Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[F:31]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)=[O:30])=[CH:24][C:23]=1[F:31]
Reactant: O=C=Nc1ccc(Cl)c(F)c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Nc1ccc(Cl)c(F)c1

Procedure:
1-(4-Chloro-3-fluoro-phenyl)-3-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl-methyl)-urea was prepared starting from intermediate D and 4-chloro-3-fluoro-phenylisocyanate. MS calcd. for C23H17Cl2FN3O2 [(M+H)+] 456.1, obsd. 455.9.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[O:16][C:15]([CH3:25])([CH3:24])[CH2:14]1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>C1COCC1>[N:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:40][CH2:39][NH:38][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[O:16][C:15]([CH3:25])([CH3:24])[CH2:14]1
Reactant: NCCc1ccccn1
Reactant: Cc1ccc2c(c1)C(N(CCCCC(=O)O)S(C)(=O)=O)CC(C)(C)O2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(N(CCCCC(=O)NCCc1ccccn1)S(C)(=O)=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
A mixture of 0.5 g (1.4 mmol) of 5-[methylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanoic acid (Example 10c) and 0.26 g (1.6 mmol) of CDI in 20 ml of THF is stirred at RT for 3 h. 0.2 g (1.6 mmol) of 2-(2-aminoethyl)-pyridine is then added and the mixture is stirred further overnight at RT. After concentrating the reaction mixture, the residue is taken up in EA and water, and the organic phase is washed 3 times with 2M sodium hydroxide solution. After drying over magnesium sulfate, concentration and purification by chromatography on silica gel using methylene chloride/methanol 9:1, 0. 0.33 g of 5-[methylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]-pentanoic acid (2-(2-pyridyl)ethyl)amide is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CCCc1cccs1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1cccs1
Temperature: 25 °C

Procedure:
A mixture of 4-(2-thienyl)butyric acid (4.25 g, 25.0 mmol) and 3 mL of concentrated sulfuric acid in 25 mL of methanol is heated at reflux for 2 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium carbonate solution. The organic layer is separated and passed through a short pad of silica gel. The filtrate is concentrated and purified by flash column chromatography eluting with 1:5 ethyl acetate:hexane to provide 4.02 g of 4-thiophen-2-yl-butyric acid methyl ester as a yellow oil, 1H NMR (DMSO-d6) δ 1.85 (quintet, J=7 Hz, 2H), 2.35 (t, J=7 Hz, 2H), 2.81 (t, J=7 Hz, 2H), 3.59 (s, 3H), 6.84 (m, 1 H), 6.95 (m, 1 H), 7.32 (dd, J=5, 1 Hz, 1H); MS 185.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24](O)=[O:25])[NH:13][C:12]43[CH2:29][C:28]([CH2:32][F:33])([CH2:30][F:31])[CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]4)=[O:25])[NH:13][C:12]43[CH2:27][C:28]([CH2:30][F:31])([CH2:32][F:33])[CH2:29]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)[C@@H]1NC2(CC(CF)(CF)C2)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Product: O=C(N[C@H]1CC[C@H](O)CC1)[C@@H]1NC2(CC(CF)(CF)C2)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
The compound (70 mg, 0.14 mmol) obtained in Step 1 above and trans-4-aminocyclohexanol (19.4 mg, 0.17 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 12 to give 56 mg (67%) of the title compound as a colorless solid.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[C@@H:14]([O:17][C@@H:18]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[CH3:19])[O:15][CH2:16][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([C@H:18]([O:17][C@H:14]2[O:15][CH2:16][C@@H:10]3[CH2:9][NH:8][CH2:12][C@H:11]3[C@@H:13]2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:19])[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=1
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21

Procedure:
(3aS,6R,7R,7aR)-2-Benzyl-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-2-methylphenyl)octahydropyrano[3,4-c]pyrrole (example 1: 2.51 g, 4.32 mmol) was combined 0.5 g 20% Pd(OH)2/C and suspended in 100 mL ethanol in a Parr apparatus. The reaction vessel was shaken vigorously under 45 psi hydrogen for 7 hr. The reaction mixture was filtered through a pad of celite and rinsed copiously with methanol. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a combination of DCM/methanol/NH4OH=90:9:1. MS: (MH)+492.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.Cl[C:15]1[CH:25]=[C:19]2[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:26])[N:16]=1>>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:26])[N:16]=[C:15]([O:11][CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=3)[CH:25]=[C:19]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(C(F)(F)F)cc1
Product: CN1CCCn2c1cc(OCCc1ccc(C(F)(F)F)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(4-(trifluoromethyl)phenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)COc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CBr)c1

Procedure:
t-Butyl-3-(hydroxymethyl)-phenoxyacetate is dissolved in dichloromethane (1.3 L) at room temperature. Triphenylphosphine (127 g, 0.48 mol) is added with stirring, followed by dropwise addition of CBr4 (146 g, 0.44 mol). The resultant mixture is stirred for 1 hour at room temperature and then evaporated in vacuo. The residue (553 g) is adsorbed onto silica-gel (100 g) and then placed on a sintered glass funnel containing 700 g of silica gel. The column is eluted with hexane (2×4000 L) followed by 4:1 hexane/EtOAc (2×4000L). The hexane/EtOAc solutions are combined and evaporated in vacuo to provide t-butyl 3-(bromomethyl)-phenoxyacetate as a colorless oil. MS Found: M+18+:318, 320.
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:11][C:12]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[N:17][CH:18]=[CH:19][N:20]=2)[CH:15]1[CH2:24][CH3:25])=[O:13])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>CO>[NH2:9][C@H:10]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:11][C:12]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[N:17][CH:18]=[CH:19][N:20]=2)[CH:15]1[CH2:24][CH3:25])=[O:13]
Reactant: CCC1c2nccnc2CCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC1c2nccnc2CCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Reaction time: 2.5 h

Procedure:
A solution of methanolic hydrogen chloride (approx. 1.6M, 1.5 mL) was added to 6-[(3R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoyl]-5-ethyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (18 mg, 0.038 mmol) dissolved in 0.25 mL of methanol. After 2.5 h, the solution was added to saturated aqueous sodium bicarbonate solution (10 mL), which was then extracted with two portions of ethyl acetate (25 mL and 15 mL). The organic layers were washed in succession with saturated aqueous brine (5 mL), dried over sodium sulfate, decanted, and concentrated. The residue was dissolved in methanol, and the resulting solution was filtered (0.45 micron PTFE membrane) and evaporated to provide the title compound as a very viscous colorless syrup. LC/MS: 379 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[Si](C(C)C)(C(C)C)C(C)C)[N:12]=[C:11]([NH:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[N:10]=1)C1C=CC=CC=1.C(OC1C=C(Cl)N=C(NC2C=NC=CC=2)N=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB(C2C=CC=C3C=2C=CN3[Si](C(C)C)(C(C)C)C(C)C)O1>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.O1CCOCC1.CN(C=O)C>[NH:19]1[C:20]2[C:16](=[C:15]([C:13]3[N:12]=[C:11]([NH:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)[N:10]=[C:9]([OH:8])[CH:14]=3)[CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(-c3cc(OCc4ccccc4)nc(Nc4cccnc4)n3)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: Clc1cc(OCc2ccccc2)nc(Nc2cccnc2)n1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Oc1cc(-c2cccc3[nH]ccc23)nc(Nc2cccnc2)n1

Procedure:
[4-Benzyloxy-6-(1-triisopropylsilanyl-1H-indol-4-yl)-pyrimidin-2-yl]-pyridin-3-yl-amine. DMF (1 mL) and dioxane (2 mL) were added through a septum to a nitrogen-purged microwave tube containing (4-benzyloxy-6-chloro-pyrimidin-2-yl)-pyridin-3-yl-amine (80 mg, 0.256 mmol), potassium carbonate (71 mg, 0.50 mmol), Pd(PPh3)4 (59 mg, 0.51 mmol), and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole (153 mg, 0.384 mmol). The mixture was subjected to microwave conditions 100 W/130° C. for 1 hour. SFC/MS analysis showed mostly the desired product. A small amount of product with loss of the TIPS group was seen as well. The reaction mixture was cooled to room temperature and filtered through Celite®. The solvent was concentrated and the crude mixture was purified by a short silica column with 99:1 methylene chloride/MeOH solvent mixture to afford 100 mg of [4-benzyloxy-6-(1-triisopropylsilanyl-1H-indol-4-yl)-pyrimidin-2-yl]-pyridin-3-yl-amine (˜75% pure by SFC/MS). This material was used without further purification.
Reaction SMILES: O=C1[N:6](CC(OC(C)(C)C)=O)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18]C=2N1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:27][C:26](=[O:28])[N:25]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:24]=2[CH:37]=1>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[N:27]([C:18]3[CH:17]=[CH:16][CH:15]=[CH:5][N:6]=3)[C:26](=[O:28])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:24]=2[CH:37]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Product: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccc(Br)cc21

Procedure:
Essentially following the procedures described for Intermediate 4, but using tert-butyl (6-bromo-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=348 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH2:11]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:25])[C@H:19]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH2:20])[CH3:12].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:11]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:25])[CH:19]([NH:20][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])[CH3:12]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CCOCCCNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOCCCNC(=O)C(CC(C)C)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C

Procedure:
2,4,6-trichloropyrimidine (1.0 g), L-leucine-3-ethoxypropylamide hydrochloride (17 mL of a 0.32 M solution in DMSO), and N,N-diisopropylethylamine (3.0 mL) were stirred for 24 h in 20 mL methyl sulfoxide at 60 C. The solution was cooled to room temperature and diluted with ethyl acetate (100 mL), then washed 4 times with 100 mL aliquots of a saturated aqueous solution of sodium chloride. Silica gel chromatography (gradient: 20–40–50–100% ethyl acetate in hexanes) followed by semi-preparative HPLC purification of mixed fractions provided 1.06 g of 2-(2,6-dichloropyrimidin-4-ylamino)-4-methylpentanoic acid (3-ethoxypropyl)amide as a colorless oil
Reaction SMILES: [F:1][C@@H:2]1[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][C:23](=[O:26])[CH:24]=2)[C:19]2[C@H:4]([C@H:5]3[C@:16]([CH3:28])([CH2:17][CH:18]=2)[C@@:8]([O:29][C:30](=[O:32])[CH3:31])([C:9](=[O:15])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:33])[CH2:6]3)[CH2:3]1>O1CCOCC1>[F:1][C@@H:2]1[C:25]2[C@:20]([CH3:27])([CH:21]=[CH:22][C:23](=[O:26])[CH:24]=2)[C:19]2[C@H:4]([C@H:5]3[C@:16]([CH3:28])([CH2:17][CH:18]=2)[C@@:8]([O:29][C:30](=[O:32])[CH3:31])([C:9](=[O:15])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:33])[CH2:6]3)[CH2:3]1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C

Procedure:
A mixture of 5.0 g of 6α-fluoro-16β-methyl-17α,21-diacetoxypregna-4,9(11)-diene-3,20-dione (prepared according to British Pat. No. 1,403,962), 100 ml of dioxane and 3.5 g of 2,3-dichloro-4,6-dicyano-1,4-benzoquinone is refluxed for 10 hours. The mixture is then cooled, filtered and evaporated to dryness. The residue is dissolved in acetone and this solution is then filtered through 100 g of alumina and concentrated to yield 6α-fluoro-16β-methyl-17α,21-diacetoxypregna-1,4,9(11)-triene-3,20-dione which is further purified by recrystallization from acetone:hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:26][CH:27]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: O=C1NCCCCC1NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCCCC1N(Cc1ccc(-n2cccn2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 83.8 %

Procedure:
4-Chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (0.16 g, 0.52 mmol), 1-[4-(bromomethyl)phenyl]-1H-pyrazole (0.26 g, 1.03 mmol), potassium carbonate (0.72 g, 5.17 mmol) and potassium iodide (0.02 g, 0.10 mmol) in 5 ml dimethylformamide were stirred at 65° C. for 5 hours. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate/heptane (90/10 to 1/0) yielded 0.20 g (87%) 4-chloro-N-(2-oxo-azepan-3-yl)-N-(4-pyrazol-1-yl-benzyl)-benzenesulfonamide as light yellow solid, MS: m/e (%)=459.1 (MH+, 100).
Reaction SMILES: [Cl:1][Si:2]([Cl:9])([Cl:8])[CH2:3][CH2:4][SiH:5]([Cl:7])[Cl:6].O1CCO[CH2:12][CH2:11]1>>[Cl:1][Si:2]([Cl:9])([Cl:8])[CH2:3][CH2:4][Si:5]([Cl:7])([Cl:6])[CH:11]=[CH2:12]
Reactant: C1COCCO1
Reactant: Cl[SiH](Cl)CC[Si](Cl)(Cl)Cl
Product: C=C[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl
Temperature: 0 °C

Procedure:
40.00 g (0.152 mol) 1,1,1,4,4-pentachloro-1,4-disilabutane was dissolved in 1000 ml 1,4-dioxane in a 2000 ml vessel. The solution was cooled down to 0° C. and acetylene was bubbled to solution until it was saturated. The solution thus obtained was slowly warmed up to room temperature. 1,4-dioxane was evaporated and obtained crude 1,1,1,4,4-pentachloro-1,4-disila-5-hexene was purified by distillation.
Reaction SMILES: CS(C)=O.[C:5]([C:9]1[C:10](=[O:30])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[N:28])[C:20]=3[CH:29]=2)[CH2:13][C:14]=1[OH:15])(=O)[CH2:6][CH3:7].Cl.[CH2:32]([O:34][NH2:35])[CH3:33].C([O-])(=O)C.[Na+]>Cl>[CH2:32]([O:34][N:35]=[C:5]([C:9]1[C:10](=[O:30])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[N:28])[C:20]=3[CH:29]=2)[CH2:13][C:14]=1[OH:15])[CH2:6][CH3:7])[CH3:33]
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)N(CC#N)C(=O)CO3)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)N(CC#N)C(=O)CO3)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 15 mL of methyl sulfoxide were added in sequence, 1.2 g (3.4 mmol) of 2-propionyl-3-hydroxy-5-(N-cyanomethyl-3-oxo-(2H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one, 0.42 g (4.4 mmol) of ethoxyamine hydrochloride an d 0.36 g (4.4 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 5 and 1/2 hours, becoming a clear amber solution. The reaction mixture was diluted with 100 mL of 0.1N HCl and extracted twice with 30 mL portions of ether. The extracts were combined, washed with water, then aqueous sodium chloride, dried over MgSO4 and filtered. Evaporation off of the solvent gave the crude product as a light amber oil which solidified upon standing. The crude solid was triturated in warm ether and the product isolated by filtration as a tan solid. The product was recovered in a yield of 1.1 g (81 percent of theoretical) and melted at 156°-159° C.; 1H NMR(CDCl3): d1.05-1.41 (m, 6H, both --CCH2CH3 's), 2.57-3.62 (m, 7H), 4.17 (q, J=7 Hz, 2H,--OCH2CH3), 4.70 (s, 2H, --OCH2C=O), 4.88 (s, 2H, --NCH2CN), 6.92-7.20 (m, 3H, aromatic H's), 15.10 (broad s, 1H, enol H); (Compound 4).
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:12][CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)CB([C:29]2[CH2:30][CH2:31][O:32][CH2:33][CH:34]=2)C1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:32]1[CH2:31][CH:30]=[C:29]([C:2]2[C:3]([O:8][CH:9]3[CH2:12][CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10]3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)NC1CC(Oc2ncccc2Br)C1
Reactant: CC1(C)CB(C2=CCOCC2)CC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC(Oc2ncccc2C2=CCOCC2)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of tert-butyl (3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (see PREPARATION 7B; 343 mg, 1 mmol), 4-(3,3,4,4-tetramethyl-borolan-1-yl)-3,6-dihydro-2H-pyran (2.27 mg, 1.1 mmol) and K3PO4 (424 mg, 2 mmol) in 1,4-dioxane (60 mL) and H2O (6 mL) was added Pd(dppf)Cl2 (36.6 mg, 0.05 mmol) then the reaction mixture was stirred at 110° C. under N2 for overnight. The reaction mixture was filtered through CELITE® and washed with CH2Cl2. The organic layer was concentrated and the crude product was purified by silica gel column to give tert-butyl (3-((3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate (242 mg, 0.7 mmol, yield 70%). ESI-MS (M+1): 347 calc. for C19H26N2O4 346
Reaction SMILES: [CH2:1]1[O:17][C:4]2([CH:8]([OH:9])[CH2:7][C:6]3([CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]3)[N:5]2[CH3:16])[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH2:2]1[O:3][C:4]2([CH:8]([O:9][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:7][C:6]3([CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]3)[N:5]2[CH3:16])[O:17][CH2:1]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1C2(CCC(=O)CC2)CC(O)C12OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2(CCC(=O)CC2)CC(OS(C)(=O)=O)C12OCCO2

Procedure:
To a mixture of 3-Hydroxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethylene ketal (1.0 g), triethylamine (1.73 mL) and methylene chloride (10 mL) was added methanesulfonyl chloride (950 mg) dissolved in methylene chloride (5 mL) in a dropwise fashion at 0° C. After 30 min the reaction mixture was washed with water, the organic layer dried over magnesium sulfate and the solvent was removed in vacuo. The resulting residue was filtered through silica gel with ethyl acetate as the eluent to afford 3-Mesyloxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethylene ketal as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([CH:8]=[CH:9][C:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH:14]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>O>[C:25]([O:1][CH2:2][C:3]1[S:7][C:6]([CH:8]=[CH:9][C:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH:14]=2)=[CH:5][CH:4]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: OCc1ccc(C=Cc2csc3ccccc23)s1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCc1ccc(C=Cc2csc3ccccc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a stirred solution of 3-[2-(5-hydroxymethyl-2-thienyl)ethenyl]-benzo[b]thiophene (5.35 g) and pyridine (50 ml) was added over 5 mins acetyl chloride (1.54 g). The mixture was stirred at ambient temperature overnight and was poured into water (500 ml). The mixture was extracted with dichlormethane, and the combined organic phase was washed with 5% aqueous hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by high performance liquid chromatography (silica gel, sample loaded in dichloromethane, eluted with 15% ethyl acetate in hexane.) The appropriate fractions were combined and concentrated. The residue was recrystallized from cyclohexane to afford 3.15 g (51%) of product, mp 66°-68° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH2:21])[N:11]=[CH:10][N:9]=1.CCN=C=NCCCN(C)C.Cl.[CH3:39][O:40][C:41]([C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46](O)=[O:47])=[O:42]>ClCCl.CN(C)C1C=CN=CC=1>[F:26][C:2]([F:25])([F:1])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][NH:7][C:8]1[N:9]=[CH:10][N:11]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:46]([C:45]2[CH:44]=[C:43]([CH:51]=[CH:50][CH:49]=2)[C:41]([O:40][CH3:39])=[O:42])=[O:47])[CH:13]=1
Reactant: Nc1ccc(Cl)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-6-(2-amino-5-chlorophenyl)pyrimidin-4-amine (500 mg, 1.32 mmol, 1.00 equiv) in dichloromethane (30 mL), EDC.HCl (380 mg, 1.98 mmol, 1.50 equiv), N,N-dimethylpyridin-4-amine (242 mg, 1.98 mmol, 1.50 equiv), and 3-(methoxycarbonyl)benzoic acid (357 mg, 1.98 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 30° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (2:1). The product was obtained as 400 mg (56%) of a yellow solid.