Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:30])[NH:16][CH:17]=[CH:18][C:19]=3[NH:20][CH2:21][C@@H:22]([OH:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].C1COCC1>O>[OH:29][C@@H:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][NH:20][C:19]1[CH:18]=[CH:17][NH:16][C:15](=[O:30])[C:14]=1[C:11]1[NH:12][C:13]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: COC(=O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
In a 200 mL round-bottomed flask, 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid methyl ester (0.87 g, 2.15 mmol) and LiOH (258 mg, 10.8 mmol) were combined with THF (20 mL1) and Water (5 mL) to give a purple suspension. The reaction was stirred at room temperature overnight. The next day the reaction was heated in dry block at 50° C. for 3.5 hr and cooled to room temperature. The reaction was dilute with water, concentrated, dilute with more water, and acidify with 1M HCl, and filtered. The resulting solid was washed with water and hexanes, and dried over house vacuum yielding 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid (0.86 g, 102% yield) as a purple solid. LC/MS calcd for C21H18N4O4 (m/e) 390.0, obsd 391.2 (M+H); 1H NMR; (DMSO-d6) δ: 13.35 (s, 1H), 11.19 (d, J=6.0 Hz, 1H), 10.97 (t, J=4.9 Hz, 1H), 7.75 (dd, J=7.7, 3.9 Hz, 2H), 7.56 (d, J=7.3 Hz, 2H), 7.22-7.44 (m, 5H), 6.20 (d, J=7.5 Hz, 1H), 5.80 (br. s., 1H), 4.92 (t, J=5.5 Hz, 1H), 3.54-3.74 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=3)=[CH:9][CH:8]=[C:7]([F:31])[C:3]=1[C:4]([NH2:6])=[O:5].[C:32]1(OS(C(F)(F)F)(=O)=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[C:32]1([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C:13]([CH2:12][O:11][C:10]2[C:2]([F:1])=[C:3]([C:7]([F:31])=[CH:8][CH:9]=2)[C:4]([NH2:6])=[O:5])=[CH:21]3)[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=1
Reactant: CC1(C)OB(c2ccc3c(c2)C=C(COc2ccc(F)c(C(N)=O)c2F)C3)OC1(C)C
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCC2=Cc3cc(C4=CCCCC4)ccc3C2)c1F
Temperature: 80 °C
Yield: 22.3 %

Procedure:
To a solution of 2,6-Difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-inden-2-ylmethoxy]-benzamide (0.10 g, 0.20 mmol) in 3 ml of anhydrous DMF and water (1.5 ml) was added trifluoromethanesulfonic acid cyclohex-1-enyl ester (0.15 g, 0.60 mmol) and potassium phosphate (0.057 g, 0.20 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(triphenyl phosphine) palladium (II) (0.02 g, 0.03 mmol). The reaction mixture was heated at 80° C. for 1 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 45% EtOAc-Hexane) to get the desired product (0.017 g, 19%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.63 (m, 4H), 2.20 (m, 2H), 2.45 (m, 2H), 5.67 (s, 2H), 6.29 (m, 1H), 7.12 (m, 1H), 7.37 (m, 1H), 7.57 (m, 2H), 7.90 (br s, 1H), 8.03 (d, J=8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES+ (401.16), HPLC (method II) Rt=14.13 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[Se](=O)=[O:22].O>O1CCOCC1>[CH:1]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1)=[O:22]
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1SC
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C=O)nc(-c2ccccc2)nc1SC
Yield: 58.9 %

Procedure:
To a solution of ethyl 4-methyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate (5 g 17.4 mmol) in 1.4-dioxane (50 mL) was added selenium dioxide (9.6 g, 86.5 mmol) and water (1.5 mL) and the reaction mixture was refluxed for 12 hours. Dioxane was removed in a vacuum and the crude solid suspended in ethyl acetate and filtered. The filtrate was concentrated and purified by column chromatography over silica gel using 10% ethyl acetate in petroleum ether as eluent to give the desired product (3.1 g). 1H-NMR (400 Hz, CDCl3): δ 10.10 (s, 1H), 8.54 (d, J=7.2 Hz, 2H), 7.56-7.43 (m, 3H), 4.47 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.64 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); MS m/z 303.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:42])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:37])(=[O:36])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:17][CH:16]=3)[C:10]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:9]2)[CH:7]=1.[C:43](Cl)(=[O:48])[CH2:44][CH2:45][CH2:46][CH3:47]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:32]([O:31][C:29]([NH:28][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[C:10]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:9][N:8]([C:6]3[CH:7]=[C:2]([NH:1][C:43](=[O:48])[CH2:44][CH2:45][CH2:46][CH3:47])[CH:3]=[CH:4][C:5]=3[Cl:42])[C:12]2=[O:13])=[CH:20][CH:19]=1)(=[O:37])=[O:36])=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCCCC(=O)Cl
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)OC(C)(C)C)cc3)c2=O)c1
Yield: 46 %

Procedure:
A solution of 78 mg (0.128 mmol) of 2-(5-amino-2-chlorophenyl)-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 25), 76 μL (77 mg, 0.64 mmol) of valeryl chloride, and 15.6 mg (0.128 mmol) of 4-(dimethylamino)pyridine (DMAP) in 1 mL of dry pyridine was stirred overnight at room temperature. The mixture was quenched by addition of water and extracted twice with ethyl acetate. The combined organic fractions were washed twice with water, then with brine, and dried over Na2SO4. The filtered solution was concentrated, and the residue was flash chromatographed twice on silica gel (gradient elution with 0.5-3% methanol in CH2Cl2) to provide 41 mg (46%) of the title compound as a white solid, mp 177°-179° C.; homogeneous by TLC (9:1 CH2Cl2 --MeOH).
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][OH:12].[CH2:14]([Sn:18]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19]I)[CH2:15][CH2:16][CH3:17]>C(OCC)(=O)C.O.CN(C)C=O>[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][O:12][CH2:19][Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)COCCN(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a mixture of sodium hydride (60%, 278 mg, 7.0 mmol) and tetrahydrofuran (20 ml) was added 2-dimethylaminoethanol (0.70 ml, 7.0 mmol) at 0° C. (external temperature). Then, the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added dropwise a mixture of tributyl-iodomethyl-tin (2.0 g, 4.6 mmol) and tetrahydrofuran (5 ml)-N,N-dimethylformamide (20 ml) at 0° C. (external temperature). Then, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, ethyl acetate was added, and the organic layer was separated. The organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography (heptane:ethyl acetate=19:1, NH silica gel) to obtain the title compound (1.7 g, 4.3 mmol, 93%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH2:19][N:18]([CH2:21][CH:22]1[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][CH2:23]1)[CH2:17][CH2:16]2)=O.O>C1COCC1>[O:27]1[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[O:24][CH2:23][CH:22]1[CH2:21][N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[C:11]([CH2:9][OH:8])[CH:12]=[CH:13][CH:14]=2)[CH2:19]1
Reactant: COC(=O)c1cccc2c1CN(CC1COc3ccccc3O1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2c1CN(CC1COc3ccccc3O1)CC2
Temperature: 80 °C

Procedure:
To a suspension of LiAlH4 (0.20 g, 5.44 mmol) in dry THF (10 ml) was added 2-(2,3-dihydrobenzo-[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid methyl ester (0.18 g, 0.54 mmol). The reaction mixture was heated under microwaves at 80° C. for 10 min. Water (10 ml) was slowly added under cooling followed by extraction with EtOAc (3×5 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][O:7][C:8]([NH:10][C@@H:11]1[C:18](=[O:19])[N:17]2[C@@H:12]1[CH2:13][CH2:14][O:15][C:16]2(C)[CH3:20])=[O:9])([O-:3])=[O:2].C(Cl)(=[O:28])C.N1C=CC=CC=1>FC(F)(F)C(O)=O.O.C(Cl)Cl>[N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][O:7][C:8]([NH:10][C@H:11]1[C@H:12]([CH2:13][CH2:14][O:15][C:16](=[O:28])[CH3:20])[NH:17][C:18]1=[O:19])=[O:9])([O-:3])=[O:2]
Reactant: CC1(C)OCC[C@@H]2[C@H](NC(=O)OCc3ccccc3[N+](=O)[O-])C(=O)N21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A quantity (3.49 g) of trans-7-[o-nitrobenzyloxycarbonylamino]-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane is dissolved in 10 ml of 2:1 mixture of trifluoroacetic acid and water. After standing at 25° C. for 10 min. most of the solvent is removed in vacuo at 25°. The residue is taken up in 50 ml of benzene and evaporated to dryness in vacuo at 25°. The last step is repeated four more times to give a residue which is taken up in 100 ml of methylene chloride and cooled to 0° C.; whereupon 0.9 ml of acetyl chloride and 1 ml of pyridine are added dropwise. After stirring 1 hour at 0° C., the resulting solution is washed with 3×50 ml of brine and dried over anhydrous magnesium sulfate. The solvent is removed and the residue is chromatographed to give trans-3-[o-nitrobenzyloxycarbonylamino]-4-[2-acetoxyethyl]-2-azetidinone (1.85 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[CH3:21])=[O:8].[C:24]([Si:28]([CH3:38])([CH3:37])[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:28]([O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=2)[C:7]([NH:9][C:10]2[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:21])=[O:8])[CH2:32]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:38])[CH3:37]
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2C)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCNC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c(C)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-(5-bromo-2-methylbenzamido)-3,5-dimethylbenzoate (0.5 g, 0.0013 mol), tert-butyl-dimethyl-(3-piperidylmethoxy)silane (0.45 g, 0.0019 mol, preparation 14) and Cs2CO3 (1.29 g, 0.0039 mol) in 1,4-dioxane (15 ml) is added Pd2(dba)3 (0.12 g, 0.00013 mol) followed by S-Phos (0.054 g, 0.00013 mol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 110° C. After 16 hours, the reaction is cooled to ambient temperature, filtered through Celite™ and washed with EtOAc. The combined filtrates are dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by flash chromatography (silica gel) using 15% ethyl acetate in hexane as eluent to afford the title compound as a brown semi solid (0.4 g, 57.3%). Mass spectrum (m/z): 525.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cnccn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cnccn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 162a (170 mg, 0.61 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (280 mg, 0.72 mmol), Pd(dppf)Cl2 (30 mg, 0.037 mmol), K3PO4.trihydrate (270 mg, 1.2 mmol), sodium acetate (180 mg, 1.2 mmol), acetonitrile (20 mL), and water (0.5 mL). The system was evacuated and refilled with N2. The reaction mixture was stirred at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 of dichloromethane/methanol to afford 162b (130 mg, 40%) as a yellow brown solid. MS-ESI: [M+H]+ 540.3
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][OH:5].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][OH:5]
Reactant: CC(=CCO)CCCC(C)CCCC(C)CCCC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Yield: 82.6 %

Procedure:
To a solution of 50.0 g (169 mmol) of 3,7,11,15-tetramethyl-2-hexadecen-1-ol in 200 mL of ethanol were added 0.3 g (3 mmol) of triethylamine and 500 mg of 5% Pd on carbon. The mixture was maintained under 50 psi (345 kPa) of hydrogen on a Parr hydrogenator for 24 h. The mixture was filtered and concentrated, and distillation afforded 41.7 g (83%) of 3,7,11,15-tetramethyl-1-hexadecanol as a clear, colorless liquid, bp 150-155° C. at 0.05 mm Hg.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9].CCN(C(C)C)C(C)C.[C:41](O)(=[O:45])[CH:42]([CH3:44])[CH3:43].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[CH3:43][CH:42]([CH3:44])[C:41]([N:26]1[CH2:25][C:21]2([C:22]3[C:18](=[CH:17][C:16]([C:14]4[CH2:15][C:11]([C:5]5[CH:4]=[C:3]([Cl:2])[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=5)([C:28]([F:30])([F:29])[F:31])[CH2:12][N:13]=4)=[CH:24][CH:23]=3)[CH2:19][O:20]2)[CH2:27]1)=[O:45]
Reactant: CC(C)C(=O)O
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CN=C(c2ccc3c(c2)COC32CNC2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a stirred solution of 5′-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 5, 900 mg, 1.76 mmol) in THF (20 mL) was added DIPEA (3.07 mL, 17.65 mmol), isobutyric acid (0.321 mL, 3.53 mmol) and T3P (5.12 mL, 8.82 mmol, 50% solution in ethyl acetate) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. Reaction was monitored by TLC, after complete consumption of staring material reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×25 mL). Combined organic layer was washed with NaHCO3 solution (30 mL), brine (30 mL), dried over sodium sulphate and concentrated to get sticky solid (1 g, crude). The crude was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 0.5% MeOH in DCM to get desired compound as pale green solid (0.4 g, 41.5%). 1H NMR (400 MHz, DMSO-d6) δ: 1.01-1.05 (m, 6H), 2.54-2.75 (m, 1H), 3.74 (d, J=17.8 Hz, 1H), 3.87 (d, J=17.92 Hz, 1H), 4.12 (s, 2H), 4.41-4.46 (m, 3H), 4.82 (d, J=17.36 Hz, 1H), 5.12 (s, 2H), 7.66 (d, J=7.96 Hz, 1H), 7.80 (s, 2H), 7.85 (s, 1H), 7.94 (d, J=7.92 Hz, 1H), LC-MS (m/z): 545.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([OH:19])[CH2:16][C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([O:19][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:16][C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(O)CC#N)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(CC#N)OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 4-(2-cyano-1-hydroxyethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (4.24 g, 15.8 mmol) and pyridine (3.07 mL, 39.5 mmol) dissolved in dichloromethane (45 mL) at 0° C. is added methanesulfonyl chloride (3.45 mL, 42.6 mmol). After 1 hour, the reaction is not complete and is warmed to room temperature. After 18 hours at room temperature 1 equivalent of pyridine and 1 equivalent of methanesulfonyl chloride is added and stirred for 4 hours. The reaction mixture is diluted with EtOAc and washed several times with saturated NaHCO3. The organic layer is dried over Na2SO4, filtered and concentrated to give crude 4-(2-cyano-1-methanesulfonyloxy-ethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester. Assuming 100% yield, 4-(2-cyano-1-methanesulfonyloxyethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (5.47 g, 15.8 mmol) and triethylamine (11.0 mL, 79 mmol) are dissolved in MeOH (60 mL) and heated at 70° C. for 1 hour and concentrated. The residue is dissolved in EtOAc and washed with water, then concentrated and chromatographed using 100% dichloromethane to give cis/trans-4-(2-cyanovinyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (3.93 g, 99% yield) as a clear oil.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:31][CH3:32])[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:31][CH3:32])[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:16])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CCCCCNC(=O)OC(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 74.2 %

Procedure:
N-Boc-6-aminocaproic acid (7.58 g) prepared by the method described in a Journal of Medicinal Chemistry (J. Med. Chem., 35, p.272 (1993)) and 7.58 g of 3-amino-9-ethylcarbazole were dissolved in 75 mL of dimethylformamide, and the solution was added with 10.4 g WSC hydrochloride and stirred at room temperature for 3.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with 1 N aqueous sodium hydroxide, 10% aqueous citric acid and saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 10.3 g of 3-(N-Boc-6-aminocaproyl)amino-9-ethylcarbazole.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.[Br:18]Br>C(O)(=O)C.C(Cl)Cl>[Br:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:17])[N:7]([CH:4]1[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]1)[CH2:16]2
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1Nc2ccc(Br)cc2CN1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (0.2 g, 0.87 mmol) was dissolved in acetic acid (2 mL). To this solution was added a solution of bromine (1.8 mL, 35.14 mmol) in acetic acid (0.5 mL) dropwise over 5 min. After stirring for at room temperature for 1 h, the reaction mixture was diluted with methylene chloride, washed with water (2×), brine (2×), dried over sodium sulfate, filtered, and concentrated to afford 0.16 g (59%) which was used immediately without further purification. LC/MS: tR=0.91 min, 310.15 (MH)+.
Reaction SMILES: OCC[N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[CH3:10].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14]>>[C:11]([O:17][CH2:18][CH2:19][C:7]1[CH:6]=[C:5]([CH3:10])[NH:4][C:8]=1[CH3:9])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(C)n1CCO
Product: CC(=O)CC(=O)OCCc1cc(C)[nH]c1C
Temperature: 145 °C
Yield: 60.5 %

Procedure:
A mixture of 28 g (0.20 mol) of 1-(2-hydroxyethyl)-2,5-dimethylpyrrole and 31.2 g (0.24 mol) of ethyl acetoacetate was heated at 145° C. for six hours. Residual ethanol was removed in vacuo and kugelrohr distillation of the residue gave 27 g (61%) of a pale green oil. NMR: (CDCl3) δ 2.1 (9H, s), 3.3 (2H, s), 4.0 (4H, m) 5.6 (2H, s).
Reaction SMILES: Cl[C:2]1[CH:26]=[CH:25][C:5]2[S:6][C:7]([C:10]3[N:14]4[N:15]=[C:16]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=[CH:18][C:13]4=[N:12][CH:11]=3)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[H][H]>CO.[Pd]>[CH3:9][C:8]1[C:4]2[CH:3]=[CH:2][CH:26]=[CH:25][C:5]=2[S:6][C:7]=1[C:10]1[N:14]2[N:15]=[C:16]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: Cc1c(-c2cnc3ccc(NCCCCO)nn23)sc2ccc(Cl)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1c(-c2cnc3ccc(NCCCCO)nn23)sc2ccccc12
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of 4-(3-(5-chloro-3-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)butan-1-ol (20 mg, 0.0517 mmol, 1.0 equiv) in methanol (2.00 mL) was added Pd/C and placed under a balloon of hydrogen. After 3 h, the reaction mixture was filtered through a plug of silica gel to provide 15 mg of the white solid, 82%.