Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>C(Cl)Cl>[F:24][C:4]([F:3])([F:23])[C:5]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([S:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=3)(=[O:42])=[O:41])[CH2:19][CH2:18]2)=[CH:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (200 mg, 0.5 mmol, Example 91, Step 1), CH2Cl2 (5 mL) and triethylamine (0.35 mL, 2.5 mmol). 3-Methoxybenzenesulfonyl chloride (113 mg, 0.55 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min at 0° C., the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% hexanes in EtOAc) to give 1,1,1,3,3,3-hexafluoro-2-(4-(4-((3-methoxyphenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol (120 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:30])[C:5]([C:12]([NH:14][C:15]1[CH:20]=[C:19]([OH:21])[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][C:16]=1[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:13])=[CH:6][NH:7]2.[CH2:31]=O>[Pd]>[C:26]([C:16]1[CH:17]=[C:18]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:19]([OH:21])=[CH:20][C:15]=1[NH:14][C:12]([C:5]1[C:4](=[O:30])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][CH3:31])[NH:7][CH:6]=1)=[O:13])([CH3:29])([CH3:28])[CH3:27]
Reactant: C=O
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(NC(=O)c2c[nH]c3cccc(N)c3c2=O)cc1O
Agent: [Pd]
Product: CNc1cccc2[nH]cc(C(=O)Nc3cc(O)c(C(C)(C)C)cc3C(C)(C)C)c(=O)c12
Reaction time: 8 h

Procedure:
A flask charged with 5-amino-N-(2,4-ditert-butyl-5-hydroxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide (23 mg, 0.06 mmol), Pd/C (5 mg, 0.05 mmol) and formaldehyde (5 μL of 38% w/v, 0.06 mmol) was evacuated under vacuum, followed by purging with N2. Methanol (1 mL) was added followed by evacuating under vacuum. The reaction mixture was stirred overnight under an atmosphere of hydrogen, filtered through a plug of celite and concentrated to get N-(2,4-ditert-butyl-5-hydroxy-phenyl)-5-methylamino-4-oxo-1H-quinoline-3-carboxamide. LC/MS: m/z 422.5 (M+H)+ at 2.24 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1I)(=[O:3])[CH3:2].[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:30]#[C:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)c(I)c1NC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(-c2ccccc2)c(C#Cc2ccccc2)c1NC(C)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Nitrogen was bubbled through a mixture of ethyl 2-(5-acetamido-4-iodo-3-phenyl-pyrazol-1-yl)acetate (34.95 g, 84.58 mmol), phenyl acetylene (18.6 mL, 169.16 mmol), triethylamine (300 mL) and DMF (120 mL) for 1.5 h. Copper iodide (1.61 g, 8.46 mmol) and bis(triphenylphosphine)palladium(II) dichloride (3 g, 4.23 mmol) were added and the reaction mixture was stirred at 90° C. under nitrogen for 2 h. The reaction mixture was concentrated in vacuo, and the residue was co-evaporated with toluene to remove excess DMF. The residue was diluted with ethyl acetate (300 mL) and washed with water (2×100 mL). The organic phase was filtered through celite, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated from ethyl acetate, yielding the title compound as a solid (25.67 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[C:13]1(=[O:25])[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][CH2:16][CH:15]3[CH2:14]1.Cl>O1CCOCC1>[C:4]([CH:14]1[CH:15]2[C:24]3[C:19]([CH2:18][CH2:17][CH2:16]2)=[CH:20][CH:21]=[CH:22][C:23]=3[C:13]1=[O:25])([C:3]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CC2CCCc3cccc1c32
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)C1C(=O)c2cccc3c2C1CCC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
To a suspension of 50% sodium hydride (7.4 g) in anhydrous dioxane (50 ml), under nitrogen, a solution of diethyl oxalate (34.5 g) in anhydrous dioxane (20 ml) and then a solution of 2a,3,4,5-tetrahydro-acenaphthen-1-one (20.4 g) in anhydrous dioxane (130 ml) are added under stirring at room temperature. The reaction mixture is kept under stirring at a temperature varying between about 25° C. and about 45° C. for 4 hours, then it is diluted with ice water (1500 ml) and acidified to pH=4 with 2N HCl. The precipitate is filtered, washed with water and then purified by treatment with methanol to give 2-ethoxalyl-2a,3,4,5-tetrahydroacenaphthen-1-one (30.8 g), m.p. 92°-94° C., which is reacted with methylhydrazine (5.7 g) in acetic acid (300 ml) at 50° C. for 1 hour.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH:12]1[CH2:16][CH2:15][N:14]=[C:13]1[NH2:17].[Na].C(NC(C=C([C:29]1[C:30]([NH2:39])=[C:31]([CH:35]=[C:36]([Br:38])[CH:37]=1)[C:32]([O-])=[O:33])C)=O)(C)(C)C>CC(O)C>[NH2:39][C:30]1[CH:29]=[CH:37][C:36]([Br:38])=[CH:35][C:31]=1[C:32]([NH:17][C:13]1[NH:14][CH2:15][CH2:16][N:12]=1)=[O:33]
Reactant: NC1=NCCN1
Reactant: CC(=CC(=O)NC(C)(C)C)c1cc(Br)cc(C(=O)[O-])c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CC(C)O
Product: Nc1ccc(Br)cc1C(=O)NC1=NCCN1

Procedure:
A mixture of 4,5-dihydro-1H-imidazol-2-ylamine tosylate (0.523 g; 2.03 mmol) and sodium (37 mg; 1.63 mmol) in 2-propanol (16 ml) is refluxed for 30 min. 1-(tert-Butylcarbamoyl)-prop-1-en-2-yl-2-amino-5-bromobenzoate (example 15) (0.300 g; 0.812 mmol) is added and the mixture is refluxed over night. The precipitate formed is filtered off and discarded. The filtrate is evaporated, and the residue is purified by preparative RP-HPLC (column: Xbridge C18 (Waters); water-ACN; modifier: ammonia) to yield the title compound (C10H11BrN4O).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:18])=[CH:8][CH:7]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:18])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CN1CCCCCC1Cc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(CC2CCCCCN2C)cc1

Procedure:
Add a solution of 0.75 g of acetyl chloride in 5 ml of benzene drop by drop to a solution of 1.9 g of the title compound of Example 22 and 1 g of triethylamine in 10 ml of benzene. After an hour concentrate the resulting product, take it up with water and diethyl ether, collect the organic phase and concentrate it to obtain the title compound.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:30][C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][C:45]=1[CH:46]([CH3:56])[C:47]([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=1)=[O:48])[O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1>C1COCC1>[Cl:30][C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][C:45]=1[CH:46]([CH3:56])[C:47]([OH:48])([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=1)[C:2]([F:4])([F:3])[F:1])[O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1
Reactant: Cc1cc(C(=O)C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)ccn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2M solution of (trifluoromethyl)trimethylsilane in THF (0.23 ml) and a 0.1M solution of tetrabutylammonium fluoride trihydrate in THF (0.42 ml) were added to 4-{3-chloro-4-[1-methyl-2-(2-methyl-pyridin-4-yl)-2-oxo-ethyl]-phenoxy}-benzonitrile (80 mg) in THF (1 ml). The mixture was stirred for 1 h at room temperature and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:1) to give the title compound (60 mg) as a light yellow solid. MS (m/e)=447.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([O:9]CC)=O)[CH:3]=1.O.[NH2:13][NH2:14]>CO>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:13][NH2:14])=[O:9])[CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(C)on1
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)NN)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of ethyl 5-methylisoxazole-3-carboxylate (3.0 g, 19 mmol) in methanol (30 ml) at 0° C. under nitrogen was added hydrazine hydrate (3.04 g, 95 mmol) over 0.3 h. The reaction was stirred at 0° C. for 0.25 h and at RT for 1 h. The white precipitate was filtered off and washed with methanol to give the title-compound (0.78 g, 29%) as a white solid, 1H NMR (250 MHz, CDCl3) δ 2.41 (3H, d, J=0.8 Hz, CH3), 4.07 (2H, br s, NH2), 6.44 (1H, q, J=0.8 Hz, Ar—H), 7.99 (1H, br s, N—H); MS (ES+) m/e 142 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:11][C@H:10]([N:22]([C:27](=[O:31])[C:28]([OH:30])=O)[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]1[C:62]([NH2:67])=[CH:63][CH:64]=[CH:65][CH:66]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][C:28](=[O:30])[C:27]([N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C@H:10]1[CH2:11][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1)=[O:31]
Reactant: COCCCCNc1ccccc1N
Reactant: CC(C)CN(C(=O)C(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCNc1ccccc1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)amino}(oxo)acetic acid (10.3 g), HOBt (4.13 g) and WSC.HCl (6.28 g) were dissolved in DMF (50 ml), N-(4-methoxybutyl)benzene-1,2-diamine (4.67 g) and diisopropylethylamine (11.3 ml) were added, and the mixture was stirred at room temperature for 15 hr and at 60° C. for 2 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (9.11 g).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:11]([CH:34]=1)[C:12]([NH:14][C:15]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])(=O)C>CO.O1CCOCC1>[CH2:36]([O:35][C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:34][C:11]=1[C:12]([NH:14][C:15]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (1.6 mL) was added to a solution mixture of tert-butyl 2-(5-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.58 g) in methanol (3.0 mL) and dioxane (2.0 mL), followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and water and chloroform were added to the residue, followed by adjusting the pH to 4.0 with 2.0 mol/L hydrochloric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 0.52 g of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10]Br.[Cl:12][C:13]1[CH:21]=[CH:20][C:19]2[NH:18][C:17]3[CH2:22][CH2:23][NH:24][CH2:25][C:16]=3[C:15]=2[CH:14]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:12][C:13]1[CH:21]=[CH:20][C:19]2[NH:18][C:17]3[CH2:22][CH2:23][N:24]([CH2:10][CH2:9][CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)[CH2:25][C:16]=3[C:15]=2[CH:14]=1
Reactant: BrCCCc1ccccn1
Reactant: Clc1ccc2[nH]c3c(c2c1)CNCC3
Agent: Br
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Clc1ccc2[nH]c3c(c2c1)CN(CCCc1ccccn1)CC3

Procedure:
The title compound was prepared following the procedure of Example 1 with the exception that 3-pyridinylpropyl bromide hydrobromide was used instead of 4-pyridinylbutyl bromide hydrobromide and 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was used instead of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The product as converted to the dihydrochloride salt; mp. 240°-242° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][OH:9].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][O:9][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[C:17]=1[C:18]#[N:19]
Reactant: COc1ccc(CO)cc1OC
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc(F)c2C#N)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a cold (ice water) suspension of sodium hydride (316 mg; 7.9 mmol) in anhydrous DMF (10 mL) is added a solution of 3,4-dimethoxybenzyl alcohol (1.33 gm; 7.9 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 30 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1 g; 7.2 mmol) in anhydrous DMF (15 mL), and allowed to room temperature over 3 hours. The reaction mixture is poured into ice water with vigorous stirring and refrigerated overnight. The resulting precipitate is removed by filtration and dried under vacuum overnight at 30° C. to give 1.81 grams of 2-(3,4-dimethoxybenzyloxy)-6-fluorobenzonitrile.
Reaction SMILES: [C:1]([O:6]C)(=O)[C@@H:2]([CH3:4])[OH:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C(OCC)(=O)C>[OH:3][C@H:2]([CH3:4])[C:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:6]
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H](C)O
Solvent: CCOC(C)=O
Product: C[C@@H](O)C(=O)N1CCOCC1
Temperature: 85 °C
Yield: 87 %

Procedure:
A mixture of methyl (R)-lactate (175 g) and morpholine (440 ml, 3 eq) was heated at 85° C. for 40 h. The mixture was evaporated under reduced pressure. Purification of the residue by silica gel chromatography (using n-hexane:ethyl acetate=1:1 ˜ethyl acetate as an eluent) gave 4-[(R)-2-hydroxypropionyl]morpholine (232.4 g, 87% yield) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]O)=[CH:22][CH:21]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:32])[F:33])=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Temperature: 0 °C
Reaction time: 14 h
Yield: 33 %

Procedure:
To an ice cold solution of (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (100 mg, 455 μmol), 5-(4-trifluoromethoxy-phenyl)-pent-4-yn-1-ol (111 mg, 455 μmol) and tributylphosphine (160 μl, 546 μmol) in tetrahydrofuran (10 ml) was added N,N,N′,N′-tetramethyl azodicarboxamide (94 mg, 546 μmol). The cooling bath was removed and stirring continued for 14 h. The mixture was filtered over celite and the solvent removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to obtain 65 mg (150 μmol, 32%) of the title compound as colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[NH4+]>C1COCC1>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=Cc1ccc(O)cc1

Procedure:
4-Acetoxystyrene (105 grams, 0.65 mole) in THF (400 ml) was stirred at room temperature with 14.8 Molar ammonium hydroxide (52 ml, 0.77 mole) for 18 hours. Afterward, the solution was washed three times with brine (250 ml) and dried over anhydrous magnesium sulfate. Solvent was removed in a rotary evaporator and the viscous liquid was dried under high vacuum for 24 hours to give a waxy solid. Typically, this waxy solid is around 90% pure (by NMR), remainder being THF.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([N:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:40])[CH2:9]2)=[C:4]([C:41]([F:44])([F:43])[F:42])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[CH:19][CH:18]=3)(=[O:15])=[O:16])[C@H:10]([CH3:40])[CH2:9]2)=[C:4]([C:41]([F:44])([F:42])[F:43])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCNCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87.3 %

Procedure:
To a 50 mL flask containing tert-butyl 4-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)-1-naphthyl]piperazine-1-carboxylate (185.2 mg) and 5 mL of CH2Cl2 was added 3 mL of TFA. This was stirred at room temperature for 4.5 hr. Reaction was complete as determined by TLC. Solvent and TFA was removed under vacuum. The resulting residue was dissolved in CH2Cl2, washed with sat. K2CO3 until pH=8, then washed with saturated brine, dried over Na2SO4 and concentrated down to yield (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(4-piperazin-1-yl-1-naphthyl)sulfonyl]piperazine as a yellow solid (136.3 mg, 87.3% yield). HRMS: calcd for C26H28F4N4O2S+H+, 537.19418. found (ESI-FTMS, [M+H]1+), 537.1968. HPLC Method 1: room temperature, 5.003 min, 94.44%, HPLC Method 2: room temperature, 6.254 min, 93.74%.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)[CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C@@H:30]([N:32]2[CH2:37][CH2:36][C@H:35]([OH:38])[C@@H:34]([CH3:39])[CH2:33]2)[CH3:31])[CH2:25][CH2:24]1>>[OH:38][C@H:35]1[CH2:36][CH2:37][N:32]([C@@H:30]([CH3:31])[CH2:29][N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:28][CH2:27]2)[CH2:33][C@@H:34]1[CH3:39]
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCC5CCC5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid, 82 (see example 22) and amine 56.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([CH3:27])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+].Cl>CCO>[CH3:27][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(C)c2c(CC(=O)O)csc2c1
Yield: 76.8 %

Procedure:
To a mixture of methyl(4-methyl-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (222.5 mg) and EtOH (5 mL) was added 1N NaOH (1 mL) at room temperature, and the mixture was refluxed for 2 h. The mixture was neutralized with 1N HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (165 mg).
Reaction SMILES: C(ON=O)CC(C)C.I[CH2:10][I:11].[NH2:12][C:13]1[N:17]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]([CH2:31][CH2:32][CH3:33])=[N:15][C:14]=1C#N>C(Cl)(Cl)Cl>[C:13]([C:14]1[N:15]=[C:16]([CH2:31][CH2:32][CH3:33])[N:17]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:10]=1[I:11])#[N:12]
Reactant: CCCc1nc(C#N)c(N)n1CCOCCNC(=O)OC(C)(C)C
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCCc1nc(C#N)c(I)n1CCOCCNC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 66 %

Procedure:
A solution of isoamylnitrite (96 mL, 715 mmol), diiodomethane (475 mL), and chloroform (240 mL) was heated to 80° C. over a period of one hour. A solution of tert-butyl 2-[2-(5-amino-4-cyano-2-propyl-1H-imidazol-1-yl)ethoxy]ethylcarbamate (64.3 g, 191 mmol) in chloroform (240 mL) was added dropwise over a period of 115 minutes. During the addition the reaction temperature was decrease to 74° C. The reaction was allowed to cool to 50° C., and the chloroform was removed under reduced pressure. The resulting liquid was diluted with a small volume of dichloromethane and was purified by chromatography on silica gel (eluting sequentially with hexanes and ethyl acetate) and dried under high vacuum at 60° C. for eight hours to provide 56.3 g (66%) of tert-butyl 2-[2-(4-cyano-5-iodo-2-propyl-1H-imidazol-1-yl)ethoxy]ethylcarbamate as a dark orange oil containing a small amount of diiodomethane.