Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:49]([CH2:60][O:61][C:62](=[O:69])[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:48][C@H:47]([O:70][C@H:71]2[C@H:84]([O:85][C:86](=[O:93])[C:87]3[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=3)[C@@H:83]([CH2:94][O:95][C:96](=[O:103])[C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)[O:82][C@H:73]([O:74]CC3C=CC=CC=3)[C@H:72]2[O:104][C:105](=[O:112])[C:106]2[CH:111]=[CH:110][CH:109]=[CH:108][CH:107]=2)[C@H:46]1[O:113][C:114](=[O:121])[C:115]1[CH:120]=[CH:119][CH:118]=[CH:117][CH:116]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(Cl)(Cl)Cl.[Pd]>[C:1]([O:9][C@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:49]([CH2:60][O:61][C:62](=[O:69])[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:48][C@H:47]([O:70][C@H:71]2[C@H:84]([O:85][C:86](=[O:93])[C:87]3[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=3)[C@@H:83]([CH2:94][O:95][C:96](=[O:103])[C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)[O:82][CH:73]([OH:74])[C@H:72]2[O:104][C:105](=[O:112])[C:106]2[CH:107]=[CH:108][CH:109]=[CH:110][CH:111]=2)[C@H:46]1[O:113][C:114](=[O:121])[C:115]1[CH:120]=[CH:119][CH:118]=[CH:117][CH:116]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](O[C@@H]3[C@H](OC(=O)c4ccccc4)[C@@H](OCc4ccccc4)O[C@H](COC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](O[C@H]3[C@H](OC(=O)c4ccccc4)[C@@H](COC(=O)c4ccccc4)OC(O)[C@H]3OC(=O)c3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 93.1 %

Procedure:
The benzyl glycoside 51 (385 mg, 0.235 mmol) was dissolved in MeOH (5 mL) and chloroform (5 mL). Palladium on charcoal (5%, 538 mg) was added. The mixture was stirred under hydrogen at 100 psi for 3 days. TLC indicated complete conversion. The mixture was filtered through a plug of Celite and rinsed with EtOAc (5×1 mL). The combined filtrate and washings were evaporated to dryness, co-evaporated with DCM (3 mL) to give the hemiacetal 52 as pale-yellow foam (338 mg, 93%), used without further purification or characterization in the next step.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13](=[O:26])[NH:14][CH:15]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:16](=[O:19])[NH:17][CH3:18])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][CH:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([NH:14][CH:15]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[C:16](=[O:19])[NH:17][CH3:18])=[O:26]
Reactant: CNC(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C(NC(=O)C(N)C(C)(C)C)C1CCCCC1

Procedure:
Compound 20 was kept in dichloromethane-trifluoroacetic acid 2:1 for 1 h at rt and concentrated to dryness. The residue was dried in a vacuum for 16 hrs. Reversed phase C18 HPLC showed >95% purity M+H+283.1.
Reaction SMILES: [CH2:1]([SnH](CCCC)CCCC)CCC.[C:14]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([OH:31])[C:25]([CH3:33])([CH3:32])[CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(I)I.ClC1C=CC=CC=1>C(OCC)(=O)C.CCCCCCC>[C:14]([O:22][CH:23]1[CH2:24][C:25]([CH3:33])([CH3:32])[N:26]([O:31][CH3:1])[C:27]([CH3:29])([CH3:30])[CH2:28]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: ICI
Solvent: Clc1ccccc1
Product: CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 27 h

Procedure:
The reaction is carried out in a nitrogen atmosphere. Tributyltin hydride (20.0 grams, 68.7 mmol) is added dropwise over 2.75 hours to a solution, precooled to 10° C., of 40.0 grams (145 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 9.0 grams (33.6 mmol) of methylene iodide (diiodomethane) and 75 ml of chlorobenzene. The reaction temperature reaches 27° C. during the addition. The red mixture is stirred at room temperature for 27 hours after the addition is complete. The reaction mixture is then passed through a column of silica gel (heptane, then 100:3 heptane:ethyl acetate). Fractions containing the desired product are concentrated to give a crude solid. Tributyltin iodide is removed by washing a solution of the crude solid with aqueous ammonia. Final purification by flash chromatography on silica gel (100:3 heptane:ethyl acetate) followed by recrystallization from heptane affords 4.8 grams of the title compound as a white solid melting at 126°-127° C.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13]C)[C:7]=1[Cl:15]>ClCCl.O>[Br:5][C:6]1[C:7]([Cl:15])=[C:8]([OH:13])[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: COc1cc(Cl)cc(Br)c1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cc(Cl)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Boron tribromide as a 1 M solution in dichloromethane (41 mL, 41 mmol) was added to 1-bromo-2,5-dichloro-3-methoxybenzene (10.5 g, 41 mmol) in dichloromethane (100 mL) at −78° C. under N2. The reaction mixture was allowed to warm to room temperature, and after 21 hours, the mixture was poured into 100 g of ice, diluted with 100 g of water, and the organic layer separated. The aqueous layer was extracted with dichloromethane (200 mL) and the combined organic extracts were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. 1H NMR (CDCl3) δ 7.20 (m, 1H), 7.00 (m, 1H), 5.70 (s, 1H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:30]([O:37][C:38](=[O:44])[C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(Cl)(Cl)Cl>[CH2:30]([O:37][C:38](=[O:44])[C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h

Procedure:
Boc-L-alanine (19.5 g, 0.10 mol) was dissolved in dry tetrahydrofuran (90 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and an internal thermometer. The solution was cooled to -15° C. and N-methylmorpholine (11.4 ml, 0.10 mol) was added followed by isobutylchloroformate (13.4 ml, 0.10 mol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Five minutes after the addition was completed, a solution of L-proline benzyl ester hydrochloride (25.2 g, 0.10 mol) and N-methylmorpholine (11.4 ml, 0.10 mol) in chloroform (90 ml) was added dropwise at such a rate as to maintain the internal reaction temperature at -10° to -15° C. After the addition was completed, the reaction mixture was allowed to slowly warm to room temperature and then stirred at room temperature overnight. The reaction mixture was concentrated using a rotary evaporator, the residue diluted with ethyl acetate (500 ml)/0.2N hydrochloric acid (100 ml) and poured into a separatory funnel. The layers were separated and the aqueous phase extracted with a further 150 ml ethyl acetate. The combined organics were washed with 0.2N hydrochloric acid (2×100 ml), water (100 ml), saturated sodium bicarbonate (2×100 ml), again with water (100 ml) and finally brine (100 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. Chromatography using ethyl acetate-hexane as the eluent gave Boc-L-alanyl-L-proline benzyl ester, Rf: 0.15 (EtOAc/hexane - 30:70).
Reaction SMILES: C(OC1C=CC([O:13][C:14]2[C:15]([C:21]#[N:22])=[N:16][C:17]([F:20])=[CH:18][N:19]=2)=CC=1)C1C=CC=CC=1.[N+]([O-])([O-])=O.[Ce+3].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[F:20][C:17]1[N:16]=[C:15]([C:21]#[N:22])[C:14](=[O:13])[NH:19][CH:18]=1
Reactant: N#Cc1nc(F)cnc1Oc1ccc(OCc2ccccc2)cc1
Agent: O=S([O-])([O-])=S
Agent: O=[N+]([O-])[O-]
Agent: [Ce+3]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)c[nH]c1=O

Procedure:
In a mixture of 30 mL of acetonitrile and 15 mL of water was dissolved 1.0 g of 3-[4-(benzyloxy)phenoxy]-6-fluoro-2-pyrazinecarbonitrile. After adding 8.5 g of diammonium cerium nitrate, the mixture thus obtained was heated under reflux for 3 hours. The reaction mixture was returned to room temperature, a mixture consisting of 50 mL of ethyl acetate, 5 ml of water and 5 mL of 5% aqueous solution of sodium thiosulfate was added, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride, treated with active charcoal and dried on anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Thus, 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow-colored solid product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH:5]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[C:12](=[CH:6][N:10]([CH3:15])[CH3:11])[CH2:11]2)[CH:5]=1
Reactant: COC(=O)c1cccc(N2CCC(=O)CC2)c1
Solvent: C1COCCO1
Product: COC(=O)c1cccc(N2CCC(=O)C(=CN(C)C)C2)c1

Procedure:
A solution of methyl-3-(4-oxopiperidin-1-yl)-benzoate (2.72 g, 11.66 mmol) and DMF-dimethylacetal (6.24 mL, 46.64 mmol) in 1,4-dioxane (50 mL) was refluxed for 43 hours. The reaction mixture was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 5% MeOH in EtOAc to 8% MeOH in EtOAc) to obtain the title compound as a red oil which slowly crystallized on standing (1.52 g, 45%).
Reaction SMILES: [OH:1][CH:2]([C:12]1[S:13][C:14]([C:17]2[CH:22]=[C:21]([NH:23][C:24]3[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH:20]=[C:19]([CH3:34])[CH:18]=2)=[CH:15][N:16]=1)[C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.C(Cl)CCl.C1C=CC2N(O)N=[N:45]C=2C=1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C=O)C.O>[OH:1][CH:2]([C:12]1[S:13][C:14]([C:17]2[CH:22]=[C:21]([NH:23][C:24]3[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH:20]=[C:19]([CH3:34])[CH:18]=2)=[CH:15][N:16]=1)[C@@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([NH2:45])=[O:10])[CH2:7][CH2:8]1
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)[C@H]3CC[C@@H](C(=O)O)CC3)s2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)[C@H]3CC[C@@H](C(N)=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cis-4-{hydroxy[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}cyclohexanecarboxylic acid (24 mg, 0.049 mmol), EDC (19 mg, 0.097 mmol), HOBt (13 mg, 0.097 mmol) and diisopropylethyl amine (51 uL, 0.292 mmol) in DMF (1 mL) was added ammonium chloride (7.8 mg, 0.15 mmol) and the mixture was stirred at room temperature for 16 h. The solution was then diluted with water and extracted with ethyl acetate (3×). The organic layers were combined, dried with magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography to afford cis-4-{hydroxy[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}cyclohexanecarboxamide as a white solid. MS ESI calc'd. for C23H25F3N5O2S [M+H]+ 492. found 492. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J=4.9, 1H), 7.96 (s, 2H), 7.45 (s, 1H), 7.27 (d, J=4.9, 1H), 7.16 (s, 1H), 7.13 (s, 1H), 6.68 (s, 1H), 6.14 (d, J=4.9, 1H), 4.76-4.56 (m, 1H), 3.15 (d, J=5.2, 1H), 2.31 (s, 3H), 2.24 (s, 1H), 1.86 (d, J=5.9, 2H), 1.73 (s, 1H), 1.67 (d, J=8.6, 1H), 1.49-1.31 (m, 4H). rhSyk=+++
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:17]=[C:16]([N+:18]([O-])=O)[NH:15][N:14]=2)=[O:12])=[CH:4][CH:3]=1.[Cl-].[NH4+]>O1CCCC1.C(O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:17]=[C:16]([NH2:18])[NH:15][N:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1cc([N+](=O)[O-])[nH]n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(C(=O)NCCc2ccc(Cl)cc2)n[nH]1
Temperature: 105 °C
Reaction time: 16 h
Yield: 7 %

Procedure:
To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid [2-(4-chloro-phenyl)-ethyl]amide (160 mg, 5.42 mmol, 1 eq) in tetrahydrofuran and ethanol (1 mL/3 mL) was added a saturated solution of ammonium chloride (1 mL) and iron (97 mg, 1.73 mmol, 3.2 eq). The mixture was stirred at 105° C. for 16 h. After cooling, the mixture was filtrated on a short pad of celite and washed with ethanol (10 mL), tetrahydrofuran (10 mL) and water (10 mL). The filtrate was evaporated, water (10 mL) was added and the aqueous phase was extracted with dichloromethane (2×15 mL). The organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo to afford 5-amino-1H-pyrazole-3-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide as beige powder (100 mg, 70% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([O:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([NH2:27])=[C:22]([CH3:28])[CH:21]=2)[CH:16]=[CH:15][N:14]=1.O>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:13]1[N:18]=[C:17]([O:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([NH2:27])=[C:22]([CH3:28])[CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1c(O)cccc1Cl
Reactant: Cc1cc(Oc2ccnc(Cl)n2)c(C)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccnc(Oc3cccc(Cl)c3C)n2)c(C)cc1N
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 1.43 g (10 mmol) 3-chloro-2-methyl-phenol and 0.4 g sodium hydride (60% in paraffine, 10 mmol) in 20 ml THF were stirred for 30 min at ambient temperature. After adding 1.25 g (5 mmol) 4-(2-chloro-pyrimidin-4-yloxy)-2,5-dimethyl-phenylamine the mixture was stirred for 20 hrs at 60° C. After cooling down to ambient temperature 20 ml water was added and the organic layer was separated, dried over magnesium sulfate, concentrated in vacuo, column chromatography (cycclhexane/ethyl acetate, 2:1) and a second column chromatography (dichloromethane) yielded 640 mg (30%) with a purity of 85%; log P (pH=2.3)=2.81.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[CH:13]([N-]C(C)C)(C)[CH3:14].[Li+].BrCCCl>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:11]#[N:12])[CH2:14][CH2:13]2)=[CH:2]1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCBr
Solvent: C1CCOC1
Product: N#CC1(c2c[nH]c3ccccc23)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
1H-indole-3-ylacetonitrile (18.7 g) was dissolved in tetrahydrofuran (240 mL) and, after cooling to −30° C., lithium diisopropylamide (2.0M heptane/tetrahydrofuran/ethylbenzene solution, 240 mL) was added dropwise, followed by stirring at −5° C. for 30 minutes. The reaction mixture was cooled to −30° C. and 1-bromo-2-chloroethane (11.0 mL) was added dropwise, followed by stirring for 2 hours while heating to 0° C. The reaction mixture was poured into ice/hydrochloric acid (2N, 360 mL) and extracted with ethyl acetate. The organic layer was washed in turn with water, an aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain a compound and the compound was recrystallized from (hexane:ethyl acetate=1:1) to obtain the titled compound having the following physical properties (8.67 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH2:23]([N:25]([CH2:44][CH3:45])[C:26](=[O:43])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)[CH3:24].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:29]3[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=3[CH3:33])[C:26]([N:25]([CH2:44][CH3:45])[CH2:23][CH3:24])=[O:43])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CCN(CC)C(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1ccc(C)c(-c2nc(SC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1

Procedure:
5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.720 g, 2.1 mmol), N,N-diethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide from above (1.09 g, 3.15 mmol), and K2CO3 (0.868 g, 6.3 mmol), were taken up in dioxane (42 mL) and water (8.5 mL). The mixture was degassed with argon for 30 min and tetrakis-(triphenylphosphine)palladium(0) (0.183 g, 0.15 mmol) was added. The mixture was then heated under argon at 950 C for 18 h. The solvents were pumped off and after aqueous workup, the crude material was flashed on silica gel (150 g) eluted with a EtOAc/CH2Cl2 gradient to give the title compound as a white amorphous solid. mp 127-129° C. LC-MS m/z 498 (M+H)+, 2.11 min (ret time).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C@H:13]([C:17]([NH2:19])=[O:18])[CH:14]([CH3:16])[CH3:15].C(NC(C)C)(C)C.COCC(O)C>>[CH3:15][CH:14]([CH3:16])[CH:13]([NH:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[C:17]([NH2:19])=[O:18]
Reactant: Clc1ccnc2ccccc12
Reactant: CC(C)[C@H](N)C(N)=O
Solvent: CC(C)NC(C)C
Solvent: COCC(C)O
Product: CC(C)C(Nc1ccnc2ccccc12)C(N)=O
Yield: 15.6 %

Procedure:
4-Chloroquinoline (0.82 g, 5 mmol), valinamide (0.64 g, 5.5 mmol) and diisopropylamine (1.9 ml, 11 mmol) were mixed with 1-methoxy-2-propanol (8 ml) and heated with stirring at reflux for 48 hours. The solvent was removed under reduced pressure, the residue was partitioned between water and ethyl acetate, the phases were separated, the aqueous phase was washed 3 times with ethyl acetate and basified with 50% NaOH. A precipitate formed that was filtered off and dried in air to give 0.2 g of a solid (0.78 mmol, 14%). MS (APCI) M/z=243.6 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=2[C:4]#[N:5])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1c(Cl)cncc1-c1ccc(OCc2ccccc2)cc1
Temperature: 150 °C
Yield: 51.5 %

Procedure:
A mixture of 3,5-dichloroisonicotinonitrile (2.50 g, 14.45 mmol), 4-(benzyloxy)phenylboronic acid (3.63 g, 15.90 mmol), potassium phosphate (6.13 g, 28.9 mmol) and palladium tetrakis(triphenylphosphine) (0.835 g, 0.723 mmol) was pumped and backfilled with nitrogen 3 times. N,N-Dimethylacetamide (40 mL) was added. The mixture was again pumped and backfilled with nitrogen 3 times and heated with a 150° C. oil bath for 1 h. The mixture was diluted with ethyl acetate (400 mL), washed twice with 1:1 mixture of brine and water (100 mL), brine (100 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with toluene and eluting with 10-35% ethyl acetate in hexanes, gave 3-(4-(benzyloxy)phenyl)-5-chloroisonicotinonitrile as a white solid (2.387 g, 52% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.72 (1H, s), 8.69 (1H, s), 7.51-7.60 (2H, m), 7.40-7.50 (4H, m), 7.33-7.40 (1H, m), 7.10-7.19 (2H, m), 5.15 (2H, s); MS (ES+) m/z: 321 (M+H); LC retention time: 4.323 min (analytical HPLC Method A).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[F:16])C.O.O.[OH-].[Li+].Cl>O1CCCC1>[CH2:14]([S:11]([C:9]1[CH:8]=[CH:7][C:6]([F:16])=[C:5]([CH:10]=1)[C:4]([OH:17])=[O:3])(=[O:12])=[O:13])[CH3:15]
Reactant: CCOC(=O)c1cc(S(=O)(=O)CC)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To 10.8 mmol 5-ethanesulfonyl-2-fluoro-benzoic acid ethyl ester in 26 ml tetrahydrofuran was added 26 ml water and 16.1 mmol lithium hydroxide monohydrate and the reaction mixture was stirred at room temperature for 45 minutes. After such time, the reaction mixture was acidified with 1N HCl, tetrahydrofuran was evaporated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give the title compound as a white solid (96%). MS (m/e): 232.1 ([M+, 100%).
Reaction SMILES: P(O)(O)(O)=O.[OH:6][C@H:7]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[C@@H:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=1)[CH3:9].[OH-].[Na+].P(=O)(O)(O)O.O>CO>[OH:6][C@H:7]([C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)[C@@H:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)[CH3:9]
Reactant: CCOC(=O)COc1ccc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](NCCc1ccc(OCC(=O)O)cc1)[C@H](O)c1ccc(O)cc1
Temperature: 40 °C
Yield: 110.1 %

Procedure:
To ethyl 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate phosphate (62.0 g) was added 2 mole/L aqueous sodium hydroxide solution (393 mL), and the mixture was heated to 40° C. of internal temperature with stirring to dissolve. 4 Mole/L aqueous phosphoric acid solution (115 mL) was added dropwise to the solution at 40-46° C. of internal temperature. After stirring at room temperature overnight, the resulting crystals were collected by filtration and washed with water to obtain white crystals. The resulting crystals suspended in a mixed solvent (200 mL) of water and methanol (1/8) were heated under reflux for 30 minutes. After cooling to room temperature, the crystals were collected by filtration and dried at 40-50° C. for 3 hours under reduced pressure to give 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-phenoxy]acetic Acid (Crystalline Form α) (50.0 g). A powder X-ray diffraction pattern of the crystalline polymorph (crystalline form α) is shown in the following FIG. 1.