Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10].C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(I)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(Br)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
2-Bromo-5-iodopyridine (2.5 g, 8.8 mmol) was dissolved under nitrogen in 50 ml THF. Bis-(triphenylphosphine)-palladium(II)dichloride (618 mg, 880 μmol, 0.1 equiv.), ethynyltrimethylsilane (950 mg, 1.34 ml, 9.6 mmol, 1.1 equiv.), triethylamine (1.78 g, 2.44 ml, 17.6 mmol, 3 equiv.) and copper(I)iodide (84 mg, 440 μmol, 0.05 equiv.) were added and the mixture was stirred for 3 hours at 50° C. The reaction mixture was cooled and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with an ethyl acetate:heptane gradient 0:100 to 15:85. The desired 2-bromo-5-trimethylsilanylethynyl-pyridine (1.95 g, 7.7 mmol, 87% yield) was obtained as a white solid, MS: m/e=254.1/256.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:15]3[N:16]([C:20]([O:22]C(C)(C)C)=O)[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.[C:36]([O:43][CH2:44][CH3:45])(=[O:42])[CH2:37][CH2:38]C([O-])=O.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:15]3[N:16]([C:20](=[O:22])[CH2:38][CH2:37][C:36]([O:43][CH2:44][CH3:45])=[O:42])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3C(=O)OC(C)(C)C)nc1Cl
Reactant: CCOC(=O)CCC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(=O)N1CCOc2cc(NC(=O)c3nc(Cl)c(CC)[nH]3)ccc21
Yield: 38.3 %

Procedure:
The same operation as in Example (93a) was performed using tert-butyl 7-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate obtained in Example (95c) (0.11 g, 0.27 mmol), a 4 N hydrochloric acid/ethyl acetate solution (8 ml, 32 mmol), monoethyl succinate (150 mg, 1 mmol), WSC hydrochloride (288 mg, 1.5 mmol), N,N-diisopropylethylamine (0.52 g, 4 mmol) and DMAP (10 mg). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1, 2/1, 2/3, 0/1) gave 45 mg of the title compound as a light yellow solid (38%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](O)=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](=[O:44])[NH:53][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: NCc1ccccc1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)NCc4ccccc4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 50.0 mg of (2S,4R,5R)-2-carboxymethyl-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 9b) are reacted with benzylamine to afford the title compound as yellow oil. Rf=0.50 (dichlormethane-methanol 9:1); Rt=5.17.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:2]=1.[C:12]1(O)[CH:17]=[CH:16]C=[CH:14][CH:13]=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([C:7]([O:9][C:10]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C)cc1
Reactant: Oc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: Cc1ccc(C(=O)Oc2ccccc2)cc1
Temperature: 190 °C
Reaction time: 6 h

Procedure:
A thermometer and Claisen head were attached to a three-necked flask having an internal volume of 500 ml. A receiver having a gage was attached to the Claisen head via a condenser to make a distillation apparatus. Into this apparatus were charged methyl p-toluate 75 g (0.50 mole), phenol 376 g (4.0 mole) and titanium tetraisopropoxide 1.42 g (5.0 mmole). The contents were reacted with stirring in a 190° C. bath. The reaction was conducted at atmospheric pressure for six hours while removing methanol produced in the reaction. Then, the temperature of the bath was elevated to 196° to 198° C., and phenol was removed by distillation in an amount of as much as 150 g. The remaining phenol and methyl p-toluate were removed by distilling under vacuum (85 mmHg). Then, the vacuum pressure was decreased to obtain phenyl p-toluate. The boiling point was 183° to 185° C./18 mmHg, and the product was a slightly yellow colored white solid. The yield was 72.98 g, (69% in terms of methyl p-toluate). The melting point was 74° to 76° C.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O.CCCCCC>O1CCCC1>[F:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:36][C:35]1[CH:34]=[C:33]([F:32])[CH:40]=[CH:39][CH:38]=1
Reactant: O=Cc1cccc(F)c1
Reactant: FCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: FCCCC=Cc1cccc(F)c1
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a mixture of 4-fluorobutyltriphenylphosphonium bromide 273 g (660 mmol) and tetrahydrofuran (abbreviated THF hereinafter) 1000 ml, potasium-tert-butoxide 88 g (684 mmol) was added under ice cooling and stirred for one hour. Then, under ice cooling, a solution of 3-fluorobenzaldehyde 74 g (596 mmol) in THF 200 ml was added dropwise, and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into hexane 1000 ml, and the crystals deposited were filtered off. The filtrate was concentrated, and distilled (93° C./6 mmHg) to obtain 3-(5-fluoro-1-pentenyl)fluorobenzene 86 g. (Yield:79.6%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][NH:19][C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].Br[CH2:24][C:25]#[N:26].[H-].[Na+]>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:24][C:25]#[N:26])[C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=C2SCN(CC#N)C2=O)cc(C(C)(C)C)c1O
Yield: 40.7 %

Procedure:
7.03 g of 5-{[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-thiazolidinone and 2.64 g of bromoacetonitrile were reacted in the presence of 0.97 g of 60% sodium hydride in mineral oil and 330 ml of tetrahydrofuran. Work-up of the reaction mixture provided 3.21 g of the desired title product, m.p. 186°-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:18][CH:17]=3)=[O:15])[C:6]=2[CH:27]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:27][C:6]=2[C:7]=1[C:14](=[O:15])[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:20][CH:21]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCC#N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCC#N)cc1
Temperature: 32.5 °C
Reaction time: 3 h

Procedure:
4.0 g of (5-amino-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VI) is dissolved in 40 ml of dichloromethane. The mixture is warmed to 30-35° C. and 1.05 g of pyridine is added at this tempereature in 5 minutes. At this temperature 1.5 g of methane sulfonyl chloride is added in 5 minutes and the mixture is stirred at 30-35° C. for 3 hours: The mixture is cooled to 20° C. and washed with 2×15 ml of water, 2×15 ml of NaHCO3 of 5% and 1×15 ml of water. The phases are separated and the dichloromethane is evaporated.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([CH:11]=1)[NH2:10])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:25](OCCC(C)C)=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:11]=[C:9]2[C:8]([CH:12]=[N:25][NH:10]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a solution of 5-tert-butyl-2-methylaniline (2.48 g, 15.2 mmol) in CHCl3 (40 ml) at 0° C. was slowly added acetic anhydride (3.3 ml, 34.9 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. Potassium acetate (446 mg, 4.55 mmol) was added followed by slow addition of isoamyl nitrite (4.4 ml, 32.6 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc and washed with water, sat'd NaHCO3 and brine then dried over MgSO4 and concentrated. The residue was dissolved in THF/MeOH (1:1, 40 mL) and 10% NaOH (4.5 mL) was added. The reaction mixture was stirred at room temperature for 10 min then neutralized with 1.0 M HCl, diluted with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to afford 1.02 g (39%) of 6-tert-butyl-1H-indazole as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.03 (s, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.48 (s, 1H), 7.29 (dd, J=8.7, 1.5 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:35]=[CH:34][C:11]([C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[CH:18]=[CH:17][C:16]=3[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:13])=[CH:10][CH:9]=2)[CH2:3]1.[N+:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45]([NH:48][C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)(=[O:47])=[O:46])=[CH:41][CH:40]=1)([O-:38])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N+:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45]([N:48]([C@H:2]2[CH2:6][CH2:5][N:4]([CH2:7][C:8]3[CH:35]=[CH:34][C:11]([C:12]([NH:14][C:15]4[CH:20]=[C:19]([C:21]5[S:22][CH:23]=[CH:24][CH:25]=5)[CH:18]=[CH:17][C:16]=4[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:13])=[CH:10][CH:9]=3)[CH2:3]2)[C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)(=[O:46])=[O:47])=[CH:41][CH:40]=1)([O-:38])=[O:37]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN2CC[C@@H](O)C2)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cccnc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN2CC[C@H](N(c3cccnc3)S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
To a solution of 243 (0.98 g, 1.81 mmol) in THF (10 mL) at 0° C., was added compound 246 (0.61 g, 2.17 mmol), triphenylphosphine (0.76 g, 2.89 mmol) and diethyl azodicarboxylate (DEAD) (0.51 g, 2.90 mmol), the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was partitioned between EtOAc and H2O, organic phase was collected, washed successively with saturated NH4Cl and brine, dried over MgSO4, filtered and concentrated to give a light brown oil which was purified by flash chromatography (eluent: 50% AcOEt in hexanes to 100% AcOEt) to give intermediate 247 (0.65 g, 47% yield).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[N:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.Cl.[NH+]1C=CC=CC=1>O>[CH:22]1[C:23]2[N:11]([C:4]3[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(OC)c1-n1c2ccccc2c2ccccc21
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Oc1cccc(O)c1-n1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 60.6 %

Procedure:
9-(2,6-Dimethoxyphenyl)-9H-carbazole (10.00 g) and pyridinium hydrochloride (50.0 g) were placed in the 250 ml round-bottom flask, equipped with magnetic stirrer and immersed in the pre-heated oil bath (230° C., 45 min). The reaction mixture was cooled down to room temperature, diluted with 400 ml water and extracted with ethyl acetate (3×150 ml). Organic fractions were combined, dried over sodium sulfate anhydrous, filtered and evaporated, providing 5.5 g of pure 2-carbazol-9-yl-benzene-1,3-diol. 2-Carbazol-9-yl -benzene-1,3-diol (5.5. g, 20 mmol) and pyridine (6.0 ml) were dissolved in 50 ml DCM (anhydrous) and cooled in the ice bath. Solution of triflic anhydride (6.0 ml) in 20 ml DCM was added dropwise upon intensive stirring, reaction mixture was warmed up to room temperature and stirred overnight. The reaction mixture was washed with water, dried over sodium sulfate, filtered and evaporated, providing crude triflate. Pure material (white solid, 6.0 g) was obtained by column chromatography on silica gel (eluent hexane/ethyl acetate 1/1 mixture).
Reaction SMILES: Br[CH2:2][CH:3]=[CH2:4].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=2)[N:9]=[CH:8][C:7]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([NH:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:20])([F:21])[F:19])=[CH:13][N:12]=2)[N:9]=[CH:8][C:7]=1[N+:22]([O-:24])=[O:23])[CH:3]=[CH2:4]
Reactant: Nc1c([N+](=O)[O-])cnn1-c1ncc(C(F)(F)F)cc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNc1c([N+](=O)[O-])cnn1-c1ncc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1.0 g (0.0082 mol) of 3-bromopropene was added with stirring to a mixture of 2.3 g (0.0075 mol) of 5-amino-4-nitro-1-(3-chloro-5-trifluoromethyl-2-pyridyl)pyrazole, 0.6 g (0.0041 mol) of potassium carbonate and 50 ml of dimethylformamide and it was stirred at 100° C. for 2 hours. After cooling, it was concentrated under reduced pressure and the residue was partitioned between water and methylene chloride. The organic phase was dried, filtered off with suction through silica gel and concentrated, 1.6 g (61.3% of theory) of the title compound being obtained as a viscous resin. After chromatographing on silica gel and concentrating, colorless crystals of m.p. 94-95° C. were obtained (Active Compound Example No. 9.003).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][NH2:32])[CH2:21]1.C(N(C(C)C)CC)(C)C>C(#N)C>[NH2:32][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:22]1[CH2:23][CH2:24][N:20]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:21]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: NCc1ccccc1C1CCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccccc1C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A suspension of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.13 g, 4.0 mmol), 2-(3-pyrrolidinyl) benzenemethanamine (1.25 g, 5.0 mmol), and a diisopropylethylamine (2.07 g, 16.0 mmol) in acetonitrile (50 mL) was heated at gentle reflux for 24 hours. The suspension was allowed to cool to room temperature; the precipitated solids were filtered, washed successively with cold acetonitrile and ether, and dried in vacuo to give the title compound (0.73 g, 43%) as a white solid, after recrystallization from methanol, mp 226°-228° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4]1.[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14]>C1COCC1>[Cl:9][CH2:10][CH2:11][NH:12][C:13]([NH:8][CH2:7][CH2:6][C:3]1([O:2][CH3:1])[CH2:5][CH2:4]1)=[O:14]
Reactant: COC1(CCN)CC1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: COC1(CCNC(=O)NCCCl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A 0° C. solution of 2-(1-methoxycyclopropyl)ethanamine (0.361 g, 2.413 mmol) in THF (15 mL) was treated drop-wise with 2-chloroethyl isocyanate (0.226 mL, 2.65 mmol), allowed to warm to RT, stirred overnight, then concentrated to dryness. The residue was treated with toluene and concentrated to dryness (twice) to afford 1-(2-chloroethyl)-3-(2-(1-methoxycyclopropyl)ethyl)urea (429 mg, 81%) as a yellow oil. MS (ESI) m/z: 221.1 (M+H+).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:35]([CH2:36][CH2:37][C@:20]12[CH3:21])[C@:33]1([CH3:34])[C:28](=[CH:29][CH2:30][CH2:31][CH2:32]1)[CH2:27][CH2:26]3>C(OCC)C>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:35]([CH2:36][CH2:37][C@:20]12[CH3:21])[C@:33]1([CH3:34])[C:28](=[CH:29][CH2:30][CH2:31][CH2:32]1)[CH2:27][CH2:26]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30 ml of dihydropyran containing 450 mg of p-toluenesulfonyl chloride is added 6.0 g of the product of Step B and the solution is stirred at room temperature for 1 hour. The solution is the diluted with ethyl ether and washed with a 20% pyridine water mixture twice, and then water, then brine, and dried and evaporated to yield a pale yellow oil which crystallizes (8.5 g), and has a m.p. of 92°-96° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]3[CH2:15][CH2:14][NH:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:17]I>CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]3[CH2:15][CH2:14][N:13]([CH3:17])[CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CCNC2
Reactant: CI
Solvent: CC(C)=O
Product: CN1CCn2c(nc3cc(Br)ccc3c2=O)C1
Yield: 62.2 %

Procedure:
A solution of 9-bromo-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one (200 mg, 0.71 mmol, 1 equiv) and MeI (101 mg, 0.71 mmol, 1 equiv) in acetone (35 mL) was stirred at room temperature for 2 h. Then the reaction mixture was then concentrated and purified by column chromatography to give 130 mg of the desired product. MS (ESI): 294/296 (MH+).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7]=[CH:6]2)[O:4][CH2:3][CH2:2]1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1(C=CC(O)=CC=1)O>C(#N)C>[O:1]1[CH2:2][CH2:3][O:4][C:5]21[CH2:9][C@@H:8]1[CH2:7][C@@H:6]2[CH2:12][CH:11]1[C:10]([O:14][CH3:15])=[O:13]
Reactant: C=CC(=O)OC
Reactant: C1=CC2(CC1)OCCO2
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: COC(=O)C1C[C@H]2C[C@H]1CC21OCCO1

Procedure:
A reaction mixture of 1,4-dioxaspiro[4.4]non-6-ene (5 g), methyl acrylate (10.24 g), and hydroquinone (0.13 g) was heated at 100° C. in acetonitrile (12 mL) for three days. After cooling, the solvent was removed, and residue was purified by flash chromatography on silica gel eluting with 4:1 hexane/ethyl acetate to provide the title compound as a mixture of two isomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([CH:22]=O)=[C:13]([CH2:24][O:25][CH3:26])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].[OH-].[K+]>CN(C)C=O.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([CH:22]=[N:28][OH:29])=[C:13]([CH2:24][O:25][CH3:26])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COCc1c(C=O)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: COCc1c(C=NO)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13.5 g of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde is dissolved in 150 ml of dry dimethyl formamide (DMF) and there are added thereto 6 g of hydroxylamine hydrochloride and a solution of 6 g of potassium hydroxide in 30 ml of ethanol. The reaction mixture is stirred for one hour at room temperature, filtered, and the residue washed with 2×20 ml of DMF. The DMF fraction is combined with 200 ml of ice water, the precipitate is filtered off, washed with water, and dried. Yield: 9.6 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:16]([O-])=O>C(=O)([O-])O.[Na+]>[NH2:16][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:12](=[O:15])(=[O:14])[NH2:13])[C:3]=1[O:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: COc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
4-Methoxy-3-nitro-5-sulphamyl-benzoic acid (2.8 g) was dissolved in 1N sodium hydrogen carbonate solution (12 ml), and hydrogenated, using Pd-on-carbon as a catalyst, and the 3-amino-4-methoxy-5-sulphamyl-benzoic acid was isolated as described in Example 1 B. After several recrystallizations from water and drying at 78°C in vacuo, the melting point was 210°C under decomposition.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:27][CH2:26][C:9]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17](=[O:18])[C:8]=2[CH2:7]1)=[O:5])C.[OH-].[K+].C(O)C.Cl>O>[C:4]([CH:6]1[CH2:27][CH2:26][C:9]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17](=[O:18])[C:8]=2[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1CCc2c(c(=O)c3cccnc3n2-c2cccc(Cl)c2)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCc2c(c(=O)c3cccnc3n2-c2cccc(Cl)c2)C1
Reaction time: 21 h

Procedure:
Saponify 7-ethoxycarbonyl-10-(3-chlorophenyl)-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridin-5(10H)-one (7.1 g) with potassium hydroxide (1.10 g) in a solvent of ethanol and water (142 ml, 9:1 by volume). After 21 hours at 25° C., add water (200 ml), cool the resulting solution in ice, and acidify (pH 2) the solution with concentrated hydrochloric acid. Collect the resulting precipitate on a filter, and crystallize it from ethanol to provide 7-carboxy-10-(3-chlorophenyl)-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridin-5(10H)-one, m.p. 279°-280.5° C.