Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]1[CH2:12][C:11]2[CH:13]=[C:14](Br)[CH:15]=[N:16][C:10]=2[NH:9][C:8](=[O:18])[CH2:7]1)[CH3:2].[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:25]([O:24][C:20](=[O:23])/[CH:21]=[CH:22]/[C:14]1[CH:15]=[N:16][C:10]2[NH:9][C:8](=[O:18])[CH2:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH2:12][C:11]=2[CH:13]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CN1CC(=O)Nc2ncc(Br)cc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC(=O)Nc2ncc(/C=C/C(=O)OC(C)(C)C)cc2C1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A suspension of (7-Bromo-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-4-yl)acetic acid ethyl ester (6.18 g, 17.4 mmol) in propionitrile (70 mL) and DMF (17 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with tert-butyl acrylate (10.2 mL, 69.6 mmol) and (i-Pr)2EtN (6.4 mL, 37 mmol) and was then de-oxygenated with Ar for 10 min. Pd(OAc)2 (0.39 g, 1.7 mmol) and P(o-tol)3 (1.06 mg, 3.48 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. After heating to reflux for 14 h, the mixture was allowed to cool and then concentrated in vacuo. The resulting residue was diluted with CH2Cl2 and filtered through Celite. The orange filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (200 mL) and washed with H2O (100 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with H2O (2×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3) and again by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (2.55 g, 39%) as an off-white solid: MS (ESI) m/e 376 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]([Cl:25])([Cl:24])[CH:7]1[O:12][CH:11]([C:13]([Cl:16])([Cl:15])[Cl:14])[C:10]2[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:9]=2[O:8]1>S(=O)(=O)(O)O>[N+:1]([C:20]1[C:9]2[O:8][CH:7]([C:6]([Cl:5])([Cl:24])[Cl:25])[O:12][CH:11]([C:13]([Cl:16])([Cl:14])[Cl:15])[C:10]=2[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc2c(c([N+](=O)[O-])c1)OC(C(Cl)(Cl)Cl)OC2C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Nitric acid (d=1.54, 10 ml.) was added to a stirred suspension of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylic acid (5 g.) in concentrated sulphuric acid (25 ml.), and the resulting suspension was stirred at room temperature for 2 hrs. The reaction mixture was filtered, and the solid product was crystallised from a mixture of petroleum ether (b.p. 60°-80° C.) and ether to give 8-nitro-2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylic acid, m.p. 211°-212° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[N+:18]([O-])=O)=[CH:5][CH:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[NH2:18])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(C=Cc2ccc(C)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCc2ccc(C)cc2N)cc1
Yield: 96.7 %

Procedure:
To a solution of the product from Example 106A (164 mg, 0.6 mmol) and 10% palladium on charcoal (50 mg) in ethanol (20 ml) was hydrogenated with a hydrogen balloon for three days. The solvent was filtered through celite, washed with ethanol and evaporated under vacuum to provide the title compound (140 mg, 97%).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[CH2:11]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:26])=[C:22]([CH:25]=2)[CH2:23]Cl)=[CH:15][CH:14]=1)[CH3:12]>>[CH2:9]([O:8][P:1]([CH2:23][C:22]1[CH:25]=[C:18]([CH2:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:11][CH3:12])=[CH:28][CH:27]=2)[CH:19]=[CH:20][C:21]=1[F:26])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CCc1ccc(Cc2ccc(F)c(CCl)c2)cc1
Product: CCOP(=O)(Cc1cc(Cc2ccc(CC)cc2)ccc1F)OCC
Temperature: 155 °C
Reaction time: 16 h

Procedure:
Triethyl phosphite (0.8 mL) was added to [5-(4-ethylbenzyl)-2-fluorobenzyl chloride (0.65 g), and the mixture was stirred for 16 hr at 150-160° C. The mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to give the title compound (0.70 g) as a colorless oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:16])=[CH:15][CH:14]=2)=[O:13])[CH2:29][CH2:30]1
Reactant: Cc1cc(C)c(N2CCNCC2)cn1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)cn1
Yield: 37 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (165 mg) described in Preparation Example 16 and 1-(4,6-dimethylpyridin-3-yl)piperazine (131 mg) described in Preparation Example 95 and by the reaction and treatment in the same manner as in Example 87, the title compound (105 mg) was obtained.
Reaction SMILES: [CH2:1]1[C@@H:3]([NH2:4])[C@@H:2]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][CH2:12][OH:13]>[Pd]>[C:5]1([CH2:2][CH2:1][CH2:3][NH:4][C:12]([C:11]2([CH:8]([CH3:9])[CH3:7])[CH2:6][CH2:5][CH2:2][CH2:1][CH2:3]2)=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CCO
Agent: [Pd]
Product: CC(C)C1(C(=O)NCCCc2ccccc2)CCCCC1
Yield: 100 %

Procedure:
Compound 1 (33 mg, 0.12 mmol) and 10% Pd on carbon (30 mg), in EtOH (1 mL) was stirred under hydrogen for 18 h. The reaction mixture was filtered over celite and concentrated to give 1-isopropyl-cyclohexanecarboxylic acid (3-phenyl-propyl)-amide (33 mg, 100%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ (ppm) 0.86 (6H, d, J=6.8 Hz), 1.00–1.40 (5H, m), 1.50–1.65 (4H, m), 1.80–1.90 (4H, m), 2.67 (2H, t, J=7.5 Hz), 3.33–3.48 (2H, m), 5.59 (1H, s), 7.17–7.31 (5H, m). Mass Spec [M+H]+=288.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:24]([C:26]([NH2:28])=[O:27])[N:25]=1)[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([C:21]1[S:22][C:23]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([NH2:28])=[O:27])[N:25]=1)[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)c1nc(C(N)=O)c(-c2ccccc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nc([C@H](N)Cc2ccc3ccccc3c2)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
2-((1R)-1-(tert-Butoxycarbonylamino)-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid amide (0.155 g; 0.327 mmol) was dissolved in methylene chloride (4 ml) and trifluoroacetic acid (4 ml) was added. The reaction mixture was stirred 1 hour at room temperature and the solvent was removed in vacuo. The residue was dissolved in methylene chloride and evaporated (2×2 ml). The residue was dissolved in diethyl ether (2 ml). Hydrochloric acid (1 N; 3 ml) and methanol (10 ml) were added. The solvent was removed in vacuo to afford 0.106 g of 2-((1R)-1-amino-2-(2-naphthyl)-ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid amide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[Na+].Cl>O.C(#N)C>[ClH:5].[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: ClCCCN1CCOCC1
Reaction time: 1 h
Yield: 60.8 %

Procedure:
5 ml acetonitrile, 2.3 ml (23 mmol) of 1-bromo-3-chloropropane and 1 ml (11.5 mmol) of morpholine were added successively into a reaction flask. The mixture was stirred for 1 h, and 0.5 ml of 5% NaOH solution was added. After stirring at room temperature for 12 h, 3 ml concentrated hydrochloric acid and 10 ml water were added into the mixture. The lower layer was discarded, and the upper layer was alkalified with 5% NaOH and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, then filtrated. The filtrate was concentrated to dry in a reduced pressure, and a small amount of ethanol/NaOH solution was added dropwise into the residue. The mixture was shaken and placed in a refrigerator for standing, then concentrated to dry in a reduced pressure to obtain 1.4 g white solid with the yield of 60%. m.p. 168-170° C.
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][N:26]([CH3:54])[C:27](=[O:53])[NH:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[N:39]=[C:38]3[C:50](O)=[O:51])[CH:32]=[N:33][CH:34]=1.C(N(C(C)C)CC)(C)C.NC1C=NC=CC=1>CN(C=O)C>[CH3:25][N:26]([CH3:54])[C:27](=[O:53])[NH:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[N:39]=[C:38]3[C:50]([NH:16][C:11]2[CH:10]=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:51])[CH:32]=[N:33][CH:34]=1
Reactant: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C(=O)O)nn3C2CCCCO2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C(=O)Nc2cccnc2)nn3C2CCCCO2)c1
Temperature: 25 °C

Procedure:
HATU (0.190 g, 0.5 mmol) was added to a solution of 5-(5-(3,3-dimethylureido)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXXIV) (0.39 g, 1.21 mmol) and diisopropylethylamine (0.174 mL, 1.0 mmol) in DMF stirred at room temperature under argon. After stirring 5 min, the solution was added with 3-aminopyridine (CXXV) (0.047 g, 0.5 mmol). The solution was stirred overnight at room temperature under argon. The DMF was removed under reduced pressure, and the residue was treated with water, sonicated briefly and filtered. The solids were washed with cold water and dried at room temperature. The product was purified by column chromatography using a 4 g Thomson normal phase silica gel cartridge (100% DCM→5:95 MeOH:DCM) to afford 5-(5-(3,3-dimethylureido)pyridin-3-yl)-N-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (CXXVI) as an off white solid (323 mg, 0.67 mmol, 55% yield). 1H NMR (DMSO-d6) δ ppm 10.56 (s, 1H), 9.06 (d, J=2.0 Hz, 1H), 8.75 (d, J=1.6 Hz, 1H), 8.64 (s, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.46 (s, 1H), 8.34-8.29 (m, 2H), 8.26 (m, 1H), 8.03 (d, J=7.0 Hz, 1H), 7.88 (dd, J=7.0, 1.2 Hz, 1H), 7.43 (dd, J=6.64, 3.84 Hz, 1H), 6.07 (dd, J=8.0, 1.8 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.98 (s, 6H), 2.63-2.60 (m, 1H), 2.11-2.06 (m, 2H), 1.83-1.81 (m, 1H) 1.52 (m, 2H); ESIMS found for C21H23N5O4 m/z 410.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:40])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][C:21]=3[CH2:35][C:36]([O:38]C)=[O:37])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C1COCC1.CO.S([O-])(O)(=O)=O.[K+]>S([O-])([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:40])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[CH:22][C:21]=3[CH2:35][C:36]([OH:38])=[O:37])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A solution of (S)-9-chloro-5-[p-tert-butoxycarbonylaminomethyl-o-(methoxycarbonylmethyl)phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H -pyrido[1,2,3-de]quinoxaline-2,3-dione (1.82 g, 3.18 mmol) in a mixture of 1N aqueous sodium sulfate (20 mL), THF (20 mL), and methanol (20 mL) was stirred for 4 h at room temperature. The mixture was acidified to pH 3 by addition of 5% potassium hydrogen sulfate and extracted with a 1:1 mixture of ethyl acetate and THF. The organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residual solid was washed with dichloromethane, and dried in vacuo to give 1.499 g of the title compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(O)C>CCCCCC>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCCC1O
Solvent: CCCCCC
Solvent: CCO
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCC[C@H]1O

Procedure:
Racemic (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone of Example 5 was subjected to chiral HPLC (Chiralpak AD, 21.1×250 mm, 50% ethanol in hexane). The first peak which eluted displayed a positive optical rotation and was arbitrarily assigned the (R)-configuration. The title compound was isolated as a white solid, [α]D=+34.30 (c=1.0, chloroform).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=1>>[N+:38]([C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1)([O-:40])=[O:39]
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2cccc([N+](=O)[O-])c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-3-nitro-benzene following the procedure of Example 478: MS (ESI) m/z529.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:37]1([C:40](O)=[O:41])[CH2:39][CH2:38]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:40]([CH:37]4[CH2:39][CH2:38]4)=[O:41])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(=O)C1CC1)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.9 %

Procedure:
To a solution of (1S,2R,4aS,5R,8R,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b -hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 139, 100 mg, 0.19 mmol) and 4-dimethylaminopyridine (30 mg, 0.25 mmol) in tetrahydrofuran (10 ml) was added cyclopropanecarboxylic acid (400 mg, 4.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.58 mmol) and the resulting mixture stirred at room temperature for 18 h. The reaction mixture was passed through a Sepak® cartridge (silica, 1.5 g) to remove insoluble material and the solvent removed in vacuo. The crude product was purified to give the title compound (20 mg, 18%).
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Cl.CC([O-])=O.[Na+].[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[C:19]([OH:24])[N:18]=1>O>[NH2:16][C:17]1[NH:22][C:21]2=[N:23][CH:1]=[CH:2][C:20]2=[C:19]([OH:24])[N:18]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: CCOC(CBr)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(O)c2ccnc-2[nH]1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A mixture of 136.7 g of bromoacetaldehyde diethylacetal, 347 mL of water, and 17.3 mL of concentrated HCl was heated to about 90° C. with vigorous stirring for about 30 minutes, at which time a clear solution was obtained. The solution was cooled to room temperature and 68.3 g of NaOAc was added. The resulting solution was added, with stirring, to a suspension of 100 g of 2,4-diamino-6-hydroxypyrimidine and 34.2 g of NaOAc in 739 mL of water, which had been heated to 70°-85° C. The reaction was allowed to proceed for 2 hours at 70°-85° C., at which time the reaction was complete. The mixture was cooled to 0° C. and held for about 1.5 hours. The mixture was then filtered and the collected product was washed with 500 mL of water and 500 mL of acetone, and dried, affording 72.3 g (79%) of 2-amino-4-hydroxypyrrolo[2,3-d]pyrimidine. A small sample was further purified by slurry in hot methanol, filtration, and drying, mp>300° C. 1H NMR (300 MHz, DMSO-d6) δ6.03 (s, 2 H), 6.13 (m, 1 H), 6.56 (dd, J=3.3, 2.3 Hz, 1 H), 10.23 (bs, 1 H), 10.93 (bs, 1 H).
Reaction SMILES: C(OC([P:8]([CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1)(=[O:12])[O:9][CH2:10][CH3:11])OCC)C.C(O)C.C[Si](Cl)(C)C>ClCCl>[CH2:10]([O:9][P:8]([CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1)[OH:12])[CH3:11]
Reactant: CCOC(OCC)P(=O)(OCC)C1CCCO1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOP(O)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 g of ethyl 1,1-diethoxymethyl(tetrahydrofuran-2-yl)phosphinate in 10 ml of dichloromethane containing 1% (b.v.) of ethanol is treated with 0.71 g of trimethylsilylchloride. The faintly cloudy solution is stirred overnight at room temperature after which time thin layer chromatography indicates complete reaction. Removal of the solvent in vacuo affords a colourless oil which after distillation yields P-tetrahydrofuran-2-yl-phosphonous acid ethyl ester, b.p. 90°/8 ×10-2 mbar.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:16]>CCOC(C)=O>[ClH:16].[ClH:16].[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][NH2:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NOC1CCNCC1

Procedure:
1-tert-Butoxycarbonyl-4-piperidyloxyamine (120 mg) was dissolved in a 5M HCl solution in EtOAc (3 mL). After 1 h the solvent was removed under reduced pressure to give the title compound III-a (100 mg, 96%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.95 (3H, bb), 8.96 (2H, bb), 4.33 (1H, m), 3.13 (2H, m), 3.00 (2H, m), 2.09 (2H, m), 1.85 (2H, m).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9].S(Cl)([Cl:18])=O>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)Oc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(C)Oc1cccc(CCl)c1
Yield: 88.8 %

Procedure:
By the method of Example 1, Step H, 1.98 g (0.0095 mole) of methyl 2-(3-hydroxymethylphenoxy)propionate and 1.24 g (0.0105 mole) of thionyl chloride were reacted in the presence of five drops of pyridine in 40 mL of methylene chloride, yielding 1.93 g of methyl 2-(3-chloromethylphenoxy)propionate as a yellow liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:6]=1)=[O:4].O[Li].O>O.C1COCC1.CO>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]2[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cn(CCN(C)C)c2cc(Cl)ccc12
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The ester was hydrolyzed in a mixture of H2O/THF/MeOH (ratio 1:1:1) with LiOH.H2O (3 eq.). The reaction mixture was stirred at 40° C. overnight. The acid was extracted several times with EtOAc, and the combined organic phases were dried over Na2SO4. Recrystallisation in Et2O afforded 35 mg (34% overall yield) of the title compound as a white solid.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]CC)=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl>[OH-].[Na+]>[C:1]([CH2:6][C:7]([OH:9])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl isobutyrylacetate (20.47 g, 129 mmol) and 1.5 M aq NaOH (250 mL) is stirred at room temperature overnight. The solution is then cooled to 0° C. and acidified to pH 1-2 by the slow addition of conc. HCl (˜35 mL). The solution is then saturated with NaCl and extracted thrice with EtOAc and once with CHCl3. The combined extracts are dried over Na2SO4 and concentrated to 14.46 g (86%) of isobutyrylacetic acid as an oil. 1H NMR (CDCl3, 300 MHz) reveals a mixture of keto and enol forms (˜4:1), in favor of the keto form. Keto form: δ 3.57 (s, 2H), 2.73 (sept, J=6.9 Hz, 1H), 1.16 (d, J=6.9 Hz, 6H) ppm. Enol form: 11.85 (s, 1H), 5.03 (s, 1H), 2.44 (sept, J=6.9 Hz, 1H), 1.10 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Cl[CH2:17][CH2:18][CH2:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=[O:21]>>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][C:20]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)=[O:21])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C(CCCCl)N1CCc2ccccc21
Agent: Cl
Product: O=C(CCCN1CCN(c2cccc(Cl)c2)CC1)N1CCc2ccccc21

Procedure:
from 1-(3-chlorophenyl)piperazine, dihydrochloride and 4-chloro-1-(2,3-dihydro-1H-indol-1-yl)butan-1-one. Mp 102–107° C. 1H NMR (DMSO-d6): 1.75–1.85 (m, 2H); 2.35 (t, 2H); 2.45–2.55 (m, 6H); 3.10–3.20 (m, 6H); 4.10 (t, 2H); 6.75 (d, 1H); 6.85 (d, 1H); 6.90 (s, 1H); 6.95 (t, 1H); 7.10 (t, 1H); 7.15–7.25 (m, 2H); 8.10 (d, 1H). MS m/z: 384 (MH+), 265, 188.