Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([NH:7]C(=O)[C:3]=12)=[O:6].Br[CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18].[C:20](=[O:23])([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:16][C:17](=[O:19])[CH2:18][N:7]1[C:5](=[O:6])[C:4]2[C:10](=[CH:11][CH:12]=[C:2]([Br:1])[CH:3]=2)[C:20]1=[O:23])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OCCBr
Reactant: O=C1NC(=O)c2c(Br)cccc21
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)c2ccc(Br)cc2C1=O
Yield: 99.4 %

Procedure:
Bromophthalimide (35 g, 155 mmol) and bromoethylacetate (31 g, 186 mmol) were dissolved in 700 ml of acetone. Potassium carbonate (64.2 g, 465 mmol) was added and resulting suspension was stirred at reflux for 18 h. After cooling, the mixture was filtered. Filtrate was evaporated to give 48.12 g (154 mmol) of solid product. 1H NMR (200 MHz, CDCl3) δ 8.00 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 4.41 (s, 2 H), 4.21 (q, J=7.0 Hz, 2 H), 1.28 (t, J=7.0 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44]([C:46]1[CH:47]=[N:48][N:49]([CH3:51])[CH:50]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:44][C:46]4[CH:47]=[N:48][N:49]([CH3:51])[CH:50]=4)[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cn1cc(C=O)cn1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3Cc2cnn(C)c2)cc1
Reaction time: 120 h
Yield: 41.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 4-formyl-1-methylpyrazole (0.4 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 5 days. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethanol:ethyl acetate 1:3→1:2) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-(1-methylpyrazol-4-ylmethyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 87) (96.1 mg) as yellow crystals.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl[CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(OCC)(=O)C>CN(C)C=O.C1(C)C=CC=CC=1>[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1ccc(O)cc1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Oc1ccc(C(C)C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
Sodium hydride (55% suspension in oil, 5.22 g) was added to a solution of 4-isopropylphenol (15.0 g) in a mixture of dimethylformamide (63 ml) and toluene (75 ml). The mixture was stirred at ambient temperature for 1 hour. To the reaction mixture, diethyl 2-chloromalonate (18.5 g) was added. The mixture was stirred at 60° C. for 2.5 hours. At the end of this time ethyl acetate was added to the reaction mixture. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=4/1 as the eluant to afford the desired compound (21.5 g) as a syrup.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]3[C:12]([CH2:13][N:4]2[CH2:3][C:2]1=[O:14])=[CH:11][CH:10]=[CH:9][CH:8]=3.C(O)(=O)C.[Br:19]Br>O>[Br:19][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]1[NH:1][C:2](=[O:14])[CH2:3][N:4]1[CH2:13]2
Reactant: BrBr
Reactant: O=C1CN2Cc3ccccc3N=C2N1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CN2Cc3cc(Br)ccc3N=C2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a vigorously stirred solution of 1.87 g. (0.01 mole) of 1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one in 40 ml. of glacial acetic acid was added dropwise at room temperature 1.60 g. (0.01 mole) of bromine. The mixture was stirred at room temperature for one hour, water (50 ml.) was added and the volume concentrated (10-15 ml.) in vacuo. Additional water (50 ml.) was added, the solution made basic with ammonium hydroxide, warmed and the insoluble material filtered under suction. The colorless solid was washed with water, dried and crystallized from 50 ml. of 5% hydrochloric acid yielding 0.8 g. (30% yield) of a colorless solid: m.p. >275°. Purification was effected by crystallization from methanol/ether; m.p. 275° to yield the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.O.[Cl-].[NH4+]>CO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cc(Cl)ccc1Br
Temperature: 23 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
A solution of 1-bromo-4-chloro-2-nitrobenzene (13.92 g, 58.87 mmol) in MeOH (300 mL) was treated with water (50 mL), ammonium chloride (22.99 g, 429.8 mmol), and iron powder (325 mesh, 16.44 g, 294.4 mmol). The suspension was stirred at 23° C. for 18 hours. The resulting suspension was filtered through celite. The filter cake was washed with MeOH (500 mL). The combined filtrate and washings were concentrated, and partitioned in EtOAc/water (500 mL/200 mL). The organic layer was separated. The aqueous layer was washed with EtOAc (2×200 mL). The organic layers were combined, washed with brine (200 mL), dried (MgSO4), and concentrated in vacuo affording 11.51 g of 2-bromo-5-chlorobenzenamine.
Reaction SMILES: F[C:2]([N:7](C)C)(F)[CH:3]([F:5])[F:4].B(F)(F)F.CN([C:17](=[CH2:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C.[CH3:24][NH:25]N>C(#N)C>[F:5][CH:3]([F:4])[C:2]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][N:25]([CH3:24])[N:7]=1
Reactant: CN(C)C(F)(F)C(F)F
Reactant: C=C(C(=O)OCC)N(C)C
Reactant: CNN
Agent: FB(F)F
Solvent: CC#N
Product: CCOC(=O)c1cn(C)nc1C(F)F
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
10.8 g of N-1,1,2,2-tetrafluoroethyldimethylamine were initially charged in 50 ml of acetonitrile under argon and 26 g of boron trifluoride as a 17% solution in CH3CN were added at RT. The mixture was stirred for 30 min and then admixed with 8.67 g of ethyl dimethylaminoacrylate. The mixture was stirred at RT for 2 h and then added slowly to the solution of 3.4 g of methylhydrazine in 10 ml of acetonitrile at 10° C. After stirring at RT for 2 h, the acetonitrile was removed completely under reduced pressure and the product was admixed with water and filtered off. Distillation under reduced pressure or washing with cyclohexane afforded 10 g of the product with the purity of 99% and an m.p. of 62-63° C.
Reaction SMILES: [Cl-].[C:2]([CH:4]1[CH2:9][CH2:8][NH2+:7][CH2:6][CH2:5]1)#[N:3].C(N(CC)CC)C.[CH2:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>ClCCl>[CH2:17]([S:19]([N:7]1[CH2:8][CH2:9][CH:4]([C:2]#[N:3])[CH2:5][CH2:6]1)(=[O:21])=[O:20])[CH3:18]
Reactant: CCS(=O)(=O)Cl
Reactant: N#CC1CC[NH2+]CC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(C#N)CC1
Reaction time: 1 h

Procedure:
In a dry round bottom flask was placed 4-cyanopiperidinium chloride (13, 5 g, 45.4 mmol) dichloromethane (150 ml) and triethylamine (18.98 ml, 136 mmol). To the reaction was added dropwise ethanesulfonyl chloride (4.56 ml, 45.4 mmol) and the solution stirred 1 hour and quenched with water (100 ml). The mixture was extracted with dichloromethane (3×50 ml) and the combined organic fractions dried (MgSO4), filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 1-(ethylsulfonyl)piperidine-4-carbonitrile (14) as a white solid. MS 203 (M+1)
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[H][H]>O1CCOCC1.[Pd]>[C:9]([NH:8][C:6](=[O:7])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=1)[O:4][C:1](=[O:3])[CH3:2])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(=O)OC(C(=O)NC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(=O)OC(C(=O)NC(C)(C)C)c1ccc(N)cn1

Procedure:
5 g (16.9 mmol) of 2-acetoxy-2-(5-nitro-2-pyridyl)-N-tert.-butyl-acetamide are dissolved in 50 ml of 90% strength aqueous dioxane, 250 mg of 10% strength palladium-on-active charcoal are added and hydrogenation is carried out at room temperature until the uptake of hydrogen is complete. For working up, the catalyst is filtered off and the filtrate is evaporated. The residue is dried.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C(I)C.C([O:13][CH2:14][CH3:15])(=O)C.[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[C:22](#[N:24])[CH3:23]>C(OCC)(=O)C.C(OC(C)C)(C)C>[NH2:24][C:22]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[CH2:15][CH:14]([OH:13])[CH2:21][CH2:20]2
Reactant: CC#N
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)OC(C)C
Solvent: CCI
Product: Nc1cccc2c1CC(O)CC2

Procedure:
To a solution of step-a product (30 g, 0.118 mol) in acetonitrile (240 ml, 8 times), cesium carbonate (71.7 g, 0.22 mol, 1.9 eq) was added and stirred for some time. Ethyl iodide (19.8 g (10.19 ml), 0.12 mol, 1.1 eq) was added and the overall reaction mixture was stirred for 1 hr at rt. Progress of the reaction was monitored by TLC (10% ethyl acetate/hexane, Rf˜0.6). On completion of the reaction, filtered the contents, washed with acetonitrile (2×50 ml) and distilled off the solvent. Residue obtained was diluted with ethyl acetate (200 ml) and washed with water 92×100 ml). Dried the contents over sodium sulfate and distilled off the solvent completely. The crude obtained was taken in diisopropyl ether (100 ml), stirred for 10-15 min and filtered. Solid obtained was washed with diisopropyl ether again and dried to yield the required product as an off white solid (23 g, 69% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[SH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Reactant: Sc1ccccn1
Product: O=C1CCc2cc(OCCCSc3ccccn3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(3-bromopropoxy)-3,4-dihydro-carbostyril and 2-mercapto-pyridine.
Reaction SMILES: [OH:1][CH:2]1[CH:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:15])[C:4](=[CH2:16])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH:12]([CH:11]1[CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:15])[C:4](=[CH2:16])[CH2:3][C:2]1=[O:1])([CH3:14])[CH3:13]
Reactant: C=C1CC(O)C(C(C)C)CC2=C(C)CCC12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C=C1CC(=O)C(C(C)C)CC2=C(C)CCC12
Yield: 90.8 %

Procedure:
A solution, cooled to -10°, of 1.10 g of 6-hydroxy-7-isopropyl-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene (isomer A) in 50 ml of acetone was treated within 10 minutes with 2 ml of Jones reagent (5.3 mM CrO3) and the reaction mixture obtained then poured on to ice-cold bicarbonate solution. Extraction with ether, washing the extracts with bicarbonate solution and water, drying with sodium sulphate, concentration and distillation under reduced pressure yielded 990 mg (yield 90%) of 7-isopropyl-1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene (isomer A) in the form of a colourless oil; b.p.0.01 ca 75°; IR(film):νmax = 3100, 1708, 1642, 1460, 1440, 1390, 1370, 1255, 1205, 1140, 1090, 1062, 1005, 970, 900, 800 cm-1. The compound has a sweet, spicy, woody odour. In analogous manner there were obtained from 1.10 g of the B-isomer of 6-hydroxy-7-isopropyl-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene, 890 g (yield 81%) of the B-isomer of the corresponding 6-oxo-octahydroazulene; b.p.0.01 ca 75°; IR(film):νmax =1390, 1710, 1642, 1470/60/40, 1390, 1370, 1265, 1180, 1092, 1062, 1000, 970, 900 cm-1. The compound has a fresh woody, slighly spicy, camphorous odour.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:28])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([S:26][CH3:27])[CH:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[OH:29]OS([O-])=O.[K+].[OH2:35]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:28])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([S:26]([CH3:27])(=[O:29])=[O:35])[CH:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: O
Reactant: CSc1cc(NCC(C)C)c2ncc(-c3ccc(C(=O)NC4CC4)cc3)n2n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CNc1cc(S(C)(=O)=O)nn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 0 °C

Procedure:
To a solution of 410 mg (1037 μmol) of N-cyclopropyl-4-{8-[(2-methylpropyl)amino]-6-(methylsulfanyl)imidazo[1,2-b]pyridazin-3-yl}benzamide, which was prepared according to example 193, in 15 mL of DMF was added and 1912 mg (3110 μmol) OXONE (potassium peroxymonosulfate) in small portions. The mixture was stirred over night, then cooled to 0° C. and poured onto 200 mL of cold water. The precipitate was collected and dried under vacuum to yield 291 mg of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:22]([CH3:23])=[CH:21][C:15]2[N:16]=[C:17]([CH:19]=C)[S:18][C:14]=2[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[O:35]=O>CO>[C:1]([O:5][C@@H:6]([C:12]1[C:22]([CH3:23])=[CH:21][C:15]2[N:16]=[C:17]([CH:19]=[O:35])[S:18][C:14]=2[C:13]=1[O:24][S:25]([C:28]([F:29])([F:31])[F:30])(=[O:26])=[O:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc2cc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(OS(=O)(=O)C(F)(F)F)c2s1
Reactant: O=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C=O)sc2c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A solution of 91A (170 mg, 0.353 mmol), DCM (5.0 mL), and MeOH (5.0 mL) was cooled to 78° C. and perfused with oxygen gas for 3 min. Then using an ozonator, a stream of O3 in oxygen gas was bubbled through the solution for 5 min. After this, the reaction was stirred for 10 min, then sparged with oxygen gas for 2 min to drive out unreacted ozone in solution. While the reaction was still at 78° C., dimethylsulfide (200 μL) was added and the reaction allowed to warm to 0° C. After 30 min, 10% w/v aq Na2S2O3 (5 mL) was added and the reaction was warmed to 23° C. and stirred for 10 min. The reaction was diluted with H2O (20 mL) and extracted with DCM (3×15 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated. More DCM was added and the reaction was concentrated once more to remove residual methanol, giving 91B (165 mg, 97% yield). 1H-NMR: 400 MHz, (CDCl3) δ: 10.04 (s, 1H), 8.00 (s, 1H), 5.60 (s, 1H), 4.22-4.00 (m, 2H), 2.51 (s, 3H), 1.16 (s, 9H), 1.14 (t, J=6.8 Hz, 3H). 19F-NMR: 376 MHz, (CDCl3) δ: −73.6.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[S:30][C:31]([CH3:34])=[N:32][N:33]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:34][C:31]1[S:30][C:29]([NH:28][S:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][CH:4]=[C:5]3[C:16]4[C:8](=[CH:9][CH:10]=[C:11]5[C:15]=4[S:14][CH:13]=[N:12]5)[NH:7][C:6]3=[O:17])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[N:33][N:32]=1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Cc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Product: Cc1nnc(NS(=O)(=O)c2ccc(NC=C3C(=O)Nc4ccc5ncsc5c43)cc2)s1
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(5-methyl[1,3,4]thiadiazol-2-yl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (m, 3H), 7.6 (d, 2H), 7.1 (d, 1H); ESI-MS m/z 469 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C[Sn](C)(C)[C:32]1[CH:37]=[N:36][CH:35]=[C:34]([CH3:38])[N:33]=1>CN(C)C(=O)C>[CH3:38][C:34]1[N:33]=[C:32]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]5)[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:37]=[N:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Reactant: Cc1cncc([Sn](C)(C)C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Temperature: 150 °C
Yield: 58 %

Procedure:
A solution of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate (90 mg; 0.22 mmol and palladium(0)tetrakis(triphenylphosphine) (25 mg, 0.022 mmol in N,N-dimethylacetamide; 2.0 mL was added trimethyl-(6-methylpyrazin-2-yl)stannane (112 mg; 0.436 mmol). The reaction mixture was heated at 150° C. for 45 min in a microwave (Biotage). The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc then washed with water. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 50% EtOAc) to give tert-butyl 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperazine-1-carboxylate 60 mg in 58% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@@H:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][C@H:20]([C:31](OC)=[O:32])[CH2:19]2)=[O:16])[N:10]=[N:9]1.[CH3:39][OH:40]>C1COCC1.O.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:18]2[CH2:19][C@@H:20]([C:31]([N:8]3[CH2:3][CH2:2][O:40][CH2:39][CH2:12]3)=[O:32])[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23]2)=[O:16])[N:10]=[N:9]1
Reactant: CO
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3F)c2CO)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.05 g) was dissolved in THF (10 ml)-methanol (8 ml)-water (8 ml), 8M aqueous sodium hydroxide solution (600 μl) was added and the mixture was stirred at 70° C. for 1.5 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue, morpholine, 1-hydroxybenzotriazole (150 mg) and triethylamine (700 μl) were dissolved in acetonitrile (20 ml), WSC•HCL (555 mg) was added and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with water. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (764 mg).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[NH:18]1C=CN=C1>CN(C=O)C.CCCCCC.CCOC(C)=O>[Si:10]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][C:3]=1[NH2:18])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(CO)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3.0 g (20 mmol) of 3-aminobenzyl alcohol, 3.36 g (22.0 mmol) of t-butyidimethylsilyl chloride and 1.52 g (22.0 mmol) of imidazole were dissolved in 20 mL of DMF. The solution was stirred at rt for 16 h and then diluted with 250 mL of hexane and 250 mL of EtOAc. The organic phase was washed twice with brine, dried over MgSO4 and concentrated to give 4.8 g of 3-([t-butyidimethylsilyloxy]methyl-benzenamine as a clear oil. This was dissolved in 100 mL of CH2Cl2, cooled with stirring to −65° C. and 2.17 g (20.0 mmol) of t-butyl hypochlorite was added. After 10 min of stirring, a solution of 2.68 g (20.0 mmol) of ethyl methylthioaceatate in 10 mL of CH2Cl2 was added, and the solution was stirred for 1 h. TEA (2.02 g, 20.0 mmol) was added and the reaction was warmed to rt over 1 h. The solution was washed with water and concentrated to an oil. This was redissolved in 100 mL of ether, 12 mL of 2 N hydrochloric acid was added, and the mixture was stirred overnight. The ether phase was separated and concentrated to an oil. This was chromatographed on silica gel eluting with hexane:EtOAc (initially a 3:1 ratio increasing to 1:2) to yield 0.82 g (20%) of 4-hydroxymethyl-3-methylsulfanyl-1,3-dihydro-indol-2-one: 1H NMR (DMSO-d6): δ 1.89 (s, 3H), 4.45 (s, 1H), 4.62 (m, 2H), 5.1 (bs, 1H), 6.87 (d, J=7.7 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 7.17 (t, J=7.7 Hz, 1H), 10.44 (s, 1H). Further elution yielded 0.53 g (13%) of 6-hydroxymethyl-3-methysulfanyl-1,3-dihydro-indol-2-one: 1H NMR (DMSO-d6): δ 1.99 (s, 3H), 4.48 (s, 2H), 4.50 (s, 1H), 5.1 (bs, 1H), 6.84 (s, 1H), 6.94 (d, J=7.6 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 10.54 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13](Cl)(=O)[C:14](Cl)=O.[CH3:19][N:20]([CH:22]=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:20]1[CH2:22][CH2:14][CH2:13][CH2:19]1)=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Solvent: ClCCl
Product: O=C(c1cc(F)c(F)cc1Cl)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-chloro-4,5-difluorobenzoic acid (1.0 g) in DCM (10 ml) was treated with oxalyl chloride (0.45 ml) followed by a drop of DMF. The mixture was stirred at RT for 1 h before evaporating under reduced pressure. The solid was dissolved in DCM (20 ml) and pyrrolidine (2 ml) was added and stirred at RT overnight. The mixture was diluted with water, extracted with DCM, dried (MgSO4) and evaporated under reduced pressure to give an oil (1.45 g).