Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:18](=[O:19])[CH:17]([CH3:20])[O:16][C:15]2[CH:21]=[C:22]([S:25]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:27])=[O:26])[CH:23]=[CH:24][C:14]1=2.[CH3:43][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+].FC(F)(F)C(O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=[CH:5][C:4]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:43])([CH3:20])[O:16][C:15]2[CH:21]=[C:22]([S:25]([NH:28][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:26])=[O:27])[CH:23]=[CH:24][C:14]1=2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)C(=O)N3c2ccc(C(F)(F)F)cc2OC)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)C(C)(C)Oc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(2-Methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-2-methyl-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (from the product of Step 2 in Example 263; 110 mg, 0.178 mmol) was dissolved in THF (710 μl) in a 5 mL vial and cooled to 0° C. Lithium bis(trimethylsilyl)amide (1.0 m solution in THF, 69.1 μl, 0.355 mmol) was added dropwise, followed by methyl iodide (16.65 μl, 0.266 mmol), and the reaction was stirred for 30 min at 0° C. until reaction was complete by LCMS. Saturated ammonium chloride solution (aq; 5 mL) was added to the reaction mixture and it was warmed to RT, then extracted with EtOAc (3×5 mL), dried organics over Na2SO4, filtered and concentrated via rotary evaporation. Crude 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-2,2-dimethyl-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was dissolved in DCM (177 μl) then treated with 2,2,2-trifluoroacetic acid (328 μl, 4.42 mmol) and stirred at rt for 30 min until reaction was complete by LCMS. The reaction mixture was concentrated and purified via reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 μm column with a gradient 5-95% acetonitrile and water with 0.1% TFA modifier to yield title compound. m/z ESI 514.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][C:24]1([OH:34])[CH2:33][CH2:32][C:27]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:26][CH2:25]1>ClCCl.O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][C:24]1([OH:34])[CH2:33][CH2:32][C:27]3([O:31][CH2:30][CH2:29][O:28]3)[CH2:26][CH2:25]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCC1(O)CCC2(CC1)OCCO2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a 0° C. solution of 4-chloro-3-nitroquinoline (7.50 g, 36.0 mmol) and triethylamine (7.5 mL, 54 mmol) in dichloromethane (150 mL) was added 8-(aminomethyl)-1,4-dioxaspiro[4.5]decan-8-ol (8.10 g, 43.1 mmol). The reaction was allowed to warm to rt and stir overnight, then was concentrated under reduced pressure to yield a yellow solid. The solid was stirred in water (500 mL) and was isolated by filtration, dried under vacuum, and recrystallized from toluene (280 mL) to yield 8-{[(3-nitroquinolin-4-yl)amino]methyl}-1,4-dioxaspiro[4.5]decan-8-ol as bright yellow crystals (12.3 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](F)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(C([Cl:29])=O)=C(Cl)C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[Cl:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(F)c2)C1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2Cl)C1

Procedure:
In analogy to (RS)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (Example 1, steps a-g) using 4-bromo-2-chlorobenzoyl chloride (CAS 21900-55-0) instead of 4-bromo-3-fluorobenzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[C:40]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:47]=1[F:48])#[N:41].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[C:40]([C:42]1[CH:43]=[C:44]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)[CH:45]=[CH:46][C:47]=1[F:48])#[N:41]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(F)c(C#N)c2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
To 300.0 mg (0.49 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 12 ml toluene were added 11.4 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 97.4 mg (0.59 mmol) (3-cyano-4-fluoro-phenyl)boronic acid in 3.0 ml ethanol and 88.7 mg (1.53 mmol) potassium fluoride in 3.0 ml water. The mixture was stirred at 100° C. for 3 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 206 mg (58%) tert-butyl 4-{3-[(3R)-3-({1-[5-(3-cyano-4-fluorophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[CH:9][N:10]=2)[N:7]=1.[Br:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[Br:12][CH2:13][CH2:14][CH2:15][C:16]([NH:11][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)=[O:17]
Reactant: O=C(Cl)CCCBr
Reactant: Nc1cnc2ccc(Cl)nn12
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(CCCBr)Nc1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To 1.0 g (5.930 mmol) of 6-chloroimidazo[1,2-b]pyridazin-3-amine dissolved in 15 mL of THF was added 4-bromobutanoyl chloride (1.21 g, 6.52 mmol) and pyridine (0.96 mL, 11.86 mmol). This mixture was stirred for 1 hr at rt, and then diluted with 30 mL EtOAc and quenched with aq. NaHCO3. The organic layer was separated and washed with brine, dried over MgSO4, and concentrated. The solid obtained (1.39 g, 74% yield) was pure enough to be used for the next step without further purification.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>C(O)C>[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]3=[O:11])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc3c(c2)CCC3)C1=O
Yield: 71.7 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 2,3-dihydro-1H-inden-5-amine (0.593 g; 4.36 mmol) in ethanol (3 mL). 1-(2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxylic acid 0.255 g (71%) was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:10])[C:7]([OH:9])=[O:8].[ClH:11].[CH2:12](O)[CH3:13]>>[ClH:11].[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:10])[C:7]([O:9][CH2:12][CH3:13])=[O:8]
Reactant: CCO
Reactant: NCCCCC(O)C(=O)O
Agent: Cl
Product: CCOC(=O)C(O)CCCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.1 mole of 6-amino-2-hydroxyhexanoic acid in 150 ml of anhydrous ethanol is saturated with dry hydrogen chloride gas and is stirred overnight at room temperature. The reaction mixture is then concentrated in vacuo to give ethyl 6-amino-2-hydroxyhexanoate hydrochloride.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(C#C[Si](C)(C)C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 12, [5-iodo-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 36) was reacted with trimethylsilylacetylene to give the title compound as brown oil. MS: 503.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:18][C:17]2[C:12](=[N:13][CH:14]=[N:15][CH:16]=2)[N:11]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:18][C:17]2[C:12](=[N:13][CH:14]=[N:15][CH:16]=2)[N:11]=1
Reactant: COc1cc(O)ccc1-c1nc2ncncc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ncncc2[nH]1

Procedure:
Prepared analogously to Example 1 from 8-(2'-methoxy-4'-hydroxy-phenyl)-purine and methanesulfonic acid chloride.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].Cl.[Br:17][CH2:18][CH2:19]O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:19][CH2:18][Br:17])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: OCCBr
Agent: Cl
Product: O=C(O)c1cc(OCCBr)c2ccccc2c1O
Reaction time: 2 h
Yield: 50 %

Procedure:
To 150 ml of 2-bromoethanol, 60 g (0.3 mol) of 1,4-dihydroxy-2-naphthoic acid was added, and the reaction was carried out at 90° C. with stirring for 2 hours while introducing hydrogen chloride gas. After being cooled (10°-20° C.), precipitated crystals were separated by filtration to obtain 47.4 g (50% yield) of 1-hydroxy-4-(β-bromoethoxy)-2-naphthoic acid.
Reaction SMILES: [C:1]1([N:7]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:8]2[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]4([C:32]5[C:31](OC)=[CH:30][CH:29]=[C:28]([N:35]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)[C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:12]=3[C:11](OC)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N2C(Cl)=NN=N2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:42]1([N:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:28]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:13]4([C:12]5[CH:11]=[CH:10][CH:9]=[C:8]([N:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)[C:50]6[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=6)[C:20]=5[C:19]5[C:14]4=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:32]=3[CH:31]=[CH:30][CH:29]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COc1ccc(N(c2ccccc2)c2ccccc2)c2c1C1(c3ccccc3-2)c2ccccc2-c2c(N(c3ccccc3)c3ccccc3)ccc(OC)c21
Agent: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(N(c2ccccc2)c2cccc3c2-c2ccccc2C32c3ccccc3-c3c(N(c4ccccc4)c4ccccc4)cccc32)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A well-stirred suspension of 35.5 g (50 mmol) of 4,4′-bis(diphenylamino)-1,1′-dimethoxy-9,9′-spirobifluorene, 18.1 g (100 mmol) of 1-phenyl-5-chlorotetrazole and 27.6 g (200 mmol) of K2CO3 is heated under reflux for 18 h in 250 ml of acetone. After cooling, the precipitated solid is filtered off with suction and dried. The solid is dissolved in 200 ml of toluene, 6 g of Pd/C (5%) are added, and the mixture is stirred at 40° C. for 8 h under a hydrogen atmosphere. After removal of the solvent, the residue is washed three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol and subsequently recrystallised three times from DMF (about 10 ml/g). Yield: 21.1 g (32.43 mmol), 65.0%, purity: 99.9% (HPLC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12](=[O:15])[CH2:13]Cl)[CH3:10].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:10]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(F)c1
Temperature: 0 °C

Procedure:
3-Fluoro-phenol (100 g, 892 mmol) is dissolved in acetone (250 ml) and after addition of chloro-acetic acid ethyl ester (114 ml, 1.07 mol) and K2CO3 (249 g, 1.78 mol) the mixture is refluxed for 24 h. After cooling down to 0° C., the mixture is filtrated and the filtrate is evaporated under reduced pressure. Yield: 198 g (100%) of a red oil.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH2:6].C(=O)(O)[O-].[Na+].[C:12]([O:15][C:16]([CH3:20])([CH3:19])[CH2:17]Br)(=[O:14])[CH3:13]>C(O)C>[C:16]([O:15][C:12](=[O:14])[CH2:13][NH:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])([CH3:20])([CH3:19])[CH3:17]
Reactant: CSCCCN
Reactant: CC(=O)OC(C)(C)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CSCCCNCC(=O)OC(C)(C)C
Yield: 116.9 %

Procedure:
To a mixture of 3-methylthiopropylamine (30.0 g, 0.285 mol) and sodium bicarbonate (12.0 g, 0.142 mol) in 250 ml of ethanol was added dropwise bromo-t-butyl acetate (27.8 g, 0.142 mol). After 5 hours the ethanol was removed on a rotary evaporator and the residue partitioned between water and chloroform. The chloroform layer was dried, filtered and concentrated to give 36.4 g of crude N-(3-methylthiopropyl)glycine t-butyl ester as an oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[Cl-].[C:25]([OH:35])(=[O:34])/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCCCCCCCCCCCC[N+](CC1C=CC=CC=1)(C)C.C(Cl)(Cl)Cl>CS(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[C:25]([O-:35])(=[O:34])/[CH:26]=[CH:27]/[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: O=C([O-])/C=C/c1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Benzalkonium chloride (0.001 mol) was dissolved in warm distilled water. trans-Cinnamic acid (0.001 mol) was added to the benzalkonium solution. The reaction solution was stirred at 90° C. for 4 hours. The reaction solution was cooled to room temperature then 60 mL of chloroform was added. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and an orange viscous liquid was obtained in 90% yield. 1H and 13C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=liquid at room temperature.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)=[N:5]2.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])=[CH:13][CH:12]=1)=[N:5]2
Reactant: Nc1ccc(Oc2ccc3nccn3n2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2ccc3nccn3n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of 4-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (181 mg, 0.80 mmol) and triethylamine (0.011 mL, 0.08 mmol) in tetrahydrofuran (10 mL) was added phenyl isocyanate (0.104 mL, 0.96 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and precipitated from ethyl acetate to give the title compound (223 mg, 81%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:4].[H-].[Na+].I[CH3:18].O>CC(N(C)C)=O>[F:1][C:2]([F:13])([F:14])[C:3]([N:5]([CH:6]1[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]1)[CH3:18])=[O:4]
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C(=O)C(F)(F)F)C1CCC(O)CC1
Temperature: 0 °C

Procedure:
5 g of 2,2,2-trifluoro-N-(4-hydroxy-cyclohexyl)-acetamide (148) were dissolved in 25 mL of dimethyl acetamide, 625 mg of 95% sodium hydride were added and the reaction mixture was cooled to 0° C. 1.64 mL of iodomethane were added slowly and the reaction mixture was allowed to warm to room temperature. Upon completion, the reaction mixture was poured into water, extracted three times with methyl tert.butyl ether and the combined organic layer was extracted once with brine, dried over sodium sulfate and evaporated to dryness. The residue was taken up in water and lyophilized to remove remainders of dimethyl acetamide to yield 4.0 g of product. Rt=0.95 min (Method C). Detected mass: 226.2 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:29][CH3:30])[C:8]2[C:9]([CH2:16][NH:17][C:18]3[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][S:27][CH3:28])=[CH:20][N:19]=3)=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:34]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1)[CH3:35].O>CN(C)C=O>[F:43][C:42]([F:44])([F:45])[C:40]1[CH:41]=[C:36]([CH:34]([N:17]([CH2:16][C:9]2[C:8]([N:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:29][CH3:30])=[CH:13][CH:12]=[C:11]([O:14][CH3:15])[N:10]=2)[C:18]2[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][S:27][CH3:28])=[CH:20][N:19]=2)[CH3:35])[CH:37]=[C:38]([C:46]([F:47])([F:48])[F:49])[CH:39]=1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1CNc1ncc(OCCSC)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC1CCCC1)c1ccc(OC)nc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A solution of N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (168 mg, 0.39 mmol) in N,N-dimethylformamide (1 mL) stirred under ice cooling was added with sodium hydride (50% in oil, 24 mg, 1.4 mmol), and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to −78° C., added with a solution of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (250 mg, 0.78 mmol) obtained in Step 2 in N,N-dimethylformamide (0.5 mL), and the mixture was stirred for 12 hours with warming to room temperature. The reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the target compound, N-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (88.1 mg, 34%), as pale yellow oil.
Reaction SMILES: C(CC[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:8][CH:7]=1)(O)=O.B(C1C=CC([NH:53][C:54](=[O:60])[CH2:55][CH2:56][C:57]([OH:59])=[O:58])=CC=1)(O)O.B(O)O>>[C:57]([CH2:56][CH2:55][C:54]([NH:53][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH3:42])([CH3:43])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:8][CH:7]=1)=[O:60])([OH:59])=[O:58]
Reactant: O=C(O)CCC(=O)Nc1ccc(B(O)O)cc1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(NC(=O)CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the methods described above for (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 4-(4-boronophenylamino)-4-oxobutanoic acid as the reactant boronic acid. The product was isolated as a white solid (2.98 mg, 9%). LCMS: m/e 628.63 (M−H)−, 3.71 min (method 2). 1H NMR (599 MHz, DMSO-D6_CDCl3) δ ppm 0.91 (s, 3H), 0.93 (s, 3H), 0.98 (s, 3H), 0.99 (s, 3H), 1.02 (s, 3H), 1.03-1.71 (m, 17H), 1.71 (s, 3H), 1.84-1.93 (m, 2H), 2.09 (dd, J=17.87, 5.57 Hz, 1H), 2.20 (d, J=12.30 Hz, 1H), 2.29-2.39 (m, 1H), 2.59-2.62 (m, 2H), 2.97-3.10 (m, 1H), 3.30-3.33 (m, 2H), 4.61 (br. s, 1H), 4.74 (s, 1H), 5.24 (d, J=5.27 Hz, 1H), 7.03 (d, J=8.79 Hz, 2H), 7.51 (d, J=8.20 Hz, 2H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[O:12][C:11]([CH3:20])([CH3:19])[CH2:10][C:9]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[O:12][C:11]([CH3:19])([CH3:20])[CH:10]=[C:9]2[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: CCOc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1Br)C(CC)=CC(C)(C)O2

Procedure:
Following General Procedure C, ethylmagnesium bromide (3.0 M in THF, 7.04 mL, 21.1 mmol) was added to a solution of 6-bromo-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 5, 1.2 g, 4.2 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.