Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([F:17])[C@H:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]=C)=[N+:2]=[N-:3].C(O)(C(F)(F)F)=[O:19].[OH2:25]>O1CCOCC1.CCOC(C)=O>[N:1]([CH2:4][C@@H:5]([F:17])[C@H:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:19])=[O:25])=[N+:2]=[N-:3]
Reactant: C=C[C@@H](OCc1ccccc1)[C@H](F)CN=[N+]=[N-]
Reactant: O
Reactant: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@@H](F)[C@H](OCc1ccccc1)C(=O)O
Temperature: 50 °C
Yield: 100 %

Procedure:
To a stirring solution of 4 (51.2 g, 32.5 mmol) in dioxane (600 ml) was added a solution of TFA (16.02 ml, 208 mmol) in water (200 ml) and the reaction was heated at 50° C. for 17 hours. The reaction mixture was diluted with EtOAc (800 mL) and washed with sat. aq. NaHCO3 (2×800 mL), brine (400 mL), dried over MgSO4, filtered and concentrated under vacuum to yield 5 (49.9 g, 32.5 mmol, 100% yield): MS m/z calcd for C78H82N6O24 (M+Na+) 1509.5. found 1509.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([C:25](Cl)=[O:26])[C:21]([Cl:24])=[N:22][CH:23]=1>C1(C)C=CC=CC=1.O>[Br:17][C:18]1[CH:19]=[C:20]([C:25]([NH:1][C:2]2[C:3]([Cl:10])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=2[CH3:8])=[O:26])[C:21]([Cl:24])=[N:22][CH:23]=1
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Reactant: Cc1cc(Cl)nc(Cl)c1N
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)nc(Cl)c1NC(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
3-Amino-2,6-dichloro-4-methylpyridine (0.51 g, 2.85 mmol) was dissolved in toluene (35 mL) and pyridine (0.27 mL, 3.28 mmol) was added. 5-Bromo-2-chloro-3-pyridinecarbonyl chloride (0.80 g, 3.14 mmol) was then added dropwise over 30 min. The resulting mixture was stirred at room temperature for 1 h, diluted with water and extracted with toluene (2×). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting thick oil was triturated with CH2Cl2, and the white solid collected via suction filtration to give the title compound (0.41 g, 36% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15]C4C=CC=CC=4C#N)=[CH:13][CH:12]=3)[C:3]=12.[OH-:39].[Na+].OO.[O:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl>[C:14]([OH:43])(=[O:15])[CH3:24].[C:44]([OH:43])(=[O:39])[CH3:45].[C:48]([OH:43])(=[O:15])[CH3:47].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:25]=[C:45]([CH:44]=[CH:13][CH:12]=3)[O:46][C:47]3[CH:48]=[CH:12][CH:11]=[CH:10][C:3]=3[C:2]([NH2:1])=[O:39])[C:3]=12
Reactant: C1COCCO1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5C#N)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(Oc5ccccc5C(N)=O)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 100 °C

Procedure:
A mixture of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile (0.111 g, 0.218 mmol, 1 equiv), 25% aqueous sodium hydroxide (1 mL), and 30% H2O2 (1 mL) in dioxane (1 mL) was heated at 100° C. for 16 h. An additional portion of 30% H2O2 (1 mL) was added and the reaction mixture was heated at 100° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature and diluted with CH2Cl2 (15 mL). The organic portion was separated and the solvents were removed under reduced pressure to afford a pale yellow solid which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to afford cis-2-(3-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzamide triacetate salt as an off-white solid (0.020 g, 0.038 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 8.23 (1H, s), 7.75 (1H, d, J=7.7 Hz), 7.64 (3H, d, J=6.7 Hz), 7.56 (1H, s), 7.48 (1H, t, J=7.5 Hz), 7.27 (1H, t, J=7.4 Hz), 7.19 (2H, d, J=8.6 Hz), 7.06 (1H, d, J=7.7 Hz), 4.76-4.82 (1H, m), 2.20-2.50 (11H, m), 2.14 (3H, s), 2.04-2.08 (2H, m), 1.89 (9H, s), 1.58-1.70 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 10.79 min. MS: MH+ 527.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14]CC)=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC)cc(F)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
To a solution of ethyl 2-(4-fluoro-1-hydroxy-6-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (134 mg, 0.50 mmol) in THF (2 mL) was added dropwise an aqueous solution of lithium hydroxide (102 mg, 2.5 mmol) in water (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and acidified to pH=2 with diluted hydrochloride acid. The resulting mixture was extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (43 mg, Yield: 36%). 1H NMR (400 MHz, DMSO-d) δ 12.20 (s, 1H), 9.45 (s, 1H), 7.09-7.09 (d, J=1.6 Hz, 1H), 6.91-6.95 (m, 1H), 5.51-5.55 (m, 1H), 3.80 (s, 3H), 2.91-2.97 (m, 1H), 2.27-2.33 (m, 1H). MS (ESI) m/z=481 [2M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH:11]([CH3:17])[CH2:10][CH2:9]1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH:11]([CH3:17])[CH2:10][CH2:9]1
Reactant: OB(O)c1ccccc1
Reactant: CC1CCC(c2ccccc2Br)n2cncc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1CCC(c2ccccc2-c2ccccc2)n2cncc21

Procedure:
To a solution of 5-(2-bromophenyl)-8-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine (573 mg, 1.97 mmol) in DME (10 mL) is added phenylboronic acid (480 mg, 3.94 mmol), aqueous Na2CO3 (2M, 4 mL, 8.0 mmol), and Pd(PPh3)4 (500 mg). The reaction mixture is stirred at reflux overnight. The mixture is partitioned between EtOAc and brine. The organic layer is washed by brine, dried over Na2SO4 and concentrated to give an oil, which is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 289 (M+H)
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29]([O:31]C)=[O:30])[CH:5]=1)(=[O:3])[NH2:2].[OH:33][Li].O>C1COCC1.O>[C:29]([C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:6]1[N:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[N:9]=[C:4]([C:1]([OH:33])=[O:3])[CH:5]=1)([OH:31])=[O:30].[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29]([OH:31])=[O:30])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: [Li]O
Reactant: COC(=O)[C@@H]1CCCN1c1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(N2CCC[C@H]2C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Product: O=C(O)c1cc(N2CCC[C@H]2C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 72 h
Yield: 29 %
Yield: 40 %

Procedure:
To a mixture of the (S)-methyl 1-(6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylate (0.439 g, 1.01 mmol) in 5:1 THF/water (10 mL) was added LiOH.H2O (0.084 g, 2.00 mmol). After stirring 3 days the reaction was quenched with 1N aqueous HCl (2.00 mL). The mixture was evaporated in vacuo then chromatographed using reverse-phase HPCL with a 40-100% acetonitrile in water (+0.1% TFA) gradient. The first product to elute was the (S)-6-(2-carboxypyrrolidin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylic acid (A) followed by the (S)-1-(6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (B). Separately, product fractions for each product were pooled and concentrated to give solid suspensions. The solid precipitates were filtered, rinsed with water, and dried under vacuum at 50° C. to give (S)-6-(2-carboxypyrrolidin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylic acid (A) as a light tan powder (0.170 g, 0.402 mmol, 40% yield) and (S)-1-(6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (B) as an off-white powder (0.125 g, 0.296 g, 29% yield). (S)-6-(2-carboxypyrrolidin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylic acid (A): 1H NMR (400 MHz, DMSO-d6): Exists as a ˜80:20 ratio of rotamers: 13.71-12.30 (2H, br m), 8.43 (0.4H, d, J=8.8 Hz), 8.37 (1.6H, d, J=8.8 Hz), 7.32-7.24 (2H, m), 7.20-7.13 (2H, m), 7.09-6.99 (2.8H, m), 6.79 (0.2H, s), 4.62-4.55 (1H, m), 3.87-3.48 (2H, m), 2.38-2.29 (1H, m), 2.24-1.98 (3H, m). LC/MS: m/z=424.1 [M+H]+. (S)-1-(6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (B): 1H NMR (400 MHz, DMSO-d6): Exists as a 80:20 ratio of rotamers: 13.05 (0.2H, br s), 12.60 (0.8H, br s), 8.57 (0.4H, d, J=8.8 Hz), 8.51 (1.6H, d, J=8.8 Hz), 8.35 (1H, s), 7.81 (1H, s), 7.32-7.24 (2H, m), 7.20-7.13 (2H, m), 7.08-6.97 (2.8H, m), 6.79 (0.2H, s), 4.62-4.52 (1H, m), 3.86-3.72 (0.4H, m), 3.66-3.55 (1.6H, m), 2.40-2.28 (1H, m), 2.22-1.95 (3H, m). LC/MS: m/z=423.1 [M+H]+.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]>CN1CCCC1=O>[CH3:1][S:2][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(C(F)(F)F)cc1SC
Reaction time: 3 h
Yield: 94.5 %

Procedure:
Dry sodium thiomethoxide (0.385 g, 0.0055M) was added to a solution of methyl 2-chloro-4-trifluoromethylbenzoate (1.19 g, 0.005M) in anhydrous N-methylpyrrolidinone (10 ml) at 5° C. After 3 hours the mixture was acidified, extracted (ether), washed (water) and evaporated to give methyl 2-methylthio-4-trifluoromethylbenzoate (1.18 g, 94% yield), 1H NMR 2.44(s,3H), 3.89(s,3H), 7.33(1H), 7.41(1H), 8.02(1H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](I)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[F:15][C:16]([F:20])([F:19])[CH:17]=[CH2:18].C(OP(Cl)(=O)[O-])C.N12CCN(CC1)CC2>CC(C)=O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:18]=[CH:17][C:16]([F:20])([F:19])[F:15])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: C=CC(F)(F)F
Reactant: CC(=O)Nc1ccc(S(=O)(=O)I)cc1
Agent: C1CN2CCN1CC2
Agent: CCOP(=O)([O-])Cl
Solvent: CC(C)=O
Product: Nc1ccc(S(=O)(=O)C=CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-trifluoromethylvinyl 4-aminophenyl sulfone is prepared by the addition of 4-acetamidobenzenesulfonyl iodide to 1,1,1-trifluoropropene followed by dehydrohalogenation and removal of the N-acetyl protective group by hydrolysis in a hydrochloric acid-ethanol mixture. The product is dissolved in acetone (25.1 g or 0.1 mol), an acetone solution of 0.1 mol (17.3 g) of ethylphosphorochloridate in acetone added, followed by 11.2 g of 1,4-diazabicyclo[2.2.2]octane in 10% acetone solution. The reaction mixture is stirred for one hour at room temperature, filtered, most of the acetone evaporated, and the residue is mixed with chloroform, washed and worked up. There is thus obtained 4-diethoxyphosphoramidophenyl 2-trifluoromethylvinyl sulfone: ##SPC59##
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH2:16]=[O:17]>>[OH:17][CH2:16][NH:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Reactant: C=O
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCO)S1

Procedure:
A suspension of 5 g. of 2-(2-amino-5-thiadiazolyl)-1-methyl- 5-nitroimidazole in 200 ml. of 36% aqueous formaldehyde solution is stirred for 20 hours at room temperature. The suspension is cooled in ice, and the insoluble solid is collected by filtration and washed with acetone. The yield of the title compound is 6.15 g., melting point 177° C. with decomposition (rapid heating).
Reaction SMILES: [C:1]([CH2:5][CH2:6][C:7](Cl)=[O:8])([O:3]C)=[O:2].[OH:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].[CH2:18](N(CC)CC)C>C(OCC)(=O)C>[C:7]([OH:8])(=[O:10])[CH2:6][CH2:5][C:1]([OH:3])=[O:2].[CH3:18][CH:13]1[CH2:14][C:15](=[O:16])[NH:11][C:12]1=[O:17]
Reactant: O=C1CCC(=O)N1O
Reactant: CCN(CC)CC
Reactant: COC(=O)CCC(=O)Cl
Solvent: CCOC(C)=O
Product: CC1CC(=O)NC1=O
Product: O=C(O)CCC(=O)O
Yield: 72.9 %

Procedure:
A solution of 3-carbomethoxypropionyl chloride (5 g, 33.2 mmoles) and N-hydroxysuccinimide (3.8 g, 33.2 mmoles) in ethyl acetate (60 ml) was cooled to 5° C. While stirring, triethylamine (4.3 g, 33.2 mmoles) was slowly added to the cooled solution over a 15 min interval. The mixture was allowed to equilibrate to room temperature (22° C.) and react for an additional 3 h. The formed triethylamine salt was filtered, washed with ethyl acetate and the filtrate evaporated under vacuum. The powder was recrystallized from ethyl acetate/hexane to give 5.5 g (24.2 mmoles) (72% yield) of white needles mp 84°-86° C.). 1H-NMR (CDCl3) δ 2.44(2Ha,app.t, J=8Hz); 2.64(2Ha',app.t, J=8Hz); 2.86 (4Hb,s); 3.66(3Hc,s)ppm. IR (Nujol) 1840, 1800, 1775, 1725 cm-1`.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:23])[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH:13]2[CH2:14][N:11]([CH2:10][CH2:9][C@H:8]([NH2:7])[CH3:23])[CH2:12]2)=[CH:21][CH:20]=1
Reactant: C[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)CCN1CC(Oc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of {(R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-carbamic acid tert-butyl ester (0.019 mg, 0.053 mmol) in DCM (1 ml) is treated with trifluoroacetic acid (0.042 ml) and stirred at room temperature overnight. The solvent is evaporated and the residue partition between DCM and 1M sodium hydroxide solution. The aqueous phase is extracted with more DCM (×3) and the combined organic phases washed with brine, dried over magnesium sulphate and evaporated to afford (R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propylamine. [M+H] 255.22
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=1.[N:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1>C1COCC1>[N:21]1[CH:26]=[CH:25][C:24]([C:27]([C:16]2[S:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([F:6])([F:19])[F:20])=[CH:13][CH:12]=3)=[N:18][CH:17]=2)([OH:29])[CH3:28])=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccncc1
Reactant: FC(F)(F)c1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78556.6 %

Procedure:
To a stirred solution of DIPA (0.09 mL, 0.000655 mmol) in THF (7 mL) at −78° C. was added n-BuLi (0.54 mL, 0.000873 mmol) and the mixture stirred at 0° C. for 30 min. After the reaction mixture was cooled to −78° C., a solution of 2-(4-(trifluoromethyl)phenyl)thiazole (0.1 g, 0.000436 mmol) in THF (2 mL) was added dropwise over 30 min. 1-(Pyridin-4-yl)ethanone (0.05 mL, 0.000480 mmol) in THF (2 mL) was then added and the reaction mixture was stirred for an additional 1 hour at −78° C. The work up and purification was done as described in Example 23, Step 2, to provide 1-(pyridin-4-yl)-1-(2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)ethanol (0.12 g, 80%) as off-white solid in 99% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.52 (dd, 2H), 8.07 (d, 2H), 7.90 (s, 1H), 7.80 (d, 2H), 7.50 (dd, 2H), 6.71 (s, 1H), 1.94 (s, 3H); LC-MS m/z calculated for [M+H]+ 351.07, found 351.1.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH2:20])[N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:21]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][C@@H:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:22]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].C([O-])(O)=O.[Na+]>O1CCOCC1>[C:1]12([CH2:11][O:12][C:13]3[N:14]=[C:15]([NH2:20])[N:16]=[C:17]([N:28]4[CH2:27][CH2:26][C:25]5([CH2:21][N:22]([C:36]([O:38][CH2:39][C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)=[O:37])[C@H:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:24]5)[CH2:30][CH2:29]4)[CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Nc1nc(Cl)cc(OCC23CC4CC(CC(C4)C2)C3)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCC45CC6CC(CC(C6)C4)C5)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 95 °C

Procedure:
4-(Adamantan-1-ylmethoxy)-6-chloro-pyrimidin-2-ylamine (89 mg, 0.30 mmol), (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (157 mg, 0.45 mmol) and NaHCO3 (76 mg, 0.9 mmol) were dissolved in dioxane (1.5 mL) and heated to 95° C. for 64 h. Then the reaction was cooled to RT, quenched with water, and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provides (S)-2-benzyl 3-ethyl 8-(6-(adamantan-1-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
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.[O:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]([CH3:29])[NH:24][CH2:23][CH2:22]3)=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[CH:27][CH:28]=[C:19]([C:16]5[CH:17]=[CH:18][O:14][CH:15]=5)[CH:20]=4)[CH:25]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3ccoc3)ccc21
Product: CC1c2ccc(-c3ccoc3)cc2CCN1C(=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 6-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])=O>ClCCl>[ClH:18].[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][Cl:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cccc(CN2CCCCC2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCc1cccc(CN2CCCCC2)c1

Procedure:
A solution of the above alcohol (2.05 g) in dry dichloromethane (60 ml) was treated with a solution of thionyl chloride (3.3 ml) in dry dichloromethane (10 ml) and heated under reflux for 2.5 hours. The product was evaporated in vacuo to produce an oil which was crystallised from dry tetrahydrofuran to give colourless crystals of 3-piperidinomethylbenzyl chloride hydrochloride (m.p. 156°-160° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36](=O)[CH2:37]Br)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:42]([NH2:45])(=[O:44])[CH3:43]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:41]=[CH:40][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]5[N:45]=[C:42]([CH3:43])[O:44][CH:37]=5)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:15])([F:16])[F:17])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(N)=O
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(C(=O)CBr)cc(C#N)nc3c2)nn1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4coc(C)n4)cc(C#N)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of (S)-1-(1-{[4-(bromoacetyl)-2-cyanoquinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (0.16 g, 0.25 mmol) and acetamide (16 mg, 0.28 mmol) in DMF (0.25 mL) was stirred at room temperature for 4 h then at 100° C. overnight. The reaction mixture was diluted in ethyl acetate, washed with water, brine and dried over MgSO4. The crude compound was purified on silica gel (eluting solvent: 2% to 5% acetone in dichloromethane) to give the desired titled product. 1H NMR (acetone-d6): δ 8.9 (d, 1H), 8.72 (s, 1H), 8.53 (s, 1H), 8.42 (d, 2H), 8.30 (d, 2H), 8.25 (s, 1H), 8.05 (s, 1H), 7.77 (d, 1H), 6.05 (s, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 2.6 (s, 3H), 1.15 (t, 3H); and also the reduced compound 1-{1-[(4-acetyl-2-cyanoquinolin-7-yl)methyl]-1H-1,2,3-triazol-4-yl}-1-(trifluoromethyl)propyl 4-nitrobenzoate. 1H NMR (acetone-d6): δ 8.55 (m, 2H), 8.45 (m, 3H), 8.3 (d, 2H), 8.07 (s, 1H), 7.82 (d, 1H), 6.05 (s, 2H), 3.05 (m, 1H), 2.85 (s, 3H), 2.82 (m, 1H), 1.12 (t, 3H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12]N1C(=O)CCC1=O.O.CCOCC>CN(C=O)C>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2
Reactant: O=C1CCc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)ccc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-dihydro-1H-quinolin-2-one (10.0 g, 67.9 mmol) in 100 ml dry DMF was added dropwise a solution of N-bromosuccinimide (12.7 g, 71.3 mmol) in 150 ml dry DMF at 0° C. The mixture was stirred at 0° C. for 2 h, then 400 ml water was added and the solution was extracted with ethyl acetate (3×150 ml). The organic phase was washed with water (2×200 ml), then dried over MgSO4 and evaporated, affording a yellow solid which was purified by washing with cold ether providing pure 6-bromo-3,4-dihydro-1H-quinolin-2-one (13.6 g, 60.3 mmol, 89%) as colorless needles.