Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:6]=2[CH3:26])[CH2:3][CH2:2]1.C(O[CH:30]=[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33])C>>[CH:1]1([N:4]([CH:30]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:6]=2[CH3:26])[CH2:2][CH2:3]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(NC3CC3)c2C)CC1
Product: CCOC(=O)C(=CN(c1c([N+](=O)[O-])cc(F)c(N2CCN(C(=O)OCC)CC2)c1C)C1CC1)C(=O)OCC
Yield: 51.9 %

Procedure:
To N-cyclopropyl-2-methyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline (7.1 g) is added diethyl ethoxymethylenemalonate (4.6 g), and the mixture is reacted at 150°-170° C. for 17 hours. After cooling, the solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography (solvent, dichloromethane:n-hexane=2:1→dichloromethane) to give diethyl [N-cyclopropyl-N-[3-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-4-fluoro-6-nitrophenyl]aminomethylene]malonate (5.4 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].I[CH2:10][C:11]([OH:13])=[O:12]>CN(C=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:10][C:11]([OH:13])=[O:12])[CH3:2]
Reactant: CCOCCO
Reactant: O=C(O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCOCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
2-Ethoxyethanol (0.88 mL, 11 mmol) and sodium hydride (60% in oil, 1.08 g, 27 mmol) were stirred in DMF (20 mL) for 5 min. Iodoacetic acid (2.02 g, 10.9 mmol) was dissolved in DMF (20 mL) and added dropwise to the suspension. The thick orange suspension was stirred at rt for 3 hours. The reaction was quenched by slowly adding water (10 mL), followed by hydrochloric acid (4 M, 5 mL). The reaction mixture was extracted with dichloromethane (3×50 mL) and the combined organic layers dried over sodium sulfate, filtered and evaporated yielding a clear oil. The residue was purified by distillation under reduced pressure to give the product (1.1 g, 68%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[NH:6]1)=[O:4].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][CH3:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N=C=NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]1[C:25](=[O:26])[C@@H:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH3:29])=[O:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C1Cc2cc(OC)ccc2N1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC)cc2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-methoxyindoline-2(R/S)-carboxylic acid methyl ester (1.5 g, 7.23 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (1.62 g, 7.96 mmol) dissolved in dried dichloromethane (15 ml) under nitrogen at 10° C., was added diisopropylcarbodiimide (1.00 ml, 7.96 mmol). The mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was evaporated under vacuum to afford a brown solid which was purified by column chromatography on silica gel using dichloromethane as eluent. A white foam was obtained which was the mixture of two diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:22]([C:23]#[N:24])[C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:25])[F:26])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(C=C(C#N)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
4-Formylbenzoic acid methyl ester (8.60 g, 52.39 mmol) was dissolved in warm methanol (50 mL) and 4-trifluoromethoxyphenylacetonitrile (10.54 g, 52.39 mmol) was added. The mixture was stirred and potassium carbonate (7.75 g, 56.05 mmol) was added. The mixture was heated to 60° C. and more methanol (20 mL) was added and stirring was continued for 1 hour. The precipitate was filtered off and added in small portions to a stirred and cold 4 M hydrochloric acid solution. The precipitate was filtered off, washed with water and dried to afford 14.4 g (79%) of 4-[2-cyano-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].C([O:34]CCOCCO)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]([NH2:29])=[O:34])[CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N2CCN(CCCCc3c[nH]c4ccc(C#N)cc34)CC2)c1
Reactant: CCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(N2CCN(CCCCc3c[nH]c4ccc(C(N)=O)cc34)CC2)c1
Reaction time: 3 h

Procedure:
A mixture of 30.6 g of 3-[4-(4-m-methoxyphenylpiperazino)butyl]-5-cyanoindole, 27.1 g of NaOH, 520 ml of water and 420 ml of diethylene glycol monoethyl ether is stirred for 3 hours at a bath temperature of 140°. It is cooled and worked up in a conventional manner, and 3-[4-(4-m-methoxyphenylpiperazino)butyl]indole-5-carboxamide is obtained.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[C:27]4([CH3:35])[CH3:34])=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[CH3:36]N(C=O)C.[H-].[Na+].CI>O>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([CH3:36])[C:28](=[O:33])[C:27]4([CH3:35])[CH3:34])=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC1(C)C(=O)Nc2ccc(COC(=O)N3CCN(C[C@@]4(C)Cn5cc([N+](=O)[O-])nc5O4)CC3)cc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)C(C)(C)c2cc(COC(=O)N3CCN(C[C@@]4(C)Cn5cc([N+](=O)[O-])nc5O4)CC3)ccc21
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a mixture of 3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (300 mg, 0.62 mmol) and DMF (3 ml), sodium hydride (27 mg, 0.68 mmol) was added followed by stirring for 30 minutes with cooling on ice-bath. To the reaction mixture, methyl iodide (97 mg, 0.68 mmol) was added followed by stirring at room temperature for 2 hours. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water twice and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to afford 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (140 mg, 45%) as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]3[C:14](=[C:15]([CH2:19][OH:20])[C:16]=2[CH2:17][OH:18])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29]>ClCCl>[CH:28]([NH:31][C:32](=[O:18])[OH:33])([CH3:30])[CH3:29].[CH:28]([NH:31][C:32](=[O:18])[OH:33])([CH3:30])[CH3:29].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]3[C:14](=[C:15]([CH2:19][OH:20])[C:16]=2[CH2:17][OH:18])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)N=C=O
Agent: OCc1c(CO)c(-c2ccc(Cl)c(Cl)c2)n2c1CCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)O

Procedure:
A solution of 2,3-dihydro-5-(3',4'-dichlorophenyl)-6,7-bis(hydroxymethyl)-1H-pyrrolizine (6.244 g, 0.02 mol) and triethylamine (0.5 mL) in dichloromethane (45 mL) was treated with isopropyl isocyanate (7 mL, ca. 10 equiv) and refluxed for 1.5 h. The mixture was concentrated to dryness in vacuo and the off-white residue was crystallized from ethyl acetate-isopropyl ether to give about an 81% yield of 2,3-dihydro-5-(3',4'-dichlorophenyl)-6,7-bis(hydroxymethyl)-1H-pyrrolizine Bis(isopropylcarbamate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH:24]=3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[H][H]>CC(O)=O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2oc(-c3ccc(F)cc3)nc2-c2ccccn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2oc(-c3ccc(F)cc3)nc2-c2ccccn2)CC1

Procedure:
A mixture of tert-butyl 4-[2-(4-fluorophenyl)-4-(pyridin-2-yl)-1,3-oxazol-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate (0.2 g, 0.475 mmol) and Pd/C (0.10 g, 10%, 0.095 mmol) in AcOH (20 ml) was hydrogenated on a shaker at 45 psi hydrogen for 2 days. Then the catalyst was filtered off, and the filtrate was concentrated. The resulting residue was purified by reverse phase HPLC to give the title compound. LC-MS m/e 424.25 [M+1]+.
Reaction SMILES: [CH3:1][P:2]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[O:3]C>Cl>[CH3:1][P:2]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:3])[OH:5]
Reactant: COP(C)(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Product: CP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A solution of 1 g of methyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate in 10 ml of 6N HCl is refluxed for 16 hours. After cooling, the solid product is collected by filtration and dried, yielding P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]/[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[C:18](OCC)(OCC)(OCC)[CH3:19]>>[CH3:18][C:19]1[N:8]2[C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:16][N:17]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCCCn1/c(=N\N)[nH]c(=O)c2[nH]cnc21
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(C)nnc12
Temperature: 100 °C
Yield: 91.6 %

Procedure:
A mixture of (2Z)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (3.1 g, 0.013 mol) and triethyl orthoacetate (20 mL, 0.1 mol) was heated at 100° C. for 3 h. The suspension was cooled to room temperature and the solid formed was filtered and washed with DCM/Hex (1:1) mixture to provide the desired product (3.1 g, 91% yield). LCMS calculated for C12H17N6O (M+H): 261.1. Found: 261.1.
Reaction SMILES: C([NH:8]CC(O)=O)(OC(C)(C)C)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20]1)=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH3:8].[CH3:13][C:14]1[CH:15]=[C:16]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20]1)=[O:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cc1cc(C)cc(C(=O)N2CCNC(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N
Reaction time: 60 h

Procedure:
To a solution of BOC glycine (0.918 g, 5.24 mmol), (+)-(3,5-dimethylbenzoyl)-3-(3,4-dichlorophenyl)piperazine (enantiomer B)(1.80 g, 4.95 mmol) (prepared in Example 19), DEC (0.983 g, 5.13 mmol), HOBT (0.687 g, 5.07 mmol) and Hunig's base (0.92 mL, 5.1 mmol) in CH2Cl2 (100 mL) was left stirring for 2.5 d. The reaction mixture was added to CH2Cl2 (200 mL) and washed with sat. NaHCO3 (3×100 mL), brine (100 mL), dried with MgSO4 and concentrated. The crude material was treated with MeOH saturated HCl (25 mL) for 10 h and concentrated. The resulting residue suspended in 0.3N NaOH (150 mL) and extracted with CH2Cl2, (3×50 mL). The combinded organic layers were washed with brine (50 mL), dried with MgSO4, concentrated, and purified by flash chromatography on silica gel, eluting with 20:1:0.2 CH2Cl2 /MeOH/conc. aq. NH3 to give 0.95 g of the titled product as a white solid. HRMS (FAB, M+H+); m/e calc'd [C31H24Cl2N3O2 ]+ : 420.1246 found 420.1254.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][C:9](=[O:11])[O:8][C:7](=O)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:14][OH:15]>N1C=CC=CC=1>[OH:15][N:14]1[C:9](=[O:11])[CH2:10][C:5]2([CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:6][C:7]1=[O:8]
Reactant: NO
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CC2(CCCC2)CC(=O)N1O

Procedure:
A solution of 8-oxaspiro[4.5]decan-7,9-dione (5.0 g) and hydroxylamine hydrochloride (2.1 g) in 75 ml of anhydrous pyridine was heated to 80° C. with stirring under N2.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15](S(C3C=CC=CC=3)(=O)=O)[CH:14]=2)[CH:4]=1.[C:31]1([Mg]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)C.[OH-].[Na+].Cl>COCCOC>[C:31]1([C:7]2[NH:8][C:3](=[O:2])[CH:4]=[C:5]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[N:6]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(S(C)(=O)=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCOC
Product: O=c1cc(-c2c[nH]c3ncccc23)nc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of EXAMPLE 1B (89 mg, 0.20 mmol) in 1,2-dimethoxyethane (2 mL) at 0° C. was added dropwise 3M phenylmagnesium bromide in diethyl ether (0.133 mL, 0.40 mmol)). The mixture was slowly warmed to room temperature and stirred for 15 minutes. To the solution was added dropwise 1M aqueous sodium hydroxide (2 mL, 2 mmol). The mixture was stirred at room temperature for 1 day and concentrated. The residue was dissolved in 12% aqueous HCl (0.62 mL, 2.25 mmol) and heated at 90° C. for 4 hours. The mixture was concentrated and purified by reverse phase HPLC to provide the title compound. MS (ESI) m/e 289 (M+H)+; 1H NMR (DMSO-d6) δ 6.78 (s, 1H), 7.25 (dd, J=7.93, 4.58 Hz, 1H), 7.54-7.65 (m, 3H), 8.24-8.34 (m, 3H), 8.44 (s, 1H), 8.69-8.75 (m, 1H), 12.32 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C@:12]12[CH2:19][O:18][CH2:17][C@H:16]1[CH2:15][O:14][N:13]2[C@@H](C1C=CC=CC=1)CC.C(O)CC.[ClH:33]>[Pd].[Cl-].[Zn+2].[Cl-].O>[ClH:33].[NH2:13][C@:12]1([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][C:2]=2[F:1])[C@H:16]([CH2:15][OH:14])[CH2:17][O:18][CH2:19]1
Reactant: CC[C@H](c1ccccc1)N1OC[C@@H]2COC[C@@]21c1cc(NC(C)=O)ccc1F
Agent: [Pd]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCCO
Product: CC(=O)Nc1ccc(F)c([C@]2(N)COC[C@H]2CO)c1
Temperature: 50 °C

Procedure:
A mixture of N-(4-fluoro-3-((3aS,6aS)-1-((R)-1-phenylpropyl)hexahydrofuro[3,4-c]isoxazol-6a-yl)phenyl)acetamide (1.0 equiv., volumes are in mL/g of this compound), zinc chloride (0.2 equiv), and a 20% weight loading of water wet, sulfided 5% Pd/C catalyst is slurried in a mixture 1-propanol (4 mL/g), water (3.8 mL/g), and HCl (0.9 equiv, 33 weight % in water). The mixture is heated at 50° C. under hydrogen pressure (about 300-400 kPa) for about 16 hours. The catalyst is removed by filtration at about 50° C. and the filter cake is rinsed with 1-propanol (2.9 mL/g). Most of the water is removed from combined filtrates by azeotropic distillation using additional 1-propanol (10.5 mL/g). Additional HCl (0.1 equiv., 33 weight % in water) is added to the mixture and the solids are collected by filtration, rinsed twice with 1-propanol (1 mL/g) and dried to give the title compound. LC-MS (m/z): 269 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24]([OH:26])=O)[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2].[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24]([NH:35][CH3:34])=[O:26])[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)O)ccc2-n2cccc23)cc1OC
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)NC)ccc2-n2cccc23)cc1OC

Procedure:
A solution of 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylic acid (40 mg, 0.090 mmol), HATU (34 mg, 0.090 mmol), N-methylamine hydrochloride (6.0 mg, 0.090 mmol) and iPr2NEt (62 μL, 0.36 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O). Pure fractions were combined and evaporated to yield 1′-(4-ethyl-3-methoxybenzoyl)-N-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxamide. ESI-MS m/z calc. 459.5, found 460.5 (M+1)+; Retention time: 1.73 minutes (3 min run).
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([OH:18])[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([Cl:17])[N:11]=2)[CH2:4]1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:30])[CH3:29].Cl.[OH-].[Na+]>ClCCl>[Cl:17][C:12]1[N:11]=[C:10]([NH:9][C@H:5]2[CH2:6][CH2:7][CH2:8][C@:3]([CH2:2][NH:1][C:28](=[O:30])[CH3:29])([OH:18])[CH2:4]2)[C:15]([F:16])=[CH:14][N:13]=1
Reactant: NC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reaction time: 0.08 h

Procedure:
(1S,3S)-1-(aminomethyl)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanol, 46b, (0.19 g, 0.69 mmol) was dissolved in dichloromethane (15 mL) and treated with DIPEA (1.20 mL, 6.91 mmol) and acetyl chloride (0.10 mL, 1.38 mmol). After 5 minutes, the reaction mixture was diluted into 1N HCl (30 mL), and the aqueous layer was brought to a basic pH by addition of 1N NaOH. The resulting suspension was extracted with dichloromethane (50 mL). The organic layer was dried on Na2SO4 and concentrated in vacuo to provide the crude product, which was purified by silica gel chromatography (20-100% EtOAc/hexanes gradient) to afford 195 mg of N-{[(1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclo-hexyl]methyl}acetamide as a white foamy solid. LCMS RT=2.82 (M+1) 317.33.
Reaction SMILES: CN1CCCNCC1.ClC1C=CC(S(NC2C=CC=CC=2)(=O)=O)=CC=1[N+]([O-])=O.C([O-])([O-])=O.[K+].[K+].[CH3:35][N:36]1[CH2:42][CH2:41][CH2:40][N:39]([C:43]2[CH:48]=[CH:47][C:46]([S:49]([NH:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)(=[O:51])=[O:50])=[CH:45][C:44]=2[N+:59]([O-])=O)[CH2:38][CH2:37]1.O.NN.Cl.CCOCC>C(Cl)Cl.CCO.C1COCC1.C(OCC)C.CCOC(C)=O.[Ni]>[NH2:59][C:44]1[CH:45]=[C:46]([S:49]([NH:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)(=[O:50])=[O:51])[CH:47]=[CH:48][C:43]=1[N:39]1[CH2:40][CH2:41][CH2:42][N:36]([CH3:35])[CH2:37][CH2:38]1
Reactant: CN1CCCN(c2ccc(S(=O)(=O)Nc3ccccc3)cc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: CN1CCCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCCN(c2ccc(S(=O)(=O)Nc3ccccc3)cc2N)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-Chloro-3-nitrobenzenesulfonyl chloride (460 mg, 1.8 mmol) was added to a colorless solution of aniline (250 mg, 2.7 mmol) in CH2Cl2 (10 mL) followed by pyridine (0.80 mL, 10.0 mmol). The resulting orange solution was stirred at room temperature for 30 minutes, after which time the mixture was concentrated under vacuum. Acidification with 2M aq. HCl followed by extraction using EtOAc and drying with Na2SO4 followed by filtration through a plug of silica, gave 500 mg (62%) of 4-chloro-3-nitro-N-phenylbenzenesulfonamide. 1H NMR (CDCl3) δ 8.30 (d, 1H), 7.80 (dd, 2H), 7.55 (d, 1H), 7.20 (m, 5H). MS(negESI) m/z=311(M−H+). 1-Methylhomopiperazine (258 mg, 2.3 mmol) was added to a solution of 4-chloro-3-nitro-N-phenylbenzenesulfonamide obtained as above (500 mg, 1.6 mmol) in CH2Cl2 (20 mL) followed by addition of K2CO3 (310 mg, 2.3 mmol). The reaction mixture was heated to reflux. After 2.5 h, the solution was concentrated under vacuum. After adjusting to pH=6, the product was extracted using EtOAc to give, after drying with Na2SO4 and concentration, 450 mg (72%) of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide as an orange oil. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.60 (dd, 1H), 7.15 (m), 6.95 (d, 1H), 3.45 (m, 2H), 3.30 (m, 2H), 2.75 (m, 2H), 2.60 (m, 2H), 2.35 (s, 3H), 1.95 (m, 2H). MS (posESI) m/z=391(M+H+). To a solution of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide (225 mg, 0.58 mmol) in EtOH/THF (4/1, 25 mL) activated Raney-Ni (slurry in EtOH) and hydrazine monohydrate (142 μL, 2.9 mmol) were added. After stirring for 30 minutes at room temperature, the mixture was filtered and the yellow solution concentrated to give yellow oil. The oil was dissolved in a mixture diethyl ether/EtOAc followed by addition of excess of HCl/ether. The resulting precipitate was filtered and washed with ether to give, after drying under vacuum at 40° C., 88 mg (38%) of 3-amino-4-(4-methyl-1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide as a beige solid. Mp 84-85° C. MS (posESI) m/z=361 (M+H+). 1H NMR (MeOH-d3) δ 7.85 (d, 2H), 7.60 (d, 1H), 7.15 (m, 5H), 3.50 (m, 7H), 3.15 (m, 2H), 3.00 (s, 3H), 2.30 (m, 1H), 2.20 (m, 1H). Anal. (C18H24N4SO2.2HCl) C, H, N, S.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:12][CH2:13][CH2:14][CH2:15][N:4]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: OCCCBr
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(I)nn2CCCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10.00 g, 38.31 mmol) in tetrahydrofuran (150 mL) was treated with 3-bromo-1-propanol (15.98 g, 114.93 mmol) and triphenylphosphine (20.1 g, 76.62 mmol). Diethylazodicarboxyate (13.34 g, 76.62 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 min, after which the ice bath was removed and was stirred for 30 minutes at room temperature. The reaction mixture was partially concentrated and ethyl acetate (200 mL) was added. The precipitate was filtered and the filtrate was concentrated to dryness. The crude compound was purified by flash chromatography on silica gel using 100% ethyl acetate as the eluent. The afforded 7.8 g (53%) of 1-(3-bromopropyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.230 (s, 1H), 4.419-4.385 (t, 2H), 3.530-3.498 (t, 2H), 2.370-2.304 (q, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.05 min (100%), MH+ 422.9.