Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N-:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[OH:8])(C)(C)C.[H-].[Na+].[OH2:18]>O1CCCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]2[O:8][C:1](=[O:18])[NH:5][CH2:6]2)=[N:10][CH:11]=1
Reactant: O
Reactant: CC(C)(C)[N-]CC(O)c1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCC(c2ccc(Br)cn2)O1
Temperature: 0 °C
Yield: 72 %

Procedure:
Compound 14a (70 mg, 0.85 mmol) was dissolved in dried tetrahydrofuran (5 mL), cooled to 0° C. NaH (51 mg, 1.28 mmol) was added, and after its completion, the reaction mixture was raised to room temperature, and then raised to 50° C. to react for 4 hrs. The reaction was monitored by TLC (petroleum ether/ethyl acetate=8/1). After the reaction completed, water was added, and the mixture was extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. Column chromatography (petroleum ether/ethyl acetate=5/1) afforded 150 mg of white solid (compound 14b), yield 72%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=O.CC(OC(C)=O)=O.C(N(C(C)C)CC)(C)C.Cl>C(OCC)(=O)C.O>[CH3:21][O:20][C:18]([C:17]1[CH:22]=[CH:23][C:14]([CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([OH:11])=[O:10])=[CH:15][CH:16]=1)=[O:19]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C=C(C(=O)O)c2ccc(C)cc2)cc1
Temperature: 30 °C
Reaction time: 6 h
Yield: 65.5 %

Procedure:
A mixture of 4-methylphenylacetic acid (3 g, 20 mmol) and methyl 4-formylbenzoate (3.3 g, 20 mmol) was dissolved under stirring with Ac2O (8 mL). To this mixture, diisopropylethylamine (DIPEA) (5.2 mL, 30 mmol) was added and stirred at 30° C. for 6 hours. Upon completion, as monitored by TLC using 100% ethyl acetate as eluent, the reaction mixture was poured into water and pH was adjusted to 3 using aqueous dilute HCl (1:1). The aqueous layer was extracted with ethyl acetate (2×150 mL). The combined ethyl acetate layer was washed with water till the washings were neutral and dried over anhydrous Na2SO4. The ethyl acetate layer was evaporated to dryness to obtain a sticky compound, which was triturated with cold dichloromethane (DCM) to furnish a pale yellow solid. It was filtered and dried under vacuum to afford the title compound (3.88 g, 66% yield).
Reaction SMILES: C(OC([C:6]1[C:7]([N:15]2[CH2:20][CH2:19][C:18]([NH2:32])([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=O)C.O>[OH-].[K+]>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:18]2([NH2:32])[CH2:19][CH2:20][N:15]([C:7]3[CH:6]=[CH:11][N:10]=[C:9]4[NH:12][N:13]=[CH:14][C:8]=34)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1N1CCC(N)(Cc2ccc(C(C)(C)C)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(CC2(N)CCN(c3ccnc4[nH]ncc34)CC2)cc1
Yield: 46.7 %

Procedure:
4-[4-Amino-4-(4-tert-butyl-benzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (23 mg, 0.053 mmol) was suspended in 2M potassium hydroxide (1 mL) and irradiated in a microwave reactor (250 W) for 2 hours at 120° C. After cooling, water (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2×4 mL). The organic layers were dried (Na2SO4) and concentrated to give a yellow solid (9 mg, 47%). LC-MS (LCT2) m/z 364 [M+H+], Rt 2.80 min.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:6](=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:10][CH:9]=1.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:6](=[O:26])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][CH2:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=1
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(SCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(SCc2ccccc2C(=O)O)cc1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
Methyl 2-{[(4-{2-[(2,4-difluorobenzyl)(heptyl)amino]-2-oxoethyl}phenyl)thio]methyl}-benzoate (31 mg, 0.057 mmol) was dissolved in THF (1 ml) and cooled in an ice-bath. Lithium hydroxide (2 mg, 0.075 mmol) in water (1 ml) was added. After the addition, the cooling bath was removed and the mixture was stirred overnight. LC-MS showed there was very little product. More lithium hydroxide (3 mg) was added and the mixture was stirred for 6 days more and HPLC showed about 30% product. More (3 mg) of lithium hydroxide was added and the mixture was stirred for 13 days more. It was evaporated in vacuum to remove THF. The residue was acidified with 10% hydrochloric acid, pH˜3, and extracted with ethyl acetate (×2). The organic phases were combined, dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 500 g/3 ml) using DCM, MeOH/DCM (0.5:99.5) as eluant gave 17 mg desired product, yield 56%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@:15]2([CH2:19][N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)[C@H:17]([CH3:18])[O:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@:15]([OH:16])([C@H:17]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[CH3:18])[CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](n1nccn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
To a stirred solution of 1H-1,2,3-triazole (1.49 g) in dimethylformamide (35 ml) was added portionwise 60% sodium hydride in oil (0.63 g) under ice-cooling. Ten minutes later, to the mixture was added (2R,3S)-2-(4-fluorophenyl)-3-methyl-2-[(1H-1,2, 4-triazol-1-yl)methyl]oxirane (3.34 g), followed by stirring for 4 hours at 80° C. After cooling, the mixture was concentrated. The residue was partitioned with ethyl acetate (300 ml) and saturated saline. The organic layer was washed with saturated saline, dried and distilled under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 150 g, eluent: dichloro methane/acetone=3:2>1:1). The first eluate gave Compound 36 (1.02 g), followed by recrystallization from dichloromethane-diisopropyl ether to afford colorless prisms. Then a second eluate gave Compound 37 (1.05 g), followed by recrystallization from dichloromethane-diisopropyl ether to afford a colorless crystalline powder.
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][C:16](Br)([C:22]([O:24]CC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(B([CH2:35][CH3:36])CC)C.O=O>CS(C)=O.O>[C:1]([C:9]1[N:10]2[C:15](=[CH:14][CH:13]=1)[C:16]([C:22]([O:24][CH2:35][CH3:36])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Reactant: CCB(CC)CC
Agent: O=O
Agent: OO
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21

Procedure:
To a mixture of a compound of formula VII, preferably 2-benzoyl-[3-bromo-3,3-di(ethoxycarbonyl)propyl]pyrrole, in a suitable solvent, is added an alkyl radical. A preferred alkyl radical, the methyl radical, is derived from the reaction of ferrous sulfate and hydrogen peroxide in dimethyl sulfoxide. In an alternative preferred embodiment, the alkyl radical is derived from a trialkylborane, preferably triethylborane, with oxygen (air) in a nonpolar solvent. The reaction mixture is allowed to stir until the reaction is complete. The reaction mixture is poured into water and extracted with a polar solvent, such as methylene chloride or diethyl ether. The combined organic extracts are washed, dried and concentrated under reduced pressure to yield a compound of formula I, preferably diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate, which may be isolated by conventional means.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[N:3]=1.[C:10]([O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>>[NH2:9][C:4]1[N:3]=[C:2]([C:21]2[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:15]([O:14][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:16])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1cnc(N)nc1Cl
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cnc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 120 °C
Yield: 49.9 %

Procedure:
To 4-chloro-5-methylpyrimidin-2-amine (150 mg, 1.04 mmol), tetrakistriphenylphosphine Palladium (0) (60 mg, 0.052 mmol) and 3-(tert-butoxycarbonyl)phenylboronic acid (347 mg, 1.56 mmol), 1,2-DME (3 mL) and Na2CO3 (1.04 mL, 2 M, 2.08 mmol) were added and heated to 120° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered using EtOAc and the filtrate was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 3-(2-amino-5-methylpyrimidin-4-yl)benzoate (148 mg, 50%). ESI-MS m/z calc. 285.1, found 286.5 (M+1)+. Retention time 1.33 minutes.
Reaction SMILES: [N+:1]([C:4]1[C:5](SC#N)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][C:12]=2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:8][CH:9]=1)([O-:3])=[O:2].[NH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C>C1COCC1.CCOC(C)=O>[C:25]([O:24][C:23](=[O:29])[NH:22][C:12]1[CH:13]=[CH:14][C:15]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:16][C:11]=1[NH:10][C:7]1[N:6]=[C:5]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)([CH3:26])([CH3:28])[CH3:27]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1Nc1ncc([N+](=O)[O-])c(NC2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
tert-Butyl 2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)-4-(trifluoromethoxy)phenylcarbamate (0.94 g, 2.0 mmol) was dissolved in 40 mL anhydrous THF, then added 0.22 g (2.2 mmol) 4-amino-tetrahydropyran, and 0.7 mL (4.0 mmol) N,N-diisopropylethylamine. The mixture was stirred at room temperature under Argon balloon for 3 hrs till HPLC showed the completion of reaction. The orange-red solution was diluted with EtOAc, washed with brine twice, and then dried over Na2SO4. Solvents were removed under vacuum to give 1.0 g orange-yellow solid as the crude product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.CCN(CC)CC>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNC1
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCCl)c2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCN3CCCC3)c2n1
Temperature: 70 °C
Yield: 72.2 %

Procedure:
A solution of 5-butyl-3-(6-chlorohex-1-yn-1-yl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (30 g, 65.8 mmol), pyrrolidine (16.32 mL, 197 mmol) and Et3N (27.5 mL, 197 mmol) in Acetonitrile (400 mL) was heated at 70° C. for 16 hours. Further pyrrolidine (7 g) was added and the solution was heated at 70° C. for 8 hours. The cooled solution was evaporated and the residue was purified on a silica cartridge (750 g) eluted with EtOAc (2 column volumes) followed by 20-30% MeOH (+1% Et3N)/EtOAc (16 column volumes) to give the title compound as a yellow gum (23.3 g).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]3[N:15]=[C:16]([CH3:19])[O:17][CH:18]=3)=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3].CC(C)([O-])C.[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[N:41]=[N:42][N:43]([C:45]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:44]=2)=[CH:30][CH:29]=1.[Cl-].[Na+]>CS(C)=O>[CH2:1]([C:4]1[N:8]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[N:41]=[N:42][N:43]([C:45]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:44]=3)=[CH:32][CH:33]=2)[C:7]2[CH:9]=[C:10]([C:14]3[N:15]=[C:16]([CH3:19])[O:17][CH:18]=3)[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cc(-c3coc(C)n3)cc(C)c2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1nc2c(C)cc(-c3coc(C)n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.8 g (11 mMol) of 2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazole and 1.7 g (15 mMol) of potassium tert.butoxide in 60 ml of dimethylsulphoxide is stirred for 15 minutes at ambient temperature. Then 6.0 g of (11 mMol) of 4'-bromomethyl-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl are added and the mixture is stirred for a further 3 hours at ambient temperature. Then the solution is stirred into about 150 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (500 g of silica gel; eluant: petroleum ether/ethyl acetate=1:1)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[NH2:22][C@@H:23]([CH2:26][CH3:27])[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:17](=[O:18])[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=2)=[CH:15][CH:14]=1)([CH3:21])[CH3:20])[CH2:26][CH3:27]
Reactant: COCc1cccc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Reactant: CC[C@H](N)CO
Product: CC[C@@H](CO)NC(=O)C(C)(C)c1ccc(-c2cccc(COC)c2)cc1
Yield: 52 %

Procedure:
Prepared in a similar manner to Example 27 from 2-(3′-(methoxymethyl)biphenyl-4-yl)-2-methylpropanoic acid (example 39a) and (S)-2-aminobutan-1-ol. Yield: 52%. 1H NMR (DMSO-d6, 400 MHz) δ 7.61 (m, 4H), 7.44 (m, 3H), 7.31 (d, 1H, J=7.2 Hz), 6.83 (d, 1H, J=8.5 Hz), 4.57 (t, 1H, J=5.8 Hz), 4.84 (s, 2H), 3.68 (m, 1H), 3.34 (m, 1H), 3.33 (s, 3H), 3.22 (m, 1H), 1.56 (m, 1H), 1.49 (s, 6H), 1.29 (m, 1H), 0.76 (t, 3H, J=7.3 Hz). 13C NMR (DMSO-d6, 100 MHz) δ 175.5, 145.8, 139.8, 139.2, 137.8, 128.9, 126.5, 126.5, 126.4, 125.6, 125.6, 73.6, 63.0, 57.6, 52.5, 46.1, 27.1, 27.0, 23.5, 10.6. M+H=356, m.p.=73-75° C.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.[OH-].[NH4+]>[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>[CH2:1]1[O:9][C@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C2CO2)cc1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc([C@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A 500-mL flask, equipped with a temperature probe, a mechanical stirrer, a vacuum adapter, and a dip tube, was charged with (S,S)-Co(salen) (5.51 g, 0.0083 mol, 0.500 mol %), styrene oxide (200.0 g, 1.66 mol, 100 mol %), and water (59.8 g, 3.32 mol, 200 mol %). A slight vacuum was applied to the flask to draw air into the reaction mixture through the dip tube (subsurface), and agitation was initiated. The flask was placed in a water bath and p-nitrobenzoic acid (2.83 g, 0.0166 mol, 1.00 mol %) was added in one portion. After stirring overnight at room temperature, the reaction was deemed complete by HPLC. The reaction mixture was a brown solution with suspended orange solids. Ammonium hydroxide (4.15 g, 4.63 mL, 28% NH3, 0.0332 mol, 2.00 mol %) was added and the reaction mixture was stirred at room temperature for 1 h. A dark brown solution was obtained. Air flow through the reaction mixture was stopped, and the reaction mixture was washed with water (2×200 mL). The organic layer was fractionally distilled to give (S)-styrene oxide (67.86 g, 67.9% yield, 99.6% ee). The aqueous layer was treated with activated carbon and warmed to a gentle boil. After cooling and filtration, the aqueous layer was concentrated to give (R)-styrene glycol (95.25 g, 95.3% yield, 93.9% ee).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][NH:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][N:7]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc(NCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Reaction time: 12 h
Yield: 81.7 %

Procedure:
5-{[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid methyl ester (900 mg, 2.72 mmol) was then dissolved in THF (20 mL) and lithium hydroxide monohydrate (686 mg, 16.34 mmol) in water (15 mL) added and the resulting mixture stirred for 12 h. After evaporation the mixture was diluted with water (10 mL) and citric acid (10%) and extracted with ethyl acetate (2×80 mL). The combined extracts were then dried with sodium sulfate, filtered and evaporated to afford 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid (703 mg, 91%) as an off white solid. MS: m/e=317.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([NH2:11])=[C:9]2[C:4]([N:5]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[CH2:6][CH2:7][CH2:8]2)=[N:3]1.CCN(CC)CC.[CH3:28][O:29][CH2:30][C:31](=O)[CH2:32][CH3:33].C1(C)C=CC=CC=1.[BH3-]C#N.[Na+]>C(Cl)Cl.CO.Cl[Ti](Cl)(Cl)Cl>[CH3:28][O:29][CH2:30][CH:31]([NH:11][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][N:5]2[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])[CH2:32][CH3:33]
Reactant: CCC(=O)COC
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC(COC)Nc1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
2-Methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-44; 101 mg, 0.373 mmol) was dissolved in CH2Cl2 (2 mL). Et3N (0.25 mL, 1.79 mmol) and the 1-methoxy-butan-2-one (65 mg, 0.636 mmol) were added at room temperature. A solution of TiCl4 in toluene (1 M; 0.35 mL, 0.35 mmol) was added dropwise via syringe. The mixture was then stirred at room temperature overnight. NaCNBH3 (120 mg, 1.9 mmol) in methanol (1 mL) was added slowly. The stirring continued at room temperature for 0.5 h and the reaction was quenched by the addition of 2 N NaOH (2 mL). EtOAc was added and the layers were separated. The organic layer was washed with water, brine and dried over MgSO4. The solvent was removed and the residue purified by chromatography on SiO2 (gradient elution: 2% MeOH in CH2Cl2 containing 0.1% NH4OH to 3% MeOH in CH2Cl2 containing 0.15% NH4OH over 20 minutes) to yield 102 mg of 5-40 (0.286 mmol; 77%).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:27])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:20]2[C:10]3([CH2:17][O:18][C:19]=2[CH:24]=1)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]3=[O:27]
Reactant: COc1ccc2c(c1)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (98%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.23-8.11 (br, 1H), 7.30-6.90 (m, 4H), 6.69 (d, J=8.4 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 6.39 (dd, J=8.4, 1.8 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 3.78 (s, 3H); MS (ES+) m/z 268.3 (M+1).
Reaction SMILES: [CH:1]1([C@H:7]([OH:21])[CH2:8][NH:9][CH2:10][C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:11]12([CH2:10][N:9]3[CH2:8][C@H:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[O:21][C:30]3=[O:32])[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]3)[CH2:20]1)[CH2:18]2
Reactant: O[C@H](CNCC12CC3CC(CC(C3)C1)C2)C1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1O[C@@H](C2CCCCC2)CN1CC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution of (S)-1-cyclohexyl-2-((1-adamantylmethyl)amino)ethanol (22 mg, 0.077 mmol) and Et3N (15.6 mg, 0.154 mmol) in dry CH2Cl2(2 mL) at 0° C. was added triphosgene (9.2 mg, 0.031 mmol) in dry CH2Cl2(2 mL). The mixture was stirred for 30 min and then concentrated in vacuum to give the crude product, which was purified by preparative TLC to afford (S)-3-((1-adamantyl)methyl)-5-cyclohexyloxazolidin-2-one (5 mg, 21%). 1H NMR (MeOD, 400 MHZ): δ=1.18-1.97 (m, 25H), 2.75-2.95 (m, 2H), 3.42 (t, 1H), 3.72 (t, 1H), 4.83 (m, 1H); MS: m/z=318.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1ccc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
To a suspension of 4,5-diphenylimidazole (500 mg, 2.27 mmol) in 5 mL CH2Cl2 at rt were added TEA (348 μL, 2.50 mmol) and trityl chloride (664 mg, 2.38 mmol). The mixture was stirred at rt for 18 h, then was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes gradient) to afford 692 mg of Intermediate 19.1 as a pale green solid.