Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:12]1[C:20]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:19][C:18]2[C:13]1=[N:14][C:15]([C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1)=[N:16][C:17]=2[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH:9]([CH3:11])[CH3:10].[CH3:40][N:41]1[CH2:45]CC[C:42]1=[O:46]>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:15]2[N:14]=[C:13]3[C:18]([N:19]=[C:20]([N:21]4[CH2:26][CH2:25][N:24]([C:42]([N:41]([CH3:45])[CH3:40])=[O:46])[CH2:23][CH2:22]4)[N:12]3[CH2:8][CH:9]([CH3:11])[CH3:10])=[C:17]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:16]=2)=[CH:34][N:35]=1
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(N2CCN(C(=O)N(C)C)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 24 h
Yield: 43 %

Procedure:
Triethylamine (64 μl) and 2-acetamide-4-dimethylcarbamoyl chloride (35 μl) were added to an N-methylpyrrolidone solution (1 ml) of 5-(9-isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-ylamine (100 mg) and the resulting mixture was stirred for 24 hours. The reaction mixture was partitioned with ethyl acetate and water, the insoluble solid was collected by filtration, and then the organic layer of the filtrate was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was combined with the solid separately collected by filtration followed by the addition of dimethyl sulfoxide (3 ml) and water (3 ml), the resulting mixture was stirred, and the insoluble matter was collected by filtration, washed with water, and dried to give the title compound (50 mg, 43%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]4)[C:11]3=[O:24])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CN(C(O[N:33]1N=N[C:35]2C=CC=C[C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.C(N)C>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:15][CH2:16][N:17]([CH2:20][C:21]([NH:33][CH2:34][CH3:35])=[O:22])[CH2:18][CH2:19]4)[C:11]3=[O:24])=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)CN1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)CN1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
A mixture of mg 42.7 mg (0.13 mmol) [2-(4-Cyclopropyl-phenyl)-1-oxo-2,8-diaza-spiro[4.5]dec-8-yl]-acetic acid, 54.2 mg (0.195 mmol) TBTU, 26 mg (0.26 mmol) NEt3 and 8.7 mg (0.195 mmol) ethylamine in 2 mL DMF was stirred at room temperature for 16 h and evaporated to dryness. The residue was taken up in DMF and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 16.2 mg (35%) of the title compound. MS m/e: 356.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:20]1[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:27][O:26][C:23]1[CH:22]=[N:21][C:20]([N:1]2[CH2:6][CH2:5][CH:4]([C@H:7]3[CH2:9][C@H:8]3[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]2)=[N:25][CH:24]=1
Reactant: COc1cnc(Cl)nc1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (2.5 g, 14.77 mmol) was dissolved in DMF (30 ml) at RT under N2 and cesium carbonate (7.22 g, 22.15 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-methoxypyrimidine (2.56 g, 17.72 mmol) was added. The mixture was stirred at 100° C. overnight. The mixture was diluted with EtOAc (100 ml), washed with sat. NH4Cl (100 ml), dried over MgSO4, and the volatiles evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (100 g SNAP, 20˜60% EtOAc in hexane) to afford the titled compound. LC/MS (m/z): 278 (M+H)+. Rf was 0.4 @ 50% EtOAc in hexanes (blue spot on CAM stain).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2cc(Br)ccc2n1
Agent: Cl
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Clc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 6-bromo-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 15, Step 1; 0.3042 g), 1-(4-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.3708 g), triethylamine (Aldrich; 0.55 mL), and ethylene glycol (5.6 mL) is stirred for 1 h at 80° C. After cooling, the mixture is partitioned between water and dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) to give, after crystallization from ethyl acetate/methanol/dichlormetane, 0.1756 g of the title compound; mp 154-155° C.; MS m/z 404, 406, 408; IR (mineral oil) 1495, 1500, 1224, 823, 812 cm-1 ; 1H NMR (CDCl3) δ2.72, 3.19, 3.76, 6.83, 7.20, 7.22, 7.47, 7.52, 8.24.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[OH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:15]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=2[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Oc1cc(F)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1cc(F)ccc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 2,5-difluorophenol: 1H-NMR (CDCl3) δ 7.95 (1H, d, J=2.8 Hz), 7.46 (1H, dd, J=8.8, 2.8 Hz), 7.20–7.10 (1H, m), 6.95 (1H, d, J=8.8 Hz), 6.85–6.73 (1H, m), 6.68–6.56 (1H, m), 3.85 (3H, s).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].Cl>C(Cl)Cl>[CH3:11][S:12]([O:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:10])([F:1])[CH2:3][CH2:4]1)(=[O:14])=[O:13]
Reactant: OCC1CCC(F)(F)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4,4-Difluorocyclohexyl)methanol (0.7 g, 4.11 mmole) was stirred in CH2Cl2 (5 ml) and cooled in an ice bath. TEA (0.499 g, 4.93 mmoles) was added followed by methanesulfonyl chloride (0.518 g, 4.52 mmoles). Stirring was continued overnight while allowing to warm to room temp. 1.0 N HCl (30 ml) and CH2Cl2 (30 ml) was added and stirred for 5 min. The organic layer was dried over Na2SO4 and evaporated giving (4,4-difluorocyclohexyl)methyl methanesulfonate (142) as an oil. Yield (0.92 g, 98%): 1H NMR (400 MHz, DMSO-d6) δ 4.06 (d, J=6.4 Hz, 2H), 3.14 (s, 3H), 2.04-1.95 (m, 2H), 1.88-1.70 (m, 5H), 1.29-1.19 (m, 2H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:31][CH2:30][CH2:29][N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:11][N:8]([CH:37]3[CH2:38][CH2:39][C:34]([OH:33])([C:41]4[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=4)[CH2:35][CH2:36]3)[CH2:9]2)=[O:32])=[N:17]1
Reactant: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(CCO)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in the previous step) and 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:15])[CH2:12][C:13]#[N:14].[NH4+].[Cl-].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:15])[CH2:12][C:13]1[N:18]=[N:19][NH:20][N:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC(=O)Nc1nc2ccccc2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1nn[nH]n1)Nc1nc2ccccc2s1
Temperature: 120 °C
Yield: 17.5 %

Procedure:
N-(benzo[d]thiazole-2-yl)-2-cyanoacetamide (0.1 g), NH4Cl (5.0 eq, 0.1 g), and NaN3 (5.2 eq, 0.13 g) were dissolved on 2.1 mL of DMF (dimethylformamide), and heated at 120° C. for 6 hours. DMF was removed under reduced pressure distillation, and 10 ml of water and 5% NaOH solution were added thereto. The aqueous layer was washed with 15 ml of Et2O, and treated with activated carbon. To the obtained reaction mixture, 10% aqueous hydrochloric acid, making the solution with pH 2. The obtained reaction mixture was extracted with methylene chloride, to produce N-(benzo[d]thiazole-2-yl)-2-(2H-tetrazole-5-yl)acetamide (20%, 21 mg) in light yellow solid phase.
Reaction SMILES: [CH2:1]([C:3]([CH2:14][CH3:15])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[C:4]([NH2:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:14]([C:3]([CH2:1][CH3:2])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH2:6])=[O:5])[CH3:15]
Reactant: CCC(CC)(C(N)=O)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(C(N)=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of α,α-diethyl-2-hydroxy-benzeneacetamide (Example 266b, 1.21 g) in DMF (9.93 mL) was treated with potassium carbonate (0.807 g) and benzyl bromide (0.694 mL) under nitrogen. The resulting mixture was stirred at room temperature for 16 h.
Reaction SMILES: [S:1]1[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:2]1[CH2:3][CH2:4][CH2:5]2)=O.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1.C1(C)C=CC=CC=1>O>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:7](=[O:9])[CH:6]3[S:1][CH:2]([CH2:3][CH2:4][CH2:5]3)[C:10]2=[O:11])[CH2:18][CH2:19]1
Reactant: O=C1OC(=O)C2CCCC1S2
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C2CCCC(S2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
Tetrahydrothiopyran-2,6-dicarboxylic anhydride (2.4 g., 14 mmole) and 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (3.5 g., 15 mmole) were dissolved in 250 ml. of toluene and refluxed for 48 hours with water removal via a Dean-Shark trap. The solvent was removed in vacuum and replaced with chloroform. The mixture was filtered through 75 g. of silica gel and concentrated in vacuum and the residue was crystallized from isopropanol with addition of 4N isopropanolic HCl. A second crystallization from isopropanol gave 1. g. of the title compound as the monohydrochloride; m.p. 238°-241° C. (d).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[C:7](=[O:12])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C([O-])(=O)C.[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>CN(C)C=O.[Cu]>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[C:7](=[O:12])[CH2:8][C:9](=[O:11])[N:10]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[C:4]=2[CH:3]=1
Reactant: Brc1cccnc1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3cc(F)ccc32)C(C)C)cc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
A mixture of 0.880 g of 2-(7-Fluoro-2,4-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (2.20 mmol), 420 mg of copper (bronze, 6.61 mmol, 3 equiv), 476 mg of potassium acetate (4.85 mmol, 2.2 equiv), and 0.290 mL of 3-bromopyridine (4.85 mmol, 2.2 equiv) in 10 mL of dimethylformamide was heated at 100° C. under nitrogen for 3 hrs. An additional 0.132 mL of 3-bromopyridine (2.43 mmol, 1.1 equiv) was added and the reaction was maintained for an additional 2 hrs. The reaction mixture was cooled to ambient temperature, filtered through a sintered glass funnel and then evaporated in vacuo to a residue. The residue was partitioned between ethyl acetate and aqueous ammonium hydroxide (5 mL conc. diluted to 100 mL). After separating the layers, the organic layer was washed with aqueous ammonium hydroxide (5 mL conc. diluted to 100 mL), and then saturated aqueous brine. The organic phase was then extracted three times with aqueous HCl (1N). The acid layers were combined and neutralized with aqueous sodium hydroxide (1N). The neutralized mixture was extracted twice with methylene chloride. The methylene chloride layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue was triturated with hexane and then concentrated in vacuo to provide 0.705 g of the title compound as a tan solid. H NMR (300 MHz, CDCl3) d 8.60 (m, 2H), 8.08 (b, 1H), 7.54 (b, 1H), 7.39 (m, 1H), 7.15 (m, 2H), 7.00 (m, 3H), 6.57 (dd, 1H, J=2.7, 9.2), 4.95 (m, 1H), 4.32 (d, 1H, J=17.9), 4.14 (d, 1H, J=17.8), 3.85 (s, 3H), 3.61 (d, 1H, J=12.1), 3.52 (d, 1H, J=12.1), 1.06 (d, 6H, J=6.8); low resolution MS (FAB)m/e 477 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH2:30]1[C@@H:35]2[CH2:36][CH2:37][CH2:38][N:34]2[CH2:33][C@H:32]([CH2:39]O)[O:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:39][C@@H:32]5[O:31][CH2:30][C@@H:35]6[CH2:36][CH2:37][CH2:38][N:34]6[CH2:33]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC[C@H]1CN2CCC[C@H]2CO1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@H]1CN2CCC[C@H]2CO1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and [(3R,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl]methanol (prepared as described in WO 2004/006846) following General Procedure J.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C1(=O)O[CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:14][CH2:13][OH:12]
Reactant: COc1ccc(F)cc1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc(F)cc1OCCO
Yield: 79.8 %

Procedure:
A suspension of 8.75 g of 5-fluoro-2-methoxyphenol, 10.9 g of ethylene carbonate and 8.50 g of potassium carbonate in 12 ml of toluene was refluxed for 2.5 hours. The reaction mixture was diluted with benzene, washed with water, dried and evaporated. The residue was distilled to give 9.15 g of 2-(5-fluoro-2-methoxyphenoxy)ethanol as colorless oil, b.p. 138°-140° C. (8mmHg).
Reaction SMILES: O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:21]([CH2:24][CH2:25][C:26]1[S:30][C:29]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[CH:28][CH:27]=1)=[N+]=[N-]>C1COCC1>[NH2:21][CH2:24][CH2:25][C:26]1[S:30][C:29]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[CH:28][CH:27]=1
Reactant: CC(C)OC(=O)c1ccc(CCN=[N+]=[N-])s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)c1ccc(CCN)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Water (0.1 mL) and triphenylphosphine (288 mg, 1.1 mmol) were added sequentially to a solution of the azide from step 3 (239 mg, 1.0 mmol) in THF (2.0 mL) and the reaction was stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and then 1.0 N aqueous HCl (7.5 mL) was added. The mixture was extracted with EtOAc (2×5 mL). The aqueous phase was basified with 2.0 M aqueous NaOH (5 mL). The mixture was extracted with EtOAc (3×10 mL) and these extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford 175 mg (82%) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O.[NH2:28][NH2:29]>CCO>[CH2:1]([C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:28][NH2:29])=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)OC)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a suspension of methyl 4-[(4-heptylbenzoyl)amino]benzoate (823 mg, 2.33 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (1×2 mL) and water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 619 mg of the title compound (75%) as a white solid in 99.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH3:24])([OH:13])[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:23]([O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:24]
Reactant: CCOc1ccccc1OCC1(O)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccccc1OCC1(O)CCNC1
Reaction time: 16 h
Yield: 91.2 %

Procedure:
A solution of 10.0 g (0.0305 mole) of 1-benzyl-3-(2-ethoxyphenoxy)methyl-3-pyrrolidinol in 125 ml of absolute ethanol was treated with Pd/C catalyst and warmed while shaking under a hydrogen atmosphere on a Parr hydrogenation apparatus for 16 hours. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure. The white crystalline residue (7.1 g) was recrystallized from benzene isooctane to yield 6.6 g of product (91%), m.p. 108°-110° C.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:47])[C@@H:9]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][CH:11]([O:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C:12](=[O:27])[NH:13][CH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=1[O:25][CH3:26])([CH3:6])([CH3:5])[CH3:4]>CC(O)C>[C:3]([O:7][C:8](=[O:47])[C@@H:9]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][C@H:11]([O:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C:12](=[O:27])[NH:13][CH2:14][C:15]1[C:16]([O:25][CH3:26])=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=1[O:21][CH3:22])([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1cc(OC)c(CNC(=O)C(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OS(=O)(=O)c2ccc(C)cc2)c(OC)c1
Solvent: CO
Solvent: CC(C)O
Product: COc1cc(OC)c(CNC(=O)[C@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OS(=O)(=O)c2ccc(C)cc2)c(OC)c1

Procedure:
Following the procedure in the preparation of 11, compound 11″ was prepared from alcohol 10″ (1.69 g, 3.40 mmol) as a pale white foamy solid (2.12 g, 96% yield): [α]26D=+14.1 (c=1.01, MeOH); HPLC of 11″ for purity: 97.7%, [major peak: Rt=23.7 min; minor peak: 16.2 min; column: Chiralcel ODH (250×4.6 mm), UV detector, 210 nm, 5% 2-propanol in hexanes; flow rate: 1.0 mL/min]. 1H NMR (200 MHz, CDCl3) δ 7.75 (d, 2H, J=8.4 Hz), 7.25 (d, 2H, J=8.4 Hz), 6.91 (br s, 1H), 6.14 (s, 2H), 5.12 (br s, 1H), 4.94 (t, 1H, J=6.0 Hz), 4.52 (dd, 1H, J1=14.0 Hz, J2=6.0 Hz), 4.30 (dd, 1H,//=14.4 Hz, J2=5.2 Hz), 4.18 (br s, 1H), 3.84 (s, 3H), 3.82 (s, 6H), 2.42 (s, 3H), 2.32-2.22 (m, 2H), 1.45 (s, 9H), 1.43 (s, 9H). 13C NMR (50 MHz, CDCl3) δ 170.7, 167.1, 161.2, 159.5, 155.5, 145.5, 133.1, 130.1, 128.2, 106.3, 90.9, 82.4, 79.9, 56.0, 55.6, 50.8, 35.0, 32.7, 28.5, 28.1, 21.8. HRMS calcd for C31H45N2O11S (M+H)+: 653.2744. found: 653.2729.
Reaction SMILES: [CH2:1]([C:3]1[NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[C:4]=1[CH2:26][CH3:27])[CH3:2].[H-].[Na+].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>CN(C=O)C.O>[CH2:1]([C:3]1[N:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[C:4]=1[CH2:26][CH3:27])[CH3:2]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CCc1[nH]c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1CC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(CC)c(CC)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 6,7-diethyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazine (step 1) (14 mg, 0.039 mmol) in dry DMF (1 ml) under nitrogen was treated with NaH (1.733 mg, 0.043 mmol). The resulting mixture was stirred at RT for 20 minutes and treated with ethyl 7-bromoheptanoate (8.44 μl, 0.043 mmol). After stirring at RT for 3 hours, the mixture was added to water and the pH was adjusted to pH1 using 2M HCl. The aqueous was extracted with EtOAc (×3) and the combined organic extracts were sequentially washed with water (×1) and brine (×1), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (with trace hydrolysis acid product present);
Reaction SMILES: Cl.[CH2:2]([NH:5][N:6]=[CH:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH:22]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:21][CH2:20][C:19]=3[CH:30]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH3:4].C(O)C.[OH-].[Na+]>C(O)(=O)C>[CH2:2]([NH:5][N:6]=[CH:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH:22]([CH2:24][C:25]([OH:27])=[O:26])[CH2:21][CH2:20][C:19]=3[CH:30]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH3:4]
Reactant: CCCNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)OCC)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1

Procedure:
0.25 g (0.54 mmol) of the ester from Example 81 were stirred at room temperature overnight with 5 ml ethanol and 0.7 ml 2 N aqueous sodium hydroxide. The mixture was brought to pH 4 with 2 N acetic acid, and the precipitate of the acid (338) was filtered with suction, washed successively with water and with acetone, and dried in vacuo. Yield: 0.16 g (74%) of a pale yellow powder, m.p. 241-242° C. (dec.).