Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[H-].[Na+]>CN1C(=O)CCC1>[CH3:15][O:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[CH2:19][CH2:18]1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: COC1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc2oc(N3CCC(OC)CC3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
To a solution of methyl 2-chlorobenzoxazole-4-carboxylate (210 mg, 0.99 mmol) in NMP (5 mL) was added 4-methoxypiperidine (230 mg, 1.98 mmol) in NMP (5 mL) at room temperature. NaH was added to the mixture in two portions in 5 min. The mixture was stirred at room temperature for 18 h. The reaction was quenched by adding 10 mL of CH3OH followed by concentration to dryness. The crude material was purified by column chromatography (silica gel, 50% EtOAc in hexane) to afford methyl 2-(4-methoxypiperidin-1-yl)benzoxazole-4-carboxylate (146 mg, 50%) as a yellow solid. MS consistent.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:60][O:61][C:62](=[O:70])[CH2:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>C(Cl)Cl>[CH3:60][O:61][C:62](=[O:70])[CH2:63][CH:64]1[CH2:65][CH2:66][N:67]([C:12](=[O:13])[C:11]([CH3:15])([CH3:16])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:25][CH:24]=2)[CH2:68][CH2:69]1
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1cccc(Cl)c1
Reactant: COC(=O)CC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCN(C(=O)C(C)(C)C(NC(=O)c2ccc(C#N)cc2)c2cccc(Cl)c2)CC1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
N-4-Cyanobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanine (300 mg, 0.84 mmol) was dissolved in methylene chloride (30 ml). To the resulting solution, BOP reagent (409 mg, 0.92 mmol) and triethylamine (1 ml) were added under cooling with ice and the mixture was stirred for 30 minutes. To the reaction mixture was added 4-piperidineacetic acid methyl ester (572 mg, 3.36 mmol) and the resulting mixture was stirred overnight. After the solvent was distilled off, the residue was applied to a silica gel column (2.2×20 cm) and eluted with a mixed solution (hexane:ethyl acetate=3:1). The desired fractions were collected and the solvents were distilled off to yield an oil of N-4-cyanobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid methyl ester (270 mg, 65.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[Al+3].[Cl-].[Cl-].[Cl-]>[C]=S>[Cl:9][CH2:10][CH2:11][C:12]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:8])[CH:4]=1)=[O:13]
Reactant: O=C(Cl)CCCl
Reactant: Cc1ccccc1Cl
Agent: [Al+3]
Agent: [C]=S
Agent: [Cl-]
Product: Cc1cc(C(=O)CCCl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
23.43 ml of 2-chlorotoluene and 26.6 g of 3-chloropropionyl chloride are mixed in 25 ml of carbon sulfide and 32 g of AlCl3 in 125 ml of carbon sulfide are added over 45 minutes. After stirring for 3 hours at RT, the solvent is evaporated and then 1 liter of water is added. The reaction medium is extracted with ether and then with benzene, and then the organic phase is washed with a saturated Na2CO3 solution and then with water. It is dried over Na2SO4 and then the residue is chromatographed on a silica column, eluting with an AcOEt/cyclohexane (5/95; v/v) mixture. 27.25 g of the expected compound are obtained.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.[OH:25][CH2:26][C@@H:27]([NH:29][C:30]([NH2:32])=[NH:31])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:32]=[C:30]([NH:29][C@@H:27]([CH3:28])[CH2:26][OH:25])[N:31]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H](CO)NC(=N)N
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](CO)Nc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one (9) (50 mg, 0.155 mmol) in DMF (541 μl), (S)-1-(1-hydroxypropan-2-yl)guanidine (147 mg, 0.773 mmol) and potassium carbonate (214 mg, 1.546 mmol) were added, and the reaction mixture was stirred at 90° C. for 3 hours. The crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (23.9 mg, 41%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].[Br-].[Na+].C([Br:32])C>CN1CCCC1=O>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Br:32])(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)OCCCCCCCl
Reactant: CCBr
Agent: C=C(C)C(=O)OCCOC(=O)C(=C)C
Agent: [Br-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C=C(C)C(=O)OCCCCCCBr

Procedure:
6-Chlorohexyl methacrylate ethylene glycol bismethacrylate co-polymer (4.1 meq Cl/g, approximately 0.9 molar % cross-linking) (c.f. Example 17) (7.30 g) was reacted with sodium bromide (3.1 g) and ethyl bromide (32.7 g) in N-methylpyrrolidone (200 ml) at 65° for 6 days. The slurry was then sieved and the fraction <53 μM discarded. The remaining polymer was washed with water, methanol, acetone and diethylether and dried under vacuum for 16 hours to give 6-bromohexyl methacrylate ethylene glycol bismethacrylate co-polymer (6.82 g, 3.4 meq Br/g, no Cl detected).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH:22]=[C:23]([C:29]([O:31]CC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1>CC(CCC)C>[I:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[NH:21][CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:29]2=[O:31]
Reactant: CCOC(=O)C(=CNc1ccc(I)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCC(C)C
Product: CCOC(=O)c1c[nH]c2ccc(I)cc2c1=O

Procedure:
Diphenyl ether (175 ml) was heated to reflux temperature, and Intermediate 10 was gradually added down an air condenser. Once all the reagent had been added the mixture was heated under reflux for a further 30 min. The mixture was then cooled and 2-methylpentane (200 ml) was added. The solid formed was collected by filtration to give the title compound (24.6 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH2:9]([O:11][C:12](=[O:20])[CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15])[CH3:10].N1C=CC=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([CH3:15])=[N:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:17]=1[CH3:18])=[O:20])[CH3:10]
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccccn2)c1C

Procedure:
Similar to Example 1, 2-pyridylhydrazine (7.5 mmol, 0.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (7.5 mmol, 1.3 g) were mixed in a solution of 50% pyridine in ethanol, then heated under reflux. The solvents were removed under vacuum and the residue purified over silica. The named product crystallized upon standing (m.p. 49° C.-50° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[H-].[Na+].Cl>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:11]([O:1][CH2:2][C:3]([CH2:8][O:9][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])([CH2:6][O:7][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[CH2:4][OH:5])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: OCC(CO)(CO)CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(CO)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 22 h
Yield: 22.5 %

Procedure:
To pentaerythritol (1.5 g, 11.0 mmol) were added DMF (100 ml), 1-bromooctadecane (11.4 g, 34.2 mmol) and sodium hydride (60 wt %, 1.54 g, 38.5 mmol), and the mixture was stirred at 100° C. for 22 hr. The reaction mixture was cooled to room temperature, chloroform (150 ml) was added, and 1N hydrochloric acid (150 ml) was added further dropwise. After stirring, the aqueous layer was removed, and the organic layer was further washed with 1N hydrochloric acid (100 ml) and water (100 ml). The organic layer was evaporated under reduced pressure, and the residue was precipitated with methanol (150 ml), and the obtained precipitate was washed with methanol (150 ml). The crude crystals were dried and purified by silica gel column chromatography (hexane:chloroform=1:1→hexane:ethyl acetate=10:1) to give 2,2,2-tris(octadecyloxymethyl)ethanol (2.21 g, 2.47 mmol, yield 23%).
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>CCOCC>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:3])=[O:21])=[CH:15][CH:14]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(-c2nc3ccccc3o2)cc1
Solvent: CCOCC
Product: COC(=O)Cc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 1 h

Procedure:
To a solution of diazomethane in 75 ml. of ether is added, portionwise, as a solid, 1.0 gm. of 4-(benzoxazol-2-yl)phenylacetic acid. Nitrogen is evolved and after 1 hour the excess diazomethane is consumed by adding acetic acid. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. Recrystallization from methanol gives methyl 4-(benzoxazol-2-yl)phenylacetate, m.p. 109°-112° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1>C(#N)C>[Cl:20][C:21]1[C:26]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Temperature: 100 °C
Reaction time: 40 h
Yield: 99.6 %

Procedure:
The title compound was prepared according to the procedure described in WO 00/76984. A mixture of N-Boc-piperazine (11.47 g, 61.5 mmol), K2CO3 (8.5 g, 61 mmol) and 2,3-dichloropyrazine (9.20 g, 61.7 mmol) in acetonitrile (100 mL) was stirred at 100° C. for 40 h. The reaction mixture was concentrated, dissolved in toluene, washed with water, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (7:3) as eluent to give 18.3 g (100%) of the title product. HRMS m/z calcd for C13H19N4O2 (M)+298.1197, found 298.1206.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[C:9]2[C@H:16]([CH3:17])[CH2:15][CH2:14][C:10]=2[N:11]=[CH:12][N:13]=1.B1([C:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=2)OC(C)(C)C(C)(C)O1.O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C@H:16]1[C:9]2[C:8]([C:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCc2ncnc(C3=CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 110 °C
Yield: 67 %

Procedure:
A solution of Na2CO3 (0.36 mL, 2M) was added to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (101 mg, 0.60 mmol), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid, pinacol ester (204 mg, 0.66 mmol) in 1,4-dioxane (1.8 mL). The mixture was sparged with N2 for 2 minutes. The catalyst Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) was added in one portion. The mixture was heated at 110° C. under N2 for 8 hours. Water (20 mL) was added to the mixture and extracted with DCM (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (first with 0-50% EtOAc/hexane, then with 0-4% MeOH/DCM gradient elution) to give (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate as an oil (127 mg, 67%). 1H NMR (CDCl3, 500 MHz) δ 8.91 (s, 1H), 6.31 (s, 1H), 3.64-3.55 (m, 1H), 3.10-3.03 (m, 2H), 2.98-2.90 (m, 2H), 2.83-2.78 (m, 1H), 2.42-2.34 (m, 2H), 1.77-1.69 (m, 2H).1.49 (s, 9H), 1.19 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-difluorobenzoic acid (0.100 g, 0.633 mmol) in DCM (3.16 ml) were added oxalyl chloride (0.066 ml, 0.759 mmol) and DMF (0.490 μl, 6.33 μmol) at 0° C. The reaction mixture was stirred for overnight at room temperature. The reaction mixture was concentrated in vacuo, which was used for the next step without further purification. 1H-NMR (CDCl3, Varian 400 MHz) δ 6.92-9.98 (1H, m), 7.01-7.06 (1H, m), 8.16-8.22 (1H, m).
Reaction SMILES: [CH2:1](N1CCCC(CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)C1)[CH3:2].[CH2:29]([O:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:55][CH3:56])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[C:36]([NH2:57])[N:35]=1)[CH2:30][CH2:31][CH3:32].ICC>>[CH2:29]([O:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:55][CH3:56])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]2[CH2:50][CH2:51][N:52]([CH2:1][CH3:2])[CH2:53][CH2:54]2)=[C:36]([NH2:57])[N:35]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCC3CCNCC3)c2n1
Solvent: CCI
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-(butyloxy)-8-(methyloxy)-9-[6-(4-piperidinyl)hexyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH2:17][CH2:18][CH3:19])[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.Br[CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([O:25][CH3:26])=[O:24]>>[Cl:1][C:2]1[C:3]([O:20][CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([O:25][CH3:26])=[O:24])=[C:4]([CH2:17][CH2:18][CH3:19])[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CCCc1c(O)c(Cl)cc2c(-c3ccccc3)noc12
Product: CCCc1c(OC(C(=O)OC)c2ccccc2)c(Cl)cc2c(-c3ccccc3)noc12

Procedure:
The phenol of step 1 (0.25 g, 0.86 mmol) was coupled with commercially available methyl 2-bromo-2-phenylacetate (0.20 g, 0.86 mmol) as was described for example 9, step 5. The product was purified by chromatography on silica gel eluting with ethyl acetate:hexane (10:90).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[CH3:10][C@@H:11](O)[CH2:12][CH:13]=[CH2:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C@H:13]([CH2:12][CH:11]=[CH2:10])[CH3:14]
Reactant: C=CC[C@@H](C)O
Reactant: Oc1cc(Cl)ccc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(Cl)ccc1Br
Reaction time: 20 h
Yield: 92.1 %

Procedure:
To a solution of 2-bromo-5-chlorophenol (0.40 g, 1.93 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.397 mL, 3.86 mmol, 2 equiv), and PPh3 (1.01 g, 3.86 mmol, 2 equiv) in THF (6.4 mL) was added DEAD (0.61 mL, 3.86 mmol, 2 equiv). After stirring 20 h, reaction diluted with ether and washed with 1 N NaOH. The ether layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-10% EtOAc in hexane) to provide the product as a colorless oil (0.49 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.3 Hz, 1H), 6.89 (d, J=2.3 Hz, 1H), 6.83 (dd, J=8.5, 2.3 Hz, 1H), 5.90 (ddt, J=17.1, 10.1, 7.2 Hz, 1H), 5.21-5.11 (m, 2H), 4.49-4.39 (m, 1H), 2.60-2.50 (m, 1H), 2.48-2.38 (m, 1H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12]O.[CH3:14][O:15][C:16]([O:20][Si](C)(C)C)=[C:17](C)C.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>ClCCl.O>[CH3:14][O:15][C:16](=[O:20])[CH2:17][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: COc1ccc2[nH]cc(CO)c2c1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
To a solution of 5-methoxy-1H-indol-3yl-methanol 141 (115 mg, 0.643 mmol) dissolved in dichloromethane (3 ml), (1-methoxy-2-methyl-propenyloxy)-trimethylsilane (200 mg, 1 mmol) and magnesium perchlorate (164 mg, 0.74 mmol) were added. The reaction was allowed to stir at ambient temperature for 3-4 hours after which the mixture was diluted with water (50 ml) and dichloromethane (DCM, 100 mL). The organic layer was separated and washed with water (50 mL; 3×). The organic layer was washed once with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give an oil and purified with flash chromatography (silica with 80% hexane, 20% ethyl acetate to afford 142 as a light colored oil (150 mg; 88% yield; M+1=262.3).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.[Br:13][C:14]1[C:15]([NH2:20])=[N:16][N:17]([CH3:19])[CH:18]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:13][C:14]1[C:15]([NH:20][C:10]([C:3]2[CH:2]=[N:1][N:5]3[CH:6]=[CH:7][CH:8]=[N:9][C:4]=23)=[O:12])=[N:16][N:17]([CH3:19])[CH:18]=1
Reactant: Cn1cc(Br)c(N)n1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Br)c(NC(=O)c2cnn3cccnc23)n1
Yield: 62.9 %

Procedure:
A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (165.5 mg, 1.014 mmol, 1.01 eq), 4-bromo-1-methyl-1H-pyrazol-3-amine (177.4 mg, 1.008 mmol, 1.0 eq), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (497 mg, 1.31 mmol, 1.30 eq), N,N-diisopropylethylamine (0.25 mL, 1.4 mmol, 1.4 eq), and 4-dimethylaminopyridine (33.8 mg, 0.277 mmol, 0.27 eq) in 5 mL N,N-dimethylformamide was heated at 50° C. for 4 days. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (20 to 80% ethyl acetate in dichloromethane (containing 5% methanol)) to yield 203.6 mg (63%) of N-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=321.1; 1H NMR (400 MHz, CD3OD) δ: 9.16 (d, 1H), 8.84 (d, 1H), 8.68 (s, 1H), 7.76 (s, 1H), 7.28 (d of d, 1H), 3.88 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl.O>[C:20]([NH:1][C:2]1[C:3]([I:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1I
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(NC(C)=O)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of methyl 3-amino-2-iodobenzoate (70.0 g, 253 mmol) in methylene chloride (1000 mL) was added triethylamine (52.8 mL, 379 mmol) and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added acetyl chloride (35.9 mL, 505 mmol) at 0° C. and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/10) to give the title compound (76.6 g, yield 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[N:19]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:18](=[O:37])[N:17](COC(=O)C(C)(C)C)[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])[C:21]3[C:20](=[O:28])[N:19]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:18](=[O:37])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
4-[1,3-Bis(2,2-dimethylpropionyloxymethyl)-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (277 mg) was dissolved in a solvent mixture of tetrahydrofuran (3 ml) and methanol (6 ml), sodium hydride (21 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour and 10 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation from the organic layer to give 214 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8]C(=O)C)[CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(F)ccc1C
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(F)cc1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
The product from Step (a) (5.00 g, 29.9 mmol, 1 equiv) was dissolved in concentrated H2SO4 (30 mL) and cooled to 0° C. Concentrated HNO3 (2.2 mL) was added slowly via pipet, and the solution gradually became dark brown. After 30 minutes at 0° C., the reaction mixture was poured onto ice (˜200 mL), and the mixture was allowed to stir and warm to room temperature. The solid precipitate was collected by filtration and washed several times with water. The solid was suspended in 6N HCl (30 mL) and the mixture was heated to reflux for 5 hours, then stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O and neutralized with solid K2CO3. The resulting precipitate was collected by filtration and rinsed several times with water, affording 2.82 g (55%) of the title compound as a brown solid. MS (ES+) m/e 171 [M+H].