Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:29])[CH:3]=1.[Na+].[CH3:31][S:32]([O-:34])=[O:33].[OH-].[Na+]>CS(C)=O.O>[F:29][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cc3F)nc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Temperature: 110 °C
Yield: 64.1 %

Procedure:
A mixture of 1,1-dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.781 g, 1.68 mmol), methanesulphinic acid sodium salt (0.86 g, 80%, 6.71 mmol), Cul (1.28 g, 6.71 mmol) and NaOH (81 mg, 2.02 mmol) in DMSO (20 mL) and water (0.5 mL) was degassed, purged with N2 and heated at 110° C. for 48 h. After cooled to ambient temperature, the mixture was poured into water (75 mL) and EtOAc (75 mL), and filtered through Celite®. The solid on Celite® was further washed with EtOAc. The filtrate and washing were combined and transferred to a separatory funnel. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow solid. The crude product was purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 followed by trituration with hot hexanes containing 1% of MeOH to give 0.5 g (64%) of 1,1-dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.40 (d, 1H, J=3.0 Hz), 8.15-8.10 (m, 1H), 7.90-7.75 (m, 3H), 7.50 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.20-4.10 (m, 2H), 4.00 (d, 2H, J=6.3 Hz), 3.18 (s, 3H), 2.90-2.75 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 465 (M+H).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:48])[C:19]([C:23]3[N:24]=[C:25]([NH:28][C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:49])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[NH2:50][C:51]1[C:52]2[N:53]([N:58]=[N:59][N:60]=2)[N:54]=[C:55]([SH:57])[CH:56]=1>C(#N)C>[NH2:50][C:51]1[C:52]2[N:53]([N:58]=[N:59][N:60]=2)[N:54]=[C:55]([S:57][CH2:5][C:6]2[CH2:7][S:8][C@@H:9]3[CH:16]([NH:17][C:18](=[O:48])[C:19]([C:23]4[N:24]=[C:25]([NH:28][C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[S:26][CH:27]=4)=[N:20][O:21][CH3:22])[C:15](=[O:49])[N:10]3[C:11]=2[C:12]([OH:14])=[O:13])[CH:56]=1
Reactant: Nc1cc(S)nn2nnnc12
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CC#N
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cc(N)c4nnnn4n3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a stirred solution of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (0.697 g; 0.001 mole) in anhydrous acetonitrile (50 ml), 8-amino-6-mercaptotetrazolo[1,5-b]pyridazine (0.336 g; 0.002 mole) was added and the resulting slurry was refluxed under a slow stream of nitrogen for 24 hours. Another portion of the mercapto compound (0.168 g; 0.001 mole) was added, and after further 16 hours of stirring at the reflux temperature, the mixture was cooled, the undissolved matter (unreacted mercapto compound) filtered off, the acetonitrile solution evaporated to dryness, the resulting foam taken up in warm methylene chloride (5 ml) and diethyl ether added (25 ml). The resulting white precipitate was collected by filtration and washed with a small amount of ethyl acetate and then with diethyl ether, thus giving 0.650 g of 3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)-thiomethyl]-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer). This material was reacted with 50% aqueous formic acid, as described in Example 1, thus giving the title product, which was shown by T.L.C., I.R. and NMR to be identical to the product prepared in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH2:13]OS(C)(=O)=O)=[CH:9][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)=[N:7]1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH2:13][N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)=[CH:9][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)=[N:7]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Reactant: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Yield: 55 %

Procedure:
Following the procedure of Example 1(10), 2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as slightly-yellow needles (yield: 55.0%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:22]2[CH:23]=[CH:24][C:20]([CH3:19])=[N:21]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: Cc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CSc1nc(N)nc(-n2ccc(C)n2)c1C#N
Temperature: 70 °C
Yield: 11.2 %

Procedure:
To a stirred solution of 2.05 g (8.36 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 15 ml NMP were added 3.00 g (9.20 mmol) cesium carbonate and 0.74 ml (9.20 mmol) 3-methyl-pyrazole and the mixture heated at 70° C. for 16 h. The reaction mixture was then poured into 400 ml ice-water and the resulting precipitate collected by filtration. Chromatography (ethyl acetate/hexane 1/1 then 2/1) afforded 230 mg (11%) 2-amino-4-(3-methyl-pyrazol-1-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 247 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:12]=[O:13])=[CH:14][CH:15]=2)=[N:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ncc(O)cn2)cc1
Reactant: OCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1ccc(-c2ncc(OCCCCCCCCO)cn2)cc1
Yield: 55 %

Procedure:
A solution of 6.1 g of 4-(5-hydroxypyrimidin-2-yl)benzaldehyde and 6.0 g of 8-chloro-1-octanol in 100 ml of ethyl methyl ketone was treated with 16.9 g of finely powdered potassium carbonate and the mixture was heated under slight reflux overnight. The suspension was suction filtered and the filtrate was concentrated in a vacuum. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) gave 5.5 g of 4-(5-[8-hydroxyoctyloxy]-pyrimidin-2-yl)benzaldehyde.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([O:38]C)=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1.Cl>CO.C(OCC)(=O)C.O1CCOCC1>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cncnc6)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(-c2cncnc2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1 M aqueous NaOH solution (167 μL) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(pyrimidin-5-yl)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (35 mg) in methanol (3 mL). The mixture is stirred at 40° C. for 1 hour. After addition of 1 N hydrochloric acid (167 μL) the mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried (MgSO4) and concentrated. The product thus obtained is dissolved in 1,4-dioxane and lyophilized to give the title compound. Yield: 29 mg; LC (method 11): tR=1.14 min; Mass spectrum (ESI+): m/z=511 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH:14]=C)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC[O:18]CC.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[C:7]([C:6]1[C:5]([OH:12])=[C:4]([CH2:13][CH:14]=[O:18])[CH:3]=[C:2]([Cl:1])[CH:11]=1)([O:9][CH3:10])=[O:8]
Reactant: CCOCC
Reactant: C=CCc1cc(Cl)cc(C(=O)OC)c1O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: COC(=O)c1cc(Cl)cc(CC=O)c1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Osmium tetroxide (1.0 g, 3.9 mmol) was added to a mixture of methyl 5-chloro-2-hydroxy-3-(2-propenyl)benzoate (4c) (22.7 g, 0.1 mol), ether (400 ml), and water (400 ml). After stirring at room temperature for 5 minutes, sodium periodate (47.06 g, 0.22 mol) was added in portions. The mixture was stirred at room temperature for another 21 hours, and then poured into 800 ml of water. The layers were separated and the aqueous layer extracted with ethyl ether (2×400 ml). The organic layers were combined, dried over anhydrous Na2SO4 and then filtered through a column of Florisil (85 g) to remove inorganic impurity. Evaporation of the ether yielded 5c quantitatively as a brown solid, m.p. 49°-59° C., which appeared hygroscopic. The crude product was used for the next reaction without purification. NMR (CDCl3) δ 10.90 (s, 1H, OH), 9.67 (t, 1H, J= 1.5 Hz, CHO), 7.70 (d, 1H, J=3 Hz, aromatic proton), 7.23 (d, 1H, aromatic proton), 3.97 (s, 3H, CH3) and 3.70 (d, 2H, CH2).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].[OH-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>O.C(O)CC>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:9]1[C:10]2[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=2[N:7]=[CH:8]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: Cn1c(=O)c2c(ncn2CCCCCCBr)n(C)c1=O

Procedure:
1,3-dimethylxanthine is dissolved in a mixture of 250 ml of water and 750 ml of n-propanol by adding an equimolar quantity of sodium hydroxide and heating. An equivalent amount of 1,6-dibromohexane is quickly added to the solution and the mixture is boiled under reflux for 1 hour. After evaporation of the n-propanol, 7-(6-bromohexyl)-1,3-dimethylxanthine is isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CC1C=CC(S(O)(=O)=O)=CC=1.[F:37][C:38]([F:46])([F:45])[C:39]([C:41]([F:44])([F:43])[F:42])=[O:40]>C1(C)C=CC=CC=1.O>[F:37][C:38]([F:46])([F:45])[C:39]([C:18]1[CH:19]=[C:14]([CH2:13][CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:5]=3)[C:9]2=[O:12])[CH:15]=[N:16][CH:17]=1)([OH:40])[C:41]([F:44])([F:43])[F:42]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(cc1N1CCOCC1)CC(Cc1cccnc1)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1)C2=O
Temperature: 120 °C

Procedure:
To a stirred solution of 243 (0.08 g, 0.236 mmol) in toluene was added PTSA (0.090 g, 0.472 mmol) and kept stirring at 120° C. Hexafluoroacetone 244 (0.129 g, 0.590 mmol) was added to the reaction and heated to 100° C. for 16 h. Reaction was cooled to RT, diluted with water, extracted with ethyl acetate twice, the organic layer dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel eluting the compound at 30% ethyl acetate in hexane as thick sticky solid 2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 245. 1HNMR (400 MHz, CDCl3) δ ppm 7.06 (m, 2H), 6.88 (s, 1H), 6.90 (s, 1H), 6.123 (s, 1H), 3.88 (m, 7H), 3.49 (m, 1H), 3.08 (m, 2H), 3.03 (m, 6H), 2.29 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]4[NH:15][C:16](=O)N[C:13]=4[CH:12]=3)[O:10][C:3]=12.[O:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][C:29]=2[C:30]#[N:31])[CH2:23][CH2:22]1>>[N:15]1([C:14]2[CH:19]=[CH:20][C:11]([C:9]3[O:10][C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[C:33]4[CH:34]=[CH:35][C:28]([O:27][CH:24]5[CH2:23][CH2:22][O:21][CH2:26][CH2:25]5)=[C:29]([CH:32]=4)[C:30]#[N:31])[CH:8]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:9][O:10][CH2:3][CH2:16]1
Reactant: O=c1[nH]c2ccc(-c3cc4nccc(Cl)c4o3)cc2[nH]1
Reactant: CC1(C)OB(c2ccc(OC3CCOCC3)c(C#N)c2)OC1(C)C
Product: N#Cc1cc(-c2ccnc3cc(-c4ccc(N5CCOCC5)cc4)oc23)ccc1OC1CCOCC1

Procedure:
from 5-(7-chloro-furo[3,2-b]pyridin-2-yl)-1,3-dihydro-benzoimidazol-2-one and 2-(tetrahydro-pyran-4-yloxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile; HPLC/MS: 1.811 min, [M+H]=453;
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6]C(=O)[O:8][C:9](=O)[C:4]=2[CH:3]=1.[NH4+:14].[OH-]>>[NH2:6][C:5]1[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=1[C:9]([NH2:14])=[O:8]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.2 %

Procedure:
6-Bromo-1H-benzo[d][1,3]oxazine-2,4-dione (56.0 g, 230 mmol) was suspended in 1 N aq. NH4OH (600 mL, 2.6 equivalents), and the suspension was stirred 3 d at room temperature. After filtration, the collected solid was washed with water and subsequently dissolved in tetrahydrofuran. This solution was filtered, evaporated to dryness, and dried by repeated azeotropic distillation with toluene. The solid was suspended in CH2Cl2, filtered, and washed once CH2Cl2 with yielding 35.4 g (71.2%) 2-amino-5-bromo-benzamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[F:11][C:12]([F:17])([F:16])S([O-])=O.[Na+].C(OO)(C)(C)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:12]([F:17])([F:16])[F:11])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: O=S([O-])C(F)(F)F
Reactant: Clc1cc2[nH]ncc2cn1
Agent: CC(C)(C)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1n[nH]c2cc(Cl)ncc12
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Ref: PCT Int. Appl., 2010086251, 2010. To a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine (1a, 1 g, 6.51 mmol), sodium trifluoromethanesulfinate (3.05 g, 19.54 mmol) in 10 mL of DCM and 4 mL of H2O, 70% tert-butyl hydroperoxide (4.19 g, 32.6 mmol) aqueous solution was added. The heterogeneous reaction mixture was stirred vigorously at r.t. After 28 hr, LCMS analysis showed partial conversion. Additional sodium trifluoromethanesulfinate (3.05 g, 19.54 mmol) and tert-butyl hydroperoxide (4.19 g, 32.6 mmol) was added and the reaction mixture was stirred over the weekend. Water, DCM and aqueous Na2S2O3 was added. A yellow solid was filtered off and the filtrate was extracted with DCM. The organic layer was concentrated and purified (50 g silica gel, eluting with 1:30 MeOH/DCM) to give 6-chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine as a yellow solid, which was further purified by recrystallization from MeOH/DCM/Hexane (200 mg, 13%). MS ESI calc'd. for C7H3ClF3N3[M+1]+ 222, found 222.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[OH-].[Na+].CN(C)[CH:20]=[O:21]>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(Cl)cc12
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To stirred dimethylformamide (20 mL) at 0° C. was added dropwise phosphorus oxychloride (4.6 mL, 49 mmol). The mixture was stirred for 10 min and a solution of 5-chloroindole (5.0 g, 33 mmol) in dimethylformamide (5 mL) was added dropwise. The mixture was heated to 40° C. for 45 min, cooled to room temperature and then treated with a solution of sodium hydroxide (5.9 g, 148 mmol) in water (20 mL). The mixture was heated to 50° C. for 10 min, cooled to room temperature, poured onto crushed ice (100 mL) and filtered. The filter cake was recrystallised (methanol) to give the product as a white solid (3.5 g, 59%): mp 215-216° C.; Found: C, 60.13; H, 3.40; N, 7.75%. C9H6ClNO requires: C, 60.19; H, 3.37; N, 7.79%.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.C(N(CC)C(C)C)(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>CN(C=O)C>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([C:37]([O:39][CH3:40])=[O:38])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: COC(=O)Cl
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30.0 mg, 0.0679 mmol), N,N-diisopropylethylamine (59.1 μL, 0.340 mmol) and DMF (100 mL) was treated with methyl chloroformate (5.25 μL, 0.0679 mmol) and stirred at rt for 1 h prior to semi-preparative HPLC to afford the isolation of the title compound. 1H NMR (400 MHz, CD3OD) ppm: 8.32 (br. s., 1H), 7.58-7.66 (m, 2H), 7.46 (d, 1H, J=8.1 Hz), 7.14-7.22 (m, 1H), 7.00-7.12 (m, 2H), 6.73 (s, 1H), 4.26 (d, 2H, J=12.9 Hz), 3.71 (s, 3H), 3.33-3.37 (m, 1H), 2.9-3.17 (m, 2H), 1.85-2.06 (m, 4H); MS (ES+): m/z 391.06 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][CH2:15][C:16](=[O:22])[CH2:17][C:18](=[O:21])[CH2:19][CH3:20].S(Cl)(Cl)=O.CCOCC>CC(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:17]([C:16](=[O:22])[CH2:15][CH3:14])[C:18](=[O:21])[CH2:19][CH3:20])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: CCC(=O)CC(=O)CC
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCC(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(=O)CC
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-dihydroxy-5-nitrobenzaldehyde (7.6 g) and 3,5-heptanedione (8.0 g) in 50 ml of 2-propanol was added thionyl cloride (3.5 ml) with stirring at 20° C. Ether (60 ml) was added and the solution was filtered and allowed to stand overnight. The resulting crystal were filtered. Yield 1.2 g, mp 133°-135° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:23]([F:24])=[C:22]([OH:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:28][C@@H:29]([NH:31][C:32](=[O:38])OC(C)(C)C)[CH3:30].[C:39]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl.C(OCC)(=O)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:23]([F:24])=[C:22]([O:25][CH2:28][C@@H:29]([NH:31][C:32](=[O:38])[CH3:39])[CH3:30])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[F:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2c1F
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of 2-(4-(benzyloxy)-3-fluorophenyl)-7-fluoro-1,3-benzoxazol-6-ol (1.13 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (0.841 g) and triphenylphosphine (1.26 g) in THF (20 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 2.52 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give a white solid. To the obtained solid was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate/methanol, and the solution was subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was recrystallized (hexane/ethyl acetate) to give the title compound as white crystals (1.08 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[S:16]([CH2:22][C:23]#[N:24])([CH2:19][C:20]#[N:21])(=[O:18])=[O:17]>C(O)C.N1CCCCC1>[C:20]([CH2:19][S:16](/[C:22](=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)/[C:23]#[N:24])(=[O:18])=[O:17])#[N:21]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: N#CCS(=O)(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)CC#N)cc(C(C)C)c1O
Yield: 6.2 %

Procedure:
A mixture of 500 mg of 3,5-diisopropyl-4-hydroxybenzaldehyde and 700 mg of sulphonyl diacetonitrile in 6 ml of ethanol was refluxed with a few drops of piperidine for 4 hours. Ethanol was removed in a rotavap and the mixture worked up with ethyl acetate, diluted acid and brine. A portion of the crude was then purified by HPLC on a C-18 column to provide 50 mg of the titled compound along with 30 mg of (E,E)-2-[[1-Cyano-2-(3,5diisopropyl-4-hydroxyphenyl)ethenyl]sulfonyl]-3,5-diisopropyl-4-hydroxyphenyl)acrylonitrile.