Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[S].[Br:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([N+:24]([O-:26])=[O:25])[C:16]=1N.[Cl-].[NH4+:29].[OH-].[Na+].Cl>O.C(O)C>[Br:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([NH2:29])=[C:17]([N+:24]([O-:26])=[O:25])[CH:16]=1
Reactant: [NH4+]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A mixture of sodium sulfide nonahydrate (96 g, 400 mmol) and sulfur (12.8 g, 400 mmol) in a mixture of 400 mL of water and 100 mL of ethanol was heated at reflux under nitrogen for 1 h. The solution was added to a stirred suspension of 2-bromo-4,6-dinitrobenzenamine (104.8 g, 400 mmol) and ammonium chloride (20.8 g, 400 mmol) in a mixture of 400 mL of water and 700 mL of ethanol. The mixture was stirred at 65° C. for 30 min. Then 400 mL of 2N NaOH solution was added dropwise during a period of 30 min and the mixture was then stirred for a further 15 minutes at 65° C. After cooling, the mixture was poured onto a mixture of 2N HCl (400 mL), 1 kg ice and 1 L of water, stirred for 15 min to complete the reaction and extracted with ethyl acetate (1 L×3). The combined organic layers were dried over sodium sulphate and evaporated to give the crude product (90 g, 97%) as a rust-colored solid, which was used for the next step without further purification; LC/MS: MS (ES+) m/e 232 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 5.48 (s, 2H), 6.07 (s, 2H), 7.39 (d, J=2.7 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH:42][C:43]3[N:48]=[C:47]([O:49][CH2:50][C:51]([F:54])([F:53])[F:52])[N:46]=[C:45]([NH:55][C:56]4[CH:64]=[CH:63][C:59]([C:60](O)=[O:61])=[CH:58][CH:57]=4)[N:44]=3)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.[NH2:65][CH2:66][C:67]([CH3:78])([CH3:77])[CH2:68][NH:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73]>CN(C=O)C.CCOC(C)=O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH:42][C:43]3[N:48]=[C:47]([O:49][CH2:50][C:51]([F:54])([F:53])[F:52])[N:46]=[C:45]([NH:55][C:56]4[CH:57]=[CH:58][C:59]([C:60]([NH:65][CH2:66][C:67]([CH3:78])([CH3:77])[CH2:68][NH:69][C:70](=[O:76])[O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[O:61])=[CH:63][CH:64]=4)[N:44]=3)[CH2:40][CH2:41]2)=[CH:35][CH:34]=1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Yield: 71.3 %

Procedure:
iPr2NEt (0.266 g) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (0.610 g) were added into a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (0.760 g) and tert-butyl 3-amino-2,2-dimethylpropylcarbamate (0.352 g) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 16 hrs before 200 mL of EtOAc was added. The organic phase was washed with water (2×25 mL) and brine (20 mL), dried over MgSO4, and concentrated to give crude product tert-butyl 3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropylcarbamate (0.75 g) which was dissolved in CH2Cl2 (3 mL) and TFA (1.3 mL). After being stirred at room temperature for 16 hours, the mixture was concentrated to give a crude product, N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide (0.63 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(/[CH:14]=[CH:15]/[CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C/C=C/C1(c2ccc(F)cc2)CCCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCCC1(c2ccc(F)cc2)CCCCC1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a solution of (E)-4-(1-(4-fluorophenyl)cyclohexyl)but-3-enoic acid (37.3 mg, 0.142 mmol) in MeOH (10 mL) was added about 50 mg of 10% Pd/C (50% wet) and the solution was stirred under H2 (50 psi) for 4 hrs. After removal of the catalyst by filtering thru Celite, the solvent was evaporated off to give 4-(1-(4-fluorophenyl)cyclohexyl)butanoic acid (30 mg, 0.113 mmol, 80% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.80 (1 H, br. s.), 7.42-7.49 (1 H, m), 7.21-7.27 (2 H, m), 6.98 (2 H, t, J=8.79 Hz), 2.11 (2 H, t, J=7.47 Hz), 1.97-2.07 (2 H, m), 1.17-1.61 (10 H, m).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:29][C@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[N:4]=1.Br.CC#N>CC(O)=O>[CH3:33][O:32][CH2:31][C@H:30]([NH:29][C:5]1[NH:4][C:3](=[O:2])[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=1)[CH3:34]
Reactant: COC[C@@H](C)Nc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Agent: Br
Solvent: CC#N
Solvent: CC(=O)O
Product: COC[C@@H](C)Nc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 90 °C
Yield: 71.3 %

Procedure:
(R)-4-methoxy-N-(1-methoxypropan-2-yl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (98 mg, 0.21 mmol) was dissolved in AcOH (3 mL) and then hydrobromic acid (0.1 mL, 0.85 mmol) was added. The mixture was heated at 90° C. for 3.5 hours. The mixture was concentrated and the residue was treated with NaHCO3 solution. The solution was extracted with EtOAc (3×). The organic was washed with NaHCO3, dried over Na2SO4, filtered and concentrated to obtain the crude. The crude was treated with hot MeCN and kept at RT. The solid was filtered and washed with MeCN and dried under vacuum to obtain (R)-2-((1-methoxypropan-2-yl)amino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (67 mg, 59.2% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.67 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.25 (m, 2H), 7.97 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.75 (br s, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 4.19 (m, 1H), 3.85 (s, 3H), 3.38 (m, 2H), 3.30 (s, 3H), 2.34 (s, 3H), 1.15 (d, J=6.7 Hz, 3H); MS (ESI) m/z: 448.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:26][NH2:27]>O1CCOCC1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([NH:26][NH2:27])[N:15]=[C:14]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CN(CCOc1cc(Cl)nc(N2CCOCC2)n1)C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CN(CCOc1cc(NN)nc(N2CCOCC2)n1)C(=O)OC(C)(C)C

Procedure:
[2-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (5.6 g) was dissolved in dioxane (100 mL) and hydrazine (6 mL) was added. The solution was heated to reflux for one hour, at which point the solvent was evaporated. The solid was dissolved in dichloromethane (200 mL) and washed with 10% sodium carbonate (10 mL). The organic layer was dried over magnesium sulfate and evaporated to give [2-(6-hydrazino-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester, which was used without purification in the next reaction.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.N(CCO)CCO.[NH2:44][C:45]1[C:58]2[C:57](=[O:59])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50](=[O:60])[C:49]=2[C:48]([OH:61])=[CH:47][C:46]=1Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].C[N+](C)(C)CC1C=CC=CC=1.O>[NH2:44][C:45]1[C:58]2[C:57](=[O:59])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50](=[O:60])[C:49]=2[C:48]([OH:61])=[CH:47][C:46]=1[O:14][C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: OCCNCCO
Solvent: O
Product: Nc1c(Oc2ccc(Cl)cc2)cc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 140 °C
Yield: 97 %

Procedure:
35 parts of potassium carbonate, 65 parts of p-chlorophenol, 4 parts of a 50% strength aqueous solution of diethanolamine dodecylbenzenesulfonate to act as a dispersant, 7 parts of a 50% strength aqueous solution of trimethylbenzylammonium chloride and 70 parts of 1-amino-2-chloro-4-hydroxyanthraquinone (95% pure) are introduced into 250 parts of water (resulting in a pH of 11), and the mixture is heated for 15 hours at 140° C., under a pressure of about 4.5 bar, whilst stirring. When it has cooled, the reaction mixture is poured into 350 parts of 10% strength sodium carbonate solution and the suspension is stirred for 1 hour at 70° C. and then filtered. The product is washed neutral and dried, giving 88 parts of 97% pure 1-amino-2-(4'-chlorophenoxy)-4-hydroxyanthraquinone, corresponding to a yield of 97% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][CH3:28].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:12]([O:11][C:10](=[O:16])[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[C:2][C:20]2[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=[CH:18][C:19]=2[O:27][CH3:28])[CH:4]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: COc1ccc([N+](=O)[O-])cc1I
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
tert-Butyl (3-ethynylphenyl)carbamate was stirred with 2-iodo-1-methoxy-4-nitrobenzene (2.60 g, 9.31 mmol) and bis(triphenylphosphine)palladium(II) chloride (163 mg, 0.23 mmol) in N,N-dimethylformamide (15 mL), and triethylamine (2.59 mL, 18.6 mmol) was added. The reaction mixture was heated at 80° C. for 15 minutes. Purification by preparative LCMS (pH 10) gave the desired compound (1.38 g, 40%). 1H NMR (300 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.25 (m, 2H), 7.71 (s, 1H), 7.42 (d, 1H), 7.25 (m, 2H), 7.18 (d, 1H), 4.00 (s, 3H), 1.42 (s, 9H). LCMS for C20H21N2O5 (M+H)+: m/z=369.1.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]=3[CH:25]=2)=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4].O.[NH2:29][NH2:30].C(O)(=O)C>C(O)C>[F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:29][NH2:30])[C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]=3[CH:25]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:4]
Reactant: CC1(C)Cc2cc(C(=O)c3ccc(OS(=O)(=O)C(F)(F)F)cc3)ccc2O1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Cc2cc(C(=NN)c3ccc(OS(=O)(=O)C(F)(F)F)cc3)ccc2O1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 1.6 grams (0.004 mole) of (4-trifluoromethylsulfonyloxyphenyl)(2,3-dihydro-2,2-dimethylbenzofuran-5-yl) ketone in 75 mL of ethanol was stirred, and 0.6 mL (0.0121 mole) of hydrazine hydrate followed by 0.5 mL of acetic acid were both added via syringe. Upon completion of addition the reaction mixture was heated at reflux for 7 hours and then was allowed to cool to ambient temperature where it was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was stirred with diethyl ether and water. The mixture was placed in a separatory funnel, and the layers were separated. The organic layer was washed with aqueous 10% sodium hydroxide solution, two portions of water, and with a saturated, aqueous solution of sodium chloride. The organic layer was concentrated under reduced pressure to yield 1.6 grams of (4-trifluoromethylsulfonyloxyphenyl)(2,3-dihydro-2,2-dimethylbenzofuran-5-yl) ketone hydrazone as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: COC(=O)CCC1ON=C(C2C=C(NC(=O)CC)SC=2)N=1.COC(=O)CCC1ON=C(C2C=C(NC(=O)CC(C)C)SC=2)N=1.[CH3:45][O:46][C:47](=[O:71])[CH2:48][CH2:49][C:50]1[O:54][N:53]=[C:52]([C:55]2[CH:59]=[C:58]([NH:60][C:61]([O:63][CH2:64][C:65]3C=CC=CC=3)=[O:62])[S:57][CH:56]=2)[N:51]=1>>[CH3:45][O:46][C:47](=[O:71])[CH2:48][CH2:49][C:50]1[O:54][N:53]=[C:52]([C:55]2[CH:59]=[C:58]([NH:60][C:61]([O:63][CH2:64][CH3:65])=[O:62])[S:57][CH:56]=2)[N:51]=1
Reactant: COC(=O)CCc1nc(-c2csc(NC(=O)OCc3ccccc3)c2)no1
Agent: CCC(=O)Nc1cc(-c2noc(CCC(=O)OC)n2)cs1
Agent: COC(=O)CCc1nc(-c2csc(NC(=O)CC(C)C)c2)no1
Product: CCOC(=O)Nc1cc(-c2noc(CCC(=O)OC)n2)cs1

Procedure:
3-[3-(5-Propionylaminothiophen-3-yl)-1,2,4-oxadiazol-5-yl]propionic acid methyl ester; 3-{3-[5-(3-Methylbutyrylamino)thiophen-3-yl]-1,2,4-oxadiazol-5-yl}propionic acid methyl ester; and 3-[3-(5-Benzyloxycarbonylaminothiophen-3-yl)-1,2,4-oxadiazol-5-yl]propionic acid methyl ester.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:12]23[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]4)[CH2:13]2)[CH2:19]3)[CH:5]=1.[OH-].[Na+].CCO.Cl>C1COCC1.O.CCOC(C)=O>[C:12]12([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[O:10][CH3:11])[C:3]([OH:22])=[O:2])[CH2:13][CH:14]3[CH2:20][CH:18]([CH2:17][CH:16]([CH2:15]3)[CH2:21]1)[CH2:19]2
Reactant: COC(=O)c1ccc(OC)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a stirred solution of methyl-3-(1-adamantyl)-4-methoxybenzoate (0.27 g, 0.85 mmol) in THF (30 ml) was added a solution of NaOH (0.04 g) in H2O (1 ml), followed by the addition of EtOH (2 ml). The mixture was refluxed for 4 h, then cooled to room temperature and acidified with 1M HCl solution. The crude product was taken in EtOAc (100 ml) and the organic layer was washed with H2O, and dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title product (0.22 g, 85%) as colourless solid. 1H-NMR (CDCl3) 1.77 (s, 6H), 2.03 (s, 3H), 2.09 (s, 6H), 3.89 (s, 3H), 6.88 (d, 1H, J=8.44 Hz), 7.93-7.98 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:14]=[C:13]([O:15][CH2:16][CH:17]([F:19])[F:18])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][CH2:7]C(F)F)=[O:5].[CH3:20][O-:21].[Na+].O>C1COCC1>[F:18][CH:17]([F:19])[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:21][CH3:20])[N:14]=1
Reactant: O=C(OCC(F)F)c1ccc(OCC(F)F)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCC(F)F)nc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.4 %

Procedure:
To a stirred solution of 2,2-difluoroethyl 2-chloro-6-(2,2-difluoroethoxy)nicotinate (2.9 g, 9.8 mmol, Step-1) in THF (35 mL) is added sodium methoxide (1.58 g, 29.2 mmol) at 0° C. Then the mixture is stirred at rt for 15 hours. The mixture is poured into water and extracted with DCM (10 mL×3). The combined organic layer is washed with water, brine, and dried over sodium sulfate. The organic solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1 to 1:4) to give 615 mg (26% yield) of the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:13].[Cl:14]N1C(=O)CCC1=O.C(Cl)Cl.CCCCCCC>CN(C)C=O>[NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])([CH3:12])[O:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[F:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)Oc2ccc(F)c(N)c2O1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)Oc2c(Cl)cc(F)c(N)c2O1
Yield: 72.7 %

Procedure:
In a flask were placed 2.23 g (0.0122 mole) of 4-amino-2,2-dimethyl-5-fluoro-1,3-benzodioxole and 40 mL of N,N-dimethylformamide. To this solution was added in a dropwise manner a solution of 1.79 g (0.0134 mole) of N-chlorosuccinimide in N,N-dimethylformamide while maintaining the temperature at ambient conditions. The solvent was evaporated under reduced pressure, leaving a residue which was passed through a column of silica gel eluting with methylene chloride/heptane (1:1 ). Product-containing fractions were combined and the solvent evaporated, yielding 1.93 g of 4-amino-7-chloro-2,2-dimethyl-5-fluoro-1,3-benzodioxole as the residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(Oc2ccccc2[N+](=O)[O-])(c2ccccc2)CC1
Reaction time: 1 h
Yield: 32.8 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (7.65 g, 40 mM) in dry DMSO (100 ml) was treated with sodium hydride (2.0 g of 50% dispersion in oil 42 mM), the mixture stirred for 1 hour and then treated with 2-fluoronitrobenzene (5.65 g, 40 mM). After 24 hours the reaction mixture was poured in to water (500 ml) and extracted with ether (2×500 ml). The organic extract was washed with brine, dried and the solvents removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave the title compound (4.1 g) m.p. 80°-2° C.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][CH2:15][C:16]1[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:20][CH:21]=1.[CH3:27][C:28]1[N:29]=[C:30]([S:33](Cl)(=[O:35])=[O:34])[S:31][CH:32]=1.COC(C)(C)C>N1C=CC=CC=1>[CH3:27][C:28]1[N:29]=[C:30]([S:33]([NH:4][C:5]2[CH:13]=[C:12]3[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][C:6]=2[O:14][CH2:15][C:16]2[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:20][CH:21]=2)(=[O:35])=[O:34])[S:31][CH:32]=1
Reactant: Cc1csc(S(=O)(=O)Cl)n1
Reactant: CCOC(=O)c1cnc(COc2cc3c(cc2N)CCC3)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: CCOC(=O)c1cnc(COc2cc3c(cc2NS(=O)(=O)c2nc(C)cs2)CCC3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 712 mg of ethyl 5-{[(6-amino-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyrazine-2-carboxylate trihydrochloride were added 35.6 mL of pyridine and 35.0 mL of a 0.21 M 4-methyl-1,3-thiazole-2-sulfonyl chloride/tert-butyl methyl ether solution, followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added a 5% w/v aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 95:5) to obtain 256 mg of ethyl 5-{[(6-{[(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyrazine-2-carboxylate.
Reaction SMILES: B.C1C[O:5]CC1.[Cl:7][C:8]1[CH:15]=[C:14]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C@H:17]2[CH2:21][C:20](=[O:22])[N:19]([CH2:23][CH:24]=[CH2:25])[CH2:18]2)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].O.OO.[OH-].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:15]=[C:14]([N:16]([C@H:17]2[CH2:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][CH2:25][OH:5])[CH2:18]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: C1CCOC1
Reactant: C=CCN1C[C@@H](N(Cc2ccccc2C)c2ccc(C#N)c(Cl)c2)CC1=O
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cc1ccccc1CN(c1ccc(C#N)c(Cl)c1)[C@H]1CC(=O)N(CCCO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
Borane-THF (1.0 M, 0.25 mL, 0.25 mmol) was added to a solution of 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-5-oxo-1-(2-propen-1-yl)-3-pyrrolidinyl]amino}benzonitrile (20.0 mg, 0.05 mmol), and the reaction mixture stirred at room temperature overnight. Upon complete consumption of the starting material; the reaction mixture was diluted with THF (5 mL), and H2O (1.0 mL, 2.6 mmol) was added dropwise at 0° C. The mixture then warmed to room temperature over 30 min. Hydrogen peroxide (30 wt % in H2O, 36.2 mg, 0.32 mmol) and 2 N NaOH (0.06 mL, 0.12 mmol) were added at 0° C., and the resulting mixture stirred at 25° C. for 1 h and at 60° C. for 2 h. The reaction mixture was cooled and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated to give a crude mixture of the desired terminal alcohol and secondary alcohol racemate. The title compound (3.0 mg, 14% yield) was isolated as a white solid by HPLC purification: 30×100 Xterra Prep, eluting with water (solvent A) and acetonitrile (solvent B), no TFA; 40 to 100% (solvent B) over 17 min at a flow rate of 30 mL/min. LC-MS (ES) m/e 398.7 (M+H)+.
Reaction SMILES: C[Si]([CH2:5][C:6]#[N:7])(C)C.C([N-]C(C)C)(C)C.[Li+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:25](=O)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:31])[CH3:32])/[C:25](=[CH:5]\[C:6]#[N:7])/[CH2:24]1)=[O:22])([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C(=O)C1
Reactant: C[Si](C)(C)CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)/C(=C\C#N)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of trimethylsilylacetonitrile (1.3 ml) in tetrahydrofuran (THF) (30 ml) was added at −78° C. lithium diisopropylamide (2.0 M in hexane, 4.7 ml). The resulting mixture was stirred at −78° C. for 0.5 hours, and then a solution of 1-(t-butoxycarbonyl)-4-(t-butyldimethylsilyloxy)piperidin-3-one (3 g) in THF (10 ml) was added at the same temperature. The resulting mixture was stirred for one hour while the temperature was raised to room temperature. The mixture was concentrated in vacuo, and the residue was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate (9:1) as the eluent to afford the title compound (880 mg, yield: 27%) as the less polar isomer as a yellow oil.