Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Br:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23](Cl)[S:24][C:20]=2[CH:19]=1.CC#N>C1COCC1.O>[Br:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[S:24][C:20]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc3ccc(Br)cc3s2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (7.02 g, 34.9 mmol) in THF (67.1 ml) at 0° C. was added NaH (0.915 g, 95%, 36.2 mmol). Upon completion of addition, the reaction mixture was warmed to rt, where it stirred for 30 minutes. A solution of 6-bromo-2-chlorobenzo[d]thiazole (6.67 g, 26.8 mmol) in THF (30 mL) was then added and the resulting mixture was heated to 50° C., where it stirred overnight. At the conclusion of this period, the solvent was removed under reduced pressure to yield a residue. CH3CN (167 mL) was added to the residue, and the resulting mixture was stirred for 20 min. After this time, H2O (233 mL) was added, and the resulting mixture was stirred at rt for 10 min. The resulting precipitate was collected by filtration. The resulting solid was rinsed with cool CH3CN—H2O (3×20 mL, 1:2, v/v) and then dried in vacuum to afford Compound 1A as a white solid (10.5 g, 25.3 mmol, 94% yield. HPLC purity is 100%). 1H NMR (500 MHz, chloroform-d) δ ppm 7.77 (d, J=1.9 Hz, 1H), 7.49-7.54 (m, 1H), 7.44-7.49 (m, 1H), 5.35 (ddd, J=7.6, 4.1, 3.9 Hz, 1H), 3.68-3.82 (m, 2H), 3.31-3.43 (m, 2H), 2.01-2.15 (m, 2H), 1.88 (dddd, J=12.6, 8.4, 4.1, 3.9 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[CH:22]([C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)=O>>[F:19][C:18]([F:20])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:8][N:7]([CH2:22][C:24]5[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=5)[CH2:6][CH:5]4[CH2:1]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: N#Cc1ccc(C=O)cc1
Product: N#Cc1ccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cc1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-formylbenzonitrile was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 4-[[5-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]methyl]benzonitrile.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH2:12][C:13](=O)[CH3:14])(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH3:14][C:13]1[NH:3][N:2]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2ccccc2)n[nH]1
Reaction time: 14 h
Yield: 155.2 %

Procedure:
Hydrazine hydrate (9.0 mL, 99 mmol, 35 wt. % in H2O; 0.64 equiv) was added to a solution of benzoylacetone (25.00 g, 154.1 mmol, 1 equiv) in ethanol (250 mL). After stirring 14 h, more hydrazine hydrate (8.0 mL, 88 mmol, 0.57 equiv) was added. After 2 h, the reaction solution was concentrated (95° C.) to give the title compound as a white solid (24.31 g, 99.7%). HRMS Calculated for C10H11N2: m/z 159.0922. Found: 159.0917.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][CH:14]=[C:15]([C:23](=[O:25])[CH3:24])[CH:16]=2)=[N:7][CH:6]=[N:5]1.[CH3:26][N:27]([CH:29](OC)OC)[CH3:28]>>[CH3:26][N:27]([CH3:29])/[CH:28]=[CH:24]/[C:23]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11]1[N:21]([CH:22]=[C:9]([C:8]3[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[CH:6][N:7]=3)[N:10]=1)[CH2:20][CH2:19][O:18]2)=[O:25]
Reactant: CC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CCO)nc1-2
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CCO)nc1-2
Temperature: 130 °C
Reaction time: 48 h
Yield: 104.9 %

Procedure:
A mixture of 1-{4-[1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}ethan-1-one (115 mg, 0.290 mmol) and DMF-DMA (69 mg, 0.58 mmol) in xylenes (10 mL) was stirred at 130° C. for 48 h under nitrogen atmosphere. The mixture was then concentrated under reduced pressure, the residue was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.3% NH4HCO3 to give (2E)-3-(dimethylamino)-1-{4-[1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}prop-2-en-1-one (120 mg, 90% yield). LCMS (ESI) m/z: 395.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[C:5]([N+:18]([O-])=O)[C:3]=1[NH2:4]>CO.[Pd]>[CH3:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[C:5]([NH2:18])[C:3]=1[NH2:4]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(N)c1N
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A solution of 2-Methyl-6-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.3 g, 19.06 mmol) in methanol (50 mL) was purged with nitrogen gas. Palladium on carbon (10% by wt, 50 mg) was added and the reaction mixture was stirred under a hydrogen balloon for 16 h. The reaction was filtered through Celite and the filter cake was rinsed with methanol. The filtrate was concentrated and the resulting material was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give a dark oil. The oil was triturated with 10% ether in hexanes to give a tan colored solid (4.2 g, 16.9 mmol, 89% yield). MS (ESI) m/z 248.9 [M+1]+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:36])[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH2:25][CH2:26][C:27]#[N:28])[CH:20]=[C:19]([Cl:37])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[OH2:39].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:27]([CH2:26][CH2:25][N:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[C:23](=[O:36])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=[C:19]([Cl:37])[CH:20]=1)(=[O:39])[NH2:28]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)c2ccccc2Cl)c1)c1ccncc1
Reactant: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2-{3-chloro-5-[(2-chloro-phenyl)-(2-cyano-ethyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.055 g) and water (0.020 ml) in a mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stirred at room temperature for 2 h and then the solvent removed under reduced pressure. The residue was purified by preparative hplc to give title compound (0.035 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25].Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[CH2:21]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:18]([C@@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:20])=[CH:31][CH:32]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CCCCCc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of (S)—N-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (10.0 g, 36.1 mmol) and 4-pentylaniline (4.91 g, 30.1 mmol) in chloroform (150 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.92 g, 36.1 mmol). The reaction was allowed to proceed overnight and then washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and concentrated to afford crude product as an off-white, foamy solid. This material was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:26][C:27]1[CH:28]=[C:29]([SH:33])[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:1][C:2]1[C:7]([N:8]2[C:12]([S:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=3)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)n(-c2cccnc2F)n1
Reactant: Cc1cccc(S)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Sc2cccc(C)c2)n(-c2cccnc2F)n1
Temperature: 130 °C
Reaction time: 28 h

Procedure:
A solution of ethyl 1-(2-fluoropyridin-3-yl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-3-carboxylate (575 mg), 3-methylbenzenethiol (224 mg) and sodium carbonate (238 mg) in toluene (7.5 mL) was sufficiently deaerated, tris(dibenzylideneacetone)dipalladium(0) (41 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (52 mg) were added, and the mixture was further deaerated. Under an argon atmosphere at 130° C., the mixture was stirred for 28 hr and allowed to cool to room temperature. Ethyl acetate was added and the mixture was filtered through a basic silica gel pad. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a crude yellow oil (yield 334 mg).
Reaction SMILES: C(OC([N:6]1[C:10]2[S:11][C:12]([C:14](=[O:25])[NH:15][C:16]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[CH:13][C:9]=2[C:8]([NH:26][C:27](=[O:42])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH:34][C:35]([C:37]2[NH:38][CH:39]=[CH:40][CH:41]=2)=[O:36])=[N:7]1)=O)C>CO>[CH3:24][C:16]([NH:15][C:14]([C:12]1[S:11][C:10]2[NH:6][N:7]=[C:8]([NH:26][C:27](=[O:42])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:35]([C:37]3[NH:38][CH:39]=[CH:40][CH:41]=3)=[O:36])[C:9]=2[CH:13]=1)=[O:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccccc2NC(=O)c2ccc[nH]2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Solvent: CO
Product: CC(C)(NC(=O)c1cc2c(NC(=O)c3ccccc3NC(=O)c3ccc[nH]3)n[nH]c2s1)c1ccccc1

Procedure:
5-(1-Methyl-1-phenyl-ethylcarbamoyl)-3-{2-[(1H-pyrrole-2-carbonyl)amino]benzoylamino}-thieno[2,3-c]pyrazole-1-carboxylic acid ethyl ester as crude from the previous reaction was treated with a 10% solution of TEA in methanol (25 mL) overnight. The solvent was evaporated under vacuum and the product was purified by flash chromatography (eluant dichloromethane/methanol 97/3) (78.5 mg, 36%),
Reaction SMILES: [N:1]1([C:6]2C=C(C=C(C(F)(F)F)[CH:12]=2)N)[CH:5]=[CH:4][N:3]=C1.[NH2:17][C:18]1[CH:19]=[C:20](C(F)(F)F)C=C(Br)[CH:23]=1.OC1C=CC=C2C=1N=CC=C2.N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+].[OH-].[NH4+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[C:19]([C:18]1[N:17]2[CH:12]=[CH:6][N:1]=[CH:5][C:4]2=[N:3][CH:23]=1)#[CH:20]
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1cnc2cnccn12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 3-((Trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazine (0.15 g, 0.7 mmol) in 3.5 mL of THF was added 1.05 mL (1.05 mmol) of tetrabutylammonium fluoride (1.0M in THF) at ambient temperature. The solution was stirred for 15 min, concentrated, and the crude product purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.078 g of product. 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline: A mixture of 3-Amino-5-bromobenzotrifluoride (4.0 g, 0.0167 mol), 8-hydroxy quinoline (0.362 g, 0.0025 mol), CuI (0.476 g, 0.025 mol), imidazole (1.36 g, 0.0199 mol), and potassium carbonate (2.52 g, 0.0183 mol) in 17 mL of DMSO (degassed with argon for ˜10 min) was heated at 120° C. under an atmosphere of argon for 15 h; the HPLC indicated no starting material. A 14% aqueous solution of ammonium hydroxide was added to the cooled mixture and this was stirred for 1 h at ambient temperature. Water (50 mL) and EtOAc (200 mL) were added and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with EtOAc/hexanes) to provide 2.51 g of product.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](O)(=O)[CH3:12]>>[C:1]1([NH:7][C:8]2[S:9][CH:11]=[CH:12][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: CC(=O)O
Product: c1ccc(Nc2nccs2)cc1
Temperature: 100 °C

Procedure:
10 g (65.7 mmol) of phenylthiourea 37 were dissolved in 100 ml of acetic acid. 9.9 ml of the acetal 38 were added and the mixture was heated at 100° C. for 2 h. The solvent was removed i.v. and the residue was partitioned between 300 ml of 1N NaOH and 300 ml of ethyl acetate. The aqueous phase was extracted twice with in each case 100 ml of ethyl acetate and the combined organic phases were dried using magnesium sulfate. The solvent was removed and the residue was precipitated from 50 ml of diisopropyl ether. The solid was filtered off with suction and dried at 50° C. i.v. 2.5 g of aniline 39 were obtained. The diisopropyl ether mother liquor was evaporated and the residue was chromatographed on silica gel using heptane/ethyl acetate 2:1. This resulted in a further 3.5 g of 39 being obtained. Yield 6.0 g (52%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.CCOC(C)=O.CCCCCC>C(O)C.[Pd]>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(O)cc2O1

Procedure:
A solution of 7-hydroxycoumarin (5.0 g, 0.031 mol; Aldrich Chemical Company) in absolute ethanol (200 mL) was hydrogenated under pressure in a Parr apparatus over 10% Pd/C (Catalyst; 500 mg, 50% water; Kodak, Inc., Rochester, N.Y.) for 24 hours at 55° C. Thin layer chromatography (TLC; Silica gel: EtOAc/hexane: 1:1) showed completion of the reaction. The reaction mixture was then filtered over a bed of Celite (Rohm and Haas Co., Philadelphia, Pa.) and evaporated in vacuo to provide the crude product (4.5 g). A portion (2.5 g) of this material was recrystallized from toluene and dried under vacuum to provide 7-hydroxydihydrocoumarin. Yield: 1.83 g; melting point 133°-135.5° C.;
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:11]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:12]=3[S:13][C:14]=2C(O)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C>[F:25][C:22]([F:23])([F:24])[C:18]1[C:12]2[S:13][CH:14]=[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)[C:11]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)N1CCC(c2c(C(=O)O)sc3c(C(F)(F)F)cccc23)CC1
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(c2csc3c(C(F)(F)F)cccc23)CC1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 747 %

Procedure:
A mixture of 3-(1-acetyl-piperidin-4-yl)-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid (4.13 g, 1.1 mmol), Cu powder (0.706 g, 11.1 mmol), and quinoline (20 mL) was heated to 200° C. under nitrogen. After 10 min, no gas evolution was observed and the reaction cooled at room temperature. The mixture was diluted with ethyl acetate (100 mL), filtered through a Celite bed and the filtrate washed with 1 N HCl (2×100 mL), 5% aqueous potassium carbonate (100 mL), water (100 mL), and brine (100 mL) successively. The organics were dried over magnesium sulfate, filtered, and concentrated to give an amber oil. The oil was chromatographed on silica, eluting with 10% methanol/ethyl acetate to afford 2.69 g (74%) of the desired product as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:32])[CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:32])[CH2:18][CH:19]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CC(c1ccccc1)c1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CC(C1CCCCC1)C1CCCCC1
Yield: 99 %

Procedure:
A solution of (2S,3S)-2-t-butoxycarbonylamino-1-cyclohexyl-5,5-diphenyl-3-hydroxypentane (0.74 g) in acetic acid (50 ml) was hydrogenated over platinum oxide (0.2 g) at 3 atmospheric pressure of hydrogen gas for 2 hours at 37° C. The solution was filtered and concentrated in vacuo to give (2S,3S)-2-t-butoxycarbonylamino-3-hydroxy-1,5,5-tricyclohexylpentane (753 mg) as an oil. Rf: 0.72 (n-hexane:ethyl acetate, 2:1, V/V)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[C:10](=O)([O:14]CC)[O:11][CH2:12][CH3:13].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH2:8][C:10]([O:11][CH2:12][CH3:13])=[O:14])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)s1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(Br)s1
Temperature: 56 °C

Procedure:
To a solution of 1-(5-bromothiophen-2-yl)ethanone (4.10 g, 19.99 mmol) and Diethyl carbonate (30 mL, 248 mmol) in THF (40 ml) at room temperature was added sodium hydride (1.679 g, 42.0 mmol). The resulting off-white slurry solution was gradually warmed to 56° C., and became dark brown clear solution. The reaction mixture was heated at 56° C. for 1.5 hour. The reaction mixture was poured into ice-HOAc—H2O, and extracted with ethyl acetate. The organic phase was washed (brine), dried (MgSO4) and concentrated to give a brown liquid. The crude product was purified via flash chromatography (silica gel cartridge with eluent of 0-5% ethyl acetate/hexane) to afford ethyl 3-(5-bromothiophen-2-yl)-3-oxopropanoate as an amble liquid, 4.713 g (85%). HPLC: Rt 2.856 min.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCCC1>[N+:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: OB(O)Oc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(Cl)c1-c1ccccc1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
In a stream of nitrogen, a one-liter three-necked flask was charged with 75.0 g (390.6 mmol) of 2,3-dichloronitrobenzene, 47.6 g (390.6 mmol) of phenylboric acid, 9.0 g (7.8 mmol) of tetrakis(triphenylphosphine)palladium, 250 mL of tetrahydrofuran, and 518 g (976.5 mmol) of an aqueous tripotassium phosphate solution with 40 wt. % concentration. The mixture was heated under reflux for 8 hours. The reaction mixture was cooled to room temperature, and then separated into an aqueous phase and an organic phase. The organic phase was washed with an aqueous saturated ammonium chloride solution and then with an aqueous saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and then a solvent was distilled off under reduced pressure. The thus-obtained solid was recrystallized from ethanol to give 62.8 g of 2-nitro-6-chlorobiphenyl as a light yellow needle crystal (yield: 680).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:15][CH3:16])[C:5]2[N:6]([N:8]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[N:10]=2)[CH:7]=1.[NH2:17][C:18]1[C:19]([F:25])=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].N1C=CC=CC=1.CS(C)=O>C(#N)C>[F:25][C:19]1[C:18]([NH:17][S:11]([C:9]2[N:10]=[C:5]3[C:4]([O:15][CH3:16])=[N:3][C:2]([Br:1])=[CH:7][N:6]3[N:8]=2)(=[O:13])=[O:12])=[C:23]([CH3:24])[CH:22]=[CH:21][N:20]=1
Reactant: Cc1ccnc(F)c1N
Reactant: COc1nc(Br)cn2nc(S(=O)(=O)Cl)nc12
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1nc(Br)cn2nc(S(=O)(=O)Nc3c(C)ccnc3F)nc12

Procedure:
A solution of 1.36 g (4.14 mmol) of 6-bromo-2-chlorosulfonyl-8-methoxy[1,2,4]triazolo[1,5-a]pyrazine in 15 mL of dry acetonitrile was placed in a flask equipped with a drying tube and was treated sequentially with 1.56 g (12.4 mmol) of 3-amino-2-fluoro-4-methylpyridine, 0.34 mL (4.21 mmol) of pyridine and 60 μL (0.85 mmol) of dimethyl sulfoxide at room temperature. The reaction became progressively darker and after 15 hours the volatiles were removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with four portions of 1M hydrochloric acid and one portion of water and was dried over sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the residue obtained was purified by flash column chromatography on silica gel using a 0.5 to 4 percent ethanol/dichloromethane gradient as eluent. The solid obtained was further purified by extraction with diethyl ether to obtain 373 mg (22 percent of theory) of the desired product as an off-white powder melting at 210°-211° C. (dec); Mass Spectrum, m/e 417 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:14]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:12][C:5]2=[N:6][C:7]=1[C:8](=[N:10]O)[CH3:9].[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[F:1][C:2]1[CH:3]=[C:4]2[N:14]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:12][C:5]2=[N:6][C:7]=1[CH:8]([NH2:10])[CH3:9]
Reactant: CC(=NO)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)N)c(F)cc32)cc1
Temperature: 60 °C
Yield: 69.4 %

Procedure:
A mixture of 1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone oxime (0.75 mg, 2.16 mmol), zinc powder (7.06 g, 108 mmol), and NH4Cl (2.31 g, 43.2 mmol) in MeOH (30 mL) and HOAc (6 mL) was heated at 60° C. for 2 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was suspended in ammonia solution (50 mL) and extracted with DCM (50 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude was purified by SiO2 chromatography eluting with DCM/MeOH/Et3N to afford 0.5 g (97.7%) of 1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine as a yellow solid. MS (ESI): m/z=334.3 [M+1]+.