Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:65][C:66]1[S:67][CH:68]=[CH:69][N:70]=1>CN(C=O)C.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:65][C:66]3[S:67][CH:68]=[CH:69][N:70]=3)=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Nc1nccs1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(-c2cc(C(=O)Nc3nccs3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 81.5 %

Procedure:
A solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (440 mg, 1.00 mmol) in DMF (15 mL) was mixed with DIEA (0.697 mL, 4.0 mmol), HATU (418 mg, 1.1 mmol) and 2-aminothiazole (150 mg, 1.5 mmol). The reaction mixture was stirred over night, diluted with H2O (0.5 mL), and concentrated under vaccum to remove DMF. Flash chromatography (load column with DCM, mobile phase EtOAc/Hexane) then provided the title compound as a white solid 425 mg (81%).
Reaction SMILES: S([O-])(O)(=O)=O.[K+].C([O:10][C:11]1[O:12][CH2:13][C:14](=O)[C:15]=1C(OC(C)C)=O)(C)C.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH:33]([F:35])[F:34])=[CH:26][CH:25]=1>C(#N)CCC>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:32][CH:33]([F:35])[F:34])[C:14]2[CH2:13][O:12][C:11](=[O:10])[CH:15]=2)=[CH:26][CH:25]=1
Reactant: CC(C)OC(=O)C1=C(OC(C)C)OCC1=O
Reactant: FC(F)CNCc1ccc(Cl)nc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCC#N
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Temperature: 25 °C
Yield: 95 %

Procedure:
0.6 g of potassium hydrogensulphate was added at room temperature to a suspension of 1.0 g of isopropyl 2-isopropoxy-4,5-dihydro-4-oxofuran-3-carboxylate and 0.85 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethylamine in 15.8 g of butyronitrile. The mixture was heated to reflux for 5 hours. Subsequently, it was cooled to room temperature and washed with 10 ml of water. The solvent was removed under reduced pressure. This gave 1 g of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one (this corresponds to 95% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[C:8]([OH:10])=O)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([C:8]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:10])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc(C(=O)O)ccc1OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C(=O)N2CCCCC2)ccc1OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 4-ethoxy isopthalic acid 3-ethyl ester (600 mg, 2.5 mmol) in 10 mL of acetonitrile was added piperidine (429 mg, 5.0 mmol). The resulting mixture was cooled to 0° C. To this solution was added HBTU (1.4 g, 3.78 mmol, in 5 mL of acetonitrile) followed by N,N-diisopropylethylamine (2.2 mL, 12.6 mmol). The reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated in vacuo. The residue was diluted with 10% potassium carbonate and extracted with methylene chloride. The organic extract was concentrated and purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 632 mg (2.07 mmol, 82%) of pure 2-ethoxy-5-(piperidine-1-carbonyl)-benzoic acid ethyl ester. LC-MS: 306.3 [(M+H)+].
Reaction SMILES: COC([C:5]1[C:6]([N:14]([CH2:21][CH2:22][CH2:23][C:24](OCC)=[O:25])[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)=O.CC(C)([O-])C.[K+].Cl.[Cl-].[Li+]>C1COCC1.[Cl-].[Na+].O>[CH:18]([O:17][C:15]([N:14]1[C:6]2[C:7]3[CH2:8][CH2:9][CH2:10][C:11]=3[CH:12]=[CH:13][C:5]=2[C:24](=[O:25])[CH2:23][CH2:22][CH2:21]1)=[O:16])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CCCN(C(=O)OC(C)C)c1c(C(=O)OC)ccc2c1CCC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)N1CCCC(=O)c2ccc3c(c21)CCC3
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Add a solution of 4-[(3-Ethoxycarbonyl-propyl)-isopropoxycarbonyl-amino]-indan-5-carboxylic acid methyl ester (510 mg, 1.30 mmol) in THF (20.4 mL) to a solution of potassium tert-butoxide (2.60 μL, 2.60 mmol, 1 M in THF) in THF (18 mL) at room temperature under an atmosphere of nitrogen. After 30 min, pour the mixture into ice/water. Treat aqueous phase with 1M HCl to pH neutral and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Dissolve the former crude in DMSO (11 mL) and add water (2 drops) followed by addition of lithium chloride (134 mg, 3.2 mmol) and heat the resulting solution at 160° C. for 30 minutes. Cool the mixture to room temperature and pour into brine. Extract the mixture with ethyl acetate. Dry the organic layers over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (302 mg, 81% over two steps): MS (ES+): 288 (M+H).
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[CH:6]([NH2:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[IH:17].CS[C:20]1[NH:21][CH2:22][CH2:23][N:24]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)C.CCOCC>[IH:17].[NH:21]1[CH2:22][CH2:23][NH:24][C:20]1=[N:16][CH:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH:10]=[CH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2
Reactant: NC1c2ccccc2C=Cc2ccccc21
Reactant: CSC1=NCCN1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: C1=Cc2ccccc2C(N=C2NCCN2)c2ccccc21
Reaction time: 8 h

Procedure:
1.04 grams (0.005 mole) of 5H-dibenzo[a,d]cyclohepten-5-ylamine, 1.22 grams (0.005 mole) of 2-methylmercapto-4,5-dihydroimidazole hydroiodide, and 1.5 milliliters of triethylamine were mixed together in 20 milliliters of ethanol and heated at reflux temperature for 16 hours. Thereafter most of the ethanol was evaporated, some n-butanol added and the resulting mixture heated under reflux for 15 hours. At the end of this period, the solvent was removed under reduced pressure, and residue obtained to which was added first, aqueous sodium bicarbonate, then ether and the resulting mixture stirred and decanted to recover the non-dissolving solid as residue. The solid was stirred overnight with ether, filtered and crystallized from ethanol. It was purified by chromatographing on a silica gel column employing 6 percent methanol in chloroform as eluant to obtain the desired N-(2-imidazolidinylidene)-5H-dibenzo[a,d]cyclohepten-5-amine hydroiodide product. Elemental analyses were as follows:
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:17][C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:14][O:13][C:11]([C:10]1[CH:9]=[CH:8][C:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:18]([Cl:17])=[O:20])=[CH:16][CH:15]=1)=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCNc1ccc(C(=O)OC)cc1
Solvent: C1CCOC1
Product: CCCCCN(C(=O)Cl)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Yield: 275.2 %

Procedure:
A solution of methyl 4-pentylaminobenzoate (43) (200 mg, 0.91 mmole) in 5 mL of THF was treated with 95 mg of triphosgene (0.35 eq.), stirred at reflux for three hours, then poured onto 50 mL ice-water and extracted with three portions of 50 mL of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 250 mg of 4-methoxycarbonylphenyl-pentyl-carbamoyl chloride (45) which was used without purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[Cl:14][C:15]1[C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[N:16]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:21]([C:20]2[C:15]([Cl:14])=[N:16][C:17]([C:24]([F:27])([F:25])[F:26])=[CH:18][CH:19]=2)=[O:22])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CNc1ncc(C(F)(F)F)cc1NC(=O)c1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.5 %

Procedure:
A mixture of 0.42 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.50 g of 2-chloro-6-trifluoromethylpyridine-3-carboxylic acid, 0.64 g of EDCI hydrochloride, 30 mg of HOBt and 2.5 ml of pyridine was stirred at room temperature for 7 hours. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane, and then dried to obtain 0.81 g of 2-chloro-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 2-Chloro-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:14])[C:12]#[CH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Mg]Cl)#C.COC1C=C(C=CC=1OC)C=O.Br[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:42]/[C:43]1[NH:44][CH:45]=[CH:46][C:47]=1[O:48][CH3:49])/[C:35](=[O:41])[NH:36]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:14])[C:12]#[C:13][C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2/[C:34](=[CH:42]/[C:43]2[NH:44][CH:45]=[CH:46][C:47]=2[O:48][CH3:49])/[C:35](=[O:41])[NH:36]3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CC(O)c1ccc(OC)c(OC)c1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1OC

Procedure:
Using Method C above, 3-(3,4-dimethoxyphenyl)-3-hydroxy-1-propyne (150 mg, 0.78 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 3,4-dimethoxybenzaldehyde (Aldrich) according to Method A above) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2) (146 mg, 0.4 mmol) using (Ph3P)2PdCl2 (40 mg) (Aldrich) and CuI (22 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-(3,4-dimethoxyphenyl)-3-hydroxy-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 121 mg, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:40])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:32][CH:33]=2)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)=[O:6])[CH3:2]
Reactant: CCCCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)cc1
Solvent: CCOC(C)=O
Product: CCCCCCc1ccc(CCc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)cc1
Yield: 94 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step c) but using ethyl{{4-[(4-hexylphenyl)ethynyl]benzyl}[4-(trifluoromethyl)benzyl]amino}(oxo)acetate in EtOAc gave the title compound as a colorless oil (94%). 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, 0.8H, J=8.1 Hz), 7.60 (d, 1.2H, J=8.1 Hz), 7.39 (d, 0.8H, J=8.1 Hz), 7.33 (d, 1.2H, J=8.1 Hz), 7.18 (m, 4H), 7.11 (s, 4H), 4.54 (s, 1.2H), 4.49 (s, 0.8H), 4.42-4.30 (m, 4H), 2.90 (m, 4H), 2.59 (t, 2H, J=7.8 Hz), 1.61 (m, 2H), 1.39-1.30 (m, 9H), 0.89 (t, 3H, J=6.8 Hz). M−(LC/MS(ESI)): 552; M+(LC/MS(ESI)): 554. HPLC (Condition A), Rt: 6.46 min (HPLC purity: 99.2%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[CH2:13][Cl:14])[CH2:7][CH2:6][CH2:5]2.B.C1COCC1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][Cl:14])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(CCl)N1CCCc2cc(Br)ccc21
Agent: B
Solvent: C1CCOC1
Product: ClCCN1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A round bottom flask was charged with 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloroethanone (compound 1, 0.546 g, 1.892 mmol) and treated with borane-THF complex (1M in THF, 18.9 mL, 18.9 mmol, 10 equivalents) and the resulting mixture stirred overnight at room temperature. After cooling to 0° C., the reaction was quenched by dropwise addition of methanol (5 mL) and stirred for 10 minutes at 0° C. The mixture was concentrated under reduced pressure and purified directly on silica gel eluting with 10% ethyl acetate/90% hexanes to yield a viscous residue, 2 (0.519 g, 100%). 1H-NMR (CDCl3) δ 7.11 (dd, 1H, J=8.7, 2.4 Hz), 7.08-7.04 (m, 1H), 6.42 (d, 1H, J=8.7), 3.64-3.56 (m, 4H), 3.35 (t, 2H, J=5.6 Hz), 2.73 (t, 2H, J=6.3 Hz), 1.97-1.89 (m, 2H). MS (ESI+): 274/276 (MH+, 100).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.Br[CH2:15][C:16]#[C:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1)[C:16]#[C:17][CH3:18]
Reactant: CC#CCBr
Reactant: CCCc1cc2c(cc1O)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1cc2c(cc1CCC)OCO2
Yield: 84 %

Procedure:
Following the same procedure as in Example 2, 3.65 g (0.02 moles) of 5-hydroxy-6-propyl-benzo[1.3]dioxole were reacted with 2.7 g (0.02 moles) of 1-bromo-2-butyne and 2.8 g (0.02 moles) of anhydrous potassium carbonate in 15 ml of acetone. After the work up of the reaction as in Example 2, a residue was obtained that after distillation at 115-117° C./0.2 mbar gave 3.9 g of a liquid product that, after some time, crystallized with m.p. 39° -40 ° C. and whose NMR and MS analyses correspond to those of the aforementioned compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[CH2:22]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:25]>C(OCC)C>[Br:25][CH2:22][C:9]1[N:10]([CH:19]([CH3:21])[CH3:20])[C:11](=[O:18])[C:12]2[C:17]([C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: BrP(Br)Br
Reactant: CC(C)n1c(CO)c(-c2ccc(F)cc2)c2ccccc2c1=O
Solvent: CCOCC
Product: CC(C)n1c(CBr)c(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
A solution of 4-(4-fluorophenyl)-3-hydroxymethyl-2-isopropyl-1-oxo-1,2-dihydroisoquinoline [5.0 g; prepared as described in Reference Example 2(e)] in diethyl ether (200 ml) was treated with phosphorus tribromide (2.0 ml). The resulting mixture was stirred and heated at reflux for 90 minutes, and then cooled and diluted with diethyl ether (200 ml). The solution was washed with water (3×50 ml), dried over magnesium sulphate, and evaporated to dryness, to give 3-bromomethyl-4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinoline in the form of a white solid (5.8 g), m.p. 116°-119° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[NH2:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OCc2ccccc2)c([N+](=O)[O-])cc1OC
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N)c(OCc2ccccc2)cc1OC

Procedure:
To a hot suspension (60° C.) of 260 g 2-benzyloxy-4,5-dimethoxy-nitrobenzene in 900 ml of ethanol, 1350 ml of glacial acetic acid and 900 ml of water, 282.6 g of iron powder was added portion-wise over 30 min. Thereafter the mixture was refluxed for 1/4 h. The reaction mixture was poured into 10 l of water and the oily product was extracted with dichloromethane. After drying the solvent was evaporated. Yield: 116 g (50%). Melting point: 74° C.
Reaction SMILES: [NH2:1][CH:2]([CH:8]([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].Cl>[OH-].[Na+].O1CCOCC1>[CH2:15]([O:14][C:12]([NH:1][CH:2]([CH:8]([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(CCC(=O)O)C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCC(NC(=O)OCc1ccccc1)C(F)F

Procedure:
To a solution of 2 mmole of 4-amino-4-difluoromethylbutyric acid in 5 ml of 1 N sodium hydroxide at 0° C. are added simultaneously from two syringes 2 mmole of benzyl chloroformate in 1 ml of dioxane and 2 ml of 1 N sodium hydroxide. After 30 minutes at 0° C. the solution is acidified by the addition of 6 N hydrochloric acid, then extracted well with dichloromethane. The organic phase is dried and concentrated to afford 4-benzyloxycarbonylamino-4-difluoromethylbutyric acid which is dissolved in 15 ml of dichloromethane and treated with 2 mmole of thionyl chloride at 25° C. for 1 hour after which 4 mmole of propyl amine is added. The solution is stirred at 25° C. for one hour, then washed with water, dried and concentrated. The residue is treated with 6 ml of a solution of dioxane containing 40% w/w hydrogen bromide and allowed to stand for 30 minutes at 25° C. after which 50 ml of ether is added. The resulting precipitate is collected to afford N-propyl 4-amino-4-difluoromethylbutyramide hydrobromide.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[C:9](=[N:11][OH:12])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[I-].[K+].II.[Al].S(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH3:10][C:9]1[C:8]([C:13]2[CH:14]=[CH:15][C:16]([S:19][CH3:20])=[CH:17][CH:18]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:12][N:11]=1
Reactant: CSc1ccc(C(=Cc2ccccc2)C(C)=NO)cc1
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(-c2c(C)noc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 1-phenyl-2-(4-methylthiophenyl)-1-buten-3-one oxime (Step 2) (11.2 g, 0.0395 mol), sodium bicarbonate (13.6 g, 0.162 mol), and potassium iodide (22.95 g, 0.138 mol) in tetrahydrofuran (200 ml) and water (160 ml) was added iodine (10 g, 0.0395 mol). The reaction vessel was covered with aluminum foil and heated at reflux for 4 hours. Thin layer chromatography indicated the reaction was completed. The reaction was cooled to room temperature, sodium bisulfite was added and the reaction was extracted with ethyl acetate. The organic extracts were dried and the solvent was removed to give the crude isoxazole. The crude was purified by chromatography on silica gel using mixtures of ethyl acetate and toluene. The isoxazole was recrystallized from ethyl acetate and hexane to give pure compound as a crystalline solid (8.3 g, 75%): mp 88°-90° C. Anal. Calc'd. for C17H15NOS (281.38): C, 72.57; H, 5.37; N, 4.98; S, 11.40. Found: C, 72.20; H, 5.27; N, 4.58; S, 11.69.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[CH3:10][C:11]1([CH3:29])[O:15][C@@H:14]([CH2:16][O:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:13][O:12]1.CNN>ClCCl>[CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[CH3:10][C:11]1([CH3:29])[O:15][C@@H:14]([CH2:16][O:17][NH2:18])[CH2:13][O:12]1
Reactant: CC1(C)OC[C@H](CON2C(=O)c3ccccc3C2=O)O1
Agent: CC1(C)OC[C@H](CO)O1
Agent: CNN
Solvent: ClCCl
Product: CC1(C)OC[C@H](CON)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a stirring solution of (S)- or (R)-2-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (74.9 g, 0.27 mol) in dichloromethane (480 mL) at 3-5° C. was added methylhydrazine (15.8 mL, 0.29 mole) dropwise. The color of the suspension turned from yellow to white. The cooling bath was removed and the mixture was stirred for 2 hrs at ambient temperature. The resulting suspension was concentrated on a rotary evaporator. To the white solid was added ether (0.5 L) and the resulting mixture was stirred for 1.5 h at ambient temperature. The white precipitate was filtered and washed with ether (0.2 L). The filtrate was concentrated on rotary evaporator to give (S)- or (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (39.0 g, 98.3%): 1H NMR (CDCl3): δ 1.35 (s, 3H), 1.42 (s, 3H), 3.73 (m, 3H), 4.05 (m, 1H), 4.33 (m, 1H), 5.39 (m, 2H); MS (APCI+)=148.1 (M++1)
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7]([C:9]3[C:18]([O:19][CH2:20][CH3:21])=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=3[O:22][CH2:23][CH3:24])[CH:6]=[N:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([N:4]2[CH:8]=[C:7]([C:9]3[C:18]([O:19][CH2:20][CH3:21])=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=3[O:22][CH2:23][CH3:24])[CH:6]=[N:5]2)[CH2:2][CH2:3]1
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cnn(C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C2CC2)c1

Procedure:
To a solution of Methyl 4-(1-cyclopropyl-1H-pyrazol-4-yl)-3,5-diethoxybenzoate (20 mg) in MeOH (3 ml) was added aqueous 1N NaOH (240 ul) at room temperature, and the reaction mixture was stirred for over night. The mixture was concentrated under reduced pressure and aqueous 1N HCl (240 ul) was added to the residue. The mixture was concentrated under reduced pressure and dried in vacuo to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])#[N:6].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1C=CC=CC=1.O>[C:5]([C:7](=[C:2]([CH3:4])[CH3:1])[C:8]([O:10][CH3:11])=[O:9])#[N:6]
Reactant: CC(C)=O
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(C#N)=C(C)C
Yield: 58.4 %

Procedure:
87 g (1.5 mol) of acetone were initially charged in 100 ml of benzene. After addition of 131 g (1.33 mol) of methyl cyanoacetate, 16 g (0.28 mol) of acetic acid and 9.7 g (0.13 mol) of ammonium acetate, the mixture was heated at reflux on a water separator for 10 hours. For work-up, the mixture was washed twice with ¼-concentrated hydrochloric acid and water. The solution was dried with magnesium sulfate and the solvent was removed, and the resulting crude product was distilled. 108 g (55% yield) of methyl 2-cyano-3-methyl-but-2-enoate were isolated (B.p. 95° C./5.2 mbar).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C)C=O.O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2
Reactant: NC(=O)c1ccc2nc3ccsc3c(=O)n2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc3ccsc3c(=O)n2c1
Temperature: 95 °C

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide (1.4 g, 0.006 mol), p-toluenesulfonyl chloride (1.6 g, 0.008 mol), and pyridine (1.4 ml, 0.017 mol) in dimethylformamide (10 ml) is heated at 95° C. for 75 minutes. The mixture is cooled, diluted with water (5 ml) and stirred. The precipitate is filtered, washed with water, with ethanol and dried. Recrystallization from dimethylformamide gives the product (0.8 g.), mp 263°-264° C. (dec).