Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[CH3:31][C:32]1([CH3:41])[O:36][C@H:35]([CH2:37][CH:38]=O)[C:34](=[O:40])[O:33]1>CCOCC.CCOCC.C1COCC1>[CH3:2][O:3][CH:4]=[CH:38][CH2:37][C@H:35]1[O:36][C:32]([CH3:41])([CH3:31])[O:33][C:34]1=[O:40]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OC(=O)[C@@H](CC=O)O1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC=CC[C@H]1OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 60.1 %

Procedure:
(Conditions modified from Duttone, F. E., et. al., J. Med. Chem. 2003, 46, 2057) To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (1.19 g, 3.48 mmol) in anhydrous ether (50 mL) at −10° C. under nitrogen was added phenyllithium (1.93 mL, 3.48 mmol) 1.8 M solution in diethyl ether, over 1 minute using a syringe. The mixture was stirred at 0° C. for 30 minutes and then cooled to −78° C. A solution of (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (Preparation D, Step B; 0.500 g, 3.16 mmol) in ether/THF 1:1 (50 mL) was introduced via addition funnel, and the reaction mixture was stirred at −78° C. for 1 hour and then warmed to ambient temperature and stirred for 4 hours. The crude was filtered and the residue was purified over silica gel (5-50% EtOAc in hexanes) to afford (R)-5-(3-methoxyallyl)-2,2-dimethyl-1,3-dioxolan-4-one (0.355 g, 1.90 mmol, 60% yield) as a clear, colorless oil (mixture of (E)- and (Z)-isomers).
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO[C:22](OC)([CH3:24])[CH3:23]>C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>[C:4]([O:3][C:1]([N:8]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:18][O:19][C:22]1([CH3:24])[CH3:23])=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A solution of Boc-L-Tyrosinol (1 g, 3.74 mmol), p-toluenesulfonic acid (0.0356 g, 0.187 mmol), and dichloromethane (DCM) (7.66 mL) was added 2,2 dimethoxypropane (2.3 mL, 18.7 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen. Reaction mixture was washed with sodium bicarbonate (20 mL). Organic layer was separated and washed with sodium bicarbonate (20 mL). The sodium bicarbonate layers were combined and washed with DCM (20 mL). DCM layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to obtain a crude mixture that was purified by silica gel flash chromatography, using EtOAc/hexane (gradient system) to obtain product (0.87 g, 83%): 1H NMR (400 MHz, CDCL3): δ 1.42-1.68 (m, 15H), 2.57-2.63 (m, 1H), 3.00-3.14 (m, 1H), 3.74-3.80 (m, 2H), 3.91-4.05 (m, 1H), 6.77 (t, 2H, J=8.8 Hz), 7.08 (dd, 1H, J=8.0 Hz, J=16 Hz).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([CH3:14])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.[B:21](OC)([O:24]C)[O:22]C>C1COCC1.Cl>[CH3:13][O:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:14])[C:3](=[O:15])[C:2]=1[B:21]([OH:24])[OH:22]
Reactant: COc1c(Br)c(=O)n(C)c2ccccc12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(B(O)O)c(=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of 3-bromo-4-methoxy-1-methylquinolin-2(1H)-one (2.7 g, 10.07 mmol) in THF (5 mL) was added n-butyllithium (2.5 M in Hexane, 4.03 mL) under nitrogen atmosphere at −78° C. and the reaction mixture was maintained at this temperature for 1 h. A cooled solution of trimethyl borate (1.35 mL, 12.08 mmol) was added at −78° C., and the reaction mixture was maintained at this temperature for 2 h. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with 1M HCl and a white solid precipitated from the solution. The precipitate was filtered, washed with water and EtOAc, then dried under high vacuum to provide (4-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)boronic acid (1.5 g, MS: 234.1 [M+H+].)
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH2:31]>>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Cc1cccc(C)c1N
Product: Cc1cccc(C)c1Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2,6-dimethylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.14 (s, 6H), 2.31 (s, 3H), 4.40 (d, J=3.2 Hz, 2H), 5.52 (bs, 1H), 5.71 (s, 1H), 6.90 (bs, 1H), 7.04-7.14 (m, 4H), 7.46 (t, J=9.4 Hz, 1H), 8.45 (d, J=4.8 Hz, 1H); MS (ESI) m/z 335.0 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:13]=2)[O:3]1.[CH2:21]=O.[BH4-].[Na+]>CO>[CH3:21][N:17]1[CH2:18][CH2:19][CH:14]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:20])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:15][CH2:16]1
Reactant: C=O
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (0.500 g, 1.80 mmol) and 37% aqueous formaldehyde solution (0.269 mL, 3.61 mmol) in MeOH (10.0 mL) were combined and stirred at 40° C. for 2 h. Then sodium borohydride (205 mg, 5.41 mmol) was carefully added to the reaction mixture left to stir for 16 h. The reaction was concentrated in vacuo to a solid. The crude product was dissolved in EtOAc and washed with water several times. The organic layer was collected, dried with sodium sulfate, filtered and concentrated in vacuo to a solid to yield the desired product. 1H NMR (400 MHz, CD3OD): δ 7.90 (s, 1H), 7.67 (s, 1H), 4.16-4.26 (m, 1H), 3.00 (d, J=12.13 Hz, 2H), 2.34 (s, 3H), 2.25 (td, J=11.75, 3.28 Hz, 2H), 2.03-2.15 (m, 4H), 1.31 (s, 12H).
Reaction SMILES: Cl.[CH2:2]1[C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][NH:5]2)[CH2:3]1.N1C=CC=CC=1.CCN(C(C)C)C(C)C.[Cl:25][C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.Cl>C(Cl)Cl>[CH2:3]1[C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][N:5]2[C:26]([Cl:25])=[O:28])[CH2:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCC2(CC2)NC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1CCCCC12CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a vigorously stirred pale yellow solution of 4-azaspiro[2.5]octane hydrochloride (ABCR, 443 mg, 3.00 mmol), pyridine (0.36 mL, 4.5 mmol) and DIPEA (0.52 mL, 3.0 mmol) in DCM (10 mL) at 0° C. was added a solution of triphosgene (594 mg, 2.00 mmol) in DCM (5 mL) dropwise over 5 min. The resulting orange solution was stirred at 0° C. for 30 min, and at RT for 66 h. Aq. HCl solution (1M, 15 mL) was added and the mixture stirred for 30 min. The aqueous was extracted with DCM (4×15 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave the title compound as a red-brown oil (100% yield). 1H NMR (300 MHz, CDCl3): ˜2:1 ratio of rotamers, 0.71-0.76 (1.33H, m), 0.82 (0.67H, br s), 1.00-1.04 (1.33H, m), 1.09 (0.67H, br s), 1.53-1.59 (2H, m), 1.64-1.72 (2H, m), 1.75-1.83 (2H, m), 3.61-3.74 (2H, m).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(P([N:65]=[N+:66]=[N-:67])(C2C=CC=CC=2)=O)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[N:65]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=[N+:66]=[N-:67]
Reactant: OCCCCCc1ccc(Oc2ccccc2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCCCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the product from Step 1 (3.5 mmol) in 15 mL of THF at -0° C. was added triphenylphosphine (921 mg), followed by diethylazodicarboxylate (0.55 mL) and diphenylphosphoryl azide (0.75 mL). The solution was allowed to warm to room temperature overnight. After 48 hours, the reaction was poured into ethyl acetate and sat. aq. NaHCO3 solution, then washed with brine, dried (Na2SO4) and concentrated in vacuo to provide the crude product. Purification by chromatography on silica gel (50% CH2Cl2 /hexane) provided 360 mg of the titled compound.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:8]([CH3:17])=[CH:7][N:6]=1)(=O)=O.[O:18]1CCOCC1>>[CH3:17][C:8]1[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:10][C:5](=[O:18])[NH:6][CH:7]=1
Reactant: Cc1cnc(S(C)(=O)=O)nc1-c1cccnc1
Reactant: C1COCCO1
Product: Cc1c[nH]c(=O)nc1-c1cccnc1
Reaction time: 1 h
Yield: 97 %

Procedure:
2-Methanesulfonyl-5-methyl-4-pyridin-3-yl-pyrimidine (1.3 g, 5.22 mmol) was dissolved in dioxane (80 ml) and then 2N NaOHaq (21 ml, 42 mmol) was added dropwise at room temperature. After stirring for 1 hour, the solution was neutralized with 37% HClaq. The residue was purified by flash chromatography with DCM-MeOH—NH4OH (9-1-0.1) to give 951 mg of the title compound as a light brown powder. (97% yield).
Reaction SMILES: [ClH:1].O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5]>C(N)CC>[ClH:1].[CH2:4]([NH:5][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5])[CH2:6][CH3:8]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: CCCN
Product: CCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Temperature: 25 °C

Procedure:
21.5 g of glucosamine hydrochloride were suspended in 17.7 g of n-propylamine and heated at 70° until a clear solution resulted. The product precipitated on cooling down to room temperature.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:20][CH3:21])[CH:13]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:40])C=1.[Na]>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:20]([CH3:21])=[O:40])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(SC)c1
Agent: [Na]
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(S(C)=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a solution of 200 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfanyl-benzonitrile (prepared according to the method described in example 23) in 4 ml of dichloromethane at 0° C. was added 74 mg of meta-chloroperbenzoic acid. The resulting mixture was stirred at 0° C. for 2 hours then kept in the freezer overnight. A saturated aqueous solution of sodium hydrogenocarbonate was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 203 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfinyl-benzonitrile, which was transformed into 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfinyl-phenyl}-4H-[1,2,4]oxadiazol-5-one according to the method described in example 1.
Reaction SMILES: C(O)C.C(O[Na])C.[O:8]=[CH:9][C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1.Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH:9]([C:10]1[CH:18]=[CH:17][C:15]([O:16][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:12]([O:13][CH3:14])[CH:11]=1)=[O:8]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: CCO[Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1OC
Temperature: 80 °C
Yield: 36 %

Procedure:
In a co-solvent including ethanol (3 mL) and DMF (3 mL), 1N ethoxy sodium (NaOEt) (2.96 mL, 2.96 mmol) was added dropwise to a solution including vanillin (300 mg, 1.97 mmol) and ethyl α-bromoisobutyrate (0.43 mL, 2.93 mmol), and then, the reaction mixture was heated at a temperature of 80° C. overnight. Ethanol was evaporated, and the residual was distributed between ether and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (EtOAc) (4:1) to obtain Compound 122a (188.7 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:28][CH3:29])[C:8](=[O:27])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([O:24][CH2:25][CH3:26])[C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:28][CH3:29])[C:8](=[O:27])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([O:24][CH2:25][CH3:26])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(Cl)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(4-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.240 g, 0.54 mmol) in THF (30 mL) was added aqueous 0.10 M LiOH (15 mL) and the solution was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with methylene chloride (2×50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 2 g/15 mL) with ethyl acetate as the eluent afforded 0.138 g (61%) of a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=[C:2]([NH:17][C:18]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][NH:24]3)=[CH:20][CH:19]=2)[N:7]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc3cn[nH]c3c2)n1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A mixture of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine (1 g, 3.6 mmol), 6-aminoindazole (0.5 g, 3.7 mmol), tetrahydrofuran (10 ml), and diisopropylethylamine (0.65 ml, 3.7 mmol) was stirred for 1 hour. After concentrating under reduced pressure, the residue was treated with water (25 ml) and stirred for 10 minutes. The solid was filtered, treated with hydrochloric acid (1 M, 10 ml), stirred vigorously for 10 minutes, and filtered. The solid was purified by flash chromatography on silica eluting with 5% methanol-dichloromethane to yield the title compound (600 mg, 45% yield). 1H NMR (DMSO-d6) 13.04 (br s, 1H), 10.90-10.97 (m, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.71 (m, 2H), 7.53 (m, 1H), 7.41 (m, 1H), 7.34 (m, 1H), 2.50-2.54 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6]2.S(=O)(=O)(O)O.[CH3:19]OS(OC)(=O)=O.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:19][N:3]1[C:2]([CH3:1])=[C:10]2[C:5]([CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:9]2)=[N:4]1
Reactant: Cc1[nH]nc2cc([N+](=O)[O-])ccc12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c2ccc([N+](=O)[O-])cc2nn1C
Temperature: 50 °C

Procedure:
3-methyl-6-nitro-2H-indazole (0.85 g, 5 mmol, 1 equiv) was dissolved in DMSO (4 ml) and treated with sulphuric acid (0.26 ml, 5 mmol, 1 equiv) to yield a thick slurry that was treated with dimethylsulfate (1.36 ml, 14 mmol, 2.8 equiv). The reaction mixture was heated to 50° C. under nitrogen for 72 hrs. The reaction mixture was cooled down to room temperature and treated with a saturated solution of sodium bicarbonate (10 ml). The reaction mixture was extracted with DCM (2×20 ml). The organic layers were washed with water (20 ml). Propanol was added and the organic layers were evaporated under vacuum to yield a solid which was filtered and washed with heptane (5 ml). The desired compound was collected as a brown solid (0.48 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[C@H:9]([OH:12])[CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:33]1[CH:38]=[CH:37][CH:36]=CC=1>C(OCC)(=O)C>[CH:38]1([NH:33][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:36][CH2:37]1
Reactant: c1ccncc1
Reactant: OC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: O[C@H](CNC1CC1)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Reaction time: 3 h

Procedure:
(2S,3S)-3-(3-Fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol (example 47, step 5) (0.6 g, 2.1 mmol) was dissolved in pyridine (5 mL) and para-toluenesulfonyl chloride (0.44 g, 2.3 mmol) was added. The mixture was stirred for 3 hours then the reaction mixture was diluted with ethyl acetate and washed with water, followed by a saturated aqueous solution of copper sulfate, a 2N aqueous solution of hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M solution in ethanol, 25 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via flash column chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give (1S,2R)-3-(cyclopropylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol as a colorless oil. The freebase was dissolved in diethyl ether (5 mL) and treated with a 1N ethereal solution of hydrochloric acid (1 equivalent). The white precipitate was collected and dried under vacuum to give 80 mg (12%) of (1S,2R)-3-(cyclopropylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol hydrochloride. HRMS: calcd for C20H21FN2O+H+, 325.17107; found (ESI, [M+H]+), 325.1728.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:25]>>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH:20]2[CH3:25]
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(Br)cccc21
Product: CC1c2cccc(Br)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:15])[CH2:13]Cl>ClC1C=CC=C(Cl)C=1>[CH:10]1[C:5]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:13][C:12](=[O:15])[NH:11][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CCl)Nc1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1cccc(Cl)c1
Product: O=C1Cc2ccccc2-c2ccccc2N1
Temperature: 170 °C
Reaction time: 24 h
Yield: 81.8 %

Procedure:
AlCl3 (12.1 g) was added to a solution of N-biphenyl-2-yl-2-chloro-acetamide (9.9 g) in 1,3-dichlorobenzene (99 mL). The reaction mixture was stirred for 24 hours at 170° C., cooled to 0° C. and poured into ice-water (1500 mL). The suspension obtained was filtered off, the precipitate washed with water (250 mL), 2 portions of hexane/dichloromethane 4:1 (25 mL), 2 portions of water (125 mL) and 2 portions of hexane (25 mL) affording 5H,7H-dibenzo[b,d]azepin-6-one (6.9 g, 82.5%) as an off-white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:7]([OH:14])=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[H-].[Na+].I[CH:19]([CH3:21])[CH3:20].O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:7]([O:14][CH:19]([CH3:21])[CH3:20])=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[CH:9]=1)[CH:5]=[O:6]
Reactant: CC(C)I
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)cc(C(C)(C)C)c(OC(C)C)c1C=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
A stirred, cooled (ice bath) solution of 3-bromo-5-tert-butyl-6-hydroxy-2-methyl-benzaldehyde (Intermediate 140, 0.58 g, 2.14 mmol) in anhydrous N,N-dimethylformamide (10 mL) was treated with sodium hydride (0.34 g of 60% suspension in mineral oil, 8.56 mmol). After 30 minutes, 2-iodopropane (1.3 mL, 12.84 mmol) was added and the reaction mixture was heated at 75° C. overnight. The reaction mixture was then cooled and poured into iced water and extracted with diethyl ether. The organic extract was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography using 2-4% ethyl acetate in hexane as the eluent afforded the title product (0.43 g, 64%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH2:7][NH:8][C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:11][O:12][CH3:13])C>C(#N)C>[CH3:17][O:16][C:14](=[O:15])[C@@H:9]([N:8]1[CH2:7][C:6]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:5][C:4]1=[O:3])[CH2:10][CH2:11][O:12][CH3:13]
Reactant: CCOC(=O)C=C(CN[C@@H](CCOC)C(=O)OC)Oc1ccccc1Cl
Solvent: CC#N
Product: COCC[C@@H](C(=O)OC)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
A solution of 3-(2-chloro-phenoxy)-4-((S)-3-methoxy-1-methoxycarbonyl-propylamino)-but-2-enoic acid ethyl ester (112 mg, 0.29 mmol) in acetonitrile (2 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 130° C. for 2 h, 150° C. for 2 h, and 160° C. for 3 h. The mixture was then concentrated in vacuo and purified by AnaLogix IntelliFlash flash chromatography (8 g column, 20% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methoxy-butyric acid methyl ester (71 mg, 39% over two steps) as a clear colorless oil.