Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]([NH2:15])(=[O:14])[CH3:13]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:15]=[C:12]([CH3:13])[O:14][CH:7]=2)=[CH:4][CH:3]=1
Reactant: CC(N)=O
Reactant: O=C(CBr)c1ccc(Br)cc1
Product: Cc1nc(-c2ccc(Br)cc2)co1
Reaction time: 2.5 h

Procedure:
4-Bromophenacyl bromide (21.3 g) and acetamide (11.3 g) were heated together at 130° C. under argon. After 2.5 h the reaction mixture was allowed to cool, and partitioned between water (150 ml) and Et2O (150 ml). The organic phase was washed with aqueous NaOH (0.5N), aqueous HCl (0.5M) and saturated aqueous NaCl solution (100 ml of each), dried (MgSO4) and evaporated to give a brown solid which was recrystallised from hexanes to give the title compound (D37) as an orange solid (4.1 g). LCMS electrospray (+ve) 239 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccc3C(F)(F)F)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
2-Trifluoromethylaniline (0.483 g, 3.000 mmol), triethylamine (0.304 g, 3.000 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.507 g, 3.000 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.374 g, 1.000 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.259 g, 0.500 mmol, 50%).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[C:16]([O:25][CH3:26])[C:15]=2[O:27][CH3:28])=[CH:9][CH:8]=1)C.Cl>[OH-].[Na+].O1CCOCC1>[CH3:28][O:27][C:15]1[C:16]([O:25][CH3:26])=[C:17]([O:23][CH3:24])[C:18]([O:21][CH3:22])=[C:19]([CH3:20])[C:14]=1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([OH:29])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C=Cc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(C=CC(=O)O)cc2)c(OC)c(OC)c1OC
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
The compound (1.35 g, 3.36 mmol) obtained in Step 4 of Example 1 was dissolved in a mixture of an aqueous solution of 2 N sodium hydroxide (30 ml) and 1,4-dioxane (15 ml), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was acidified by adding concentrated hydrochloric acid and then was extracted with ethyl acetate. The extract was washed with water, dried, and then the solvent was distilled off to yield the title compound (1.20 g, 3.23 mmol, yield 96%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][NH:9]C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:17].CCOC(C)=O>>[ClH:17].[NH:8]([CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[NH2:9]
Reactant: CN1CCC(NNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1CCC(NN)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 2-(1-methylpiperidin-4-yl)hydrazinecarboxylate (350 mg, 1.53 mmol) in sat. HCl/EtOAc solution (20 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to afford 4-hydrazinyl-1-methylpiperidine hydrochloride (253 mg, 100% yield), which was used in the next step without further purification. LCMS (ESI) m/z: 130.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: COc1cccc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1sccc1NC(=O)c1cccc(OC)c1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
To a solution of methyl-3-amino-2-thiophenecarboxylate (8.00 g, 50.9 mmol) in acetonitrile (100 mL) was added potassium carbonate (1.1 eq., 56.0 mmol, 7.73 g) followed by m-anisoyl chloride (1.05 eq., 53.4 mmol, 7.51 mL) and the mixture heated under reflux for 1 hour. A white precipitate forms. The mixture was cooled in ice-water, diluted with water (100 mL) and the white solid collected by filtration and dried to yield compound 1 (12.78 g). Upon standing, an additional quantity of product precipitated from the water-acetonitrile solution; this was collected in the same fashion. (Total yield: 14.08 g, 95%).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]3)=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[CH2:28](O)[CH:29]([CH3:31])[CH3:30]>>[ClH:1].[ClH:1].[ClH:1].[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:20][CH2:19]3)=[O:16])[CH2:13][CH2:14]2)[CH2:5][CH2:4]1
Reactant: CC(C)CO
Reactant: O=C(O)CN1CCC(NC(=O)N2CCN(C3CCNCC3)CC2)CC1
Agent: Cl
Product: CC(C)COC(=O)CN1CCC(NC(=O)N2CCN(C3CCNCC3)CC2)CC1

Procedure:
Prepared from 4-[[4-(4-piperidinyl)-piperazin-1-yl]carbonylamino]piperidinoacetic acid dihydrochloride and isobutanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].C([BH3-])#N.[Na+]>O1CCCC1.C(O)(=O)C.C(Cl)(Cl)Cl>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][C:25]([CH2:28][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: C1COCCN1
Reactant: O=Cc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc(CN4CCOCC4)cn3)CC2)cc1
Yield: 59.5 %

Procedure:
Morpholine (250 mg, 2.87 mmol) was added to a suspension of 6-[4-(4-nitrophenyl)piperazin-1-yl]pyridine-3-carbaldehyde (750 mg, 2.41 mmol) and sodium cyanoborohydride (454 mg, 7.23 mmol) in a mixture of tetrahydrofuran (10 mL) and acetic acid (0.5 mL) at ambient temperature then heated at reflux for 3 h. The mixture was then concentrated in vacuo to give a gummy solid which was dissolved in chloroform (40 mL), washed with water (2×20 mL), brine (2×15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude compound. Purification by column chromatography over neutral alumina using 20-30% of ethyl acetate in petroleum ether afforded 4-[[6-[4-(4-nitrophenyl)piperazin-1-yl]-3-pyridyl]methyl]morpholine (550 mg, 59%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:24]>Cl.CCOCC>[ClH:24].[ClH:24].[N:11]1([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccccn23)CC1
Agent: Cl
Solvent: CCOCC
Product: c1ccn2c(N3CCNCC3)cnc2c1

Procedure:
A solution of 4-imidazo[1,2-a]pyridin-3-yl-piperazine-1-carboxylic acid tert-butyl ester (950 mg, 3.14 mmol) in DCM (10 mL) and 2.0N HCl in Et2O (5 mL) was stirred for 12 hours. A precipitate formed and was filtered off to give 3-piperazin-1-yl-imidazo[1,2-a]pyridine dihydrochloride as a red solid (800 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O>C1COCC1.OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: Cn1nnnc1C(C(=O)Cl)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
The acyl chloride prepared in Step A was dissolved into 150 mL of tetrahydrofuran and was chilled to -78° C. under argon. To this pale brownish solution at -78° C. was added 8.0 mL lithium aluminum hydride in THF solutions (1.0 Molar). Analytical TLC after 15 minutes showed only one mobile spot at Rf =0.23 (50% EtOAc in hexanes v/v). The crude reaction mixture was diluted with 2M H2SO4 (20 ml). The aqueous layer was extracted with ethyl acetate (40 mL×2). Organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give 3.64 g (100%) of the title compound. The crude allylic alcohol was used immediately in the next step without further purification. MS (CI): m/e=328 for (M+H)+ ;
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)(=[O:23])=[O:22])[CH2:17][C@@H:16]2[CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:7][C:4]([F:5])([F:6])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)(=[O:23])=[O:22])[CH2:17][C@H:16]2[CH2:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[CH:11][CH:10]=1)([OH:8])[C:2]([F:36])([F:1])[F:37]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](CC2CCOCC2)C1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@H](CC2CCOCC2)C1

Procedure:
1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.89 (d, J=4.9 Hz, 1H), 7.70-7.61 (m, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.31-7.23 (m, 1H), 6.96 (d, J=9.2 Hz, 2H), 4.18 (br. s., 1H), 3.95-3.64 (m, 4H), 3.60-3.44 (m, 1H), 3.40-3.23 (m, 2H), 2.70 (dd, J=2.9, 11.7 Hz, 1H), 2.57 (dt, J=3.6, 11.4 Hz, 1H), 1.86-1.65 (m, 2H), 1.65-1.38 (m, 3H), 1.38-1.08 (m, 3H). m/z (ESI, +ve ion) 573.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.169 μM; GK-GKRP EC50 (LC MS/MS)=0.281 μM.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[C:14]([O:18][C:19]([N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:11]([S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:22]1[N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH:25]=[CH:24][CH:23]=1)(=[O:10])=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CC(C)S(=O)(=O)c1ccccc1Br
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: [Na+]
Solvent: COCCOC
Product: CC(C)S(=O)(=O)c1ccccc1-c1cccn1C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 83 %

Procedure:
To 21B (0.53 g, 2.0 mmol), 3A (0.51 g, 2.4 mmol) and sodium carbonate (4.0 mL, 2M, 8.0 mmol) in 1,2-dimethoxyethane (25 mL, flushed and degassed (3×) with nitrogen) was added Pd(PPh3)4 (0.23 g, 0.2 mmol) under nitrogen. The reaction was heated to 95° C. for 3 h. The catalyst was filtered over celite and washed with ethyl acetate. The organic layer was washed with water, brine and then dried over sodium sulfate. The solvent was removed and the crude residue was purified by flash column chromatography to give 0.58 g of product 21C (69% yield).
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:12]=[CH:11][C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[CH:16][NH:17]3)=[CH:9][C:6]=1[C:7]#[N:8]>C(O)CCC>[NH:17]1[C:18]2[C:14](=[C:13]([C:10]3[CH:9]=[C:6]4[C:5](=[CH:12][CH:11]=3)[NH:3][N:2]=[C:7]4[NH2:8])[CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: NN
Reactant: N#Cc1cc(-c2cccc3[nH]ccc23)ccc1F
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2ccc(-c3cccc4[nH]ccc34)cc12
Temperature: 25 °C
Yield: 83.2 %

Procedure:
Hydrazine hydrate (0.4 mL, 12.7 mmol) was added to a solution of 2-fluoro-5-(1H-indol-4-yl)benzonitrile (1.2 g, 5.08 mmol) in n-butanol (25 mL). The mixture was heated to reflux under nitrogen for 3 days. The reaction was cooled to room temperature and the solvent was removed. The residue was purified on a silica gel column eluting with DCM: MeOH (95:5) to give 1.05 g (83%) of 5-(1H-indol-4-yl)-1H-indazol-3-ylamine as a white foam.
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]2[NH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([CH2:4][CH2:5][C:6]2[NH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: C(=C/C1CC1)\c1ccc[nH]1
Agent: [Pd]
Solvent: CCO
Product: c1c[nH]c(CCC2CC2)c1

Procedure:
A solution of cis-/trans-2-(2-cyclopropylvinyl)-pyrrole (1.7 g., 0.073 mole) in ethanol (100 ml.) was hydrogenated over 10% palladium on charcoal at room temperature and 3.5 kg./cm2 (50 p.s.i.). The solution was filtered, the solvent evaporated and the residue distilled to give the required 2-(2-cyclopropylethyl)pyrrole as an oil (4.93 g.), B.P. 100°-103°./13 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:46])OC2C=CC=CC=2)[CH:32]=1>>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38](=[O:46])[NH:37][C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4cccnc4)cc3)nc(N3CCOCC3)n2)cc1
Yield: 6 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][N+:18]([O-])=O)[CH:11]=1)[CH3:8]>C1COCC1>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][NH2:18])[CH:13]=[CH:14][CH:15]=1)[CH3:8]
Reactant: CCOc1cccc(CC[N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cccc(CCN)c1
Yield: 53.5 %

Procedure:
To a solution of LiAlH4 (1M in THF, 13 mL) was added dropwise a solution of 1-ethoxy-3-(2-nitro-ethyl)-benzene (0.5 g, 2.6 mmol) in THF (8 mL). The mixture was refluxed for two hours before allowing to cool and adding dropwise to rochelles salt. The mixture was extracted with ethyl acetate, dried with sodium sulfate and evaporated to dryness. The resulting yellow oil was purified by chromatography on silica, eluting with 3 to 15% MeOH/NH3 in dichloromethane, yielding the subtitled compound as a yellow oil (0.23 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[N:9]2
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc(Br)cc1N
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc2cc(Br)ccc2n1
Reaction time: 20 h
Yield: 13 %

Procedure:
To a stirred solution of 4-bromo-o-phenylenediamine (3.1 g, 16.6 mmol) in 1-methyl-2-pyrrolidinone (150 mL) was added dropwise ethyl bromopyruvate at room temperature under nitrogen. After 20 hours, the reaction mixture was partitioned between water and diethyl ether. The organic phase was separated and the aqueous phase was extracted with diethyl ether twice more. The organic extracts were combined, washed twice with water, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give an oil. The crude product was partially purified by flash chromatography over silica with dichloromethane to give a tan solid. The impure product was purified on a Chiralpak AS-H column with 95% carbon dioxide at 140 bar at 35° C. and 2 mL/min with 5% co-solvent (methanol:chloroform (80:20) to give 0.614 g (13%) of ethyl 6-bromo-2-quinoxalinecarboxylate as a tan solid. 1H NMR (CDCl3, 400 MHz): δ 9.52 (s, 1H), 8.37 (d, J=2 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 7.93 (dd, J=9, 2 Hz, 1H), 4.59 (quartet, J=7 Hz, 2H), 1.50 (t, J=7 Hz, 3H). ESI-LCMS m/z 281 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]([CH3:8])[CH2:6][O:5][C:3]1=[O:4].[NH3:9].ClCCl.CO>C(O)C>[CH3:1][C@@H:2]([C@@H:7]([CH3:8])[CH2:6][OH:5])[C:3]([NH2:9])=[O:4]
Reactant: C[C@@H]1C(=O)OC[C@@H]1C
Reactant: N
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: C[C@H](C(N)=O)[C@@H](C)CO
Yield: 60.9 %

Procedure:
(2S,3R)-2,3-dimethylbutyrolactone (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (2S,3R)-2,3-dimethyl-4-hydroxybutyramide.
Reaction SMILES: C([NH:5][S:6]([C:9]1([CH2:12][CH:13]=[CH2:14])[CH2:11][CH2:10]1)(=[O:8])=[O:7])(C)(C)C.CC1(S(N)(=O)=O)CC1>>[CH2:12]([C:9]1([S:6]([NH2:5])(=[O:8])=[O:7])[CH2:11][CH2:10]1)[CH:13]=[CH2:14]
Reactant: C=CCC1(S(=O)(=O)NC(C)(C)C)CC1
Agent: CC1(S(N)(=O)=O)CC1
Product: C=CCC1(S(N)(=O)=O)CC1
Yield: 40 %

Procedure:
Example 4,1-allylcyclopropylsulfonamide, was obtained in 40% yield from N-tert-butyl-(1-allyl)cyclopropylsulfonamide according to the procedure described in the synthesis of 1-Methylcyclopropylsulfonamide. The compound was purified by column chromotography over SiO2 using 2% MeOH in CH2Cl2 as the eluent: 1H NMR (CDCl3) δ 0.88 (m, 2H), 1.37 (m, 2H), 2.66 (d, J=7.0 Hz, 2H), 4.80 (s, 2H), 5.16 (m, 2H), 5.82 (m, 1H); 13C NMR (CDCl3) δ 11.2, 35.6, 40.7, 119.0, 133.6.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([O:29]C2CCCCO2)[CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.CCOC(C)=O>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1
Reactant: CCCOC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCOC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](O)C[C@H]1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
A 20 mL vial equipped with a magnetic stirbar was charged with 218 mg (0.42 mmol) of THP-ether 15 dissolved in 5 mL of methanol. To this was then added 350 mg (1.39 mmol) of pyridinium p-toluenesulfonate and the mixture was stirred at 25° C. over 8 h. The reaction was sampled by TLC (Rf of product was 0.5 in EtOAc) and worked up by concentration in vacuo to remove methanol. The residual products were taken up in ethyl acetate and filtered through 20 g of silica gel eluting with 300 mL of EtOAc. The filtrate was concentrated to yield 156 mg of products which were further purified by FCC through 25 g of silica gel, eluting with 1:1 EA-hexanes then 100% EA to yield 140 mg of product triol 16 as an oil; 1H NMR (CDCl3): 0.94 (t, J=7.2 Hz, 3H), 1.17 (d, J=6 Hz, 3H), 1.22-1.72 (m, 18H), 1.91 (m, 2H), 2.05-2.36 (m, 4H), 3.30 (br s, 1H), 3.78 (m, 1H), 4.02 (m, 5H), 4.5 (m, 2H), 5.50 (m, 2H). 13C NMR: 10.53, 21.52, 22.09, 23.74, 25.03, 26.83, 29.08, 29.49, 32.90, 34.42, 36.75, 38.52, 43.59, 53.53, 57.75, 60.98, 66.06, 67.50, 72.56, 74.98, 133.27, 135.79, 174.24.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.C(N(CC)CC)C.C(O)(=O)C(O)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:34]1>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:33]2[CH2:38][CH2:37][CH2:36][C@@H:35]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:34]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCNC1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@@H](CNC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.478 g, 1.76 mmol) in CH2Cl2 was added triethylamine (0.98 mL, 0.712 g, 7.04 mmol), and the mixture was cooled to 0° C. To the reaction mixture was added tert-butyl ((R)-piperidin-3-yl)methylcarbamate oxalate (prepared analogously to 2-(7-Methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol, oxalate salt, see Example 130; 700 mg, 2.3 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was quenched with water, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-2% EtOAc in CH2Cl2 gave tert-butyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (700 mg, 88%). LC/MS: nm/z 449.5 (M+H)+ at 2.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).