Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][NH2:12])[CH2:9][NH2:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C([O:23][C:24](=O)[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=O)(C)(C)C.II>CC(O)(C)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][N:12]3[C:24](=[O:23])[NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]3=[N:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C=O
Reactant: NCC(CN)c1ccc(N)cc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 39 %

Procedure:
A mixture of 2-(4-aminophenyl)propane-1,3-diamine.3HCl (632 mg, 2.30 mmol) and powdered K2CO3 (3.18 g, 23.0 mmol) in 30 mL t-BuOH was heated at 83° C. for 45 min, then tert-butyl(2-formylphenyl)carbamate (560 mg, 2.53 mmol) was added. At 6.5 hours the reaction was allowed to partially cool, approximately 25 mg tert-butyl(2-formylphenyl)carbamate was added, then iodine (48 mg, 0.188 mmol) added, stirred 5 min at rt, and the heating resumed at 83° C. After 1.5 hours the temperature was lowered to 75° C. and the reaction continued an additional 15 hours. The reaction was partitioned between EtOAc and aqueous Na2CO3 solution plus Na2S2O3, the EtOAc layer washed with brine, dried with Na2SO4, and evaporated. The resulting solid was chromatographed eluting with CHCl3/MeOH to give the title compound as a yellow-tan solid (262 mg, 39%). 1H NMR (DMSO-d6) δ: 10.65 (br. s, 1H), 7.97 (dd, J=7.9, 1.5 Hz, 1H), 7.39-7.45 (m, 1H), 6.98-7.08 (m, 2H), 6.93-6.98 (m, 2H), 6.51-6.57 (m, 2H), 4.96 (br. s, 2H), 4.12-4.20 (m, 1H), 3.61-3.70 (m, 1H), 3.36-3.53 (m, 2H), 2.73-2.85 (m, 1H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[C:13]1[CH3:20])(=O)=O>CN(C)C=O>[N:1]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[C:13]1[CH3:20])=[N+:2]=[N-:3]
Reactant: Cc1nc([N+](=O)[O-])cn1CCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc([N+](=O)[O-])cn1CCN=[N+]=[N-]

Procedure:
To 2 parts of sodium azide is added a solution of 5 parts of 2-(2-methyl-4-nitro-1-imidazolyl)ethyl methanesulfonate (U.S. Pat. No. 3,882,136) in 60 parts of N,N-dimethylformamide. The resultant mixture is stirred at approximately 55° for 4 hours, then cooled and thereupon partitioned between water and toluene. The toluene phase is separated, washed with water, dried over anhydrous magnesium sulfate, and stripped of solvent by vacuum distillation. Crystallization of the residual oil from a mixture of ethyl acetate and hexane affords 1-(2-azidoethyl)-2-methyl-4-nitroimidazole as colorless crystals melting at 73°-75°. The product has the formula ##SPC7##
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[S:19][C:18]([CH3:20])=[N:17][CH:16]=2)[N:3]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[I:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:14][C:15]2[S:19][C:18]([CH3:20])=[N:17][CH:16]=2)[N:3]=1
Reactant: Cc1ncc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ncc(Cn2nc(I)c3c(N)cccc32)s1
Temperature: 85 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 5-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-2-methylthiazole (332 mg, 0.830 mmol) in EtOH/water (4:1, 10 mL) was added iron powder (463 mg, 8.30 mmol) and ammonium chloride (44.4 mg, 0.83 mmol). The resulting mixture was heated at 85° C. with vigorous magnetic stirring for three hours. The mixture was cooled to ambient temperature, concentrated, and EtOAc (40 mL) and triethylamine (10 mL) were added. The resulting mixture was heated at 85° C. for 20 minutes, then cooled to 45° C., filtered through a Celite plug, and the plug was rinsed with MeOH (30 mL). The combined organic filtrates were concentrated, the residue was extracted with DCM (3×30 mL), the combined organic extracts dried over sodium sulfate, filtered and concentrated to afford the desired product (307 mg).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][C@@H:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C@H:14](O)[CH2:13]3)[C:8]2=[O:27])=[CH:4][CH:3]=1.CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[F:36][C@H:14]1[C@H:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:16][CH2:17][N:12]([CH:9]2[CH2:10][CH2:11][N:7]([CH2:6][C:5]3[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=3)[C:8]2=[O:27])[CH2:13]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(F)cc4)C3=O)C[C@H]2O)cc1
Solvent: ClCCl
Product: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(F)cc4)C3=O)C[C@H]2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one from step B (2.5 g, 6.3 mmol) in 50 mL DCM was added DAST (4.1 mL, 31 mmol) and the reaction was stirred at ambient temperature for 1 h. The reaction was then quenched with a sat.bicarbonate solution (200 mL) and the mixture was extracted with 200 mL of DCM. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via silica gel chromatography eluting with 28% ethyl acetate in hexane to give (±)-rel-3-((3S,4S)-3-fluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one (900 mg, 1.6 mmol) as a mixture of four diastereomers. LCMS (method P) RT 0.89 min, m/z 401.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH2:5][CH:6]1[CH2:8][CH2:7]1)[C:3]#[N:4].CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:20][C:19](=[O:28])[NH:1][C:2]([C:3]#[N:4])([CH3:9])[CH2:5][CH:6]1[CH2:8][CH2:7]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CC1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)(CC1CC1)NC(=O)OCc1ccccc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of 2-Amino-3-cyclopropyl-2-methyl-propionitrile (Example 66a, 5.01 g, 30.9 mmol) in dry THF (119 mL) was added DIEA (12.1 mL, 67.9 mmol) and benzyl carbonochloridate (CAN 501-53-1, 5.57 mL, 37.1 mmol). The reaction was stirred at 45° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography eluting with a gradient of heptane/ethylacetate to yield the title compound (6.2, 60%) as a colorless oil. MS (ESI, m/z): 259.5 (M+H+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:36]([NH:39][CH2:40][CH2:41][CH3:42])[CH2:37][CH3:38]>O1CCCC1>[CH2:36]([N:39]([CH2:40][CH2:41][CH3:42])[C:19](=[O:21])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:1])[F:22])=[CH:8][CH:7]=1)[CH2:37][CH3:38]
Reactant: CCCNCCC
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.21 g, 0.010 mole), and 1,1'-carbonyldiimidazole (1.62 g, 0.010 mole), in anhydrous tetrahydrofuran (75 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 3 hours. The nitrogen flow was stopped and a solution of dipropylamine (1.31 g, 0.013 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (50 ml) and filtered. The filter cake was washed with water and recrystallized twice from isopropyl ether-petroleum ether, giving 1.26 g (31%) of a white solid, mp 138°-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:13])[CH:10]([CH3:12])[CH3:11]>C(#N)C>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cccc(O)c1
Solvent: CC#N
Product: CC(C)C(=O)Nc1cccc(O)c1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
3-Aminophenol (1.0 g) was dissolved in acetonitrile (10 ml), the solution was added with isobutyryl chloride (488 mg) under ice cooling, and the mixture was stirred for 1 hour. The reaction mixture was filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was crystallized from hexane-ethyl acetate to obtain the title compound (392 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH:8]=2)[CH2:24][CH2:23]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Fc1ccc(-c2cncc(CCl)c2)cc1
Solvent: CC#N
Product: Fc1ccc(-c2cncc(CN3CCN(c4ncccn4)CC3)c2)cc1

Procedure:
Starting from 1.10 g of 3-chloromethyl-5-(4-fluorophenyl)pyridine (“B”) [obtainable, for example, by radical chlorination of 3-methyl-5-(4-fluorophenyl)-pyridine], reaction with 0.82 g of 1-(2-pyrimidinyl)piperazine in 200 ml of acetonitrile at room temperature analogously to Example 1 gives 1-(2-pyrimidinyl)-4-[(5-(4-fluorophenyl)-3-pyridyl)methyl]piperazine, m.p. 97-98°, after customary work-up.
Reaction SMILES: [CH3:1][C@:2]12[CH2:10][CH2:9][C@@H:8]3[C:11]4[CH:12]=[CH:13][C:14]([OH:19])=[CH:15][C:16]=4[CH2:17][CH2:18][C@H:7]3[C@@H:6]1[CH2:5][CH2:4][C@H:3]2[OH:20].C(#N)C.C([O-])([O-])=O.[Na+].[Na+].[NH2:30][S:31](Cl)(=[O:33])=[O:32]>Cl>[S:31]([O:19][C:14]1[CH:13]=[CH:12][C:11]2[C@H:8]3[CH2:9][CH2:10][C@@:2]4([CH3:1])[C@H:6]([C@@H:7]3[CH2:18][CH2:17][C:16]=2[CH:15]=1)[CH2:5][CH2:4][C@H:3]4[O:20][S:31](=[O:33])(=[O:32])[NH2:30])(=[O:33])(=[O:32])[NH2:30]
Reactant: NS(=O)(=O)Cl
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@H]2O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CC[C@H]2OS(N)(=O)=O
Reaction time: 9 h
Yield: 17.5 %

Procedure:
52 mg (0.19 mM) of 13β-methyl-1,3,5(10)-gonatrien-3,17α-diol are dissolved 10 ml acetonitrile accompanied by heat and 500 mg of (anhydrous) Na2CO3 are added. After the solution is cooled, 30 mg (0.26 mM) of H2NSO2Cl are added and the solution is stirred vigorously. At one-hour intervals, 9 portions of H2NSO2Cl are added for every 10 mg. After 9 hours, the solution is worked up by stirring in diluted hydrochloric acid solution and the steroid is extracted with ether. The residue remaining after the concentration of the extract is absorbed in 4 ml of an acetonitrile/ethanol mixture (3:1) and separated by preparative HPLC (ET 125/8/4 Nucleosil 120-5C18 Macherey-Nagel, RT7.0) using acetonitrile as eluent. After concentration of the fraction with the Rt=7.0 (Rt=0.2; gel benzene; acetone=4:1) or Rt=8.1 (Rf=0.22 gel, benzene/acetone 4:1), 28.9 mg of the 3,17α-disulfamate (35.4%) and 9.8 mg (14.6%) of the 3 monosulfamate are isolated in the form of white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(O)(=O)C>[C:9]([O:8][C:7](=[O:13])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:22]([CH3:21])(=[O:24])=[O:23])([CH3:10])([CH3:12])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl N-(4-aminobutyl)carbamate (13.8 g, 73.4 mmol) and triethylamine (15.3 mL, 110 mmol) was cooled to 0° C. Methanesulfonyl chloride (6.3 mL, 81 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Aqueous acetic acid (200 mL of 10%) was added. The organic layer was then separated and washed with water (200 mL), saturated aqueous sodium bicarbonate (200 mL), water (200 mL), and brine; dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 18.9 g of tert-butyl[4-(methanesulfonylamino)butyl]carbamate as an off-white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]([CH2:15][NH2:16])[OH:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:16][CH2:15][CH2:13][OH:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(NCCO)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tetrahydrofuran. Ethanolamine (1.1 mL, 18.6 mmol) and and N,N-diisopropylethylamine (3.9 mL, 22.3 mmol) were added, and the reaction was allowed to stir at ambient temperature for 30 minutes. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil that was a mixture of the title compound and 4-chloromethyl N-(2-hydroxyethyl)benzenesulfonamide. The resulting oil was dried in vacuo (3.7 g, 68%). ES-MS m/z 250 (M+H) and 294 (M+H).
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:12]1.C[Mg]Br.C1(C)C=CC=CC=1>[Cu]Cl.O>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Cl[Cu]
Agent: C[Mg]Br
Solvent: O
Solvent: Cc1ccccc1
Product: CP(C(C)(C)C)C(C)(C)C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.025 g (0.25 mol (corresponding to 0.5% by mol)) of copper(I) chloride and 30 ml of tetrahydrofuran were placed. To the contents of the flask, 55 ml (0.055 mol) of a tetrahydrofuran solution of methylmagnesium bromide having a concentration of 1 mol/liter was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at the same temperature for 5 hours. Then, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 40 ml of toluene and 40 ml of water were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 750° C. to 810° C. under reduced pressure of 20 Torr were collected. As a result, 7.4 g (purity: 98.7%) of the aimed di-tert-butylmethylphosphine was obtained as an oily substance. The yield was 91.1%.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[N:30]=1)[C:25](O)=[O:26])=[O:21]>>[CH3:31][C:29]1[N:30]=[C:22]([C:20]([O:19][CH3:18])=[O:21])[CH:23]=[C:24]([C:25](=[O:26])[NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[C:3]([CH3:2])[CH:4]=2)[CH3:16])[CH:28]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Reactant: COC(=O)c1cc(C(=O)O)cc(C)n1
Agent: Cl
Product: COC(=O)c1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)cc(C)n1
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (110 mg, clear colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (97 mg, 0.36 mmol, Amine-17, single enantiomer) and 2-(methoxycarbonyl)-6-methylisonicotinic acid (70 mg, 0.36 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([OH:10])[N:7]=[C:6]([NH:11][CH:12]([CH3:14])[CH3:13])[N:5]=1)[CH3:2].[OH-].[K+].COCCOCCOC.Cl[CH:27]([F:29])[F:28]>O>[F:28][CH:27]([F:29])[O:10][C:8]1[N:9]=[C:4]([NH:3][CH2:1][CH3:2])[N:5]=[C:6]([NH:11][CH:12]([CH3:13])[CH3:14])[N:7]=1
Reactant: CCNc1nc(O)nc(NC(C)C)n1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: CCNc1nc(NC(C)C)nc(OC(F)F)n1
Temperature: 90 °C

Procedure:
A mixture of 200 g (1.02 moles) of 2-ethylamino-4-hydroxy-6-isopropylamino-1,3,5-triazine, 454 g (8.11 moles) of potassium hydroxide, 1150 ml of diethylene glycol dimethyl ether and 1150 ml of water was vigorously stirred, and heated to 90° C. Chlorodifluoromethane gas was blown into the reaction mixture until 2-ethylamino-4-hydroxy-6-isopropylamino-1,3,5-triazine was no longer detected by thin-layer chromatography. After the reaction, the reaction mixture was cooled to room temperature, extracted with methylene chloride. The methylene chloride layer was washed with water twice or thrice, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column. The column was eluted with n-hexane/ethyl acetate (5:1) to give 58.9 g of 2-difluoromethoxy-4-ethylamino-6-isopropylamino-1,3,5-triazine.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:12]Br>ClCCl>[Br:12][C:8]1[C:9]([NH2:11])=[CH:10][C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=1
Reactant: BrBr
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: ClCCl
Product: Nc1cc2c(cc1Br)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
A solution of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (32 g, 212 mmol) in dichloromethane (1 liter) was treated with a solution of bromine (10.8 ml, 212 mmol) in dichloromethane (100 ml) at 0° C. After the addition the mixture was stirred at room temperature for 1 hour then washed with saturated aqueous sodium bicarbonate solution containing a small amount of sodium sulphite. The organic organic extract was dried and evaporated affording an oil that was chromatographed on silica gel eluting with dichloromethane to afford an oil (14.8 g, 30%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][CH:19]([OH:22])[CH:20]=[CH2:21]>C(Cl)Cl>[OH:22][CH:19]([CH3:18])[CH:20]=[CH:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Reactant: C=CC(C)O
Solvent: ClCCl
Product: CC(O)C=Cc1ccc2[nH]cc(C3CCN(C)CC3)c2c1

Procedure:
Obtained by a procedure similar to that described in Example 1, using 5-bromo-3-(N-methyl-4-piperidyl)-1H-indole (EP-A-0303507) and but-3-en-2-ol, as a foam. Rf 0.50 (SS 4). Found: C,72.85; H,8.22; N,9.17. C18H24N2O; 0.17 CH2Cl2 requires C,73.08; H,8.22; N,9.38%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:17]([F:29])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:30](O)(=[O:34])[C@H:31]([CH3:33])[OH:32].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:29][C:17]1[C:18]([C:20]2[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:30](=[O:34])[C@@H:31]([OH:32])[CH3:33])[CH2:3]3)=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: C[C@H](O)C(=O)O
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](N)C4)cc3)ncc2F)n1C(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](NC(=O)[C@H](C)O)C4)cc3)ncc2F)n1C(C)C
Yield: 30.4 %

Procedure:
N-{4-[(3S)-3-Aminopyrrolidin-1-yl]phenyl}-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 153; 220 mg, 0.556 mmol), L—lactic acid (61 mg, 0.667 mmol), HOBt mono hydrate (103 mg, 0.667 mmol) and Hunig's base (0.12 ml, 0.667 mmol) in DCM (5 ml) were reacted with EDAC (128 mg, 0.667 mmol) at room temperature under nitrogen for 18 hours. The mixture was diluted with DCM (20 ml) and washed with water (20 ml), 1 N aqueous potassium hydroxide (20 ml) and saturated aqueous sodium chloride (15 ml). The mixture was dried and after evaporation under reduced pressure purified by HPLC on a Phenomenex column, (0-50% acetonitrile/water, 0.2% TFA). The fractions were diluted with water (20 ml), basified with solid potassium carbonate, and extracted twice with EtOAc/DCM (20 ml, 2:1). The solution was washed with saturated aqueous sodium chloride (15 ml), dried and after evaporation under reduced pressure gave the title compound as a yellow solid, (79 mg, 30%). NMR: 1.20 (d, 3H), 1.37 (d, 6H), 1.90-2.04 (m, 1H), 2.11-2.27 (m, 1H), 2.47 (s, 3H), 3.00-3.09 (m, 1H), 3.20-3.47 (m, 3H), 3.91-4.00 (m, 1H), 4.32-4.47 (m, 1H), 5.38 (s, 1H), 5.40-5.49 (m, 1H), 6.49 (d, 2H), 7.30 (s, 1H), 7.32 (d, 2H), 7.76 (d, 1H), 8.40 (d, 1H), 9.06 (s, 1H); m/z 468.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>CCOCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])=[O:5])[CH3:2]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)C1Cc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)C(=O)N1c2ccccc2CC1C(=O)OCC

Procedure:
To a chilled and stirred mixture of 2,3-dihydroindole-2-carboxylic acid ethyl ester (4.78 g., 25.0 mmole), triethylamine (2.7 g., 26.7 mmol), and anhydrous ether (500 ml) was added dropwise methacryloyl chloride (2.9 g., 27.7 mmole) dissolved in a small amount of ether. After the completion of the addition, the ice bath was removed, and the reaction mixture was stirred for 4 hours. The precipitate which separated was removed by filtration, and the filter residue was washed with ether. The combined filtrate and washing were washed with wafer (two 700- ml portions), then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure on a rotary evaporator gave the product as an oil. The product was purified by preparative HPLC (Prep LC/System 500, Waters Associates), using a micro porasil column eluted with a mixture of hexane (95%) and ethyl acetate (5%). The crude oil may be used directly in the following reaction.