Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11](CC(O)=O)[N:12]=2)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2ncc(-c3ccsc3)o2)cc1
Yield: 41.3 %

Procedure:
A mixture of 2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl acetic acid (1.5 g), diphenylphosphoryl azide (1.28 ml) and triethylamine (0.83 ml) in t-butanol (30 ml) was refluxed for one day. After cooling the reaction mixture, the solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Chloroform was added to the residue, the mixture was heated and insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate:n-hexane=1:9→1:7) to obtain 4-(t-butoxycarbonylamino)methyl-2-(4-fluorophenyl-5-(3-thienyl)oxazole (501 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([CH3:11])[CH2:6]1.Cl.Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[CH3:11][N:7]1[CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][N:23]2[CH2:24][CH2:25][N:20]([C:15]3[N:14]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:21][CH2:22]2)[O:9][C:8]1=[O:10]
Reactant: CN1CC(CCCCl)OC1=O
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: CN1CC(CCCN2CCN(c3ncccn3)CC2)OC1=O
Yield: 40.6 %

Procedure:
Following the procedure of Examples 5, 5-(3-chloropropyl)-3-methyl-2-oxazolidinone (5.0 g, 0.0282 mol), 1-(2-pyrimidinyl)piperazine dihydrochloride (6.70 g, 0.0282 mol), potassium carbonate (23.4 g, 0.1695 mol), and potassium iodide (0.5 g) in 1-butanol (100 mL) gave an oil (3.5 g, 41% yield) which was dissolved in a hot mixture of isopropyl ether and isopropanol, filtered hot, and brought to the cloud point by the addition of light pet ether. Upon cooling, a solid precipitated which was collected by filtration, rinsed with light pet ether, and dried under high vacuum to give 1.38 g, mp 79°-89° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[F:18])[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.[Cl:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=3[F:18])[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(Cl)n1
Reactant: OB(O)c1ccnc(Cl)c1
Product: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.61) (1.50 g, 4.35 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.75 g, 4.8 mmol) according to the general procedure IVb. Obtained as a light red solid (0.64 g, 35%). MS (ISP) 422.0 [(M+H)+]; mp 146° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11](O)=O)[CH2:6]2)OCC1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:29]1([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:29]1([C:35]2[CH2:40][CH2:39][N:38]([CH2:11][CH:7]3[CH2:8][CH2:9][CH2:10][C:5](=[O:1])[CH2:6]3)[CH2:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C(O)C1CCCC2(C1)OCCO2
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCC(CN2CC=C(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decane-7-carboxylic acid (Step A) (99.3 g) and triethylamine (80.8 g) in 1000 mL of dichloromethane is cooled in an ice bath, and treated dropwise with isobutyl chloroformate (80.1 g), dropwise, under nitrogen. After 30 minutes, a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (84.7 g) in 500 mL of dichloromethane is added dropwise over a 2-hour period. The mixture is stirred at room temperature for 2 additional hours. The solvent is removed in vacuo. The residue is suspended in 1000 mL of ethyl acetate, cooled to 0° C., and sequentially washed with ice-cold 1N aqueous hydrochloric acid solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product is purified by flash chromatography (silica; hexane:ethyl acetate, 3:1) to give 107.1 g of the title compound as a yellow oil (silica; Rf =0.4; 1% methanol, 99% chloroform); Mass Spectrum (Electron Ionization) (MS (EI)) 327 (M, 26.1%), 141 (100%).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:22]([NH2:24])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])[CH2:11][CH2:12][CH3:13])=[O:8]>C(O)(=O)C.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:22]([NH2:24])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])[CH2:11][CH2:12][CH3:13])=[O:8]
Reactant: CCC[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N[C@H](C(N)=O)[C@@H](C)CC
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@H](C(N)=O)[C@@H](C)CC
Yield: 98.1 %

Procedure:
4.75 g (10 mmoles) of Z-Glp-Nva-Ile-NH2 are dissolved in 200 ml of acetic acid, 1 g of a 10% palladium-on-carbon catalyst is added, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the residue is triturated with ether. 3.34 g (98%) of Glp-Nva-Ile-NH2 are obtained; m.p.: 267°-270° C. (decomposition), Rf5 =0.61, [α]D25 =-50.2° (c=1%, in acetic acid).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)(=O)C.O>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Yield: 76.3 %

Procedure:
To a solution of 3-hydroxy-7beta-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (1) in dimethylformamide (9.5 parts, dried over Molecular Sieves) at -50° C. under nitrogen is added sodium borohydride (4 equivalents) at -53° to -48° C. over 3 minutes. After 30 minutes at the same temperature, glacial acetic acid (1.4 parts) and then water (10 parts) are added to the mixture gradually, and extracted with ethyl acetate. The extract is washed with 5% aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated. The residue is crystallized from a mixture of dichloromethane (4 parts) and n-hexane (1.7 parts) to give 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (2). Yield: 76.3%. mp. 196°-198° C. (decomposition).
Reaction SMILES: [CH2:1]([N:5]([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:28]([C:30]1[C:31](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[O:32][C:33]([CH3:40])([C:36]([F:39])([F:38])[F:37])[C:34]=1[CH3:35])#[N:29]>C(O)C.O1CCCC1>[CH2:24]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH:35][C:34]3[C:33]([CH3:40])([C:36]([F:39])([F:37])[F:38])[O:32][C:31](=[C:41]([C:42]#[N:43])[C:44]#[N:45])[C:30]=3[C:28]#[N:29])=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)c(OC)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)cc2)c(OC)c1
Temperature: 50 °C
Reaction time: 9 h
Yield: 38.9 %

Procedure:
In 15 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 500 mg (1.37 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]benzaldehyde and 380 mg (1.50 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at 50° C. for 9 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 320 mg of a black powder (yield: 38.9%; mp: 175-177° C.)
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[C-:29]#[N:30].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.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.[Cu]I>[Cl:27][C:19]1[CH:18]=[C:17]([CH:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:29]#[N:30])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C#N)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 73.4 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (616.0 mg, 1.266 mmol), potassium cyanide (210.0 mg, 3.225 mmol), tetrakis(triphenylphosphine)palladium(0) (30.0 mg, 0.026 mmol), copper(I) iodide (605.0 mg, 3.177 mmol), and 18-crown-6 (33.0 mg, 0.125 mmol) in anhydrous N,N-dimethylformamide (6 mL) was heated at 150° C. under nitrogen. After 2.75 h, the mixture was allowed to cool to 25° C. The mixture was then concentrated to remove solvent. The residue was diluted with methylene chloride and ethyl acetate and then filtered through a pad of celite. The celite pad was then washed well with ethyl acetate and methylene chloride. The filtrate was then concentrated in vacuo and absorbed onto silica gel (Merck Silica gel 60, 230–400 mesh). Biotage chromatography (FLASH 40L, Silica, 1/3 to 1/1 ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-cyano-pyrazin-2-yl)-3-cyclopentyl-propionamide (402.3 mg, 73.4%) as an off-white foam: (ES)+-HRMS m/e calcd for C20H21ClN4O3S (M+H)+ 433.1096, found 433.1101.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].C1COCC1>O>[N:11]1([C:8]2[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)c1cnc(N2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
5-Piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester (Preparation 42, 85.1 g, 384 mmol) was added to a solution of sodium hydroxide (61.5 g, 1.53 mol) in water (760 mL). The mixture was stirred mechanically for 1 hour at room temperature. THF (300 mL) was added and stirring was continued for 3 hours. The volatile solvents were removed in vacuo and the remaining aqueous solution was adjusted to pH 4. The mixture was cooled on ice to induce precipitation of the product. The resulting solid was collected by filtration and dried in vacuo to give the title compound as a white solid (56 g) in a 70% yield.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11](C)(C)C)=[O:9])[C:5]2[CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[S:17][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].[F-].[K+]>O1CCOCC1.CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd]>[CH:22]1([C:3]2[C:4]3[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:5]=3[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:28]=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2CC(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)Cn1c(-c2ccccc2C=O)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
Methyl 5-bromo-6-cyclohexyl-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (prepared by analogy to Example 7, Step 2, substituting tert-butyl bromoacetate with methyl bromo acetate), 2-formyl benzene boronic acid (1.3 eq.), KF (3.2 eq.) and Pd(t-Bu3P)2 (0.2 eq.) were mixed in dioxane (0.1M). The mixture was degassed, flushed with nitrogen and left stirring for 5 h at RT. Then all volatiles were evaporated i. vac. and the residual material was isolated by chromatography (PE:EtOAc, 9:1). The product was obtained as a yellowish solid (80%). MS (ES+) m/z 440 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.[NH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1>>[Br:1][C:2]1[C:7]([N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Product: OC1CCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)CC1
Yield: 26.8 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and piperidin-4-ol, 292 was obtained as an off-white solid (9.50 mg, 26.8%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.26-9.20 (m, 2H), 8.99 (s, 1H), 8.61 (d, J=3.7 Hz, 1H), 8.41 (d, J=7.9 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.55 (dd, J=8.0, 4.8 Hz, 1H), 4.75 (d, J=3.7 Hz, 1H), 3.91-3.71 (m, 3H), 3.18 (d, J=10.1 Hz, 2H), 1.96 (d, J=11.1 Hz, 2H), 1.65 (dd, J=18.8, 9.2 Hz, 2H); ESI MS m/z=451.2 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[S:10]([Cl:14])(=O)(=[O:12])[OH:11]>O>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[S:10]([Cl:14])(=[O:12])=[O:11]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1c(F)cccc1F
Solvent: O
Product: Cc1c(F)ccc(S(=O)(=O)Cl)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.9 %

Procedure:
To 1,3-difluoro-2-methylbenzene (5.00 g, 39.0 mmol), chlorosulfuric acid (10.5 mL, 158 mmol) was added with cooling on ice, and the mixture was stirred at room temperature for 5 hours. To the reaction solution, water (100 mL) was added with cooling on ice, followed by extraction with dichloromethane (100 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography to yield the title compound (8.65 g, 98%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:23].[Na+]>CO.[OH-].[Na+]>[NH2:23][CH:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A mixture of tert-butyl 4-acetylpiperidine-1-carboxylate (145 g, 0.64 mol) and ammonium acetate (225 g, 2.9 mol) in methanol (2 L) was stirred at room temperature for 1.5 hours. Sodium cyanoborohydride (30 g, 0.48 mol) was added in one portion and the stirring was continued overnight at room temperature. The reaction mixture was poured in 2N aq. NaOH (2 L) and extracted with dichloromethane (2×1 L). The combined extracts were washed with water (1 L), brine (0.3 L), and evaporated to dryness. The residue was dissolved in TBME (1.5 L), dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by bulb to bulb distillation at 180° C. and 0.1 mbar to afford the title compound as a colorless oil that partly solidified upon standing (131 g, 90% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH3:19]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[CH3:19]
Reactant: O=C1CCc2cc(O)ccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc2c(c1)CCC2=O
Reaction time: 144 h
Yield: 99.3 %

Procedure:
5-Hydroxy-1-indanone (2.5 g, 16.0 mmol) was dissolved in acetone (60 ml) and potassium carbonate (waterfree, 5.15 g, 36.9 mmol) and ethyl iodide (2.88 ml, 35.3 mmol) were added. The reaction was stirred at it under an atmosphere of nitrogene for 6 days. The mixture was filtered, the filtrate collected and the solvent evaporated at reduced pressure. Chromatography on silica (flashmaster, hex to hex/EtOAc 2/3 in 20 min, 15 min hex/EtOAc 2/3) gave the product as off-white solid (2.8 g, 99%). [1H-NMR (DMSO-d6, 600 MHz) δ 7.54 (d, 1H), 7.07 (s, 1H), 6.94 (d, 1H), 4.13 (q, 2H), 3.05-3.03 (m, 2H), 2.58-2.56 (m, 2H), 1.35 (t, 3H); LCMS RtJ=0.88 min; [M+H]+=177.2]
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:26]=[C:25]2[C:9]([CH2:10][C:11]3([C:18]42[NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:19]4)[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)=[CH:8][CH:7]=1.FS([C:31]([F:36])([F:35])C(O)=O)(=O)=O.O.CCOC(C)=O>C(#N)C>[F:35][CH:31]([F:36])[O:17][CH:14]1[CH2:15][CH2:16][C:11]2([C:18]3([NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:19]3)[C:25]3[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][F:1])[CH:26]=3)[CH2:10]2)[CH2:12][CH2:13]1
Reactant: CC1=NC2(NC1=S)c1cc(OCCCF)ccc1CC21CCC(O)CC1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1=NC2(NC1=S)c1cc(OCCCF)ccc1CC21CCC(OC(F)F)CC1
Temperature: 60 °C
Yield: 103.5 %

Procedure:
6′-(3-Fluoropropoxy)-4-hydroxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Intermediate 33, 290 mg, 0.77 mmol) was suspended in dry acetonitrile (10 mL). Cuprous iodide (14.67 mg, 0.08 mmol) was added and the resulting mixture was heated at 60° C. for 5 min under an atmosphere of argon. 2-(Fluorosulphonyl)difluoroacetic acid (0.127 mL, 1.16 mmol) was added in a stream and the reaction mixture was heated for 20 min. Additional 2-(Fluorosulphonyl)difluoroacetic acid (0.042 mL, 0.39 mmol) was added, and the mixture was heated for an additional 45 min. The mixture was cooled to r.t. Water and EtOAc were added, and the phases were separated and the aqueous phase was re-extracted with EtOAc twice. The combined organic phases were dried using a phase separator and concentrated to give 340 mg of 4-(difluoromethoxy)-6′-(3-fluoropropoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione, which was suspended in ammonia (7 M in methanol, 4 mL, 28 mmol), and heated in the MW at 100° C. for 60 min. The mixture was concentrated, re-dissolved in ammonia (7 M in methanol, 4 mL, 28 mmol) and heated at 100° C. for 60 min. This procedure was repeated eight times in total. The mixture was cooled to r.t., concentrated, and purified by flash column chromatography using a gradient of 0-50% EtOAc in heptane, followed by 0-20% MeOH (containing 1% NH3) in EtOAc, to give 82 mg (25% yield) of the title compound. MS (MM-ES+APCI)+m/z 410.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH:10]([CH3:29])[CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[CH3:62][C:63]1([CH3:68])[CH2:67][CH2:66][NH2+:65][CH2:64]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([C:24]([N:65]4[CH2:66][CH2:67][C:63]([CH3:68])([CH3:62])[CH2:64]4)=[O:25])[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH:10]([CH3:29])[CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1(C)CC[NH2+]C1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCc2c1nc1ccnn1c2N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C)(C)C)CCc2c1nc1ccnn1c2N1CC(C(=O)N2CCC(C)(C)C2)C1
Reaction time: 0.5 h

Procedure:
To 300 mg (0.57 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) in 6.0 mL DMF was added 484 mg (1.51 mmol) TBTU and 243 μL (1.41 mmol) DIPEA and stirring was continued at room temperature for 30 min. Then 84.3 mg (0.62 mmol) of 3,3-Dimethyl-pyrrolidinium chloride was added and the reaction mixture was stirred additional 4 h. The reaction mixture was filtered and the purified by HPLC.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[OH-].[K+].[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH:9]([CH3:11])[CH3:10]>C(O)(C)C.N#N>[C:13]1([CH:8]([CH:9]([CH3:11])[CH3:10])[OH:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)C(=O)c1ccccc1
Agent: N#N
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)O
Product: CC(C)C(O)c1ccccc1
Reaction time: 4 h

Procedure:
12.2 mg (2×10-5 moles) of [Ir(PPEI)COD]+ClO4- (+) were suspended in 50 ml of isopropanol and oxidized with air for 4 hours. The resulting yellow solution was then degasified at reflux for 20 minutes in a nitrogen flow and successively treated with 4.4 ml of a deaerated isopropanol solution of KOH (4 mg of KOH), effecting a preliminary reduction for 30 minutes at reflux in N2. 3.0 ml of deaerated isobutyrophenone was then added to the solution. After 120 minutes a conversion to phenylisopropylcarbinol (+) of 92.1% with an e.e. of 13% was obtained. Ratios: