Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[C:8]3[CH2:31][S:30][CH2:29][CH2:28][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]3[CH2:31][S:30](=[O:42])[CH2:29][CH2:28][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)[N:12]=2)=[CH:32][CH:33]=1
Reactant: COc1cc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CSCC3)ccc1-n1cnc(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CS(=O)CC3)ccc1-n1cnc(C)c1
Yield: 18.7 %

Procedure:
4-(4-Fluorobenzyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (254 mg, 0.55 mmol) and meta-chloroperbenzoic acid (95 mg, 0.55 mmol) was slurrified in DCM (4 mL). Saturated NaHCO3 and water were added to the reaction mixture, the organic phase was separated and the solvent was evaporated. The crude product was purified on preparative HPLC yielding 4-(4-fluorobenzyl)-N-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine 6-oxide (49.0 mg, 18%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COCCOC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[NH:23][C:22](=O)[C@H:21]([CH3:25])[NH:20][C:19](=O)[C:18]=2[CH:27]=1.[OH-].[Na+]>O.O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[NH:23][CH2:22][C@H:21]([CH3:25])[NH:20][CH2:19][C:18]=2[CH:27]=1
Reactant: C[C@@H]1NC(=O)c2cc(Cl)ccc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: O
Product: C[C@H]1CNc2ccc(Cl)cc2CN1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a cooled (0° C.) suspension of 8.53 parts of lithium aluminum hydride in 392 parts of 1,2dimethoxyethane there were added dropwise 20.19 parts of (S)-7-chloro-3,4-dihydro-3-methyl-1H-1,4-benzodiazepine-2,5-dione (prepared as intermediate 43) under argon. The mixture was left at room temperature for 3 hours and was then refluxed for 29 hours. After cooling to 0° C., there were added successively a mixture of 8.5 parts of water and 22.7 parts of tetrahydrofuran, 9.86 parts of NaOH (15%) and 25.5 parts of water. The whole was stirred for 24 hours and was then filtered. The precipitate was refluxed in 178 parts of tetrahydrofuran for 5 min and filtered off again. The combined filtrates were evaporated and the residual oil crystallized on standing, yielding 18.4 parts (100%) of (S)-7-chloro2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepine (interm. 59).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:46][C:47]1[CH:48]=[C:49](O)[CH:50]=[CH:51][CH:52]=1.[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58]>C1C=CC=CC=1.CCOCC.C(O)C>[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58].[F:46][C:47]1[CH:52]=[C:51]([CH:50]=[CH:49][CH:48]=1)[O:20][C@@H:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cccc(F)c1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)/C=C/C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: CN1CC[C@@H](Oc2cccc(F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.79 g of diethyl azodicarboxylate in 125 ml of benzene is added, over a 90 minute period and at 5° C. under a nitrogen atmosphere, to a mixture of 4.72 g of cis-1-methyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 3.08 g of 3-fluorophenol and 125 ml of dry benzene. After stirring 18 hours at room temperature, the solid is filtered off and washed well with hexane. The filtrate is concentrated in vacuo to an oil, which is stirred 18 hours with hexane. The resulting mixture is filtered, and the resultant gummy solid is washed well with hexane. The filtrate is concentrated in vacuo to an oil which is taken up in ether and extracted with 2 N HCl solution. The acid extracts are then extracted with dichloromethane. The dichloromethane extracts are washed with 10% by weight aqueous NaOH solution, then with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated to afford an oil. This material is chromatographed on silica gel, using acetone as solvent. An oil is thus obtained, which is taken up in ether and treated dropwise with a solution of 1.55 g of fumaric acid in a mixture of 100 ml of ether and 50 ml of absolute ethanol. The solvent is removed in vacuo and the resulting gum is triturated to a solid with ether. The solid is filtered, washed with ether, and dried to afford a solid, mp s 160°, 161°-164° C. Recrystallization from ethyl acetate and then from a mixture of ethyl acetate and acetone affords trans-4-(3-fluorophenoxy)1-methyl-3-phenylpiperidine fumarate, mp s 155°, 156.5°-158° C.
Reaction SMILES: OO.[Cl:3][C:4]1[O:5][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:7][N:8]=1.C([O-])([O-])=[O:18].[K+].[K+]>CS(C)=O>[Cl:3][C:4]1[O:5][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]([NH2:13])=[O:18])=[CH:7][N:8]=1
Reactant: N#Cc1cccc(-c2cnc(Cl)o2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cccc(-c2cnc(Cl)o2)c1
Temperature: 25 °C
Yield: 111.7 %

Procedure:
30% H2O2 (28.7 mL, 281.0 mmol) was slowly added to a 0° C. mixture of 3-(2-chlorooxazol-5-yl)benzonitrile (8.20 gm, 40.10 mmol) and K2CO3 (3.88 gm, 28.10 mmol) in DMSO (75 mL). The ice bath was removed and the reaction mixture was stirred at rt. After 24 h the reaction mixture was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl (2×), dried over MgSO4, filtered and concentrated to give the product, 3-(2-chlorooxazol-5-yl)benzamide, (7.00 gm, 31.40 mmol, 78% yield) as a light yellow solid. Anal. Calcd. for C10H7ClN2O2 m/z 222.0, found: 223.0 (M+H)+. Crude product was used without purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][CH:6]=1.C1C(=O)N([Br:19])C(=O)C1>CC#N.CCOC(C)=O>[Br:19][C:6]1[S:5][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(C)cs1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C)c(Br)s1
Temperature: 50 °C
Yield: 50.5 %

Procedure:
The reaction solution of ethyl 4-methylthiazole-2-carboxylate of preparation 83 (240 mg, 1.40 mmol), NBS (277 mg, 1.14 mmol) in CH3CN (5 mL) was heated at 50° C. for overnight under nitrogen. ˜20% starting material was present by LCMS. Additional portion of NBS (70 mg) was added. The reaction solution was heated at 60° C. for 4 hr, diluted with EtOAc (30 ml), washed with water (2×20 mL), brine, dried over sodium sulfate and purified with a silica gel column by ISCO CombiFlash® chromatography eluting with 0%-20% EtOAc/Heptane to give the title compound as a yellowish oil (177 mg, 50.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH:25]4[CH2:27][CH2:26]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(=O)C.O>C(O)C.[Fe]>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reaction time: 0.25 h

Procedure:
30.00 g of 4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-6-nitroquinazoline are suspended in a mixture of 900 ml of ethanol, 120 ml of glacial acetic acid, and 300 ml of water. The suspension is refluxed, producing a clear solution. 17.24 g of iron powder is then carefully added batchwise, while the reaction mixture effervesces each time. About 15 minutes after it has all been added, a precipitate is formed. The reaction mixture is stirred for a further 15 minutes and then evaporated to dryness in vacuo. The residue in the flask is taken up in 1000 ml of methylene chloride/methanol (9:1) and combined with 30 ml of 33% aqueous ammonia solution. The iron slurry is filtered off and washed with methylene chloride:methanol (9:1). The brown filtrate is filtered through a silica gel pack and evaporated to dryness. The residue in the flask is stirred with 60 ml of diethylether, suction filtered and dried in the air.
Reaction SMILES: [CH2:1]([N:4]1[C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([O:18][CH:19]([CH3:21])[CH3:20])[CH:11]=[C:10]3[C:22]([F:25])([F:24])[F:23])[O:7][CH2:6][C@H:5]1[CH2:26][CH3:27])[CH:2]=[CH2:3].CCN(CC)CC>CCOC(C)=O.[Pd]>[CH2:26]([C@@H:5]1[CH2:6][O:7][C:8]2=[C:9]3[C:14](=[CH:15][CH:16]=[C:17]2[N:4]1[CH2:1][CH2:2][CH3:3])[N:13]=[C:12]([O:18][CH:19]([CH3:20])[CH3:21])[CH:11]=[C:10]3[C:22]([F:23])([F:25])[F:24])[CH3:27]
Reactant: C=CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1CC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1CC
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of (3R)-4-allyl-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.24 g, 0.63 mmol) and 0.1 mL Et3N in 3 mL EtOAc was added 10% Pd on carbon (0.08 g) and the mixture was vigorously stirred under H2 atmosphere for 1 h. The reaction mixture was filtered through Celite and concentrated to give 0.23 g (96% yield) of (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-4-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. Rf0.7 (9:1 hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.41 (d, 1H, J=9.1), 7.22 (d, 1H, J=9.1), 7.17 (s, 1H), 5.47 (septet, 1H, J=6.2), 4.30 (dd, ABX, 1H, J=10.5, 1.6), 3.86 (dd, ABX, 1H, J=10.5, 2.5), 3.47–3.35 (m, 1H), 3.23–3.11 (m, 2H), 1.70–1.55 (m, 4H), 1.38 (d, 3H, J=6.2), 1.37 (d, 3H, J=6.2), 1.02–0.91 (m, 6H).
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35]>>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[C:8]2[CH:12]=[C:11]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(C(CC)CC)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1sc(C(CC)CC)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 61.7 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-({cyclohexyl[2-ethyl-5-(1-ethylpropyl)thiophen-3-yl]methyl}amino)benzoic acid (250 mg) synthesized in Example 75 (2) and ethyl 3-(methylamino)propanoate (95.1 mg) to give the title compound (186 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)(=[O:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[Sn]Cl.CCCCCC.CCOC(C)=O>C(O)C>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:14])=[O:13]
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1OC
Agent: Cl[Sn]Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(NS(=O)(=O)c2ccccc2N)cc1OC
Yield: 87.8 %

Procedure:
A mixture of N-(3,4-dimethoxyphenyl)-2-nitrobenzenesulfonamide (2.5 g, 7.39 mmol) and SnCl2 (8.34 g, 36.9 mmol) in ethanol was heated at 100° C. for 5 h in a sealed tube with TLC monitoring (hexane:EtOAc, 1:1). After concentration in vacuo H2O (30 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by gradient flash chromatography, eluting with 20-25% EtOAc in hexane yielded the title compound (2.0 g, 6.49 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[S:12]([NH2:15])(=[O:14])=[O:13].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:18][N:19]([CH3:21])[CH:20]=[N:15][S:12]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:9]([O-:11])=[O:10])(=[O:14])=[O:13]
Reactant: COc1cccc([N+](=O)[O-])c1S(N)(=O)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1S(=O)(=O)N=CN(C)C

Procedure:
A solution of 2-methoxy-6-nitro-benzenesulfonamide (904 mg, 3.89 mmol) and N,N-dimethyl-formamide dimethyl-acetal (0.78 mL, 5.83 mmol) in DMF (20 mL) is heated for 30 min to 60° C. Evaporation of volatiles at 50° C. under reduced pressure, addition of MeOH to the solid residue, and filtration gives N-[1-dimethylamino-methylidene]-2-nitro-6-methoxy-benzenesulfonamide.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
Thionyl chloride (5 ml) and dimethylformamide (1 drop) were added to a solution of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzoic acid (1 g) in dichloromethane (5 ml), and the mixture was refluxed for 3 hours. After the reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzoyl chloride as crystals. Then, the crystals were dissolved in dichloromethane (14 ml). The solution was dropwise added to a solution of 4-aminopyridine (250 mg) and diisopropylethylamine (375 mg) in dichloromethane (6 ml) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. After the reaction, water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=15:1) to give 940 mg of (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[O:11][C:10](I)=[N:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[Cl-].[Li+].C[Sn](C)(C)[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>O1CCOCC1.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.[Cu]I>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[O:11][C:10]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)c1ccncc1
Reactant: CCOC(=O)c1nc(I)oc1Cc1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccncc2)oc1Cc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
A mixture of Ethyl 5-(4-chlorobenzyl)-2-iodo-1,3-oxazole-4-carboxylate (261 mg, 0.666 mmol), Tetrakis(triphenylphosphine)palladium(0) (38.5 mg, 0.0333 mmol), Copper(I) iodide (38.1 mg, 0.200 mmol) and Lithium chloride (84.8 mg, 2.00 mmol) under atmosphere of argon was dissolved in 1,4-Dioxane (18 mL) and Trimethyl(4-pyridyl)tin (207 uL, 1.20 mmol) was added. The mixture was heated at 100° C. for 2 h. The mixture was evaporated and the residue was purified by chromatography to afford Ethyl 5-(4-chlorobenzyl)-2-pyridin-4-yl-1,3-oxazole-4-carboxylate (0.133 g, 58.2%). LCMS (FA) ES+ 343.2, 345.1
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](=[O:44])[C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][CH:33]([C@H:36]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)[OH:44])[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Br)cc2)CC1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC([C@@H](O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To a solution of (+)-DIP-chloride™ (6.42 g, 20.0 mmol) in THF (10 mL) at 0° C. was added 4-(4-bromobenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.68 g, 10.0 mmol). The mixture was stirred at room temperature for 29 hours to give (R)-4-[(4-bromophenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (ee 82% determined by both chiral HPLC and Mosher ester) as a crystalline solid (2.22 g, 54%) following work-up and purification. This material was recrystallized (CH2Cl2/hexane) five times to provide a white solid (1.27 g, 35%) with 95% ee.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C(NC(C)C)(C)C.[C:34]([CH:36]1[CH2:38][CH2:37]1)#[CH:35]>CCOC(C)=O.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.[Cu]I>[CH:36]1([C:34]#[C:35][C:2]2[CH:15]=[CH:14][C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:9][CH:10]=4)[C@:5]4([CH2:25][O:24][C:23]([NH2:26])=[N:22]4)[C:4]=3[CH:3]=2)[CH2:38][CH2:37]1
Reactant: C#CC1CC1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(C#CC3CC3)ccc1O2
Temperature: 50 °C

Procedure:
A vial was charged with (4R)-2′-bromo-7′-(2,2-dimethylpropoxy)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (52.5 mg, 126 μmol), tetrakis(triphenylphosphine)palladium(0) (14.5 mg, 12.6 μmol), copper(I) iodide (4.79 mg, 25.2 μmol), diisopropylamine (629 μl, 126 μmol), and ethynylcyclopropane (32.0 μl, 377 μmol). The vial was heated in a 50° C. oil bath for 15 h. The reaction mixture was diluted with EtOAc and filtered through celite. The filtrate was evaporated, and the crude residue was purified by chromatography on a 12-g Redi-Sep column, eluting with 0-5% MeOH/DCM to give (4S)-2′-(cyclopropylethynyl)-7′-(2,2-dimethylpropoxy)spiro[1,3-oxazole-4,9′-xanthen]-2-amine as a white solid. MS m/z=403.2 [M+H]+. Calc'd for C25H27N2O3: 403.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([NH:13][CH:14]3[CH2:16][CH2:15]3)=O)=[CH:9][CH:8]=2)[N:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1COCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([NH:13][CH:14]3[CH2:16][CH2:15]3)=[S:28])=[CH:9][CH:8]=2)[N:6]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Solvent: C1CCOC1
Product: Nc1nc(-c2ccc(C(=S)NC3CC3)cc2)cs1
Temperature: 70 °C

Procedure:
A solution of 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide (265 mg, 1 mmol), in THF (5 mL), was treated with Lawesson's reagent (0.75 eq) and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. MS: 275.4 (M+H+).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccccn3)cc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCNCC2)c(Cl)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
According to Scheme 5 Step 4: HCl 4 M in dioxane (12.3 mmol, 3.07 mL) was added to a solution of tert-butyl 4-(2-chloro-4-(picolinamido)phenyl)piperazine-1-carboxylate (2.46 mmol, 1.02 g) in DCM (10 mL). The reaction mixture was stirred at room temperature overnight. After evaporation, DCM was added and then a NaOH 1 M solution. The aqueous phase was extracted with DCM. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (60:40) as eluent to afford N-(3-chloro-4-(piperazin-1-yl)phenyl)picolinamide (0.97 mmol, 308 mg, 40%) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[CH2:12]([O:14][C:15](=[O:28])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH2:26][CH2:25][CH2:24][C:23]=2Br)[CH:17]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)C.O.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>[CH2:12]([O:14][C:15](=[O:28])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH2:26][CH2:25][CH2:24][C:23]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:17]=1)[CH3:13]
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)c1cccc(C2=C(Br)CCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc(C2=C(c3ccccc3OC)CCC2)c1

Procedure:
A mixture of 2-methoxyphenylboronic acid (510 mg, 3.36 mmol), 3-(2-bromo-cyclopent-1-enyl)-benzoic acid ethyl ester (840 mg, 2.85 mmol), potassium carbonate (3.18 g, 23.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (370 mg, 0.32 mmol) was stirred and heated in 1:1 toluene/ethanol (30 ml) at 90° C. under nitrogen for 4 hours. After cooling the mixture was diluted with diethyl ether/water and the organic phase dried (MgSO4), evaporated to dryness and the residue purified on Biotage using ethyl acetate/iso-hexane (1:19) to yield the title compound as a colourless gum. (615 mg, 67%).