Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:10]2[CH2:11][CH2:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:14][C:9]2=[CH:8][C:7]1=[O:19])=[O:5])[CH3:2].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>COCCOC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O.O>[CH2:1]([O:3][C:4]([CH:6]1[N:10]2[C:11]([CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[F:20])=[CH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:14][C:9]2=[CH:8][C:7]1=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)C=C2N=C(C(C)(C)C)CCN21
Reactant: Fc1ccccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C1C(=O)C=C2N=C(C(C)(C)C)C=C(Cc3ccccc3F)N21
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
To 6-ethoxycarbonyl-2-(tert-butyl)-4H-pyrrolo[1,2-a]pyrimid-7-one (0.5 g, 1.9 mmol.) in DME (5 ml), tetrabutylammonium fluoride (4 ml, 4.0M in THF) was added, and a white foamy material formed. 2-Fluorobenzyl bromide (0.38 ml, 3 mmol.) was added and the mixture was stirred at room temperature for 2 days. Concentration of the reaction mixture in vacuo produced an oil, which was dissolved in acetone (20 ml) and diluted with water until the solution turned a slight cloudy. Partially concentration to remove acetone by nitrogen flow resulting precipitation. The precipitates were collected by filtration and washed with water (20 ml×2), ether (20 ml×3) and dried. The desired product (0.57 g) was obtained with excellent purity; MS: 371 (M+H)+, 325; NMR (CDCl3, δ): 8.29 (1H, s), 7.43-7.14(5H, 2m), 5.99 (1H, s) 5.18 (2H,s ), 4.35 (2H, q), 1.37(3H, s), 1.26 (9H, s).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:3]3[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:14][CH2:15]1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: C1COCCN1
Product: Clc1ccc2ncnc(N3CCOCC3)c2n1
Yield: 71 %

Procedure:
The title compound was synthesized in 71% yield from 4,6-dichloro-pyrido[3,2-d]pyrimidine and morpholine by the procedure of example 65, and was characterized by its mass spectrum as follows: MS (m/z): 251.1 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.C(O)(=O)C(O)=O.[OH:33][CH2:34][CH:35]([CH3:39])[CH2:36][CH2:37][NH2:38].C(N(CC)CC)C>C(O)CC>[OH:33][CH2:34][CH:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: CC(CO)CCN
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Clc1ncnc2nc[nH]c12
Agent: O=C(O)C(=O)O
Solvent: CCCO
Solvent: CCN(CC)CC
Product: CC(CO)CCNc1ncnc2c1ncn2C1CCCCO1
Yield: 75 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (2318 mg) 4-hydroxy-3-methylbutylamine oxalate, and 5 mL of triethylamine was refluxed in n-propanol for 3 hours and subsequently 24 hrs at laboratory temperature. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and partitioned into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of hexane. The solid residue was filtered off and the crude product crystallized from methanol. Yield 75%, white solid. TLC (CHCl3:methanol (4:1) (v:v): single spot; HPLC: purity>98%. 1H-NMR (400 MHz, DMSO): 0.88d (3H, J=6.6 Hz); 1.34m (1H); 1.56m (3H); 1.70m (1H); 1.71m (1H); 1.93m (2H); 1.94m (1H); 2.26m (1H); 3.25m (1H); 3.52bs (2H); 3.67m (1H); 4.0d (1H, J=11.3 Hz); 4.42t (1H, J=5.1 Hz); 5.61d (1H, J=10.6 Hz); 7.70bs (1H); 8.20s (1H); 8.30s (1H). MS (ES): [M+H]+=306 (100).
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].CC[O-].[Na+].[CH3:9][CH:10]1[CH:14]([C:15](OC)=[O:16])[C:13](=O)[CH2:12][S:11]1>C(O)C>[CH3:9][CH:10]1[C:14]2[C:15]([OH:16])=[N:4][CH:2]=[N:3][C:13]=2[CH2:12][S:11]1
Reactant: COC(=O)C1C(=O)CSC1C
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1SCc2ncnc(O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a solution of formamidine HCl salt (37.3 g, 463 mmol) in ethanol (300 mL) was slowly added NaOEt (21%, 169 mL, 453 mmol). The mixture was stirred at room temperature for 1 hour and then filtered. To the filtrate was added methyl 2-methyl-4-oxo-tetrahydrothiophene-3-carboxylate (79 g, 453 mmol). The mixture was stirred at room temperature for 1 hour and then refluxed overnight. After cooling, the solvent was removed and the residue was purified by silica gel chromatography, eluted with Hexane/ethyl acetate (2:1-0:1)-DCM/MeOH (20:1) to afford 5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-ol (36 g, 47%). 1H NMR (CDCl3, 400 MHz) δ 12.83 (s, 1H), 4.68 (m, 1H), 4.32-4.08 (m, 2H), 1.66 (m, 3H). MS (APCI+) [M+H]+ 169.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O.[CH2:16](O)[CH3:17]>>[ClH:14].[CH2:16]([O:8][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH2:1])=[CH:11][CH:10]=1)[CH3:17]
Reactant: CCO
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(CN)cc1
Product: Cl
Temperature: 25 °C

Procedure:
20.0 g (132 mM) of 4-aminomethylbenzoic acid are suspended in 200 ml ethanol (EtOH) abs. and cooled with ice. 28.0 g (17 ml) (236 mM) thionylchloride are added drop by drop. The clear mixture is then refluxed for 3 hours. After cooling to room temperature, EtOH is evaporated. 50 ml of toluene/EtOH 1/1 are added and evaporated three times. The residue is dried to get 27 g of (1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][C@H:21]([C:24]([O:26]C)=[O:25])[CH2:22][OH:23])=[O:19])=[C:5]2[OH:28].[OH-].[Na+].O>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][C@H:21]([C:24]([OH:26])=[O:25])[CH2:22][OH:23])=[O:19])=[C:5]2[OH:28]
Reactant: COC(=O)[C@H](CO)NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@@H](CO)C(=O)O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
Methyl N-((6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)-L-serinate (180 mg, 439 μmol) was dissolved in THF (4392 μL). NaOH in water (4392 μL, 21961 μmol) was added, and the reaction was stirred at ambient temperature for 3 hours. The pH was adjusted to about 3, and the resulting mixture was diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 20 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (95 mg) after it was precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven. MS m/e=396 (M+H)+. Calculated for C18H18NO7 395.08.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[CH:13]=1)=[O:11].Br[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[CH:25]=[N:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[CH:13]=1)=[O:11]
Reactant: Cc1cc(C(=O)Nc2cc(O)ccc2F)n(C)n1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.9 %

Procedure:
A mixture of N-(2-fluoro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (9.80 g, 39.3 mmol), 5-bromo-2-nitropyridine (7.14 g, 35.1 mmol), cesium carbonate (14.8 g, 45.3 mmol) and N,N-dimethylformamide (80 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=90/10→0/100) to give N-{2-fluoro-5-[(6-nitropyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (7.68 g, 59%) as a white solid. To a solution of N-{2-fluoro-5-[(6-nitropyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (7.68 g, 20.7 mmol) thus-obtained in methanol (50 mL) was added palladium carbon (50% water-containing product, 700 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (6.20 g, 88%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[OH-].[Li+].[C:26](OC(=O)C)(=[O:28])[CH3:27]>O>[C:26]([NH:21][S:20]([C:11]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:23])=[O:22])(=[O:28])[CH3:27]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1

Procedure:
3-Nitro-4-phenoxy-5-sulphamyl-benzoic acid (10 g) was dissolved in water (250 ml) by adjusting the pH to 8 by addition of 1N lithium hydroxide. Then acetic anhydride (12 g) was added dropwise, while stirring and keeping the pH constant at pH 9 by means of 1N lithium hydroxide, using an automatic titrator. After the acetic anhydride was consumed, the reaction mixture was acidified by addition of 4N hydrochloric acid. The precipitated 5-acetylsulphamyl-3-nitro-4-phenoxy-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. The compound with a melting point of 270°-271° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3][CH:2]=1.[Si]([C:13]#[N:14])(C)(C)C.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CC([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[O:18]1[CH2:19][CH2:20][N:15]([CH:7]([C:5]2[CH:4]=[N:3][CH:2]=[N:1][CH:6]=2)[C:13]#[N:14])[CH2:16][CH2:17]1
Reactant: O=Cc1cncnc1
Reactant: C[Si](C)(C)C#N
Reactant: C1COCCN1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC(c1cncnc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a mixture of pyrimidine-5-carbaldehyde (2 g, 18.52 mmol) and TMSCN (3.67 g, 37.0 mmol) in HOAc (50 mL) was added morpholine (2.42 g, 27.8 mmol) at room temperature and NaOAc (3.34 g, 40.7 mmol) was followed. The resulting mixture was stirred at room temperature overnight. Saturated aqueous Na2CO3 solution was added to quench the reaction mixture, the pH was adjusted to about 7 and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude 2-morpholino-2-(pyrimidin-5-yl)acetonitrile (2.5 g, yield: 66%). 1H NMR (CDCl3 400 MHz): δ9.25 (s, 1H), 8.92 (d, J=10.0 Hz, 2H), 4.87 (s, 1H), 3.79-3.70 (m, 4H), 2.67-2.56 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([OH:15])=O)=[N:3]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:4]2[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:2]([CH3:1])[N:3]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cn1nc(C(=O)O)cc1-c1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
1-Methyl-5-phenylpyrazole-3-carboxylic acid (2.1 g), 5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (3.4 g) and diethyl cyanophosphate (2.7 g) were added to dimethylformamide (25 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (3.1 g), melting point: 156–157° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)[N:3]=[CH:4][C:5]=2[C:18]2[CH:19]=[N:14][CH:15]=[N:16][CH:17]=2)[N:10]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: OB(O)c1cncnc1
Product: Cc1ccc2c(-c3cncnc3)cnc(Nc3nc(C(F)(F)F)cs3)c2n1

Procedure:
The title compound, MS: m/e=389.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 5-pyrimidineboronic acid and 2-amino-4-(trifluoromethyl)thiazole.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[CH:27]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][CH:24]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH:39][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][C@@H:24]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(COc2ccccc2)OCC1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](COc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
Add triethylamine (0.009 mL, 0.066 mmol) and acetic anhydride (0.004 mL, 0.044 mmol) to a solution of (2R,5R)-(5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-phenoxymethyl-morpholine-4-carboxylic acid tert-butyl ester (0.021 g, 0.044 mmol) in tetrahydrofuran (0.44 mL) and stir at room temperature for 1 hour. Concentrate and purify (silica gel chromatography, eluting with 50:50 to 60:40 ethyl acetate:hexanes) to give the title compound as a white foam (0.010 g, 45.5%).
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:15])[C@H:11]\1[CH2:10][CH2:9][C@@H:8]2[C@H:12](O)[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC(N=NC(OC)=O)=O>O1CCCC1>[Br:1]/[CH:2]=[C:3]1/[C@H:11]2[C@:7]([CH3:15])([CH2:6][CH2:5][CH2:4]/1)/[C:8](=[CH:12]\[CH3:13])/[CH2:9][CH2:10]2
Reactant: C[C@@H](O)[C@H]1CC[C@H]2/C(=C/Br)CCC[C@]12C
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C/C=C1/CC[C@H]2/C(=C/Br)CCC[C@]12C
Temperature: 25 °C
Reaction time: 40 h
Yield: 69 %

Procedure:
Under a nitrogen atmosphere, a solution of (R)-1-{(E,3S,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-1H-indene-3-yl}ethanol (Compound 19: 20.8 mg, 0.07613 mmol) and triphenylphosphine (50 mg, 0.1903 mmol) in tetrahydrofuran (0.35 ml) was cooled in an ice bath, and azodicarboxylic acid dimethyl ester (2.7 M in toluene, 73.3 μl, 0.1979 mmol) was added dropwise thereto. The reaction mixture was stirred at the same temperature for 5 minutes and at room temperature for 40 hours, and then evaporated under reduced pressure. The obtained crude product was purified by flash column chromatography to obtain (1Z,3aR,4E,7aS)-4-(bromomethylene)-1-ethylidene-octahydro-7a-methyl-1H-indene (13.4 mg, 69.1%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18]C(=O)C1C=CC=CC=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.[OH-].[Na+]>O1CCOCC1.CO>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:32][C:31]1[CH:33]=[CH:34][C:28]([F:27])=[CH:29][C:30]=1[CH3:35])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][OH:18])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl
Reactant: Cc1cc(F)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1Nc1c(C(=O)C(C)C)cnc2c(CO)cccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-isobutyryl-4-chloro-8-benzoyloxymethylquinoline (1.84 g, 5 mmol) and 4-fluoro-2-methylaniline (0.78 ml, 7 mmol) in dioxan (25 ml) was heated at reflux for 2 hours, then the solvent evaporated. A solution of sodium hydroxide (0.8 g, 20 mmol) in methanol (50 ml) was added and the mixture stirred at room temperature for 1.5 hours. The resulting precipitate was filtered off and recrystallized from methanol to give (0.48 g, 27%), m.p. 139°-140°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=C1.S(Cl)(Cl)=O.[CH3:10][C:11]1[S:12][C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1NCC#N>O1CCCC1>[CH3:10][C:11]1[S:12][C:13]([C:17]([NH:3][CH:4]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[C:5]#[N:1])=[O:19])=[C:14]([CH3:16])[N:15]=1
Reactant: c1c[nH]cn1
Reactant: N#CCNc1cccs1
Reactant: Cc1nc(C)c(C(=O)O)s1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)NC(C#N)c2cccs2)s1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of imidazole (2.27 g; 40 mmol) in dry tetrahydrofuran (60 ml) was added dropwise thionyl chloride (1.20 g; 10 mmol) under ice-cooling while stirring. After the resultant mixture was turned to room temperature, 2,4-dimethyl-5-thiazolecarboxylic acid (1.57 g; 10 mmol) was added thereto at once, and stirring was continued for 30 minutes. To the mixture was added dropwise a solution of 2-(2-thienyl)aminoacetonitrile (1.65 g; 12 mmol) in dry tetrahydrofuran under ice-cooling, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, tetrahydrofuran was removed under reduced pressure to separate the residue. Water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude oil. The oil was purified by silica-gel column chromatography (eluent:n-hexane:ethyl acetate=2:1 volume) to give crude crystals. Recrystallization from n-hexane/ethyl acetate gave 1.80 g of 2-(2,4-dimethylthiazole-5-carboxamido)-2-(2-thienyl)acetonitrile as colorless crystals. m.p., 127.5°-128.5° C. Yield, 65%.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.C(OCC)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[O:20]1[CH:8]2[CH:7]1[CH2:6][C:5]1[CH:4]=[CH:3][CH:2]=[C:1]([OH:11])[C:10]=1[CH2:9]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Oc1cccc2c1CC=CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Oc1cccc2c1CC1OC1C2

Procedure:
prepared as described hereinbefore, by mixing a cooled solution (temperature less than about 30°C.) of 5,8-dihydro-1-naphthol in ethyl acetate with m-chloroperbenzoic acid and mixing the resulting slurry with a mixture of ethyl ether and aqueous sodium bicarbonate, to form 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol ##SPC33##
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]([C:11](O)=O)=[N:8][NH:9][CH:10]=1.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1.C(Cl)CCl.C1C=CC2N([OH:41])N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:19][C:20]1[N:25]=[CH:24][C:23]2[N:26]=[C:11]([C:7]3[C:6]([NH:5][C:4](=[O:41])[C:3]4[C:2]([F:1])=[CH:17][CH:16]=[CH:15][C:14]=4[F:18])=[CH:10][NH:9][N:8]=3)[NH:27][C:22]=2[CH:21]=1
Reactant: Nc1cnc(Cl)cc1N
Reactant: O=C(O)c1n[nH]cc1NCc1c(F)cccc1F
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]nc1-c1nc2cnc(Cl)cc2[nH]1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.5 %

Procedure:
A mixture of 4-(2,6-difluorobenzylamino)-1H-pyrazole-3-carboxylic acid (100 mg, 0.37 mmol) (Example 16D), 6-chloro-pyridine-3,4-diamine (54 mg, 0.37 mmol), EDC (72 mg, 0.40 mmol), HOBt (57.3 mg, 0.40 mmol) and Et3N (0.075 ml, 0.55 mmol) in DMF (20 ml) was stirred at ambient temperature for 48 h and then partitioned between EtOAc and saturated aqueous sodium bicarbonate and the organic portion dried (MgSO4), filtered and evaporated. The amide intermediate was dissolved in AcOH (3 ml), heated at reflux for 1 h, and then heated in the microwave (150 W) at 160° C. until the reaction was complete. The reaction mixture was allowed to cool, a solid crystallised out, which was filtered and then washed with petroleum ether and dried to give the required product (9 mg). (LC/MS: Rt 2.74, [M+H]+ 375)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[H-].[Na+].CI.[C:19]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:19][NH:6][C:5]1[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C([O-])O
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-nitro-4-trifluoromethylaniline (200 mmol, 41.2 g) in DMF (200 mL) cooled to 0° C. was added portionwise NaH (210 mmol, 8.4 g of a 60% suspension in mineral oil) (exothermic, gas evolution). The reaction was allowed to reach ambient temperature for 45 min, then cooled back to 0° C. MeI (220 mmol, 13.7 mL) was added via syringe (exothermic) and the resulting slurry was stirred for 2 h. The reaction mixture was poured into a 1:1 mixture of saturated NaHCO3 and brine (1 L) to provide the product as a bright orange precipitate, which was filtered, washed with water and dried in vacuo. 1H NMR (500 MHz, CDCl3), δ (ppm): 8.52 (d, J=1.2 Hz, 1H), 8.31 (br s, 1H), 7.70 (d, J=8.9 Hz, 1H), 6.98 (d, J=9.2 Hz, 1H), 3.13 (d, J=5.3 Hz, 3H). LC-MS (ESI, Method C): 3.34 min, m/z 221.1 (M+1).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]1[S:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]#[N:14].N>>[NH2:6][C:7]1[S:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]([NH2:14])=[O:2]
Reactant: Cc1nsc(N)c1C#N
Reactant: O=S(=O)(O)O
Agent: N
Product: Cc1nsc(N)c1C(N)=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a chilled solution of sulfuric acid (7.2 volumes, 12.9 equivs) was charged 5-amino-3-methylisothiazole-4-carbonitrile (method 4) (1.0 equiv). The temperature was maintained below 55° C. The reaction mixture was heated to 70° C. and held for 1 hour until TLC showed disappearance of starting material. The mixture was cooled to 60-65° C. before the ammonia (21 volumes) was charged to pH 10. The mixture was cooled to 20° C., aged overnight and filtered. The resulting solid was washed with dilute ammonia (3.6 volumes) and dried at 40° C. to give a pale brown solid (typical yield 80%).1H NMR (300 MHz, DMSO-d6) δ 2.46(s, 3H), 6.28 (s, 1H).