Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].[OH2:21].CCCCCC>C(O)(=O)C>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:21])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18]
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C2
Reactant: O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 30 %

Procedure:
1.10 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is refluxed for 2 hours in 10 ml. of acetic acid and 7.5 ml. of water containing 2.24 gm. of ceric ammonium nitrate. The solution is poured into water and extracted with ethyl acetate. The extract is washed, dried and evaporated and the residue chromatographed on silica gel, eluting with 40:60:1 ethyl acetate:hexane:acetic acid, so as to isolate a 30% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([O:23][C:24](=[O:45])[NH:25][C:26]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:19]([O:23][C:24](=[O:45])[NH:25][C:26]1([C:30]2[CH:31]=[CH:32][C:33]([C:2]3[C:7](=[O:8])[C:6]4[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=4[O:4][C:3]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:34][CH:35]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=c1c(Br)c(-c2ccccc2)oc2ccccc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=O)cc2)CCC1
Temperature: 80 °C
Reaction time: 21 h
Yield: 29 %

Procedure:
To a round-bottom flask was added 3-bromo-2-phenyl-1-benzopyran-4-one (27.1 mg, 0.09 mmol) and {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50.4 mg, 0.135 mmol) in toluene:ethanol (4:1, 2.5 mL) and 2 M aqueous sodium carbonate (1 mL). The solution was degassed for 20 minutes, after which time, tetrakis(triphenylphosphine) palladium (5.2 mg, 5 mol %) was added. The reaction mixture was heated to 80° C. using an oil bath with a water cooled reflux condenser, while stirring for 21 hours. The reaction mixture cooled to RT, suspended in ethyl acetate and washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (10:1 to 5:1 hexane:EtOAc gradient) to give a white solid (12.2 mg, 94%). 1H-NMR (400 MHz, CDCl3) δ 8.30 (d, 1H), 7.66 (dd, 1H), 7.53 (dd, 1H), 7.38-7.45 (m, 3H), 7.30-7.36 (m, 3H), 7.27 (d, 2H), 7.19 (d, 2H), 5.11 (bs, 1H), 2.35-2.58 (m, 4H), 1.91-2.09 (m, 1H), 1.77-1.88 (m, 1H), 1.38 (bs, 9H).
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH2:21](I)[CH3:22]>>[CH2:21]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:22]
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Reactant: CCI
Agent: [H-]
Agent: [Li+]
Product: CCn1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 255 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 9 mg of lithium hydride and 0.081 ml of ethyl iodide were used. As a result, 204 mg of 3-ethyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=2)[CH:19]([CH2:31][O:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[N:39]1([C:28]([C:26]2[N:27]=[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH2:18][CH:19]3[CH2:31][O:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[S:24][CH:25]=2)=[O:30])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(C(=O)O)cs2)C(COc2cccnc2)C1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C(=O)N3CCOCC3)cs2)C(COc2cccnc2)C1
Reaction time: 8 h
Yield: 44.6 %

Procedure:
Diisoproylcarbodiimide (0.028 mL, 0.178 mmol) was added to a solution of 2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylic acid (68 mg, 0.162 mmol), morpholine (16 mg, 0.178 mmol), diisopropylethylamine (0.031 mL, 0.178 mmol), and N-hydroxybenzotriazole (24 mg, 0.178 mmol) in CH2Cl2 (2 mL). After stirring overnight, little reaction had taken place. TBTU (0.162 mmol) was added, and stirring was continued at rt for 4 h. The reaction mixture was quenched with 1 N NaOH (2 mL) and stirred for 1 h. The reaction mixture was diluted with EtOAc (20 mL) and was washed with 1 N NaOH (2×10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (50 to 100% EtOAc in hexanes gradient), yielding 35.4 mg (45%) of the title compound. LC-MS: RT=6.77 min, [M+H]+=490.9. Rf=0.07 in 100% EtOAc.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1.[CH3:27][NH2:28].Cl.CCOCC>CS(C)=O.O>[ClH:1].[CH3:27][NH:28][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cc(OCCCl)ccc12
Reactant: CN
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CNCCOc1ccc2c(S(=O)(=O)c3cccc4ccccc34)n[nH]c2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 6-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.075 g, 0.19 mmoles) and methylamine (0.28 mL, 0.56 mmoles) in DMSO (1 mL) was stirred under nitrogen at 100° C. for 4 hours. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCl in ether (0.2 mL, 0.2 mmoles) was added, then dried, to afford the title compound as the HCl salt (0.07 g, 0.19 mmoles), MS: (ES+) 381 [M+H]+
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][N:10]=[C:9]1[S:18][CH2:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[F:32])[O:22][N:21]=1)(=O)=O.[H-].[Na+].CO>CN(C=O)C>[Cl:31][C:29]1[CH:28]=[CH:27][C:26]([F:32])=[C:25]([C:23]2[O:22][N:21]=[C:20]([CH:19]3[S:18][C:9]4=[N:10][N:11]=[C:12]([C:13]5[S:14][CH:15]=[CH:16][CH:17]=5)[N:8]4[CH2:7][CH2:6]3)[N:24]=2)[CH:30]=1
Reactant: CS(=O)(=O)OCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Fc1ccc(Cl)cc1-c1nc(C2CCn3c(nnc3-c3cccs3)S2)no1
Yield: 8 %

Procedure:
To a solution of 2-[3-({[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}thio)-5-(2-thienyl)-4H-1,2,4-triazol-4-yl]ethyl methanesulfonate (43 mg) in DMF (2 ml) was added sodium hydride (10 mg) at −78° C. while stirring. The mixture was allowed to come to r.t. and stirred for another 3 h before addition of MeOH (1 ml) and concentration onto silica gel. Purification by chromatography on silica gel using DCM:EA:MeOH 70:30:2 as eluent provided 2.8 mg of the title compound. 1H NMR: 8.07 (dd, 1H), 7.56 (m, 1H), 7.51 (dd, 1H), 7.47 (dd, 1H), 7.17-7.23 (m, 2H), 4.86 (dd, 1H), 4.60 (m, 1H), 4.38 (m, 1H), 2.82 (m, 2H)
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:5](=[O:6])[CH2:4][CH2:3]1.C[O-].[Na+].[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=O)=[CH:17][CH:18]=1.S(=O)(=O)(O)O>C(OC)(C)(C)C.O>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[C:4]2[CH2:3][CH:2]([CH3:1])[O:7][C:5]2=[O:6])=[CH:17][CH:18]=1
Reactant: CC1CCC(=O)O1
Reactant: COc1ccc(C=O)cc1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: COc1ccc(C=C2CC(C)OC2=O)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
74 g (0.5 mol) of 4-methyl-γ-butyrolactone are added to a suspension of 27 g (0.50 mol) of sodium methoxide in 400 g of methyl tert-butyl ether and, over the course of 1 h, 68 g (0.5 mol) of anisaldehyde are added thereto with stirring at room temperature. The mixture is maintained under reflux for a further 1 h and then cooled, and 200 g of iced water are added to the mixture and the pH is adjusted to 5 using 10% sulphuric acid. After the phases have separated, the product is distilled. This gives 65 g of the desired compound in a yield of 48% of theory. The specific absorbance E{fraction (1/1)} of the novel compound according to the present invention is 1.250, measured at a wavelength of λmax 310 nm.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:13]=2[O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:13]=2[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1c(CNc2ccc(C(C)=O)cc2)cccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cccc(CNc2ccc(C(C)=O)cc2)c1OCCCC(=O)O
Yield: 71.5 %

Procedure:
4-[2-[[(4-Acetylphenyl)amino]methyl]-6-methoxy-phenoxy]butanoic acid, ethyl ester (250 mg, 0.65 mmol) is dissolved in 5 mL of methanol/water (3:2) and treated with 313 mg (2.27 mmol) of potassium carbonate according to the procedure described for Example 4 to give 166 mg (71%) of 4-[2-[[(4-acetylphenyl)amino]-methyl]-6-methoxy-phenoxy]butanoic acid as a red colored solid: m.p. 85°-95° C.; The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3400, 1720, 1630, 1580 cm-1 ; MS (CI) m/e calculated for C20H23 O5NNa: 380.1473, found 380.1482; 358 (M+H), 233, 223, 221, 136.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[C:19]([Cl:29])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:15]3[C:10]([CH:11]=[N:12][C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[C:19]([Cl:29])[CH:18]=4)=[N:14]3)=[C:8]([CH3:9])[N:7]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CC(NC(=O)c1cccc(Br)c1)c1cnc(Nc2ccc(N3CCOCC3)c(Cl)c2)nn1
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2cccc(Br)c2)n2nc(Nc3ccc(N4CCOCC4)c(Cl)c3)ncc12
Yield: 22.3 %

Procedure:
In a similar manner as described for Example 9, 3-bromo-N-(1-{3-[(3-chloro-4-morpholin-4-ylphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 24) (0.040 g, 0.080 mmol) and 1,2,4-triazole (35 mg, 0.50 mmol) in pyridine (1 mL) and phosphorus oxychloride (0.023 mL, 0.24 mmol) gave 7-(3-bromophenyl)-N-(3-chloro-4-morpholin-4-ylphenyl)-5-methylimidazo[5,1-f][1,2,4]triazin-2-amine (0.0089 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.92 (s, 1H), 9.29 (s, 1H), 8.61 (dd, J=1.9, 1.8 Hz, 1H), 8.45 (ddd, J=8.1, 1.5, 1.1 Hz, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.72 (dd, J=8.7, 2.6 Hz, 1H) 7.67 (ddd, J=8.1, 2.0, 1.0 Hz, 1H) 7.54 (dd, J=8.1, 7.8 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 3.78-3.73 (m, 4H), 2.98-2.94 (m, 4H), 2.55 (s, 3H). MS m/z 499, 501 (M+1, M+3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]([CH3:17])=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH:9]([CH3:14])[CH2:8][CH:7]2[O:15][CH3:16].[CH2:21]([N:23]1[C:27]([OH:28])=[CH:26][CH:25]=[N:24]1)[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(CC)(C)C.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:3]=[C:4]([C:18]([C:26]2[CH:25]=[N:24][N:23]([CH2:21][CH3:22])[C:27]=2[OH:28])=[O:20])[C:5]([CH3:17])=[C:6]2[C:11]=1[S:10](=[O:12])(=[O:13])[CH:9]([CH3:14])[CH2:8][CH:7]2[O:15][CH3:16]
Reactant: COC1CC(C)S(=O)(=O)c2c(F)cc(C(=O)O)c(C)c21
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2cc(F)c3c(c2C)C(OC)CC(C)S3(=O)=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
In a 50-ml flask, 0.70 g (0.0023 mol) of 8-fluoro-4-methoxy-2,5-dimethylthiochroman-6-carboxylic acid-1,1-dioxide, 0.28 g (0.0025 mol) of 1-ethyl-5-hydroxypyrazole and 0.52 g (0.0025 mol) of DCC (N,N'-dicyclohexylcarbodiimide) were added to 5 ml of tert-amyl alcohol at the same time, and the mixture was stirred at room temperature for 30 minutes. Then, 0.17 g (0.00125 mol) of anhydrous potassium carbonate was added. The reaction mixture was allowed to react at 80° C. for 8 hours, and then the reaction solvent was distilled off under reduced pressure. The remainder was dispersed in a 2% potassium carbonate aqueous solution and ethyl acetate to separate it into two phases. Further, the aqueous phase was acidified with 5% hydrochloric acid. and the precipitated oil was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 0.70 g of 8-fluoro-4-methoxy-2,5-dimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound 40) shown in Table 5. The yield thereof was 78%.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]1)[CH:17]=[CH:16]2)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O>[C@H:24]1([NH:23][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:14]=3)[N:19]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: O=C(NC(=S)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=S)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Yield: 58 %

Procedure:
1-Benzoyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-thiourea (1.5 g, 3.4 mmol) was suspended in 50 mL methanol. 4.1 mL 1N sodium hydroxide solution was added and the reaction mixture was refluxed for 2 h. The reaction mixture was diluted with 80 mL water and extracted with dichloromethane (2×100 mL). The organic phases were pooled, dried with sodium sulfate and evaporated. The residue was recrystallized from dichloromethane and diethylether. The title compound (660 mg, 58%) was obtained as an off-white solid; MS: m/e=335.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH3:12].[C:13](Cl)(Cl)=[S:14].[OH-].[Na+]>O.Cl>[N:1]([C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH3:12])=[C:13]=[S:14]
Reactant: S=C(Cl)Cl
Reactant: Cc1c(N)ccc2c1OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N=C=S)ccc2c1OCCO2

Procedure:
1.90 g of 6-amino-5-methyl-benzodioxan is dissolved in 50 mL of water containing 11.8 mL of 1.0N hydrochloric acid. 1.10 mL of thiophosgene is added dropwise while stirring vigorously. After 4 hours of stirring at room temperature, the mixture is made basic with 50% sodium hydroxide solution, and then extracted with methylene chloride. The extracts are dried over sodium sulfate and concentrated. The residue is found to be 2.0 g of 6-isothiocyanato-5-methylbenzodioxan.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:7]([CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C@H:16]([C:13]([OH:12])([CH3:15])[CH3:14])[C@@H:17]2[CH3:21])[C:7]([CH3:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(C#N)c(Cl)cc1F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1cc(C#N)c(Cl)cc1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using 2-chloro-4-fluoro-5-methylbenzonitrile (848 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (784 mg, 10.6 mmol), the title compound was obtained as a colorless solid (yield: 590 mg) by an operation similar to that in Example 3.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[CH3:18][O:19][CH2:20][CH2:21]Cl>CN(C)C=O>[CH3:18][O:19][CH2:20][CH2:21][N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Reactant: COCCCl
Agent: [H-]
Solvent: CN(C)C=O
Product: COCCN1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 28.5 g (0.13 mol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), in 200 ml of N,N-dimethylformamide is added over 1.5 hours to a suspension of 6.24 g (0.13 mol) of solution hydride in 30 ml of N,N-dimethylformamide. The mixture is stirred for 1 hour at ordinary temperature and a solution of 14.7 g (156 mmol) of 2-methoxyethyl chloride in 100 ml of dimethylformamide is then run in. The mixture is heated at 70° C. for 5 hours and stirred at ordinary temperature for 15 hours and evaporated to dryness, the residue is taken up with 200 ml of 0.5N hydrochloric acid, extraction is carried out with benzene and the extract is washed with water and dried. After evaporation of the benzene layer, the residue is purified by chromatography on a silica column using a methylene chloride/ether mixture as the eluent. This gives 45% of a pure product of Rf=0.45 (A).
Reaction SMILES: I[C:2]1[C:10](=[O:11])[N:9]2[C:5]([N:6]([CH3:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=32)=[N:4][C:3]=1[CH3:17].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].FC1C=C(C2C(=O)N3C=CSC3=NC=2C)C=C(F)C=1>C1(C)C=CC=CC=1.O.C(O)C>[CH3:17][C:3]1[N:4]=[C:5]2[N:9]([C:10](=[O:11])[C:2]=1[C:24]1[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=1)[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:6]2[CH3:16]
Reactant: Cc1nc2n(C)c3ccccc3n2c(=O)c1I
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nc2n(C)c3ccccc3n2c(=O)c1-c1ccc(OC(F)(F)F)cc1

Procedure:
A solution of Step 3 intermediate (1.2 g, 3.512 mmol), 4-trifluoromethoxyphenyl boronic acid (0.864 g, 4.212 mmol), Pd[(C6H5)3P]4 (0.161 g, 1.420 mmol), Na2CO3 (2.32 g) was reacted together in a mixture of toluene (20 ml), ethanol (5 ml) and water (5 ml) according to the procedure outlined in Step 3, Intermediate 3 to afford the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 3.78 (s, 3H), 7.33-7.46 (m, 4H), 7.52-7.57 (m, 1H), 7.68-7.71 (m, 1H), 8.40-8.43 (s, 1H); ESI-MS (m/z) 374.62 (M+H)+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[S:18][C:19]([Cl:27])=[CH:20][C:21]=1[CH:22]=[CH:23][C:24](=[O:26])[CH3:25]>C(O)C>[Cl:16][C:17]1[S:18][C:19]([Cl:27])=[CH:20][C:21]=1[CH:22]1[CH2:3][C:2](=[O:1])[CH2:25][C:24](=[O:26])[CH2:23]1
Reactant: CC[O-]
Reactant: CC(=O)C=Cc1cc(Cl)sc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: O=C1CC(=O)CC(c2cc(Cl)sc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-dichlorothiophene (100.0 g) and dichloromethylmethylether (165.3 g) in dichloromethane (800 ml) was added dropwise a solution of titanium tetrachloride (272.7 g) in dichloromethane (160 ml) at −10 to −15° C. taking 50 minutes, and at the same temperature, the mixture was stirred for 30 minutes. The reaction solution was poured into ice, and the organic layer was washed with water, sodium hydrogen carbonate solution, water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 2,5-dichloro-3-formylthiophene (115.0 g) as oil. To a mixture of acetone (1000 ml), sodium hydroxide (28.6 g) and water (1200 ml) was added at 0° C. a solution of 2,5-dichloro-3-formylthiophene (58.6 g) in acetone (200 ml) for 1.5 hours, and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the crystals were filtered, washed with water and dried to give 4-(2,5-dichlorothiophen-3-yl)-3-buten-2-one (136.6 g). To a solution of 20% sodium ethoxide in ethanol (211 g) was added diethyl malonate (99.3 g) at room temperature, and then 4-(2,5-dichlorothiophen-3-yl)-3-buten-2-one (136.6 g) little by little. The mixture was stirred at room temperature for 30 minutes, heated for 2 hours while stirring, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated, to which was added 2M sodium hydroxide (340 ml). The mixture was stirred at 100° C. for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (340 ml) for 15 minutes, and the mixture was stirred at 100° C. for 1.5 hours. The mixture was cooled, and precipitated crystals were filtered and washed with ethyl acetate-isopropylether (1:4) and isopropylether to give 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (78.9 g) as colorless crystals.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[N:21]=[C:20]([Cl:22])[C:19](O)=[C:18]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[CH2:29][OH:30])[N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:22][C:20]1[N:21]=[C:16]([Cl:15])[N:17]=[C:18]2[C:19]=1[O:30][CH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]12
Reactant: OC[C@@H]1CCCN1c1nc(Cl)nc(Cl)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Clc1nc(Cl)c2c(n1)N1CCC[C@H]1CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [(S)-1-(2,6-dichloro-5-methoxy-pyrimidin-4-yl)-pyrrolidin-2-yl]-methanol (900 mg, 3.24 mmol) and lithium chloride (360 mg, 8.48 mmol) in anhydrous DMF (10 mL) was heated at 160° C. for 10 mins in a microwave reactor, then concentrated in vacuo to give 2,4-dichloro-6-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyrimidin-5-ol. DIAD (700 μL, 3.56 mmol) was added to a solution of 2,4-dichloro-6-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyrimidin-5-ol (3 mmol) and triphenyl phosphine (900 mg, 3.43 mmol) in 1,4-dioxane (10 mL) and the mixture stirred at RT for 1 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 20% ethyl acetate in cyclohexane) affording (S)-6,8-dichloro-2,3,3a,4-tetrahydro-1H-5-oxa-7,9,9b-triaza-cyclopenta[a]naphthalene. LCMS (method A): RT=2.98 min, [M+H]−=246/248.
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][C:7]([CH3:11])=[CH:8]C=O.C(O)C.[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>CCOCC>[CH2:23]([O:22][CH:15]([O:19][CH2:20][CH3:21])[CH:6]=[C:7]([CH3:11])[CH3:8])[CH3:24]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)=CC=O
Agent: O=P(O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(C=C(C)C)OCC
Yield: 65 %

Procedure:
Bull. Soc. Fr. 1965, 1007-1014 discloses the use of phosphoric acid. 3-Methyl-2-butenal is stirred with ethanol, triethyl orthoformate and phosphoric acid at room temperature for 40 hours. The reaction mixture is then taken up in ether, washed with 0.5 N aqueous ammonia and dried over sodium sulfate. Subsequent distillation affords 3-methyl-2-butenal diethyl acetal in a yield of 65%.