Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]2[CH:25]=[CH:24][C:13]3[C:14](=[O:23])[CH:15]=[C:16]([C:18]([O:20]CC)=[O:19])[O:17][C:12]=3[C:11]=2[CH2:26][CH2:27][CH3:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].C(O)C>O>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]2[CH:25]=[CH:24][C:13]3[C:14](=[O:23])[CH:15]=[C:16]([C:18]([OH:20])=[O:19])[O:17][C:12]=3[C:11]=2[CH2:26][CH2:27][CH3:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: CCCc1c(COc2ccc3c(=O)cc(C(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(COc2ccc3c(=O)cc(C(=O)O)oc3c2CCC)ccc(C(C)=O)c1O

Procedure:
A solution of 0.6 g. of the ethyl ester from Example 1 and 4.5 g. of sodium bicarbonate was heated to reflux in 100 ml. of ethanol and 25 ml. of water for four hours. The solution was then concentrated under reduced pressure. The residue was taken up in water. The solution was made acidic with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with water, dried over sodium sulfate, and evaporated to dryness. The residue was crystallized from ethanol/water to afford 0.2 g. of the desired title product, m.p. 195°-205° C.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[I:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28].[CH3:29][O:30][C:31](=[O:37])[CH:32]([CH3:36])[C:33](O)=[O:34].CCN(CC)CC.[OH-].[Na+]>CCOC(C)=O>[I:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][C:33](=[O:34])[CH:32]([CH3:36])[C:31]([O:30][CH3:29])=[O:37]
Reactant: COC(=O)C(C)C(=O)O
Reactant: NCCc1ccccc1I
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(C)C(=O)NCCc1ccccc1I
Temperature: 25 °C
Reaction time: 144 h
Yield: 78.5 %

Procedure:
A solution of T3P in AcOEt (50%, 26.2 mL, 44.0 mmol) was added dropwise at 0° C. under N2 to a clear solution of 2-(2-iodophenyl)ethanamine (9.45 g, 38.2 mmol), 3-methoxy-2-methyl-3-oxopropanoic acid (5.05 g, 38.2 mmol) and Et3N (10.7 mL, 76.0 mmol) in AcOEt (350 mL). The mixture was stirred at RT for 6 days. A 2N aqueous solution of NaOH (50 mL) was then added to the reaction and the mixture was extracted with AcOEt. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The yellow oil obtained was purified by flash chromatography (SiO2, cHEx/AcOEt 100:0 to 50:50) to afford the title compound (10.83 g) as a clear oil. UPLC-MS: MS 362.2 (M+H+); UPLC rt 0.95 min.
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]([NH2:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]3)=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: COc1ccc(/C=C/c2ccc(N)cc2)cc1
Product: COc1ccc(/C=C/c2ccc(N3CC(C(=O)O)CC3=O)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36c), the reaction of (E)-4-[2-(4-methoxy-phenyl)-vinyl]-phenylamine with itaconic acid yields the (RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a brown solid; MS: m/e=336 (M−H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27]I>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH3:27])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CI
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C#N)c1cccc(Oc2ccccc2C)c1OC
Yield: 94.3 %

Procedure:
Sodium hydride (50%, 1 g), ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (6.2 g) and methyl iodide (4.1 g) were treated in a similar manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]propionate (6.1 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH:4]([CH3:15])[N:5](C(OCC)=O)[CH2:6]2>Cl>[CH3:1][N:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH:4]([CH3:15])[NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CCN(C)C2C1C
Agent: Cl
Product: CC1NCC2CCN(C)C21

Procedure:
16.9 g (79.6 mol) of ethyl 2,8-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 130 ml of concentrated hydrochloric acid. The mixture is concentrated, the residue is taken up in 50 ml of water, and the mixture is rendered alkaline with potassium carbonate and extracted five times using 50 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C@H:11]2[O:16][C:15](=[O:17])[NH:14][CH2:13][CH2:12]2)[CH:7]=[C:8]([CH3:10])[CH:9]=1.Br[CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[CH:32][C:31]=1[O:40][CH3:41]>C1COCC1>[CH3:3][C:4]1[CH:5]=[C:6]([C@H:11]2[O:16][C:15](=[O:17])[N:14]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[CH:32][C:31]=3[O:40][CH3:41])[CH2:13][CH2:12]2)[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Reactant: Cc1cc(C)cc([C@@H]2CCNC(=O)O2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC[C@@H](c2cc(C)cc(C)c2)OC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of sodium hydride (60% in oil; 7.4 mg; 0.185 mmol) in THF (1.5 mL) at 0° C. under N2 was added a solution of (6S)-6-(3,5-dimethylphenyl)-1,3-oxazinan-2-one (Intermediate 21; 30 mg; 0.148 mmol) in THF (2 mL) dropwise. The reaction was stirred at 0° C. for 20 min prior to addition of 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 13; 50 mg; 0.123 mmol) as a solution in THF (1.5 mL). The reaction was allowed to warm to room temperature and stirred for 72 h, then quenched with H2O and partitioned between EtOAc (25 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified first by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) and then by chiral HPLC (Chiralpak AD column; 15% IPA/heptane) to afford (6S)-6-(3,5-dimethylphenyl)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazinan-2-one as a clear oil. LCMS=530.3 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.66 (d, J=7.8 Hz, 1H), 7.61 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 7.01-6.96 (m, 4H), 6.70 (d, J=12.1 Hz, 1H), 5.23-5.13 (m, 1H), 4.66-4.49 (m, 2H), 3.78 (s, 3H), 3.26-3.20 (m, 1H), 3.17-3.06 (m, 1H), 3.01-2.93 (m, 1H), 2.34 (s, 6H), 2.18-2.13 (m, 1H), 2.09-2.02 (m, 1H), 1.29-1.24 (m, 6H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.[CH3:12][O-:13].[Na+].[OH-].[Na+]>CC#N.CO>[CH3:12][O:13][C:2]1[O:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cnc(Cl)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: COc1ncc(C(=O)O)o1
Yield: 69.9 %

Procedure:
To a solution of ethyl 2-chlorooxazole-5-carboxylate (510 mg, 2.90 mmol) in anhdryous MeCN (10 mL) and anhydrous MeOH (10 mL) is added NaOMe (628 mg, 11.62 mmol). The crude is stirred at reflux for 2 hrs. To this crude is added additional MeOH. The crude is refluxed for another 4 hrs. The crude is cooled and then concentrated and is redissolved in MeOH (10 mL). To this crude is added 1 N NaOH (10 ml, 10 mmol). The crude is stirred at room temperature for 3 hrs. The crude is quenched with concentrated HCl, PH adjusted to 7 via pH paper indicator. The crude is concentrated to remove MeOH. The crude is diluted in water. The aq. layer is acidified with concentrated HCl and diluted in EtOAc. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated to give 2-methoxyoxazole-5-carboxylic acid (290 mg). This acid is used without further purification. HPLC retention time=0.58 minutes (condition B); MS 144.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:12]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:19][C:20]([F:43])([F:42])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]>>[CH2:1]=[C:2]1[C:12]([N:13]2[CH2:14][CH2:15][N:16]([CH2:40][CH2:39][CH2:38][C:25]3([C:23](=[O:24])[NH:22][CH2:21][C:20]([F:19])([F:42])[F:43])[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:31]4[C:26]3=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:17][CH2:18]2)=[CH:11][CH:10]=[CH:9][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccc(N2CCNCC2)c1C
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Product: C=C1C(N2CCN(CCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)=CC=CC1C(=O)OCC

Procedure:
The procedure of step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 53 and the compound prepared in step (a) of Example 93 were used as the starting compound. Thus, ethyl 2-methyly-3-[4-[3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]propyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][C@H:5]1[C@H:7]([C:8](O)=[O:9])[C:6]1([CH3:12])[CH3:11].S(Cl)([Cl:21])=O>>[Cl:21][C:8]([C@H:7]1[C@H:5]([CH:4]=[C:3]([C:13]([F:16])([F:15])[F:14])[C:2]([F:18])([F:17])[F:1])[C:6]1([CH3:12])[CH3:11])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](C=C(C(F)(F)F)C(F)(F)F)[C@@H]1C(=O)O
Product: CC1(C)[C@@H](C=C(C(F)(F)F)C(F)(F)F)[C@@H]1C(=O)Cl

Procedure:
A mixture of (+)-cis/trans-3-(3,3,3-trifluoro-2-trifluoromethyl-prop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (0.4 g) and thionyl chloride (5.0 ml) was heated at the reflux temperature for a period of 2 hours, after which the excess thionyl chloride was removed by distillation under reduced pressure, leaving (+)-cis/trans-1-chlorocarbonyl-3-(3,3,3-trifluoro-2-trifluoromethyl-prop-1-en-1-yl)-2,2-dimethylcyclopropane.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14](O)[CH:15]=[CH2:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].O>C(OCC)C>[O:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[CH2:16][Cl:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Reactant: Cl
Solvent: O
Solvent: CCOCC
Product: ClC/C=C/c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3-Phenoxyphenyl)prop-2-en-1-ol (0.05 g) was dissolved in diethyl ether (2 cm3) which had been previously saturated with hydrogen chloride gas, and the solution was stirred at the ambient temperature for 2 hours. Water was added to the mixture and the products extracted into further diethyl ether. The combined ethereal layers were dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure. The residual oil was purified by column chromatography on a silica gel support, eluted with hexane containing 5% by volume ethyl acetate, to give E-3-(3-phenoxyphenyl)-1-chloroprop-2-ene (0.03 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([CH3:13])[CH:3]=1.[CH3:14][C:15]1([CH3:22])[C:19]([CH3:21])([CH3:20])[O:18][BH:17][O:16]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH3:13])[CH:3]=[C:2]2[B:17]1[O:18][C:19]([CH3:21])([CH3:20])[C:15]([CH3:22])([CH3:14])[O:16]1
Reactant: CC1(C)OBOC1(C)C
Reactant: COc1ccc2c(c1)c(I)cn2C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
The 3-iodo-5-methoxy-1-methyl-1H-indole (9.90 g, 34.5 mmol) in 1,4-dioxane (200 mL) was treated with PdCl2(dppf)-CH2Cl2 (1.41 g, 1.72 mmol), TEA (33.6 mL, 241 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (28.7 g, 224 mmol). The mixture was heated to about 100° C. for about 40 min. The mixture was cooled to rt and concentrated under reduced pressure. The material was stirred with EtOAc (300 mL) at rt for about 30 min and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 100% DCM to give 5-methoxy-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (3.7 g, 37%): LC/MS (Table 2, Method a) Rt=2.68 min; MS m/z 288 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[N:3]=1.C(O)(=O)C.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(Oc2ccc(OCc3ccccc3)cc2)nc2nc(-c3ccco3)nn12
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(Oc2ccc(O)cc2)nc2nc(-c3ccco3)nn12

Procedure:
A solution of 7-amino-5-(4-benzyloxyphenoxy)-2-(2-furyl)[1,2,4]triazolo[1,5-a][1,3,5]triazine (1.0 g) in methanol (400 ml) containing palladium-on-carbon catalyst (10% w/w, 200 mg) and acetic acid (20 ml) was treated with hydrogen gas at atmospheric pressure. The reaction was monitored by tlc analysis (system as Example 1) and once no further starting material was detected, the catalyst was removed by filtration. Solvent was evaporated from the filtrate. The solid residue obtained was crystallised from ethanol to give 7-amino-2-(2-furyl)-5-(4-hydroxyphenoxy)-[1,2,4]triazolo[1,5-a][1,3,5]triazine as colourless hygroscopic crystals, m.p. 292°-294° C.; microanalysis, found: C, 53.5; H, 3.6; N, 26.4; H2O, 2.1%; C14H10N6O3 0.33H2O requires: C, 53.2; H, 3.4; N, 26.6; H, 3.6; N, 26.4; H2O, 2.1 %; NMR: 6.7(dd, 1H, furyl-4H), 6.8(d, 2H, phenyl), 7.0(d, 2H, phenyl), 7.1(d, 1H, furyl-3H), 7.9(d, 1H, furyl-5H), 8.7-9.1(d, 2H, NH2), 9.4(br s, 1H, OH;m/e 310 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Br)c(N2CCNCC2)n1
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
A solution of 3-bromo-2-chloro-6-picoline (0.2 g), piperazine (0.083 g) and triethylamine (0.096 g) in acetonitrile (5 ml) was heated in the microwave apparatus: 30 min at 120° C. followed by 60 min at 150° C. and 30 min at 170° C. The mixture was concentrated and the product was purified by chromatography (SiO2, CH2Cl2=>CH2Cl2/CH3OH 4:1) to give 1-(3-bromo-6-methyl-pyridin-2-yl)-piperazine (0.05 g) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]2[N:9]([C:10]=1[C:11]1[C:12]([F:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.S(=O)(=O)(O)[OH:21]>>[Cl:1][C:2]1[C:3]([C:18]([NH2:19])=[O:21])=[C:4]2[N:9]([C:10]=1[C:11]1[C:12]([F:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(Cl)c(-c2cccnc2F)n2c1CCCC2
Product: NC(=O)c1c(Cl)c(-c2cccnc2F)n2c1CCCC2

Procedure:
2-Chloro-3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide is prepared according to the method described in Example 10, from 1.8 g of 2-chloro-3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 30 cm3 of 60% sulphuric acid. 1.3 g of 2-chloro-3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide is thus obtained in the form of a white powder melting at 191° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)=[CH:3][CH:2]=1.[OH-].[K+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CC(C)=O.C(OCC)(=O)C>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]=2)=[CH:30][CH:29]=1
Reactant: c1ccc(-c2nc(Nc3ccncc3)c3ccccc3n2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccncc2)c2nc(-c3ccccc3)nc3ccccc23)cc1
Temperature: 25 °C

Procedure:
4-(4-pyridylamino)-2-phenyl quinazoline, 1 equivalent, was dissolved in reagent grade acetone, to this was added 5 equivalents of potassium hydroxide and 1.5 equivalents of 4-methoxybenzyl chloride. The mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature the reaction mixture was concentrated and the residue taken up in ethyl acetate and washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate and concentrated to give an oil. This crude material was dissolved in ethyl acetate and chromatographed as in Example 1. EIMS confirmed the product.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:10]=1.C(O)(=O)C>O>[O:1]=[CH:2][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:10]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCCC3OCCO3)cc2)S1
Solvent: CC(=O)O
Solvent: O
Product: O=CCCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 40.4 %

Procedure:
A solution of 6.30 g of 5-{4-[2-(1,3-dioxolan-2-yl)ethoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Preparation 106) in 50 ml of a 4:1 mixture of acetic acid and water was stirred at 60° C. for 6 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.20 g of the title compound, melting at 48-51° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10](=O)[NH:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10](=[S:29])[NH:9]2)[CH:7]=1
Reactant: CC1(c2cc(Br)ccc2F)NC(=O)COCC1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC1(c2cc(Br)ccc2F)NC(=S)COCC1(F)F

Procedure:
To a solution of 5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (2.0 g, 5.93 mmol) in THF (25 mL) was added Lawesson's reagent (2.87 g, 7.1 mmol) at rt and heated to reflux temperature for 16 h. Reaction mixture was concentrated under reduced pressure and directly purified by column chromatography on silica gel using 4% ethyl acetate in Hexane to furnish title compound as colorless gum. Yield=1.0 g (50%). LCMS: RtH8=1.75 [M+H]+=354.8, 355.7,
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:17](=O)[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22]([NH2:24])=[NH:23].OS(O)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH3:20][O:21][C:22]1[NH:24][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:23]=1
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 61.6 %

Procedure:
A mixture of 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, ethyl ester (16.46 g, 62.6 mmol), o-methylisourea hydrogen sulfate (14.00 g, 81.4 mmol), and sodium bicarbonate (15.8 g, 18.8 mmol) in dimethylformamide (9.4 ml) was heated at 70° C. (oil bath) under argon overnight. The cooled reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed several times with water, washed with saturated sodium chloride, dried (potassium carbonate) and evaporated. The residue was passed through a pad of silica gel, crystallized from isopropyl ether/hexanes and then triturated with 60% isopropyl ether hexanes (50 ml) to give 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester as light yellow crystals (12.32 g), melting point 101°-103° C.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][C:19]=1[CH3:23])[CH:10]=O.[CH2:24]1[CH2:31][CH:30]([NH2:32])[C:28](=[O:29])[NH:27][CH2:26][CH2:25]1>CO>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][C:19]=1[CH3:23])[CH2:10][NH:32][CH:30]1[CH2:31][CH2:24][CH2:25][CH2:26][NH:27][C:28]1=[O:29]
Reactant: COc1cc(C=O)ccc1OCCc1scnc1C
Reactant: NC1CCCCNC1=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CNC2CCCCNC2=O)ccc1OCCc1scnc1C
Reaction time: 2 h

Procedure:
Acetic acid (9.4 mmol) was added to 3-Methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzaldehyde (6) (2.3 mmol) and DL-α-amino-ε-caprolactam (2.3 mmol) in minimal amount of methanol and stirred for 2 h. MeOH (0.2 M) was added followed by NaH3BCN (2.3 mmol), and the reaction was stirred for 19 h. The product (7) was obtained by purification upon reverse phase HPLC.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:18]=[C:19]([CH3:26])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24]>CS(C)=O>[CH3:26][C:19]1[CH:18]=[CH:17][C:22]([N+:23]([O-:25])=[O:24])=[C:21]([CH:20]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(C)ccc2[N+](=O)[O-])sc2ccccc12
Yield: 111.9 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (3 g), 3-fluoro-4-nitrotoluene (2.1 g) and dimethyl sulfoxide (25 ml), ethyl 2-(5-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate (5.4 g) was obtained. Without purification, in the same manner as in Starting Material Synthesis Example 19 and using 10% palladium-carbon (1.5 g), ethyl 2-(2-amino-5-methylanilino)benzo[b]thiophene-3-carboxylate (1.6 g) was obtained.