Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)[OH:4].[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1>N1C=CC=CC=1.CCOCC.O>[CH:26]1([C:30]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([C:3]([OH:4])([C:5]4[C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]([CH3:14])[CH:6]=4)[C:2]([F:1])([F:24])[F:25])=[CH:23][CH:22]=3)[CH:18]=[N:19]2)=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CCC1
Reactant: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)C3CCC3)c2)C(F)(F)F)c2ccccc21
Temperature: 100 °C
Yield: 74.6 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol (0.122 mmol) and cyclobutanecarbonyl chloride (0.159 mmol) in 1 mL pyridine was heated at 100° C. for 1.5 hours, cooled to room temperature and diluted with ether and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue purified by flash silica gel chromatography using 25% ethyl acetate in hexanes. The product-rich fractions were concentrated in vacuo to afford 0.091 mmol of the title compound, m.p. 79° C.-81° C.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.C(Br)C=C.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:3]([C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1)[CH:1]=[CH2:2]
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C=CCBr
Product: C=CCC1(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
9.9 ml (70.32 mmol) of diisopropylamine were initially charged in 35 ml of THF, 28.1 ml (70.32 mmol) of a 2.5 M solution of n-butyllithium in n-hexane were added at −40° C. and the mixture was stirred for 30 min. The reaction mixture was then cooled to −78° C., and a solution of 10 g (70.32 mmol) of tert-butyl cyclopropanecarboxylate in 5 ml of THF was added dropwise. The mixture was stirred at −78° C. for 4 h, and a solution of 5.8 ml (66.81 mmol) of allyl bromide in 5 ml of THF was then added dropwise. The reaction mixture was slowly warmed to RT overnight, and aqueous ammonium chloride solution was then added carefully. The mixture was extracted three times with methyl tert-butyl ether. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. This gave 10.7 g (83.5% of theory) of the target compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][SH:12].Br[CH2:17][CH:18]([OH:21])[CH2:19][OH:20].CO>O.CC(C)=O>[OH:21][CH:18]([CH2:19][OH:20])[CH2:17][S:12][CH2:11][C@@H:10]([C:13]([OH:15])=[O:14])[NH2:9]
Reactant: N[C@@H](CS)C(=O)O
Reactant: OCC(O)CBr
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: N[C@@H](CSCC(O)CO)C(=O)O
Reaction time: 72 h

Procedure:
Triethylamine (6 g, 8.2 ml, 58 mmoles) was added to L-cysteine hydrochloride (3 g, 19 mmole) and 3-bromo-propan-1,2-diol (4.2 g, 2.36 ml, 27 mmole) in water and the homogeneous solution kept at room temperature for 3 days. The solution was reduced in vacuo at 40° C. to a white residue which was boiled with methanol (100 ml), centrifuged and the residue dissolved in water (5 ml). This aqueous solution was added to acetone (300 ml) and the precipitate isolated by centrifugation. The precipitate was purified by several precipitations from water with acetone to give S-(2,3-dihydroxypropyl)cysteine as a white amorphous powder (2.4 g, 12.3 mmol, 64.7%).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=3)[N:12]=2)=[CH:7][C:6]=1[CH3:26])[CH:2]([CH3:4])[CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:58]([CH2:60][NH2:61])[OH:59]>CN(C=O)C.CC(=O)OCC>[OH:59][CH2:58][CH2:60][NH:61][C:23](=[O:24])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C:8]3[CH:9]=[N:10][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[C:6]([CH3:26])[CH:7]=3)[O:15][N:14]=2)=[CH:17][CH:18]=1
Reactant: Cc1cc(-c2nc(-c3ccc(CC(=O)O)cc3)no2)cnc1CC(C)C
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(-c3ccc(CC(=O)NCCO)cc3)no2)cnc1CC(C)C
Reaction time: 72 h
Yield: 46.4 %

Procedure:
To a solution of {4-[5-(6-isobutyl-5-methyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetic acid (50 mg, 142 μmol) in DMF (3 mL), EDC HCl (33 mg, 171 μmol), HOBt (23 mg, 171 μmol) and DIPEA (28 mg, 213 μmol) is added. The mixture is stirred at rt for 5 min before ethanolamine (10 mg, 157 μmol) is added. Stirring is continued at rt for 72 h. The mixture is diluted with EA, washed with water, and concentrated. The crude product is purified on prep. TLC plates with DCM containing 10% of MeOH to give N-(2-hydroxy-ethyl)-2-{4-[5-(6-isobutyl-5-methyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetamide (26 mg) as a white solid; LC-MS: tR=0.82 min, [M+1]+=395.15; 1H NMR (CDCl3): δ1.01 (d, J=6.5 Hz, 6H), 2.19-2.29 (m, 1H), 2.46 (s, 3H), 2.53 (s br, 1H), 2.80 (d, J=7.3 Hz, 2H), 3.44 (q, J=4.8 Hz, 2H), 3.69 (s, 2H), 3.71-3.75 (m, 2H), 5.96 (s br, 1H), 7.46 (d, J=7.5 Hz, 2H), 8.18 (d, J=7.8 Hz, 2H), 8.17 (s), 8.19 (s), 8.22 (s, 1H), 9.20 (s, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Br[CH2:10][C:11]1[NH:16][C:15]2=[N:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=[C:14]2[CH:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:12]=1[C:34]#[N:35].O>CN(C=O)C>[C:23]([O:22][C:20]([N:18]1[CH:19]=[C:14]2[C:15]([NH:16][C:11]([CH2:10][N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[C:12]([C:34]#[N:35])[CH:13]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[N:17]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)n1cc2c(n1)NC(CBr)=C(C#N)C2c1ccccc1Cl
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1cc2c(n1)NC(CN1CCOCC1)=C(C#N)C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (22.9 g), di-t-butyl dicarbonate (19.4 g) and dimethylaminopyridine (0.5 g) in tetrahydrofuran (200 ml) was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (21.8 g) as white crystals. 2-(t-Butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (5.0 g), N-bromosuccinimide (2.5 g) and azobisisobutyronitrile (66 mg) were suspended in benzene (50 ml) and the suspension was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (2:1)) and crystallized from ethyl acetate to give 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine as white crystals. To a suspension of sodium hydride (32 mg) in DMF (10 ml) was added morpholine (70 μl) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.36 g) and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water, and the precipitated crystals were collected by filtration and washed with hexane to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (450 mg) as white crystals. A solution of 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (440 mg) in trifluoroacetic acid (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and 4M hydrochloric acid-dioxane solution was added. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (250 mg) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:10]([CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:10]([CH2:17][CH:18]2[CH2:19][O:20][C:29](=[O:31])[O:21]2)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(Br)c(N(CC(O)CO)C(=O)C(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Br)c(N(CC2COC(=O)O2)C(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A solution of N-[3-bromo-6-(methyloxy)-2-pyridinyl]-N-(2,3-dihydroxypropyl)-2,2-dimethylpropanamide (7.628 g, 21.130 mmol) in DCM (100 ml) and pyridine (3.407 ml, 42.26 mmol) at −78° C. under argon was treated with a solution of triphosgene (6.27 g, 21.130 mmol) in DCM (20 ml) over 5 min and the reaction was then allowed warm to rt and stirred at rt for 30 min. The reaction was then carefully treated with saturated sodium bicarbonate solution (200 ml), extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), and evaporated and chromatographed (0-50% ethyl acetate:Hexane) to give the product as a white solid (5.722 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.[CH3:50][S:51]([CH2:54][CH2:55][C:56](O)=[O:57])(=[O:53])=[O:52]>C(Cl)Cl.C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:56](=[O:57])[CH2:55][CH2:54][S:51]([CH3:50])(=[O:53])=[O:52])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2cc(N3CCNCC3)ncc2Cl)c(C)c1
Reactant: CS(=O)(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cnc(-c2cc(N3CCN(C(=O)CCS(C)(=O)=O)CC3)ncc2Cl)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To a solution of 5′-chloro-3,5-dimethyl-2′-(piperazin-1-yl)-2,4′-bipyridine (2.3 g, 15.1 mmol) and HOBT (2.55 g, 18.9 mmol) in CH2Cl2 (60 mL) was added NMM (5.67 g, 56.7). After stirring for 30 min at room temperature, EDCI (3.63 g, 18.9 mmol) and 3-(methylsulfonyl)propanoic acid (3.9 g, 12.6 mmol) were added and the mixture was stirred at 30° C. for 18 hours. TLC (CH2Cl2/MeOH=10:1) showed the starting material was consumed completely. After removal of the solvent in vacuo, the residue was dissolved in CH2Cl2 (180 mL), washed with saturated aq. NaHCO3 (40 mL), saturate aq. NH4Cl (40 mL) and brine (40 mL). The resulting material was dried over Na2SO4 and concentrated in vacuo to give title compound (4.8 g, 90%) as white solid. 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.15 (s, 1H), 7.36 (s, 1H), 6.53 (s, 1H), 3.69-3.66 (m, 2H), 3.58-5.53 (m, 4H), 3.48-3.46 (m, 2H), 3.41-3.37 (m, 2H), 2.94 (s, 3H) 2.89-2.86 (m, 2H), 2.31 (s, 3H), 2.10 (s, 3H); m/z for C20H25ClN4O3S 437.3 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[S:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.C(O)(=O)C>ClCCl>[C:1]([O:10][CH2:9][CH2:8][S:7][CH2:11][CH2:12][OH:13])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCSCCO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: C=C(C)C(=O)OCCSCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
A solution of methacryloyl chloride (16.7 g; 0.160 mol) in dichloromethane (100 ml) was added dropwise at 5° C. to a solution of thiodiethanol (20 g; 0.164 mol) and triethylamine (33.7 g; 0.334 mol) in dichloromethane (50 ml). After addition was complete, the solution was stirred at ambient temperature for 16 hrs. The excess triethylamine was neutralised with glacial acetic acid and the volume reduced on a rotary evaporator. The soluble organic products were extracted in diethyl ether and separated by filtration. Thiodiethanol monomethacrylate was purified by preparative flash chromatography, using silica gel (eluant=1:1 diethyl ether:hexane). Fractions containing pure product were collected and combined to yield thiodiethanol monomethacrylate (8.5 g; 0.044 mol, 28% yield) as a light coloured oil. Several attempts at distillation of TEDMA at reduced pressure and in the presence of excess stabiliser resulted in rapid polymerisation of the monomer. Thiodiethanol monomethacrylate was stored at 4° C. in the presence of 100 ppm 3,5-di-tert-butylcatechol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([F:29])=[CH:24][N:23]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:18][C:24]3[C:25]([F:29])=[CH:26][N:27]=[C:22]([Cl:21])[N:23]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 4-(N-benzylpiperazino)aniline and 2,4-dichloro-5-fluoropyrimidine gave N4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 2.81 (m, 4 H), 3.37 (m, 6 H), 6.85 (br, 1 H), 6.93 (d, J=9.0 Hz, 2 H), 7.40 (m, 5 H), 7.50 (d, J=9.3 Hz, 2 H), 8.02 (d, J=2.7 Hz, 1H); LCMS: ret. time: 20.56 min, purity: 97.75%; MS (m/e): 398.00 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([NH2:32])[CH2:27]1)(OC(C)(C)C)=O.[ClH:33]>O1CCOCC1>[ClH:33].[NH2:32][C@H:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:27]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](N)C3)s2)noc1C(F)(F)F
Reaction time: 12 h
Yield: 71 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and N-Boc-3-(S)-aminopiperdine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried then chromatographed on silica gel with EtOAc/hexanes (50 then 75%) as eluant to afford intermediate N-Boc protected product as a colorless solid (87 mg, 76%). The Boc-protected intermediate was dissolved in 1,4-dioxane (5 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane and stirred for 12 hr, after which time the reaction mixture was evaporated to approximately ½ volume and diluted with ethyl ether (20 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (70 mg, 71% overall). 1H NMR (D2O) 1.36 (m, 1 H), 1.58 (m, 2 H), 1.90 (s, 3 H), 1.96 (m, 1 H), 3.08 (m, 3 H), 3.21 (m, 1 H), 3.65 (m, 1 H), 4.18 (br d, J=11.4, 1 H), 7.06 (br d, 1 H), 7.09 (br d, 1 H). 19F NMR −64.6. LC/MS 4.40 min, [M+1]+ 360.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][C:12](=[O:13])NC2=O)=[CH:4][CH:3]=1.[OH-:15].[Na+]>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:14][C:12]([OH:13])=[O:15])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=C1CN(c2ccc(O)cc2)C(=O)N1
Agent: [Na+]
Solvent: O
Product: O=C(O)CNc1ccc(O)cc1
Temperature: 50 °C
Yield: 6.9 %

Procedure:
Example 1 of U.S. Pat. No. 4,436,910 was generally repeated as follows: p-hydroxyphenyl hydantoin (100 mM, 19.2 g) was treated with NaOH (100 mM, 4.0 g) and Ca(OH)2 (200 mM, 14.2 g) in 200 ml water at 140° C. for four hours in an autoclave. After cooling to 50° C., the precipitated CaCO3 which separated out was filtered off. The recovered mother liquor was analyzed by HPLC. It was found to contain 1.16 g p-hydroxyphenyl glycine (7% yield) in solution. Substantial amounts of decomposition (by-product) was indicated by HPLC analysis. This control experiment demonstrates that the p-hydroxyphenylglycine product when subjected under the reaction conditions [Ca(OH)2, NaOH, 140° C., H2O] suffers severe decomposition to several unwanted and unidentified products. It was quite unexpected then to find that the use per se of only a calcium base material like calcium hydroxide facilitates the production of the corresponding hydantoic acid salt in very high yields. The hydantoic acid salt can then be subjected to decarbamoylation with nitrous acid under acidic conditions to produce p-hydroxyphenylglycine, and which can in turn be optically resolved by processes such as described in U.S. Pat. Nos. 5,120,855 and 3,094,741, both of which are incorporated herein by reference in their entirety.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>C(#N)C>[NH2:9][C:7]([C@H:2]([NH:1][CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:8]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)C[C@@H](N)C(N)=O
Solvent: CC#N
Product: CC(C)C[C@@H](NCCCS(=O)(=O)O)C(N)=O
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of D-Leucinamide (6.0 mmol) in acetonitrile (35 mL) was added 1,3-propanesultone (666 mg, 5.5 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with MeCN (2×20 mL). The solid was suspended in EtOH (50 mL). The suspension was stirred at reflux for 1 hour. The mixture was cooled to room temperature. The solid material was filtered, washed with acetone (1×20 mL) and dried in a vacuum oven (50° C.), affording the title compound (1.03 g, 74%): 1H NMR (D2O, 500 MHz) δ ppm 3.81 (m, 1H), 3.07 (m, 2H), 2.85 (t, 2H, J=7.3 Hz), 2.03 (m, 2H), 1.68 (t, 1H, J=7.8 Hz), 1.58 (m, 2H), 0.83 (m, 6H). 13C (D2O, 125 MHz) δ ppm 171.45, 59.39, 48.01, 45.41, 39.02, 24.24, 22.21, 21.47, 21.13. [α]D=−13.7° (c=0.0019 in water), ES-MS 251 (M−1).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:15]1[N:16]=[C:17]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:18]2[C:19](=[O:27])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH3:14].C(N(CC)C(C)C)(C)C>C(O)C>[CH3:32][C:28]1[N:18]2[C:19](=[O:27])[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:15]([CH:12]([NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH2:13][CH3:14])[N:16]=[C:17]2[CH:31]=[CH:30][CH:29]=1
Reactant: CCC(N)c1nc2cccc(C)n2c(=O)c1-c1ccccc1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1-c1ccccc1

Procedure:
A mixture of 6-bromo-9H-purine (Aldrich, 0.0152 g, 0.07656 mmol), 2-(1-aminopropyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.019 g, 0.064 mmol), and N,N-diisopropylethylamine (0.0134 mL, 0.07666 mmol) in ethanol (0.5 mL) was refluxed under nitrogen overnight. The mixture was cooled and purified on RP-HPLC at pH 10 (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the product as the free base. LCMS calculated for C23H22N7O (M+H)+: m/z=412.2. Found: 412.4. 1H NMR (DMSO-d6, 300 MHz) δ 8.07 (2H, m), 7.60 (1H, dd, J=9.0 and 6.9 Hz), 7.39-7.32 (7H, m), 7.00 (1H, m), 6.85 (1H, br d, J=6.9 Hz), 5.13 (1H, m), 2.81 (3H, s), 1.72 (2H, m), 0.65 (3H, t, J=7.2 Hz) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:14])[C:10]([F:13])([F:12])[F:11].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1.C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C1(C)C=CC=CC=1.[Cu]I>[N:15]1([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C@@H:9]([OH:14])[C:10]([F:13])([F:12])[F:11])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O[C@H](c1ccc(Cl)cc1Br)C(F)(F)F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O[C@H](c1ccc(Cl)cc1-n1cnc2ccccc21)C(F)(F)F
Temperature: 130 °C

Procedure:
To a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (1 g, 3.5 mmol) and 1H-benzo[d]imidazole (408 mg, 3.5 mmol) in toluene (24 mL) was added sequentially, CuI (131 mg, 0.69 mmol), K2CO3 (1.19 g, 8.63 mmol), and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (196 mg, 1.38 mmol). The reaction mixture was purged with N2 and then heated at 130° C. in a sealed tube for 12 h. Afterward, the reaction was cooled to RT. The solid was removed by filtration and the filtrate was concentrated and purified by flash column (EtOAc in hexane=0 to 50%) to afford —(R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethanol as a white solid.
Reaction SMILES: N1(O[C:11]2[C:12]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)C2C=CC=CC=2N=N1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C@@H:35]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([S:51]([NH2:54])(=[O:53])=[O:52])=[CH:47][C:46]=2[S:55]([C:58]([F:61])([F:60])[F:59])(=[O:57])=[O:56])[CH2:36][S:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.CCOCC>[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C@@H:35]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([S:51]([NH:54][C:11]3[C:12]4[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)(=[O:52])=[O:53])=[CH:47][C:46]=2[S:55]([C:58]([F:61])([F:59])[F:60])(=[O:57])=[O:56])[CH2:36][S:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(On3nnc4ccccc43)c2C1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ncnc(NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)c2C1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 20.4 %

Procedure:
tert-Butyl 4-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (448 mg, 1.264 mmol), (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3(trifluoromethylsulfonyl)benzenesulfonamide (910 mg, 1.643 mmol), and potassium carbonate (524 mg, 3.79 mmol) were combined in N,N-dimethylformamide (6.3 mL) and stirred for 1.5 hours at 85° C. and then for 2.5 hours at 95° C. The reaction was then cooled to room temperature and stirred for 16 hours. The reaction was treated with water (˜30 mL) and sonicated. A dark brown solid stuck to the flask. The solid was washed several times with water and then several times with diethyl ether. This residue was then treated with methanol (˜15 mL), and the off-white precipitate formed was removed by filtration. The dark brown filtrate was concentrated in vacuo to afford a brown solid. The water and ether washes were combined and diluted with more water and ether. The layers were separated, and the organic layer was dried over sodium sulfate, filtered and concentrated down. This residue was combined with the brown solid and purified by flash chromatography on silica gel (0 to 10% methanol/ethyl acetate followed by 0 to 30% methanol/dichloromethane) to afford the title compound (199 mg, 13% yield). MS (ESI) m/e (M+H)+=773.5.