Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH3:22][N:23]1[C:27]([C:28]2([C:31](=N)OCC)[CH2:30][CH2:29]2)=[N:26][CH:25]=[N:24]1.[S].C(O)(=O)C>C(O)C>[CH3:22][N:23]1[C:27]([C:28]2([C:31]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]6[CH2:21][CH2:20][CH2:19][CH2:18]6)=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH2:30][CH2:29]2)=[N:26][CH:25]=[N:24]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(c2ncnn2C)CC1
Agent: [S]
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1ncnc1C1(c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)CC1
Temperature: 80 °C
Yield: 18 %

Procedure:
(R)-(1-(5,6-Diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone, prepared during the previous step, was added to a suspension of ethyl 1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclopropanecarbimidate (0.39 g, 2.0 mmol), sulfur (20 mg, 0.31 mmol) and acetic acid (0.96 mL, 15.5 mmol) in ethanol (10 mL) at room temperature. The reaction mixture was heated to 80° C. for 16 h. The mixture was concentrated under reduced pressure and the resulting crude was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified via preparative TLC to afford the title compound (120 mg, 18%). MS (ES+APCI) (M+H) 421.2; LCMS retention time: 3.311 min (Method Y1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O)(=[O:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:47]I>C(Cl)Cl.C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][I:47])(=[O:3])[CH3:2]
Reactant: II
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(=O)OCCCCCCCCCCCCCCCCCI
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
17-Acetoxy-heptadecanol (4.4 g, 13.99 mmol), Ph3P (4.4 g, 16.78 mmol) and imidazole (1.57 g, 23.08 mmol) were dissolved in the mixture of CH2Cl2 (40 ml) and benzene (20 ml). The mixture was cooled to 0° C. and solid I2 (4.26 g, 16.78 mmol) was added in one portion. The mixture was stirred at 0° C. for 15 min and at room temperature for 30 min. The reaction was quenched by the addition of EtOH (1.5 ml), stirred for 10 min at room temperature, diluted with hexane-EtOAc (1:1) mixture and washed with aqueous NaHCO3—Na2S2O3 solution. The organic extract was dried Na2SO4 and evaporated. Residue was stirred with hexane (300 ml) for 20 min and the suspension was filtered to remove Ph3PO. The filtrate was evaporated and the residue was chromatographed on silica gel in hexane-EtOAc (98:2) to give 17-acetoxy-heptadecyl iodide (5.89 g, 99%).
Reaction SMILES: [C:1]([O:6][OH:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[OH-].[Na+].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>O>[C:12]([O:7][O:6][C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC(C)(C)OO
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(C)OOC(=O)C(C)(C)C

Procedure:
The reaction is effected in a reactor arrangement of a first reactor of type D with two reactors of type B connected downstream in series. 0.26 kg/l·h of an 88% by weight solution of tert-amyl hydroperoxide in water, 0.47 kg/l·h of a 25% by weight solution of potassium hydroxide in water, 0.50 kg/l·h of a 25% by weight solution of sodium hydroxide in water and 0.26 kg/l·h of pivaloyl chloride are fed to the first reactor. The metering rates are based on the total volume of the reactor arrangement in litres. Cooling with cooling water keeps the internal temperature in the first reactor at 25° C. and in the two downstream reactors at 15° C. The reaction mixture withdrawn from the third reactor is mixed with 0.79 kg/l·h of demineralized water and 0.08 kg/l·h of isododecane, and the organic phase is removed. The organic phase is washed successively with an 8% by weight solution of sodium hydroxide in water, with a solution of 10% by weight of sodium sulphite in water comprising acetic acid and with demineralized, water, and then dried with calcium chloride. 0.42 kg/l·h of a 75% by weight solution of tert-amyl peroxypivalate in isododecane is obtained (80.6% based on pivaloyl chloride).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[N:37][CH:38]=2)O1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:33]2[CH:38]=[N:37][C:36]([N:39]3[CH2:40][CH2:41][NH:42][CH2:43][CH2:44]3)=[CH:35][CH:34]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(N3CCNCC3)nc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (54 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid purified by HPLC to yield 5-chloro-3-((5-(6-(piperazin-1-yl)pyridin-3-yl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=407).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:21][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:32]4[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared following Example 46, was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester via General Procedure A. Purification on silica yielded 130. NMR (DMSO): 1.61-1.68 (2H, m), 2.01-2.08 (2H, m), 2.12-2.18 (2H, m), 2.94 (3H, s, Me), 3.02-3.11 (3H, m), 3.76-3.80 (4H, m, CH2), 3.89 (2H, s, CH2), 3.96-3.99 (4H, m, CH2), 7.02 (2H, s, NH2), 7.32 (1H, s, Ar) and 9.10 (2H, s, Ar). MS: (ESI+): MH+=490.34
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5]Cl.[Cl:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:7][Si:8]([Cl:10])([Cl:9])[CH2:2][CH2:3][CH2:4][CH2:5][Si:8]([Cl:10])([Cl:9])[Cl:7]
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCCCCCl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CCCC[Si](Cl)(Cl)Cl
Yield: 82.9 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.44 g (1.50 mmol) of tetrabutylphosphonium chloride, 0.95 g (7.5 mmol) of 1,4-dichlorobutane, and 10.16 g (75.0 mmol) of trichlorosilane were reacted at 150° C. for 20 hrs. The resulting mixture was distilled to give 2.02 g of 1,4-bis(trichlorosilyl)butane (yield; 83%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=O)[CH:11]=O.[BH4-].[Na+]>C(O)C>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]1[CH2:11][NH:4][CH2:1][CH2:2][NH:3]1
Reactant: O=CC(=O)c1cccs1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1csc(C2CNCCN2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
A solution of 8.2 g of ethylenediamine in 250 ml of ethanol was added to a solution of 17.64 g of the above aldehyde in 250 ml of ethanol at 0° C. This mixture was stirred at room temperature for 1.5 hours, recooled to 0° C. and 9.6 g of sodium borohydride was added. This mixture was stirred overnight, quenched with water and the ethanol removed. The residue was extracted with dichloromethane, washed with water, dried and evaporated. The residue was crystallized with ether-hexane, giving 12 g of 2-(2-thienyl)piperazine.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>O1CCOCC1>[Cl:32][CH2:33][C:34]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:35]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(OC(=O)CCl)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.8 parts of methyl 3-hydroxy5-oxo-2-styrylcyclopent-1-eneheptanoate and 2 parts of pyridine in 80 parts of dioxane is added, at 0°-5°, a solution of 2.4 parts of chloroacetyl chloride in 20 parts of dioxane. The resulting reaction mixture is stirred at that temperature for about 30 minutes, then at room temperature for about 5 hours. At the end of that reaction period the mixture is poured carefully into ice water and the resulting aqueous mixture is extracted with ether. The ether solution is washed successively with dilute hydrochloric acid and dilute aqueous sodium bicarbonate, then dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. The resulting product is purified by dry column chromatography on silica gel containing 8% of water, using 18% ethyl acetate in benzene, to afford pure methyl 3-chloroacetoxy-5-oxo-2-styrylcyclopent-1-eneheptanoate. This compound is represented by the following structural formula ##SPC7##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[CH:20][CH:19]=3)=[O:17])[C:8]=2[CH:29]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[CH:22][CH:23]=3)=[O:17])[C:8]=2[CH:29]=1
Reactant: [H][H]
Reactant: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OCCC#N)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCC#N)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1 g of (5-nitro-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VII) is dissolved in 15 ml of methanol and 0,1 g of 10 w/w % wet Pd/C catalyst is added and the reaction mixture is heated to 50° C. with a stirring of 800 round/min. Hydrogen pressure of 5 bar is set in the reactor and the mixture is stirred at this temperature for 2 hours. After cooling to room temperature the catalyst is, filtered off and the solvent is evaporated.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH:14]2[C@@H:12](O2)[C:11](=[O:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][O:17][C:18](=[O:25])[CH2:19][S:20][CH2:21][CH2:22][CH2:23][SH:24].[Si](O[C@@H]1CC(=O)C=C1)(C(C)(C)C)(C)C>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:25])[CH2:19][S:20][CH2:21][CH2:22][CH2:23][S:24][C:12]1[C:11](=[O:15])[CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH:14]=1
Reactant: COC(=O)CSCCCS
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)[C@@H]2OC12
Agent: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Solvent: ClCCl
Product: COC(=O)CSCCCSC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
The epoxide 3 prepared above was diluted with CH2Cl2 (30 mL), (3-mercaptopropylsulfanyl)acetic acid methyl ester 4 (1.93 g, 10.7 mmol), prepared according to Chem. Pharm. Bull. 28 (2), 1980, 558-566, was added and the solution was cooled to 0° C. Basic alumina (11.9 g) was added and the reaction mixture was warmed to room temperature. After stirring for 18 h the mixture was filtered through celite and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 6:1 hex/EtOAc) to yield 3.6 g (80%) of the above titled compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][N:9]([CH3:21])[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=2)[CH2:11]1.C1([O:28][C:29](=O)[NH:30][C:31]2[CH:36]=[C:35]([C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH:34]=[C:33]([CH2:43][CH3:44])[CH:32]=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH2:43]([C:33]1[CH:32]=[C:31]([NH:30][C:29]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[CH2:8][N:9]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[CH2:11]2)[CH3:21])=[O:28])[CH:36]=[C:35]([C:37]2[N:41]([CH3:42])[N:40]=[N:39][N:38]=2)[CH:34]=1)[CH3:44]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: CN(C[C@@H]1CCCC[C@H]1N)C1CCc2cc(F)ccc2C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(NC(=O)N[C@@H]2CCCC[C@H]2CN(C)C2CCc3cc(F)ccc3C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
A mixture of N-(2RS)-{[(1S,2R)-2-aminocyclohexyl]methyl}-6-fluoro-N-methyl-1,2,3,4-tetrahydronaphthalen-2-amine (60 mg, 206 μmol), phenyl[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]carbamate (52 mg, 206 μmol), triethylamine (57 μL, 412 μmol) and acetonitrile (2 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The solution was washed with aqueous sodium hydroxide (1.0 N), dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonia, to provide an amorphous solid (40 mg, 37%) which was a mixture of two diastereomers by NMR.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])([CH3:8])([CH3:7])[CH3:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:29][C:30](=[O:65])/[C:31](/[CH3:64])=[CH:32]/[C@:33]34[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]3[C@@H:35]3[C@@:48]([CH3:51])([CH2:49][CH2:50]4)[C@@:47]4([CH3:52])[C@@H:38]([C@:39]5([CH3:56])[C@@H:44]([CH2:45][CH2:46]4)[C:43]([CH3:54])([CH3:53])[C@@H:42](O)[CH2:41][CH2:40]5)[CH2:37][CH2:36]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:16][C:11]([CH3:17])([CH2:12][C:13]([O:15][C@H:42]1[CH2:41][CH2:40][C@@:39]2([CH3:56])[C@@H:44]([CH2:45][CH2:46][C@:47]3([CH3:52])[C@@H:38]2[CH2:37][CH2:36][C@H:35]2[C@@:48]3([CH3:51])[CH2:49][CH2:50][C@@:33]3(/[CH:32]=[C:31](\[CH3:64])/[C:30]([NH:29][C:26]4([C:23]5[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=5)[CH2:27][CH2:28]4)=[O:65])[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]32)[C:43]1([CH3:53])[CH3:54])=[O:14])[C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:18]
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Reactant: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of DMAP (415 mg, 3.40 mmol), EDC (652 mg, 3.40 mmol) and 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (425 mg, 2.039 mmol) in DCM (10 mL) stirred at 20° C. for 30 min was added (E)-N-(1-(4-chlorophenyl)cyclopropyl)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylamide (650 mg, 0.680 mmol). The reaction mixture was stirred at 20° C. for 2 h. The mixture was washed with saturated ammonium chloride, water, and saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column eluting with petroleum ether/Ethyl acetate (3:1) to afford 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(4-chlorophenyl)cyclopropyl)amino)-2-methyl-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (300 mg, 52%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.30-7.22 (m, 2H), 7.22-7.14 (m, 2H), 6.59 (s, 1H), 6.32 (s, 1H), 4.51 (dd, J=5.4, 10.9 Hz, 1H), 3.28-3.10 (m, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.55 (s, 3H), 2.41-2.21 (m, 2H), 2.12-0.71 (m, 61H).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][NH:40][CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][N:40]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:1])[F:45])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN3CCNCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCN(S(C)(=O)=O)CC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of crude 2-[3,5-bis(trifluoromethyl)phenyl]-N-4-[4-(4-fluoro-2-methylphenyl)-6-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-3-pyridinyl]-N,2-dimethylpropanamide (D80, 100 mg, 0.16 mmol) in 5 mL of dichloromethane were added triethylamine (44 μL, 0.32 mmol, 2 eq.) and, at 0° C., methanesulfonyl chloride (18 μL, 0.24 mmol, 1.5 eq.). The reaction was left at room temperature overnight. Additional 3 eq. of methanesulfonyl chloride were added. It was then diluted with dichloromethane, extracted with sat. NaHCO3, the organics dried (Na2SO4), and the solvent was removed. The product was purified by flash chromatography (silica, EtOAc). Obtained 60 mg of the title compound.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)[CH:3]([CH3:5])[CH3:4].C(N(C(C)C)C(C)C)C.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O>[C:24]([NH:28][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([CH:2]([OH:1])[CH:3]([CH3:4])[CH3:5])[CH:7]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: CC(C)C(O)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(O)c1cccc(C(=O)NC(C)(C)C)c1
Yield: 82.5 %

Procedure:
A mixture of 3-(1-hydroxy-2-methylpropyl)benzoic acid (677 mg, 3.49 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uronium hexafluorophosphate (1.73 g, 4.54 mmol), N-ethyl-N-isopropylpropan-2-amine (1.21 mL, 6.97 mmol) and tert-butylamine (510 mg, 6.97 mmol) in N,N-dimethylformamide (12.0 mL) was subjected to microwave irradiation at 100° C. for 10 minutes. The reaction mixture was concentrated under vacuum and purified with silica column chromatography (eluting with 9% to 33% ethyl acetate in heptane) to afford the title compound (718 mg). MS (ESI) m/z 250.4 [M+H]+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]1[C:12]([C:13](=[O:29])[NH:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:23]=3)[CH:20]=2)=[C:11]([C:30](O)=[O:31])[CH:10]=[N:9]1>>[N:24]1([C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:13]([C:12]4[N:8]([CH3:7])[N:9]=[CH:10][C:11]=4[C:30]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:31])=[O:29])=[CH:20][N:19]3[N:21]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1
Reactant: C1COCCN1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1

Procedure:
Using morpholine and 1-Methyl-5-(2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (68 mg,95%). MS: m/z=425 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[NH:8][N:7]=1.[C:14]([S:17][CH2:18][CH2:19][C:20](Cl)=[O:21])(=[O:16])[CH3:15]>O.C(=O)([O-])[O-].[Na+].[Na+]>[C:14]([S:17][CH2:18][CH2:19][C:20]([N:8]1[CH:9]([C:11]([OH:13])=[O:12])[CH2:10][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7]1)=[O:21])(=[O:16])[CH3:15]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: O=C(O)C1CC(c2ccco2)=NN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)SCCC(=O)N1N=C(c2ccco2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
(±)-3-(2-Furanyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid (4.5 g) is dissolved in 200 cc of water containing 1.38 g of sodium carbonate (pH 9.4) at 10° C. 3-(Acetylthio)propionyl chloride (4.15 g) and 20% sodium carbonate solution are added simultaneously maintaining the pH between 8.5 and 9.4 and the temperature at 10° C. The final reaction mixture (pH 9.7) is stirred at room temperature for 2 hours and extracted with ethyl acetate (discarded) and the aqueous layer made strongly acid with 20% HCl. A precipitate forms which is extracted into ethyl acetate immediately. The solvent is dried and removed to yield 4.5 g of crystalline material which cannot be recrystallized.
Reaction SMILES: [C:1]1(N2C(S(CCC)(=O)=O)=NN=N2)[CH:6]=CC=C[CH:2]=1.[K].C[Si](C)(C)N[Si](C)(C)C.[CH:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1)=O.O>COCCOC>[CH:28](/[C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1)=[CH:2]\[CH2:1][CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: CCCS(=O)(=O)c1nnnn1-c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: O
Solvent: COCCOC
Product: CC/C=C/[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-phenyl-5-propylsulfonyl-1H-tetrazole (3.34 g) and anhydrous ethylene glycol dimethyl ether (60 ml) at −60° C. was added 0.5 M hexamethyldisilazane potassium solution (in toluene, 26.6 ml), and the mixture was stirred for 30 minutes. Under the same condition, a solution of t-butyl trans-4-formylcyclohexylcarbamate (3.02 g) in anhydrous ethylene glycol dimethyl ether (15 ml) was added thereto and the reaction mixture was gradually warmed to 25° C. and stirred overnight. To the reaction mixture was added water, and the mixture was stirred for 1 hour, then extracted with diethyl ether, and the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 1.31 g of t-butyl trans-4-[(E)-1-butenyl]cyclohexyl-carbamate.