Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]([CH3:20])([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:42][CH2:43][C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[Cl:42][CH2:43][C:44]([NH:19][C:15]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:22][CH2:23][N:24]2[C@H:29]3[CH2:30][CH2:31][C@@H:25]2[CH2:26][CH:27]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[CH2:28]3)[CH2:9][CH2:10]1)=[O:21])([CH3:20])[CH:16]([CH3:17])[CH3:18])=[O:45]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(N)C(C)C)CC1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(NC(=O)CCl)C(C)C)CC1
Yield: 52.4 %

Procedure:
2-chloro-N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}carbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.524 g, 99%). 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Chloro-acetyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-chloro-N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}acetamide (0.030 g, 52%) as an oil. ES-LCMS m/z 636 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]\[CH2:21]O)[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:42]([O:46][C:47]([NH:49][O:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:42]([O:46][C:47]([N:49]([CH2:21]/[CH:20]=[CH:19]\[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:10]2[CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:12][N:11]=2)[CH:14]=1)[O:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: OC/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)ON(C/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of the product of Step 3, above (15, 1.8 g, 6 mmol), PPh3 (1.9 g, 7.2 mmol) and N,O-di-tert-butoxycarbonylhydroxylamine (1.85 g, 7.8 mmol) in THF (25 ml) was added dropwise a solution of diethylazodicarboxylate (1.2 ml, 7.2 mmol) in THF (5 ml) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 hours and solvent was removed under reduced pressure. The resultant residue was purified by column chromatography on silica gel (eluent=ethyl acetate:n-hexane, 1:7) to afford 3.0 g (98% yield) of the title compound (16) as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Cl:11][C:12]([O:15]C(Cl)=O)(Cl)Cl>O1CCCC1>[O:10]=[C:2]1[N:3]([C:12]([Cl:11])=[O:15])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccccc2[nH]1
Solvent: C1CCOC1
Product: O=C(Cl)n1c(=O)[nH]c2ccccc21

Procedure:
It was prepared by suspending 5 g of 2,3-dihydro-1H-benzimidazole-2-one in 200 ml of distilled tetrahydrofuran and by adding 13.5 ml of trichloromethylchloroformate. The reaction mixture was refluxed for 3 hrs until a clear solution was obtained. After cooling the separated solid was removed by filtration and after concentration to dryness of the mother liquors 6.5 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[OH:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(#N)C>[CH2:23]([NH:27][C:28]([O:22][CH:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: O=C1c2cccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCCCN=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNC(=O)OC1c2ncccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 3 h

Procedure:
A suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-7-hydroxy-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1 g.) in acetonitrile (100 cc.) containing n-butyl isocyanate (7.25 cc.) and triethylamine (0.5 cc.) is heated at the reflux temperature for 1 hour 30 minutes. n-Butyl isocyanate (7.25 cc.) and triethylamine (0.5 cc.) are then added and heating at the reflux temperature is continued for a further 3 hours. The solution is filtered and the filtrate is concentrated under reduced pressure (40 mm.Hg). The residue obtained is triturated with diisopropyl ether (20 cc.). The solid is filtered off and is recrystallised from acetonitrile (35 cc.) to give 7-n-butylaminocarbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.96 g.) melting at 215° C.
Reaction SMILES: [CH:1]1([C:6](O)([CH3:12])[CH2:7][CH2:8][CH2:9][C:10]#[N:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.C1(C(C)CCCC#N)CCCC=1>C(O)(=O)C.CC(OC)(C)C>[C:1]1(=[C:6]([CH3:12])[CH2:7][CH2:8][CH2:9][C:10]#[N:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)(CCCC#N)C1CCCC1
Agent: CC(CCCC#N)C1=CCCC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CC(CCCC#N)=C1CCCC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
Crude 5-cyclopentyl-5-hydroxyhexanenitrile (18 g; 0.1 mol) from example 13(a) was added into a solution of sulphuric acid (15 ml) in acetic acid (150 ml). The reaction mixture was stirred at 5° C. for 1 hour, then poured into ice (100 g), diluted with MTBE (100 ml), washed with saturated sodium bicarbonate solution (5×300 ml) and brine (2×300 ml), dried (MgSO4), concentrated in vacuo, and bulb-to-bulb distilled to give 2.1 g (13% yield) of 5-cyclopentylidene-hexanenitrile and 5-(cyclopent-1-enyl)-hexanenitrile mixture (GC: 43+57%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCOCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (47.08 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified via flash silica gel chromatography (5% MeOH/CHCl3) providing the title compound in 18% yield (25 mg, 0.043 mmol).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[NH:31][C:32](=[O:36])[O:33][CH2:34][CH3:35])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[H-].[Na+].Br[CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54]>CN(C)C=O.[Cl-].[Na+].O>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([C:32]([O:33][CH2:34][CH3:35])=[O:36])[CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCCBr
Reactant: CCOC(=O)Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCN(C(=O)OCC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reaction time: 0.5 h

Procedure:
Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (140 mg) is dissolved in N,N-dimethylformamide (1 ml), and thereto is added sodium hydride (63%) (12 mg) under ice-cooling, and the mixture is stirred at the same temperature for 30 minutes. To the reaction mixture is added ethyl 5-bromo-pentanoate (68 μl), and the mixture is stirred at 0° C. to room temperature overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give ethyl 5-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethoxycarbonyl-amino]-pentanoate (137 mg). MS (m/z): 780 [M+H]+
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:8]=[CH:9][CH:10]=1.[F:21][CH:22]1[CH2:25][N:24]([C:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:36])[C:32]=2[C:33](O)=[O:34])=[O:27])[CH2:23]1>>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:33]([C:32]4[N:31]([CH3:36])[N:30]=[CH:29][C:28]=4[C:26]([N:24]4[CH2:23][CH:22]([F:21])[CH2:25]4)=[O:27])=[O:34])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Reactant: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)O
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1

Procedure:
The title compound was prepared in analogy to example 82 from 2-(3-(2-fluoroethoxy)phenyl)imidazo[1,2-a]pyrimidin-7-amine (120 mg) and 4-(3-fluoroazetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (100 mg, 440 μmol). Light brown solid (132 mg, 60%). MS (m/z)=482.2 [M+H+].
Reaction SMILES: OCC=C(CCC=C(CCC=C(C)C)C)C.N1C=CN=C1.CN(C)C=O.[Si:27]([Cl:44])([C:40]([CH3:43])([CH3:42])[CH3:41])(C1C=CC=CC=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:40]([SiH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[Cl:44])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH](Cl)c1ccccc1
Yield: 99 %

Procedure:
Synthesis was carried out with farnesol as a starting material. A protective group was bonded to the hydroxy group of farnesol using imidazole, anhydrous dimethylformamide, anhydrous dichloromethane, and tert-butyldiphenylsilyl chloride (TBDPS) to obtain a TBDPS-protected form (compound represented by (ei) below) (yield: 99%). Next, this compound was reacted with m-chloroperbenzoic acid in an anhydrous dichloromethane solvent to obtain an epoxy form (compound represented by (eii) below) (yield: 29%). Next, the epoxy was subjected to periodic acid oxidation using orthoperiodic acid in a mixed solvent of ether and tetrahydrofuran to obtain an aldehyde form (compound represented by (eiii) below) (yield: 73%). A Grignard reagent was prepared from ethyl iodide and magnesium in an anhydrous ether solvent and then reacted with the aldehyde to form an alcohol form (compound represented by (eiv) below) (yield: 80%). The secondary hydroxy group of the racemic alcohol form and (S)-MaNP acid were subjected to reaction in the presence of N,N-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, and (+)-10-camphorsulfonic acid in an anhydrous dichloromethane solvent to obtain diastereomers. Then, the diastereomers were optically resolved by HPLC, and the absolute configuration was determined by NMR to optically obtain a compound represented by (ev) below (yield: 84%). The TBDPS protective group was then deprotected using tetra-n-butylammonium hydrate in anhydrous tetrahydrofuran to obtain a diol form (compound represented by (evi) below) (yield: 91%). Next, the primary hydroxy group was replaced by chlorine using N-chlorosuccinimide and dimethyl sulfide in an anhydrous dichloromethane solvent at −40° C. or lower to obtain a chloride (compound represented by (evii) below) (yield: 70%). Next, the chloride was diphosphorylated using tris-tetra-n-butylammonium hydrogen pyrophosphate in anhydrous acetonitrile to obtain a compound represented by (eviii) below (compound represented by the formula (E)) as the substance of interest (yield: 59%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:10][C:11]([CH3:14])([OH:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC>[CH3:10][C:11]([OH:13])([CH3:14])[CH2:12][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
A mixture of 4-nitro-1H-pyrazole (1.6 g, 13.9 mmol), 1-chloro-2-methylpropan-2-ol (1.5 g, 13.9 mmol) and Cs2CO3 (9.1 g, 27.8 mmol) in DMF (20 mL) was stirred at 80° C. for 5 h. The reaction mixture was cooled to RT and diluted with EA (200 ml). The organic phase was washed by water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol as a yellow oil (2.0 g, 78%), which was used for the next step without further purification. MS (ES+) C7H11N3O3 requires: 185, found: 186 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cncn2)c(F)c1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
A solution of 5.0 g (72.4 mmol) of 1H-1,2,4-triazole and 25.22 g (144.8 mmol) of dibasic potassium phosphate in 150 mL DMSO was treated with 11.52 g (72.4 mmol) of 3,4-difluoronitrobenzene followed by warming at 90° C. for 3 h. The solution was cooled and added to 500 mL water, and the resulting white solid was collected by filtration and washed with water. The white solid obtained was dried in vacuo (60° C./10 mmHg) to afford 10.79 g (72%) of the title compound as a white solid. High Resolution Mass Spectrum: Calculated for C8H5FN4O2 : 208.0396. Found: 208.0408.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].II.[Cl-].[Zn+2:12].[Cl-]>C1COCC1>[Zn:12]([CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)CCBr
Reactant: [Zn+2]
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(F)(F)CC[Zn]CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
To magnesium (1.373 g, 56.5 mmol) in a 500 mL tear-shaped flask applied vacuum then nitrogen, added 50 mL THF, added 3-bromo-1,1,1-trifluoropropane (6.02 mL, 56.5 mmol), and then 1 crystal of iodine. Within 1 minute the mixture became warm and by 5 minutes was refluxing. The mixture was cooled for 2 minutes with an ice bath to control the exothermic reaction then allowed to warm back up to rt. By 65 minutes, nearly all of the Mg had dissolved. Added zinc(II) chloride (3.85 g, 28.3 mmol) which caused a small amount of heat to be generated. Nearly all was dissolved within 10 minutes to provide ˜1.1 M of Zn(CH2CH2CF3)2 in THF. To 5-bromo-2-chloropyrimidine (7.72 g, 39.9 mmol) and bis(tri-t-butylphosphine)palladium(0) (404 mg, 0.791 mmol) applied vacuum then placed under an atmosphere of nitrogen, added 80 mL THF, and then added over ˜2 minutes 60 mL of the ˜1.1 M of Zn(CH2CH2CF3)2 in THF. The reaction was quenched after 23 hour)s with 300 mL saturated NH4Cl+300 mL EtOAc, the organic layer was then washed with 300 mL saturated NaHCO3 then 300 mL water, dried with MgSO4, filtered, then concentrated to 7.6 g brown oily solids. This material was purified by flash chromatography (0-10% EtOAc/hexanes) to yield product (3.86 g, 18.4 mmol, 46% yield) as a pale yellow solid. MS (ESI) 211.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(O[C:35]([N:37](C)[C:38]1([C:42](O)=[O:43])[CH2:41][CH2:40][CH2:39]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:42]([C:38]4([NH:37][CH3:35])[CH2:41][CH2:40][CH2:39]4)=[O:43])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)C1(C(=O)O)CCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC1(C(=O)N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50.0 mg, 0.12 mmol), 1-(tert-butoxycarbonyl(methyl)amino)cyclobutanecarboxylic acid (27.5 0.12 mmol), HATU (45.8 mg, 0.12 mmol) and di-isopropylethylamine (20 μL, 0.12 mmol) in 1 mL of DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The resulting crude mixture was dissolved in 5 mL of DCM and 4 mL of TFA, and was stirred for 2 h followed by concentration in vacuo. The crude product was purified by RP-HPLC to afford (4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)(1-(methylamino)cyclobutyl)methanone; ESMS m/z 527.2 (M+H+).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13](Br)[C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(O)C>[CH2:15]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:14]#[CH:13]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C#CCON1C(=O)c2ccccc2C1=O
Yield: 63.3 %

Procedure:
A stirred solution of 163.1 grams (1.00 mole) of N-hydroxyphthalimide, 448.0 grams (3.74 moles) of 2-propynyl bromide, 72.0 grams (0.52 mole) of potassium carbonate and 60.0 grams (0.82 mole) of dimethylformamide was heated under reflux for 16 hours. The reaction mixture containing a hardened solid was cooled. The solid was broken up by the addition of ethanol and stirring. The solid was collected by filtration and washed with additional ethanol, then with water until the washings were free of bromide ion when tested with silver ion. The solid was dried in a vacuum desiccator then recrystallized from hot ethanol to give 127.3 grams of N-2-propynoxyphthalimide; mp 146°-148.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][N:16]([CH:25]([CH3:27])[CH3:26])[C:15]=3[N:14]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[Cl:28][CH2:29][CH2:30][N:31]=[C:32]=[O:33].C(OC(C)C)(C)C>O1CCOCC1>[Cl:28][CH2:29][CH2:30][NH:31][C:32]([NH:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[C:4]([NH:12][C:13]2[N:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][N:16]([CH:25]([CH3:27])[CH3:26])[C:15]=3[N:14]=2)[CH:3]=1)=[O:33]
Reactant: O=C=NCCCl
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)NCCCl)cc(S(C)(=O)=O)c3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (300 mg; 0.768 mmol) was diluted under nitrogen atmosphere in 3 ml of dry 1,4-dioxane, then a solution of 2-chloroethyl-isocyanate (0.09 ml; 0.999 mmol) in 2 ml of dry 1,4-dioxane was added drop-wise. The reaction mixture was stirred at room temperature for 3 h, then warmed to 60° C. and maintained at that temperature for 3 h. The reaction mixture was then concentrated in vacuo. The crude obtained was treated with isopropyl ether. The solid obtained was filtered. 261 mg (0.001 mol; 68.5 yield) of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[N:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C@H:52]([OH:55])[CH2:53][OH:54].C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:50][CH2:51][C@H:52]([OH:55])[CH2:53][OH:54])=[O:24])=[C:16]2[N:15]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: NC[C@H](O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC[C@H](O)CO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 42.3 %

Procedure:
A mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C, 400 mg, 1.16 mmol), HATU (486 mg, 1.28 mmol), and (S)-3-aminopropane-1,2-diol (318 mg, 3.49 mmol) in dry DMF (3.0 mL) was stirred for 1-2 minutes at ambient temperature. Diisopropylethylamine (DIEA) (0.62 mL, 3.49 mmol) was added and the reaction was flushed with N2, sealed and stirred at ambient temperature for 18 hours. The reaction mixture was added to H2O (15 mL), mixed and extracted with EtOAc. The combined EtOAc extracts were washed with H2O, saturated NaHCO3 and dried over MgSO4/activated carbon. The solution was eluted through a SiO2 column eluting first with EtOAc then 10% MeOH/EtOAc. The 10% MeOH/EtOAc pool was concentrated and the residual, colorless glass was dissolved in a minimal amount of CH2Cl2. Hexane was added and the resulting white suspension was sonicated and concentrated to give the title product as a white solid (205 mg, 42%). MS (apci) m/z=418.1 (M+H).