Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][O:2][CH3:3].Cl.CC(O[Na])=O.[CH3:10][NH:11][C:12]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:25])[C:17](=O)[CH2:16][CH2:15][CH2:14][CH2:13]1>CO.O.O>[CH3:3][O:2][N:1]=[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25])[NH:11][CH3:10]
Reactant: CNC1(c2ccccc2Cl)CCCCC1=O
Reactant: CON
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC1(c2ccccc2Cl)CCCCC1=NOC
Temperature: 25 °C

Procedure:
To as solution of NH2OMe. HCl and CH3COONa. H2O in MeOH:H2O (7:3) stirred at room temperature for 15 minutes, was added ketamine and the resulting solution was stirred at reflux for 16 hrs before cooling to room temperature. The reaction mixture was filtered and the filtrate was partitioned between CH2Cl2 and sat. NaHCO3 solution. The filtrate was extracted with CH2Cl2 (2×30 mL) and the combined organic layer was washed with brine solution. The organic layer was dried over anhydrous. Na2SO4 and concentrated under reduced pressure. The crude reaction mixture received was purified over silica gel column chromatography by eluting with initially CH2Cl2 and later with (1:9) MeOH:CH2Cl2 to receive methoxime 3 as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.9-8.0 (m, 1H), 7.2-7.4 (m, 3H), 3.91-4.0 (m, 3H), 3.3 (td, J=4.10, 13.96 Hz, 1H), 3.2 (td, J=4.49, 13.73 Hz, 1H), 2.4-2.5 (m, 3H), 2.1-2.3 (m, 1H), 1.6-1.8 (m, 3H), 1.4-1.5 (m, 1H), 1.2-1.4 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 156.3, 135.5, 132.4, 132.2, 131.9, 131.0, 128.3, 67.4, 62.7, 39.4, 28.8, 26.1, 24.7, 22.0.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][O:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH2:33][OH:34])=[CH:27][CH:26]=1>ClCCl>[S:2]([O:34][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([CH2:29][C:28]2[CH:38]=[CH:39][C:25]([O:24][CH2:23][C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]=3)=[CH:26][CH:27]=2)[CH:31]=1)(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Reaction time: 24 h

Procedure:
To methanesulfonyl chloride (0.002 mol) and triethylamine (0.002 mol) in dichloromethane (40 ml) at 0° C. is added 3-(4-(2-quinolinylmethyloxy)benzyl)benzyl alcohol (0.0018 mol) in dichloromethane (40 ml) dropwise. After 24 hours, the reaction mixture is washed with water, dried and evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)benzyl alcohol mesylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([CH:19]3[CH2:21][CH:20]3[C:22]([O:24]CC)=[O:23])[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:4][CH:3]=1.C1CC(NC2C3C(=CC(Cl)=C(Cl)C=3)C(C3C=CN=CC=3)=NN=2)CC1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([CH:19]3[CH2:21][CH:20]3[C:22]([OH:24])=[O:23])[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC1c1c(-c2ccncc2)c(-c2ccc(F)cc2)nn1CCO
Agent: Clc1cc2c(NC3CCCC3)nnc(-c3ccncc3)c2cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC1c1c(-c2ccncc2)c(-c2ccc(F)cc2)nn1CCO

Procedure:
To a solution of ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylate prepared in accordance with Example A-196 (0.21 g, 0.00045 mol) in 10 mL of methanol was added a solution of sodium hydroxide (0.09 g, 0.0022 mol) in 2 mL of water. The reaction mixture was stirred at reflux for 6 hours. After the solvent was removed, the residue was dissolved with 10 mL of 1N HCl and stirred for 30 minutes. The pH was then adjusted to 5-6 by addition of 1N sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium and filtered. The filtrate was concentrated and the crude was purified by recrystallization from ethanol and ether to give 0.1 g of product, 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylic acid, as a white solid (60% yield), mp: 253-255° C.; 1H NMR (CD3OD): δ 8.46 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 4.39 (t, J=5.0 Hz, 2H), 4.03 (m, 2H), 2.60 (m, 1H), 1.51 (m, 2H), 0.97 (m, 2H); Anal. Calc'd For C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44. Found: C, 64.92; H, 4.77; N, 11.20.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:25]([C:28]1[CH:33]=[CH:32][C:31](F)=[CH:30][CH:29]=1)(=[O:27])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:25]([C:28]1[CH:29]=[CH:30][C:31]([N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][OH:8])[CH2:2]2)=[CH:32][CH:33]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)c(C)c1
Reactant: OCC1CNCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(N3CCOC(CO)C3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of morpholin-2-ylmethanol (30 mg, 0.256 mmol) in tetrahydrofuran (THF) (3 mL) stirred under nitrogen at room temperature was added triethylamine (0.071 mL, 0.512 mmol) dropwise. The reaction mixture was stirred at room temperature for 10 minutes then N-(2,4-dimethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (86 mg, 0.256 mmol) was added. The reaction mixture was stirred at room temperature overnight. LCMS analysis showed no product, so the solvent was removed under a stream of nitrogen and the crude treated with LiHMDS (1M in THF, 0.768 mL, 0.768 mmol) and THF (2 mL). The reaction vessel was sealed and heated by microwaves (Biotage Initiator) to 150° C. for 30 minutes. After cooling, LCMS analysis showed some conversion, so the reaction vessel was resealed and reheated by microwaves (Biotage Initiator) to 150° C. for a further 30 minutes. No further conversion was seen by LCMS, so ethyl acetate (10 mL) was added to the mixture and the organic phase washed with water (10 mL) then dried using a hydrophobic frit. Solvent was removed under a stream of nitrogen to give the crude product. The crude was purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 4 mg. LCMS [LCMS2] Rt 1.29 min, m/z (ES+) 433 (M+H).
Reaction SMILES: [Ca:1].[Na].[B].[B:4]([OH:7])([OH:6])[OH:5].[S:8](=[O:12])(=[O:11])([OH:10])[OH:9]>>[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[Ca+2:1].[B:4]([OH:7])([OH:6])[OH:5]
Reactant: [Ca]
Reactant: O=S(=O)(O)O
Agent: OB(O)O
Agent: [B]
Agent: [Na]
Product: O=S(=O)([O-])[O-]
Product: [Ca+2]

Procedure:
Another process to obtain boric acid starting from minerals containing calcium, sodium and boron, such as ulexite, is described by Werner Janik et al in the Polish Pat. No. 218,576, issued Sept. 26, 1979 appearing in German publication No. 3,029,349, issued on Apr. 16, 1981. It includes the manufacture of boric acid from Peruvian ulexite by heating said ulexite in 96% sulfuric acid in an amount sufficient to precipitate calcium sulfate, resulting in a suspension of calcium sulfate in a solution of boric acid plus other secondary products. The calcium sulfate is separated from the solution and is then treated with ion exchange apparatus in order to obtain the boric acid by acidification, crystallization and purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].[CH2:14]([O:16]C(=O)OCC)C.Cl>C1C=CC=CC=1>[OH:9][C:8]1[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[O:11][C:14](=[O:16])[CH:10]=1
Reactant: CC(=O)c1ccc(C)cc1O
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc2c(O)cc(=O)oc2c1
Temperature: 25 °C

Procedure:
A solution of 42 g (0.28 mol) of 4-methyl-2-hydroxyacetophenone in benzene (150 mL) was added over 30 min., to a suspension of NaH (50% oil), (30 g, 0.63 mol) in 400 mL of benzene at reflux. Then diethylcarbonate (67.8 mL, 0.56 mol) in benzene (500 mL) was added over 15 min. The reaction mixture was refluxed for 16 h and more NaH (13 g, 0.28 mol) was added followed by more diethylcarbonate (33 g, 0.28 mol). After another 6 h at reflux the reaction mixture was cooled to room temperature and 2N HCl was added (1.5 L) to form a white precipitate. The solid was then filtered and added to a solution of NaOH (4N, 800 mL). The resulting basic solution was then extracted with Et2O (2×500 mL) and the basic solution acidified with conc. HCl to give a white solid which, after filtration and drying, gave the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[OH-].[Na+]>O.CCOCC>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCCCCCc1ncccn1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: BrCCCCCCOCCCCCCc1ncccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2-pyrimidinehexanol (1.18 g), 1,6-dibromohexane (4 ml), 50% sodium hydroxide (4 ml) and TAB (100 mg) was vigorously stirred at room temperature for 17 h, then diluted with water (40 ml) and ether (50 ml). The organic phase was dried and evaporated in vacuo to an oil which was purified by FCC. Elution with hexane followed by hexane-ether (1:1) gave the title compound as a colourless oil (670 mg), t.l.c. (ether) Rf 0.24
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:37](O)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O=C(O)c1ccccc1
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1[C@H](OC(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To a stirred solution of compound 1B (69.1 g, 0.282 mol), Ph3P (88.7 g, 0.338 mol) and benzoic acid (41.32 g, 0.338 mol) in anhydrous THF (1.35 L) cooled to 0° C. was added a solution of DEAD (62 mL, 0.33 mol) in anhydrous THF (50 mL) dropwise over 1 h through an addition funnel. After the addition, the resulting light yellow solution was stirred at rt until the reaction was complete (˜8 h). The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to yield a crude product as a semi-solid. The crude product was suspended in 25% EtOAc/hexane and stirred vigorously for 3 h. The resulting suspension was filtered and the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×). The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane as described above to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified by flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane to furnish pure compound 1C (88.4 g) as a light yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Br:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-aminophenyl)morpholine-4-carboxylate (3.07 g, CAS-1002726-96-6) in DMF (30 ml) was added NBS (1.96 g) and the mixture was stirred at room temperature for 15 min. The reaction mixture was then poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo to afford tert-butyl (RS)-2-(4-amino-3-bromophenyl)morpholine-4-carboxylate (4.0 g, quant.) as a light brown solid which was used in the next step without further purification. MS (ISP): 359.0 ([{81Br}M+H]+), 357.0 ([{79Br}M+H]+), 303.0 ([{81Br}M+H—C4H8]+), 301.0 ([{79Br}M+H—C4H8]+).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]1[CH:11]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(=O)n(-c2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1cc(=O)n(-c2ccccc2)c2ccccc12
Yield: 51 %

Procedure:
Diethyl 1,2-dihydro-2-oxo-1-phenylquinol-4-ylmalonate (2.7 g.) was dissolved in ethanol (50 ml.), and a solution of sodium hydroxide (2.85 g.) in water (3 ml.) was added. The mixture was heated under reflux for 1 hour, and then cooled and poured into water (200 ml.) to give a solution which was treated with decolourising carbon, filtered, and adjusted to pH 3 by addition of hydrochloric acid. The precipitate was collected by filtration, washed with water, drained, and crystallised from methanol to give 1,2-dihydro-2-oxo-1-phenylquinol-4-ylacetic acid, m.p. 185.5-186° C. (decomposition), in 51% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:29][C:30]2[CH:35]=[CH:34][C:33]([O:36]C3CCCCO3)=[CH:32][CH:31]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:20][CH:19]3[CH2:21][CH:15]([CH2:16][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)[CH2:14]2)=[CH:5][CH:4]=1)#[N:2].C(O)(=O)C.O.[OH-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:29][C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH:15]3[CH2:21][CH:19]([CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]3)[CH2:20]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CCCC(Oc3ccc(OC4CCCCO4)cc3)c3ccc(C#N)cc3)C2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CCCC(Oc3ccc(O)cc3)c3ccc(C#N)cc3)C2)C1
Temperature: 35 °C
Reaction time: 48 h
Yield: 72.7 %

Procedure:
tert-Butyl 7-{4-(4-cyanophenyl)-4-[4-(tetrahydro-2H-pyran-2-yloxy)-phenoxy]butyl}-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (iv) above; 2.33 g; 4.0 mmol), was dissolved in THF (40 mL), acetic acid (20 mL) and H2O (10 mL). The mixture was stirred at 35° C. for 2 days. The mixture was made basic with 10 M NaOH (whilst cooling). Extraction with DCM, separation of the organic layer, evaporation of the solvent and chromatography on silica (CH3CN) gave 1.43 g (72%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:15]2[CH2:17][CH2:16]2)[C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:18][CH2:19][C:20](Br)=[O:21]>>[C:7]([C:6]1[C:5]([CH:15]2[CH2:16][CH2:17]2)=[CH:4][S:3][C:2]=1[NH:1][C:20](=[O:21])[CH2:19][Br:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Br)CBr
Reactant: Nc1scc(C2CC2)c1C(=O)c1ccccc1
Product: O=C(CBr)Nc1scc(C2CC2)c1C(=O)c1ccccc1

Procedure:
reacting the 2-amino-3-benzoyl-4-cyclopropylthiophene with bromoacetyl bromide to form 3-benzoyl-2-(α-bromoacetamido)-4-cyclopropylthiophene (IV),
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:15](=[O:23])([O:17][C:18](=O)C(C)Cl)[NH2:16].CN(C)P([N:31]([CH3:33])[CH3:32])(N(C)C)=O>>[CH3:18][O:17][C:15]([NH:16][C:2]1[N:3]=[C:4]2[CH:5]=[C:6]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=[CH:33][N:31]2[CH:32]=1)=[O:23]
Reactant: Nc1cc(Sc2ccccc2)ccn1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC(Cl)C(=O)OC(N)=O
Product: COC(=O)Nc1cn2ccc(Sc3ccccc3)cc2n1

Procedure:
A mixture of 2-amino 4-phenylthio pyridine, 1.0 g. (0.00494 mole) and 0.82 g. of methylchloroacetyl carbamate are heated in hexamethylphosphoramide following the procedures of Example 5 to yield 2(methoxycarbonylamino) 7-(phenylthio) imidazo [1,2-a] pyridine, m.p. 221°-223° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]=[N+:15]=[N-:16])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: COc1cccc(N=[N+]=[N-])c1
Reaction time: 2 h

Procedure:
A solution of 9.26g. (0.08 mole) of 3-methoxyaniline in 40 ml. of water and 20 ml. of concentrated HCl was cooled to 0° C. There was then added a solution of 6.07g. (0.088 mole) of NaNO2 in 20 ml. of water, and the reaction mixture was aged for 1/2 hour. There was next added 70 ml. of hexane followed by dropwise addition of a solution of 5.72g. (0.088 mole) of NaN3 in 20 ml. of water. After addition was complete, the reaction mixture was aged for 2 hours at room temperature. The aqueous and organic components were separated and the aqueous component was extracted with 50 ml. of hexane. The hexane component and extract were dried over MgSO4 and concentrated under reduced pressure to 10.77g. (50.5%) of a yellow oil. Structure of the product as 3-methoxyphenylazide was confirmed by IR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[N:11][C:10]=2[C:18](NOCCOC=C)=[O:19])=[C:4]([F:27])[CH:3]=1.[CH3:28][C:29]1([CH3:37])[O:33][C@@H:32]([CH2:34][O:35][NH2:36])[CH2:31][O:30]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[N:11][C:10]=2[C:18]([NH:36][O:35][CH2:34][C@H:32]2[CH2:31][O:30][C:29]([CH3:37])([CH3:28])[O:33]2)=[O:19])=[C:4]([F:27])[CH:3]=1
Reactant: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Reactant: CC1(C)OC[C@H](CON)O1
Product: CC1(C)OC[C@H](CONC(=O)c2ncc3cncn3c2Nc2ccc(Br)cc2F)O1

Procedure:
The desired compound was prepared in an analogous fashion to 5-(4-bromo-2-fluorophenylamino)-N-(2-(vinyloxy)ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamide, using (R)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine as the starting material. LCMS (method D1): RT=0.954 min, [M+H]+=480/482.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([CH3:3])[CH3:2].[CH3:12][C:13]([S@@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)/[CH:7]=[N:18]/[S@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)c1cccc(C=O)c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: CC(C)c1cccc(/C=N/[S@@](=O)C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 3-isopropylbenzaldehyde (0.711 g, 4.75 mmol) in THF (5 mL) was added (S)-2-methyl-2-propanesulfinamide (0.534 g, 4.32 mmol) and Ti(OiPr)4 (2.75 mL, 8.64 mmol). The resulting mixture was allowed to stir over night at rt where it was then quenched with aqueous NH4Cl (5 mL) and diluted with EtOAc (100 mL). The mixture was then filtered through celite using excess EtOAc to rinse, concentrated to an oil crude and separated by silica gel (EtOAc:Hexanes) to isolate the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH:5]=[N:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cncc(-c2ccc(OC(F)(F)F)cc2)c1)c1ccccc1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 11.8 g (41.4 mmol) of N-(5-bromopyridin-3-yl)benzamide, 12.8 g (62.1 mmol) of [4-(trifluoromethoxy)phenyl]boronic acid and 11.4 g (82.7 mmol) of potassium carbonate were dissolved in 70 ml of 1,2-dimethoxyethane, 21 ml of water and 156 ml of DMF. The mixture was flushed with argon, 0.24 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was triturated with methyl tert-butyl ether. The solid was filtered off and the filtrate was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 2:1=>1:5). The separated solid and the appropriate fraction from the chromatography were combined. Yield: 6.7 g (45% of theory)
Reaction SMILES: [NH2:1][C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH:20](O)=[O:21].C(OC(=O)C)(=O)C>O>[NH:1]([CH:20]=[O:21])[C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=CO
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CN[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
444.7 g (1.67 mole) of commercially available H-Orn(Z)-OH was dissolved in 3.5 L (93 moles) of formic acid. The solution was cooled in an ice bath, and 1.17 L (12 moles) of acetic anhydride was subsequently added in dropwise fashion over two hours while the temperature of the reaction mixture was maintained between about 5° and 15° C. The resultant reaction mixture was stirred at room temperature for about two hours after the addition was completed, and the reaction vessel was refrigerated overnight. 1.5 L of cold water was then added, and the solution was concentrated to dryness under reduced pressure. The residual, light yellow syrup was taken up into EtOAc, washed with water and then with saturated NaCl, and then dried overnight over sodium sulfate. After filtration and evaporation to dryness, the residual syrup was dissolved in 5 L of ethyl ether. The solution was cooled in a dry ice bath and seeded. The resulting crystalline product was filtered, washed with ethyl ether, air dried for two hours and finally dried in a lyophilizer. 431.6 g (1.47 mole, 88%) of For-Orn(Z)-OH was obtained.