Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=C(C2OC=CN=2)C=C(C(N2CCC[C@@H]2COC)=O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.[Si]([O:67][C@H:68]([C@H:96]1[CH2:100][C@@H:99]([O:101][CH2:102][CH2:103][CH3:104])[CH2:98][N:97]1C(OC(C)(C)C)=O)[C@@H:69]([NH:79][C:80](=[O:95])[C:81]1[CH:86]=[C:85]([N:87]2[CH2:91][CH2:90][CH2:89][C:88]2=[O:92])[CH:84]=[C:83]([O:93][CH3:94])[CH:82]=1)[CH2:70][C:71]1[CH:76]=[C:75]([F:77])[CH:74]=[C:73]([F:78])[CH:72]=1)(C(C)(C)C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=C(N2CCCC2=O)C=C(O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.C(OCC)(=O)C>[F:78][C:73]1[CH:72]=[C:71]([CH2:70][C@H:69]([NH:79][C:80](=[O:95])[C:81]2[CH:86]=[C:85]([N:87]3[CH2:91][CH2:90][CH2:89][C:88]3=[O:92])[CH:84]=[C:83]([O:93][CH3:94])[CH:82]=2)[C@H:68]([OH:67])[C@H:96]2[CH2:100][C@@H:99]([O:101][CH2:102][CH2:103][CH3:104])[CH2:98][NH:97]2)[CH:76]=[C:75]([F:77])[CH:74]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(OC)cc(N3CCCC3=O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(O)cc(N3CCCC3=O)c2)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(OC)cc(N3CCCC3=O)c2)C1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Step 13 (A): (2R,4R)-tert-Butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-methoxy-5-(2-oxopyrrolidin-1-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate (Preparation I, 27 mg, 0.037 mmol) in DMF (1 mL) were added cesium carbonate (24 mg, 0.074 mmol) and methyl iodide (25 mg, 0.185 mmol) and the reaction mixture was stirred at 80° C. for 3 h, at rt for 3 days and microwaved at 80° C. for 6 h. Ethyl acetate (100 mL) was added and the mixture was washed with H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% EtOAc/Hexane step gradient) to give 20 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.07 (3H, s), 0.85 (9H, s), 0.88 (3H, m), 1.46-1.54 (11H, m), 2.02-2.07 (1H, m), 2.10-2.16 (2H, m), 2.20 (1H, m), 2.59 (2H, m), 2.64 (1H, dd, J=10, 15 Hz), 2.92 (1H, m), 3.28-3.37 (3H, m), 3.76 (1H, dd, J=5, 10 Hz), 3.84 (3H, s), 3.88-3.92 (2H, m), 3.98 (1H, m), 4.04-4.13 (2H, m), 4.58 (1H, m), 6.60 (1H, m), 6.78 (2H, d, J=5 Hz), 7.23 (1H, s), 7.34 (1H, s), 7.80 (1H, s), 8.05 (1H, brd s). MS (ESI) (M+H)+ 746.41.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:33])[N:24]([CH2:29][CH2:30][C:31]#[N:32])[CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:20]=[C:19]([Cl:34])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[C:31]([CH2:30][CH2:29][N:24]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:23](=[O:33])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=[C:19]([Cl:34])[CH:20]=1)(=[O:39])[NH2:32]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)CC2CC2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CCN(CC1CC1)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 18 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-cyclopropylmethyl-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.07 g) in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 18 h and then concentrated under reduced pressure to give the title compound as a light brown oil (0.071 g).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19](C(C)=C)[C:18]3=[O:29])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[ClH:39]>O>[ClH:39].[ClH:39].[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:29])[CH2:10][CH2:9]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 76 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 280 parts of ethanol are added 120 parts of a hydrochloric acid solution and 250 parts of water. The whole is stirred for 30 minutes at room temperature. Upon cooling in an ice-bath, the product is precipitated. It is filtered off, washed with 2-propanone and with 2,2'-oxybispropane, and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride.hydrate; mp. 237.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[C:5]([CH2:20][NH:21]C=O)[CH:4]=1)#[N:2].[ClH:24]>C(O)C>[ClH:24].[NH2:21][CH2:20][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:19]=[CH:18][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[B:15]([OH:16])[O:14][CH2:13][C:12]=2[CH:17]=1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(CNC=O)c1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(CN)c1
Yield: 98 %

Procedure:
To a solution of 5-[4-cyano-2-(formylaminomethyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (250 mg, 0.812 mmol) in ethanol (16 mL) was added 6 M HCl (4 mL), and the mixture was refluxed for 2 h. The solvent was removed under reduced pressure, and the residue was treated with ether to give 5-(2-aminomethyl-4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole hydrochloride (247 mg, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].Br[C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OC(=O)C)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=2)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(-c3cc(C)ccn3)c2s1
Temperature: 80 °C

Procedure:
A mixture of 1-[5-Benzyloxy-7-bromo-benzothiazol-2-yl]-3-ethyl-urea (406 mg, 1.0 mmol), bis(neopentyl)glycolato diboron (452 mg, 2.0 mmol) and potassium acetate (294 mg, 3.0 mmol) in dimethyl sulfoxide (7 ml) was purged with nitrogen for 5 minutes. Bis(diphenylphosphino)ferrocene palladium(II)chloride complex (82 mg, 0.1 mmol) was added, the reaction mixture sealed and heated at 80° C. for 16 h. The reaction mixture was cooled to ambient temperature. 2-Bromo-4-methylpyridine (258 mg, 1.5 mmol) was added followed by aqueous cesium carbonate solution (3.7M, 0.405 ml, 1.5 mmol). The reaction mixture was purged with nitrogen for 5 minutes, treated with tetrakistriphenylphosphine palladium (0) (115 mg, 0.1 mmol), sealed and heated at 80° C. for 8 h. The reaction mixture was cooled to ambient temperature, diluted with ethylacetate (150 ml), washed with water (3×20 ml) followed by brine (25 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash silica chromatography eluting with 1:1 ethyl acetate:petrol ether to give 1-[5-Benzyloxy-7-(4-methyl-pyridin-2-yl)-benzothiazol-2-yl]-3-ethyl-urea as an off white solid (290 mg, 69%).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].CS([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[O:19])[CH2:13][CH2:12]1)(=O)=O>>[CH2:1]([S:3]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)=[O:19])[CH2:13][CH2:12]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: CCS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 43 %

Procedure:
Ethylsulfonyl chloride (63 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (40 mg, 0.105 mmol, 43% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.77 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.2 Hz, 1H), 3.63 (m, 1H), 3.52 (d, J=12.3 Hz, 2H), 3.05 (m, 5H), 1.89 (d, J=10 Hz, 2H), 1.47 (m, 2H), 1.22 (t, J=4.8 Hz, 3H).
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Cl[C:61]1[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][N:66]=1.CC1(C)C(C)(C)OB([C:77]2[CH:82]=[CH:81][C:80]([OH:83])=[CH:79][CH:78]=2)O1>>[OH:83][C:80]1[CH:81]=[CH:82][C:77]([C:61]2[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][N:66]=2)=[CH:78][CH:79]=1
Reactant: N#Cc1nccnc1Cl
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: N#Cc1nccnc1-c1ccc(O)cc1

Procedure:
Compound 86A was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with 3-chloropyrazine-2-carbonitrile and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 10.14 (s, 1H), 8.95 (d, J=2.45 Hz, 1H), 8.73 (d, J=2.45 Hz, 1H), 7.83-7.85 (m, 2H), 6.95-6.99 (m, 2H). ESI (+)/MS: 211 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:6][C:5]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:4][CH:3]=1.NC1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)=[O:18])[CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(Cl)c(-c2cccc([N+](=O)[O-])c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: Nc1ccccc1
Product: Nc1cccc(-c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc2Cl)c1
Reaction time: 20 h
Yield: 76.8 %

Procedure:
6-Chloro-3′-nitro-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide (0.46 g, 0.0011 mol) was dissolved in methanol (40 mL), and palladium hydroxide on carbon (20%; 88 mg; 50% wet; 0.000063 mol) was added. The resulting mixture was hydrogenated at 60 psi and 20° C. for 20 h, at which time LCMS showed near complete conversion to the aniline (accompanied by 3% de-chlorination). The reaction mixture was filtered; and rinsed thoroughly. The filtrate was concentrated in vacuo to give 0.33 g of product. The product was purified by prep HPLC/MS using a 30 mm×100 mm C18 column; 35% CH3CN—H2O (0.1% TFA), 1 min, to 55% at 6 min; 60 mL/min; detector set at m/z 391; retention time, 5.5 min. The resulting mixture was freeze dried to yield 258 mg white solid TFA salt. 1H NMR (DMSO-d6) δ 10.62 (br s, 1H, amide NH); 8.20 (s, 1H); 8.04 (d, 1H); 8.00 (m, 2H); 7.75 (d, 1H); 7.59 (t, 1H); 7.45 (d, 1H); 7.35 (t, 1H); 7.00 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[C:28]2[Cl:34].C(O)(C)C.ClC1C2C(=CC=C(NC3C4C=C(C5CCNCC=5)NC=4N=CN=3)C=2)NN=1.C(N(CC)C(C)C)(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][N:29]=[C:28]5[Cl:34])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Clc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)cc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]nc(Cl)c5c4)ncnc3[nH]2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (49.6 mg, 0.148 mmol) and 5-amino-3-chloroindazole (26.5 mg, 0.155 mmol) in isopropyl alcohol (2.5 mL, 0.033 mol) in a sealed tube was heated to 90° C. (bath temp.) for 3.5 h. The bath temperature was increased to 105° C., and heating was continued overnight. The bath temperature was increased to 120° C., and heating was continued for 5 d. LC/MS at that time indicated loss of Boc group, i.e., (3-chloro-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine, C18H16ClN7, MW=365.83. Solvents were evaporated. The reddish residue was suspended in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (52 μL, 0.30 mmol) and di-tert-butyldicarbonate (33 mg, 0.15 mmol) were added, and the mixture was stirred at rt for 2 h. DMF was evaporated, water and CH2Cl2 were added, and the insoluble brown material was filtered off and washed with CH2Cl2 and water. The layers of the filtrate were separated; the organic layer was washed with water (2×) and brine and dried over MgSO4. The drying agent was filtered off, and the filtrate was concentrated, redissolved in MeOH, passed a through 0.45 μm filter, and purified by MDP. One obtained the title compound as light tan solid. MS (ES+): m/z 465.9/467.9 (100/38) [MH+]. HPLC: tR=2.7 min (ZQ2000, polar—5 min). 1H NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.37-2.44 (brs, 2H), 3.51-3.58 (mc, 2H), 3.99-4.07 (m, 2H), 6.36 (s, 1H), 6.54 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 8.12 (s, 1H), 9.21 (s, 1H), 11.88 (brs, 1H), 13.43 (brs, 1H).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([CH2:11][CH2:12][CH:13]=[C:14]([F:16])[F:15])[C:6]([O:8]CC)=[O:7])C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[F:15][C:14]([F:16])=[CH:13][CH2:12][CH2:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(CCC=C(F)F)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)C(CCC=C(F)F)C(=O)O
Reaction time: 15 h

Procedure:
34.9 g of 2-(4,4-difluorobut-3-en-1-yl)malonic acid diethyl ester are added to 50 ml of methanol. 50 g of potassium carbonate dissolved in 150 ml of water are slowly added dropwise at room temperature and then the mixture is heated to reflux temperature and stirred at that temperature for 15 hours. The reaction mixture is concentrated to dryness by evaporation in a rotary evaporator and the residue is treated with concentrated hydrochloric acid until a pH value of 1 has been obtained and then extracted three times using 150 ml of diethyl ether each time. The combined ether phases are dried over sodium sulfate and concentrated by evaporation. The title compound is obtained in the form of a colourless oil.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH:27]1[CH:33]=O>C1COCC1>[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[CH:27](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][C:31]1=[O:32]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1C=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/C1CCCC(=O)N1CC#CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 37 mg, 0.91 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (217 mg, 0.83 mmol) in THF (4 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ˜0.92 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid and water (1:1, 15 mL) and extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10% →50% EtOAc/CH2Cl2, gradient) afforded 175 mg (58%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH:28]=[N:27][NH:26][C:25]=3[CH2:24]2)[C:11](=O)[N:10]1[CH3:32].C(N(CC)CC)C.[F:40][C:41]([F:47])([F:46])[S:42](Cl)(=[O:44])=[O:43].[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49].C(Cl)Cl>ClCCl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:42]([C:41]([F:47])([F:46])[F:40])(=[O:44])=[O:43])[CH:28]=3)[CH2:24]2)[CH2:11][N:10]1[CH3:32]
Reactant: CN1C(=O)[C@H](N2Cc3cn[nH]c3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@H](N2Cc3cn(S(=O)(=O)C(F)(F)F)nc3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-1-methyl-6-oxopiperidin-3-yl]carbamate (60 mg, 0.138 mmol) in dichloromethane (4 mL) at room temperature, triethylamine (0.048 mL, 0.346 mmol) and trifluoromethanesulfonyl chloride (0.029 mL, 0.277 mmol) were added. The mixture was stirred overnight at room temperature. The residue was purified by preparative TLC on silica gel, eluting with CH2Cl2/MeOH/aqueous NH3 (95/4/1) to give first eluting isomer as isomer A and second eluting isomer as isomer B. Isomer A was treated with 1:1 TFA/CH2Cl2 for 1 h to give the title compound. LC-MS: 465.84 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.O.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=1)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccccn1)Cc1cccc(CCOC2CCCCO2)c1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccccn1)Cc1cccc(CCO)c1

Procedure:
(2-Pyridin-2-yl-ethyl)-{3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzyl}-carbamic acid tert-butyl ester (8 g) in tetrahydrofuran (100 mL) was treated with acetic acid (10 mL) and water (10 mL). The reaction was refluxed for 8 hour. Another 10 mL acetic and 10 mL water were added and the reaction heated at reflux for a further 2 hours. The reaction was cooled and the volatiles removed under vacuum. The reaction mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo. The yellow residue was passed through a plug of silica, eluting with ether then ethyl acetate to elute the desired product (4.1 g).
Reaction SMILES: [Mg].CCO[Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].II.Br[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1>C1COCC1>[CH2:13]([O:12][Si:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[C:18]1[CH:23]=[CH:22][C:21]([Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[CH:20][CH:19]=1)[CH3:14]
Reactant: Brc1ccc(Br)cc1
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)c1ccc([Si](OCC)(OCC)OCC)cc1
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A mixture of magnesium turnings (15 g) and TEOS (450 mL, 2 mol) in THF (300 mL) were placed under nitrogen in a 1 L three-neck round bottom flask equipped with magnetic stir bar, condenser, and addition funnel. A small crystal of iodine was added and the mixture was brought to reflux. A solution of 1,4-dibromobenzene (48 g, 204 mmol) in THF (100 mL) was added dropwise over 2 h. Within 30 min of initiating the addition, the reaction became mildly exothermic. The reaction mixture was kept at reflux for 1 h after the completion of the addition of dibromide. The gray-green mixture was allowed to cool to room temperature before the THF was removed in vacuo. Hexane (200 mL) was added to precipitate any remaining magnesium salts in solution and the mixture was quickly filtered under nitrogen to produce a clear, light brown solution. Hexane was removed in vacuo. The product was purified by fractional distillation. The product was recovered as a clear liquid at 130–5° C. (0.2 mmHg) in 43–47% yield. 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 4H, ArH), 3.86 (q, J=7.00 Hz, 12H, OCH2CH3), 1.23 (t, J=7.00 Hz, 18H, ArH); 13C NMR (125 MHz, CDCl3) δ 133.25,57.98, 17.43; 29Si NMR (99 MHz, CDCl3) δ−58.25; MS m/e calc'd for CI (M) C18H34Si2O6: 402.1894, found 402.1886.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:31]([O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32])[CH2:2]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.0 g, 33.0 mmol; from Preparation B above) and triethylamine (6.8 mL, 36 mmol) were dissolved in CHCl3 (80 mL) and cooled to 0° C. N-(Benzyloxycarbonyloxy)succinimide (9.0 g, 36.1 mmol), dissolved in CHCl3 (70 mL), was slowly added 0° C. The solution was allowed to reach r.t, and was stirred at r.t overnight. CHCl3 (200 mL) was added and the solution was washed with water, then dried and evaporated. The residue was then dissolved in ether and washed with 2 M HCl in order to remove any remaining unreacted starting material. Drying and evaporation gave 10 g (88%) of the sub-title compound.