Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:21]=1)[C:10]([CH3:29])([CH3:28])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][C:10]1([CH3:29])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:21]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cncc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
To a stirred mixture solution of 3,3-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.5 g, 6.5 mmol) in methanol (15.0 mL) and tetrahydrofuran (16.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.1 g, 90%) as a white solid: LC/MS m/e calcd for C21H25N3O3 (M+H)+: 368.45, observed: 368.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(N(CC)CC)C.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:18]([NH2:25])[C@H:17]1[OH:26]>CCCCO>[Cl:8][C:4]1[N:3]=[C:2]([NH:25][C@@H:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][C@@H:17]2[OH:26])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: O[C@H]1Cc2ccccc2[C@H]1Nc1cncc(Cl)n1
Temperature: 115 °C
Yield: 54.5 %

Procedure:
To a solution of 2,6-dichloropyrazine (5.0 g, 34 mmol) in n-BuOH (30 mL) was added triethylamine (6.8 g, 9.4 mL, 67 mmol) and (1R,2S)-(+)-cis-1-amino-2-indanol (5.0 g, 34 mmol). The mixture was heated at 115° C. overnight. The solution was cooled to rt and concentrated. Dissolve material in EtOAc (200 mL) and remove insoluble material by vacuum filtration. Wash filtrate sequentially with 4 N NaOH and sat. aq. NaCl. Dry organic extract over MgSO4, filter and concentrate. Purify by biotage MPLC (90 g column, 10% ethyl acetate/hexanes) to afford 4.85 g (57%) of (1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol as a solid: 1H NMR (CDCl3) δ 2.83–2.87, 3.08–3.13, 3.32, 4.54, 5.11, 5.28–5.31, 7.18–7.28, 7.73, 8.12; MS (ESI+) for C13H12ClN3O m/z 262 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:11]/1)=[O:5].[CH3:31][O:32][CH2:33]/[CH:34]=[CH:35]/B1OC(C)(C)C(C)(C)O1.[F-].[Cs+].C(OCC)(=O)C>C(COC)OC.CO>[C:12]([C:10]1[N:9]([CH3:16])[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)/[C:7](=[N:6]/[C:4](=[O:5])[C:3]2[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:2]=2/[CH:35]=[CH:34]/[CH2:33][O:32][CH3:31])/[CH:11]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2Br)n1C[C@H]1CCCO1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC/C=C/c1ccc(C(F)(F)F)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Yield: 51.6 %

Procedure:
To a solution of Example 88 (146 mg, 0.299 mmol) and (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (148 mg, 0.747 mmol) in dimethoxyethane (1 mL) and methyl alcohol (0.5 mL) was added palladium tetrakistriphenyl phosphine (86 mg, 0.075 mmol) and cesium fluoride (159 mg, 1.05 mmol). This mixture was microwaved at 100° C. for 10 min. To the reaction was added ethyl acetate and the mixture was filtered through celite and purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% solvent A in hexanes, solvent A: 10% MeOH in ethyl acetate) to afford the title compound (74 mg, 52%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.44 (s, 9H) 1.71-1.85 (m, 3H) 1.98-2.07 (m, 1H) 3.37 (s, 3H) 3.69-3.82 (m, 2H) 3.88 (s, 3H) 4.11-4.13 (m, 2H) 4.18-4.32 (m, 2H) 4.48-4.58 (m, 1H) 6.22 (dt, J=15.96, 6.30 Hz, 1H) 7.03 (s, 1H) 7.46-7.53 (m, 1H) 7.57-7.65 (m, 2H) 8.20 (s, 1H); MS (DCI/NH3) m/z 480 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([NH:49][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:48]1)=[O:42])[CH3:39]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CCOC(=O)N1CCC(N)CC1
Product: CCOC(=O)N1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 4-amino-piperidine-1-carboxylic acid ethyl ester according to conditions described in general procedure C. 1H NMR (400 MHz, DMSO-d6) δ 1.05-1.19 (m, 5 H), 1.43-1.70 (m, 8 H), 2.79 (s, 2 H), 3.23-3.28 (m, 4 H), 3.70-3.98 (m, 5 H), 6.16-6.34 (bd, 1 H), 6.95 (d, J=12.4 Hz, 1 H), 7.10-7.20 (m, 2 H), 7.38 (d, J=8.0 Hz, 1 H), 7.42 (s, 1 H), 7.53-7.60 (m, 3 H), 7.79 (d, J=7.7 Hz, 1 H), 7.96 (d, J=8.0 Hz, 1 H), 8.21 (s, 1 H), 10.40 (s, 1 H).
Reaction SMILES: C[O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25]/[CH:26]=[C:27](\[CH3:34])/[CH2:28][CH2:29][C:30]([O:32]C)=[O:31].[I-].[Li+].C(OCC)(=O)C.Cl>N1C(C)=CC(C)=CC=1C>[OH:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=CCc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2)CCC(=O)O

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate (28 g) in 2,4,6-collidine (100 ml) was heated to 65° C. and lithium iodide (50 g) was added. After 3 days the solution was added to ethyl acetate and dilute hydrochloric acid. The organic layer was dried and evaporated to afford (E) 6-(1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoic acid.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Na].[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>C(O)C>[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:2][C:3]#[N:4])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: N#CCCl
Agent: [Na]
Solvent: CCO
Product: N#CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 80.8 %

Procedure:
A solution of 3.78 g (0.0500 mol) of chloroacetonitrile in 10 ml of anhydrous ethanol is run over the course of 20 minutes into a solution of 1.04 g (0.0453 mol) of sodium and 10 g (0.0453 mol) of p-(p-chlorophenoxy)-phenol in 50 ml of anhydrous ethanol and the mixture is then heated to the reflux temperature for 4 hours. It is evaporated to dryness under reduced pressure and the residue is dissolved in diethyl ether, which is washed with water and with dilute sodium hydroxide solution. After drying over dry sodium sulphate and evaporating the solvent from the organic phase, 12 g of an orange-coloured oil are obtained. Purification of this oil by distillation under reduced pressure gives 9.5 g of a limpid pale yellow oil which is insoluble in water.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH2:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C.Cl>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CBr)cc1
Reactant: CCCCCCCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCCCCCCOC(=O)c1ccc(CBr)cc1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
In 30 ml of benzene was dissolved 2.3 g of 4-bromomethylbenzoic acid chloride, 1.37 g of n-octyl alcohol and 5 ml of triethylamine were added to the solution, and a reaction was carried out at room temperature with stirring overnight. Then, 30 ml of ethyl acetate and 10 ml of 2N HCl were added to the reaction mixture, and the organic layer was separated, washed with water and dried on magnesium sulfate. The solvent was removed by distillation, and the residue was separated and purified by the silica gel column chromatography to obtain 3.0 g of octyl 4-bromomethylbenzoate.
Reaction SMILES: ClC1C(=O)C2C(C(=[O:13])C=1Cl)=CC=CC=2.[N+]([O-])([O-])=O.[Na+].[N+:20]([C:23]1[C:24](=[O:34])[C:25]2[C:30]([C:31](=[O:33])[CH:32]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)([O-:22])=[O:21]>CO.O>[OH:13][C:32]1[C:31](=[O:33])[C:30]2[C:25]([C:24](=[O:34])[C:23]=1[N+:20]([O-:22])=[O:21])=[CH:26][CH:27]=[CH:28][CH:29]=2
Reactant: O=C1C=C([N+](=O)[O-])C(=O)c2ccccc21
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(O)=C([N+](=O)[O-])C(=O)c2ccccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A suspension of 2,3-dichloro-1,4naphthoquinone (6,83g; 0.03 mole) in methanol (40ml) was stirred during the addition of a solution of sodium nitrate (6.9g; 0.1 mole) in water (50ml) and the mixture stirred at 80° C for 3 hrs. Solution was attained after about 1 hr and the nitro naphthoquinone began to separate after 2 hrs. After cooling in ice and the yellow crystalline solid was filtered off, taken up in water (200ml), charcoalised and precipitated the product by addition of one-third the volume of concentrated hydrochloric acid, filtered off, washed well with 5N HCl and dried in vacuo over P2O5 /NaOH to give 5.30 g (81%) of material of m.p. 162°-163° C (d) which was identical to that prepared above.
Reaction SMILES: [Cl:1][C:2]([Cl:37])([Cl:36])[CH2:3][O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23]CC2C=CC(C(F)(F)F)=CC=2)=[O:22])[CH:15]=1.ClC(Cl)(Cl)COC(=O)C1C=CC=CC=1CSC1C=CC=C(CC(O)=O)C=1.[F:64][C:65]([F:76])([F:75])[C:66]1[CH:71]=[CH:70][C:69]([CH:72](O)[CH3:73])=[CH:68][CH:67]=1.C(Cl)Cl>CN(C1C=CN=CC=1)C.CCCCCCC.CCOC(C)=O>[Cl:1][C:2]([Cl:36])([Cl:37])[CH2:3][O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23][CH2:73][CH2:72][C:69]2[CH:68]=[CH:67][C:66]([C:65]([F:64])([F:75])[F:76])=[CH:71][CH:70]=2)=[O:22])[CH:15]=1
Reactant: CC(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCCc1ccc(C(F)(F)F)cc1
Yield: 68 %

Procedure:
The titled compound was prepared according to the method described for 2-[3-(4-trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid 2,2,2-trichloro-ethyl ester above from 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (168 mg, 0.387 mmol), 1-(4-trifluoromethyl-phenyl)-ethanol (88 mg, 0.465 mmol), EDCxHCl (111 mg, 0.581 mmol), DMAP (4.7 mg, 0.039 mmol) and DCM (4 mL). The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (160 mg, 68%) as an oil; 1H NMR (400 MHz, CDCl3): δ 2.67 (dd, 2H), 3.23 (s, 2H), 4.03 (dd, 2H), 4.27 (s, 2H), 4.67 (s, 2H), 6.74 (br d, 1H), 6.85-6.99 (m, 6H), 7.06 (dd, 1H), 7.13 (dd, 1H), 7.22 (d, 2H), 7.79 (d, 1H); Mass spectrum: M−H+ 604.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][C:3]#[CH:4].C([Li])CCC.[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].ICCCCCC>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[C:1]([OH:6])(=[O:5])[CH2:2][C:3]#[C:4][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC
Reactant: C#CCC(=O)O
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCCI
Solvent: C1CCOC1
Product: CCCCCCC#CCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6.8 g (70 mmol) of 3-butynoic acid dissolved in 150 ml of 1:1 tetrahydrofuran (THF):hexamethyl phosphoric triamide (HMPA) and cooled to -20° C. is added via syringe a solution of n-butyl lithium in hexane (1.6N, 2 equiv). The mixture was allowed to warm to 0° C. The mixture is stirred for 30 minutes at this temperature and then 150g (1.1 equiv) of 1-iodohexane is added dropwise as a solution in 20 ml of THF. The mixture is allowed to warm to room temperature and then is partitioned between ether and water. The aqueous layer is acidified with 3N H2SO4 and extracted with ether. The combined organic extracts are washed with brine and dried (Na2SO4). Evaporation of the volatiles in vacuo and chromatography of the crude on silica gel (ethyl acetate/hexane/acetic acid; 10:90:0.1) affords 4.5 g of pure 3-decynoic acid.
Reaction SMILES: [NH2:1][C:2](N)=[S:3].[Cl:5][C:6]1[CH:11]=C(Cl)N2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1>C(O)C>[Cl:5][C:6]1[CH:11]=[C:2]([SH:3])[N:1]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1
Reactant: Clc1cc(Cl)n2ncnc2n1
Reactant: NC(N)=S
Solvent: CCO
Product: Sc1cc(Cl)nc2ncnn12
Yield: 28.9 %

Procedure:
Thiourea (1.7 g) was added all at once to a solution of 4.2 g of 5,7-dichloro-s-triazolo[1,5-a]pyrimidine in 140 ml anhydrous ethanol at room temperature, the mixture was refluxed for 30 minutes, the crystals formed upon ice cooling were filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 18 ml of 1N sodium hydroxide solution. The resulting solution was washed with 20 ml of ethyl acetate. The pH was adjusted to 1.0 with concentrated hydrochloric acid to give crystals. The crystals were collected by filtration and washed with 20 ml of water and then with 20 ml of methanol, affording 1.2 g of the objective compound as faint yellow crystals.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:42][CH:43]([F:45])[F:44])=[C:19]([C:21]2[C:25]([NH:26][C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[N:34][C:33]=34)=[O:28])=[CH:24][N:23]([CH2:38][C:39](O)=[O:40])[N:22]=2)[CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:42][CH:43]([F:45])[F:44])=[C:19]([C:21]2[C:25]([NH:26][C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[N:34][C:33]=34)=[O:28])=[CH:24][N:23]([CH2:38][C:39]([N:5]3[CH2:6][CH2:7][N:2]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:4]3)=[O:40])[N:22]=2)[CH:20]=1
Reactant: CCOC(=O)CN1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a solution of ethyl 2-(piperazin-1-yl)acetate hydrochloride (400 mg, 1.92 mmol) in DMF (10 mL) was added {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (500 mg), DIEA (440 mg, 3.40 mmol), HATU (460 mg, 1.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with 4.5% MeOH in DCM to afford 59.4 mg (11%) of ethyl 2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate as a white solid. LCMS (Method 20) [M+H]+=617.2, RT=2.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.07 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.52-3.49 (m, 4H), 3.28 (s, 2H), 3.17-3.16 (m, 1H), 2.59-2.50 (m, 4H), 1.18 (t, 3H, J=7.2 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>ClCCl>[O:8]=[C:6]1[CH:7]([C:21](=[O:24])[CH2:22][CH3:23])[C:2](=[O:1])[CH2:3][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1
Reactant: CCOC(=O)C1CC(=O)CC(=O)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(=O)C(C(=O)CC)C(=O)C1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
4.2 g of ethyl 3,5-dioxocyclohexanecarboxylate and 3.4 g of triethylamine were dissolved in 50 ml of dichloromethane, to which was added dropwise 2.9 g of propionyl chloride under stirring at room temperature. The resultant mixture was allowed to react at ambient temperature for 2 hours, after which the reaction solution was washed with solution to remove the acidic matters from the reaction solution. The organic layer was then separated from the aqueous phase, dried and concentrated to a small volume. The concentrated solution was taken up in 20 ml of toluene, followed by addition of 0.5 g of 4-N,N-dimethylaminopyridine and heating the mixture at 85° C. for 3 hours. Thereafter, the toluene was removed from the reaction solution by distillation under reduced pressure, and the residue was chromatographed on silica gel using benzene as developing solvent to afford 2.5 g of the title compound (Compound No. 9 of Table 1) as colorless flakes having a melting point of 55°-56° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=[O:13])(=[O:7])=[O:6].CC(C)=[O:26]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:12]([OH:26])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)=O
Reactant: CC(C)(COS(=O)(=O)CCCCl)C(C=O)OCc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)C(OCc1ccccc1)C(=O)O
Yield: 96 %

Procedure:
Following the general procedure of the oxidation of aldehydes to carboxylic acids of Description 13, (3R/S)-2,2-dimethyl-4-oxo-3-(phenylmethoxy)butyl (3-chloropropyl)sulfonate (12b) (7.6 g, 21 mmol) dissolved in 100 mL of acetone was reacted with 10.5 mL of Jones-reagent (2.0 M in water). After work-up, 7.6 g (96% yield) of the title compound (12) was obtained as a colorless oil. The analytical data was consistent with the proposed structure and the data obtained for the enantiopure compound (11).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.O[C:7]([C:10]1[CH:11]=[C:12]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])[CH:13]=[C:14]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])[CH:15]=1)([CH3:9])[CH3:8]>FC(F)(F)C(O)=O>[CH3:9][C:7]([C:10]1[CH:15]=[C:14]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])[CH:13]=[C:12]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])[CH:11]=1)([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH3:8]
Reactant: CC(C)(O)c1cc(C(C)(C)C#N)cc(C(C)(C)C#N)c1
Reactant: c1nc[nH]n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C#N)c1cc(C(C)(C)C#N)cc(C(C)(C)n2cncn2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1,2,4-triazole (0.69 g) in trifluoroacetic acid (3.12 ml) was added to 2,2'-[5-(1-hydroxy-1-methylethyl)-1,3-phenylene]-di(2-methylpropiononitrile), (0.27 g), and the resulting solution was stirred at room temperature for 18 hr and then evaporated to dryness. The residue was treated with aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography using methanol (1% by volume) in dichloromethane as eluant, to give 2,2'-(5-[1-methyl-1-(1H-1,2,4-triazol-1-yl)ethyl]-1,3-phenylene)di(2-methylpropiononitrile), which was characterised as the hydrochloride salt, mp 185°-188°.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]#[N:13].N1C=CC=CC=1.O>ClCCl>[C:12]([C:11]1[CH:10]=[CH:9][S:8][C:7]=1[NH:6][C:2](=[O:3])[O:4][CH3:5])#[N:13]
Reactant: N#Cc1ccsc1N
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Nc1sccc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Methyl chloroformate (7.61 g, 80.5 mmol) was added drop-wise to a stirred of 2-amino-3-cyanothiophene (10 g, 80.5 mmol) and pyridine (19.1 g, 242 mmol) in dichloromethane (250 mL) at 0° C. After addition, the mixture was warmed to room temperature and stirred overnight. The reaction was treated with water (50 mL) and extracted with dichloromethane (3×150 mL). The combined organic phase was washed with 1 N hydrochloric acid (2×150 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), and dried over sodium sulfate. It was filtered and concentrated to give a crude product, which was triturated with a solution of methyl tert-butyl ether and petroleum ether (1:1, 50 mL) to give 11 g (75%) of methyl 3-cyanothiophen-2-ylcarbamate as a pale white solid. 1H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H), 6.63-6.65 (d, 1H), 6.94-6.96 (d, 1H), 7.94 (s, 1H).
Reaction SMILES: [C:1]1([C:7](=[O:11])[CH:8]([Br:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(OCC)C>[Br-:10].[CH3:12][NH+:13]1[CH:17]=[CH:16][N:15]([CH:8]([CH3:9])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])[CH2:14]1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: Cn1ccnc1
Solvent: CCOCC
Product: CC(C(=O)c1ccccc1)N1C=C[NH+](C)C1
Product: [Br-]
Yield: 54.8 %

Procedure:
A solution of 8 ml (0.047 mol) of 90% pure 1-phenyl-1-oxo-2-bromopropane and 4.25 g (0.052 mol) of 1-methylimidazole in 100 ml of diethyl ether was stirred at room temperature for approximately 24 hours. The precipitated solid was collected by filtration, washed with diethyl ether and dissolved in methanol. This solution was diluted with diethyl ether and the resulting white solid was collected by filtration. This solid was recrystallized from methanol/diethyl ether to afford 7.65 g of 1-methyl-3-(1-methyl-2-phenyl-2-oxoethyl)-1H-imidazolium bromide as white crystals. (55% yield) mp=167°-170° C.