Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=C(C=CC=1)C=O)([O-])=O.C(N(C)C(C1CCNCC1)=O)C(C)C.[CH2:26]([N:30]([CH3:49])[C:31]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([N+:46]([O-])=O)[CH:41]=2)[CH2:35][CH2:34]1)=[O:32])[CH:27]([CH3:29])[CH3:28]>>[CH2:26]([N:30]([CH3:49])[C:31]([CH:33]1[CH2:34][CH2:35][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([NH2:46])[CH:41]=2)[CH2:37][CH2:38]1)=[O:32])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CN(C)C(=O)C1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Agent: CC(C)CN(C)C(=O)C1CCNCC1
Agent: O=Cc1cccc([N+](=O)[O-])c1
Product: CC(C)CN(C)C(=O)C1CCN(Cc2cccc(N)c2)CC1

Procedure:
The title compound is prepared according to the reactions described above starting from 3-nitro-benzaldehyde and piperidine-4-carboxylic acid isobutyl-methyl-amide yielding after reductive amination 1-(3-nitro-benzyl)-piperidine-4-carboxylic acid isobutyl-methyl-amide; LC-MS A: tR=0.61 min; [M+H]+=366.35 followed by reduction with stannous chloride the title compound LC-MS A: tR=0.48 min; [M+H]+=304.24.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br>C1COCC1>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: Cc1ccoc1C
Reactant: BrCc1ccccc1Br
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2Br)oc1C
Yield: 41.3 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using commercial 2,3-dimethylfuran (1.00 g, 10.4 mmol), commercial 2-bromobenzylbromide (2.60 g, 10.4 mmol) and 1.6M n-BuLi/hexanes (4.16 mL, 10.4 mmol) in THF. Purification on Biotage KP-Sil eluting with 100% pet. ether gave 1.14 g (41%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ1.84 (s, 3H), 2.11 (s, 3H), 3.96 (s, 2H), 5.81 (s, 1H), 7.19 (dt, 1H), 7.26-7.37 (m, 2H), 7.60 (dd, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][O:79][CH2:78][CH2:77]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3F)ncc21
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a mixture of 0.070 g (0.161 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182) and 4 mL of dimethylformamide was added 0.0346 g (0.256 mmole) of 1-hydroxybenzotriazole, 0.0950 g (0.250 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1253 g (0.936 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0248 g (0.246 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0504 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-(tetrahydro-pyran-4-yl)-benzamide (I-225).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]1[N:15]=[C:14](SC)[N:13]=[C:12]([N:18]2[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]2)[C:11]=1[N+:25]([O-:27])=[O:26])[CH3:8]>O1CCOCC1>[CH2:7]([O:9][C:10]1[N:15]=[C:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:13]=[C:12]([N:18]2[CH2:19][CH2:20][S:21](=[O:24])[CH2:22][CH2:23]2)[C:11]=1[N+:25]([O-:27])=[O:26])[CH3:8]
Reactant: C1CNCCN1
Reactant: CCOc1nc(SC)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
52 gm (0.6 mol) of piperazine were dissolved in 120 ml of boiling dioxane. 61.5 gm (0.18 mol) of 6-ethoxy-2-methylthio-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine were added over a period of 30 minutes to this solution. After refluxing for 45 minutes, the reaction mixture was poured into 1.5 liters of ice-water, and the yellow precipitate formed thereby was suction-filtered off, washed and recyrstallized from ethanol. Yield: 45.1 gm (65.8% of theory; m.p. 222°-223°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Reaction time: 24 h

Procedure:
A mixture of 3-(5-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester XLVIII (37 mg, 0.115 mmol) in EtOH (4 ml) and a catalytic amount of Degoussa-type catalyst Pd/C wet (10%) was subjected to hydrogenation conditions in a Parr apparatus at 60 psi of H2 for 20 hours. The reaction mixture was filtered through celite with MeOH. The filtrate was concentrated and subjected to the same hydrogenation conditions for 24 hours to provide 3-(5-Methoxy-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester XLIX (37 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C([Li])CCC.[CH3:28][C:29]([CH3:31])=[O:30]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:29]([OH:30])([CH3:31])[CH3:28])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CC(C)=O
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -42 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (20.0 g, 0.062 mol) was cooled to −42° C. in THF (400 mL). A solution of n-butyllithium (2.5 M in hexanes, 48 mL, 0.12 mol) was added portionwise over 10 min. The mixture gradually turned yellow. The reaction mixture was then allowed to stir at −42° C. for 30 minutes and then anhydrous acetone (10 mL, 0.1 mol) was added at once. The resulting reaction mixture was slowly warmed to 0° C. over a 2 hour period. The mixture was subsequently quenched with water, extracted with EtOAc and dried over MgSO4. The slurry was filtered and concentrated in vacuo to provide 2-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)propan-2-ol (23 g, 98%) as a yellow solid. MS (ESI+): m/z 382.1 (M+H+)2-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)propan-2-ol
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[N:10]2)[CH:3]=1.[CH3:18][C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])[CH2:20][CH3:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:29]([C:26]2[CH:27]=[CH:28][C:23]([C:19]([CH3:18])([CH3:22])[CH2:20][CH3:21])=[CH:24][CH:25]=2)(=[O:31])=[O:30])=[C:4]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[N:10]2)[CH:3]=1
Reactant: Nc1ccc(Cl)cc1-n1nnc2ncccc21
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1

Procedure:
A 4 mL scintillation vial was charged with 4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine (100 mg, 0.363 mmol), 4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride (98 g, 0.399 mmol), and pyridine (1 mL). The resultant solution was stirred 4 hours at 80° C. and then partitioned with EtOAc/1 M HCl. The organics were subsequently washed with 1 M HCl, saturated aqueous sodium bicarbonate, and brine; dried over anhydrous sodium sulfate; and removed in vacuo. The resultant residue was then purified via automated silica gel chromatography to afford the desired sulfonamide: MS (ES) M+H expected 456.2, found 456.3.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[C:14]([OH:16])=O>C1C=CC=CC=1>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[C:14]([Cl:3])=[O:16]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cc2ccccc2o1
Temperature: 25 °C

Procedure:
Thionyl chloride (12.5 ml) was added to a suspension of benzofuran-2-carboxylic acid (20 g) in anhydrous benzene (250 ml). The mixture was refluxed for 3 hours, then allowed to cool down to room temperature. Removal of the volatiles left the desired acid chloride (21.8g, 98%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.[CH2:10]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)[CH3:11]>>[CH2:10]([C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1)[CH3:11]
Reactant: Cc1ncnc(Cl)c1C
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(Nc2ncnc(C)c2C)cc1
Temperature: 150 °C
Yield: 70.4 %

Procedure:
To 4.3 g (0.03 mole) of 4-chloro-5,6-dimethylpyrimidine were added 3.6 g (0.03 mole) of p-ethylaniline; the mixture was then heated at 150° C. for about 3 minutes. The reaction mixture quickly became a solution which, on cooling, precipitated crystals. These crystals were separated and then made alkaline by the addition of 50 ml of a dilute aqueous solution of sodium hydroxide. The insolubles were extracted with about 100ml of ethyl acetate and the resulting extract was washed, in turn, with water and with a saturated aqueous solution of sodium chloride; it was then dried over anhydrous sodium sulphate. The ethyl acetate was distilledoff under reduced pressure to give crystals, which were recrystallised frombenzene, affording 4.8 g (yield 71%) of the desired Compound No. 46, in theform of colourless needles melting at 97°-98° C.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:13]2[S:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[CH:21][CH:20]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2.CO>C1COCC1>[Br:3][C:4]1[C:13]2[S:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:12]=2[C:11]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)cc3)c2c1C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Aqueous potassium hydroxide (6.0 mL, 6.0 mmol) was added to a stirred, room temperature solution of acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (0.48 g, 1.14 mmol) in THF (15 mL)/methanol (10 mL). After 1 h, the organic solvents were removed, water was added, the reaction mixture was acidified with 10% HCl and the resulting solid was washed with water and triturated with pet. ether and then dried in vacuo to provide the title compound as a white solid (0.32 g, 73%): mp: 165-168° C.; NMR (DMSO-d6); δ 9.68 (s, 1H), 8.17 (d, J=8 Hz, 1H), 7.62 (ddd, J=8, 6, 1 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.44 (ddd, J=8, 7, 1 Hz, 1H), 7.13 (d, J=9 Hz, 2H), 6.91 (d, J=9 Hz, 2H), 2.42 (d, J=1 Hz, 3H), 1.59 (d, J=1 Hz, 3H); MS (EI): 1 bromine isotope pattern 382 (95%0, MI), 384 (100%); Anal. Calc. for C20H15BrOS: C, 62.67, H, 3.95, N, 0.00. Found: C, 62.40, H, 3.91, N, 0.09.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([Si:19]([CH3:25])([CH3:24])[O:20][CH2:21][CH2:22][OH:23])([CH3:18])([CH3:17])[CH3:16].[CH2:26]([O:28][C:29](=[O:60])[C@@H:30]([O:58][CH3:59])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46]([C:49](=[O:57])[C:50]3[CH:55]=[CH:54][C:53](O)=[CH:52][CH:51]=3)=[CH:45][CH:44]=2)=[CH:34][CH:33]=1)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:60])[C@@H:30]([O:58][CH3:59])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:44]=[CH:45][C:46]([C:49](=[O:57])[C:50]3[CH:51]=[CH:52][C:53]([O:23][CH2:22][CH2:21][O:20][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:25])[CH3:24])=[CH:54][CH:55]=3)=[CH:47][CH:48]=2)=[CH:36][CH:37]=1)[CH3:27]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(O)cc3)cc2)cc1)OC
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)cc2)cc1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropyl azodicarboxilate (0.2 mmol, 0.04 mL) was added dropwise to a solution of 2-(tert-butyl-dimethyl-silanyloxy)-ethanol (0.26 mmol, 46 mg) (Example 122, Step A), (2S)-3-(4-{3-[4-(4-hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic acid ethyl ester (0.13 mmol, 65 mg) and triphenylphosphine (0.2 mmol, 38 mg) in anhydrous toluene (2 mL) at 0° C. under nitrogen. The mixture was stirred overnight at room temperature, quenched with water and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The crude mixture was chromatographed on silica gel using a 4/1 hexane/EtOAc mixture as eluent to afford the title product 1H-NMR (200.15 MHz, CDCl3): δ 7.76 (d, 4H, J=8.9), 7.13 (d, 2H, J=8.6), 6.96 (d, 4H, J=8.6), 6.83 (d, 2H, J=8.6), 4.26–4.09 (m, 8H), 4.02–3.87 (m, 3H), 3.35 (s, 3H), 2.97 (m, 2H), 2.28 (qn, 2H, J=5.9), 1.23 (t, 3H, J=7.1), 0.91 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][N:6]2[C:7](=[O:10])[C:8]=1I.[O-]P([O-])([O-])=O.[K+].[K+].[K+].B1([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)C2CCCC1CCC2.[OH-].[Na+].OO>CN(C=O)C.C(OCC)(=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH2:32]([C:8]1[C:7](=[O:10])[N:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]2=[N:4][C:3]=1[CH2:2][OH:1])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=c1c(I)c(CO)nc2ccccn12
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1c(Cc2ccccc2)c(CO)nc2ccccn12
Temperature: 80 °C
Reaction time: 12 h
Yield: 90.6 %

Procedure:
A mixture of 4.0 g (13.24 mmol) of the product from Step 4 (14), 1.0 g (1.32 mmol) of dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium(II) dichloromethane adduct, and 8.4 g (39.72 mmol) of K3PO4 in 30 mL of DMF was heated to 80° C. To the resulting solution was added dropwise 40 mL (19.9 mmol) of B-Benzyl-9-BBN and stirred at 80° C. under nitrogen for 12 hours. The reaction was then cooled to 0° C. and excess 1N NaOH was added to the reaction mixture. Excess 30% H2O2 was then added to the mixture at 0° C. resulting in significant gas evolution. Stirring continued for at least one additional hour or until gas ceased to evolve. The mixture was extracted with ethyl acetate (3×) and washed with saturated Na2O3S2 and brine. The organic layers were combined, dried over MgSO4 and activated carbon, and the solvent was removed in vacuo. The resulting material was subjected to flash chromatography on a 10 cm column. Elution with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate in hexanes, 43% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, 57% ethyl acetate in hexanes, 67% ethyl acetate in hexanes, and 100% ethyl acetate yielded 3.2 g (12.0 mmol, 91%) of 3-benzyl-2-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (15) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][OH:22])=[N:6][CH:7]=1.[NH:23]1[C:31]2[C:26](=[CH:27][C:28](O)=[CH:29][CH:30]=2)[CH:25]=[N:24]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][O:22][C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[NH:23][N:24]=[CH:25]3)=[N:6][CH:7]=1
Reactant: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2nc(COc3ccc4[nH]ncc4c3)c(Sc3ccc(Cl)cn3)o2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (intermediate B1.1, 0.12 g, 0.36 mmol) in THF (3 ml) was added 1H-indazole-5-ol (0.1 g, 0.71 mmol), Ph3P (0.19 g, 0.71 mmol) and DIAD (0.14 ml, 0.71 mmol). The reaction was stirred at rt for 3 h, concentrated and purified by flash chromatography (silica, 30-60% EtOAc/hexanes) to give 5-({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methoxy)-1H-indazole as white solid. 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.32 (d, J=2.5 Hz, 1H), 8.10 (m, 2H), 7.89 (s, 1H), 7.32 (m, 2H), 7.23 (d, J=2.2 Hz, 1H), 7.15 (t, J=8.6 Hz, 2H), 7.09 (m, 1H), 5.17 (s, 2H); HRMS exact mass talc for C22H14ClFN4O2S [M+H]+: 453.0583; observed: 453.0584.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([O-:12])=[O:11].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(Br)c1O
Yield: 80.9 %

Procedure:
2-Bromo-4-fluoro-phenol 2a (8.0 g, 41.9 mmol) was dissolved in 10 mL of sulfuric acid (50%) followed by addition of a solution of sodium nitrate (7.1 g, 83.5 mmol) in 24 mL of sulfuric acid (25%), upon cooling by an ice-water bath. The reaction mixture was reacted at room temperature for 1.5 hours and the reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL×2). The combined organic extracts were washed with water and saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 2-bromo-4-fluoro-6-nitro-phenol 2b (8.0 g, yield 80.8%) as a red solid, which was directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9](C(O)=O)=[CH:10][C:3]=12>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCCC.[Cu]>[F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][CH:9]=[CH:10][C:3]=12
Reactant: O=C(O)c1cc2c(F)cncc2s1
Agent: [Cu]
Solvent: CCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Fc1cncc2sccc12
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
A mixture of 4-fluorothieno[2,3-c]pyridine-2-carboxylic acid (765 mg, 3.88 mmol) and copper powder (629 mg, 9.91 mmol) in diphenyl ether (3.8 mL) was heated to boiling for ˜5 min. After cooling to 40° C., the reaction mixture was diluted with heptane (10 mL), filtered through a short pad of Celite, and concentrated to remove the heptane. Purification of the residue by ISCO chromatography (5 to 45% ethyl acetate:heptane) afforded 441 mg (74%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.96 (d, J=1.8 Hz, 1 H), 8.34 (d, J=2.0 Hz, 1 H), 7.61-7.88 (m, 1 H), 7.38-7.57 (m, 1 H); MS (ESI): 154.07 [M+H]+; HPLC tR=2.97 min (ZQ3, polar—4 min).
Reaction SMILES: [CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:6])[O:4]C)[CH3:2]>Cl>[CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:4])[OH:6])[CH3:2]
Reactant: CCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Product: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the method of Example 13, 1 g of methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethyl-phenoxy)phenylphosphinate is reacted with 20 ml of 6N HCl to yield P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid, m.p.=99°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH2:21])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)N2CCc3cccc(N)c32)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCc3cccc(NC(=O)c4ccccc4)c32)cc1
Yield: 82 %

Procedure:
To a solution of 19(0.1 g, 0.26 mmol), benzoyl chloride (0.09 ml, 0.78 mmol) in pyridine (1 ml) was stirred at 100-110° C. for 16H. The reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic layer was dried over anhydrous MgSO4 and evaporated to give residue that was chromatographed over silica gel (EtOAc: n-hexane=1:2) to afford 20, yield 82%.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7](OCC)=[O:8].C(O)=O.[CH3:16][N:17](C=O)C>C(N)=O>[CH3:12][C:4]1[NH:3][C:2]2[N:1]=[CH:16][N:17]=[C:7]([OH:8])[C:6]=2[CH:5]=1
Reactant: CCOC(=O)c1cc(C)[nH]c1N
Reactant: CN(C)C=O
Solvent: NC=O
Solvent: O=CO
Product: Cc1cc2c(O)ncnc2[nH]1
Yield: 51 %

Procedure:
In a sealed tube, ethyl 2-amino-5-methyl-1H-pyrrole-3-carboxylate (150 mg, 0.9 mmol, prepared according to literature procedures, J. Heterocyclic Chem., 23:1555 (1985)) was dissolved in formamide (4.5 ml), formic acid (2.3 ml) and DMF (1.0 ml) and heated to 155° C. for 12 h. The reaction was concentrated, taken up with NaHCO3 solution, and extracted with DCM to afford 6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (70 mg, 0.46 mmol, 51%, MS (ES+) [M+H]+=150). This material was dissolved in phosphorous oxychloride (5 ml) and heated to 110° C. for 1 h. The reaction was concentrated, taken up with NaHCO3, and extracted with DCM to give 4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.23 mmol, 50%). MS (ES+) [M+H]+=168.