Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38][NH2:39]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:39][CH2:38][C:34]5[S:33][CH:37]=[CH:36][CH:35]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCc1cccs1
Product: O=C(NCc1cccs1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 39.6 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 2-thiophenemethylamine (available from Aldrich Chemical Company, Inc.; 70 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-[(thiophen-2-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid (47 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.24 (br s, 1H), 9.24 (t, J=5.9 Hz, 1H), 8.48 (s, 1H), 8.36 (dd, J=16.8, 2.0 Hz, 2H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.4, 2.1 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.40 (dd, J=5.1, 1.1 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.98 (dd, J=5.0, 3.5 Hz, 1H), 4.67 (d, J=5.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C:11](=[N:14]O)[CH2:10][CH2:9]1.C(=O)([O-])[O-:28].[Na+].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C:11](=[O:28])[NH:14][CH2:10][CH2:9]1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=NO)CC3)c(F)c2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCNC(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 0.42 h

Procedure:
A stirred mixture of the compound of product of Step 3 (0.200 g, 0.549 mmol) in acetone (5.3 mL), under nitrogen, is treated first with 5% aqueous sodium carbonate (5.3 mL) and then, dropwise during 3minutes with a solution of p-toluenesulfonyl chloride (0.16 g, 0.82 mmol) in acetone (2.7 mL). Initially this mixture is a two phase solution; however, after about 25minutes a precipitate began to form. It is kept at ambient temperature (23° C.) for 4 hours and filtered. The filtrate is concentrated under reduced pressure to remove acetone and the aqueous residue is extracted with CH2Cl2. The extract is dried (MgSO4) and concentrated to give a small amount of crude product. Most of the product is in the aqueous layer which is concentrated in vacuo. The residue is combined with the crude product from the CH2Cl2 extract and chromatographed on silica gel with mixtures of MeOH--NH4OH--CH2CI2 that continued 3-5% MeOH and 0.3-0.5% NH4OH. The product is crystallized from MeOH--EtOAc to give the title compound. mp 140-146° C.;
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13][CH:12]=[N:11]3)[N:8]=[C:7]([CH3:19])[CH:6]=1>CO>[CH3:19][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13][CH:12]=[N:11]3)[N:8]=1
Reactant: C[S-]
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Agent: [Na+]
Solvent: CO
Product: CSc1cc(C)nc2c1ccc1cccnc12
Temperature: 25 °C
Yield: 84 %

Procedure:
Solid sodium methanethiolate (3.30 g, 47.7 mmol) was added to a 100 mL round-bottomed flask containing a solution of 4-chloro-2-methyl-[1,10]phenanthroline (intermediate obtained previously), (2.10 g, 9.4 mmol) in methanol (50 mL). The reaction mixture was refluxed for 18 hours and allowed to cool down to room temperature afterwards. The solvent was removed in a rotary evaporator and the residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid residue was treated with ethyl ether, filtered and dried, yielding 1.90 g of a light brown solid (84%).
Reaction SMILES: C[O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH3:15].Cl>C1COCC1.CO.[OH-].[Na+]>[CH3:15][C:11]1[C:10]2[C:14](=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:16])=[O:2])[CH:7]=[CH:8][CH:9]=2)[NH:13][CH:12]=1
Reactant: COC(=O)/C=C/c1cccc2c(C)c[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c[nH]c2c(/C=C/C(=O)O)cccc12
Temperature: 25 °C

Procedure:
(I-7). To a solution of (E)-3-(3-methyl-1H-indol-7-yl)-acrylic acid methyl ester (2, 180 mg, 0.84 mmol) in THF (5 ml) and methanol (4 ml), NaOH aq. (4 ml) was added at rt. The reaction mixture was stirred at rt over night and then the pH was adjusted to acidic by adding aqueous 2N HCl. The reaction mixture was extracted with EtOAc (2×30 ml). The combined organic phases were washed with water, brine and dried over sodium sulfate. After removal of solvent, 170 mg of I-7 was obtained. 1H-NMR (500 MHz, DMSO-d6).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:30](O)(C)C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=[O:5])([CH3:30])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c2c1COC
Reactant: CC(C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12

Procedure:
0.2 g (5 mmol) of 5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is refluxed for 2 hours in 35 ml of isopropanol with 0.15 ml (0.5 mmol) of titanium tetraisopropylate. The mixture is filtered and the filtrate concentrated by evaporation to approximately a third. 0.112 g (54% of theory) of 5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester crystallizes out, melting point 187°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8]C(=O)C)[C:5]([NH:12]C(=O)C)=[CH:4][C:3]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[OH-].[K+].O>C(O)CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:12])=[CH:4][C:3]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: CC(=O)Nc1cc(Cl)c(-n2cccc2)cc1NC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Nc1cc(Cl)c(-n2cccc2)cc1N

Procedure:
A solution 1.4 g (4.8 mmol) of N-(2-chloro-4,5-diacetamidophenyl)pyrrole and 0.4 g (9.8 mmol) of potassium hydroxide in 25 ml of ethylene glycol was stirred at 60° C. for 30 minutes. The reaction mixture was then poured into water, extracted with ethyl acetate and worked up.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH2:2][CH3:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[CH2:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:25](=[O:26])[CH2:24][Cl:23])[CH2:2][CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CCCNCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCN(CC1OCCO1)C(=O)CCl

Procedure:
N-n-Propyl-N-(1,3-dioxolan-2-ylmethyl)amine (10.5 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5.5 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-n-propyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:22][C:23]=2[NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].OS(O)(=O)=O.[CH3:42][CH2:43]O>O>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:22][C:23]=2[NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:42][CH3:43])=[O:28])=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCO
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2nc(-c3ccccc3)sc2NCCC(=O)O)CC1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2nc(-c3ccccc3)sc2NCCC(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 61 (6 mg) in EtOH (0.2 mL) was added concentrated H2SO4 (20 μL), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined org. layers were dried over Na2SO4 and concentrated to dryness. Purification by CC(CH2Cl2/MeOH 97:3) gave 3 mg of the desired product.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 85 mg (0.561 mmol) of 3-methoxybenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.45, FD-MS: M+ =561.
Reaction SMILES: C1C(=O)N(O[C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:28])=[CH:22][CH:21]=1>CC#N>[C:36]([O:35][C:33]([NH:32][CH2:31][CH2:30][NH:29][C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:9]([O:11][N:12]2[C:13](=[O:14])[CH2:15][CH2:16][C:17]2=[O:18])=[O:10])=[CH:21][CH:22]=1)=[O:28])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(N)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1

Procedure:
N,N′-Disuccinimidylcarbonate (5.49 g, 21.44 mmol, 1.1 eq) is added at room temperature to a stirred solution of N-(4-aminophenyl)({2-[(tert-butoxy)carbonyl-amino]ethyl}amino)carboxamide (6.75 g, 19.49 mmol, 1.0 eq) in CH3CN (350 mL).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5](Cl)=[O:6].Cl.[CH3:16][O:17][NH:18][CH3:19].N1C=CC=CC=1>C(Cl)Cl>[CH3:19][N:18]([O:17][CH3:16])[C:5](=[O:6])[C:4]1[CH:8]=[C:9]2[O:12][CH2:13][O:14][C:3]=1[C:2]([F:1])=[C:10]2[F:11]
Reactant: O=C(Cl)c1cc2c(F)c(F)c1OCO2
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc2c(F)c(F)c1OCO2
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
A solution of 14.4 grams (0.065 mole) of 3,4-difluoromethylenedioxybenzoyl chloride in 150 mL of methylene chloride was stirred and cooled to 0° C. To this was added 6.4 grams (0.066 mole) of O,N-dimethylhydroxylamine hydrochloride, followed by the dropwise addition of 11.0 mL (0.136 mole) of pyridine. Upon completion of addition the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was washed with two portions of aqueous 10% hydrochloric acid, two portions of aqueous IN sodium hydroxide, and two portions of an aqueous saturated solution of sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 15.1 grams of N-methyl-N-methoxy-3,4-difluoromethylenedioxybenzamide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (548 mg, 79%).
Reaction SMILES: [O:1]=[C:2]1[CH:26]=[C:25]2[C@:20]([CH3:38])([CH2:21][CH2:22][C@H:23]([O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:39])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH2:6][CH2:5]1.O[Li].O.N#N>CC(O)(C)C.O>[O:1]=[C:2]1[CH:26]=[C:25]2[C@:20]([CH3:38])([CH2:21][CH2:22][C@H:23]([O:27][Si:28]([CH:29]([CH3:31])[CH3:30])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:33])[CH3:34])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:39])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#N
Agent: [Li]O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)[Si](O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1)(C(C)C)C(C)C
Yield: 94 %

Procedure:
Methyl 7-oxo-3β-triisopropylsilyloxychol-5-en-24-oate (3) (5.85 g, 10.5 mmoles) was dissolved with warming in t-BuOH (100 ml). A solution of LiOH.H2O (1.76 g, 41.9 mmoles) in H2O (33 ml) was added, and the two phase mixture was heated at 80° with magnetic stirring in an N2 atmosphere for 2 hrs. Most of the t-BuOH was evaporated in vacuo, the residue-diluted with H2O (~50 ml), and acidified with 2N HCl (22 ml). The gummy suspension was extracted with CH2Cl2 (4 times). The extracts were washed with H2O and saturated brine and dried (MgSO4). Evaporation in vacuo gave 5.38 g of 4 as a gummy solid. NMR (CDCl3): δ0.68 (s, 3H, 18-Me); 0.95 (d, 3H, 20-Me); 1.05 (s, 18H, TIPS Me); 1.20 (s, 3H, 19-Me); 3.68 (m, 1H, 3-H); 5.67 (s, 1H, 6-H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C1COCC1.O.[OH-].[Na+]>[CH2:20]([O:19][C:17]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reaction time: 12 h
Yield: 93 %

Procedure:
A solution of 4-aminomethyl-1-Boc-piperidine (5.00 g, 23.4 mmol) in THF (60 mL), water (14 mL) and 5 N NaOH (46 mL) was treated with benzyl chloroformate. After 12 h, the mixture was partitioned between EtOAc and water and the aqueous phase washed with EtOAc (3×). The combined extracts were washed with water, brine and concentrated to afford 7.6 g (93%) of the title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:19](=[O:21])[CH3:20])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(Cl)ccc2n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazin-2-amine (18 g, 106.5 mmol) in DCM (180 mL) was added triethylamine (10.8 g, 106.5 mmol), DMAP (1.32 g, 1.06 mmol), and acetic anhydride (6 g, 106.5 mmol) sequentially at rt. The reaction mixture was stirred for 5 h at rt and the precipitate was filtered and washed with 50 mL of methanol to afford the title compound (15 g, 66%). 1H NMR (DMSO-d6, 300 MHz): δ 7.3 (d, 1H), 8.02 (d, 1H), 8.25 (s, 1H). LCMS (M+1) 211 (99%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C([N:17]=[C:18]=[S:19])(=O)C1C=CC=CC=1>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:18]([NH2:17])=[S:19]
Reactant: NCc1ccccn1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: NC(=S)NCc1ccccn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43.6 %

Procedure:
2-(Aminomethyl)pyridine (2.0 g, 18.5 mmol) was added dropwise to a stirred solution of benzoyl isothiocyanate (3.3 g, 20.2 mmol) in CH2Cl2 (30 mL) at 0° C. The mixture was stirred at 0° C. for 4 h. The solvent was evaporated in vacuo and 1M sulfuric acid (40 mL) was added. The reaction mixture was stirred at rt for 19 h. The mixture was neutralized with saturated sodium carbonate (aq.). The oil that formed in the solution during neutralization was removed with a spatula. The solid was collected, washed and dried. The solid was then dissolved in sodium hydroxide (10% aq., 15 mL) and MeOH (5 mL) and the solution was stirred at r.t. for 20 h. The reaction mixture was neutralized with 2M sulfuric acid and the aqueous solution was extracted with ethyl acetate (2×50 mL). The organic phase was treated with activated charcoal, filtered, dried (Na2SO4) and evaporated. The residue was suspended in diethyl ether, filtered, washed with diethyl ether and dried, giving the title compound (1.35 g, 44%) as a solid. The crude product was used in the next step without further purification.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:26].[ClH:1].[ClH:26].[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:19]=[C:15]([CH:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)[N:16]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:17]=2)=[CH:21][CH:22]=1
Reactant: CN(C)CCn1cc(-c2ccc(Cl)cc2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)CCn1cc(-c2ccc(Cl)cc2)nc1C1CCNCC1
Yield: 74.07 %

Procedure:
Add 4M HCl in 1,4-dioxane (2 mL) to 4-[4-(4-chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.8 g; 0.0018 mol; 1.0 equiv), in DCM and stir at RT for 6 h. Concentrate the reaction, crystallize from diethyl ether and filter to get the title compound (0.6 g; 74.07%). MS (ES+): m/z=333 (M+H)
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[CH2:22]([NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]([N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:14])=[CH:15][CH:16]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCNCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCN(CCc1ccccc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy} acetic acid (0.110 g, 0.37 mmol) in methylene chloride (3.7 mL) were added N-hexyl-2-phenylethylamine (0.080 g, 0.39 mmol) and DMAP (0.045 g, 0.37 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.071 g, 0.37 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (25 mL), and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated in vacuo.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([C:36]1[O:40][N:39]=[C:38]([NH:41][C:42](=[O:58])[C:43]([S:48]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)(=[O:50])=[O:49])([CH3:47])[CH2:44][CH2:45]O)[CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([C:36]1[O:40][N:39]=[C:38]([N:41]2[CH2:45][CH2:44][C:43]([S:48]([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=3)(=[O:50])=[O:49])([CH3:47])[C:42]2=[O:58])[CH:37]=1)([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C)(C)c1cc(NC(=O)C(C)(CCO)S(=O)(=O)c2ccc(Cl)cc2)no1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(N2CCC(C)(S(=O)(=O)c3ccc(Cl)cc3)C2=O)no1
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a solution of diethyl azodicarboxylate (0.025 g; 0.14 mmol) in methylene chloride (1 mL) was added triphenylphosphine (0.038 g; 0.14 mmol). The mixture was stirred 20 minutes and N-(5-tert-butyl-isoxazol-3-yl)-2-(4-chlorobenzenesulfonyl)-4-hydroxy-2-methyl-butyramide (0.030 g; 0.072 mmol) in 1 mL methylene chloride was added. After 18 hours the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. Removal of the volatiles from the product-rich fractions provided 0.024 g of product. 1H NMR (CDCl3) δ 7.83 (d, 2H), 7.55 (d, 2H), 6.73 (s, 1H), 4.03 (m, 1H), 3.95 (m, 1H), 3.25 (m, 1H), 2.29 (m, 1H), 1.52 (s, 3H), 1.35 (s, 9H). MS (ESI): m/e 397, 399 (M+H).