Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH:44]([OH:47])[CH2:45][OH:46])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][CH:41]([CH:44]([OH:47])[CH2:45][OH:46])[CH2:40][CH2:39]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OCC(O)C1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(O)CO)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-piperidin-4-yl-ethane-1,2-diol (prepared from 4-vinyl-pyridine using procedure reported by Aaron, H. S. et al. J. Org. Chem. 1965, 30, 1331-1333) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C35H44Cl2N5O4 [(M+H)+] 668.2765, observed 668.2767.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
2-(4-Bromo-phenoxy)-ethanol (5 g, 23 mmol) is dissolved in dichloromethane (40 mL). Triethylamine (2.8 g, 28 mmol) and 4-dimethylaminopyridine (140 mg, 1.15 mmol) were then added followed by tert-butyldimethylsilyl chloride (3.65 g, 24.3 mmol) as a solution in dichloromethane (10 mL). The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is washed with 10% aqueous citric acid, the organic layer is separated and concentrated in vacuo to afford 7.5 g (98% yield) of the title compound. 1H NMR (CDCl3) 0.05 (s, 6H), 0.85 (s, 9H), 3.85-3.94 (m, 4H), 6.72 (d, 2H, J=6.90 Hz), 7.28 (d, 2H, J=6.90 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
Ethyl 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylate (240 mg) and 27 mg of lithium hydroxide monohydrate were dissolved in 4 mL of THF and 4 mL of H2O. The reaction was stirred for 2 h at room temperature. The mixture was evaporated, and then added H2O. The mixture was acidified with 1N HCl to pH=2˜3. The resulting solid was filtered and washed with H2O to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (250 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:12][CH:13]3[CH2:14][N:15]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:16][CH:17]3[CH2:18]2)=[O:10])=[CH:7][CH:8]=1
Reactant: CCC(=O)Cl
Reactant: O=C(c1ccc(Br)cc1)N1CC2CNCC2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N1CC2CN(C(=O)c3ccc(Br)cc3)CC2C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 99.5 %

Procedure:
1.3 (4-Bromo-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone hydrochloride (300 mg; 0.9 mmol) is dissolved in 5 ml of DCM, N-ethyldiiso-propylamine for synthesis (0.46 ml; 2.7 mmol) is added and then cooled to 0° C. Propionyl chloride for synthesis (0.095 ml; 1.09 mmol) is added dropwise followed by stirring at RT for 14 h. The reaction mixture is separated between DCM and water. The organic layer is separated, dried over MgSO4, filtered off and then reduced to dryness under vacuo to afford 316 mg (99.5%) 1-[5-(4-bromo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propan-1-one 3 as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30]C4C=CC=CC=4)=O)=[CH:23][C:22]=3[O:37][CH3:38])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:41][NH:42][C:43]([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl>[C:43]([N:42]([CH3:41])[C:28](=[O:30])[NH:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:8]2[C:7]3[CH:39]=[CH:40][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[N:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:9]2=[O:17])(=[O:19])=[O:20])=[C:22]([O:37][CH3:38])[CH:23]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1OC
Reactant: CNC(C)(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)N(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of the compound obtained in EXAMPLE 16 step A), 1 ml of N-methyl-tert-butylamine and 20 ml of DCM is stirred for 2 hours at RT. The solvent is evaporated off under vacuum and the residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.13 g of the expected product after crystallization from an iso ether/ AcOEt mixture (65/35; v/v). M.p.=208° C.
Reaction SMILES: COC([CH:5]1[C:20](=[O:21])[CH2:19][C:8]2([CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[NH:7][C:6]1=[O:22])=O>C(#N)C.O>[C:15]([O:14][C:12]([N:10]1[CH2:11][C:8]2([CH2:19][C:20](=[O:21])[CH2:5][C:6](=[O:22])[NH:7]2)[CH2:9]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C1C(=O)CC2(CN(C(=O)OC(C)(C)C)C2)NC1=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)CC(=O)N2)C1

Procedure:
6,8-Dioxo-2,5-diaza-spiro[3.5]nonane-2,7-dicarboxylic acid 2-tert-butyl ester 7-methyl ester (1.1 g; 3.5 mmol) is refluxed in acetonitrile/water (18 ml/2 ml) for 50 minutes and evaporated to dryness. The residue is triturated with CH2Cl2 to deliver the title compound as colorless crystals. 1H-NMR (400 MHz; DMSO-d6): Keto-enol tautomerism. 10.70 (s, 1H); 8.75 (s, 0.5H); 7.55 (s, 0.5H); 4.85 (s, 1H); 3.94 (bd, 2H); 3.86 (bd, 2H); 3.78 (bs (2H); 1.40 (s, 9H); MS (m/z) ES+: 255 (25; MH+); 199 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18]I)[C:4]=1[CH3:20].O1CCCCC1[O:27][CH2:28][C:29]#[C:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18][C:35]#[C:34][CH2:33][CH2:32][CH2:31][C:30]#[C:29][CH2:28][OH:27])[C:4]=1[CH3:20]
Reactant: C#CCCCC#CCOC1CCCCO1
Reactant: COc1c(C)c(CCCCI)c(OC)c2ccccc12
Product: COc1c(C)c(CCCCC#CCCCC#CCO)c(OC)c2ccccc12
Yield: 73.4 %

Procedure:
By condensing 1,4-dimethoxy-2-methyl-3-(4-iodobutyl)naphthalene (3.84 g, 10 mmole) with 1-(2-tetrahydropyranyloxy)-2,7-octadiyne (2.10 g, 10 mmole) in accordance with the procedure of the above Reference Example 46, there was produced 1,4-dimethoxy-2-methyl-3-(12-hydroxy-5,10-dodecadiynyl)naphthalene (2.78 g, 73.5%, oily product). 1,4-Dimethoxy-2-methyl-3-(4-iodobutyl)naphthalene [δ1.5 to 2.2(4H), 2.40(3H), 2.82(2H), 3.23(2H), 3.84(3H), 3.87 (3H), 7.3 to 7.5(2H), 7.8 to 8.1(2H)] as utilized in this Reference Example was produced from 1,4-dimethoxy-2-methyl-3-(4-hydroxybutyl)naphthalene [oily substance, NMR (CDCl3), δ1.5 to 1.8(5H), 2.39(3H), 2.81(2H), 3.67(2H), 3.84(3H), 3.87(3H), 7.3 to 7.5(2H), 7.9 to 8.1(2H)] in accordance with the procedure described in Japanese Patent Application No. 49433/'80.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][O:11][C:7]1[C:6]([Br:12])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:9][C:8]=1[Br:10]
Reactant: BrCCCBr
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(OCCCBr)c(Br)c1

Procedure:
A stirred mixture of 3,5-dibromo-4-hydroxyacetophenone (3.0 g, 10.1 mmol), K2CO3 (2.8 g, 20.3 mmol), 1,3-dibromo-propane (4.0 g, 19.8 mmol) in acetonitrile (100 ml) was heated at reflux for 5 hours. The solvent was removed. The crude product was extracted into dichloromethane (150 ml) and the insoluble inorganics were filtered off. The solution was concentrated to dryness again. Purification was carried out by flash chromatography on silica gel (45 g, SiO2; eluted with 1:1 hexane:dichloromethane). The material thus obtained (2.8 g) was recrystallized twice from isopropyl ether to give analytically pure 1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone, m.p.=87-88° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[Na].CN(C)[CH:10]=[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[C:12](=O)[CH3:13]>C(O)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:10]=[C:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:12]=2[CH3:13])=[CH:16][CH:17]=1)#[N:22]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(C#N)cc1
Reaction time: 5 h

Procedure:
6.2 g of cyanacetamide are added to a freshly prepared solution of 1.14 g sodium in 200 ml of absolute ethanol. 10.6 g 4-dimethylamino-3-(4-cyanophenyl)-3-buten-2-one are added and the solution is stirred 5 hours at boiling temperature, whereby the sodium salt of the title compound soon begins to crystallize out. The mixture is allowed to cool, the crystalline product is filtered and washed with ethanol and ether (m.p. of the sodium salt>300°) (m.p. of the free form>300°).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[Cl:31])[CH2:27][C:26]1([C:35](=[O:36])[NH:34][C:33](=[O:37])[N:32]1[CH3:38])[CH2:25]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:31][C:30]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26]3([C:35](=[O:36])[NH:34][C:33](=[O:37])[N:32]3[CH3:38])[CH2:27]2)=[CH:23][C:22]=1[NH:21][C:8](=[O:10])[CH2:7][N:6]1[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:2]1=[O:1]
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Reactant: CN1C(=O)NC(=O)C12Cc1cc(N)c(Cl)cc1C2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C12Cc1cc(Cl)c(NC(=O)Cn3c(=O)n(-c4ccccn4)c4ccccc43)cc1C2

Procedure:
A mixture of (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (57 mg, 0.211 mmol, described in Intermediate 4), 5′-amino-6′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, enantiomer B (51 mg, 0.192 mmol, described in Intermediate 48), PyBOP (120 mg, 0.230 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.192 mmol) was stirred in DMF (1 mL) at 50° C. for 18 h. The crude mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=517 (M+1). HRMS: m/z=517.1383; calculated m/z=517.1386 for C26H22ClN6O4.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]Cl)(=[O:3])[CH3:2].[I-:14].[Na+]>CC(C)=O>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][I:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOCCOCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)OCCOCCOCCI
Yield: 109 %

Procedure:
A mixture of 2-[2-(2-chloroethoxy)ethoxy]ethyl acetate (6.23 g) and sodium iodide (22.2 g) in acetone (60 mL) was refluxed for 4 hours. The mixture was further refluxed for 4 hours after adding sodium iodide (11.0 g). The solvent was evaporated off, and the residue was partitioend between EtOAc (50 mL) and water (50 mL). The aqueous layer was washed with 10% sodium thiosulfate and brine, dried over MgSO4, and evaporated to give 2-[2-(2-iodoethoxy)ethoxy]ethyl acetate as a pale yellow oil (9.74 g).
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:11][C:12]([CH3:14])=[O:13].O>O1CCCC1>[Cl:10][C:2]1([O:13][C:12]1([CH3:14])[CH3:11])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1(Cl)OC1(C)C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 70.8 g of potassium tert.-butylate in 500 ml of tetrahydrofuran was added over 30 minutes under an inert atmosphere to 111 g of tert.-butyl dichloroacetate and 35.5 g of acetone at 0°C and after letting the mixture return to room temperature, the mixture was stirred for 1 hour and poured into iced water. The mixture was extracted with petroleum ether and the extract was washed twice with water and dried over sodium sulfate. 40 g of alumina were added thereto and after stirring, the mixture was filtered to remove mineral products. The solvent was removed from the filtrate by distillation under reduced pressure to obtain 116.5 g of tert.-butyl 2-chloro-2,3-epoxy-3-methyl-butanoate in the form of a colorless liquid soluble in the usual organic solvents and insoluble in water.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[CH:5][N:6]=1.[CH:7]1[C:20]2[CH:19]([C:21](Cl)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:21]([CH:19]1[C:20]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[S:12][C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:22]
Reactant: O=C(Cl)C1c2ccccc2Sc2ccccc21
Reactant: Nc1ncco1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Nc1ncco1)C1c2ccccc2Sc2ccccc21
Reaction time: 16 h
Yield: 18.6 %

Procedure:
To a stirred solution of (0.048 g, 0.575 mmol) 2-amino-oxazole [Cockerill & al., Synthesis 591(1976)], and DMAP (0.003 g, 0.03 mmol) in pyridine (2 ml) was added at 0° C. (0.100 g, 0.384 mmol) 9H-thioxanthene-9-carbonyl chloride. Stirring was continued at RT for 16 h, the reaction mixture was evaporated and water (5 ml)/sat. NaHCO3 solution (2 ml) was added. The solid was filtered off, dissolved in dichloromethane, dried (MgSO4), and concentrated in vaccuo. The crude material was purified by column chromatobraphy on silica gel (methylene chloride/methanol 40:1) to give the product (0.022 g, 18%) as a white solid, m.p. 188-191° C. and MS: m/e=309.1 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: COC(=O)Cl
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 13 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 6 (1.56 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 18.
Reaction SMILES: O=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[P:8]([OH:11])([OH:10])[OH:9].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:6][C:5](=[CH2:7])[CH:4]=[C:2]([P:8]([OH:11])(=[O:9])[OH:10])[CH3:3]
Reactant: OP(O)O
Reactant: CC(=O)C=C(C)C
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=C(C)C=C(C)P(=O)(O)O

Procedure:
For example, mesityl oxide was reacted with phosphorous acid in the presence of acetic anhydride and acetic acid under mild conditions to yield 4-methylpenta-2,4-diene-2-phosphonic acid in more than 90% purity.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Product: CC1CCN(c2nc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: -40 °C
Reaction time: 3 h
Yield: 40.1 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (194 mg, 1.00 mmol) in THF (10 mL) at −40° C., 4-methylpiperidine (118 μL, 1.00 mmol) was added dropwise. The resulting mixture was stirred at −40° C. for 3 h and the solvent was removed in vacuo. The resulting yellow residue was chromatographed on silica (5-20% EtOAc:hexane) to obtain the title compound (103 mg, 40%). 1H-NMR (CDCl3; 400 MHz): δ 8.69 (s, 1H), 4.24 (br m, 2H), 3.10 (m, 2H, J=12.9, 2.7 Hz), 1.82-1.71 (m, 3H), 1.36-1.25 (m, 2H), 1.01 (d, 3H, J=4.8 Hz).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=O)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.O>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: [N-]=[N+]=NCCCC(=O)N1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCCCCN1CCCc2ccccc21

Procedure:
The 1-(4-azidobutanoyl)-1,2,3,4-tetrahydroquinoline (3.9 g) was refluxed in ether containing lithium aluminium hydride (1.8 g) for 5 hours. The solution was cooled and diluted cautiously with water. The organic phase was washed, dried and evaporated to afford the title compound as an oil, which was then converted to the dimaleate mp 79°-81°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=O)=[C:5]([C:11]([OH:13])=[O:12])[C:4]=1[O:14][CH3:15].[NH2:16][C@@H:17]([C:22]([OH:24])=[O:23])[C:18]([SH:21])([CH3:20])[CH3:19]>O>[CH3:15][O:14][C:4]1[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]2[NH:16][C@@H:17]([C:22]([OH:24])=[O:23])[C:18]([CH3:20])([CH3:19])[S:21]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=O)c(C(=O)O)c1OC
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: O
Product: COc1ccc(C2N[C@@H](C(=O)O)C(C)(C)S2)c(C(=O)O)c1OC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2.1 g (10 mmoles) of opianic acid are dissolved in 30 ml of hot water and the solution is cooled to about 60° C. After adding 1.5 g (10 mmoles) of D-penicillamine, an oily product separates from the opalescent solution which becomes crystalline after standing overnight. The title acid is obtained in a yield of 2.75 g (80.5%) and can be recrystallized from methanol by adding water, m.p.: 90°-91° C., [α]D20 =+326° (c=0.772, methanol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
Compound 114 (308 mg, 1.25 mmol) was dissolved in DCM (4 mL) and the solution was cooled in an ice-water bath. TFA (3.5 mL) was then added and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). The solution was washed with K2CO3 (sat., 3×), brine, dried and concentrated to yield 115 (175 mg, 95%) as a pale yellow oil. MS (APCI): m/z 147 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][OH:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[NH2:18].C(OCC)(=O)C>CN1CCCC1=O>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][OH:13])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: OCCn1ccc2ncnc(Cl)c21
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: OCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol (130 mg) in 1-methyl-2-pyrrolidone (1.3 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reaction mixture was stirred at 120° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature and ethyl acetate (20 mL) was added. The resultant precipitate was recrystallized from a mixed solvent of hexane/methanol (3/7), collected by filtration and dried under reduced pressure to give the title compound (206 mg) as pale purple crystals.
Reaction SMILES: C[Li].[CH3:3]C1(C)CCCC(C)(C)N1.[CH2:13]([O:15][C:16]1[C:17]([F:27])=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:19]#[N:20])[CH3:14].CI.Cl>O1CCCC1>[CH2:13]([O:15][C:16]1[C:17]([F:27])=[C:18]([C:21]([CH3:3])=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:19]#[N:20])[CH3:14]
Reactant: CCOc1ccc(C#N)c(F)c1OCC
Reactant: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]C
Solvent: CI
Solvent: C1CCOC1
Product: CCOc1cc(C)c(C#N)c(F)c1OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
Under a stream of nitrogen gas, methyl lithium (1.03 M diethyl ether solution, 18.2 mL, 18.8 mmol) was added to an ice-cooled solution of 2,2,6,6-tetramethylpiperidine (3.16 mL, 18.7 mmol) in tetrahydrofuran (30 mL), followed by 30 minutes of stirring. After cooling the reaction system to −78° C., a solution of 3,4-diethoxy-2-fluorobenzonitrile (3.90 g, 18.6 mmol) in tetrahydrofuran (20 mL) was added dropwise, and 30 minutes later, methyl iodide (1.4 mL, 22.4 mmol) was added dropwise, followed by 2 hours of stirring. The reaction system was gradually warmed to room temperature, and 1N hydrochloric acid was added to the reaction solution, after which ethyl acetate extraction was performed. The extract was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (n-hexane, ethyl acetate) to give 3.40 g of the subject compound (yield: 81.7%).