Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[C:6](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH:17]2[CH2:18][CH2:19]2)=[C:6](/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(Br)ccc1OCC1CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OC/C=C/c1cc(Br)ccc1OCC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To (E)-ethyl 3-(5-bromo-2-(cyclopropylmethoxy)phenyl)acrylate (S6) (3.78 g, 11.6 mmol, 1.00 equiv) in PhMe (30 mL) in a flame-dried round-bottom flask under a N2 atmosphere at −78 ° C. was added a 1.0 M solution of diisobutylaluminum hydride (DIBAL-H) in PhMe (26 mL, 26 mmol, 2.2 equiv) in 6 portions dropwise every 10 minutes for 1 hour. The reaction was warmed to 0 ° C. over 2 hours and then warmed to 23 ° C. and stirred at this temperature for 1 hour. The reaction mixture was poured onto a concentrated aqueous Rochelle's salt (potassium sodium tartrate) solution (400 mL). EtOAc (400 mL) was added and the mixture was stirred for 3 hour until two liquid phases separated cleanly. The phases were partitioned and the aqueous phase was extracted from with EtOAc (300 mL). The organic phases were combined and washed with brine (200 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of 10-25% EtOAc in hexanes (v/v) to afford 2.77 g of the title compound as a colorless solid (84% yield). Rf=0.15 (hexanes/EtOAc 6:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 7.53 (d, J=2.4 Hz, 1H), 7.26 (dd, J=8.8, 2.4 Hz, 1H), 6.88 (d, J=16.1 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.39 (dt, J=16.1, 5.9 Hz, 1H), 4.33 (br dd, J=4.6, 4.6 Hz, 2H), 3.79 (d, J=6.8 Hz, 2H), 1.71 (br t, J=5.1 Hz, 1H), 1.31-1.23 (m, 1H), 0.68-0.58 (m, 2H), 0.38-0.30 (m, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 155.4, 131.2, 130.5, 129.7, 128.2, 125.0, 114.2, 113.2, 73.7, 64.1, 10.3, 3.4. HRMS-FIA (m/z): calcd for C13H15BrNaO2 [M+Na]+, 305.0153; found, 305.0123.
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][CH:8]=[CH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][CH:8]=[CH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
4-[1-(1-Cyclopentylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (13 mg, 0.030 mmol) was dissolved in DCM (3 mL) and TFA (0.5 mL) was added. The resulting solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was dissolved in THF (2 mL), and 6 N NaOH (1 mL) was added. The mixture was stirred at room temperature for 1 hour, and then was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the product (10 mg, 80%).
Reaction SMILES: [OH-].[NH4+:2].N.[CH2:4]([O:8][CH2:9][CH:10]=[CH2:11])[CH:5]1[O:7][CH2:6]1>>[CH2:9]([O:8][CH2:4][CH:5]([OH:7])[CH2:6][NH2:2])[CH:10]=[CH2:11]
Reactant: [NH4+]
Reactant: C=CCOCC1CO1
Agent: N
Agent: [OH-]
Product: C=CCOCC(O)CN
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ammonium hydroxide (28%-30% (about 14.82 mol) of ammonia in water, 202 mL, 3 mol) was charged to a one liter, one-neck, round-bottom flask that was cooled in an ice bath. To the above solution allyl glycidyl ether (57.07 g, 0.5 mol) was added dropwise at 0° C. The mixture was allowed to warm up to room temperature and stirred for two days after completion of the allyl glycidyl ether addition. 3-Allyloxy-2-hydroxy-propylamine was separated by distillation at 76° C.-82° C. under 0-1 mbar as a clear liquid (˜33 g).
Reaction SMILES: C(O[C:6](=[O:26])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17](=[O:19])[NH2:18])[C:12]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:11]=2[O:10][C@@H:9]1[CH3:25])(C)(C)C.N[C@@H]1C(=O)N(CC(N)=O)C2C=C(F)C=CC=2O[C@@H]1C.[CH3:46][C:47](C)([C:51]([NH:53][CH2:54][C:55]([F:61])([F:60])[C:56]([F:59])([F:58])[F:57])=[O:52])[C:48](O)=O>>[C:17]([CH2:16][N:13]1[C:12]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:11]=2[O:10][C@H:9]([CH3:25])[C@H:8]([NH:7][C:6](=[O:26])[C:47]([CH3:48])([CH3:46])[C:51]([NH:53][CH2:54][C:55]([F:60])([F:61])[C:56]([F:59])([F:57])[F:58])=[O:52])[C:14]1=[O:15])(=[O:19])[NH2:18]
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC(N)=O)C(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: C[C@H]1Oc2ccc(F)cc2N(CC(N)=O)C(=O)[C@H]1N
Product: C[C@H]1Oc2ccc(F)cc2N(CC(N)=O)C(=O)[C@H]1NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F

Procedure:
((6R,7S)-9-Carbamoylmethyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester was deprotected according to the procedure in example 42b. The resulting 2-((6R,7S)-7-amino-2-fluoro-6-methyl-8-oxo-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-acetamide was reacted with 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the procedure described in example 2b to yield N-((6R,7S)-9-carbamoylmethyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2,2-dimethyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide, MS m/e (%): 511.3 (M−H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[N:6]=[CH:7]2.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:33]=[CH:32][C:27]([CH2:28][N:29]=[C:30]=[O:31])=[CH:26][CH:25]=1>>[NH2:14][CH2:13][CH2:12][C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:1][C:30]([NH:29][CH2:28][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:35])[F:34])=[CH:33][CH:32]=1)=[O:31])[CH:11]=[CH:10][CH:9]=2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(N)cccc2cn1
Product: NCCc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2cn1
Reaction time: 0.08 h
Yield: 9.2 %

Procedure:
To a solution of tert-butyl 2-(5-aminoisoquinolin-3-yl)ethylcarbamate (Description 116; 200 mg, 0.7 mmol) in deuterated chloroform (5 ml) was added [4-(trifluoromethyl)benzyl]isocyanate (0.506M solution in DCM) (Description 58; 1.38 ml, 0.7 mmol), and the resulting mixture heated at reflux overnight. The reaction mixture was cooled and the precipitate removed by filtration, washed with DCM and dried. The solid was dissolved in methanol (10 ml) and hydrogen chloride gas passed through the mixture for 5 mins, after which time the mixture was left standing for 1 hour. The mixture was evaporated and purified using an SCX cartridge—appropriate fractions were evaporated to give the title compound (25 mg, 9%) as a white solid. m/z (ES+) 389 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[N:15]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([F:26])[CH:17]=3)[C:13]([NH2:27])=[N:12][CH:11]=2)[CH2:5]1)(=[O:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[N:15]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([F:26])[CH:17]=3)[C:13]([NH2:27])=[N:12][CH:11]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2nc(C3CCCN(C(C)=O)C3)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N1CCCC(c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 4-(6-(1-acetylpiperidin-3-yl)-3-aminopyrazin-2-yl)-2-fluorobenzoate (50 mg, 0.134 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 M LiOH (0.500 mL, 0.500 mmol). The reaction mixture was stirred at room temperature for 4 h. The pH of reaction mixture was adjusted to ˜3 with 2 N HCl, and the product was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was proceeded for next step without purification (34 mg, 70.7%). LCMS (m/z): 359.1 (MH+), 0.534 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.C(N(CC)CC)C.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[S:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)OC(C)(C)c2cc(NS(=O)(=O)c3cccc(Cl)c3Cl)ccc21
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
To a stirred solution of 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.15 g, 0.73 mmol) in methylene chloride (5 mL) at 0° C. was added triethylamine (0.15 mL, 1.07 mmol). After 10 minutes, 2,3-dichlorobenzenesulfonyl chloride (0.27 g, 1.10 mmol) was added. The solution was stirred for 5 hours, then partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation with 30% ethyl acetate/hexane followed by trituration with ether gave 2,3-dichloro-N-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzenesulfonamide as an off-white solid (0.015 g, 5%). 1H NMR (DMSO-d6): δ 10.17 (s, 1H), 8.02 (dd, J=7.9, 1.4 Hz, 1H), 7.93 (dd, J=8.1, 1.4 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.03 (m, 3H), 3.20 (s, 3H), 1.48 (s, 6H). MS (ESI) m/z 415/417/419 ([M+H]+); MS (ESI) m/z 413/415/417 ([M−H]−).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:17]([F:20])([F:19])[F:18])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C>C(O)C.[Li+].[OH-].O>[C:11]1([C:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=2[C:17]([F:19])([F:20])[F:18])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid ethyl ester (750 mg, 2.50 mmol) in ethanol (12 mL) and 2 N aq. LiOH (6 mL) is stirred at 65° C. for 2 h. The reaction mixture is cooled to rt, diluted with water (60 mL) and extracted with DCM (50 mL). The aq. phase is acidified by adding 2 N aq. HCl (7 mL) and extracted twice with DCM (2×50 mL). These organic extracts are combined, washed with sat. aq. NaHCO3, dried over Na2SO4, evaporated and dried under high vacuum to give 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid (670 mg) as a brown solid, LC-MS: tR=0.97 min, 1H NMR (D6-DMSO): δ 7.57-7.54 (m, 1H), 7.46-7.42 (m, 5H).
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[C:5]([CH3:19])=[C:6]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:7]([O:9]CC)=[O:8]>O.C(O)C>[I:3][C:4]1[C:5]([CH3:19])=[C:6]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)c(I)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1I
Reaction time: 1 h

Procedure:
A solution of 18.2 g (276 mmol) of 85 percent potassium hydroxide in 100 mL of water was added to a mixture of 67.8 g (184 nunol) of ethyl 3-iodo-2-methyl-4-methylsulfonylbenzoate in 300 mL of ethanol with stirring. After about 1 hour, all of the solids had dissolved and after 2 hours the mixture was concentrated by evaporation under reduced pressure. The residue obtained was diluted with water and the solution obtained was extracted with ether and then diluted with ethyl acetate. Aqueous hydrochloric acid (3N) was then added until the mixture was acidic. The organic phase was separated and the aqueous phase was twice extracted with ethyl acetate. The organic phase and extracts were combined and washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The 62.1 g (99 percent of theory) of colorless solid residue was the title compound. The purified compound melts at 193° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=2)[C:29]#[N:30])=[N:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:36])(C)(C)C.CC(C)([O-])C.[K+]>>[C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=2)[C:29]([NH2:30])=[O:36])=[N:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)O
Reactant: N#Cc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: NC(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 90 °C
Yield: 44.5 %

Procedure:
To a solution of 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinonitrile (45.0 mg, 0.112 mmol) in t-butanol (5.00 mL, 502 mmol) was added potassium tert-butoxide (125 mg, 1.12 mmol) and the contents were heated to 90° C. for 12 h. The reaction mixture was allowed to cool and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2 (25 mL) and washed with 1.5 N HCl (20 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a brown solid. The solid was purified by preparative HPLC (Condition B-64 as described in general methods) to give 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinamide (21.0 mg, 44.7%) as a brown solid. LCMS Condition B-12: retention time 2.07 min, [M+1]=422.2. HPLC Condition B-1: retention time=6.85 min, Purity=96.30%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.96 (d, J=4.4 Hz, 2H), 6.84 (d, J=2.8 Hz, 1H), 7.25-7.53 (m, 8H), 7.58-7.72 (m, 3H), 7.93 (d, J=2.8 Hz, 1H), 8.31 (s, 1H), 8.92 (s, 1H), 9.12 (s, 1H), 9.51 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:21][CH3:22])=[C:10]([N:13]3[CH2:18][C@H:17]([CH3:19])[NH:16][C@H:15]([CH3:20])[CH2:14]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C=O.[BH3-][C:26]#N.[Na+]>CO>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:21][CH3:22])=[C:10]([N:13]3[CH2:18][C@H:17]([CH3:19])[N:16]([CH3:26])[C@H:15]([CH3:20])[CH2:14]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)N(C(C)=O)CC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A stirred solution of D2 (1.48 g, 4.9 mmole) in MeOH (50 ml) at room temperature under Ar was treated with aqueous formaldehyde (2.4 ml of 37% w/v, 29 mmole), followed by portionwise addition of NaBH3CN (920 mg, 15 mmole). The mixture was stirred at room temperature for 3 h, then concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with DCM. The extract was dried (Na2SO4) and concentrated under vacuum to afford the title compound as a yellow solid (1.4 g, 90%). MH+ 318.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.C(N(CC)CC)C.[CH:31]1([CH2:34][N:35]2[C:43]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][C:41]3[C:36]2=[N:37][C:38]([C:56]2[CH:57]=[N:58][C:59]([NH2:62])=[N:60][CH:61]=2)=[N:39][C:40]=3[N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH2:33][CH2:32]1.Cl.[CH3:64][N:65]([CH3:70])[CH2:66][C:67](O)=[O:68]>ClCCl.CO.CN(C)C=O>[CH:31]1([CH2:34][N:35]2[C:43]([N:44]3[CH2:49][CH2:48][N:47]([C:67](=[O:68])[CH2:66][N:65]([CH3:70])[CH3:64])[CH2:46][CH2:45]3)=[N:42][C:41]3[C:36]2=[N:37][C:38]([C:56]2[CH:61]=[N:60][C:59]([NH2:62])=[N:58][CH:57]=2)=[N:39][C:40]=3[N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH2:32][CH2:33]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC4CC4)c3n2)cn1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CN(C)CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CC1
Temperature: 50 °C
Reaction time: 20.5 h
Yield: 70.5 %

Procedure:
1-Hydroxybenzotriazole monohydrate (35.0 mg, 0.23 mmol), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65.7 mg, 0.34 mmol), and triethylamine (38.2 μl, 0.27 mmol) were added to an N,N-dimethylformamide suspension (2.0 ml) of 5-[9-(cyclopropylmethyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (99.7 mg, 0.23 mmol) and N,N-dimethylglycine hydrochloride (38.3 mg, 0.27 mmol) at room temperature. The resulting mixture was stirred for 20.5 hours and heated to 50° C. followed by the addition of triethylamine (38.2 μl, 0.27 mmol) and the resulting mixture was stirred for 6 hours. The resulting mixture was further stirred at room temperature for 17 hours and then the reaction mixture was poured into dichloromethane-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=5:1) to give the title compound (84.6 mg, 71%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>[NH4+].[Cl-]>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:3][C:2]=1[NH:1][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1N
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
tert-Butyl 3-amino-4-methoxybenzyl(methyl)carbamate (265.3 mg, 0.996 mmol) was dissolved in pyridine (3000 μl, 37.1 mmol) and cooled to 0° C. MsCl (93 μl, 1.195 mmol) was added dropwise, and the reaction was stirred at RT for 1 hour. The solution was diluted with NH4Cl sat. sol. and extracted twice with DCM. The organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum to give tert-butyl 4-methoxy-3-(methylsulfonamido)benzyl(methyl)-carbamate (249.5 mg, 0.724 mmol, 72.7% yield, MS/ESI+ 367.2 [MNa]+) that was used in the next step without further purification.
Reaction SMILES: FC1C=CC=C(F)C=1N.C(N)C.[CH2:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[N+:23]([O-])=O)[CH3:14].C(NC1C=CC=C(NCC)C=1[N+]([O-])=O)C>CN(C)C=O.O1CCCC1.CO.[Pd]>[CH2:13]([NH:15][C:16]1[C:17]([NH2:23])=[C:18]([F:22])[CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: CCNc1cccc(F)c1[N+](=O)[O-]
Agent: [Pd]
Agent: CCN
Agent: CCNc1cccc(NCC)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: CCNc1cccc(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To 2,6-difluoroaniline (8 g, 62 mmol) in dimethylformamide (100 mL) was added a 2 M solution in tetrahydrofuran of ethyl amine (93 mL, 186 mmol) and the reaction stirred at room temperature overnight. The reaction was partitioned between 1 N hydrochloric acid and ethyl acetate and dried over sodium sulfate. The product was purified by silica gel using the ISCO (0-100% ethyl acetate/hexane) to give an equal mixture of ethyl-(3-fluoro-2-nitro-phenyl)-amine and N,N′-Diethyl-2-nitro-benzene-1,3-diamine. This mixture was reduced using the parr shaker and a spatula tip of 5% Pd/C in MeOH (100 mL). Upon complete reduction, the reaction was filtered through a pad of celite and concentrated onto silica gel. The desired product was purified on silica gel using the ISCO (0-100% ethyl acetate/hexane) to give N1-Ethyl-3-fluoro-benzene-1,2-diamine (2.48 g, 52%). N1-Ethyl-3-fluoro-benzene-1,2-diamine (2.48 g, 16.1 mmol) and carbonyl diimidazole (4.38 g, 27 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature overnight. Upon disappearance of the starting material, the reaction was partitioned between 1 N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The organics were dried over sodium sulfate and concentrated to give 1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one as a white solid in near quantitative yield. MS (ES) m/z 181.1;
Reaction SMILES: [C:1]([C:5]1([CH:8]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH3:9])[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>COCCOCCOC.O.[OH-].[Li+]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:7][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([OH:6])[CH:8]([CH3:9])[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(n1cncn1)C1(C(C)(C)C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: CC(n1cncn1)C(O)(COc1ccc(F)cc1)C(C)(C)C
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A mixture of 10.0 g of 2-tert-butyl-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]-oxirane, 6.4 g of 4-fluorophenol and 0.1 g of lithium hydroxide hydrate in 10 ml of diethylene glycol dimethyl ether is heated for 18 hours to 150° C. After it has cooled, the reaction mixture is poured into ice-water and extracted with ether. The organic phase is washed with water and a saturated solution of sodium chloride, dried and concentrated. Chromatography over silica gel with a 3:1 mixture of ethyl acetate/toluene as eluant yields 11.0 g of 1-(4-fluorophenoxy)-2-tert-butyl-2-hydroxy-3-methyl-3-(1H-1,2,4-triazol-1-yl)propane with a melting point of 85°-100° C. (compound 18).