Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Cl.[CH3:14][NH:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]([CH3:14])[CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: CNC1CCOCC1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N(C)C2CCOCC2)cc1[N+](=O)[O-]
Yield: 18.5 %

Procedure:
To a stirred solution of 7.50 g (32.0(mmol) 4-bromo-2-nitro-anisole in 200 ml dioxane were added 6.86 g (45.0 mmol) methyl-(tetrahydro-pyran-4-yl)-amine hydrochloride (1:1), 1.13 g (3.0 mmol) 2-(dicyclohexylphosphino)biphenyl, 14.75 g (45.0 mmol) cesium carbonate, and 360 mg (2.0 mmol) palladium (II) acetate. The mixture was heated at reflux for 72 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/2 hexane/ethyl acetate) afforded 1.59 g (18.5%) (4-methoxy-3-nitro-phenyl)-methyl-(tetrahydro-pyran-4-yl)-amine as a red solid. ES-MS m/e (%): 267 (M+H+, 100).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C(=O)N([Br:18])C(=O)C1>CC(O)=O>[Br:18][C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: c1ccc2cnccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Brc1cc2ccccc2cn1
Temperature: 100 °C
Yield: 23.8 %

Procedure:
To a stirred solution of isoquinoline (24 g, 186 mmol) in AcOH (50 mL) was added NBS (36.2 g, 204.6 mmol) at RT and the reaction mixture was heated to 100° C. overnight. Then it was cooled to RT and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (5% EtOAc:Hexanes) to furnish the title compound (9.2 g, 23.8%) as an oil.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][C:11]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C1COCC1.OS([O-])(=O)=O.[K+]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:34](=[O:36])[CH3:35])[CH2:16]3)=[N:12][C:11]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccc(-c2[nH]c(C3CCCNC3)nc2-c2ccncc2)cc1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)C1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a stirring solution of 3-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]piperidine dihydrochloride (0.76 mmol, 0.3 g) in THF (5.0 mL) was added triethylamine (3.3 mmol, 0.33 g) and acetyl chloride (2.3 mmol, 0.18 g). The reaction was stirred at room temperature for 1H, diluted with 10% KHSO4 (50 mL) and extracted with ethyl acetate (2×50 mL). The organics were combined, washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica, eluting with 3% MeOH:CH2Cl2. The pure fractions were collected and evaporated under reduced pressure. The resulting film was evaporated from CH2Cl2 :hexanes to give 0.2 g of the title compound as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[N:9][C:8]([O:17][CH3:18])=[CH:7][CH:6]=2.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C1COCC1.CN(C=O)C.CC(=O)OCC>[C:25]([Si:28]([CH3:30])([CH3:29])[O:15][CH2:14][CH:13]([OH:16])[CH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:17][CH3:18])[N:9]=2)[N:4]=[CH:3][C:2]=1[F:1])([CH3:27])([CH3:26])[CH3:24]
Reactant: COc1ccc2ncc(F)c(CC(O)CO)c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(F)c(CC(O)CO[Si](C)(C)C(C)(C)C)c2n1
Yield: 86.5 %

Procedure:
A solution of rac-3-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-propane-1,2-diol (3.6 g, 14.2 mmol, prepared as described in WO 2008/003690) in THF (150 mL) and DMF (10 mL) was treated with imidazole (1.07 g, 1.1 eq.) and a solution of TBDMSCl (2.15 g, 1 eq.) in THF (10 mL) at 0° C., the mixture was stirred at rt for 24 h, diluted with EA and washed with water (2×100 mL) and brine, dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 1:1) to give the desired intermediate as a colourless solid (4.5 g, 87% yield).
Reaction SMILES: Br[C:2]1[C:3]2[S:9][CH:8]=[C:7]([Br:10])[C:4]=2[S:5][CH:6]=1.[C:11]([O:15][C:16]([N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][N:20]=[C:19]1[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(OC(N1CCC[C@H]1C1NC(C2SC3C=C(C4C=CC(C5NC([C@@H]6CCCN6C(=O)[C@@H](NC(OC)=O)C(C)C)=NC=5)=CC=4)SC=3C=2)=CN=1)=O)(C)(C)C>>[C:11]([O:15][C:16]([N:18]1[CH:22]=[C:21]([C:2]2[C:3]3[S:9][CH:8]=[C:7]([Br:10])[C:4]=3[S:5][CH:6]=2)[N:20]=[C:19]1[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1csc2c(Br)csc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([C@@H]2CCCN2C(=O)OC(C)(C)C)n1C(=O)OC(C)(C)C
Agent: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4sc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4s3)cc2)[nH]1)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2csc3c(Br)csc23)cn1C(=O)OC(C)(C)C

Procedure:
Compound 76 was synthesized from 3,6-dibromothieno[3,2,b]thiophene (6.71 mmol) and compound 61 (6.71 mmol), following the procedure as described for compound 63 to give compound 76 as a yellow cristal. MS (ESI, EI+) m/z=554-556 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:13]P(=O)(OCC)OCC.[H-].[Na+].[CH3:24][O:25][CH2:26][O:27][C:28]1[C:32]([CH:33]=O)=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1.O>O1CCCC1>[CH3:24][O:25][CH2:26][O:27][C:28]1[C:32](/[CH:33]=[CH:13]/[C:3]2[N:4]=[C:5]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)[S:6][C:2]=2[CH3:1])=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1nc(N2CCCCC2)sc1C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1nc(N2CCCCC2)sc1C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
To a solution of diethyl {[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]methyl}phosphonate (1.26 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.17 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.88 g) was added to the reaction mixture, and the mixture was heated under reflux for 2.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (5:95-25:75, v/v) to give 1-(4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazol-2-yl)piperidine as a yellow oil (0.69 g, yield 44%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].C1(N)CCCCC1.C(N)C(C)C>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccccc1-c1ccc(C(=O)CCC(=O)O)cc1
Solvent: NC1CCCCC1
Solvent: CC(C)CN
Product: CC(=O)Nc1ccccc1-c1ccc(C(O)CCC(=O)O)cc1
Yield: 60 %

Procedure:
Prepared analogous to Example 25 from 4-(2'-acetamido-4-biphenylyl)-4-oxo-butyric acid (m.p. 209°-210° C.). Melting point of the cyclohexylamine salt: 143° C.; melting point of the isobutylamine salt: 125°-126° C.; yield: 60% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[C:20](=[O:24])[N:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:28])[F:27]
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1Cc1cccnc1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-2(1H)-pyrimidinone and 3-(chloromethyl)pyridine hydrochloride. LC-MS (ESI): m/z 502 [M+H]+; 4.30 min (ret time).
Reaction SMILES: [C:1]([C@:3]1([OH:23])[C@H:8]([CH3:9])[CH2:7][C@H:6]2[C@H:10]3[C:19](=[CH:20][CH2:21][C@:4]12[CH3:5])[C:18]1[CH2:17][CH2:16][C:15](=[O:22])[CH2:14][C:13]=1[CH2:12][CH2:11]3)#[CH:2].C(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[C:1]([C@:3]1([OH:23])[C@H:8]([CH3:9])[CH2:7][C@H:6]2[C@H:10]3[C:19]([CH:20]=[CH:21][C@:4]12[CH3:5])=[C:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)#[CH:2]
Reactant: C#C[C@]1(O)[C@H](C)C[C@H]2[C@@H]3CCC4=C(CCC(=O)C4)C3=CC[C@@]21C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: C#C[C@]1(O)[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C=C[C@@]21C
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.4 %

Procedure:
1.9 g of 17α-ethynyl-17β-hydroxy-16α-methyl-5(10),9(11)-estradien-3-one is dissolved in 60 ml of benzene and 20 ml of methylene chloride and combined at room temperature dropwise with a solution of 3.5 g of dichlorodicyano-p-benzoquinone. The mixture is agitated for 5 hours at room temperature and worked up as described in Example A. Crystallization of ether yields 1.65 g of 17α-ethynyl-17β-hydroxy-16α-methyl-4,9,11-estratrien-3-one, m.p. 176°-179° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH:23]1([CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCCOCC1CCCCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCC2CCCCC2)CC1
Yield: 48.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.50 g) as starting compound and 5-(cyclohexylmethoxy)pentyl bromide (1.30 g) were reacted and treated in the same manner as in Example 168 to give 0.51 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(cyclohexylmethoxy)pentyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [OH:1][CH:2]([CH:24](CC1C=CC=CC=1)[O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)=[CH:28][CH:27]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1)=[O:8].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:1][CH:2]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)=[CH:28][CH:27]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: [H][H]
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCC(O)C(Cc2ccccc2)Oc2ccc(CCOCC3CC3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCC(O)COc2ccc(CCOCC3CC3)cc2)cc1
Yield: 79.9 %

Procedure:
In a manner similar to that of Example 1 (iv), 6-[4-[3-[2-hydroxy-3-[4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-N-benzylpropylamino]propionamido]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (22 g) in ethanol (350 ml) was agitated for 5 hours in a hydrogen atmosphere at 344 kPa (50 p.s.i.) in the presence of palladium hydroxide on charcoal (5 g). The catalyst was removed by filtration and solvent removed under reduced pressure to afford the title compound as a yellow foam (15 g). To a solution of this in dichloromethane (800 ml) was added a solution of methanesulphonic acid (8.60 g) in dichloromethane (100 ml) with stirring. The mixture was evaporated under reduced pressure to give a yellow solid which was crystallised from isopropanol/ethanol (50:50; 400 ml) to yield the title compound as the monomethanesulphonate salt (16 g), m.p. 185°-6° C. Conversion of this material (from another run) by base formation and retreatment with methanesulphonic acid afforded material with m.p. 186°-7° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Yield: 71.3 %

Procedure:
A solution of 190 mg (0.6 mmol) of 2-[3-(3-nitrophenyl)-propyl]-isoindole-1,3-dione in 20 ml of ethanol was treated with 50 mg of 10% palladium on charcoal and shaken in an atmosphere of hydrogen for 2 hours. The mixture was filtered and the filtrate evaporated to give 120 mg (71%) of 2-[3-(3-aminophenyl)-propyl]-isoindole-1,3-dione as a yellow oil. [Mass spectrum (ESI) MH+ =281].
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([N+:21]([O-])=O)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([Cl:19])=[CH:11][CH:10]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([Cl:19])=[CH:11][CH:10]=1)[NH2:21]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Yield: 91.6 %

Procedure:
Into a solution containing 13.8 grams (38.1 mmol) of 3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethyl-1-nitrobenzene prepared in Part A in 400 milliliters of toluene was added 2.0 grams of a 5% platinum on carbon catalyst. The resulting mixture was placed in a one liter rocking Parr hydrogenation vessel. Hydrogen was introduced into the vessel to a pressure of 120 psi. The hydrogen pressure was maintained between 100-120 psi until hydrogen uptake ceased. The contents of the reactor vessel were then removed and filtered. Removal of the solvents from the filtrate afforded 11.6 grams of 3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylaniline as a white solid having a melting point of 118° C.-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[NH:25][N:24]=NN=2)[CH:3]=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[C:4]([C:21]2[O:29][C:28]([CH2:27][Cl:26])=[N:24][N:25]=2)[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(Br)cc32)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(Br)cc32)cc1
Temperature: 130 °C
Yield: 68.1 %

Procedure:
A stirred mixture of 6-bromo-1-[(4-methylphenyl)sulfonyl]-4-(1H-tetrazol-5-yl)-1H-indazole (0.237 g, 0.565 mmol) and chloroacetyl chloride (0.136 ml, 1.696 mmol) in toluene (3 ml) was heated at 130° C. in the microwave (biotage initiator) for 20 mins. The solvent was removed in vacuo and triturated with ether (10 ml) to give the title compound as a colourless solid (0.18 g).
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6]([C:8]1[N:9]=[N:10][C:11]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:12][CH:13]=1)=[S:7])[CH3:4].N1C=CC=CC=1.NOS(O)(=O)=O>C(O)C.CO>[CH3:4][C:3]1[N:5]=[C:6]([C:8]2[N:9]=[N:10][C:11]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[CH:12][CH:13]=2)[S:7][N:2]=1
Reactant: CC(=NC(=S)c1ccc(SCCCCOc2cccc(C(F)(F)F)c2)nn1)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1nsc(-c2ccc(SCCCCOc3cccc(C(F)(F)F)c3)nn2)n1
Yield: 26.1 %

Procedure:
A mixture of intermediate 13 (0.009 mol) and pyridine (0.02 mol) in ethanol (80 ml) was stirred. A mixture of hydroxylamine-O-sulfonic acid (0.01 mol) in methanol (20 ml) was added. The mixture was stirred overnight. The solvent was evaporated. The residue was taken up in DCM. The organic solution was washed with a diluted NaOH solution and with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent:DCM). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried, yielding 1 g (26%) of 3-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[[4-[3-(trifluoromethyl)phenoxy]butyl]thio]pyridazine (compound 94).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24](O)=[O:25].Cl.[F:28][C:29]1[CH:30]=[C:31]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:32]=[CH:33][C:34]=1[F:35]>>[F:28][C:29]1[CH:30]=[C:31]([CH:36]2[CH2:41][CH2:40][N:39]([C:24]([C:11]3[CH:12]=[N:13][C:14]4[N:15]([N:16]=[CH:17][C:18]=4[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]=3[NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:25])[CH2:38][CH2:37]2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: Fc1ccc(C2CCNCC2)cc1F
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc12
Yield: 70.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2,5-dimethylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (220 mg, 0.62 mmol) obtained in step 2 and 4-(3,4-difluorophenyl)piperidine hydrochloride (WO2004/069798, 217 mg, 0.93 mmol), the title compound (232 mg, 70%) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B(O)O)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[CH:23][C:24]([NH2:29])=[N:25][C:26]=2[C:27]#[N:28])=[C:17]([F:30])[CH:16]=1>>[NH2:29][C:24]1[N:25]=[C:26]([C:27]#[N:28])[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][C:17]=2[F:30])=[N:22][CH:23]=1
Reactant: N#Cc1nc(N)cnc1-c1ccc(Br)cc1F
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2ncc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 using 2-(methylsulfonyl)phenylboronic acid and 5-(4-bromo-2-fluorophenyl)-6-cyanopyrazin-2-amine. MS (ESI): mass calcd. for C18H13FN4O2S, 368.07; m/z found, 369.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.13 (dd, J=8.0, 1.4, 1H), 7.84-7.77 (m, 1H), 7.76-7.70 (m, 1H), 7.69-7.62 (m, 1H), 7.51 (dd, J=7.6, 1.4, 1H), 7.46 (dd, J=11.0, 1.6, 1H), 7.42-7.35 (m, 3H), 2.97 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(c2ccccc2)(N2CCCCC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC(c2ccccc2)(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
The cyclohexanone derivative of Example 3 (1 g; 3.9 mmole) was dissolved in 50 ml of methanol inside a three-necked round bottom flask equipped with a condenser. 0.5 g of sodium borohydride was added portionwise to this solution. After addition, the mixture was stirred at room temperature for 2 hours. The methanol was removed under reduced pressure to give a solid residue. The solid residue was extracted with ethyl acetate. The ethyl acetate extracts were combined and washed once with water and dried over anhydrous sodium sulfate. Ethyl acetate was removed to give a solid material. The solid was recrystallized from hexane/ether (1:1; v/v) to give the desired cyclohexanol derivative as a white crystalline solid (0.89 g; 85% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH:29]4[CH2:30][O:31][CH2:32][CH:25]3[CH2:26][O:27][CH2:28]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.C12OC(CC1)CN(C1N=C(C3C=CC(N)=CC=3)N=C3N(CC(F)(F)F)N=CC=13)C2.Cl.C12OC(CC1)CNC2>>[CH:25]12[N:24]([C:12]3[N:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)[N:15]=[C:14]4[N:16]([CH2:19][C:20]([F:21])([F:23])[F:22])[N:17]=[CH:18][C:13]=34)[CH:29]([CH2:28][O:27][CH2:26]1)[CH2:30][O:31][CH2:32]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3C4COCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: C1CC2CNCC1O2
Agent: Cl
Agent: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1
Product: Nc1ccc(-c2nc(N3C4COCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
4-(4-(3,7-Dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline was prepared from 9-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane according to the method used for 4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine, except in step 5,3,7-dioxa-9-azabicyclo[3.3.1]nonane formate replaced 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:35]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:36]C([O-])=O.[K+].[Cl-].[Mg+2].[Cl-].Cl>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14])[C:10](=[O:12])[CH2:36][C:35]([O:41][CH2:42][CH3:43])=[O:40])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
A solution of (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)butanoic acid (615a) (14.52 g, 43.5 mmol) in THF (100 mL) was treated with 1,1′-carbonyldiimidazole (7.41 g, 45.7 mmol) and stirred at RT for 30 min and then at 60° C. for 2 h. The mixture was cooled to RT and then potassium ethyl malonate (Aldrich) (14.82 g, 87 mmol) and magnesium chloride (Aldrich) (8.29 g, 87 mmol) were added. The resulting suspension was stirred at 50° C. for 20 h. The suspension was concentrated and then extracted into EtOAc (2×100 mL) from saturated aq. brine (500 mL) containing 5 M aq. HCl (40 mL, 200 mmol). The combined organic extracts were washed with saturated aq. NaHCO3 (2×100 mL), dried (Na2SO4), and concentrated to give a pale yellow gum. The crude product was purified by flash chromatography on silica gel (160 g) eluting with DCM to give (4R,5S)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxohexanoate (165) (11.49 g, 28.5 mmol, 65% yield) as a colorless oil. LC-MS m/z 426.0, [M+Na]+.