Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:18]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:19]([C:21](ON1C(=O)CCC1=O)=[O:22])[CH3:20].CN1CCOCC1>CN(C=O)C>[NH:18]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C@H:19]([C:21]([NH:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:22])[CH3:20]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O

Procedure:
H-Glu(OBzl)-OH (7.0 g, 29.5 mmol) was finely ground in a mortar and pestle and then stirred with 8.88 g (32.3 mmol) of Boc-Ala-OSu for 48 hours in 250 ml DMF in the presence of 6 ml N-methylmorpholine (NMM). Some more NMM was added to maintain the reaction slightly basic during the reaction. The solvent was evaporated and the residue partitioned between 30 ml ethyl acetate and 500 ml H2O containing 2 ml of 10% H2SO4. The organic layer was then washed three times with water, dried(Na2SO4) and evaporated to dryness. The product was taken up in a small volume of ether and treated with a large volume of petroleum ether. A white amorphous solid was obtained which was homogeneous on tlc: Yield, 11.0 g (91.5%); mp 84°-88°; [α]D25 = -8.08° (c l, DMF).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C[O:7][C:8](=O)/[CH:9]=[C:10](/[O:13][CH3:14])\[CH2:11]Cl.COC(=O)C/C=C/OCCl>O>[CH3:14][O:13][C:10]1[CH2:11][N:1]([CH2:2][C:3]([OH:5])=[O:4])[C:8](=[O:7])[CH:9]=1
Reactant: NCC(=O)O
Reactant: COC(=O)/C=C(\CCl)OC
Agent: COC(=O)C/C=C/OCCl
Solvent: O
Product: COC1=CC(=O)N(CC(=O)O)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 304.6 %

Procedure:
30 g (400 mmol) of glycine was suspended in 60 ml of H2O and heated to 70° C. 10M of NAOH was added with an autotitrator up to pH 8.5. Then, 22.4 g (136 mmol) of 4-chloro-3-methoxy-but-2E-enoic acid methyl ester was added at 70° to 75° C. The pH was kept constant at 8.5 by adding 10M of NAOH. After 1 hour, another 22.4 g (136 mmol) of 4-chloro-3-methoxy-but-2E-enoic acid methyl ester was added, and, after another hour, 22.4 g (136 mmol) of 4-chloromethoxy-but-3E-enoic acid methyl ester again was added. After the final addition, the reaction mixture was stirred for another 3.5 hours at 70° to 75° C. The consumption of 10M of NAOH was then 80.3 ml, which corresponded to 2 equivalents relative to the glycine used. The reaction mixture was cooled to room temperature and diluted with 40 ml of H2O. Then, the reaction mixture was adjusted to pH 1 with concentrated HCl. The product precipitated after a short time, was filtered off and washed with saturated NaCl solution. After drying, 70.9 g of product was obtained. 3.41 g of product was obtained from the mother liquor. The total yield was 84 percent. The crude product was recrystallized from isopropanol: 68 g was recrystallized from 450 ml of isopropanol. 47 g of product, which corresponded to an 87 percent yield, was obtained. The product contained less than 0.01 percent of Cl. Other data for the product was:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:17]=1.Cl[C:19]1[N:20]([CH3:32])[C:21](=[O:31])[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[N:24]=1.C(N(CC)CC)C>O1CCCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:19]4[N:20]([CH3:32])[C:21](=[O:31])[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][N:26]=5)[N:24]=4)[CH2:15][CH2:16]3)=[CH:9][S:8][C:7]=2[CH:17]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCC(c3csc4cc(F)ccc34)CC2)nc(-c2ccncn2)cc1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 74.6 %

Procedure:
To a solution of 4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride (200 mg, 0.74 mmol) and 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (160 mg, 0.70 mmol) in tetrahydrofuran (10 mL) was added triethylamine (212 mg, 2.1 mmol). The mixture was stirred at 90° C. for 6 h. The solvent was evaporated off in vacuo and the residue was treated with water and chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from ethyl acetate gave 2-[4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (220 mg, 96%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:38][O:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[CH:30][C:29]=1[F:28])=[O:36]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1F
Temperature: 80 °C
Yield: 76 %

Procedure:
5-[2-(4-Bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (500 mg, obtained in Example 116, step 8), 3-fluoro-4-methoxycarbonyl-phenylboronic acid (320 mg, [CAS Reg. No. 505083-04-5]) and dichloro(1,1′-bis(diphenyl-phosphino)ferrocene)palladium(II)dichloromethane adduct (39 mg) were dissolved in dioxane (9 mL) and water (5 mL). To the reaction mixture was added 2.0 M aqueous Na2CO3 (0.81 mL). The mixture was heated to 80° C. for 2 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (440 mg, 76%). MS (m/e)=555.2 [(M+NH4+)+], MS (m/e)=506.1 [(M−CH3O−)+].
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10]O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>ClCCl>[C:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc(CO)no1
Solvent: ClCCl
Product: CC(C)(C)c1cc(CCl)no1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.62 g of (5-t-butyl-isoxazol-3-yl)methanol was dissolved in 12 ml of dichloromethane, and 0.9 ml of thionyl chloride was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.69 g of 5-t-butyl-3-(chloromethyl)isoxazole.
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N1C=CC=CC=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:14]([CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1)(=[O:21])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1C=CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccccc1)C1C=CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.6 %

Procedure:
To a solution of 0.320 g (3.26 mmol) of 2-cyclohexen-1-ol and 0.76 mL (9.40 mmol) of pyridine in 20 mL of CH2Cl2 was added 1.04 mnL (8.96 mmol) of benzoyl chloride via syringe. The reaction mixture was yellow with a white precipitate. The reaction was stirred at room temperature for 17 h. The reaction was quenched by the addition of 50 mL of H2O; the aqueous layer was washed with 4×50 mL of Et2O, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (35 mm, 20 cm, 10% CH2Cl2/hexane) gave 0.635 g (99%) of 3-benzoylcyclohexene as a pale yellow oil: TLC Rf=0.35 (10% CH2Cl2/hexane); IR (CCl4) 3100 (w), 3081 (w), 3038 (w), 2931 (s), 1725 (s), 1550 (s); 1H NMR (CDCl3) δ1.66-2.12 (m, 6H), 5.49 (bs, 1H), 5.79-5.83 (m, 1H), 5.97-6.01 (m, 1H), 7.41 (t, J=7.7, 2H), 7.52 (t, J=7.4, 1H); 8.02-8.04 (m, 2H); 13C NMR (CDCl3) δ19.0, 25.0, 28.4, 68.6, 125.8, 128.3, 129.6, 130.9, 132.7, 132.8, 166.2; LRMS (EI) 203 ((M+1), 3), 202 ((M+), 20), 105 (100); HRMS (EI) calculated for C13H14O2 202.0994 (M+), found 202.1003. The IR, 1H NMR, and 13C NMR matched spectral data reported by Akemark, B. et al., J. Org. Chem. 59:5729-5799 (1994).
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[C:5]1\[C:6](=[O:24])[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[N:8]=[C:9]\1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1F)C.[N:25]1([C:30]2[CH:35]=[CH:34][C:33](CN)=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:7]1[C:6](=[O:24])[C:5]2=[CH:4][N:2]([CH2:1][C:33]3[CH:32]=[CH:31][C:30]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:35][CH:34]=3)[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[N:8]1
Reactant: CN(C)/C=C1\C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Reactant: NCc1ccc(-n2cccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
(4Z)-4-[(Dimethylamino)methylidene]-2,5-bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (241 mg, 0.735 mmol) and 1-[4-(1H-pyrazol-1-yl)phenyl]methanamine (127 mg, 0.735 mmol, 1 equiv) were combined in dimethylsulfoxide (10 mL) and placed into a preheated oil bath at 100° C. for 1.5 hours. To the mixture was added potassium carbonate (102 mg, 0.735 mmol, 1 equiv) and the mixture was heated for an additional 1 hour at 140° C. Additional 1-[4-(1H-pyrazol-1-yl)phenyl]methanamine (127 mg, 0.735 mmol, 1 equiv) and potassium carbonate (102 mg, 0.735 mmol, 1 equiv) were added and the mixture was heated for an additional 1 hour at 140° C. The mixture was cooled to ambient temperature, poured into water (75 mL) and extracted with ethyl acetate (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol; then 100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 9.16 (1H, s), 8.46 (1H, d, J=2.4 Hz), 8.20 (1H, dd, J=7.8, 1.4 Hz), 7.82 (2H, d, J=8.7 Hz), 7.77 (1H, d, J=8.7 Hz), 7.72 (1H, d, J=14.6 Hz), 7.64-7.59 (2H, m), 7.55-7.52 (1H, m), 7.47 (2H, d, J=8.4 Hz), 7.47-7.38 (2H, m), 7.36-7.32 (1H, m), 6.53 (1H, dd, J=2.4, 1.7 Hz), 5.78 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 436.1560 [(M+H)+; calculated for C26H19FN5O: 436.1568].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])([CH3:4])([CH3:3])[CH3:2].[I:21]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[CH:8]=[C:7]([I:21])[C:6]=1[O:15][CH2:16][C:17]([F:18])([F:19])[F:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)c1ccc(OCC(F)(F)F)c(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(I)c(OCC(F)(F)F)c(C(C)(C)C)c1
Temperature: 38 °C
Yield: 96 %

Procedure:
2,4-Di-tert-butyl-1-(2,2,2-trifluoro-ethoxy)-benzene (5.06 g, 17.5 mmol), N-iodosuccinimide (4.74 g, 21 mmol) and p-toluenesulfonic acid monohydrate (1.33 g, 7 mmol) were combined in dichloromethane (50 mL) and heated at 38° C. for 19 h. The reaction was washed with 10% Na2S2O3 solution (2×40 mL). The aqueous was backwashed with dichloromethane (70 mL) and then the combined organic portions washed with water (75 mL) and the combined organic portions washed with water (100 mL), dried (MgSO4), filtered and evaporated in vacuo to provide a yellow oil (6.96 g). The material was purified by flash chromatography using hexane to give 5.85 g (81%) of a light pink oil. 1HNMR (250 MHz, CDCl3): δ 7.67 (d, 1H, J=2.4), 7.37 (d, 1H, J=2.4), 4.45 (q, 2H, J=8.2), 1.40 (s, 9H), 1.30 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.N1C2C=CC=C([C:29]([O:31][CH3:32])=[O:30])C=2C=C1>>[CH3:18][C:13]1([CH3:19])[C:14]([CH3:17])([CH3:16])[O:15][B:11]([C:8]2[NH:9][C:10]3[CH:2]=[CH:3][CH:4]=[C:5]([C:29]([O:31][CH3:32])=[O:30])[C:6]=3[CH:7]=2)[O:12]1
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: COC(=O)c1cccc2[nH]ccc12
Product: COC(=O)c1cccc2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 1H-indole-4-carboxylic acid, methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:6]([C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C@H:5]([CH:15]=[O:16])[CH2:4][O:3]1.[CH3:18][CH2:19][Mg+].[Br-]>CCOCC>[CH2:18]([CH:15]([C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:17])[N:6]1[C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[OH:16])[CH3:19]
Reactant: CC[Mg+]
Reactant: CCCCCCC(=O)N1[C@H](C=O)COC1(C)C
Agent: [Br-]
Solvent: CCOCC
Product: CCCCCCC(=O)N1[C@H](C(O)CC)COC1(C)C
Reaction time: 1.5 h

Procedure:
A solution of 9a (108 mg, 0.44 mmol) in ether (1 mL) is added dropwise to a cold (5°) solution of EtMgBr (3M in ether, 0.36 mL). The cold bath is removed, a crystal of iodine is added to the mixture and stirring is continued for 1.5 h at room temperature. The resulting mixture is diluted with EtOAc and washed with saturated aqueous NH4Cl solution. The aqueous phase is reextracted and the combined organic solution dried and evaporated to yield crude 10a: NMR δ0.88 (m, 1.05 (m, 1.30 (m, 1.45 (m, 2H), 1.57 (s, 3H), 1.50-1.75 (m, 5H), 2.10-2.60 (m, 2H), 3.50-4.50 (m, 4H); MS (EI) m/z 271 (M).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH3:13])[C:6]=2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:12][C@H:10]([C:8]2[N:7]([CH3:13])[C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:25]=[CH:24][N:23]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Temperature: 90 °C
Yield: 69.9 %

Procedure:
(S)-1-(6-Fluoro-1-methyl-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.093 g, 0.35 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (53 mg, 0.35 mmol) and DIPEA (313 μL, 1.72 mmol) in IPA (5 mL) were added and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue purified by flash chromatography (Si—PPC, gradient 0-10% methanol in DCM) to give 411 as a white solid (95 mg, 72%). LCMS (Method K): RT 2.76 min [M+H]+ 389. 1H NMR (DMSO-d6, 400 MHz): δ 8.70 (1H, ddd, J=4.8, 1.7, 0.9 Hz), 7.98 (1H, s), 7.91 (1H, td, J=7.8, 1.8 Hz), 7.71-7.64 (2H, m), 7.60 (1H, dq, J=7.7, 0.9 Hz), 7.46 (1H, ddd, J=7.6, 4.9, 1.0 Hz), 7.26 (2H, br s), 7.11 (1H, dd, J=10.5, 8.8 Hz), 5.59 (1H, quin, J=7.3 HZ), 3.09 (3H, s), 1.53 (3H, d, J=6.8 Hz)
Reaction SMILES: [CH3:1][C:2]1([CH:15]([CH3:17])[CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].[H-].COCCO[Al+]OCCOC.[Na+].[H-].O1CCCC1>C1C=CC=CC=1>[CH3:1][C:2]1([CH:15]([CH3:17])[CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[CH:3]1[OH:14]
Reactant: CC(C)C1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)C1(C)Cc2cc(O)c(Cl)c(Cl)c2C1O

Procedure:
2-Methyl-2-isopropyl-6,7-dichloro-1,5-indan-diol is prepared following substantially the same procedure described in Example 4, Step E, using the following substances: 2-methyl-2-isopropyl-5-hydroxy-6,7-dichloro-1-indanone (8.2 g., .03 mole); sodium bis-(2-methoxyethoxy)aluminum hydride (70% in benzene [10 ml.]; and tetrahydrofuran (100 ml.).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:24])([F:23])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:20][C:19](=[O:21])[NH:18][C@@H:17]([CH3:22])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[Br:25][C:26]1[C:27]([CH2:33]Br)=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1>C1COCC1>[F:24][C:4]([F:3])([F:23])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:20][C:19](=[O:21])[N:18]([CH2:33][C:27]3[C:26]([Br:25])=[CH:31][CH:30]=[C:29]([Cl:32])[N:28]=3)[C@@H:17]([CH3:22])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: Clc1ccc(Br)c(CBr)n1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of sodium hydride (60% in oil; 105 mg, 2.53 mmol) in THF (10 mL) at 0° C. under an atmosphere of N2 was added a solution of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 20; 68 mg, 0.21 mmol) in THF (2 mL) dropwise. The resultant mixture was stirred at 0° C. for 20 min prior to the addition of 3-bromo-2-bromomethyl-6-chloropyridine (59 mg, 0.21 mmol) as a solution in THF (1 mL). The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with H2O and was partitioned between H2O (25 mL) and EtOAC (35 mL). The aqueous layer was re-extracted with EtOAc (3×35 mL) and the combined extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazinan-2-one as a clear oil. LCMS=625.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.94-7.90 (brs, 2H), 7.83 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 5.64 (m, 1H), 5.36 (d, J=17.6 Hz, 1H), 4.46 (d, J=17.6 Hz, 1H), 3.84 (m, 1H), 2.44 (m, 1H), 2.14 (m, 1H), 1.34 (d, J=6.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:28]([C:30]1[O:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:33]4[O:34][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(C=O)o4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 5-formyl-2-furanboronic acid in General Procedure A. Purification on silica yielded 5-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-furan-2-carbaldehyde.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[C:3]([OH:5])=[O:4].[C:13]1([C@H:19]([OH:24])[C@@H:20]([NH2:23])[CH2:21][OH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OC(=O)C)C.O>[OH:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[C:3]([O-:5])=[O:4].[C:13]1([C@H:19]([OH:24])[C@@H:20]([NH2:23])[CH2:21][OH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C(O)c1ccccc1Cl
Agent: N[C@@H](CO)[C@@H](O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C([O-])[C@@H](O)c1ccccc1Cl

Procedure:
(The compound of the general formula (II)—wherein R1 is a hydroxy-methyl group, R2 is a phenyl group, R3 is a hydroxy group) Racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid (20.0 g 107 mmol) was dissolved in 60 cm3 of ethylacetate saturated with water and (1S, 2S)-(+)-1-phenyl-2-amino-1,3-propane-diol (18.0 g 107.5 mmol) was added thereto and then the mixture was seed by a salt formed from (S)-(+)-2-hydroxy-2-(2-chlorophenyl)acetate and (1S, 2S)-(+)-1-phenyl 2-amino-1,3-propane-diol at room temperature.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N+:4]([O-:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.B(F)(F)[F:11].[F:14][B-:15]([F:18])([F:17])[F:16].[H+].FF>O>[F:14][B-:15]([F:18])([F:17])[F:16].[F:14][B-:15]([F:18])([F:17])[F:16].[OH:9][N+:4]12[CH2:7][CH2:8][N+:1]([F:11])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: FB(F)F
Reactant: [O-][N+]12CCN(CC1)CC2
Agent: FF
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 159.7 %

Procedure:
A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (25.6 g, 0.2 mole), boron trifluoride gas (13.6 g, 0.2 mole), and tetrafluoroboric acid (10 M solution, 20 mL, 0.2 mole) in water (400 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 0.2 mole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 51.4 grams of 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (80% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[C:12]([NH2:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]4[CH:19]=[N:20][C:21]5[C:26]([CH:27]=4)=[CH:25][CH:24]=[CH:23][CH:22]=5)=[C:10]3[N:9]=2)[CH2:3][CH2:2]1.[Br:28]N1C(=O)CCC1=O>CC#N>[Br:28][C:13]1[C:8]([CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:9][C:10]2[N:11]([N:15]=[CH:16][C:17]=2[C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=1[NH2:14]
Reactant: Nc1cc(CN2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1c(Br)c(CN2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To crude 5-(morpholinomethyl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (44 mg) in CH3CN (8 mL) was added N-bromosuccinimide (22 mg, 0.12 mmol), followed by additional CH3CN (4 mL). The reaction was then stirred at room temperature for 30 minutes, at which time LC/MS analysis confirmed full conversion of the starting material to the product. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 6-bromo-5-(morpholinomethyl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine as a yellow solid (8.7 mg, 0.02 mmol, 7% over three steps). LCMS: 0.82 mins, m/z=439.0 and 441.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22](OC)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[NH3:30]>CO>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([NH2:30])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: N
Reactant: COC(=O)c1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: CO
Product: NC(=O)c1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 75 °C
Yield: 64 %

Procedure:
A sealed tube containing a solution of methyl 3-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoate (0.1 g, 0.21 mmol) and NH3 (3 mL of a 7 N solution in MeOH, 21 mmol) was heated at 75° C. for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Trituration with Et2O/MeOH afforded a white solid (0.06 g, 64%): mp 198-201° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.02-8.00 (m, 2H), 7.85-7.75 (m, 2H), 7.70-7.60 (m, 1H), 7.45-7.30 (m, 4H), 7.17 (t, J=3 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 5.32 (s, 2H), 5.18 (s, 2H). ESHRMS m/z 449.0295 (M+H C20H16BrF2N2O3 requires 449.0307).