Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[N:31]1([CH2:36][C:37](O)=[O:38])[CH:35]=[N:34][CH:33]=[N:32]1>>[N:31]1([CH2:36][C:37]([NH:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[O:38])[CH:35]=[N:34][CH:33]=[N:32]1
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 55 %

Procedure:
Proceeding as in Example 1, but substituting (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide and 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride, gave Compound 135, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (75 mg, 55%). 1H-NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.40-7.25 (m, 7H), 7.15-6.90 (m, 6H), 5.00 (s, 2H), 4.79-4.60 (m, 3H), 4.00 (m, 1H), 3.70-3.60 (m, 1H). MS (EI) for C26H23F2N5O4 found 508 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:27][CH2:26]2)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([O:31][CH:32]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:29][CH2:30]2)=[O:21])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COCCOCOc1ccc(C=CC=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C=CC=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)ccc1O
Yield: 63.5 %

Procedure:
To a solution of 690 mg (1.15 mmol) of the amide compound in methanol (14 ml) was added 212 mg (1.12 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 25 minutes. Water was added to the reaction mixture, which was adjusted to a pH value of 11 by the addition of an aqueous solution of sodium carbonate, and then extracted with ethyl acetate. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (50:1), to give 393 mg (0.730 mmol) of 1-[2-[5-(3-methoxy-4-hydroxyphenyl)-2,4-pentadienoyl]aminoethyl]4-benzhydroxypiperidine.
Reaction SMILES: C([Li])CCC.[CH:6]1([C:9]#[CH:10])[CH2:8][CH2:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@@:21]23[C:27]([CH3:29])([CH3:28])[C@@:24]([CH3:30])([CH2:25][CH2:26]2)[C:23](=[O:31])[O:22]3)=[O:20])=[C:14]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@@:21]23[C:27]([CH3:28])([CH3:29])[C@@:24]([CH3:30])([CH2:25][CH2:26]2)[C:23](=[O:31])[O:22]3)=[O:20])=[C:14]([C@@:32]([OH:37])([C:10]#[C:9][CH:6]2[CH2:8][CH2:7]2)[C:33]([F:34])([F:35])[F:36])[CH:13]=1
Reactant: C#CC1CC1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)OC2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Reaction time: 0.5 h

Procedure:
2.5 M n-Butyllithium (14.8 mL, 37.16 mmol) was added slowly to a solution of cyclopropyl acetylene (2.46 g, 37.16 mmol) in tetrahydrofuran (20 mL) in an ice-salt-bath under argon, and then (1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-ox abicyclo[2.2.1]heptane-1-carboxamide(9, 5 g, 12.39 mmol) was added. The reaction mixture was stirred for 0.5 hour. The reaction was quenched with 10% citric acid aqueous, the mixture was extracted with ethyl acetate and the two layers were separated. The organic layer was evaporated to dryness to give crude oil which was further crystallized with ethyl acetate and petroleum ether to give (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10) as a white or off-white powder. 1H NMR spectrum of the product was identical to that of Example 5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N#N.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][N:18]1[CH:22]=[C:21]([C:2]2[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH:20]=[N:19]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: CC(=O)Nc1cc(-c2cnn(C)c2)cc([N+](=O)[O-])c1
Yield: 81 %

Procedure:
A solution of N-(3-bromo-5-nitrophenyl)acetamide (0.5 g, 1.9 mmol) in 1,2-dimethoxyethane (20 ml) was degassed by N2 bubbling for 5 min. 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.513 g, 2.47 mmol, 1.3 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.155 g, 0.19 mmol, 0.1 eq.) and aqueous sodium carbonate (0.5 g, 4.75 mmol, 2.5 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 81% yield (0.4 g).
Reaction SMILES: Cl.[CH3:2][N:3]([CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])[CH3:4].N.[CH2:21]([Mg][Cl:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1.O>[ClH:29].[CH2:21]([C:7]1([OH:12])[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH:5]([N:3]([CH3:2])[CH3:4])[C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C(c1ccc(F)cc1)C1CCCCC1=O
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(c1ccc(F)cc1)C1CCCCC1(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.3 %

Procedure:
The base was freed from 3.2 g (11.2 mmole) of the hydrochloride of 2-[dimethylamino-(4-fluorophenyl)methyl]cyclohexanone obtained according to stage 1 with 30 ml of water and 10 ml of ammonia solution (25 vol. %), extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 2.69 g (10.8 mmole) of this base were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 6.5 ml (12.9 mmole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran), and the whole was stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath and was extracted three times at RT, with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.42 g of crude base (84.1% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 15 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.89 g of crude base (78.6% of theory) were obtained, from which 2.58 g of 1-benzyl-2-[dimethylamino-(4-fluoro-phenyl)methyl]cyclohexanol, hydrochloride (63.3% of theory) having a melting point of 178° C. were obtained according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5]([CH2:9][C:10](N2CCN(C3C=CC(NC(C4N(CC)C5C(C=4)=C(OCC)C=CC=5)=O)=CC=3)CC2)=[O:11])[S:4]1.[N:41]1([C:47]2[CH:52]=[CH:51][C:50]([NH:53][C:54]([C:56]3[N:57]([CH2:67][CH3:68])[C:58]4[C:63]([CH:64]=3)=[C:62]([Cl:65])[C:61]([Cl:66])=[CH:60][CH:59]=4)=[O:55])=[CH:49][CH:48]=2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.O=C1NC(=O)C(CC(O)=O)S1>>[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5]([CH2:9][C:10]([N:44]2[CH2:45][CH2:46][N:41]([C:47]3[CH:52]=[CH:51][C:50]([NH:53][C:54]([C:56]4[N:57]([CH2:67][CH3:68])[C:58]5[C:63]([CH:64]=4)=[C:62]([Cl:65])[C:61]([Cl:66])=[CH:60][CH:59]=5)=[O:55])=[CH:49][CH:48]=3)[CH2:42][CH2:43]2)=[O:11])[S:4]1
Reactant: CCOc1cccc2c1cc(C(=O)Nc1ccc(N3CCN(C(=O)CC4SC(=O)NC4=O)CC3)cc1)n2CC
Reactant: CCn1c(C(=O)Nc2ccc(N3CCNCC3)cc2)cc2c(Cl)c(Cl)ccc21
Agent: Cl
Agent: O=C(O)CC1SC(=O)NC1=O
Product: CCn1c(C(=O)Nc2ccc(N3CCN(C(=O)CC4SC(=O)NC4=O)CC3)cc2)cc2c(Cl)c(Cl)ccc21

Procedure:
With a method similar to that used for the preparation of 4-ethoxy-1-ethyl-1H-indole-2-carboxylic acid (4-{4-[2-(2,4-dioxo-thiazolidin-5-yl)-acetyl]-piperazin-1-yl}-phenyl)-amide hydrochloride, 4,5-dichloro-1-ethyl-1,1-indole-2-carboxylic acid (4-{4-[2-(2,4-dioxo-thiazolidin-5-yl)-acetyl]-piperazin-1-yl}-phenyl)-amide was prepared from 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide and (2,4-dioxo-thiazolidin-5-yl)-acetic acid. LCMS for C26H25Cl2N5O4S calcd. (m/e) 573, observed 574 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([OH:16])=[CH:10][C:8]=2[CH:9]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:2][CH2:3][C:5]1[O:6][C:7]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([OH:16])=[CH:10][C:8]=2[CH:9]=1
Reactant: COC(=O)c1cc2cc(O)c(C)c(C)c2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(O)cc2cc(CO)oc2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
5-Hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid methyl ester (231 mg) prepared as in Example 2, was dissolved in THF and lithium aluminum hydride (93 mg) was added. The mixture was stirred at room temperature for 4 h. Then the solution was poured into water and extracted with ethylacetate. The ethyl acetate was washed with water and brine, dried over MgSO4 and concentrated. Purification by silica gel column eluting with 50% EtOAc in hexane gave 89 mg of 2-Hydroxymethyl-6,7-dimethyl-benzofuran-5-ol. 1HNMR (CD3OD, 300 MHz) δ: 6.75, 1H), 6.47(s, 1H), 4.61 (s, 2H), 2.37(s, 3H), 2.20(s, 3H) ppm. 13CNMR (CD3OD, 75 MHz) δ: 155.87, 150.51, 148.68, 124.69, 119.93, 119.20, 103.01, 101.62, 56.32, 10.43, 10.29 ppm. MS: 175(M−OH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].[CH3:9][C:10]1[C:11](=[O:19])[NH:12][C:13](SC)=[N:14][C:15]=1[CH3:16].O.C(OCC)C>CS(C)=O>[CH3:9][C:10]1[C:11](=[O:19])[NH:12][C:13]([NH:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:14][C:15]=1[CH3:16]
Reactant: CSc1nc(C)c(C)c(=O)[nH]1
Reactant: NCc1ccccn1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cc1nc(NCc2ccccn2)[nH]c(=O)c1C
Temperature: 150 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirred solution of (pyridin-2-ylmethyl)amine (5.8 g, 54 mmol) in dimethyl sulfoxide (15 mL) at ambient temperature was added 5,6-dimethyl-2-(methylthio)pyrimidin-4(3H)-one (7 g, 41 mmol, Step A), and the resulting mixture was stirred at 150° C. overnight. Then water (100 mL) was added carefully into the hot reaction mixture. Upon cooling to ambient temperature, diethyl ether (30 mL) was added. The formed precipitate was collected by filtration and dried to afford 7.0 g (74%) of the titled product as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.77 (s, 3H), 2.04 (s, 3H), 4.55 (s, 2H), 6.81 (bs, 1H), 7.23-7.40 (m, 2H), 7.77 (t, J=7.5 Hz, 1H), 8.53 (bs, 1H), 10.84 (bs, 1H).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([NH:7][C:8](=[O:36])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:33][CH3:34])([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]3([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:20]([CH3:32])[CH:19]=2)[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])([CH3:6])[CH3:5].[OH-].[Li+]>>[CH2:16]([C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:37])=[O:2])=[O:36])=[C:10]([CH3:35])[CH:11]=1)([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:20]([CH3:32])[CH:19]=1)[CH2:33][CH3:34])[CH3:17]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)NC(C)(C)C(=O)OC)c(C)c1
Agent: [Li+]
Agent: [OH-]
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)NC(C)(C)C(=O)O)c(C)c1
Yield: 100.8 %

Procedure:
2-(4-{1-Ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-2-methyl-propionic acid methyl ester (360 mg, 0.715 mmol) and lithium hydroxide (51 mg, 2.15 mmol) are reacted and purified in a procedure analogous to Example 1I to give the title compound (353 mg, quant.).
Reaction SMILES: [Cr+6:1].N([O-])=O.[Cr+3].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8]>>[C:6]([O-:10])(=[O:9])[CH2:7][CH3:8].[Cr+3:1].[C:6]([O-:10])(=[O:9])[CH2:7][CH3:8].[C:6]([O-:10])(=[O:9])[CH2:7][CH3:8]
Reactant: [Cr+6]
Reactant: CCC(=O)O
Agent: [Cr+3]
Agent: O=N[O-]
Product: CCC(=O)[O-]

Procedure:
adding to said solution of chromium(VI) source in aqueous propionic acid, a nitrite source selected from alkali metal and ammonium nitrites, employing sufficient nitrite source to effectively reduce said chromium(VI) source to chromium(III) and allowing sufficient time at sufficient temperature to produce a clear green solution of stabilized chromium(III) propionate; and
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[Br:1][C:2]1[C:3]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2Br)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Bromo-2-chloropyridine (10.3 g, 53.4 mmol), 4-aminophenol (7.00 g, 64.1 mmol), cesium carbonate (34.8 g, 107 mmol), and DMSO (53 ml, 53.4 mmol) were added into a pressure tube. The tube was capped and placed in a preheated oil bath at 130° C. After 16 h, the reaction mixture was stirred and cooled in ice-water. Water was added slowly to the mixture and the product precipitated out as a gray solid. The solids were washed with water, dried under vacuum at RT to afford 4-(3-bromopyridin-2-yloxy)benzenamine. MS Calcd for C, H9BrN2O: [M]+=264. Found [M+H]+=265.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[N+:17]([O-])=O)=[N:5][N:6]([CH3:8])[N:7]=1)#[N:2].[ClH:20]>C(O)C>[ClH:20].[NH2:2][C:1]1[C:3]2[C:4](=[N:5][N:6]([CH3:8])[N:7]=2)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[N:17]=1
Reactant: Cn1nc(C#N)c(Nc2ccc(F)cc2[N+](=O)[O-])n1
Agent: Cl
Solvent: CCO
Product: Cn1nc2c(n1)C(N)=Nc1cc(F)ccc1N2

Procedure:
To a slurry of 5-cyano-2-methyl-4[4-fluoro-2-nitro-anilino]-1,2,3-triazole (2.62 g) in ethanol (25 ml) was added anhydrous stannous chloride (5.7 g) in concentrated hydrochloric acid (25 ml) and the solution heated at reflux for one hour, cooled and the resulting solid filtered to give a pale yellow crystalline solid; melting point 275° C.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[N:6]1)(C)(C)C>C(O)=O.Cl>[C:16]1([CH3:21])[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:7]1[C:8]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:14])[NH:5][N:6]=1
Reactant: Cc1ccccc1-c1nn(C(C)(C)C)c2ncnc(N)c12
Agent: Cl
Solvent: O=CO
Product: Cc1ccccc1-c1n[nH]c2ncnc(N)c12

Procedure:
1-tert-butyl-3-o-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine was dissolved in a solution of formic acid (2 mL) and conc. HCl (0.2 mL) and heated to reflux for 30 min. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 226.1, found 226.3.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:27].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]CCCC.[Na+].[ClH:83]>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[ClH:83].[ClH:83].[ClH:83].[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:27]
Reactant: Cn1c(=O)ccc2cc(OCCCCCNCCc3cccnc3)ccc21
Reactant: Brc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)c3ccccn3)ccc21
Temperature: 80 °C

Procedure:
1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one(182 mg), 2-bromopyridine(0.060 ml), palladium acetate (II) (11.2 mg), xantphos (32 mg), and sodium-butoxide(68 mg) were added to toluene(2 ml). The mixture was heated at 80° C. for 10 hours under nitrogen atmosphere. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution(0.58 ml) was added to a ethanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and diethyl ether were added to the residue. The precipitated insoluble matter was separated, washed with diethyl ether, and dried to give the title compound(72 mg) as a yellow powder.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[NH:5][C:4]1=[O:15].[Cl:16]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:16][C:3]1([S:2][CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[NH:5][C:4]1=[O:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSC1C(=O)Nc2cccc([N+](=O)[O-])c21
Solvent: ClCCl
Product: CSC1(Cl)C(=O)Nc2cccc([N+](=O)[O-])c21

Procedure:
A solution of 3-methylthio-4-nitrooxindole (1.58 g, 7 mmol) and N-chlorosuccinimide (1.20 g, 9 mmol) in 100 ml of methylene chloride was stirred at room temperature for 48 hours. The solvent was removed in vacuo, yielding crude 3-chloro-3-methylthio-4-nitrooxindole. The residue was dissolved in 25 ml of tetrahydrofuran and added rapidly to a vigorously stirred slurry of red mercuric oxide (1.52 g, 7 mmol) and boron trifluoride etherate (1.00 g, 7 mmol) in 100 ml of 50 percent aqueous tetrahydrofuran. After stirring for 3 hours, the solution was filtered through a Celite pad which was then washed with copious amounts of chloroform. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel. Elution with chloroform-ethanol (9:1) gave 4-nitroisatin (535 mg, 40%), mp 248°-250° (dec) (recrystallized from ethanol); ir (KBr) 3200 (NH), 1750 (C=O), 1710 (C=O), 1520 (NO2) and 1350 cm-1 (NO2); nmr (DMSO-d6) π-1.30 (1H, b s, NH), 2.20-2.80 (m, 3H, aryl H).
Reaction SMILES: [NH3:1].CO.Cl[C:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([CH3:12])[N:6]=1.C1(C)C=CC=CC=1>>[Cl:11][C:9]1[N:8]=[C:7]([CH3:12])[N:6]=[C:5]([NH2:1])[N:10]=1
Reactant: N
Reactant: Cc1nc(Cl)nc(Cl)n1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nc(N)nc(Cl)n1
Reaction time: 2.5 h
Yield: 73 %

Procedure:
A solution of ammonia, 2.0M methyl alcohol (Aldrich, St. Louis, Mo.) (36.0 mL, 72 mmol) was added dropwise at room temperature (slightly exothermic) to a stirred yellow suspension of 2,4-dichloro-6-methyl-1,3,5-triazine (from Example 7) (2.94 g, 18 mmol) in toluene (20.0 mL, 188 mmol) over 1.5 h. The resulting mixture was stirred for an additional 2.5 h, concentrated and purified (ISCO, DCM to 10% MeOH in DCM) to give the desired product 4-chloro-6-methyl-1,3,5-triazin-2-amine (1.88 g, 73%) as a yellow solid. MS (API-ES) m/z 145 (M+H)+; 1H NMR (CD3OD, 300 MHz) δ 2.32 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:18]([F:33])[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO[C:37](OC)([CH3:39])[CH3:38].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]1[C@@H:8]2[C@H:13]([C@H:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])=[C:18]([F:33])[CH:17]=3)[CH2:11][S:10][CH2:9]2)[O:14][C:37]1([CH3:39])[CH3:38])=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2ccc(NC(=O)OCc3ccccc3)c(F)c2)[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H]2CSC[C@@H](Cc3ccc(NC(=O)OCc4ccccc4)c(F)c3)[C@@H]2OC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of [(3R*,4S*,5S*)-5-(4-benzyloxycarbonylamino-3-fluoro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (50.5 g, 102.9 mmol) and acetone dimethylketal (263 mL, 2.06 mol) in CH2Cl2 (500 mL) was added p-TsOH (200 mg, 1 mmol) at 0-5° C. and the reaction mixture was stirred for 4 h at 25° C. The reaction mixture was washed with saturated NaHCO3 solution and water, dried over MgSO4, filtered and evaporated to dryness. The title compound obtained as a yellow oil was used as such in the next step: TLC (toluene-EtOAc 3:1) Rf=0.40; HPLC RtA=2.80 min; ESIMS [M−H]−=529; 1H NMR (400 MHz, CDCl3): δ 7.99 (m, 1H), 7.38 (m, 5H), 6.92 (m, 2H), 6.84 (s, 1H), 5.21 (s, 2H), 3.3-3.6 (m, 2H), 3.03 (m, 2H), 2.52 (m, 2H), 2.38 (dt, 1H), 2.34 (t, 1H), 2.20 (m, 1H), 1.58 (s, 3H), 1.52 (s, 3H), 1.43 (s, 9H).