Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][C:38]([F:41])([F:40])[F:39])[N:21]=3)[CH2:14][CH2:13]2)[CH:5]=1.[Li+].[OH-]>O.CO>[N+:26]([C:25]1[C:20]([NH:19][CH2:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([NH:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:42])=[O:2])[CH2:13][CH2:14]2)=[N:21][C:22]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][C:38]([F:41])([F:40])[F:39])=[N:23][CH:24]=1)([O-:28])=[O:27]
Reactant: COC(=O)c1cccc(CNC2CCC(CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(CN[C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)c1
Temperature: 50 °C

Procedure:
A mixture of 3-[(4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexylamino)-methyl]-benzoic acid methyl ester (75 mg, 0.13 mmol), LiOH (30 mg, 1.29 mmol) and water (3 drops) in MeOH (2 mL) was heated at 50° C. for 18 h. The reaction mixture was concentrated in vacuo then taken up in water and EtOAc. Dilute HCl was added until the aqueous phase reached pH 6. The solid that precipitated was isolated by filtration to afford the target compound (20 mg, 30%) as a white solid, m/z 575 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C.C(OC(N1CC(OC2C=C(Br)C=CC=2O)(C)C1)=O)(C)(C)C.BrCCC1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([O:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:14]([CH:19]=1)[O:13][C:10]1([CH3:12])[CH2:11][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C)(Oc2cc(Br)ccc2OCCc2ccccc2)C1
Agent: BrCCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CC(C)(Oc2cc(Br)ccc2O)C1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(Oc2cc(Br)ccc2OCCc2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
Preparation of 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester. A mixture of 3-(5-bromo-2-hydroxy-phenoxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (30 mg. 0.08 mmol), (2-bromoethyl)benzene (29 μL, 0.21 mmol), KI (42 mg, 0.25 mmol) and Cs2CO3 (82 mg, 0.25 mmol) in 3 mL DMF was stirred at rt for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc (3×). The organic layers were dried and purified by RP HPLC (Agilent) to give the title compound as an oil (22 mg, 58%). MS (ESI): mass calcd. for C23H28BrNO4, 462.4; m/z found, 408.0 [M-56+H]+. 1H NMR (CDCl3): 7.38-7.18 (m, 5H), 7.07 (dd, J=8.6, 2.3 Hz, 1H), 6.76-6.74 (m, 2H), 4.24-4.08 (m, 4H), 3.84 (d, J=9.7 Hz, 2H), 3.11 (t, J=7.1 Hz, 2H), 1.58 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:31]([F:34])([F:33])[F:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH2:15][CH:2]([OH:1])[CH:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][C:31]([F:32])([F:34])[F:33])=[CH:7][CH:6]=2)[CH3:14])[CH:18]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: FC(F)(F)Oc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(Oc1ccc(-c2ccccc2OC(F)(F)F)cc1)C(O)CCc1cccnc1
Temperature: 80 °C
Yield: 69.7 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 2-bromo(trifluoromethyloxy)benzene (0.26 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.025 g) in ethanol (3 ml). The reaction mixture was heated in a sealed vial at 80° C. for 2 hours. After cooling, the solution was is concentrated under reduced pressure and taken up in acetone and filtered through a small plug of silica. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil (0.145 g).
Reaction SMILES: [BH4-].[Na+].[O:3]1[C@H:5]2[C:6](=[O:37])[CH2:7][C@H:8]3[C@:29]([CH3:30])([C@@H:4]12)[C@@H:28]1[C@H:11]([C@H:12]2[C@:25]([CH3:31])([CH2:26][CH2:27]1)[C@@H:15]([C@H:16]([CH3:24])[CH2:17][CH2:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[CH2:10][C@H:9]3[O:32][S:33]([CH3:36])(=[O:35])=[O:34].[BH4-].[Li+].O>O1CCCC1>[OH:3][C@@H:4]1[C@@:29]2([CH3:30])[C@@H:8]([C@H:9]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:10][C@@H:11]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:24])[CH2:17][CH2:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[CH2:7][CH:6]([OH:37])[CH2:5]1
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](OS(C)(=O)=O)[C@H]4CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](OS(C)(=O)=O)[C@H]4CC(O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.42 h
Yield: 10.9 %

Procedure:
To 1-molar diborane-tetrahydrofuran complex (not stabilized with sodium borohydride, 157 ml) cooled in an ice bath, was added dropwise over about 25 minutes a solution of 1α,2α-epoxy-6β-methylsulfonyloxy-5α-cholestan-25-ol-3-one (20.0 g, 0.392 mole), in tetrahydrofuran (100 ml) with stirring under an atmosphere of nitrogen. After the addition was complete, the solution was stirred for about 25 minutes. Lithium borohydride (3.40 g, 0.155 mole) was added in 1 portion to the reaction mixture, with stirring. The suspension was stirred in an ice bath for about 6 hours and then stored in a refrigerator (ca. 3° C) overnight. Water (200 ml) was added cautiously to the reaction mixture cooled in an ice bath. An additional 200 ml of water was added to the turbid solution and the solution was extracted with methylene chloride. The layers were separated and the organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate gave 22 g of 1α,25-dihydroxy-6β-methylsulfonyloxy-5α-cholestan-3-ol as a white foam.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:6]([N:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:31])=[O:30])=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]2=[O:44])=[CH:7][C:8]([F:18])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)#[N:2].[O:45]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:1]([CH2:3][O:4][C:5]1[C:6]([N:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29]([NH:50][C:47]4[CH:48]=[CH:49][O:45][N:46]=4)(=[O:31])=[O:30])=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]2=[O:44])=[CH:7][C:8]([F:18])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)#[N:2]
Reactant: Nc1ccon1
Reactant: N#CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a solution of perfluorophenyl 1-(5-(cyanomethoxy)-2,3′-difluoro-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (250 mg, 0.394 mmol), isoxazol-3-amine (40.8 μl, 0.552 mmol) and THF (3940 μl) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF, 985 μl, 0.985 mmol) was added dropwise. The whole was warmed to rt and stirred for 30 min. An additional 1 mL of 1M LHMDS in THF was added and stirred for 30 min. The whole was quenched with 0.2 mL of TFA and concentrated. The product was purified further by RPLC on the acidic Gilson. Fractions containing the product were combined and concentrated. Precipitate was filtered with an aid of water, dried to afford pink solid. m/z (ESI), [M+H]+=535.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 5.11-5.33 (m, 2 H) 6.45 (d, J=1.76 Hz, 1 H) 6.77-6.96 (m, 2 H) 7.28-7.46 (m, 1 H) 7.50-7.59 (m, 2H) 7.59-7.72 (m, 3 H) 7.87 (dd, J=8.98, 2.08 Hz, 1 H) 8.26 (d, J=9.83 Hz, 1H) 8.40 (d, J=2.03 Hz, 1 H) 8.73 (d, J=1.76 Hz, 1 H) 11.66 (br. s., 1 H).
Reaction SMILES: [F:1][CH2:2][C@@H:3]([O:6][CH2:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[N:9][OH:10])[CH:4]=[CH2:5].C1(C=CC(O)=CC=1)O>>[F:1][CH2:2][C@@H:3]1[C@@H:4]2[C@@:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])([NH:9][O:10][CH2:5]2)[CH2:7][O:6]1
Reactant: C=C[C@@H](CF)OCC(=NO)c1ccccc1F
Agent: Oc1ccc(O)cc1
Product: FC[C@H]1OC[C@]2(c3ccccc3F)NOC[C@H]12
Temperature: 145 °C
Yield: 74.9 %

Procedure:
(S)-2-((1-fluorobut-3-en-2-yl)oxy)-1-(2-fluorophenyl)ethanone oxime (67.5 g, 279.81 mmol) was dissolved in xylenes (560 mL) and hydroquinone (5.54 g, 50.36 mmol) was added. The reaction mixture was heated to reflux (heating block temperature 145° C.) for 5 hrs. The reaction was cooled to RT and the solvent was evaporated. The residue was purified by column chromatography on amino silica (30% EtOAc in hexanes) to obtain the title compound as a yellow oil (50.53 g, 75%). 1H NMR (400 MHz, CDCl3) δ ppm 3.32-3.42 (m, 1H) 3.96 (dd, J=10.11, 1.52 Hz, 2H) 4.16-4.43 (m, 2H) 4.44-4.83 (m, 2H) 5.38 (s, 1H) 7.09 (dd, J=11.75, 8.72 Hz, 1H) 7.18 (td, J=7.58, 1.26 Hz, 1H) 7.28-7.34 (m, 1H) 7.71 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[C:15]1[CH:24]=[CH:23][C:22]([Br:25])=[C:21]2[C:16]=1[N:17]=[CH:18][CH:19]=[N:20]2.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.CCOC(C)=O.O.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]>[Br:25][C:22]1[CH:23]=[CH:24][C:15]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[N:17]2
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: Brc1ccc(Br)c2nccnc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(OC)cc(-c2ccc(Br)c3nccnc23)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A mixture of 3,5-dimethoxyphenylboronic acid (3.38 g, 18.6 mmol) in EtOH (15 mL) was added dropwise to a mixture of 5,8-dibromo-quinoxaline (Step 179.5) (10.7 g, 37.1 mmol, 2 equiv), PdCl2(dppf) (530 mg, 0.7 mmol, 0.03 equiv), Na2CO3 (2 M solution in H2O, 37 mL, 74.3 mmol, 4 equiv) in toluene (100 mL) at 105° C., under an argon atmosphere. The reaction mixture was stirred at 105° C. for 2 h, allowed to cool to rt, diluted with EtOAc and H2O, filtered through a pad of celite and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by trituration in DCM, followed by silica gel column chromatography (Hex/EtOAc, 4:1) to afford 4.54 g of the title compound as a yellow solid: ES-MS: 345 [M+H]+; tR=5.13 min (System 1); Rf=0.17 (Hex/EtOAc, 4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11]Cl.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@@H](CCl)COc1ccccc1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-2-{[(2R)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:13](=[O:30])[C:14]1[CH:19]=[CH:18][C:17]([N:20]([Si](C)(C)C)[Si](C)(C)C)=[C:16]([Cl:29])[CH:15]=1)=O)(C)(C)C>Cl>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([C:9]2([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:30])=[CH:15][C:16]=1[Cl:29]
Reactant: CCCCC1(C(=O)c2ccc(N([Si](C)(C)C)[Si](C)(C)C)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Agent: Cl
Product: CCCCC1(C(=O)c2ccc(N)c(Cl)c2)CCCN1
Yield: 226.8 %

Procedure:
A solution of 2-butyl-2-[3-chloro-4-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-benzoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.205 g, 0.391 mmol) in methanolic 1N HCl (7.8 mL) was stirred at 50° C. under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo to yield (4-amino-3-chloro-phenyl)-(2-butyl-pyrrolidin-2-yl)-methanone (0.249 g, quantitative yield) as a light brown powder and as a monohydrochloride salt.
Reaction SMILES: [F-:1].[K+].[CH:3]([O:12][CH2:13][Cl:14])([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5]>O>[CH:3]([O:12][CH2:13][F:1])([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].[CH:3]([O:12][CH2:13][Cl:14])([C:4]([F:5])([F:6])[F:7])[C:8]([F:11])([F:10])[F:9]
Reactant: [F-]
Agent: FC(F)(F)C(OCCl)C(F)(F)F
Agent: [K+]
Solvent: O
Product: FCOC(C(F)(F)F)C(F)(F)F
Temperature: 185 °C

Procedure:
A 1 liter stainless steel autoclave (Parr) was charged with 127.3 g (2.19 mole) of potassium fluoride and 434.6 g (2.01 mole) of (CF3)2CHOCH2Cl. The autoclave was then sealed and the reaction mass heated at 185° C. for 19 hours, during which time a pressure of 280 psi developed. The reactor was then cooled, the contents treated with water and the organic material distilled to afford 241 g (1.21 mole) of (CF3)2CHOCH2F and 80 g (0.4 mole) of (CF3)2CHOCH2Cl, corresponding to a 60% conversion (75% yield). The structure of (CF3)2CHOCH2F (Sevoflurane), b.p. 56° C., may be confirmed by the following instrumental data:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:24][C:22]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH3:22])=[O:6]
Reactant: Nc1ncccc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To the mixture of 2-aminonicotinic acid (2.0 g, 14.5 mmol), methylamine hydrogen chloride (1.47 g, 1.5 eq), EDC (4.49 g, 1.5 eq), HOBt (2.35 g, 1.2 eq) in DMF (20 mL) was added DIEA (7.6 mL, 3.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product 2-amino-N-methylnicotinamide (2.16 g, isolated yield ˜98%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][C:16]1[N:17]=[C:18]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[N:30]([CH3:39])[S:31]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)(=[O:33])=[O:32])[S:19][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:39][N:30]([S:31]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)(=[O:33])=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[NH:22][C:21]([C:18]1[S:19][CH:20]=[C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[N:17]=1)=[CH:29]2
Reactant: CN(c1cccc2cc(-c3nc(CCl)cs3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1csc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1)C(=O)OCC
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.15 g) in N,N-dimethylformamide (10 mL) was added diethyl malonate (0.53 g) at 0° C., and the mixture was stirred for 30 min. To the reaction mixture was added N-{2-[4-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.45 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added 10% citric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.43 g, yield 72%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:47]=[N:48][C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[CH:50][CH:51]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:45][C:46]4[CH:47]=[N:48][C:49]([N:52]5[CH2:53][CH2:54][O:55][CH2:56][CH2:57]5)=[CH:50][CH:51]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(N2CCOCC2)nc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N5CCOCC5)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 3-amino-6-morpholinopyridine as the aniline component. (29%, MS=556.3 (M+H))
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=O)=[CH:10][CH:9]=1>O1CCCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:10][CH:9]=1
Reactant: O=C(CCc1ccc(Br)cc1)N1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Brc1ccc(CCCN2CCOCC2)cc1
Temperature: -30 °C
Yield: 82 %

Procedure:
To a mixture of lithium aluminum hydride (4.4 g, 115.79 mmol, 2.00 equiv) in tetrahydrofuran (120 mL) maintained under nitrogen at −30° C. was added a solution of 3-(4-bromophenyl)-1-morpholinopropan-1-one (17.2 g, 57.91 mmol, 1.00 equiv) in tetrahydrofuran (80 mL) dropwise with stirring. The resulting solution was stirred at −30° C. for 30 min and at room temperature for 2 h. The reaction was quenched by the sequential addition of 4.4 mL of water, 13 mL of 15% aqueous sodium hydroxide solution and 4.4 mL of water. The solid was removed by filtration and the filtrate was extracted with 1×350 mL of ethyl acetate. The organic layer was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 13.5 g (82%) of 4-(3-(4-bromophenyl)propyl)morpholine as a light yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[CH2:13]([CH2:15][NH2:16])[OH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:14][CH2:13][CH2:15][NH:16][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(CCCBr)cc1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(CCCNCCO)cc1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
4-(3-Bromopropyl)benzonitrile (20 g, 0.089 mol) in acetonitrile was added to a vigorously stirred mixture of ethanolamine (27.2 g, 0.447 mol) and potassium carbonate (18.5 g, 0.133 mol) in 300 mL of dry acetonitrile. Stirring was then continued at room temperature overnight under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The crude product thereby obtained was purified by column chromatography (using methanol in chloroform) to yield 15 g of the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:14][N+:13]=3[O-])=[C:9]([OH:11])[NH:10][C:5]2=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:14][N:13]=3)=[C:9]([OH:11])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1-c1c(O)[nH]c2ccc(Br)nc12
Solvent: CCOC(C)=O
Solvent: ClP(Cl)Cl
Product: Oc1[nH]c2ccc(Br)nc2c1-c1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
728 mg of 2-(5-Bromo-2-hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-5-(morpholinomethyl)pyridine 1-oxide from example 4.1 were dissolved in ethyl acetate (20 mL) and 627 μL phosphorus trichloride (7.19 mmol) was added. After stirring the resulting suspension at ambient temperature for 2 days the precipitate was removed by filtration, washed with ethyl acetate, and dissolved in water. The aqueous layer was basified by addition of solid NaHCO3 and extracted with ethyl acetate (6×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was further purified by flash chromatography yielding the titled compound as a yellow foam (335 mg, 48%).
Reaction SMILES: C([O:5][C:6](=[O:52])[CH2:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][N:16]2[CH:20](C(C)C)[CH:19](C(=O)NC3C=CC=CC=3)[CH:18](C3C=CC=CC=3)[CH:17]2C2C=CC(F)=CC=2)OB(C2C=CC=CC=2)O1)(C)(C)C.O.CO.[O-2].[Ca+2]>C1COCC1>[N:16]1([CH2:15][CH2:14][CH2:12][CH2:13][CH2:8][CH2:7][C:6]([OH:52])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: CC(C)C1C(C(=O)Nc2ccccc2)C(c2ccccc2)C(c2ccc(F)cc2)N1CCC1CC(CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCn1cccc1
Temperature: 55 °C
Reaction time: 10 h

Procedure:
A mixture of (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-acetic acid tert-butyl ester (5 g, 0.007 mol), water (200 ml), methanol (200 ml) and calcium oxide (5.0 g, 0.09 mol) was stirred at 50-60° C. for 10 hours. After filtering the reaction mixture, the resulting clear filtrate was concentrated to about 150 ml and washed with methyl tert-butyl ether (50 ml). The aqueous layer was evaporated and the solid obtained was dissolved in THF (50 ml). The solution was filtered and concentrated to yield [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, 1H-Pyrrole-1-heptanoic acid hemicalcium salt.