Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:22]1([N:25]2[CH:29]=[C:28]([CH2:30][C:31](O)=[O:32])[C:27]([C:34]([F:37])([F:36])[F:35])=[N:26]2)[CH2:24][CH2:23]1.CCCP(O)(O)=O>C1COCC1>[CH:22]1([N:25]2[CH:29]=[C:28]([CH2:30][C:31]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]4[C:18]5[CH:17]=[N:16][CH:15]=[N:14][C:13]=5[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=4)=[O:9])[CH:3]=3)=[O:32])[C:27]([C:34]([F:37])([F:36])[F:35])=[N:26]2)[CH2:24][CH2:23]1
Reactant: O=C(O)Cc1cn(C2CC2)nc1C(F)(F)F
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Agent: CCCP(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cn(C4CC4)nc3C(F)(F)F)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 95, 50 mg, 0.17 mmol), (1-Cyclopropyl-3-trifluoromethyl-1H-pyrazol-4-yl)-acetic acid (Preparation 148, 47.1 mg, 0.21 mmol) and TEA (0.08 mL, 0.62 mmol) in THF (1 mL), 1-propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.26 mL, 0.44 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was washed with saturated sodium bicarbonate solution, dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography on silica gel (EtOAc) gave the title compound as a white solid in 77% yield, 68 mg.
Reaction SMILES: O.[CH:2]([CH:4]=O)=[O:3].[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:25][C:26]([NH2:36])([CH3:35])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.Cl>>[CH3:35][C:26]([NH:36][CH2:4][CH:2]([C:16]1[C:17]2[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=[C:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=1)[OH:3])([CH3:25])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1
Reactant: CC(C)(N)Cc1ccc(O)cc1
Reactant: O=C1COc2ccc(OCc3ccccc3)cc2N1
Reactant: O=CC=O
Agent: Cl
Solvent: O
Product: CC(C)(Cc1ccc(O)cc1)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2

Procedure:
The title compound is prepared from 10 g of (6-benzyloxy-4H-benzo[1,4]oxazin-3-one)-glyoxal hydrate and 4.6 g of 1,1-dimethyl-2-(4-hydroxyphenyl)ethylamine analogously to the method for Example 3(a). Yield: 9.0 g (64%, hydrochloride); melting point: 255° C.-258° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:14][C:15]1[N:16]=[C:17]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:18]2[S:23][C:22]([CH:24]=O)=[CH:21][C:19]=2[N:20]=1>>[Cl:14][C:15]1[N:16]=[C:17]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:18]2[S:23][C:22]([CH2:24][N:10]3[CH2:9][CH2:8][C:7]([OH:13])([CH:2]4[CH:3]=[CH:4][CH:5]=[CH:6][NH:1]4)[CH2:12][CH2:11]3)=[CH:21][C:19]=2[N:20]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OC1(c2ccccn2)CCNCC1
Product: OC1(C2C=CC=CN2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction of 2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 using standard reductive amination conditions yielded 1′-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-2′,3′,5′,6′-tetrahydro-1H-[2,4′]bipyridinyl-4′-ol, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 402. 400 MHz 1H NMR CDCl3 9.16 (s, 2H); 8.47 (d, 1H, J=4.8 Hz); 7.70 (t, 1H, J=7.7 Hz); 7.45 (d, 1H, J=7.9 Hz); 7.26 (s, 1H); 7.19 (t, 1H, J=6.2 Hz); 4.00 (t, 4H, J=4.6 Hz); 3.87 (s, 2H); 3.85 (t, 4H, J=4.7 Hz); 2.875 (d, 2H, J=11.0 Hz); 2.63 (t, 2H, J=11.2 Hz); 2.16 (m, 2H); 1.63 (d, 2H, J=12.6 Hz). LC-MS (m+1)=505.18
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:14])[C:11](=[O:13])[CH3:12])[CH:5]=[N:6][C:7]=1Cl.[CH3:15][C@@H:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:14])[C:11](=[O:13])[CH3:12])[CH:5]=[N:6][C:7]=1[N:20]1[CH2:19][CH2:18][NH:17][C@H:16]([CH3:15])[CH2:21]1
Reactant: C[C@@H]1CNCCN1
Reactant: CC(=O)N(C)Cc1cnc(Cl)c(Cl)c1
Product: CC(=O)N(C)Cc1cnc(N2CCN[C@H](C)C2)c(Cl)c1

Procedure:
A mixture of N-(5,6-dichloro-pyridin-3-ylmethyl)-N-methyl-acetamide from step (a) above (233 mg, 1.0 mmol) and (R)-(−)-2-methyl-piperazine (110 mg, 1.1 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound. MS (ESI, pos. ion) m/z: 297 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.[CH3:20][OH:21]>[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[CH2:20]([O-:21])[CH3:2]
Reactant: Cc1cccnc1-c1cc2cccnc2c(N)n1
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: CC[O-]
Product: Cc1cccnc1-c1cc2c(c(N)n1)NCCC2

Procedure:
Hydrogenate a mixture of 8-amino-6-(3-methyl-2-pyridinyl)-1,7-naphthyridine (10.0 g, 0.0425 mol) and 5% palladium-on-carbon (0.52 g) in methanol (150 mL) at 50 psi for 18 hours. Acidify with 3.4 M ethereal hydrochloric acid (12.5 mL, 0.0425 mol), dilute with methanol (200 mL) and continue hydrogenation for another 24 hours. Filter the reaction mixture through Celite, evaporate the filtrate under reduced pressure and triturate the residue in diethyl ether (450 mL). Filter and crystallize the isolated solids to obtain the hydrochloride salt of 8-amino-1,2,3,4-tetrahydro-6-(3-methyl-2-pyridinyl)-1,7-naphthyridine as a 0.1 ethanolate, C14H16N4, mp 255-257° C. (dec). CIMS: MH+ 241 (100%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[NH:27][C:28]([C:30]1[N:31]=[CH:32][C:33]3[CH2:38][N:37]([C:39](OC(C)(C)C)=O)[CH2:36][C:34]=3[N:35]=1)=[O:29])=[O:19])=[CH:12]2>C(Cl)Cl>[ClH:8].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[NH:27][C:28]([C:30]1[N:31]=[CH:32][C:33]3[CH2:38][N:37]([CH3:39])[CH2:36][C:34]=3[N:35]=1)=[O:29])=[O:19])=[CH:12]2
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)nc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2cnc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)nc2C1
Product: Cl
Reaction time: 1 h
Yield: 51.8 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of the compound (34.0 mg) obtained in Example 32 dissolved in methylene chloride (1 ml) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (1 ml), to which triethylamine (17.6 μl), acetic acid (7.21 μl), 35% formalin (8.13 μl) and sodium triacetoxyborohydride (20.1 mg) were added at room temperature. The resultant mixture was stirred for 1 hour. Methylene chloride (10 ml) and saturated aqueous solution (10 ml) of sodium hydrogencarbonate were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:methylene chloride=7:93). A 1N ethanol solution of hydrochloric acid and ethyl acetate were added to the product thus obtained to solidify it, and the resultant solids were collected by filtration to obtain the title compound (8.0 mg).
Reaction SMILES: C(O)(=O)C.[CH:5](=O)[CH:6]([CH3:8])[CH3:7].[C:10]1([C:16](=[N:25][OH:26])[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]>N>[C:30]([CH2:29][CH2:28][N:27]1[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N+:25]([O-:26])=[C:5]1[CH:6]([CH3:8])[CH3:7])([OH:32])=[O:31]
Reactant: O=C(C(=NO)c1ccccc1)c1ccccc1
Reactant: CC(C)C=O
Reactant: NCCC(=O)O
Agent: N
Solvent: CC(=O)O
Product: CC(C)c1n(CCC(=O)O)c(-c2ccccc2)c(-c2ccccc2)[n+]1[O-]

Procedure:
In 200 ml of glacial acetic acid 5.25 ml (0.1 mole) of isobutyraldehyde, 22.5 g (0.1 mole) of benzil monoxime and 8.9 g (0.1 mole) of beta-alanine is heated to reflux temperature for 3 hours. After cooling the mixture is added dropwise under vigorous stirring to one litre of concentrated aqueous ammonia. The solution is extracted with several portions of ether which is discarded. Now pH is adjusted to 7-8 by addition of hydrochloric acid, and further extractions with ether are performed on the resulting slurry. Also this ether is discarded. Finally pH is adjusted to 3 by further addition of hydrochloric acid and the precipitate is filtered off, washed with water and dried. Melting point: 245°-250° C. Thin layer chromatography reveals one spot only.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH:11]=O)[NH:8][C:7]=12.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.[BH4-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH2:11][NH:18][CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:8][C:7]=12
Reactant: O=Cc1cc2ccnc(Cl)c2[nH]1
Reactant: NC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: Clc1nccc2cc(CNC3CCCC3)[nH]c12
Reaction time: 4 h
Yield: 58.2 %

Procedure:
7-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (Example 138) (75 mg, 0.42 mmol) and cyclopentylamine (45 μL, 0.46 mmol) were dissolved in methanol (3 mL). After 4 h, sodium borohydride (25 mg, 0.67 mmol) was added in one portion. After an additional 2 h, the reaction mixture was quenched by addition of 2 N aqueous sodium hydroxide and extracted with diethyl ether. The organic layer was dried over sodium sulfate and evaporated. The residue was dissolved in acetonitrile and salted with 1 N ethereal hydrochloric acid. The precipitate was collected by filtration and crystallized from acetonitrile to give N-[(7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]-N-cyclopentylamine hydrochloride (35 mg, 30%) as a white solid: mp 241-244° C.; 1H NMR (300 M-z, CD3OD) δ1.70-1.95 (6H, m), 2.25 (2H, m), 3.75 (1H, m), 4.57 (2H, s), 7.09 (1H, s), 7.93 (1H, d, J=6.0 Hz), 8.12 (1H, J=6.0 Hz); ESI MS m/z 250 [C13H16ClN3+H]+; HPLC (Method C) >99% (AUC), tR=12.9 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:19])=[O:18])=[C:4]([C:9]([O:14][CH3:15])=[C:10]([CH2:12][CH3:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+].O1CCOCC1.C(#N)C>O>[Br:1][C:2]1[C:3]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:18])=[O:19])=[C:4]([C:9]([O:14][CH3:15])=[C:10]([CH2:12][CH3:13])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCc1cc(Br)c(NS(=O)(=O)c2ccccc2F)c(C(=O)OC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(Br)c(NS(=O)(=O)c2ccccc2F)c(C(=O)O)c1OC

Procedure:
A mixture of Example 470F (75 mg, 0.2 mmol), lithium hydroxide (70 mg, 2.0 mmol), dioxane (1.5 mL), and water (0.75 mL) was sealed in a vial and microwaved at 160° C. for 15 minutes. Purification by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mmol aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40 mL/min provided the desired compound. MS (ESI(+)) m/e 432, 434 (M+H)+; (ESI(−)) m/e 430, 432 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.68 (m, 1H), 7.57 (m, 1H), 7.28 (m, 3H), 3.65 (s, 3H), 2.49 (m, 4H), 1.09 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]=[C:26]1[C:31](C(Cl)=O)=[CH:30][CH:29]=[C:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:27]1.[CH3:40][O:41][C:42]1[CH:47]=[C:46]([O:48][CH3:49])[N:45]=[C:44]([NH2:50])[N:43]=1>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([C:31]2[C:26](=[O:25])[O:27][C:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:30]=2)=[O:17])[C@H:12]([C:22]([NH:50][C:44]2[N:43]=[C:42]([O:41][CH3:40])[CH:47]=[C:46]([O:48][CH3:49])[N:45]=2)=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: COc1cc(OC)nc(N)n1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Product: CCCCCc1ccc(C(=O)N2CC(=NOCc3ccccc3)C[C@H]2C(=O)Nc2nc(OC)cc(OC)n2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, staring from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 4,6-dimethoxy-2-pyrimidinamine the title compound was obtained in 62% purity by LC/MS. MS(ESI+): m/z=564.6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH:15][CH3:16].[C:17](=O)=O>C=O>[CH3:14][N:15]([CH2:17][C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[CH2:11])[CH3:16]
Reactant: CNC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C=O
Agent: C=O
Product: C=C(CN(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
The compound 4-nitrophenylacetic acid (30.2 g, 0.166 mole) was dissolved in 210 ml (1.7 mole) of 33% aqueous dimethylamine solution and cooled to 10° C. in an ice bath. Immediately to the reaction solution was added dropwise 150 ml of 38% aqueous formaldehyde solution, under a nitrogen atmosphere, while maintaining the temperature between 15°-20° C. When the addition of the formaldehyde was complete, the reaction mixture was stirred for 0.5 hours at 20° C., then for 0.5 hours with warming to 60° C. (evolving carbon dioxide), and then for 10 hours at room temperature. The light yellow oil, which separated from solution, was taken up in 3×30 ml portions of chloroform. The chloroform layer was extracted with 3×30 ml portions of 3N hydrochloric acid. Upon neutralization with saturated potassium bicarbonate solution an oily layer was separated, extracted with 3×30 ml portions of chloroform, washed with an equal volume of saturated sodium chloride solution, and dried over anhydrous Na2SO4. Evaporation of the chloroform provided 31.5 g (93%) of crude α-(N,N-dimethylaminomethyl)-p-nitrostyrene.
Reaction SMILES: N(N=C([C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[N:16](N=O)[C:15]=2[CH:14]=[CH:13][C:12]=1CC1C=CC=CC=1)C1C=CC=CC=1)=O.Cl.[NH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.C(O)C>[Zn].C(O)(=O)C>[CH2:25]1[C:17]2[N:16]3[C:39]4[CH:40]=[CH:41][N:36]=[CH:37][C:38]=4[C:14]4[CH2:13][CH2:12][CH:11]=[C:21]([C:15]=43)[CH:20]=[CH:19][C:18]=2[CH2:22][CH2:23][CH2:24]1
Reactant: O=NN=C(c1ccccc1)c1c(Cc2ccccc2)ccc2c1CCc1ccccc1N2N=O
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Reaction time: 4 h

Procedure:
To a mixture of 4.5 g of N-nitrosoiminodibenzyl (5-nitroso-10,11-dihydro-5H-dibenz[b,f]azepine), 6.0 g. of 4-piperidone hydrochloride and 6.5 g. of zinc dust in 30 ml. of absolute ethanol 12 ml. of glacial acetic acid are added dropwise, with constant stirring. Occasional cooling in an icebath is required to maintain the temperature at 20°-25° during the course of the reaction. After a little over 4 hours, the unchanged zinc is filtered off, washed with a minimum of absolute ethanol, and to the combined filtrate and wash there is added with stirring 8 ml. of concentrated sulfuric acid in 50 ml. of absolute ethanol. Stirring is continued while the mixture is warmed for about ten minutes, until the alcohol begins to reflux. It is then cooled down again; the inorganic insolubles are filtered off, and approximately 500 ml. of water is added to the filtrate, resulting in a voluminous white precipitate. The whole mixture is extracted with ether, and the residual aqueous phase is warmed up to transform the precipitate into granular solids, which are then filtered off and redissolved in approximately 600 ml. aqueous acetic acid. Some warming is required to completely dissolve all material. On treating this solution with 3N aqueous ammonia, the title compound is obtained as a tan-white granular solid, m.p. 134°-137°.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[C:15]2[S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:14]=2[C:13]([N+:23]([O-:25])=[O:24])=[CH:12][CH:11]=1>O>[N+:23]([C:13]1[C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][C:15]=2[C:10]([OH:9])=[CH:11][CH:12]=1)([O-:25])=[O:24]
Reactant: COc1ccc([N+](=O)[O-])c2c1sc1ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c2sc3ccccc3c12
Temperature: 165 °C

Procedure:
Solid pyridine hydrochloride (1 kg, 8.7 mol) was added to 4-methoxy-1-nitro-dibenzothiophene (iii)(35.44 g, 187 mmol) and the reaction mixed well before heating to 165° C. with continuous stirring. The mixture was maintained like this for 8 hrs, cooled, diluted with water (500 ml) and extracted into dichloromethane (3×200 ml). 3M sodium hydroxide solution was added to the organic extract until a dark solid precipitated from the solution. The filtrate was removed and the liquor acidified to pH1 using concentrated HCl. The resulting bright yellow solid that formed on acidification was then removed by filtration, washed with water and dried to give the title compound that was suitably pure to be used without any further purification. (35.44 g, 77%) m/z (LC-MS, ESP), RT=3.69 min, (M+H)=246.2, (M−H)=244.1.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(-c2csc(Br)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Yield: 52 %

Procedure:
A solution of 2-bromo-4-(4-fluorophenyl)-1,3-thiazole (4.49 g, 17.4 mmol), tert-butyl piperazine-1-carboxylate (6.48 g, 34.8 mmol) and potassium carbonate (2.4 g, 17.4 mmol) in dimethylformamide (55 ml) was stirred at 120° C. for 8 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (3.29 g, 52%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[K+].[K+]>CCO.C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([CH:10]=[CH2:11])=[CH:7][N:6]=1
Reactant: Fc1cc(Br)cnc1Cl
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cnc(Cl)c(F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 101 (5.00 g, 23.8 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (119, 21.39 mmol, Sigma-Aldrich) in a mixture of EtOH (30.0 mL) and THF (64.0 mL) under an argon atmosphere was added Pd(PPh3)2Cl2 (1.33 g, 1.90 mmol) and K2CO3 (8.20 g, 59.4 mmol). The resulting reaction mixture was heated to 60° C. and held for 16 hrs in a sealed bottle. The mixture was cooled to a temperature of about 25° C., diluted with water, and extracted with EtOAc. The organic layer was separated, washed with brine, and concentrated. The residue was chromatographed on a silica gel column eluted with EtOAc:hexanes to provide 112 as a colorless oil (85% yield). 1H NMR (CDCl3) δ: 5.48 (1H, d, J=10.97 Hz), 5.83 (1H, d, J=17.62 Hz), 6.68 (1H, dd, J=10.97, 17.62 Hz), 7.52 (1H, d, J=1.60 Hz), 8.20 (1H, d, J=1.60 Hz). LC/MS (M+1): m/z=158.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:43]=[C:44]2[CH:50]=[CH:49][NH:48][C:45]2=[N:46][CH:47]=1>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:48]1[C:45]2=[N:46][CH:47]=[C:42](/[CH:3]=[CH:2]/[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:43]=[C:44]2[CH:50]=[CH:49]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]ccc2c1

Procedure:
tert-Butyl acrylate (5.9 mL, 40.6 mmol), diisopropylethylamine (3.5 mL, 20.3 mmol) and P(o-tolyl)3 (618 mg, 2.0 mmol) were successively added to a suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.0 g, 10.15 mmol) in propionitrile (40 mL) and dimethylformamide (10 mL). The resulting mixture was purged with argon prior to the addition of palladium acetate (227 mg, 1.0 mmol). The mixture was then purged with argon a second time and refluxed overnight. The reaction mixture was filtered on Celite®. The filtrate was concentrated to dryness and the residue was solubilized in ethyl acetate (3×100 mL). The organic layers were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (1:0 to 7:3) as eluent. The title compound was obtained as a yellow solid (465 mg, 28%)
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Na].Cl[C:6]1[N:11]=[C:10]([CH:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][CH:7]=1.[H][H]>CS(C)=O.O>[CH2:1]([O:3][C:6]1[N:11]=[C:10]([CH:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=[CH:8][CH:7]=1)[CH3:2]
Reactant: [H][H]
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Reactant: CCO
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To 30.0 ml of ethanol was added 1.10 g of sodium pellets. After the sodium had dissolved, 10.14 g of 6-chloro-2-(diphenoxymethyl)pyridine in 50 ml of DMSO was added dropwise. The mixture was heated to 80° C. and held there for 24 hours. The reaction was considered complete as seen by the NMR. The reaction mixture was cooled, diluted with water and extracted with methyl chloroform. The organic layer was separated and washed with water, dried over anhydrous magnesium sulfate, filtered and the solvent removed by evaporation under reduced pressure. The crude product was then distilled and the portion which distilled over at 157°-165° C. at 0.05 millimeters of mecury was collected. The above indicated product was obtained in a yield of 8.95 g and was found to have a refractive index of n26/d=1.5768. The NMR and Infrared Spectra (IR) were consistent with the structure for the above compound. Upon analysis, the compound was found to have carbon, hydrogen and nitrogen contents of 74.56, 6.01 and 4.19 percent, respectively, as compared with the theoretical contents of 74.77, 5.92 and 4.36 percent, respectively, as calculated for the above named compound (Compound 2).