Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(-c2ccccn2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccccn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.09 min; Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].[O:14]([C:16]#[N:17])[K]>CC(O)=O.O>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:16]([NH2:17])=[O:14])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: N#CO[K]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1c[nH]c2ccc(NC(N)=O)cc12
Reaction time: 14 h
Yield: 52.7 %

Procedure:
To a solution of 21.3 g (0.124 mole) of 5-aminoindole-3-acetonitrile in 400 ml of 25% aq HOAc cooled to 0° was added 10.5 g (0.13 mole) of KOCN in 30 ml of H2O. The reaction mixture was stored at 0° for 14 hours after which a beige solid was filtered and recrystallized from methanol to give 14.0 g (53% yield) of N-(3-cyanomethyl-1H-indol-5-yl)urea. Further recrystallization affords an analytical sample: m.p. 219°-220°; i.r. (Nujol) 3455, 3300, 2250 and 1650 cm-1 ; nmr (d6 -DMSO) δ(TMS) 11.06 (1,S,indole NH ), 8.46 (1,S, --NHCO--), 7.70 (1,d,Jmeta =2 Hz), 7.37 (1,d,Jortho =9 Hz), 7.30 (1,S,indole C2H), 7.18 (1,d of d,Jortho =9 Hz, Jmeta =2 Hz), 5.73 (2,S,--CONH2) and 4.00 ppm (2,S,--CH2CN).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC(CN(CC2C=CC([N+]([O-])=O)=CC=2)C2C=CC=CC=2)=CC=1)([O-])=O>>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:9]([CH2:8][C:7]2[CH:25]=[CH:26][C:4]([NH2:1])=[CH:5][CH:6]=2)[C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)[C@@H]2CCOC2)cc1
Agent: O=[N+]([O-])c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Product: Nc1ccc(CN(Cc2ccc(N)cc2)[C@@H]2CCOC2)cc1
Yield: 109 %

Procedure:
The title compound was prepared using the methods from Example 1B substituting the product from Example 44A for the product from Example 1A to provide the title compound (1.02 g, 109% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCC1CCCCN1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCC1CCCCN1Cc1ccccc1
Yield: 100 %

Procedure:
2-Piperidineethanol (25.8 g, 0.2 mol), benzyl bromide (26.2 ml) and potassium carbonate (55.3 g) in acetonitrile (250 ml), as described above, gave 1-benzyl-2-piperidineethanol (43.8 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[Mg]Br.BrC1C=CC2C(=CC=CC=2)C=1.[Mg].[Cl-].[NH4+]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]([OH:8])[C:13]1[CH:12]=[CH:11][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Br[Mg]c1ccc2ccccc2c1
Agent: Brc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: Oc1ccc(Br)cc1C(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 5-bromosalicylaldehyde (2 g) in diethyl ether (20 ml) was added to (2-naphthyl)magnesium bromide [prepared by adding a solution of 2-bromonaphthalene in diethyl ether (30 ml) to a mixture of magnesium turnings (0.49 g) and diethyl ether (20 ml) and heating the resultant mixture to reflux for 90 minutes] and the mixture was stirred at ambient temperature for 1 hour. A saturated aqueous ammonium chloride solution (20 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of petroleum ether (b.p. 60°-80° C.) and ethyl acetate as eluent to give 5-bromo-2-hydroxy-α-(2-naphthyl)benzyl alcohol (1.98 g, 60%), m.p. 115°-117° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:16][CH2:17][CH2:18]O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH2:9]([O:16][CH2:17][CH2:18][O:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCCC1O
Reactant: OCCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: O=C1CCCCC1OCCOCc1ccccc1
Reaction time: 10 h
Yield: 67.1 %

Procedure:
A mixture of dimeric 2-hydroxycyclohexanone (13.7 g), 2-benzyloxyethanol (20 g) and p-toluensulphonic acid (2 g) were dissolved in xylene (500 ml) in a round bottom flask fitted with a Dean Stark apparatus and reluxed for 10 hrs. The resulting solution was cooled, washed with sodium hydrogen carbonate (3×50 ml) dried and concentrated under reduced pressure. The crude oil was then pruified by flash chromatography using cyclohexane/ethyl acetate 60/40 as eluant yielding 20 g of the title compound (RF=0.5).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C(O)C(O)C.Cl[S:16]([C:19]1[N:27]=[C:26]2[N:21]([C:22]([O:29][CH3:30])=[N:23][CH:24]=[C:25]2[F:28])[N:20]=1)(=[O:18])=[O:17]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][S:16]([C:19]1[N:27]=[C:26]2[N:21]([C:22]([O:29][CH3:30])=[N:23][CH:24]=[C:25]2[F:28])[N:20]=1)(=[O:17])=[O:18]
Reactant: Nc1c(F)cccc1F
Reactant: COc1ncc(F)c2nc(S(=O)(=O)Cl)nn12
Solvent: ClCCl
Solvent: CC(O)CO
Product: COc1ncc(F)c2nc(S(=O)(=O)Nc3c(F)cccc3F)nn12
Temperature: 35 °C
Reaction time: 3.5 h

Procedure:
A jacketed 250 mL (milliliter) round bottom flask equipped with a stirrer, condenser, and nitrogen inlet and outlet was loaded with 49.1 g (grams), 0.38 mol (mole) of 2,6-difluoroaniline and 25 g of 1,2-propanediol. The mixture was warmed to 35° C. by heating the jacket fluid and a solution of 30.3 g of 93 percent purity (0.10 mol) of 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine in 30.2 g of dichloromethane was added portionwise with stirring under a nitrogen blanket over 3.5 hours. A solid began to form in about one hour and all of the chlorosulfonyl starting material was consumed in 5.5 hours. The resulting mixture was cooled to 20° C. and filtered, collecting the solids. The solids were washed 2×40 mL with methanol and then with 112 g of water. The white solid obtained after drying was found to be the title compound with a purity of greater than 99 percent and to amount to 34.2 g (88.9 percent of theory).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].S(Cl)([Cl:12])(=O)=O>>[Cl:12][CH:4]([CH2:3][CH:2]([CH3:8])[CH3:1])[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)CCC(C)C
Reactant: O=S(=O)(Cl)Cl
Product: CC(=O)C(Cl)CC(C)C

Procedure:
The process for preparing the α-hydroxyketones of the invention starts from inexpensive 5-methyl-2-hexanone which is reacted with sulfuryl chloride in a first step to give 3-chloro-5-methyl-2-hexanone with high selectivity, as set forth below:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([OH:11])[CH:10]=1.Cl[CH2:24][P:25]([CH3:28])(=[O:27])[OH:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][P:25]([CH2:28][O:11][C:9]1[CH:10]=[C:5]([O:4][C:3]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:20])[F:22])=[CH:18][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:12]([O-:14])=[O:13])(=[O:26])[OH:27]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1O
Reactant: CP(=O)(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CP(=O)(O)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenol (2.5 mmol), chloromethyl methylphosphinic acid (3.8 mmol), potassium carbonate (5.0 mmol) and dimethylformamide (5 ml) is heated to 120° for 2 hours. The reaction mixture is then acidified and extracted with ether. The combined ether extracts are washed with water, dried and evaporated to dryness to yield P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphinic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][N:13]([CH3:15])[CH3:14].ClC1C=C2C(=CC=1)NC(=O)C2.COC(OC)N(C)C>>[CH3:15][N:13]([CH:12]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:2][CH:3]=2)[NH:7][C:6]1=[O:11])[CH3:14]
Reactant: CN(C)C=C1C(=O)Nc2ccc(Cl)cc21
Agent: COC(OC)N(C)C
Agent: O=C1Cc2cc(Cl)ccc2N1
Product: CN(C)C=C1C(=O)Nc2ccccc21

Procedure:
A17. 5-Chloro-3-(dimethylaminomethylene)-2(1H,3H)-indolone; 5-chlorooxindole/dimethylformamide dimethylacetal; 67%; 204°-206°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([N+:41]([O-:43])=[O:42])[CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([N+:41]([O-:43])=[O:42])[CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc(O)c([N+](=O)[O-])c1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)c([N+](=O)[O-])c3)n2)c1

Procedure:
Intermediate 4 was coupled to 4-(2-Amino-ethyl)-2-nitro-phenol by procedure F and the resulting product deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 501. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.4 (s, 1H) 8.3 (d, 1H) 8.2 (d, 1H) 8.0 (s, 1H) 7.8 (d, 1H) 7.6 (m, 3H) 7.0 (m, 1H) 4.5 (s, 2H) 4.0 (m, 2H) 3.4 (m, 2H) 3.0 (m, 5H) 2.8 (m, 2H) 1.8 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH:21]3[CH2:26][CH2:25][CH:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[CH:16]=2)[N:11]=1)([CH3:9])[CH3:8].[OH-].[Li+].O1CCCC1.O>>[C:27]([C@H:24]1[CH2:23][CH2:22][C@H:21]([O:20][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])([CH3:9])[CH3:8])[CH:19]=[CH:18]3)[CH2:26][CH2:25]1)([CH3:28])([CH3:29])[CH3:30]
Reactant: COC(=O)CCNC(C)(C)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(NCCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
A solution of 3-{1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-1-methyl-ethylamino}-propionic acid methyl ester (36.0 mg, 0.0844 mmol) and Lithium hydroxide (20.2 mg, 0.844 mmol) in Tetrahydrofuran (1 mL, 20 mmol) and Water (0.3 mL, 20 mmol) was stirred at r.t. overnight. LCMS showed a single desired product peak RT 1.57 min M+1 at m/z 413.30, 100%. The solvent was concentrated and neutralized with citric acid and concentrated and Purified on HPLC to give product (20 mg, 57%). 1H NMR (400 MHz, CHLOROFORM-d) d=8.30 (d, J=8.7 Hz, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.39 (dd, J=2.7, 9.2 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 4.43-4.28 (m, 1H), 3.23 (t, J=6.6 Hz, 2H), 2.84 (t, J=6.6 Hz, 2H), 2.26 (d, J=10.4 Hz, 2H), 1.90 (d, J=13.6 Hz, 2H), 1.79 (s, 6H), 1.49-1.32 (m, 2H), 1.32-1.17 (m, 2H), 1.17-1.00 (m, 1H), 0.90 (s, 9H).
Reaction SMILES: C([O:4][C@H:5]([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[C:11]1=[O:12])(=O)C.Cl.O1CCOCC1>CO>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][N:13]1[C:14]2[N:15]=[CH:16][N:17]([CH3:21])[C:18]=2[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:28])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(Cc2ccco2)c1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](O)CCCCn1c(=O)c2c(ncn2C)n(Cc2ccco2)c1=O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a stirring solution of (R)-1-(5-acetoxyhexyl)-3-(2-furylmethyl)-7-methylxanthine (0.42 g, 1.07 mmol) in methanol (20 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.80 ml, 3.21 mmol) and the mixture was refluxed for 5 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was treated with saturated aqueous sodium bicarbonate solution (25 ml) and the mixture was extracted with dichloromethane (3×25 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (2×25 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-3-(2-furylmethyl)-1-(5-hydroxyhexyl)-7-methylxanthine (0.30 g, 80% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([CH3:19])=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:20][C:21]1([CH3:45])[CH2:30][CH2:29][C:28]2[N:27]=[CH:26][N:25]=[C:24]([N:31]3[CH2:37][C:36]4[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:35]=4[O:34][CH2:33][CH2:32]3)[C:23]=2[CH2:22]1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:20][C:21]1([CH3:45])[CH2:30][CH2:29][C:28]2[N:27]=[CH:26][N:25]=[C:24]([N:31]3[CH2:37][C:36]4[CH:38]=[C:39]([C:2]5[CH:3]=[C:4]6[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([CH3:19])=[N:8][C:5]6=[N:6][CH:7]=5)[CH:40]=[CH:41][C:35]=4[O:34][CH2:33][CH2:32]3)[C:23]=2[CH2:22]1
Reactant: Cc1nc2ncc(Br)cc2n1COCC[Si](C)(C)C
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2n1COCC[Si](C)(C)C
Temperature: 95 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
A solution of 6-bromo-2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridine (reagent preparation 35) (0.43 g, 1.30 mmol), [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) (0.45 g, 1.30 mmol) and N,N-diisopropylethylamine (1.10 mL, 6.50 mmol) in N,N-dimethylformamide (4 mL), and water (1 mL) was degassed by bubbling nitrogen gas for five minutes followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52 mg, 0.065 mmol), then stirred at 95° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and filtered through a pad of Celite. The filtrate was washed with 1M aqueous lithium chloride (50 mL) and brine, dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (gradient 1-2% 7N ammonia in methanol in chloroform) gave 4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-7-[2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridin-6-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.54 g, 73% yield). MS (EI) for C32H42N6O2Si: 571 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]2[O:17][CH2:18][O:19][C:14]2=[CH:13][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(OC)(O[CH3:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:1][C:2]1[CH:16]=[C:15]2[O:17][CH2:18][O:19][C:14]2=[CH:13][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc2c(cc1C=CCc1ccccc1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1C=CCc1ccccc1)OCO2

Procedure:
Preparation of final product, 2-methoxy-4,5-methylenedioxy-cinnamylbenzene (MMCB): A mixture of 19 g. of 2-hydroxy-4,5-methylenedioxy-cinnamylbenzene, 18.9 g. of dimethyl sulfate, 30.0 g. of anhydrous potassium carbonate, and 200 ml. of acetone was refluxed for 2 hrs. The mixture was then concentrated, diluted with 1% aqueous sodium hydroxide (200 ml.), and cooled. The oil which formed was extracted with ethyl ether. The ether was removed by evaporation and the residue was distilled to give MMCB (17.5 g.), b.p. 180° C at 0.25 mm. (Found: C, 75.9; H, 5.94. Calc. for C17H16O3 : C, 76.1; H, 6.01). The 100 Hz NMR spectrum of MMCB in deuterated chloroform exhibited a doublet (2 protons) at δ 3.44 (J = 6.0 Hz), a singlet (3 protons) at δ 3.74, a singlet (2 protons) at δ 5.85, a multiplet (2 protons) at δ 6.13-6.37, a singlet (1 proton) at δ 6.51, a singlet (1 proton) at δ 6.68, and a multiplet (5 protons) at δ 7.10-7.40.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C@@H:4]([OH:16])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8].Cl.N[C@@H](CCCC)[C@H](O)CNS(C1C=CC=CN=1)(=O)=O.C(N(CC)C(C)C)(C)C.[C:50](=O)([O:73]C1C=CC([N+]([O-])=O)=CC=1)[O:51][C@H:52]([CH2:57][N:58]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][C:66]([C:69]([F:72])([F:71])[F:70])=[CH:65][CH:64]=2)=[N:59]1)[C:53]([CH3:56])([CH3:55])[CH3:54]>CN(C)C=O.C(OCC)(=O)C>[OH:16][C@H:4]([C@@H:3]([NH:2][C:50](=[O:73])[O:51][C@H:52]([CH2:57][N:58]1[CH:62]=[CH:61][C:60]([C:63]2[CH:64]=[CH:65][C:66]([C:69]([F:70])([F:71])[F:72])=[CH:67][CH:68]=2)=[N:59]1)[C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8]
Reactant: CC(C)(C)[C@@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCC[C@H](N)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: CCCC[C@H](N)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
To a solution of 90 mg (0.21 mmol) of N-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride & N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride and 83 mg (0.63 mmol) of N,N-diisopropylethylamine in 2 mL N,N-dimethylformamide was added 102 mg (0.21 mmol) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl 4-nitrophenyl carbonate. The reaction mixture was stirred at room temperature for 48 h. It was diluted with ethyl acetate, washed with one portion of 1M sodium hydroxide and with 1 portion of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexanes (3:1) to afford 90 mg (68%) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 8.70 (d, J=4 Hz, 1H), 8.11–7.45 (m, 10H), 6.76 (s, 1H), 6.54 (d, J=9 Hz, 1H), 4.90–4.76 (m, 2H), 4.46 (d, J=13 Hz, 1H), 4.16 (m, 1H), 3.05 (m, 1H), 1.27 (m, 1H), 1.05–0.86 (m, 14H), 0.68 (m, 3H); ES-LCMS m/z 648 (M+Na).
Reaction SMILES: [C:1]([N:4]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=[O:28])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([N:4]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([OH:29])=[O:28])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCN(C)c1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)CCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 40 °C

Procedure:
Methyl 4-[(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)(methyl)amino]-2,2-dimethylbutanoate was dissolved in methanol/tetrahydrofuran/water (2/1/1) then sodium hydroxide (3 equivalents) was added and reaction mixture heated to 40° C. for 2 h. The mixture was concentrated, the residue acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-[(4-{[(2S,4R)-4-[Acetyl-(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)(methyl)amino]-2,2-dimethylbutanoic acid.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20](O)[CH2:21][CH:22]=[CH2:23])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].S(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.CCOC(C)=O>[N:34]([CH:20]([C:18]1[N:19]=[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:15]2=[N:16][CH:17]=1)[CH2:21][CH:22]=[CH2:23])=[N+:35]=[N-:36]
Reactant: C=CCC(O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCC(N=[N+]=[N-])c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-ol (0.14 g, 0.41 mmol) in DCM (10 mL) was added thionyl chloride (0.045 mL, 0.61 mmol). The reaction mixture was stirred for about 8 h at ambient temperature and then EtOAc and saturated aqueous NaHCO3 (10 mL each) were added. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concd in vacuo. The crude chloride was dissolved in DMF (10 mL) and sodium azide (0.159 g, 2.45 mmol) was added to the reaction mixture. The reaction mixture was stirred for about 15 h at ambient temperature and then EtOAc and saturated aqueous NaHCO3 (10 mL each) were added to the reaction mixture. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel eluting with 10-60% EtOAc in heptane to provide 2-(1-azidobut-3-enyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.153 g, 87%) as an oil: LC/MS (Table 1, Method a) Rt=2.84 min; MS m/z: 369 (M+H)+.