Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:33].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[C:26]([O:25][C:24]([N:23]([CH3:31])[CH:20]1[CH2:19][CH2:18][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@H:4]([CH2:3][C:2]([OH:33])=[O:1])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:22][CH2:21]1)=[O:30])([CH3:28])([CH3:27])[CH3:29]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO)CC4)CC1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)O)CC4)CC1
Yield: 69.9 %

Procedure:
A solution of 22.3 (1.25 g, 2.79 mmol, 1.00 equiv) and dipyridinium dichromate (4 g, 10.64 mmol, 4.00 equiv) in 10 mL of DMF was stirred for 15 h at room temperature. The reaction was then quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2 to 3:5) and purified to afford 2-[(3S)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetic acid (22.4, 900 mg, 70%) as a colourless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][NH:10][C:11]2=[O:14])=[CH:7][CH:6]=1)[C:2]#[CH:3].C(N(CC)C1C=CC=CC=1)C>CCCCCC.CCOC(C)=O.C(Cl)Cl>[C:11]1(=[O:14])[C:12]2[C:13]3[CH:3]=[CH:2][CH2:1][O:4][C:5]=3[CH:6]=[CH:7][C:8]=2[CH2:9][NH:10]1
Reactant: C#CCOc1ccc2c(c1)C(=O)NC2
Solvent: CCCCCC
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1NCc2ccc3c(c21)C=CCO3
Temperature: 210 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
The mixture of 6-(prop-2-ynyloxy)isoindolin-1-one ((72), 4.4 g, 23.5 mmol) and N,N-Diethylaniline 70 ml) was stirred at 210° C. for overnight. Reaction solution was directly loaded on silica gel eluting with Hexane/EtOAc/CH2Cl2 (3:3:1 ratio) to give the title compound (2.8 g, 64%) as a brown solid. MS (ES) m/z 188.1.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[CH2:39]([CH2:41][NH2:42])[OH:40]>CCO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:42][CH2:41][CH2:39][OH:40])=[O:34])[C:15]1=[O:38]
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Solvent: CCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.035 g, 0.068 mmol) in EtOH (3 mL) under nitrogen was treated with Ethanolamine (8 mg, 0.13 mmol) for 2 h@150° C. in a microwave vessel. The reaction was then cooled to ambient temperature and the resulting suspension was filtered, washed with EtOH and Et2O and thoroughly dried under high vacuum to provide the title compound as an orange solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 3.4 (m, 5 H), 3.9 (t, J=6.0 Hz, 2 H), 4.1 (s, 2 H), 4.5 (t, J=5.8 Hz, 2 H), 4.8 (t, J=5.0 Hz, 1 H), 7.1 (ddd, J=9.0, 6.7, 2.2 Hz, 2 H), 7.3 (m, 2 H), 7.8 (m, 4 H), 8.1 (d, J=1.1 Hz, 1 H), 8.5 (d, J=1.3 Hz, 1 H), 10.0 (s, 1 H); ES+ MS: 531 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][C:16]([CH3:18])=[CH2:17])=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7](C=O)[CH2:6][CH2:5]2.Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO.O>[CH3:17][C:16]1([CH3:18])[O:1][C:2]2[C:3](=[C:4]3[C:8](=[C:9]([CH3:12])[C:10]=2[CH3:11])[NH:7][CH2:6][CH2:5]3)[CH2:15]1
Reactant: C=C(C)Cc1c(O)c(C)c(C)c2c1CCN2C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c3c1NCC3)CC(C)(C)O2
Yield: 45.7 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-6,7-dimethyl-4-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (1.23 g, 5.0 mmol) in methanol (4 mL) was added concentrated hydrochloric acid (2 mL)-methanol (1 mL) solution, and the mixture was heated to reflux for 2 hours under the nitrogen atmosphere. The reaction mixture was added to a mixture of sodium bicarbonate (3.02 g, 35.9 mmol) in water (10 mL)-ethyl acetate (10 mL) to neutralize, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate, treated with active carbon, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 497 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([CH2:17][CH:18]=O)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][CH2:6]1)=[O:4].Cl.Cl.[C@@H:24]12[NH:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][CH:26]([N:32]1[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N:34]=[C:33]1[CH3:41])[CH2:25]2.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:21][C:2]([CH3:1])([CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([CH2:17][CH2:18][N:31]2[C@H:28]3[CH2:29][CH2:30][C@@H:24]2[CH2:25][CH:26]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[CH2:27]3)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)C(=O)N1CCC(CC=O)(c2ccccc2)OC1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a solution of [3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (50.4 mg, 0.17 mmol), 1-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole dihydrochloride (64 mg, 0.17 mmol) and diisopropylethylamine (0.063 mL, 0.35 mmol) in 2 mL CH2Cl2 was added sodium triacetoxyborohydride (55 mg, 0.26 mmol) and the reaction mixture was stirred for 2 h at room temperature. After evaporation, the residue was chromatographed (5% (2M NH3/MeOH) in CHCl3) to provide 1-((1R,5S)-8-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (50.4 mg, 56%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.65 (m, 1H), 7.43-7.34 (m, 4H), 7.32-7.26 (m, 2H), 7.19-7.11 (m, 2H), 5.43 (s, 1H, J=11.2 Hz), 4.70 (d, 1H, J=10.3 Hz), 4.61 (m, 1H), 4.21 (m, 1H), 3.42-3.22 (m, 2H), 3.08 (m, 1H), 2.57 (s, 3H), 2.43-1.57 (m, 14H), 1.28 (s, 9H); ESI-MS 515 (M+H), 237 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]3)=[N:21][CH:22]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(N)cn2)C1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 55.7 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (194 mg, 0.681 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (210 mg, 0.821 mmol) to afford the desired product (205 mg, 55%) as a brown solid: ESI MS m/z 540, [C26H30BrN5O3+H]+
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([NH:11][C:12](=[O:21])[C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[Br:1][C:2]1[S:6][C:5]([CH:7]([NH:11][C:12](=[O:21])[C:13]2[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=2[F:19])[C:8]([O:10][CH3:26])=[O:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(NC(C(=O)O)c1ccc(Br)s1)c1c(F)cccc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)C(NC(=O)c1c(F)cccc1F)c1ccc(Br)s1

Procedure:
An amount of 3.415 g (9 mmol) of the product of Step B was dissolved in 19 mL of methanol. It was cooled in an ice-bath and 1.13 mL of thionyl chloride was added dropwise. The mixture was heated at reflux for 30 min. It was cooled and the methanol removed under reduced pressure. A saturated solution of sodium bicarbonate was carefully added to the residue, then extracted with ether. The combined ether extracts were washed with brine, dried (MgSO4) and concentrated to give a white solid: mp 123°-124° C. 1H-NMR (DMSO-d6) δ9.90 (d, 1H), 7.55 (m, 1H), 7.20 (m,3H), 7.00 (d, 1H), 5.90 (d, 1H), 3.75 (s,3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:32])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:31])([CH3:30])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[C:27]([N:24]1[CH2:25][CH2:26][N:21]([C:17]2[CH:16]=[C:15]([CH:12]3[C:11]([CH3:31])([CH3:30])[CH2:10][C:9]4[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([Cl:32])[CH:8]=4)[NH:13]3)[CH:20]=[CH:19][CH:18]=2)[CH2:22][CH2:23]1)(=[O:29])[CH3:28]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(C(C)=O)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCN(c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
A mixture of 2-[3-(4-acetyl-piperazin-1-yl)-phenyl]-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (247 mg, 0.54 mmol), lithium hydroxide hydrate (230 mg, 5.4 mmol), water (1.0 mL) in methanol (2 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(4-acetyl-piperazin-1-yl)-phenyl]-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (62 mg, 26%) as a white solid: LC/MS m/e calcd for C24H28ClN3O3 M+: 441.96, observed: 442.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cc(Cl)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Temperature: 130 °C
Yield: 107.9 %

Procedure:
To a solution of 3-chloro-5-(trifluoromethyl)phenol (2 g, 10.18 mmol) and 4-fluorobenzaldehyde (1.201 ml, 11.19 mmol) in DMF (30 mL), was added K2CO3 (2.109 g, 15.26 mmol). The mixture was heated at 130° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (3.3 g, 10.98 mmol, 108% yield) as a brown oil. LCMS: rt=3.89 min, [M+H+]=301
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:3].[C:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24])(=O)[CH3:18].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[CH3:3][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([CH:17]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])[CH3:18])[CH2:15][CH2:16]1)[CH3:1]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)Oc1ccccc1N1CCN(C(C)c2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
A mixture of 1-[2-(methylethoxy)phenyl]piperazine (IPP, 7.28 g, 0.033 mol), 3-acetylbenzonitrile (4.80 g, 0.033 mol), and titanium isopropoxide (11.74 g, 0.041 mol) was stirred at room temperature for 2 h, heated to 80° C. for several minutes, and then cooled to room temperature. Methanol (150 mL) was added and the mixture was heated to dissolve most of the solids. After cooling to room temperature, sodium borohydride (2.27 g, 0.060 mol) was added in portions and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated on a rotary evaporator and the residue was partitioned between 3N NaOH/CH2Cl2. The organic layer was separated, dried (K2CO3), filtered, and evaporated to an oily residue which was passed through flash grade silica using 4:1 hexane:EtOAc as eluant to give 3-[1-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]ethyl]benzonitrile as an oil (1.55 g, 13.5%).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][CH2:6][CH2:5]2)[CH2:3][CH:2]1[C:8]([OH:10])=O.C(Cl)(=O)C(Cl)=O.[NH4+:17].[OH-].C1COCC1>C(Cl)Cl.CN(C=O)C.O>[CH2:1]1[C:4]2([CH2:7][CH2:6][CH2:5]2)[CH2:3][CH:2]1[C:8]([NH2:17])=[O:10]
Reactant: [NH4+]
Reactant: O=C(O)C1CC2(CCC2)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: NC(=O)C1CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A solution of spiro[3.3]heptane-2-carboxylic acid (0.5 g, 3.57 mmol) in DCM (5 mL) was treated with oxalyl chloride (0.406 mL, 4.64 mmol) and 1 drop of DMF and stirred at RT for 2 h. The mixture was added drop-wise to a mixture of NH4OH (5 mL, 128 mmol) and THF (5 mL) and stirred at RT overnight. The mixture was treated with H2O, the solids removed via filtration, the filtrate saturated with solid NaCl, extracted with 3:1 DCM/THF (3×) and the combined organics were washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford spiro[3.3]heptane-2-carboxamide (440 mg, 89%). 1H NMR (400 MHz, DMSO-d6): δ 7.07 (s, 1H), 6.62 (s, 1H), 2.76 (m, 1H), 2.01 (m, 4H), 1.96 (t, J=7.2 Hz, 2H), 1.80 (m, 2H), 1.76-1.69 (m, 2H).
Reaction SMILES: O=S(Cl)Cl.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[C:11]([OH:13])=[O:12])([O-:7])=[O:6].[CH3:20]O>>[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[C:11]([O:13][CH3:20])=[O:12])([O-:7])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 99 %

Procedure:
SOCl2 (3.4 ml, 5.61 g, 47.1 mmol, 5 eq) was added dropwise to a stirred solution of 3,5-dinitrobenzoic acid (2.0 g, 9.43 mmol, 1 eq, Aldrich) in 20 ml anhydrous MeOH at 0° C. under Ar. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo, and the residue was dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 (×2), water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo yielding 2.12 g (9.38 mmol, 99% yield) of methyl 3,5-dinitrobenzoate.
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][C:10]1[C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:14]=[CH:15][CH:16]=1)N.[CH:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCCCCC>[CH3:9][C:10]1[C:11]([N+:17]([O-:19])=[O:18])=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: c1ccccc1
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Agent: CC(C)CCON=O
Solvent: CCCCCCC
Product: Cc1cccc(-c2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
During a two hour period isoamyl nitrite (92.43 g, 0.189 mole) was added to a stirred solution of 3-methyl-2-nitroaniline (60.0 g, 0.394 mole) in 352 ml of benzene. The reaction mixture was stirred at room temperature for approximately 18 hours, then heated at 65° for five hours. The reaction mixture was cooled and the solvent removed by distillation under reduced pressure to give an oil. The oil was diluted with n-heptane and the solvent removed by distillation under reduced pressure to give an oil. The oil was slurried with 100 g silica gel in 300 ml of n-heptane for 15 minutes, then allowed to stand for approximately 18 hours. The slurry was filtered and the filter cake rinsed with toluene. The filtrate was subjected to column chromatography on 500 g of silica gel, elution with toluene:n-heptane (15.85), to give an oil. The oil was rechromatographed on 480 g of silica gel, elution with toluene:n-heptane (15:85), to give 3-methyl-2-nitro-[1,1'-biphenyl].
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.[C:25]([O:29][C:30]([N:32]1[CH2:35][CH:34](I)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:35][CH:34]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:16][CH:15]=2)(=[O:12])=[O:13])[CH:6]=[CH:5]3)[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=S(=O)(c1ccc(-c2cnco2)cc1)n1ccc2cc(I)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Product: CC(C)(C)OC(=O)N1CC(c2ccc3c(ccn3S(=O)(=O)c3ccc(-c4cnco4)cc3)c2)C1

Procedure:
This compound was prepared from 5-Iodo-1-(4-oxazol-5-yl-benzenesulfonyl)-1H-indole and 3-iodoazetidin-1-carboxylic acid tert-butyl ester by the method outlined under 1.b). ESI-MS [m/z]: 380.05 [M-Boc-+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[C:8](=O)([O:14]C(C)(C)C)[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1.O>[C:10]([O:9][C:8]([NH:1][C@H:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@@H](N)CC(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
To a stirred suspension of (R)-3-aminobutanoic acid (2.415 g, 23.42 mmol) in dioxane (15 mL) and water (15.00 mL) was added TEA (4.90 mL, 35.1 mmol) dropwise. To the resulting light brown solution cooled at 0° C. was added portionwise di-tert-butyl carbonate (4.69 g, 26.9 mmol). The mixture was then stirred at rt for 16 hr. The reaction mixture was partitioned between water (80 mL) and EtOAc (80 mL). The separated aqueous layer was washed with EtOAc and acidified with 1 M aqueous KHSO4 to pH=3 and extracted with EtOAc (2×). The combined EtOAc extracts were washed with saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated to give (R)-3-(tert-butoxycarbonylamino)butanoic acid (4.301 g, 21.16 mmol, 90% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.92 (s, 1H), 4.14-3.96 (m, 2H), 2.56 (d, J=5.2 Hz, 2H), 1.45 (s, 9H), 1.25 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)(=[S:29])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2nc3ccccc3s2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Product: CC(=S)Nc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 101.6 %

Procedure:
A mixture of 2-(4'-acetamidophenyl)benzothiazole (0.4 g, 1.49 mmol) and Lawesson's reagent (0.37 g, 0.9 mmol) in hexamethyl-phosphoamide (HMPA) (10 ml) was stirred at 100° C. for 6 hours. The reaction mixture was poured into water. The precipitate formed was filtered off, washed with water and dried. The crude product was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (5:6)to give pale yellow crystals (0.26 g, 61%), m.p. 221.6-222.8° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]1.[I-].[Na+].[CH2:12](Br)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:12]([N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCc1ccccc1
Reactant: O=Cc1cn[nH]c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cnn(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of NaH (125 mg, 3.12 mmol, 60% dispersion in mineral oil) in THF (10 mL), was added dropwise over 5 min, a solution of 1H-pyrazole-4-carbaldehyde (250 mg, 2.60 mmol) in THF (5 mL). The mixture was stirred at rt for 45 min; sodium iodide (10 mg) was added before the addition of phenethyl bromide (0.42 mL, 3.12 mmol). After 15 min, the reaction was heated at 80° C. for 4 h, then cooled to rt, quenched with saturated solution of NH4Cl and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (Isco CombiFlash) 0-40% EtOAc/heptane provided 1-phenethyl-1H-pyrazole-4-carbaldehyde: Yield 410 mg (79%). 1H NMR (400 MHz, CDCl3) δ ppm 3.20 (t, J=7.03 Hz, 2H), 4.39 (t, J=7.05 Hz, 2H), 7.06 (dd, J=7.91, 1.46 Hz, 2H), 7.22-7.32 (m, 3H), 7.63 (s, 1H), 8.00 (s, 1H), 9.79 (s, 1H); LCMS-MS (ESI+) 200.87 (M+H).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:25]([C:26]2[S:27][C:28]3[CH:29](C(OC(C)(C)C)=O)[NH:30][CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:42]2[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=2[F:49])[S:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.O1CCOCC1.O>O1CCOCC1>[F:49][C:43]1[CH:44]=[CH:45][C:46]([F:48])=[CH:47][C:42]=1[C:23]1[S:22][C:21]([CH2:20][CH2:19][OH:18])([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=1
Reactant: CC(C)(C)OC(=O)C1NCCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-4(4H)-carboxylate (prepared according to Example 26, Steps A-D; 0.090 g, 0.113 mmol) in 1 mL of 1,4-dioxane was added 4M HCl/dioxane (1 mL). The mixture was stirred at room temperature for 16 hours then treated with 4M HCl/dioxane (2 mL) and stirred for a further 3 hours. Water (1 mL) was added and the mixture was stirred for 16 hours then concentrated and dried in vacuo. The residue was triturated with diethyl ether, filtered, washed with ether and dried in vacuo to afford the desired product as an orange/yellow solid, 0.023 g, 38%. MS ESI (+) m/z 459 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.07 (m, 2H), 4.12 (m, 1H), 3.95 (m, 1H), 3.87 (m, 2H), 3.65 (m, 2H), 3.05 (m, 2H), 2.84 (m, 1H), 2.43 (m, 2H) ppm.