac.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[S:7]([C:11]1[N:12]([CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:14][N:15]=1)([CH3:10])(=[O:9])=[O:8].CN(C)C=O>C(Cl)Cl>[S:7]([C:11]1[N:12]([CH2:16][C:17]([Cl:2])=[O:19])[CH:13]=[CH:14][N:15]=1)([CH3:10])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)c1nccn1CC(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1nccn1CC(=O)Cl
Temperature: 10 °C
Yield: 92.5 %

Procedure:
Phosphorus pentachloride (22.5 g.) dissolved in methylene chloride (150 cc.) is added dropwise and whilst cooling to 5° C., to a suspension of (2-mesyl-imidazol-1-yl)-acetic acid (12.3 g.) in methylene chloride (50 cc.). Dimethylformamide (2 cc.) is added thereafter and the mixture is then heated under reflux for 4 hours. The mixture is cooled to 10° C., the resulting solid is filtered off and washed with methylene chloride (15 ac.) to give (2-mesyl-imidazol- 1 -yl)-acetyl chloride (12.4 g.), m.p. 132°-133° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=O)c2cccc(Cl)n2)cc1

Procedure:
The intended compound was produced according to the method of Example 92 but using 6-chloropyridine-2-carboxylic acid and 4-isopropylaniline as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][C:17]([CH3:21])([CH:19]=[CH2:20])[C:16]3[N:15]=[C:14]([C:22]([OH:24])=[O:23])[CH:13]=[CH:12][C:11]=3[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][C:17]([CH2:19][CH3:20])([CH3:21])[C:16]3[N:15]=[C:14]([C:22]([OH:24])=[O:23])[CH:13]=[CH:12][C:11]=3[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)nc21
Agent: [Pd]
Solvent: CO
Product: CCC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)nc21
Yield: 28.7 %

Procedure:
The mixture solution of 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (100 mg, 0.3 mmol) and 10% palladium on active carbon (30 mg) in methanol (50 mL) was stirred at room temperature under hydrogen (14 psi) for 8 hours. The catalyst was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by preparative HPLC to afford 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (30 mg, 30%) as a yellow oil. MS (ESI+) [(M+H)+] 349.2.