Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([OH:14])=O)[C:7]1=[O:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(Cl)Cl.C(N(CC)C(C)C)(C)C.[NH2:56][C@@H:57]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)[CH2:58][C:59]([OH:61])=[O:60]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:56][C@@H:57]([C:62]2[S:63][CH:64]=[CH:65][CH:66]=2)[CH2:58][C:59]([OH:61])=[O:60])=[O:14])[C:7]1=[O:15]
Reactant: N[C@H](CC(=O)O)c1cccs1
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1

Procedure:
Into a round bottom was added 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (0.400 g, 0.00151 mol;), N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.573 g, 0.00151 mol;), Methylene chloride (14 mL, 0.23 mol;), and N,N-Diisopropylethylamine (1310 uL, 0.00754 mol;). The reaction was stirred until all contents were dissolved and preactivation was complete. (R)-3-Amino-3-thiophen-2-yl-propionic acid (0.28 g, 0.0016 mol;) was added and the reaction was allowed to stir for 1-2 hours then an LC-MS was taken which showed product at 1.47. The reaction was worked up by washing with citric acid and brine then drying with magnesium sulfate. The crude concentrated reaction was taken on directly to the next step. ES (+) MS m/e=419.08
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[N:5][CH:6]=[C:7]([Cl:12])[C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][N:27]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=2[CH:39]([CH3:41])[CH3:40])[S:28]1(=[O:30])=[O:29]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Cl:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[N:5][CH:6]=[C:7]([Cl:12])[C:8]=1[C:9]([O:11][CH2:26][N:27]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=2[CH:39]([CH3:41])[CH3:40])[S:28]1(=[O:29])=[O:30])=[O:10]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: CN(C)CCOc1ncc(Cl)c(C(=O)O)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1c(Cl)cnc(OCCN(C)C)c1Cl)C2=O
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 2.1 %

Procedure:
A mixture of 3,5-dichloro-2-[2-(dimethylamino)ethoxy)-pyridine-4-carboxylic acid hydrochloride (2.65 g, 0.0084 mol), cesium carbonate (4.1 g, 0.013 mol), tetrabutylammonium bromide (1.0 g, 0.003 mol) and DMF (25 ml) was stirred for 10 minutes, then 2-chloromethyl-4-isopropyl-6-methoxysaccharin (2.4 g, 0.0084 mol) was added. The mixture was heated to 80° C. and stirred for 1 hour. The solvent was removed in vacuo and the residue was partitioned between water/methylene chloride. The organic layer was separated, washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was dissolved in ethyl acetate and filtered through a plug of silica. Ethereal HCl was added to the filtrate and the solvent was removed in vacuo. The residue was washed with ether (50 ml), treated with saturated NaHCO3 and extracted with methylene chloride. The solvent was removed in vacuo, the residue was triturated with methanol and an off-white solid was collected by filtration. The product was dried in high vacuum to afford 0.096 g (2.1%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl 3,5-dichloro-2-[2-(dimethylamino)ethoxy]pyridine-4-carboxylate, m.p. 155°-160° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.[OH:15][CH:16]=[C:17]([CH3:23])[C:18](OCC)=O>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:18]=[C:17]([CH3:23])[C:16](=[O:15])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)=CO
Reactant: Nc1nnc(SCc2ccccc2)s1
Solvent: O
Product: Cc1cnc2sc(SCc3ccccc3)nn2c1=O
Reaction time: 0.75 h
Yield: 61 %

Procedure:
Five point six (5.6) grams of the thus obtained 2-amino-5-benzylthio-1,3,4-thiadiazole and 3.6 g of ethyl 3-hydroxy-2-methyl-2-propenoate were mixed with 7.5 g of polyphosphoric acid, and the mixture was stirred at 130°-150° C. for 45 minutes. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and water respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol. Thus 4.4 g of 2-benzylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 130°-132° C. Yield 61%.
Reaction SMILES: [Mg].BrCCBr.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:10]Br.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.Cl.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C.C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:10][C:17]1([OH:16])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(F)c(F)c2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a suspension of magnesium (1.2 g) and 1,2-dibromoethane (0.11 mL) in diethyl ether (30 mL) was added a solution of 3,4-difluorobenzyl bromide (10 g) in diethyl ether (10 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with THF (30 mL), and cooled to −78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g) in THF (10 mL) was added thereto, and the mixture was allowed to warm to room temperature, and was stirred overnight. To the reaction mixture was added a small amount of 1N hydrochloric acid at 0° C. to quench the reaction. Saturated aqueous potassium sodium tartrate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (4.9 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23](N)([NH2:26])(=[O:25])=[O:24]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH:22][S:23]([NH2:26])(=[O:25])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(N)(=O)=O
Reactant: NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 95 °C

Procedure:
To a solution of 1,4-dibenzyl-2-aminomethyl-piperazine (2.5 g, 8.46 mmol) in dioxane (50 mL), was added sulfamide (1.63 g, 16.9 mmol) and the resulting mixture was stirred at 95° C. under N2 atmosphere for several hours (monitored by TLC). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel using acetonitrile/water with gradient as eluent.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([N:21]1[CH2:25][C@@H:24]([O:26][C:27](=[O:29])[CH3:28])[CH2:23][C@@H:22]1[C:30]1[CH:35]=[C:34]([N+:36]([O-])=O)[C:33]([NH:39][C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=O)=[CH:32][C:31]=1F)(=[O:20])[CH3:19].O.O.[Sn](Cl)Cl>C(OCC)(=O)C.CN(C)C=O>[C:27]([O:26][C@@H:24]1[CH2:25][N:21]([C:18](=[O:20])[CH3:19])[C@@H:22]([C:30]2[C:31]([O:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)=[CH:32][C:33]3[N:39]=[C:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[NH:36][C:34]=3[CH:35]=2)[CH2:23]1)(=[O:29])[CH3:28]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(=O)O[C@H]1C[C@H](c2cc([N+](=O)[O-])c(NC(=O)c3ccccn3)cc2F)N(C(C)=O)C1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1C[C@H](c2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccc(S(C)(=O)=O)cc2)N(C(C)=O)C1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
10 mg of 4-methanesulfonyl-phenol and 20 mg of cesium carbonate were added to a dimethylformamide (0.5 ml) solution of 21 mg of trans-1-acetyl-2-(5-nitro-2-fluoro-4-((pyridin-2-carbonyl)-amino)-phenyl)-4-acetoxy-pyrrolidine, and the reaction liquid was stirred at 90° C. for 1 hour. 100 mg of tin(II) chloride dihydrate was added to it, and the reaction liquid was stirred at 90° C. for 5 hours. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:15]1[N:16]=[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:18]2[C:19](=[O:22])[C:20]=1[I:21])[CH2:13][CH3:14].C(N(CC)C(C)C)(C)C>C(O)C>[I:21][C:20]1[C:19](=[O:22])[N:18]2[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:17]2=[N:16][C:15]=1[CH:12]([NH:11][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2)[CH2:13][CH3:14]
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CCC(N)c1nc2cccc(C)n2c(=O)c1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1I
Yield: 82.5 %

Procedure:
A mixture of 6-bromo-9H-purine (1.65 g, 0.008270 mol), 2-(1-aminopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.58 g, 0.00752 mol), and N,N-diisopropylethylamine (1.571 mL, 0.009022 mol) in ethanol (60 mL) was refluxed under nitrogen overnight. The mixture was concentrated and the resulting residue was purified on silica gel, eluting with 0 to 10% methanol in methylene chloride, to provide the desired product (2.86 g, 82.5%). LCMS calculated for C17H17IN7O (M+H)+: m/z=462.1. Found: 462.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.31 (2H, m), 8.19 (1H, s), 8.15 (1H, s), 7.69 (1H, dd, J=8.7 and 6.9 Hz), 7.44 (1H, d, J=8.7 Hz), 6.99 (1H, d, J=6.9 Hz), 5.69 (1H, m), 2.89 (3H, s), 1.91 (2H, m), 0.95 (3H, t, J=7.2 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[CH2:5][N:6]([CH3:28])[C:7](=[O:27])[C@@H:8]([N:16]([CH2:24][CH:25]=C)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[N+]1([O-])CC[O:37]CC1.S(=O)(O)[O-].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.[Os](=O)(=O)(=O)=O.O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[CH2:5][N:6]([CH3:28])[C:7](=[O:27])[C@@H:8]([N:16]([CH2:24][CH:25]=[O:37])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1OC
Agent: O=[Os](=O)(=O)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1ccccc1CN(C)C(=O)[C@H](Cc1ccccc1)N(CC=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Combine (S)-N-(2-methoxybenzyl)-N-methyl-2-[N'-(t-butoxycarbonyl)-allylamino]-3-phenyl-propionamide (0.66 g, 1.52 mmol), N-methylmorpholine-N-oxide (0.20 g, 1.67 mmol), acetone (5 mL), and water (5 mL). Add osmium tetraoxide (0.78 mL, 0.04M in THF, 0.032 mmol) and stir under an inert atmosphere for 18 hours. Pour the reaction mixture into a saturated solution of sodium bisulfite and extract the intermediate diol into ethyl acetate. Dry the separated organic layer over MgSO4, filter, and evaporate in vacuo to give the crude diol which is used without further purification. Dissolve the crude diol in chloroform (10 mL). Add a solution of lead tetraacetate (0.74 g, 1.67 mmol) in chloroform (10 mL). Stir for 30 minutes and then pour the reaction mixture into a saturated solution of sodium bicarbonate. Extract with dichloromethane and separate the organic layer. Dry the separated organic layer over MgSO4, filter and evaporate in vacuo to give the title compound which may be used without further purification.
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-])=O.[C:10](=[S:12])=O>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[CH:4]1([N:1]=[C:10]=[S:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C=S
Reactant: O=[N+]([O-])C1CCCCC1
Agent: [Mo]
Agent: [C-]#[O+]
Product: S=C=NC1CCCCC1
Temperature: 150 °C
Yield: 1.3 %

Procedure:
Nitrocyclohexane (0.02 mole) and molybdenum hexacarbonyl (0.0002 mole) were placed in a 100 ml. rocking autoclave which was then sealed. Carbonyl sulfide (10.0 g., 0.16 mole) was charged to the autoclave from a small stainless steel cylinder, in which it was contained in the liquified state under its own vapor pressure (about 160 psig). The autoclave was then heated at 150°C. for 3 hours, after which it was cooled to ambient temperature, vented and opened. The reaction mixture was rinsed from the autoclave with 10 ml. of chloroform. The chloroform solution was separated from an insoluble residue by filtration, following which the solvent was evaporated to give 0.97 g. of product mixture. Vapor phase chromatographic analysis of this mixture showed it to contain 1.0% of nitrocyclohexane and 3.6% of cyclohexyl isothiocyanate (1.3% yield based on unrecovered nitrocyclohexane).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][NH2:44]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:44][CH3:43])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: CNC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 210, 5.16 g, 8.73 mmol) and methylamine (2M in THF).
Reaction SMILES: C(OS([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=CC=1)(=O)=O)CC#C.[NH:16]1C[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:17]([N:16]1[CH2:15][CH2:12][CH2:13][CH2:14][CH2:9]1)[CH2:18][C:19]#[CH:20]
Reactant: C1CCNCC1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C#CCCN1CCCCC1
Temperature: 80 °C

Procedure:
A solution of toluene-4-sulfonic acid but-3-ynyl ester (45.0 g) and piperidine (40 mL) in ethanol (70 mL) was treated a solution of potassium carbonate (27.8 g) in water (70 mL). The mixture was heated to 80° C. for 2 h, cooled to RT, and extracted with DCM (3×100 mL). The combined organic phases were dried (magnesium sulfate), and evaporated. Distillation of the residue (110° C., 30 mm Hg) gave the title compound as a colorless oil (17.3 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.B.C1COCC1.CO.O>C1COCC1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:12][CH:13]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Agent: B
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled homogeneous solution of 4-(trifluoromethyl)hydrocinnamic acid (9.800 g; 44.918 mmol) in anhydrous THF (250 ml) was added dropwise a solution of 1M BH3.THF (67.4 ml; 67.4 mmol) over 20 min. The resulting homogeneous solution was further stirred at 0° C., under nitrogen, for 1 h, and then at rt for 14 h. The colorless homogeneous reaction mixture was cooled to 0° C., and MeOH (100 ml) was carefully added followed by water (100 ml). MeOH and THF were then removed under vacuum. After extraction with DCM (3×100 ml), the combined organic extracts were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=9/1) to give the pure product 3-(4-trifluoromethyl-phenyl)-propan-1-ol as a colorless oil which was further dried under HV (9.180 g; 100%). LC-MS: tR=0.89 min.; [M+H]+: no ionisation.
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[CH:4]([CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5][C:6]=1[O:7][CH3:8].[CH3:17][N:18]1[C:26]2[CH:25]=[CH:24][C:23]([CH3:27])=[C:22](B(O)O)[C:21]=2[CH:20]=[N:19]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][N:18]1[C:26]2[C:21](=[C:22]([C:2]3[C:3](=[O:16])[CH:4]([CH2:9][CH:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[CH2:5][C:6]=3[O:7][CH3:8])[C:23]([CH3:27])=[CH:24][CH:25]=2)[CH:20]=[N:19]1
Reactant: Cc1ccc2c(cnn2C)c1B(O)O
Reactant: COC1=C(Br)C(=O)C(CC2CCOCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: COC1=C(c2c(C)ccc3c2cnn3C)C(=O)C(CC2CCOCC2)C1
Temperature: 140 °C
Yield: 23.1 %

Procedure:
To a stirred suspension of the 2-bromo-3-methoxy-5-(tetrahydro-pyran-4-ylmethyl)-cyclopent-2-enone (150 mg, 0.5 mmol), 1,5-dimethyl-1H-indazole-4-boronic acid (148 mg, 0.78 mmol) and freshly powdered potassium phosphate tribasic (221 mg, 1 mmol) in anhydrous, de-gassed toluene (1.5 ml) under a nitrogen atmosphere were added palladium acetate (6 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (21 mg, 0.05 mmol). The reaction was heated to 140° C. for 30 minutes in the microwave (using “normal” absorbtion). The reaction was diluted with water (10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate and evaporated to dryness under reduced pressure to give a brown oil. The crude product was purified by column chromatography (30% EtOAc/hexane to 100% EtOAc as eluent) to give 2-(1,5-Dimethyl-1H-indazol-4-yl)-3-methoxy-5-(tetrahydro-pyran-4-ylmethyl)-cyclopent-2-enone (41 mg). This material was dissolved in acetone (2 ml) and 2 M hydrochloric acid (2 ml) added. This solution was heated in the microwave (using “normal” absorbtion) for 1 h at 120° C. This solution was then extracted with dichloromethane (2×10 ml) and the organics dried over magnesium sulfate and reduced in vacuo. The crude material was purified by reverse phase preparative HPLC (eluting with acetonitrile/water) to give 2-(1,5-dimethyl-1H-indazol-4-yl)-4-(tetrahydro-pyran-4-ylmethyl)-cyclopentane-1,3-dione (4 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N+:13]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:13][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: Cn1c(=O)oc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cn1c(=O)oc2cc(N)cc(F)c21
Temperature: 25 °C

Procedure:
Iron powder (0.77 g, 0.0138 mol) is added in small portions to a mixture of 4-fluoro-3-methyl-6-nitro-1,3-benzoxazol-2(3H)-one (Step 6, 0.73 g, 3.44 mmol) and ammonium chloride (1.84 g, 3.44 mmol) in ethanol (30 ml) and water (15 ml) at 95° C. The reaction mixture is stirred vigorously and heated for 1 h, cooled to room temperature, and diluted with dichloromethane (150 ml). The mixture is filtered, washed with water and saline, dried (MgSO4) and evaporated to give product as a tan solid suitable for use in the next step (0.64 g, 99%).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8][C:9]([O:12][C:13]([N:15]1[C@H:18]([C:19]([OH:21])=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])[CH3:10].Cl.[CH3:23][NH:24][O:25][CH3:26].C([Mg]Cl)(C)C>CCOCC.C1COCC1.CO.ClCCl>[CH3:26][O:25][N:24]([CH3:23])[C:19]([C@@H:18]1[CH2:17][CH2:16][N:15]1[C:13]([O:12][C:9]([CH3:8])([CH3:10])[CH3:11])=[O:14])=[O:21]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of trimethylsilyldiazomethane in ether (2M, 9 mL) was added dropwise to a stirred, ice-bath cooled, mixture of 1-Boc-L-azetidine-2-carboxylic acid (3 g, 15 mmol), dichloromethane (20 mL) and methanol (5 mL) until yellow colour persisted. The mixture was concentrated in vacuo. The residue was treated with THF (30 mL) and N,O-dimethylhydroxylamine hydrochloride (2.04 g; 20.9 mmol) and cooled to 0° C. i-Propylmagnesium chloride in THF (2 M, 22.4 ml, 44.7 mmol) was added dropwise to the mixture and it was stirred for 30 min. After quenching with saturated aqueous NH4Cl (25 ml) and concentrated NH3 (25 ml), the mixture was extracted into ethyl acetate (150 mL). The organic extract was dried (Na2SO4) and concentrated. The residue was purified on silica gel (hexanes-ethyl acetate 0-100%) to give the title product (2.73 g, 75%). 1H NMR (500 MB, CDCl3): δ 5.03 (1H, m), 4.05 (1H, m), 3.87 (1H, m), 3.71 (3H, s), 3.22 (3H, s), 2.46 (1H, m), 2.13 (1H, m), 1.43 (9H, s).
Reaction SMILES: [BrH:1].[N+]([C:5]1[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[N:9]=1)([O-])=O.C(=O)([O-])O.[Na+]>CC1C=CC(C)=CC=1>[Br:1][C:5]1[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[N:9]=1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccc(C)cc1
Product: O=[N+]([O-])c1c[nH]c(Br)n1
Yield: 47.6 %

Procedure:
2033.5 g of 49 mass % hydrobromic acid was added dropwise to 145.6 g of 2,4-dinitroimidazole wetted with p-xylene (wetted with 12 mass % of p-xylene). The temperature of the reaction liquid was elevated to 100° C. and reacted for 5 hours. After the reaction ended, the reaction liquid was gradually neutralized with 2000 mL of a saturated sodium hydrogen carbonate aqueous solution while the solution was cooled to deposit crystals. After the crystals were filtered, the crystals were heated and dissolved in 3000 mL of water at 95° C. and 75.0 g of 2-bromo-4-nitroimidazole (yield 47.6%) (HPLC purity 100%) was obtained by cooling, filtration and drying. This was identified to be 2-bromo-4-nitroimidazole by