Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=4)[C:11]=3[CH:23]=2)=[N:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([S:21]([CH3:22])=[O:32])=[CH:19][CH:20]=4)[C:11]=3[CH:23]=2)=[N:5][N:6]=1
Reactant: CSc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nnc(-c2ccc3occ(-c4ccc(S(C)=O)cc4)c3c2)o1
Reaction time: 0.08 h
Yield: 83.9 %

Procedure:
To a solution of 2-methyl-5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (322 mg, 1.00 mmol) in dichloromethane (10 mL) was added m-chloroperbenzoic acid (70%, 259 mg, 1.05 mmol) at room temperature, and the resulting mixture was stirred for 5 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate) and recrystallized from tetrahydrofuran to give the title compound (284 mg, yield 84%) as colorless crystals.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([C:26]([F:29])([F:28])[F:27])[N:15]([CH2:30][CH2:31][OH:32])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:33]([O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][N:15]([CH2:30][CH2:31][OH:32])[C:16]=1[C:26]([F:27])([F:29])[F:28])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: OCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2O)c1C(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2OCc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.5 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole (111 mg) in N,N-dimethylformamide (0.5 mL) were added benzyl bromide (49 mg) and potassium carbonate (43 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1–5/1) to give the title compound (108 mg).
Reaction SMILES: N[C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:33]>O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:25]=[CH:26][C:8]([C:3]3[C:2]([F:33])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:9][CH:10]=2)=[CH:16][CH:17]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3F)cc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
The product from Example 3 (52.0 mg, 0.145 mmol) in 48% HBF4 (0.75 mL) and water (0.1 mL) was treated with solid NaNO2 (11.9 mg, 0.172 mmol) at 0° C. After stirring for 30 minutes, the layers were allowed to separate and the liquid was layer was removed by pipette. The remaining solid was dried under reduced pressure and slurried in toluene (1.5 mL). The suspension was heated at 100° C. for 2.5 hours, allowed to cool to room temperature, and the toluene was removed by pipette. The residue was treated with 1N NaOH (1 mL) and CHCl3 (1 mL) and stirred for 15 minutes. The phases were allowed to separate and the aqueous layer was extracted with CHCl3 (2×1 mL). The organic layers were combined, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (20% ethyl acetate in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.56 (dt, 1H), 8.12 (d, 2H), 7.98 (d, 2H), 7.84 (br s, 1H), 7.59 (d, 2H), 7.53 (ddd, 1H), 7.40 (d, 2H), 7.33 (ddd, 1H), 1.33 (s, 9H); MS (m/z) 349.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: C1CCNCC1
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCCC1

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]([CH2:20][C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.Cl.[CH3:38]O>>[CH3:38][O:18][C:17](=[O:19])[CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([F:34])([F:35])[F:36])[C:2]=2[Cl:1])[CH2:20][C@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])[CH:11]=1
Reactant: CO
Reactant: C[C@H](CN(CCCOc1cccc(CC(=O)O)c1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Agent: Cl
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)C[C@@H](C)c2ccccc2)c1
Yield: 90 %

Procedure:
To a solution of (3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-acetic acid (Example 10, 0.5 g, 3.7 mmol) in methanol (300 ml) was added concentrated hydrochloric acid (10 ml). After the resulting mixture was heated to reflux for 2 h solvent was removed under vacuum. The residue was dissolved in water and neutralized to pH=7. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, and concentrated in vacco to give the title compound as colorless oil (0.5 g, 90%). MS m/e 534.6 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.C(OCC)(=O)C>[O-:34][N+:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cc[n+]([O-])cc1)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Benzyl 4-[(4-pyridinylamino)carbonyl]-1-piperidinecarboxylate (EXAMPLE 1, Step 1) (615 mg, 1.81 mmol) was dissolved in CH2Cl2 and treated with mCPBA (3.12 g, 18.10 mmol) and aged 18 h. The reaction was diluted with ethyl acetate and washed with sat. NaHCO3. The organics were separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography to afford benzyl 4-{[(1-oxido-4-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][S:9](O)(=[O:11])=[O:10].S(Cl)(Cl)=O>S(=O)(=O)(O)N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:9]([Cl:8])(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: NS(=O)(=O)O
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 108.2 %

Procedure:
112.6 g (1.0 mol) of chlorobenzene are added dropwise at 70° C. over a period of 1 hour to 122 g (1.05 mol) of chlorosulfonic acid. The mixture is then stirred at this temperature for 15 minutes. 1 g of sulfamic acid is then added and 180 g (1.5 mol) of thionyl chloride are added dropwise at 70° C. in the course of 2 hours. Working up is carried out as described in Example 1. 228.3 g of moist 4-chlorobenzenesulfonyl chloride having a water content of 12% are obtained. This corresponds to 200.9 g of 4chlorobenzenesulfonyl chloride (94.4% of theory), calculated as dry material, having a purity of 95%.
Reaction SMILES: [CH:1]1([CH:6]([CH2:16][CH3:17])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]([CH3:30])[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1.Cl>C(O)C>[CH:1]1([CH:6]([CH2:16][CH3:17])[C:7]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][N:19]([CH3:30])[CH3:18])=[CH:24][CH:25]=2)([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCOc1ccc(Br)cc1
Reactant: CCC(C(=O)c1ccc(O)cc1)C1CCCC1
Agent: Cl
Solvent: CCO
Product: CCC(C1CCCC1)C(O)(c1ccc(O)cc1)c1ccc(OCCN(C)C)cc1

Procedure:
2-cyclopentyl-1-[p-(N,N-dimethyl-2-aminoethoxy)phenyl]-1-(p-hydroxyphenyl)-1-butanol, which was prepared from α-cyclopentyl-p-hydroxybutyrophenone and p-(N,N-dimethyl-2-aminoethoxy) bromobenzene according to the procedure of example 3, was dehydrated in ethanol in the presence of hydrochloric acid. The product was recrystallized from n-hexane, mp. 112°-120° C. and was found to be an 1:1 mixture of E- and Z-isomers.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]([OH:11])=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][N:2]1[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCOCC1
Agent: Cl
Product: O=C(CN1CCOCC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 17 %

Procedure:
Proceeding as in Example 1, but substituting 2-morpholin-4-ylacetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 155, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-morpholinoacetamido)propanamide (23 mg, 17%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.20 (br s, 1H), 7.98-7.96 (d, 1H), 7.61-7.57 (d, 2H), 7.33-7.26 (m, 5H), 7.23-7.19 (t, 2H), 7.04-6.97 (m, 4H), 4.72-4.67 (m, 1H), 4.52 (s, 2H), 3.78-3.68 (m, 2H), 3.59-3.57 (t, 4H), 2.99 (s, 2H), 2.47-2.42 (m, 4H). MS (EI) for C28H30FN3O5. found 508.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([OH:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].C(OCC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([CH3:16])[O:17][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)Cc1ccc(-c2ccc(Br)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](Cc1ccc(-c2ccc(Br)cc2)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
(2S)-1-(4′-Bromobiphenyl-4-yl)propan-2-ol (0.23 g, 0.79 mmol) and imidazole (0.11 g, 1.6 mmol) were dissolved in N,N-dimethylformamide (5 mL), and tert-butyldimethylchlorosilane (0.24 g, 1.6 mmol) was added under a nitrogen atmosphere, followed by stirring at room temperature for 1 hour. Diethyl ether was added to the reaction solution, followed by sequential washing with water and hydrochloric acid (1 M). After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.80 (hexane/ethyl acetate=10/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.25 g, 0.62 mmol) as a white solid (yield 78%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[OH-].[Na+].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:21])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: O=C1CCC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc([N+](=O)[O-])n1CCOC(=O)CCC(=O)O
Temperature: 8 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
In a 100 mL reactor with 10 mL of methanol at a temperature about 60° C., add 0.315 g of metronidazole, 2.0 mL of NaOH 1N, 0.2 g of succinic anhydride and keep the reaction medium under stirring and heating for about 2 hours. Cool the reaction medium to a temperature around 8° C. and allow it to stand for 12 hours. The reaction medium is filtered and the solvent is evaporated to dryness yielding 0.47 g of metronidazole monosuccinate. (Yield=94%)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:17])[C@@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([OH:16])[CH2:6]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1>CS(C)=O>[CH3:3][N:4]([CH3:17])[C@@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([O:16][C:22]2[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=2)[CH2:6]1
Reactant: Fc1ccc(Br)cc1
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc(Br)cc2)C1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A mixture of 8 ml of dimethylsulfoxide and 0.820 g of sodium hydride as a 50% oil dispersion was heated at 50° C. for 45 minutes and was then cooled to 20° C. 3 g of cis 7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were added thereto and the mixture stood at room temperature for 15 minutes after which 2 ml of p-bromo-fluorobenzene were added thereto. The mixture was heated at 90°±5° C. for one hour and was then cooled to 20° C. and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness to obtain 6 g of cis N,N-dimethyl-5-[4-bromophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in the form of a yellow oil.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH:7]([O:10][CH3:11])[CH2:8][NH2:9].C([O:14][C:15]([C:17]1[NH:18][N:19]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)=O)C>C1COCC1>[CH3:5][O:6][CH:7]([O:10][CH3:11])[CH2:8][NH:9][C:15]([C:17]1[NH:18][N:19]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)=[O:14]
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Reactant: COC(CN)OC
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: COC(CNC(=O)c1cc(COc2ccccc2)n[nH]1)OC
Temperature: 130 °C
Yield: 144.2 %

Procedure:
Trimethylaluminum (1.7 mL, 3.4 mmol) was added to a stirred solution of aminoacetaldehyde dimethyl acetal (0.37 mL, 3.4 mmol) in THF (2 mL) at 0° C. under nitrogen atmosphere. To this solution 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.7 g, 2.84 mmol) in THF (5 mL) was added at 0° C. The reaction was heated at 130° C. for 2 minutes under microwave irradiation. Then mixture was quenched with a 2N solution of HCl (pH-3) and diluted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid (2,2-dimethoxy-ethyl)-amide (1.25 g, quantitative) as a brown oil that was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN(C=O)C.O>[Cl:12][C:4]1[N:3]=[C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(Cl)cc(N)c2[N+](=O)[O-])CC1
Reaction time: 0.08 h

Procedure:
A solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (0.500 g, 2.40 mmol) in DMF (5 mL) was treated with K2CO3 (1.66 g, 12.0 mmol) and 1-methylpiperazine (0.267 mL, 2.40 mmol) at room temperature for 18 h. The resulting mixture was diluted with water (75 mL) and extracted three times with EtOAc (50 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 3:1 v/v for 5 min, then 3:1 to 1:0 v/v over 40 min) to yield 6-chloro-2-(4-methyl-piperazin-1-yl)-3-nitro-pyridin-4-ylamine as a bright yellow solid. 1H-NMR (400 MHz, CD3OD) δ: 6.22 (s, 1H), 3.39-3.45 (m, 4H), 2.49-2.55 (m, 4H), 2.34 (s, 3H). Mass Spectrum (LCMS, APCI pos.): Calculated for C10H14ClN5O2: 272.1 (M+H); Measured: 272.1.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:29])[CH:28]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)ccc3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.46 ml, 4.45 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 143 (1.4 g, 4.45 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.0 g of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 7:3).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[N:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cn1nc(-c2ccccc2)nc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)nn2C)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 22.8 %

Procedure:
To a solution of 1-methyl-3-phenyl-1,2,4-triazol-5-amine (320 mg, 2 mmol) in 10 mL of dry pyridine was added 427 mg of 4-methylbenzenesulfonyl chloride (224 mmol). The solution was stirred at room temperature under Argon. After 23 h, the pyridine was removed in vacuo and flashed off with toluene, and the residue was partitioned between 1M NaOH and EtOAc. The alkaline phase was made acidic and the flocculent solid was collected by filtration and taken up in acetone. The aqueous phase was extracted with EtOAc, washed with H2O and dried over Na2SO4. The acetone and the EtOAc phases were combined and evaporated in vacuo to give 0.15 g of a white solid which was taken up in hot HOAc (7 mL), diluted with water (4 mL), and seeded to give 80 mg of needles with mp 300-302° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18](Cl)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CC1OCCC1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Reactant: C1COCCN1
Solvent: O
Solvent: CC1CCCO1
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (15.2 g, 41.16 mmoles) is charged into a 250 mL 3-necked round bottomed flask, followed by addition of 2-MeTHF (61 mL, 4.0 volumes), the yellowish brown slurry is stirred at about 20° C. for 5 min. Then morpholine (19 g, 218.18 mmoles) is added over 2-5 minutes. Contents are heated to reflux and maintained at reflux for 12 hr. The slurry is cooled to 25° C., followed by addition of 2-MeTHF (53 mL, 3.5 volumes) and water (38 mL 2.5 volumes). The reaction mixture is warmed to 40° C., where upon a homogenous solution with two distinct layers formed. The layers are separated, the organic layer is filtered and concentrated to ˜3 volumes at atmospheric pressure. Four volumes 2-propanol (61 mL) are added. The solution is concentrated to ˜3 volumes followed by addition of 4 volumes 2-propanol (61 mL), re-concentrated to ˜3 volumes, followed by addition of another 6 volumes 2-propanol (91 mL), and refluxed for 15 min. The clear solution is gradually cooled to 75° C., seeded with 0.45 g 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine slurried in 2 mL 2-propanol, rinsed with an additional 2 mL 2-propanol and transferred to a crystallization flask. The slurry is cooled to between 0-5° C., maintained for 1 hr, filtered and the product rinsed with 2-propanol (30 mL, 2 volumes). The solid is dried at 60° C. in a vacuum oven to afford 16.92 g 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine. Purity of product by HPLC assay is 100.00%. XRPD and DSC data of product is consistant with reference sample. MS (ES)=420 (M+1).