Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:20]1[CH2:24][CH2:23][N:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][NH2:45].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:22]2[CH2:23][CH2:24][C@@H:20]([N:8]([C:9]3[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:18])[NH:45][O:44][CH:39]4[CH2:40][CH2:41][CH2:42][CH2:43][O:38]4)=[CH:13][N:14]=3)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:21]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 58.8 %

Procedure:
To a stirred solution of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (142 mg) in DMF (3 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (67 mg), HOBT (77 mg), and EDCI hydrochloride (109 mg), and the resulting mixture was stirred at ambient temperature for 7 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water, saturated NaHCO3 solution, and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=5:1) to give tert-butyl [(3R)-1-(diphenylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (100 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N:18][CH:19]=[CH:20][CH:21]=2.[OH:23]O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N+:18]([O-:23])[CH:19]=[CH:20][CH:21]=2
Reactant: OO
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ncccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2c(ccc[n+]2[O-])[nH]1

Procedure:
3.19 g of 2-(2-methoxy-4-methanesulfonyloxy-phenyl)imidazo[4,5-b]pyridine were dissolved in 25 ml of trifluoroacetic acid, and then 5 ml of 30% hydrogen peroxide were added dropwise thereto. The mixture was refluxed for one hour and concentrated to about one-tenth of its volume. The residue was poured onto ice and digested until it had crystallized throughout.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]2C(=O)NC(=O)NC2=O)=[CH:12][CH:11]=1.[OH-].[Na+].Cl>O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccncc1
Reactant: O=C1NC(=O)C(CCc2ccc(Cl)cc2)C(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(CCCc2ccncc2)cc1
Temperature: 200 °C

Procedure:
A mixture of 3 g (0.02 m) of 4-chloropyridine hydrochloride and 5.3 g (0.02 m) of 5-[2-(4-chlorophenyl)-ethyl]barbituric acid was thoroughly mixed with a mortar and pestle, heated in a 200° C. oil bath for 15-20 minutes, and then cooled. To the resulting product was added 5 g of NaOH and 40 mL of water, and the mixture was refluxed for several hours. After cooling the mixture, it was acidified with concentrated HCl, again refluxed for 45 minutes, and then cooled. The resulting material was diluted into water; the pH of the aqueous solution was adjusted to 7-8 with dilute NaOH; then the product was extracted into CH2Cl2. The CH2Cl2 layer was separated, filtered through phase separating paper, and concentrated. The residue was adsorbed onto silica gel and chromatographed using 5% EtOAc/CH2Cl2 >10% EtOAc/CH2Cl2 >5% MeOH/EtOAc (wash). Yield 0.82 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[F:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:23]2[CH:24]=[CH:25][C:26]([F:27])=[C:21]([F:20])[CH:22]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(F)c(F)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 3,4-difluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>C1COCC1>[OH:8][CH2:7][C@@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](N)CO
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a solution of L-(+)-leucinol (5.0 g, 42.8 mmol) in THF (65 mL) was slowly added 1,3-propanesultone (4.85 g, 40.7 mmol in THF (10 mL)). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×50 mL). The solid was dissolved in 50% water/EtOH (400 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (150 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (6.11 g, 63%). 1H NMR (D2O, 500 MHz) δ ppm 3.77 (m, 1H), 3.59 (m, 1H), 3.23 (m, 1H), 3.13 (m, 2H), 2.90 (m, 2H), 2.02 (m, 2H), 1.53 (m, 2H), 1.35 (m, 1H), 0.81 (d, 3H, J=16.1 Hz). 13C (D2O, 125 MHz) δ ppm 58.72, 58.00, 48.17, 43.54, 35.96, 24.34, 22.53, 21.62, 20.89. [α]D=+16.6° (c=0.0022 in water), ES-MS 240 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28](/[CH:34]=[CH:35]\[CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28](/[CH:34]=[CH:35]\[CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C/C=C\[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C/C=C\[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 17 h
Yield: 72.9 %

Procedure:
To a stirred solution of 8.1 (0.0529 g, 0.11 mmol) in THF (2.00 mL, 24 mmol) and EtOH (2.00 mL, 34 mmol) at 23° C. was added 1N sodium hydroxide (2.00 mL, 2.0 mmol). Stirring continued for 17 hours. The reaction mixture was concentrated in vacuo, 1N HCl was added to reach pH 1, and the resulting mixture was extracted with EtOAc (3×10 mL) dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give compound 8 as a clear oil (0.0382 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (1H, d, J=8.2 Hz), 7.40 (1H, dd, J=8.2, 2.0 Hz), 7.16 (2H, d, J=9.0 Hz), 7.08 (1H, d, J=2.0 Hz), 7.00 (1H, t, J=8.8 Hz), 6.92 (2H, d, J=9.0 Hz), 6.87 (1H, dt, J=8.9, 3.9 Hz), 6.80 (1H, m), 5.58-5.49 (2H, m), 4.99 (2H, s), 4.14 (1H, m), 3.79 (3H, s), 2.75 (1H, dd, J=15.1, 6.8 Hz), 2.64 (1H, dd, J=15.1, 8.6 Hz), 1.66 (3H, d, J=5.1 Hz), 1.23 (9H, s). m/e: 951.4 (2M−H)+, 475.1 (M−H)+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:15]1[O:16][N:17]=[C:18]2[CH:23]=[C:22]([C:24](Cl)=[O:25])[CH:21]=[CH:20][C:19]=12>ClCCl>[CH:1]1([NH:7][C:24]([C:22]2[CH:21]=[CH:20][C:19]3=[N:15][O:16][N:17]=[C:18]3[CH:23]=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)c1ccc2nonc2c1
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of cyclohexylamine (1 ml) and triethylamine (1.7 ml) in dichloromethane (20 ml) was added a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (730 mg, 4 mmol) in dichloromethane (10 ml). After stirring the mixture for 1 hour, the organic phase was washed with 1N HCl and conc. NaHCO3 solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was triturated with ether to give a white solid (265 mg, yield=27%). Mp=172-173° C., 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.90 (d, 1H, J=9.0 Hz); 7.82 (d, J=9.0 Hz, 1H); 6.09 (“s”, NH, 1H), 4.05-3.97 (m, 1H) and 2.09-1.18 ppm (m, 10H).
Reaction SMILES: [S:1]1[CH:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[C:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH:20]=2)[CH2:4][N:3]=[CH:2]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[S:1]1[CH:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH2:4][N:3]=[CH:2]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C4CN=CS4)cc23)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2c[nH]c3ccc(C4CN=CS4)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
To a mixture of 0.54 gm (1.8 mMol) 5-(4,5-dihydrothiazol-5-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 20 mL trifluoroacetic acid were added slowly 320 μL (2 mMol) triethylsilane. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residual oil was partitioned between ethyl acetate and aqueous potassium carbonate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was crystallized from acetonitrile to provide 0.40 gm (74%) of the title compound compound as a crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[C:3]=1[O:10][CH2:11][CH:12]1[O:14][CH2:13]1.[OH-].[Na+].O>C(O)C>[OH:14][CH2:13][CH:12]1[CH2:11][O:10][C:3]2[C:4]([Cl:9])=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[O:1]1
Reactant: Oc1ccc(Cl)c(Cl)c1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCC1COc2c(ccc(Cl)c2Cl)O1
Yield: 99.3 %

Procedure:
To a solution of 1.128 g of 1-hydroxy-2-(2,3-epoxypropyloxy)-3,4-dichlorobenzene dissolved in 10 ml of ethanol is added 4 ml of 2N sodium hydroxide. The mixture is heated at 80° C. for 5 minutes, to which water is then added and extracted with ether. The organic layer is washed with water, then dried and evaporated to give 1.120 g of the objective 3-hydroxymethyl-7,8-dichloro-1,4-benzodioxane (IIb) as an oil. Yield 99%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[OH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.Cl>CN(C=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([O:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(F)cc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
Potassium carbonate (3.19 g, 23.1 mmol) and 2,5-difluoronitrobenzene (7.34 g, 46.1 mmol) were added to a solution of 3-hydroxy-5-methylpyrazole (4.52 g, 46.1 mmol) in DMF (80 ml) at room temperature, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (100 ml) and extracted with ethyl acetate (100 ml×2). An organic layer was washed with water (100 ml×2), dried over anhydrous magnesium sulfate and filtered to remove magnesium sulfate, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of 3-(4-fluoro-2-nitrophenyloxy)-5-methylpyrazole (5.33 g, yield: 48.8%). mp: 81-84° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.28 (d, J=0.5 Hz, 3H), 5.71 (d, J=0.5 Hz, 1H), 7.26-7.38 (m, 2H), 7.69 (dd, J=2.8 and 7.9 Hz, 1H), 9.33 (br s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O.CO>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1ccccc1N

Procedure:
The appropriate 2-nitrobenzoic acid was initially reacted analogously to general methods 2 and 5 with the respective amine to give a 2-nitrobenzamide. Then 4 mmol of the 2-nitrobenzamide were hydrogenated in 50 ml of THF and 50 ml of methanol in the presence of a spatula tip of 10% palladium on carbon at RT under atmospheric pressure. The catalyst was filtered off with suction, the reaction mixture is concentrated, and the corresponding 2-aminobenzamide was obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][CH:18]([C:20]([OH:22])=[O:21])[NH2:19])=[CH:15][CH:14]=1>C(OCC)(=O)C>[CH2:5]([O:4][C:2]([NH:19][CH:18]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:24][CH:23]=1)[C:20]([OH:22])=[O:21])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1ccc(Br)cc1)C(=O)O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(Br)cc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl chloroformate (8.65 mL, 61.5 mmol) was added to a refluxing solution of 4-bromo-dl-phenylalanine (15 g, 61.5 mmol) in ethyl acetate (250 mL). After stirring at reflux overnight, the reaction mixture was cooled to ambient temperature, filtered through celite and concentrated in vacuo to afford 2-{[(benzyloxy)carbonyl]amino}-3-(4-bromophenyl)propanoic acid which was used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl[C:14]([C@:16]12[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:17]1[C@@H:18]1[C@@:31]([CH3:34])([CH2:32][CH2:33]2)[C@@:30]2([CH3:35])[C@@H:21]([C@:22]3([CH3:48])[C@@H:27]([CH2:28][CH2:29]2)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[O:15]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:7]([O:6][C:5]([N:4]([CH3:12])[CH2:3][CH2:2][NH:1][C:14]([C@:16]12[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:17]1[C@@H:18]1[C@@:31]([CH3:34])([CH2:32][CH2:33]2)[C@@:30]2([CH3:35])[C@@H:21]([C@:22]3([CH3:48])[C@@H:27]([CH2:28][CH2:29]2)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]2[CH:39]=[CH:40][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:46][CH:47]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[O:15])=[O:11])([CH3:8])([CH3:9])[CH3:10]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 2-aminoethyl(methyl)carbamate (17.68 mg, 0.101 mmol), Hunig'sBase (0.053 mL, 0.304 mmol) and DMAP (1.240 mg, 10.15 μmol) in DCM (1 mL) was added methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(chlorocarbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (60 mg, 0.101 mmol) in DCM (1 mL). The reaction mixture was stirred for 1 hour. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as white solid (65 mg, 88%). LCMS: m/e 729.61 (M+H)+, 2.72 min (method 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:21][CH:19]1[CH3:20]>>[OH:21][CH:19]([CH3:20])[CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1
Reactant: CC1CO1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Product: CC(O)Cn1ccc2ccc(OCc3ccccc3)cc21

Procedure:
6-Benzyloxyindole (1) (Batcho and Leimgruber, Organic Syntheses, Collective Vol. 7, p. 34 (1990)) is reacted with (±)-propylene oxide and a base in an organic solvent to yield (±)-1-(2-hydroxypropyl)-6-benzyloxyindole (2). Preferably the base is sodium hydride and the solvent is tetrahydrofuran. The temperature is 0° C. to 25° C., preferably about 10° C. Preferably an inert atmosphere, e.g., nitrogen or argon, is maintained.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:35]=[CH:36][CH:37]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([NH:28]C(=O)C(F)(F)F)[N:27]=4)[CH:24]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+].O>C(O)C>[NH2:28][C:26]1[N:27]=[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:35]=[CH:36][CH:37]=[C:6]([C:3]5([C:1]#[N:2])[CH2:4][CH2:5]5)[CH:7]=4)[CH:17]=[CH:16][CH:15]=3)=[CH:24][N:23]2[CH:25]=1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C(F)(F)F)cn5c4)c3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5c4)c3)c2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)-N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]benzamide (450 mg, 0.89 mmol) in ethanol (8.0 mL) was added 1N aqueous sodium hydroxide solution (8.9 mL), and the mixture was stirred at 45° C. for 8 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→80/20), and fractions containing the desired product were concentrated under reduced pressure to give N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 55%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[NH:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:6][CH:7]=1.[C:18](OCC1N(C)C(C(C)C)=C(SC2C=CC=CC=2)N=1)(=O)N>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:13]([CH3:18])[C:12]([CH3:14])=[N:11][C:10]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C(C)C)c(Sc2cccc(Cl)c2)[nH]1
Reactant: CC(C)c1c(Sc2ccccc2)nc(COC(N)=O)n1C
Product: Cc1nc(C(C)C)c(Sc2cccc(Cl)c2)n1C

Procedure:
Compound I-3 was obtained from 5-(3-chlorophenylthio)-4-isopropyl-2-methylimidazole by the same synthetic process as that for Compound I-1 in Example 1 (yield 47%). mp 91 to 94° C.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4].[CH:12](O)=O>O>[CH3:5][C:2]1([CH3:1])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[N:4][CH2:3]1
Reactant: O=CO
Reactant: CC(C)(CN)c1ccccc1
Solvent: O
Product: CC1(C)CN=Cc2ccccc21
Temperature: 200 °C
Yield: 79 %

Procedure:
A mixture of 2-methyl-2-phenylpropylamine (7 g, 0.047 mol) and 96% formic acid (11 ml) was slowly heated to 200° C. and kept at this temperature for 1.25 hours during which time excess formic acid and water was allowed to distil. This mixture was added at 160° C. to a mixture of polyphosphoric acid (51 g) and phosphorous pentoxide (10.5 g) that had previously been heated at 170-180° C. for 1 hour. The resultant mixture was heated at 175° C. for 2 hours, before being cooled slightly and poured into water (500 ml) with stirring. The mixture was washed with ethyl acetate and the aqueous layer basified with 40% aqueous sodium hydroxide and extracted with dichloromethane (3×200 ml). Combined halogenated organics were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a brown oil (5.95 g, 79%).
Reaction SMILES: [CH:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:11]C1C=C2C(CCC2=O)=CC=1.[BH3-]C#N.[Na+]>>[Br:11][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH:1]2[NH2:10])=[CH:5][CH:6]=1
Reactant: NC1CCc2ccccc21
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC1CCc2ccc(Br)cc21

Procedure:
The title indanamine was generated from 6-bromo-1-indanone (2.00 g, 9.50 mmol), NaBH3CN (4.20 g, 66.84 mmol) and NH4OAc (22.00 g, 0.29 mol) according to the protocols as outlined in general procedure C. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 1.59-1.73 (m, 3H), 2.44-2.56 (m, 1H), 2.70-2.82 (m, 1H), 2.84-2.98 (m, 1H), 4.29-4.40 (m, 1H), 6.98-7.18 (m, 1H), 7.26-7.38 (m, 1H), 7.4 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1.CO.[CH3:29]S(O)(=O)=O>>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:29])([CH3:23])[CH3:24])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2

Procedure:
A vessel was charged with (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.679 g, 1.933 mmol) in methanol (23.51 mL, 580 mmol). methane sulfonic acid (0.627 mL, 9.66 mmol) was added, and the vial was sealed and placed in a 70° C. oil bath for 5 hours. The volatiles were evaporated, and the residue was loaded onto a silica gel cartridge in MeOH/DCM. The column was eluted onto an 80-g Redi-Sep column with 30-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM. The fractions containing product were evaporated to give (S)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[O:13]([NH2:15])[CH3:14].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:14][O:13][N:15]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CON
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of 5-bromo-indanone (100 g, 0.474 mol) in ethanol (650 ml) under argon was added methoxylamine hydrochloride (198 g, 2.38 mol) and pyridine (125 ml). The mixture was refluxed for 2.5 hours, cooled to room temperature and poured into saturated aqueous sodium hydrogen carbonate solution. The mixture was then extracted with ethyl acetate and the organic phase dried (Na2SO4) and then concentrated in vacuo. The crude material was recrystallised from isopropanol to furnish the title compound, (110 g, 97%), as a brown solid; 1H NMR (CDCl3) 7.52 (1H, d, J 8.3 Hz), 7.43 (1H, d, J 1 Hz), 7.35 (1H, dd, J 8.3, 1 Hz), 3.97 (3H, s), 2.99 (2H, m), 2.85 (2H, m).