Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][CH2:9][N:8]([CH:11]([C:19]([O:21][CH3:22])=[O:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:7]=1.Cl>CN(C=O)C>[OH:10][CH:6]1[CH2:7][N:8]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:19]([O:21][CH3:22])=[O:20])[CH2:9][C:3]2[CH:4]=[CH:5][S:1][C:2]1=2
Reactant: COC(=O)C(c1ccccc1Cl)N1C=C(c2cccs2)OC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
5-(2-thienyl)-3-(methoxycarbonyl-o-chlorobenzyl)-1,3-oxazoline (22) (5 g, 14.7 mmol) was dissolved in 5 mL of dry DMF and the solution was added dropwise at 0-5° C. over HCl in dry DMF. The reaction was subsequently allowed to warm to room temperature and stirred to complete transformation of the starting material. The solution was partitioned between 1 M sodium bicarbonate solution and toluene. The organic phase was dried on sodium sulfate filtered through a plug of silica gel and evaporated under vacuum to yield 4.3 g of product. 1H-NMR (CDCl3, ppm) 7.45-7.55 (1H, m), 7.35-7.45 (1H, m), 7.2-7.35 (2H, m), 7.2 (1H, d), 6.68 (1H, dd), 5.09 and 5.03 (1H, 2 s), 4.68 (1H, bs), 3.5-4.0 (5H, m), 2.7-3.2 (3H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:17])[CH2:8][O:9]CC1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:26])[C:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:17])[CH2:8][OH:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(COCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C)(CO)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A suspension of the benzyl ether 8 (540 mg, 1.48 mmol) and 10% Pd—C (130 mg) in 20 mL of CH3OH was stirred under an H2 atmosphere overnight. The reaction mixture was filtered over Celite?, and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (30% EtOAc in hexane) provided a quantitative yield of 9 (407 mg, 100%) as a colorless solid: mp 44-45° C. (EtOAc/hexane); 1H NMR (CDCl3) 6.437 (3H, s), 1.442 (9H, s), 1.48 (9H, s), 3.72 (1H, d, J=11.2), 4.00 (1H, d, J=11.2), 5.32 (1H, broad s). Anal. (C13H25NO5) C, H, N.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][S:8]C(=O)C.[OH-].[K+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH3:21][C:15]([S:8][CH2:7][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(=O)SC[C@@H]1CCCCO1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC[C@@H]1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
A solution of 2.79 g (13.45 mmol) of 1-{[(2S)-oxan-2-ylmethyl]sulfanyl}ethan-1-one in ethanol (60 mL) is degassed with nitrogen over 0.5 h and 1.51 g (26.91 mmol) of KOH are added. Then 3.99 mL (26.91 mmol) of ethyl α-bromoisobutyrate are added slowly. The reaction is stirred for 18 h at room temperature under a nitrogen atmosphere. The reaction mixture is filtered, the solid is rinsed with ethanol and the filtrate is concentrated under reduced pressure. The crude material is purified by column chromatography (silica, eluent: n-heptanes, 0-20% ethyl acetate) to afford 2.68 g of ethyl 2-methyl-2-{[(2S)-oxan-2-ylmethyl]sulfanyl}propanoate (purity 90%). Yield: 72%; ES-MS: m/z 247 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.23-1.36 (5H, m), 1.45-1.59 (8H, m), 1.68 (1H, d, J=13.12 Hz), 1.83 (1H, d, J=10.99 Hz), 2.62-2.71 (1H, m), 2.72-2.80 (1H, m), 3.25-3.47 (2H, m), 3.95-4.03 (1H, m), 4.17 (2H, q, J=7.12 Hz).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:27][C@:13]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:14]=[C:15]([NH:18]C(=O)C3C=CC=CC=3)[S:16][CH2:17][C@@H:12]2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>CO>[CH2:1]([O:8][C@H:9]1[CH2:27][C@:13]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:14]=[C:15]([NH2:18])[S:16][CH2:17][C@@H:12]2[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)C[C@H](OCc3ccccc3)CC[C@H]2CS1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@@]2(c3ccccc3F)C[C@H](OCc3ccccc3)CC[C@H]2CS1
Temperature: 25 °C

Procedure:
(±)-N-[(4aR*,7R*,8aS*)-7-Benzyloxy-8a-(2-fluorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in Preparation Example 58-(6) (1.81 g) was dissolved in methanol (60 mL). Then, DBU (1.14 mL, specific gravity: 1.018 g/cm3) was added, and the mixture was stirred with heating under reflux for three hours. Then, the reaction solution was stirred at 64° C. for 14 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (1.20 g).
Reaction SMILES: C1[C@H](NCC2[C:12]3[C:13]([N:15]=[C:16]([NH2:18])[NH:17][C:11]=3[N:10]([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)C=2)=[O:14])[C@@H](O)[C@@H](O)C=1.ClC(CC#N)=O.ClCC#N.C(OC)=O>>[NH2:18][C:16]1[NH:15][C:13](=[O:14])[CH:12]=[C:11]([NH2:10])[N:17]=1
Reactant: Nc1nc(=O)c2c(CN[C@H]3C=C[C@H](O)[C@@H]3O)cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Agent: N#CCC(=O)Cl
Agent: N#CCCl
Solvent: COC=O
Product: Nc1cc(=O)[nH]c(N)n1

Procedure:
A 2-amino-4-oxo-5-cyanopyrrolo[2,3-d]pyrimidine(III) was prepared according to the method reported by Migawa, et al., "A Two Step Synthesis of the Nucleoside q Precursor 2-amino-5-cyanopyrrolo[2-3-dpyrimidine-4-one" Syn. Comm. 26:3317(1996) which involved the synthesis of chloroformylacetonitrile (110) from chloroacetonitrile (109) and methyl formate as shown in FIG. 19. Cyclocon-densation of compound 10 with 2,6-diamino-4-oxopyrimidine afforded to the key intermediate in 65-70% overall yield. Reductive amination of the 5-nitrile with the appropriate anilines or ethyl-p-aminobenzoyl-L-glutamate in the presence of Raney nickel and hydrogen at 50 psi for 5-6 hours afforded the desired analogues which were purified by column chromatograpy and were obtained in 20-62% yield. This yielded the product generally represented by compound 112. For the classical analogue, compound 407, which is the compound 112 where R2 is p-benzoyl-L-glutamate, saponification of the chromatographically purified ester afforded the desired product. This method was used to synthesize compounds 407-415, which are generally represented by compound 112 in FIG. 19 with the following substitutions:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[C:13]([CH2:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[C:22](=O)([O:30]C1C=CC=CC=1)[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1[N:5]=[C:6]2[C:11]([CH2:10][CH2:9][CH2:8][N:7]2[C:22]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])=[CH:12][C:13]=1[CH2:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17]
Reactant: COC(OC)c1nc2c(cc1CN(C)C(C)=O)CCCN2
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1CN(C)C(C)=O)CCCN2C(=O)Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N-methylacetamide (intermediate 115) (470 mg, 1.282 mmol) and diphenyl carbonate (288 mg, 1.346 mmol) in THF (5 mL) was slowly added 1.6M LHMDS in THF (1.202 mL, 1.923 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, then left to warm to room temperature. The reaction mixture was poured into saturated NH4Cl solution. The aqueous was extracted with DCM (×2). The combined organic extracts were concentrated under reduced pressure. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in heptane afforded Phenyl 7-(dimethoxymethyl)-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate. UPLC-MS 3 Rt=0.89 min; MS m/z [M+H]+ 414.3.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:9](N2C(C(C)C)COC2=O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].OO.N([O-])=[O:35].[Na+]>C1COCC1>[CH:1]1([CH2:7][CH:8]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:9]([OH:10])=[O:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: CC(C)C1COC(=O)N1C(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A solution of 2-cyclohexylmethyl-1-(4-isopropyl-2-oxooxazolidin-3-yl)-4-morpholin-4-yl-butane-1,4-dione (1.63 g, 4.13 mmol) in THF (20 mL) was treated with lithium hydroxide monohydrate (0.226 g, 5.37 mmol) and hydrogen peroxide (2 mL of a 30% solution) and the mixture was stirred overnight at ambient temperature. The mixture was treated with sodium nitrite (1.3 g) and stirred for an additional 30 minutes. The organic solvent was removed under reduced pressure and the residual mixture was diluted with water (30 mL). The dilution was extracted with methylene chloride (3×30 mL) and the aqueous layer was acidified to pH 2 with 1M hydrochloric acid and extracted with dichloromethane (3×20 mL). The combined extracts were dried (MgSO4), filtered and concentrated to dryness to provide 2-cyclohexylmethyl-4-morpholin-4-yl-4-oxobutyric acid (0.56 g, 48%).
Reaction SMILES: Cl[O-].[Na+].[CH3:4][C:5]1([CH3:28])[C@@H:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:8][C@H:7]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[NH:6]1.C(Cl)[Cl:30]>O>[Cl:30][N:6]1[C@@H:7]([C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)[CH2:8][C@H:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]1([CH3:28])[CH3:4]
Reactant: ClCCl
Reactant: COc1cc([C@H]2C[C@H](c3ccncc3)C(C)(C)N2)cc(OC)c1OC
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: COc1cc([C@H]2C[C@H](c3ccncc3)C(C)(C)N2Cl)cc(OC)c1OC
Temperature: 50 °C

Procedure:
30 Ml. of sodium hypochlorite (Cl2 = 10%) are added to a solution of 5.1 g. of 4-[trans-2,2-dimethyl-5-(3,4,5-trimethoxyphenyl)-3-pyrrolidinyl]-pyridine in 50 ml. of CH2Cl2. While stirring, the reaction mixture is heated at 50° C. for 2 hours. 10 Ml. of sodium hypochlorite are added and the reaction mixture is left to react for 2 more hours. After a further addition of 10 ml. of sodium hypochlorite and an additional 2 hours, the reaction mixture is treated with water and extracted three times with methylene chloride. The organic phase which results is washed with water, dried over sodium sulfate and evaporated under reduced pressure to yield crude 4-[trans-1-chloro-2,2-dimethyl-5-(3,4,5-trimethoxyphenyl)-3-pyrrolidinyl]-pyridine.
Reaction SMILES: O=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:15]2[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][CH:14]=2)[C:9]1=[O:23])C=CC.[CH3:24][OH:25]>ClCCl>[O:25]=[CH:24][CH2:4][CH:8]1[C:16]([CH2:17][CH3:18])([CH2:19][CH3:20])[C:15]2[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][CH:14]=2)[C:9]1=[O:23]
Reactant: CC=CCC1C(=O)c2cc(OC)ccc2C1(CC)CC
Reactant: CO
Agent: O=[O+][O-]
Solvent: ClCCl
Product: CCC1(CC)c2ccc(OC)cc2C(=O)C1CC=O
Reaction time: 0.42 h
Yield: 99 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 25 minutes while stirring through a solution, cooled to -70°, of 4.1 g of (RS)-2-(2-buten-1-yl)-6-methoxy-3,3-diethyl-1-indanone in 60 ml of anhydrous dichloromethane and 15 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 1.66 ml of dimethyl sulfide, the mixture was stirred at room temperature for 22 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 50 ml of dichoromethane and, after the addition of 8 ml of water and 8 ml of trifluoroacetic acid, stirred at room temperature for 2.5 hours. The mixture was subsequently poured into 70 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 3.9 g (99%) of (RS)-2-(2-oxoethyl)-6-methoxy-3,3-diethyl-1-indanone were obtained as a light yellow oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([NH:44]C(=O)OC(C)(C)C)[CH2:7][NH:8][C:9]1[CH:10]=[N:11][C:12]([C:24](=[O:43])[NH:25]C(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=2)[CH:14]=1)(=[O:3])[CH3:2].[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53].C([SiH](CC)CC)C>C(Cl)Cl>[OH:58][C:52]([C:54]([F:57])([F:56])[F:55])=[O:53].[C:1]([NH:4][CH2:5][CH:6]([NH2:44])[CH2:7][NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=2)[C:12]([C:24]([NH2:25])=[O:43])=[N:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(NC(=O)c2ncc(NCC(CNC(C)=O)NC(=O)OC(C)(C)C)cc2Nc2cc(C)cc(C)n2)c2ccc(OC)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCC(N)CNc1cnc(C(N)=O)c(Nc2cc(C)cc(C)n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl {1-(acetylamino)-3-[(6-{[bis(4-methoxyphenyl)methyl]carbamoyl}-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl)amino]propan-2-yl}carbamate in DCM (1 mL) were added TFA (0.2 mL) and triethylsilane (0.146 mL, 0.917 mmol). The reaction mixture was stirred at room temperature for 4 hours, and then concentrated under reduced pressure. The residue was purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to give 5-{[3-(acetylamino)-2-aminopropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide TFA salt. MS ESI calc'd for C18H26N7O2 [M+H]+ 372. found 372. 1H NMR (500 MHz, CD3OD) δ 7.84 (d, J=2 Hz, 1H), 7.41 (s, 1H), 7.21 (s, 1H), 6.95 (s, 1H), 3.60-3.42 (m, 5H), 2.54 (s, 3H), 2.43 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:13]=[CH:12]2)=[CH:7][CH:6]=1.[ClH:21]>>[N:11]1([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:20])=[O:2])=[CH:10][CH:9]=2)[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:13]=[CH:12]1.[ClH:21]
Reactant: COC(=O)Cc1ccc(-n2cnc3cnccc32)cc1
Agent: Cl
Product: O=C(O)Cc1ccc(-n2cnc3cnccc32)cc1
Temperature: 25 °C

Procedure:
A mixture of 0.349 g of (4-imidazo[4,5-c]pyridin-1-yl-phenyl)-acetic acid methyl ester and 3.5 ml of an 6 N aqueous solution of HCl is stirred and refluxed for 3 hours. The mixture obtained is allowed to cool to rt and is concentrated in vacuo. (4-Imidazo[4,5-c]pyridin-1-yl-phenyl)-acetic acid in the form of a hydrochloric acid salt is obtained: ES-MS: 254.0 [M+H]+; single peak at tR=1.20 min (System 1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[N:3]=1.CCN(CC)CC.[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Br:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:26]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:27])[CH:11]=[CH:10]2
Reactant: Nc1ccc2cc(Br)ccc2n1
Reactant: O=C(Cl)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(Br)ccc2n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-amino-6-bromoquinoline (250 mg, 1.121 mmol) in CH2Cl2 (7 mL) was added Et3N (0.94 mL, 6.726 mmol) and DMAP (137 mg, 1.121 mmol) followed by cyclohexanecarbonyl chloride (0.46 mL, 3.362 mmol). The reaction mixture was stirred at rt for 20 min and then diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 40% ethyl acetate/hexanes) to give the product. LCMS-ESI+: calc'd for C16H18BrN2O: 333.0 (M+H+); found: 333.1 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:10]=1[NH2:11])C1C=CC=CC=1>[Pd].CO>[NH2:11][C:10]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:9]=1[OH:8]
Reactant: Nc1c(F)cccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1c(O)cccc1F
Yield: 99.2 %

Procedure:
2-(Benzyloxy)-6-fluoroaniline (Step 2, 5.00 g, 0.0230 mol) and 10% palladium on carbon (0.5 g) in methanol (100 ml) are stirred under a hydrogen atmosphere (balloon) for 2 h. The catalyst is removed by filtration through a pad of celite and the filtrate concentrated to give pure product as a tan solid (2.9 g, 99%); mp 125–6° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1OCCOCCOCCOCCOCCOC1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44]C2C=NC=CC=2)[CH:39]=1.[K]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:44][C:40]2[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=2)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CBr)cc1Oc1ccccc1
Reactant: c1cncc(Oc2cccnc2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COc2cccnc2)cc1Oc1ccccc1
Temperature: 70 °C
Yield: 70.7 %

Procedure:
To a solution in toluene (25 mL) of 4-bromomethyl-2-phenoxybenzoic acid methyl ester (3.37 g), prepared as in Example 157E, was added 18-crown-6 (0.52 g) and the potassium 3-pyridyloxide (2.20 g). The reaction mixture was heated at 70° C. for 1 hour during which time a black, insoluble tar formed. The reaction mixture was cooled to ambient temperature and diluted with toluene. The toluene was decanted from the tar and the tar was dissolved in 1:1 THF-water (20 mL). The aqueous THF was added to the toluene and the mixture was washed twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a black oil. Chromatography on silica gel (1:1 ethyl acetate-hexanes) gave 4-(3-pyridyloxymethyl)-2-phenoxybenzoic acid methyl ester (2.47 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[CH:17]=[CH:18][C:19]2[S:29][C:28]3[N:30]4[C:21](=[CH:22][N:23]=[C:24]4[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>C(O)C>[ClH:32].[ClH:32].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[CH:17]=[CH:18][C:19]2[S:29][C:28]3[N:30]4[C:21](=[CH:22][N:23]=[C:24]4[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C=CC2=Cc3cnc4cccc(n34)S2)CC1
Agent: Cl
Solvent: CCO
Product: O=C(C=CC1=Cc2cnc3cccc(n23)S1)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To this crude N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylamide was added 1 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for 0.5 hour. After addition of ethanol, the mixture was stirred and the resulting precipitate was collected and washed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].N1C=CC=CC=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:6]1(=[O:16])=[O:15]
Reactant: OB(O)c1ccccc1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccccc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 9.3 %

Procedure:
A solution of 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.46 g, 1.75 mmol) in dichloromethane (10 mL) was treated with pyridine (0.16 mL, 2.6 mmol), phenylboronic acid (0.43 g, 3.5 mmol) and copper(II) acetate (0.48 g, 2.6 mmol) and stirred at 23° C. for 16 hours. The reaction mixture was quenched by the addition of ammonium hydroxide (10 mL), diluted with methanol (2.0 mL), extracted with dichloromethane (3×10 mL), dried (Na2SO4), and evaporated. Flash chromatography (SiO2, 3-40% ethyl acetate/hexanes) provided 3-(3-chloropropyl)-1-phenyl-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.055 g, 9.4%) as a yellow film:
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[N:7][C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.[OH-].[K+]>>[CH3:11][C:10]1[C:5]([C:4]([OH:18])=[O:3])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)ccnc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccnc(-c2ccccc2)c1C(=O)O
Yield: 67.9 %

Procedure:
To a stirred, cooled (0°) solution of ethyl benzoylacetate (200 g) and concentrated ammonia in ethanol (1 L) was added crotonaldehyde (110 g) at a rate 2.5 ml/min while the temperature was kept below 10° . The mixture was warmed to room temperature overnight and concentrated in vacuo to give a yellow oily residue (260 g). The residue was treated with a mixture of con H2SO4 (100 ml), con HNO3 (130 ml) and water (580 ml) and the mixture cautiously heated on a steam bath until the evolution of NO2 had subsided, then heated for another 30 min. After cooling, the supernatant was basified with con NH4OH and extracted with diethyl ether (300 ml×10). The combined ether extracts were concentrated to leave a dark brown oily residue (38 g). Purification of the residue by silica gel column chromatography (70-230 mesh, 400 g, 42×5 cm, three times) using n-hexane-ethyl acetate (2:1) as eluent afforded 15 g of ethyl-4-methyl-2-phenylnicotinate. Hydrolysis of ethyl-4-methyl-2-phenylnicotinate (15 g) with refluxing ethanolic KOH, followed by work-up afforded 4-methyl-2-phenylnicotinic acid (9 g) as colorless prisms, mp 210-212° . Treatment of 4-methyl-2-phenylnicotinic acid (9 g) with polyphosphoric acid (166.7 g) at 130° for 3 hr., afforded 1-methyl-4-azafluoren-9-one (7.5 g) as yellow prisms from n-hexane, mp 130-131° C.