Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:17])=[C:8]([CH:16]=1)[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([OH:17])=[C:8]([CH:16]=1)[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Yield: 76 %

Procedure:
Sodium hydroxide solution (0.2 N) was added to 3-(5-amino-2-hydroxybenzoyl)propionic acid (2.4 g, 0.0115 mole) until the solid dissolved. Acetic anhydride (3.0 ml) was quickly added to the solution (pH 10) with vigorous stirring at 10°-15°, after which the pH was in the range 4-5, and stirring was continued for a further hour. The precipitated solid ws collected and washed with water, and a second crop was obtained by evaporation of the filtrate and addition of water to the residue. The combined solids were recrystallised from ethanol to give 3-(5-acetamido-2-hydroxybenzoyl)propionic acid (2.2 g, 76%, m.p. 205°-206°). (Found: C, 57.13; H, 5.25; N, 5.57; M+, 251. C12H13NO5 requires C, 57.37; H, 5.22; N, 5.58%; M, 251).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20][O:21][CH3:22].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:22][O:21][CH2:20][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=2)[N:6]=1
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO

Procedure:
0.364 g (1.119 mmol) of the above prepared 2-methoxymethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester in 6 ml of abs. THF was cooled down to 0° C. and reacted with 2.8 ml of DIBAL-H-solution (1.0 M in toluene, 2.5 eq.) for 1 h. Careful quenching with icewater, filtration over a pad of Celite, twofold extraction with AcOEt, washing with NH4Cl-solution, drying over magnesium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/AcOEt=1/1) to yield finally 0.312 g of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:11]1[C:10]2[C:9](=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: CCn1nccc1Nc1c(OC)cccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cccc(OC)c3nc21
Temperature: 0 °C

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-3-methoxyanthranilic acid of example 9(d) and POCl3 (50 ml) was refluxed overnight. The reaction mixture was poured into ice-water, neutralized with NH4OH and the mixture was extracted with CH2Cl2 (3×150 ml). The CH2Cl2 extracts were combined, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel eluting with 35% EtOAc/hexane to afford 0.4 g of 4-chloro-1-ethyl-8-methoxy-1H-pyrazolo[3,4-b]quinoline, m.p. 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[C@H:14]([O:21][CH3:22])[CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:23](OCC)(OCC)(OCC)[CH3:24].C(O)(=O)C>>[CH3:22][O:21][C@@H:14]1[CH2:13][C@@H:12]([N:11]2[C:3]3=[C:4]4[S:10][CH:9]=[CH:8][C:5]4=[N:6][CH:7]=[C:2]3[N:1]=[C:23]2[CH3:24])[CH2:17][CH2:16][C@@H:15]1[CH2:18][C:19]#[N:20]
Reactant: CO[C@@H]1C[C@@H](Nc2c(N)cnc3ccsc23)CC[C@@H]1CC#N
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: CO[C@@H]1C[C@@H](n2c(C)nc3cnc4ccsc4c32)CC[C@@H]1CC#N
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
A mixture of {(1R,2R,4S)-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-2-methoxycyclohexyl}acetonitrile (racemic) (45 mg, 0.14 mmol) and triethyl orthoacetate (79 μL, 0.43 mmol) in acetic acid (0.4 mL, 7 mmol) was stirred at 120° C. for 30 min. The solvent was removed, and the residue dissolved in methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (28 mg, 58%). LCMS calculated for C18H21N4OS (M+H)+: m/z=341.1. Found: 341.0.
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([N:27]1[CH2:31][CH:30]([OH:32])[CH2:29][CH:28]1[CH:33]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[O:34][CH:35]([C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1)[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH:35]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[O:34][CH:33]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:28]2[CH2:29][CH:30]([OH:32])[CH2:31][N:27]2[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:1](=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:37][CH:38]=1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above procedure Palmitic acid (2.57 g, 10 mmol) was coupled with the amine 100 (6.10 g, 11.45 mmol) using HBTU (4.54 g, 1.2 eq.) and DIEA (5 mL, 3.00 eq). After work-up and column purification the pure amide 102d was isolated as a white solid (Yield, 6.15 g, 79%). 1H NMR (DMSO-d6, 400 MHz) δ=7.74-7.66 (m, 1H), 7.37-7.22 (m, 4H), 7.21-7.12 (m, 5H), 6.87-6.79 (m, 4H), 4.98 (d, J=3.90 Hz, 1H), 4.90 (d, J=3.90 Hz, 1H), 4.40-4.07 (m, 2H), 3.71 (s, 6H), 3.59-3.42 (m, 1H), 3.34-3.13 (m, 2H), 3.02-2.87 (m, 3H), 2.20-1.80 (m, 6H), 1.46-1.08 (m, 32H), 0.82 (t, J=6.35 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.84, 170.92, 170.81, 158.11, 157.98, 145.09, 144.74, 135.87, 135.72, 135.46, 135.41, 129.59, 129.55, 127.84, 127.74, 127.57, 126.55, 113.16, 113.07, 85.78, 85.12, 68.59, 67.45, 65.19, 63.33, 59.74, 55.61, 55.06, 54.95, 53.44, 44.58, 39.08, 38.87, 38.22, 38.02, 36.30, 35.44, 34.18, 32.54, 31.32, 29.09, 29.05, 29.00, 28.81, 28.74, 28.69, 26.20, 25.34, 24.55, 24.15, 22.12, 21.20, 14.06, 13.92.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH3:11].C(Cl)Cl.[N-:16]=[N+:17]=[N-:18].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]([CH3:11])=[N:18][N:17]=[N:16]1
Reactant: CC(=O)Nc1ccc(I)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(I)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A suspension of N-(2-chloro-4-iodo-phenyl)-acetamide (2.39 g, 8.09 mmol) in acetonitrile (40 mL) at 25° C. was treated with methylene chloride (5 mL) to obtain a clear solution. The resulting solution was then treated with sodium azide (1.05 g, 16.18 mmol), and the reaction mixture was cooled to 0° C. The reaction mixture was then treated with trifluoromethanesulfonic anhydride (3.42 g, 12.13 mmol), and the resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight. The reaction mixture was then concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and water (50 mL), and the two layers were separated. The aqueous layer was further extracted with ethyl acetate (1×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.53 g, 59%) as a white solid: mp 128-130.5° C.; EI-HRMS m/e calcd for C8H6ClIN4 (M+) 319.9327, found 319.9325.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[BH4-].[Li+]>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH2:7][OH:8])[CH:12]=1
Reactant: CCOC(=O)c1cc(I)ccc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(I)cc1CO
Temperature: 0 °C
Yield: 97.2 %

Procedure:
To a solution of ester 4 (41.0 g, 141 mmol) in THF (300 mL) was added lithium borohydride (2.0 M in THF, 212 mL). The reaction mixture was refluxed overnight. After cooling to 0° C., the reaction was quenched by addition of aq. saturated NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to yield the titled compound (34.0 g, 97%) as a white solid, which was carried on to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:25]4[NH:26][CH:27]=[CH:28][N:29]=4)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:31][CH3:32].[H-].[Na+].I[CH3:36]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:25]4[N:29]([CH3:36])[CH:28]=[CH:27][N:26]=4)=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)ccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4nccn4C)c4cccnc43)CC2)ccc1Cl
Reaction time: 1 h

Procedure:
To the solution of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone (50 mg, 0.11 mmol, 1 eq) in THF was added 60% sodium hydride (5.7 mg, 0.14 mmol, 1.3 eq) and stirred for 1 hr, followed by the addition of iodomethane (25.8 mg, 0.16 mmol, 1.5 eq). 2 hrs later, LCMS indicated that the major peak is the desired product. preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[3-(1-methyl-1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone. MS (ES) [M+H]+ found: 465.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Cl:15][C:16]1[S:17][CH:18]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH2:26])[N:20]=1>>[Cl:15][C:16]1[S:17][CH:18]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH:26][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[N:20]=1
Reactant: Nc1ccsc1-c1csc(Cl)n1
Reactant: O=C(O)Cc1cccc2cnccc12
Product: O=C(Cc1cccc2cnccc12)Nc1ccsc1-c1csc(Cl)n1

Procedure:
The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid (218 mg, 1.11 mmol) and 2-(2-chlorothiazol-4-yl)thiophen-3-amine (241 mg, 1.11 mmol) according to protocol A. Retention time (min)=3.049, method [7], MS (ESI) 385.89 (M+H); 1H NMR (300 MHz, CD3OD) δ 9.54 (s, 1H), 8.56 (d, J=6.4 Hz, 1H), 8.39 (d, J=6.4 Hz, 1H), 8.31 (d, J=8.1 Hz, 1H), 8.16 (d, J=6.8 Hz, 1H), 7.94 (dd, J=8.1, 7.2 Hz, 1H), 7.73 (d, J=5.5 Hz, 1H), 7.45 (s, 1H), 7.37 (d, J=5.5 Hz, 1H), 4.39 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[ClH:12].Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[CH2:22]2)[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:12])=[CH:4][C:3]=1[S:8]([N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[CH2:22]2)[CH2:18][CH2:19]1)(=[O:10])=[O:9]
Reactant: COc1cc2c(cc1OC)CN(CC1CCNCC1)CC2
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)CN(CC1CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
2-Chlorobenzene-1-sulfonyl chloride (301.9 mg, 1.43 mmol) was added to a solution of 2-(piperidin-4-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (472 mg, 1.3 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.5 mmol) in CH2Cl2 (25 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×30 mL), dried over Na2SO4, and evaporated to dryness. The free base was dissolved in ethyl acetate (2 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.6 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (406 mg, 63%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[Br:16]Br>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([Br:16])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1
Reactant: Nc1nc(O)cc(-c2cccc(Cl)c2)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1nc(O)c(Br)c(-c2cccc(Cl)c2)n1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To 3.13 g. (15 mM) of 2-amino-6-(m-chlorophenyl)-4-pyrimidinol is added 80 ml. of glacial acetic acid. The solution is heated to 80° C. and 0.81 ml. of Br2 is added. The mixture is allowed to stir at 80° C. for 15 minutes and cooled to 25° C. The mixture is evaporated to dryness under vacuum at 40° C. and the resulting solids heated at reflux with 150 ml. of water. The reaction mixture is cooled and filtered, and the solids washed very well with cold water. The solids are dried at 60° C. in a vacuum oven and pulverized when dry. The boiling water tritration is repeated. 3.90 G. (86.9%) of title compound is recovered. Recrystallization of the solids from water:DMF by adding DMF slowly to a stirring slurry of 3.9 g. of compound in 150 ml. boiling water until solution occurs, cooling and filtering yields analytically pure material (80% recovery).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:5]([N+:12]([O-:14])=[O:13])=[N:4][CH:3]=1.[N+:15]([O-:23])(OCCC(C)C)=O.[ClH:24]>>[Cl:24][C:9]([CH3:11])([CH3:10])[CH:8]([N:15]=[O:23])[CH2:7][N:6]1[C:2]([CH3:1])=[CH:3][N:4]=[C:5]1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)=CCn1c(C)cnc1[N+](=O)[O-]
Reactant: CC(C)CCO[N+](=O)[O-]
Reactant: Cl
Product: Cc1cnc([N+](=O)[O-])n1CC(N=O)C(C)(C)Cl
Yield: 60 %

Procedure:
3-Chloro-3-methyl-2-nitroso-1-(5-methyl-2-nitro-1H-imidazol-1-yl) butane was prepared in 60% yield from 1-(5-methyl-2-nitro-1H-imidazol-1-yl)-3-methyl-2-butene (1.0 g, 5.12 mmol, Example 27), isoamyl nitrate (5.0 mL) and concentrated HCl (5.0 mL) following the procedure described for the preparation of its positional isomer (Example 27B) as a light blue solid; mp. 102-105° C. (decomp); 1H NMR (DMSO-d6) δ 1.73 [s, 6H, C(CH3)2], 2.32(s, 3H, imi-CH3), 5.53(s, 2H, NCH2), 6.97 ( s. 1H, imi-CH) and 11.58 (s, 1H, NOH). MS m/e 261 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH:3]=[CH:4][CH:5]=[CH:6][C:7]1[CH:8]=[C:9]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=1[Cl:13].C=O>C(O)=O>[ClH:13].[ClH:13].[CH3:1][C:2]([CH3:29])([CH3:28])[CH:3]=[CH:4][CH:5]=[CH:6][C:7]1[CH:8]=[C:9]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:21])[CH:10]=[N:11][C:12]=1[Cl:13]
Reactant: CC(C)(C)C=CC=Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Agent: C=O
Solvent: O=CO
Product: CN1CCC[C@@H]1COc1cnc(Cl)c(C=CC=CC(C)(C)C)c1
Product: Cl
Temperature: 70 °C
Yield: 156.9 %

Procedure:
To 5-(5,5-dimethyl-1,3-hexadienyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 77a (145 mg, 0.34 mmol) was added formalin (37%, 4 mL) and formic acid (2 mL), and the mixture was heated at 70° C. for 3 hours. The solvent was concentrated, and solid NaHCO3 was added to the residue. At pH 8 the mixture was extracted with methylene chloride, which was dried over MgSO4 and concentrated. The residue was chromotographed on a silica gel column, eluting with methylene chloride:methanol 100:4 to afford to give the free base of the title compound (72.5 mg, 66% yield). MS (DCI/NH3) m/z 335 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.10 (s, 9H), 1.77 (m, 2H), 2.00 (m, 1H), 2.28 (m, 1H), 2.45 (m, 3H), 2.70 (m, 1H), 3.10 (m, 1H), 3.43 (m, 1H), 4.00 (m, 1H), 4.38 (m, 1H), 5.95 (m, 1H), 6.20 (m, 1H), 6.70 (m, 2H), 7.38 (m, 1H), 7.93 (m, 1H). The base was converted to the salt by treatment with hydrogen chloride in ether/THF to give the title compound. mp 194° C. (dec). MS (DCI/NH3) m/z 335 (M+H)+. 1 H NMR (D2O, 300 MHz) δ: 1.07 (s, 9H), 1.78-2.05 (m, 2H), 2.17-2.28 (m, 1H), 2.90 (dd, J=5.1, 31.9 Hz, 3H), 3.12 (m, 1H), 3.50 (m, 3H), 4.41 (m, 2H), 6.04 (d, J=15.6 Hz, 1H), 6.30 (dd, J=10.2, 15.2 Hz, 1H), 6.70 (d, J-15.6 Hz, 1H), 7.10 (ss, J=10.2, 15.6 Hz, 1H), 7.84 (d, J=3.0 Hz, 1H), 8.06 (d, J=3.1 Hz, 1H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:18])[NH:7][C:3]2[CH:2]=[C:1]([CH:6]=[CH:5][CH:4]=2)[NH2:8])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1cccc(N)c1
Solvent: ClCCl
Product: Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Reaction time: 2 h

Procedure:
m-Phenylenediamine (10.8 g.) is dissolved in methylene chloride (500 ml.) at room temperature and a solution of p-chlorophenyl isocyanate (15.35 g.) in methylene chloride (50 ml.) is added dropwise with vigorous stirring. The mixture is stirred for 2 hours after the addition is complete, and the product is filtered off, washed with methylene chloride and dried. This solid thus obtained is crystallized from methanol (3 1.) to give 3-(3-p-chlorophenylureido)aniline, which slowly decomposes on heating to 310° C. without melting, but is analytically pure.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][O:3]1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[O:16]1[C:17]2[C:7]([N:6]3[CH2:5][CH2:4][O:3][C:2]3=[O:1])=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2N2CCOC2=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1OCCN1c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A mixture of tert-butyl 9-(2-oxo-1,3-oxazolidin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (230 mg, 0.688 mmol), ethyl acetate (3 ml) and 4N hydrogen chloride-ethyl acetate solution (3 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (118 mg, 63.4%) as a solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:25](O)=[O:26]>>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[CH:11][C:10]=1[CH:25]=[O:26]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(-n2cnnn2)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(-n2cnnn2)ccc1O
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 4-tetrazol-1-yl-phenol (0.01 mol) in trifluoroacetic acid (20 ml) and hexamethylenetetramine (0.04 mol) was heated at 70° for 18 h, cooled to room temperature and quenched with 2N solution of sulfuric acid (50 ml). The mixture was extracted with ethyl acetate (3×100 ml), dried (MgSO4), filtered and concentrated to give a residue which was purified by FCC (dichloromethane/methanol (9:1)) to afford the title compound in 30% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:29].Cl.[CH3:31][NH2:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)C>[ClH:28].[CH3:31][NH:32][C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: CN
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CNC(=N)c1cccc(COc2cc(C)cc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol), as prepared in step (a) of Example 6, in methylene chloride (10 mL) was added 37% HCl in ethanol (15 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was evaporated and the residue was concentrated in vacuo from methylene chloride several times. The residue was dissolved in ethanol (10 mL), treated with methylamine hydrochloride (270 mg, 4.0 mmol) and Na2CO3 (212 mg, 2.0 mmol), and then stirred at room temperature for 2 days. The reaction mixture was partitioned between metiylene chloride (150 mL) and 10% K2CO3. The organic phase was washed with 10% K2CO3 (50 mL) and dried over K2CO3. After removing the solvent in vacuo, HCl in methanol (30 mL) was added and the solvent was removed in vacuo. The residue was then purified by flash column chromatography (10% methanol/methylene chloride) and crystallized from methanol/ethyl acetate to give the title compound as white crystals (145 mg, 30%). 1H-NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3H), 3.01 (s, 3H), 5.10 (s, 2 H), 6.53 (s, 1H), 6.56 (s, 1H), 6.87 (s, 1H), 7.58 (t, 1H, J=7.0 Hz), 7.63 (t, 1 H, J=7.6 Hz), 7.73 (m, 2H), 7.86 (m, 3H), 7.94 (d, 1H, J=4.0 Hz), 9.05 (br s, 1H), 9.55 (br s, 1H), and 9.94 (br s, 1H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C22H21N2O4SCl: 445.1 (M+H). Found: 445.0.
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[S:1]([C:5]1[S:13][C:8]2[CH:9]=[N:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2c(s1)CNCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc2c(s1)C=NCC2
Temperature: 80 °C
Yield: 26.4 %

Procedure:
To a partial suspension of 2-sulfamoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (3.05 g, 14 mmol) in ethyl acetate (200 ml) was added activated manganese dioxide (3.0 g). This mixture was warmed to 80° C. Every two hours an additional 3.0 g of activated manganese dioxide was added until 12 g total had been added. This mixture was filtered hot and the collected manganese dioxide was re-extracted with hot ethyl acetate. The combined ethyl acetate extracts were evaporated to give 2.1 g of crude product. This material was purified by chromatography on silica gel eluting with a gradient 0-5% methanol/ethyl acetate. Recrystallization from ethyl acetate gave pure product (0.8 g, 26.5% yield); m.p. 161°-164° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](SC)=[N:8][CH:9]=2)[NH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:27][CH2:24][CH2:25][CH3:26])=[N:8][CH:9]=2)[NH:4][N:3]=1
Reactant: CCCN
Reactant: CSc1ncc2c(Br)n[nH]c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CCCNc1ncc2c(Br)n[nH]c2n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a mixture of 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (0.49 g, 2.0 mmol) in THF (5 mL) was added meta-chloroperoxybenzoic acid (0.52 g, 99%, 3 mmol) at room temperature. The white mixture was stirred for 2 h and n-propylamine (0.82 mL, 10 mmol) was added at 0° C. The resulting solution was heated at 40° C. for 12 h. After removal of the solvent, MeOH was added and the mixture was filtered. The white solid was washed with MeOH (3×) and dried to provide 3-bromo-N-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (0.45 g, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.19 (bs, 1H), 8.63 (s, 1H), 7.69 (bs, 1H), 3.29-3.17 (m, 2H), 1.61-1.49 (m, 2H), 0.88 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 161.61, 156.98, 152.71, 120.06, 106.66, 42.68, 21.72, 11.47; MS m/z 256.1 [M+1].