Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[C:13]([O:22][CH3:23])(=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O-])=[O:19]>>[CH3:23][O:22][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:11][CH3:12])[C:5]=1[O:9][CH3:10]
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: COc1cccc(OC)c1OC
Product: COC(=O)CCCCC(=O)c1ccc(OC)c(OC)c1OC
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 93.1 %

Procedure:
150 g of polyphosphoric acid (Acros) was added to a mixture of 1,2,3-trimethoxybenzene (10.0 g, 59.47 mmol), and mono-methyl adipate (13.04 mL g, 89.20 mmol) in a 250 mL round bottom flask equipped with a mechanical stirrer. The reaction mixture was stirred for 2.5 h at 45° C. The reaction mixture was then poured into a 1000 mL beaker containing around 500 mL of ice, and stirred well. Tan colored product precipitated out which was then filtered and washed with water and dried under vacuum. 17.18 g (93%) of 65 was obtained, which was pure by NMR. Rf: 0.42 (40:60 EtOAc:Hexanes)
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[O:17]1CCOCC1.CO>[OH-].[K+].Cl.O>[N+:11]([C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([OH:17])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: C1COCCO1
Reactant: NC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
2 4-Dinitro-5-hydroxybenzamide. A solution of 5-chloro-2,4-dinitrobenzamide (5.50 g, 0.022 mmol) in p-dioxane/methanol (1:1, 120 mL) and 6N aqueous KOH (20 mL) is stirred at room temperature for 2 h. After acidification with concentrated HCl, the mixture is diluted with water and extracted into EtOAc. Workup gives 2,4-dinitro-5-hydroxybenzamide (4.91g, 98%) as yellow cubes. 1H NMR (DMSO) δ8.64 (1H, s), 8.16 (1H, brs), 7.81 (1H, brs), 7.13 (1H, s), 5.80 (1H, brs).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:13]=1.[OH-].[K+].O>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]([C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([C:14]4[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=4)[CH:19]=3)[NH:24][CH:25]=2)[OH:8])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cccc(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-nitrobenzaldehyde (534, 1.08 g, 7.17 mmol) in methanol (34 mL) was added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 1.08 g, 5.52 mmol, prepared as described in Example 17) and potassium hydroxide (1.55 g, 27.6 mmol). The reaction was stirred at room temperature for four hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The mixture was purified by silica gel column chromatography eluting with 4% methanol in dichloromethane to provide two different compounds, a white solid (P-1399, R═H, 1.20 g, 63%) MS (ESI) [M+H+]+=347.2, and a light yellow solid (535, R=Me, 0.434 g, 22%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][N:9]=1.Br[CH:20]([CH3:22])[CH3:21]>O>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:20]([CH3:22])[CH3:21])[N:9]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)n1nc(Cl)c2ccccc2c1=O
Temperature: 50 °C
Yield: 102.7 %

Procedure:
Potassium carbonate (459 mg, 3.32 mmol) was added to a solution of 4-chlorophthalazin-1(2H)-one (300 mg, 1.661 mmol) and 2-bromopropane (409 mg, 3.32 mmol) and heated to 50° C. for 3 hrs. After 3 hrs the reaction was diluted with water and extracted with EtOAc (2×). The organic layer was washed with water followed by brine, dried over MgSO4, filtered and evaporated to give the crude product 4-chloro-2-isopropylphthalazin-1(2H)-one (380 mg, 103% yield), which was used as is in the next step. MS: MS m/z 223.15(M++1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[O-:24]I(=O)(=O)=O.[Na+].CC(O)C.Cl>CC(C)=O.O.[Ru]=O>[C:19]([O:18][C:17]([NH:16][C@H:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)[C:2]([OH:24])=[O:1])=[O:23])([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CCc1ccc(C(F)(F)F)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)O
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of tert-butyl (1R)-1-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propylcarbamate IV (41.3 g; 0.124 mol) in 60% aqueous acetone was added a solid sodium (meta)periodate (266 g; 1.24 mol) followed by ruthenium(II) oxide hydrate (1.65 g; 12.4 mmol). The greenish suspension was stirred for 3 h before adding propan-2-ol (500 mL) and stirring for an additional 30 min to consume excess oxidant. The resulting suspension was filtered through Celite, and the filtrate was concentrated under reduced vacuum to give a brown oil. To the brown foam was added 1 N HCl to pH=1 which was followed by extraction with EtOAc. The organic layer was washed with brine and dried with MgSO4. The crude residue was then purified on a silica gel column (10:1 hexane:EtOAc) to obtain (2R)-2-[(tert-butoxycarbonyl)amino]-4-[4-(trifluoromethyl)phenyl]butanoic acid V (18 g; 51.8 mmol, 42% yield). 1H NMR (CDCl3) 1.46 (brs, 9H), 1.93-2.30 (m, 2H), 2.68-2.87 (m, 2H), 4.12-4.47 (m, 1H), 5.04-5.23 (m, 1H), 7.30 (d, J=8, 2H), 7.55 (d, J=8, 2H); ESIMS found for C16H20F3NO4 m/z 348.3 (M+H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:7][N:8]([C@H:20]([CH3:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[CH:9](C1C=CC=C(Cl)C=1)[C:10]([OH:12])=O.[BH4-].[Na+]>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:7][N:8]([C@H:20]([CH3:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[CH2:9][CH:10]([C:4]1[CH:5]=[CH:6][CH:33]=[C:34]([Cl:1])[CH:35]=1)[OH:12]
Reactant: Cl
Reactant: COc1ccc(C[C@@H](C)N(Cc2ccc(OC)c(OC)c2)C(C(=O)O)c2cccc(Cl)c2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C[C@@H](C)N(Cc2ccc(OC)c(OC)c2)CC(O)c2cccc(Cl)c2)cc1OC

Procedure:
A solution of 5 g. of (R)-N-(3,4-dimethoxybenzyl)-N-(3-chlorophenylcarboxymethyl)-1-(3,4-dimethoxyphenyl)-prop-2-ylamine hydrochloride in 100 mL of methanol at -78° C. is treated with 0.71 g. of sodium borohydride, added in several portions over one hour. The mixture is stirred for an additional hour and then allowed to reach room temperature. The solvent is removed by evaporation to yield (R)-N-(3,4-dimethoxybenzyl)-N-[2-(3-chlorophenyl)-2-hydroxyeth-1-yl]-1-(3,4-dimethoxyphenyl)-prop-2-ylamine, which is dissolved in methylene chloride, washed with 3N aqueous sodium hydroxide and brine, and dried over magnesium sulfate. 1H NMR (250 MHz, CDCl3) d 1.02 (d, 3H, J=6.3 Hz), 2.4-2.7 (m, 4H), 3.1-3.25 (m, 1H), 3.35 (1/2ABq, 1H, J=13.3 Hz), 3.69 (s, 3H), 3.75 (s, 3H), 3.81 (br. s, 6H), 3.7-3.8 (m, 1H), 4.21 (m, minor isomer CHOH), 4.55 (m, major isomer CHOH), 6.52-6.76 (m, 6H), 7.19-7.33 (m, 4H). The product contains 97.9% R,R diastereoisomer and 2.1% S,R diastereoisomer.
Reaction SMILES: [C:1]1([N:7]=[C:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCCCCC>[C:1]1([N:7]=[C:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Solvent: CCCCCC
Product: C(=Nc1ccccc1)=Nc1ccccc1

Procedure:
A mixture of 3.619 g. of the copolymer prepared as described in Example 2 and a solution of 30.5 g. of phenyl isocyanate in 100 ml. of n-hexane was heated under reflux for 9.25 hours. At the end of this time the solid catalyst was removed by filtration and the filtrate was evaporated to dryness to yield diphenyl carbodiimide. An infrared spectrum of the product revealed only a trace of unreacted isocyanate. In contrast, a solution of phenyl isocyanate in n-hexane, heated under reflux for the same length of time but in the absence of catalyst, showed no significant amount of absorption corresponding to carbodiimide linkages in the infrared spectrum.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O-:18])=[O:17])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].OS([O-])(=O)=O.[K+]>C1COCC1.CO.[Cl-].[Na+].O>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(CC(=O)[O-])CC1
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl(dimethyl)silyl(2R)-){[4-(2-butynyloxy)phenyl]sulfonyl}amino)(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)ethanoate (0.76 g ,1.24 mmol) in 8 mL of THF/methanol (1:1) was added 1 N NaOH (1.25 mL, 1.25 mmol) and the reaction was stirred at room temperature overnight. Reducing the solvent to one quarter volume, then adding brine, the aqueous layer was neutralized with 1M KHSO4 to pH˜4 and then extracted with ethyl acetate. The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to obtain 0.68 g of (2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}amino)(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl) ethanoic acid. Electrospray Mass Spec 494.2 (M−H)−.
Reaction SMILES: C(OC[N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[C:17]([CH:42]=[CH:43][CH:44]=2)[C:18]([NH:20][C@@H:21]([CH2:23][C:24]([N:26]2[CH2:31][CH2:30][C@@:29]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)([OH:32])[C:28]([CH3:41])([CH3:40])[CH2:27]2)=[O:25])[CH3:22])=[O:19])=[N:11]1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>O.CC#N>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C@@:29]2([OH:32])[CH2:30][CH2:31][N:26]([C:24](=[O:25])[CH2:23][C@H:21]([NH:20][C:18](=[O:19])[C:17]3[CH:42]=[CH:43][CH:44]=[C:15]([C:12]4[N:11]=[N:10][NH:14][N:13]=4)[CH:16]=3)[CH3:22])[CH2:27][C:28]2([CH3:41])[CH3:40])=[CH:38][CH:37]=1
Reactant: C[C@H](CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)c1cccc(-c2nnn(COCc3ccccc3)n2)c1
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)c1cccc(-c2nn[nH]n2)c1

Procedure:
Example 4 was prepared from 3-(2-(benzyloxymethyl)-2H-tetrazol-5-yl)-N—((R)-4-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-4-oxobutan-2-yl)benzamide using the conditions described in Example 2. MS (ESI+)=497.2 (M+H)+. 1H NMR (CD3OD, 500 MHz) (NMR shows several rotamers) δ ppm 8.55 (s, 0.6 H), 8.49 (s, 0.4 H), 8.23 (d, J=7.8 Hz, 0.6 H), 8.20 (d, J=7.8 Hz, 0.4 H), 8.05 (d, J=8.2 Hz, 0.6 H), 8.00 (d, J=7.8 Hz, 0.4 H), 7.75-7.66 (m, 1 H), 7.47 (d, J=8.7 Hz, 0.9 H), 7.36-7.28 (m, 2.1 H), 7.22 (d, J=8.7 Hz, 1 H), 4.64-4.48 (m, 1.4 H), 4.11 (dt, J=13.3, 2.5 Hz, 0.6 H), 4.05 (dd, J=12.8, 1.8 Hz, 0.6 H), 3.69-3.54 (m, 1.4 H), 3.13 (td, J=12.9, 3.4 Hz, 0.6 H), 3.10-3.03 (m, 1 H), 2.98 (dd, J=15.1, 6.0 Hz, 0.4 H), 2.70-2.56 (m, 1.6 H), 2.53 (dd, J=15.1, 7.3 Hz, 0.4 H), 1.58-1.48 (m, 1 H), 1.42 (d, J=6.9 Hz, 1.8 H), 1.36 (d, J=6.4 Hz, 1.2 H), 1.35-1.26 (m, 0.6 H), 0.90 (t, J=6.9 Hz, 0.4 H), 0.84 (s, 1.2 H), 0.84 (s, 1.2 H), 0.77 (s, 1.8 H), 0.69 (s, 1.8 H); HPLC Method: Inj. Vol.=5 uL; Start % B=10, 12 Min. 100%, 15 Min. 100%, Flow Rate=1 ml/min, Wavelength 1=220, Wavelength 2=254, Solvent A=0.05% TFA in H2O:MeCN (95:5), Solvent B=0.05% TFA in H2O:MeCN (5:95), Col-1: Sunfire C18 3.5 um, 4.6×150 mm; Retention Time=11.08 min., Col-2: Xbridge Phenyl 3.5 um, 4.6×150 mm; Retention Time=10.57 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([C:20](O)=O)=[CH:18][C:17]([O:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[N:16]1.C(Cl)(=O)C(Cl)=O.C[N:39](C)[CH:40]=[O:41]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([CH2:20][C:40]([NH2:39])=[O:41])=[CH:18][C:17]([O:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:27])[F:28])=[N:16]1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C(=O)O)cc1SCC(F)(F)F
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2CC(N)=O)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.84 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxylic acid was dissolved in 10 mL of dichloromethane, and 0.2 mL of oxalyl dichloride and N,N-dimethylformamide in a catalytic amount were added, followed by stirring at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, and the resulting product was dissolved in 10 mL of tetrahydrofuran, and the solution was dropwise added to a mixed solution comprising 30 mL of a 25 mass % ammonia water and 40 mL of tetrahydrofuran at −30° C. Then, stirring was carried out for 12 hours while the temperature was slowly increased to room temperature. Then, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:3) to obtain 0.80 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxyamide.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH:18]([CH3:20])[CH3:19])[N:12]=3)[CH:9]=2)[N:4]([S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[N:41]=[C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:44]2)[CH:39]=[N:38][CH:37]=1)CCC.O>CN(C=O)C.[Cu]I.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>[CH:18]([O:17][C:13]1[N:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:28])=[CH:29][CH:30]=2)(=[O:22])=[O:23])[CH:3]=[C:2]3[C:36]2[N:41]=[C:40]([NH:42][C@@H:43]3[CH2:48][CH2:47][CH2:46][N:45]([C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[CH2:44]3)[CH:39]=[N:38][CH:37]=2)[CH:16]=[N:15][CH:14]=1)([CH3:20])[CH3:19]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cncc(OC(C)C)n4)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(-c4cncc(OC(C)C)n4)ccc32)cc1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
3-Iodo-5-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indole (0.4 g, 0.753 mmol) and (R)-tert-butyl 3-(6-(tributylstannyl)pyrazin-2-ylamino)piperidine-1-carboxylate (0.51 g, 0.903 mmol) in DMF (10 mL) was purged with argon for 15 min and added CuI (225 mg, 1.18 mmol) and Pd(PPh3)4 (105 mg, 0.09 mmol). The reaction mixture was heated at 100° C. for 2 h and cooled to RT. To the reaction mixture was added water and precipitate was formed. The precipitate was collected by filtration, washed with water and dried overnight. The crude product was purified by chromatography (eluting with 50% EtOAc/hexane) to obtain (R)-tert-butyl 3-(6-(5-(6-isopropoxy-pyrazin-2-yl)-1-tosyl-1H-indol-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (0.2 g, 57%). MS (ESI, pos. ion) m/z: 684 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][OH:14]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([OH:8])[CH2:7][NH:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H]2CO2)cc1
Reactant: NCCO
Product: OCCNC[C@H](O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To (R)-4-chloro-styrene oxide (1.84 g, 11.9 mmol), 2-aminoethanol (2.18 g, 3.0 equivalents) was added. The mixture was stirred at 25° C. for 17 hours, to obtain the reaction mixture of the title compound (chemical purity: 70.9 area %). Ethyl acetate (5 mL) and saturated brine (5 mL) were added to the reaction mixture, and the organic layer and aqueous layer were separated. The obtained organic layer was washed twice with distilled water (5 mL), and was concentrated and dried under vacuum, to obtain 1.47 g of the title compound as viscous white solid. A solution consisting of ethyl acetate (4 mL) and hexane (10 mL) was added thereto under heating at 50° C., and the mixture was stirred for 1 hour and then cooled to 25° C. The resulting crystals were collected by filtration under reduced pressure, then washed with hexane (3 mL) and dried under vacuum, to obtain 993 mg of the title compound as white crystals (yield: 39%; chemical purity: 92.5 area %). The retention time in the chemical purity analysis method was 1.7 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[CH3:17][CH:18]([CH3:23])[CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl.CCOC(C)=O>[CH3:17][CH:18]([CH3:23])[CH2:19][C:20]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:21]
Reactant: CC(C)CC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 113914.3 %

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (14.4 g, 0.1 mol) and pyridine (19.4 mL) in CH2Cl2 (150 mL) at 0° C., a solution of 3-methylbutyryl chloride (12 g, 0.1 mmol) in CH2Cl2 (140 mL) was added slowly. The reaction mixture was stirred for 1 h at 0° C. and for a further 1 h at rt. The mixture was concentrated to give a residue, which was diluted with EtOAc (500 mL) and filtered. The filtrate was washed with 10% aq Na2CO3 (200 mL) and water (200 mL). The combined aqueous layers were extracted with EtOAc (100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4 and concentrated to give crude 5-(3-methylbutanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (26 g), which was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10](OC)=[O:11])=[N:5]2.[BH4-].[Na+]>C(O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH2:10][OH:11])=[N:5]2
Reactant: COC(=O)c1ccc2nccn2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of methyl imidazo[1,2-b]pyridazine-6-carboxylate (1-3) (891 mg, 5.03 mmol) in ethanol (25 mL) was added NaBH4 (420 mg, 11.1 mmol) at room temperature. The suspension was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuum. The residue was purified by chromatography on silica gel to afford the title compound (630 mg). MS (m/z): 150 (M+1)+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:17]([O:19][CH3:20])[CH3:18])[C:13](OC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>CO>[OH:14][CH2:13][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:17]([O:19][CH3:20])[CH3:18]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@@H](C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (2S,3S)-methyl 2-(((benzyloxy)carbonyl)amino)-3-methoxybutanoate (prepared according to the literature procedure: Bioorg. Med. Chem. Lett. 15 (2005) 1447-1449, 1.60 g, 5.68 mmol) in a 3:1 mixture of tetrahydrofuran and methanol (12 mL), sodium borohydride (0.43 g, 11.38 mmol) was added and the mixture was stirred at room temperature for 2 hours. The volatiles were removed and the residue was dissolved in ethyl acetate (25 mL) and washed with brine (10 mL). Removal of the solvent afforded crude product which was purified by silica gel column chromatography using a gradient of ethyl acetate in pet. ether. Yield: 1.32 g (92%). 1H NMR (400 MHz, DMSO-d6) δ: 1.01 (d, 3H), 3.22 (s, 3H), 3.36-3.42 (m, 3H), 3.57-3.60 (m, 1H), 4.57 (t, 1H), 5.02 (s, 2H), 6.98-7.01 (m, 1H), 7.31-7.37 (m, 5H). MS (ES) MH+: 254.4 for C13H19F3NO4.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:27][CH2:26][C:25]3[N:24]=[C:23]([CH3:28])[O:22][C:21]=3[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:12][C:11]=1[CH3:33].C(N(CC)CC)C>ClCCl>[CH3:33][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:27][CH2:26][C:25]3[N:24]=[C:23]([CH3:28])[O:22][C:21]=3[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CN)c(C)c1)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CNC(=O)C3CC3)c(C)c1)CC2
Reaction time: 1 h
Yield: 67 %

Procedure:
Cyclopropanecarbonyl chloride (26 mg, 0.25 mmol) was added to a solution of (4-aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulen-6-yl)-methanone hydrochloride from Example E119.2 (85 mg, 0.22 mmol) in dichloromethane (5 ml) and triethylamine (to pH9) at room temperature. The mixture was stirred for 1 h then purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to give a white solid identified as the title compound (62 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[O:24])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: CC(C)(N)CO
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC(C)(C)CO)cn2)cn1
Yield: 63 %

Procedure:
As described for example 43c, 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.203 mmol) was converted, using 2-amino-2-methylpropan-1-ol instead of isopropylamine, to the title compound (56 mg, 63%) which was obtained as a white foam after purification by chromatography (reverse phase HPLC then silica, ethyl acetate). MS: m/e=436.2 [M+H]+.