Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([C@@H:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[N:13]=2)=[CH:8][CH:7]=1.Cl.[CH:31]1([N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40])[CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([C@@H:22]3[CH2:26][CH2:25][N:24]([C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:35]([CH:31]4[CH2:34][CH2:33][CH2:32]4)[CH3:42])[CH2:23]3)[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][C:4]4[CH:27]=[CH:28][CH:29]=[C:2]([F:1])[CH:3]=4)=[CH:7][CH:8]=3)[C:20]=12
Reactant: CN(C/C=C/C(=O)O)C1CCC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3)cc1)nn2[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1)C1CCC1
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a solution of 4a (134 mg, 0.344 mmol), (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid hydrochloride (0.344 mmol) and HATU (122 mg, 0.38 mmol) in DMF (1.5 ml) was dropwise added DIPEA (134 mg, 1.032 mmol) at rt. Stirring was continued for 30 min at rt (monitored by HPLC). The reaction mixture was diluted with EA, washed with water and brine, and dried over sodium sulfate. Filtration followed by concentration under reduced pressure provided a residue which was purified by flash chromatography using silica gel (1-12% MeOH/DCM) to give 32 mg of the title compound (4b). MS (ESI) m/e (M+1H)+: 542.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:5])=[CH2:4].[OH:6][CH2:7][CH:8](CO)[CH2:9][OH:10]>CN(C)C=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:4][C:3]1([CH3:5])[O:6][CH2:7][CH:8]([CH2:9][OH:10])[CH2:1][O:2]1
Reactant: OCC(CO)CO
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC1(C)OCC(CO)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
A solution of 2-methoxypropene (1 g) in N,N-dimethylformamide (150 ml) was added to 2-(hydroxymethyl)-1,3-propanediol (500 mg). p-Toluenesulfonic acid (10 mg) was added thereto, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with n-butanol. The n-butanol layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give (2,2-dimethyl[1,3]dioxan-5-yl)-methanol (378 mg, yield 55%).
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:18]1([C:22]([C:4]2[C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[C:1]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:2][CH:3]=2)=[O:23])[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1cccs1
Reactant: COC(=O)COc1cccc2c1CCCC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)COc1ccc(C(=O)c2cccs2)c2c1CCCC2
Yield: 85 %

Procedure:
To a solution maintained at 0° C. of 12.5 g of the ester obtained according to (a) and 8.79 g thiophene-2-carboxylic acid chloride in 130 ml methylene chloride, there are added little by little 7.9 g aluminium chloride. The mixture is then maintained at reflux temperature for 6 hours and then poured into a mixture of ice and hydrochloric acid. The final product is recrystallised from methanol. There are obtained, with an 85% yield, 16.35 g of the ester which melts at 85° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH2:10][C:11]#[N:12].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:10][C:11]#[N:12]
Reactant: COc1ccc(Br)c(CC#N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CCc1cc(O)ccc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
To (2-bromo-5-methoxy-phenyl)-acetonitrile (2.6 g, 11.5 mmol) in CH2Cl2 (20 mL) at 0° C. under N2 was added boron tribromide (1M in CH2Cl2; 25.4 mL, 25.4 mmol). The mixture was stirred for 15 minutes at 0° C., and at mom temperature overnight. After a work-up with H2O and CH2Cl2, the crude material was purified by silica gel chromatography to give the desired product as a white solid (1.5 g).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1[C:9]([C:10](N)=[O:11])=[CH:8][N:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-:16].[Na+].[Na+]>O>[F:2][C:3]([F:14])([F:13])[C:4]1[C:9]([C:10]([OH:16])=[O:11])=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: NC(=O)c1cnccc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cnccc1C(F)(F)F
Yield: 89.7 %

Procedure:
5 ml of 35% concentrated hydrochloric acid (10 ml, 57 mmol) was added to 4-trifluoromethylnicotinamide (90 g, 10 mmol), and the mixture was heated under reflux for 5 hours. Water (50 ml) was added, and the mixture was adjusted to pH 3 using sodium carbonate, and then extracted with ethyl acetate twice. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 1.71 g (yield 89.7%) of the title compound.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20].C1(OC2C=CC=CC=2)C=CC=CC=1>>[F:24][C:23]1[CH:22]=[C:21]2[C:19](=[CH:18][C:17]=1[F:16])[NH:20][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:13]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(F)c(F)cc2c1=O
Temperature: 130 °C
Reaction time: 17 h

Procedure:
Diethyl ethoxymethylenemalonate was added to 3,4-difluoroaniline at ambient temperature and the mixture was stirred at 130° C. for 17 hours. After diphenyl ether was additionally added to the reaction mixture, stirring was done at 260° C. for one hour. A solid obtained by leaving the reaction mixture to stand for cooling to ambient temperature was filtered, to obtain ethyl 6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][NH:26][CH3:27].O1CCCC1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10](=[O:11])[N:26]([CH3:27])[CH3:25])=[CH:15][CH:16]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionic acid (432 mg, 1.29 mmol) was dissolved in DMF (5.0 mL), and a solution of dimethylamine in tetrahydrofuran (2.92 mL, 5.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (370 mg, 1.94 mmol), and 1-hydroxybenzotriazole (262 mg, 1.94 mmol) were added. The reaction mixture was stirred at room temperature for 72 hours, and then poured into an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (103 mg, 22% yield).
Reaction SMILES: C(N[C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26][CH3:27])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:8]([NH2:28])[N:7]=1)CCC.FC(F)(F)C(O)=O.[CH3:36][C@H:37]([O:41]C1NC(N)=C2C(N=1)=NC(OC)=N2)[CH2:38][CH2:39][CH3:40].BrCCCCCl.N1CCCCCC1>>[N:19]1([CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:11]([O:26][CH3:27])=[N:10][C:9]3[C:13]2=[N:14][C:6]([O:41][C@@H:37]([CH3:36])[CH2:38][CH2:39][CH3:40])=[N:7][C:8]=3[NH2:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCN3CCCCCC3)c2n1
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Agent: C1CCCNCC1
Agent: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 36 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1-bromo-4-chlorobutane, and hexahydro-1H-azepine but with three sequential MDAPs using Method B followed by Method A (×2).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([NH2:10])=[C:5]([OH:11])[N:4]=1.[OH-].[Na+].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][CH2:20][C:21](Cl)=[O:22].S1C=CC=C1CCC(O)=O>S(Cl)(Cl)=O.O>[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([NH:10][C:21](=[O:22])[CH2:20][CH2:19][C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[C:5]([OH:11])[N:4]=1
Reactant: O=C(Cl)CCc1cccs1
Reactant: Nc1nc(O)c(N)c(O)n1
Agent: Cl
Agent: O=C(O)CCc1cccs1
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: Nc1nc(O)c(NC(=O)CCc2cccs2)c(O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,5-diaminopyrimidine-4,6-diol hydrogen chloride (1.04 g, 5.8 mmol) in sodium hydroxide (17.8 mmol) solution (25 ml of H2O) was added 3-thiophen-2-ylpropionyl chloride (6.4 mmol). The latter was prepared by refluxing 3-thiophen-2-ylpropionic acid (6.4 mmol) in thionyl chloride (500 μL) for 1 hour whereupon the excess of thionyl chloride was removed by evaporation in vacuo. The reaction mixture was stirred at room temperature for 18 hours. The pH of the suspension was adjusted to approximately 6 and the solids were filtered off. The title compound (1.25 g) was characterized by its mass spectrum: MS m/z (%): 515 ([M+H]+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:29])[CH:11]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:12][N:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:29])[CH:11]([N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[CH2:12][N:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: CN(C)CC(C(O)c1ccc([N+](=O)[O-])cc1)N1CCC(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CC(C(O)c1ccc(N)cc1)N1CCC(Cc2ccccc2)CC1

Procedure:
A solution of 5 g (+) threo 1-(p-nitro-phenyl)-2-(4-benzylpiperidin-1-yl)-3-dimethylaminopropan-1-ol and 0.5 g of Pd/C 10% in 50 ml of ethanol was hydrogenated at normal pressure at 50° C. After removal of the catalist, the solution was concentrated to small volume affording 3.1 g of (+) threo 1-(p-amino-phenyl)-2-(4-benzylpiperidin-1-yl) -3-dimethylaminopropan-1-ol, m.p. 121-125° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([N:40]([CH2:43][C@H:44]1[N:49]([CH2:50][CH2:51][C@@H:52]([NH:61][C:62]2[CH:67]=[CH:66][C:65]([S:68]([NH2:71])(=[O:70])=[O:69])=[CH:64][C:63]=2[S:72]([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73])[CH2:53][S:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:48][CH2:47][O:46][CH2:45]1)[CH2:41][CH3:42])[CH3:39]>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:71][S:68]([C:65]3[CH:66]=[CH:67][C:62]([NH:61][C@H:52]([CH2:51][CH2:50][N:49]4[CH2:48][CH2:47][O:46][CH2:45][C@H:44]4[CH2:43][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[CH2:53][S:54][C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)=[C:63]([S:72]([C:75]([F:76])([F:78])[F:77])(=[O:74])=[O:73])[CH:64]=3)(=[O:69])=[O:70])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCN(CC)C[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Product: CCN(CC)C[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 55 %

Procedure:
The title product (100 mg, yield: 55%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 89. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid, (INTERMEDIATE 13, 84 mg, 0.16 mmol) and 4-((R)-4-((R)-3-((diethylamino)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 92, 100 mg, 0.16 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, eluting with 0→20% MeOH/DCM for 19 minutes), providing the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:50]=[CH:49][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:39]=2[NH2:48])=[O:36])=[CH:33][CH:32]=1>>[NH2:48][C:39]1[CH:40]=[C:41]([C:44]([F:46])([F:47])[F:45])[CH:42]=[CH:43][C:38]=1[NH:37][C:35]([C:34]1[CH:49]=[CH:50][C:31]([CH2:30][NH:29][C:26]([C:22]2[C:23]3[C:18](=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)=[O:27])=[CH:32][CH:33]=1)=[O:36]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: NCc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2N)cc1
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)NCc5ccc(C(=O)Nc6ccc(C(F)(F)F)cc6N)cc5)cccc4c3)c2cc1OC
Yield: 69.9 %

Procedure:
The title compound (46.7 mg, 70% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-amino-4-trifluoromethylphenyl)benzamide (37.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 668 (M+1).
Reaction SMILES: [CH2:1]([C@H:4]1[C@:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[F:20])([CH3:10])[N:8]=[C:7]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]([CH3:37])([CH3:36])[S:5]1(=[O:39])=[O:38])[CH:2]=[CH2:3].[CH3:40][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>C1COCC1>[CH2:1]([C:4]1([CH3:40])[S:5](=[O:38])(=[O:39])[C:6]([CH3:37])([CH3:36])[C:7]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:8][C@@:9]1([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20])[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: C=CCC1(C)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a mixture of tert-butyl N-[(2S,3R)-2-allyl-3-(2-fluoro-5-nitro-phenyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (0.22 g, 0.38 mmol) in THF (2 mL) at −78° C. was added potassium bis(trimethylsilyl)amide, 1M in THF (1.13 ml, 1.13 mmol) and the solution was stirred for 15 minutes. Iodomethane (0.070 ml, 1.13 mmol) was added and the mixture was stirred at −78° C. for 0.5 h. The reaction was quenched by water, extracted with ethyl acetate. The combined extracts were washed with brine, dried and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a BioTage column (25 g), eluting with a gradient of 5% to 40% EtOAc in hexane, to provide tert-butyl N-[(5R)-6-allyl-5-(2-fluoro-5-nitro-phenyl)-2,2,5,6-tetramethyl-1,1-dioxo-1,4-thiazin-3-yl]-N-tert-butoxycarbonyl-carbamate (0.19 g, 85% yield) as a white solid. m/z (ESI) 606.1 (M+Na)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([C:14]#[N:15])=[CH:4][N:3]=1.[CH:16]([NH:19][CH2:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25])([CH3:18])[CH3:17].Cl>CC(O)CC>[C:14]([C:5]1[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:7][C:2]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([S:24](=[O:26])(=[O:25])[NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH:16]([CH3:17])[CH3:18])=[CH:28][CH:29]=2)=[N:3][CH:4]=1)#[N:15]
Reactant: N#Cc1cnc(Cl)nc1N1CCOCC1
Reactant: CC(C)NCCCNS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCC(C)O
Product: CC(C)NCCCNS(=O)(=O)c1ccc(Nc2ncc(C#N)c(N3CCOCC3)n2)cc1
Yield: 18.8 %

Procedure:
2-Chloro-5-cyano-4-morpholinopyrimidine (Method 55; 425 mg, 1.90 mmol), 4-[N-(3-isopropylaminopropyl)sulphamoyl]aniline (Method 1; 514 mg, 1.90 mmol) and 1M ethereal hydrogen chloride (189□l, 3.79 mmol) in 2-butanol (2 ml) was heated at 95° C. for 15 hours. The mixture was allowed to cool, silica was added and the volatiles were evaporated. The residue was purified by chromatography eluting with DCM/methanolic ammonia (100:0) increasing in polarity to (92:8) and the product was recrystallized from methanol to give the title compound (164 mg, 19%). NMR: 0.89 (d, 6H), 1.44 (m, 2H), 2.40 (t, 2H), 2.56 (m, 1H), 2.76 (t, 2H), 3.68-3.74 (m, 4H), 3.83-3.90 (m, 4H), 7.69 (d, 2H), 7.83 (d, 2), 8.49 (s, 1H), m/z: 460.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:4]12[CH2:5][C:6]([OH:8])=[O:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13]3)=[O:2].[CH2:30]([Mg]Br)[CH:31]([CH3:33])[CH3:32]>C1COCC1>[OH:2][CH:1]([C@H:3]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:4]12[CH2:5][C:6]([OH:8])=[O:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13]3)[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](C=O)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)CC(O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12CC(=O)O

Procedure:
A solution of 17β-formyl-6-t-butylcarboxy-6-azaandrost-4-en-3-one (550 mg, 1.37 mmol), prepared in part B above, in THF (10 mL) is treated with isobutylmagnesium bromide (2.0M in diethyl ether, 2.0 mL, 4.0 mmol) at 0° C. After 20 minutes the reaction is quenched with saturated aqueous NaHSO4, extracted with ethyl acetate (2×40 mL), dried over MgSO4, concentrated and chromatographed on silica gel (50% ethyl acetate/hexanes) to give crude 17β-(1-hydroxy-3-methylbutyl)-6-t-butylcarboxy-6-azaandrost-4-en-3-one of sufficient purity to carry on to the following steps; yield: 168 mg (26%); FAB mass spec. MH+ 460.
Reaction SMILES: N1([C:6](N2C=CN=C2)=[O:7])C=CN=C1.[I:13][C:14]1[CH:15]=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH:22]([NH:25][CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]2)[CH:18]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[I:13][C:14]1[CH:15]=[N:16][N:17]([C@H:19]2[CH2:20][CH2:21][C@H:22]([N:25]3[CH2:26][CH2:27][O:28][C:6]3=[O:7])[CH2:23][CH2:24]2)[CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCCNC1CCC(n2cc(I)cn2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C1OCCN1[C@H]1CC[C@H](n2cc(I)cn2)CC1
Temperature: 60 °C

Procedure:
Di-imidazol-1-yl-methanone (1.32 g; 8.14 mmol; 2.9 eq.) was added in one portion to a solution of 2-[4-(4-Iodo-pyrazol-1-yl)-cyclohexylamino]-ethanol (intermediate 25; 997 mg; 2.83 mmol; 1.0 eq.) and Dimethyl-pyridin-4-yl-amine (60 mg; 0.49 mmol; 0.17 eq.) in CHCl3 (30 mL). The reaction suspension was heated at 60° C. for 20 min then cooled and poured into a 1 N HCl solution. It was extracted with DCM (twice), combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH; 96:4) followed by a trituration in Acetonitrile afforded the title compound as a white solid (239 mg; 23%). 1H NMR (300 MHz, DMSO) δ 7.96 (d, J=0.5 Hz, 1H), 7.51 (d, J=0.5 Hz, 1H), 4.30-4.12 (m, 3H), 3.63-3.46 (m, 3H), 2.11-2.00 (m, 2H), 1.91-1.58 (m, 6H). HPLC (Condition A): Rt 2.98 min (purity 99.0%). MS (ESI+): 362.2.
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24][CH2:25]Br)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24][CH2:25][C:1]#[N:2])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCBr)C1
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCC#N)C1
Temperature: 110 °C

Procedure:
To an aqueous solution (3.0 ml) of potassium cyanide (85.0 mg) was added a solution of 1,4-bis(t-butoxycarbonyl)-2-(2-bromoethyl)piperazine (393 mg) in ethanol (3.0 ml), followed by stirring under heat at 110° C. for 3 hours. After the removal of ethanol by distillation under reduced pressure, methylene chloride (100 ml) was added to the residue. The organic layer was washed with distilled water until the water phase became neutral. The resulting organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (silica gel 15 g, hexane:ethyl acetate=2:1), whereby the title compound (145.0 mg, 43%) was obtained as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]2=[O:34])([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH:35]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)=[CH2:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][C:18]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([S:43]([C:40]3[CH:41]=[CH:42][C:37]([CH:35]=[CH2:36])=[CH:38][CH:39]=3)(=[O:45])=[O:44])[CH2:30][C:29]2=[O:34])([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20]1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(C(=O)OC(C)(C)C)CC3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
Triethylamine (735 mg) was added to a solution of 1-{[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidinyl]methyl}-2-piperazinone (1.4 g) in dichloromethane (80 ml), and 4-vinylbenzenesulfonyl chloride (885 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. An aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane, dried, concentrated, and purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain the colorless amorphous title compound (1.50 g).