Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])(=[O:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:12](=[O:14])[CH3:13])[CH:16]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(=O)c1cccc(N)c1
Product: CC(=O)c1cccc(NC(=O)c2cc(Cl)ccc2O)c1
Yield: 80 %

Procedure:
Using 5-chlorosalicylic acid and 3-acetylaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14](OC2N(C3C=CC=CC=3)N=NN=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:28][CH3:29])[C:7]=1[CH2:30][CH2:31][CH2:32][CH3:33])=[O:5])[CH3:2].[H][H]>O1CCCC1.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:28][CH3:29])[C:7]=1[CH2:30][CH2:31][CH2:32][CH3:33])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCCCc1c(C(=O)OCC)cc(Oc2nnnn2-c2ccccc2)c2c(OC)cccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCc1c(C(=O)OCC)ccc2c(OC)cccc12

Procedure:
A solution of 1-butyl-5-methoxy-4-[(1-phenyl-1H-tetrazole-5-yl)oxy]-2-naphthalenecarboxylic acid ethyl ester in a mixture of tetrahydrofuran (25 mL) and ethanol (75 mL) was hydrogenated over 10% palladium on carbon (1.3 g) at 50° C. and three atmospheres. After the uptake of hydrogen had stopped, the catalyst was removed by filtration and the filtrate was concentrated to dryness. The resulting material was dissolved in diethyl ether (150 mL) and the solution extracted with 1N sodium hydroxide (2×50 mL). After the base extracts were backwashed with diethyl ether, the combined organic layers were dried (MgSO4) and evaporated to yield 3.6 g of 1-butyl-5-methoxy-2-naphthalenecarboxylic acid ethyl ester as an oil. A portion was distilled on a Kugelrohr apparatus (140° C.; 0.1 mm) to furnish the analytical sample. Anal. Calcd for C18H22O3 : C, 75.50; H, 7.74 Found: C, 75.02; H, 7.97
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:26]([CH2:25][CH2:24][CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCCCOc1ccccc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCOc3ccccc3)CC1)O2

Procedure:
Compound 144 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (3-bromopropoxy)benzene and conditions outlined in procedure V. LCMS: 436 [M+H]; Rt=1.05 min.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[OH:4][CH2:3][C@H:2]([NH:1][C:12](=[O:11])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2R)-2-amino-2-phenylethanol (400 mg, 2.91 mmol) in CH2Cl2 (15 mL) was added BOC2O (636 mg, 2.91 mmol) and DIPEA (507 μL, 2.91 mmol). The reaction was stirred at room temperature for 18 hours, diluted with EtOAc (75 mL) and washed with H2O, brine, 1N HCl, brine, saturated NaHCO3, and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 50% EtOAc/hexanes afforded tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate. Rf=0.23 (40% EtOAc/hexane). 1H NMR (CDCl3, 600 MHz) δ 7.27-7.37 (m, 5H), 5.27 (bs, 1H), 4.78 (bs, 1H), 3.83 (bs, 2H), 2.46 (bs, 1H), 1.44 (bs, 9H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.S1C=CC=C1CC([NH:21][C@@H:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12)=O.CO>C(Cl)Cl>[NH2:21][C@@H:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([O:33][CH:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.33 h
Yield: 68.8 %

Procedure:
A suspension of phosphorus pentachloride (4.71 g., 22.5 mmole) in methylene dichloride (35 ml.) was warmed uuntil most of the phosphorus pentachloride had dissolved. A solution of pyridine in methylene dichloride (18.2 ml., as a 10% v:v solution, ca22.5 mmole pyridine) was added, and the white suspension was warmed to 23° for 10 minutes, then cooled to 0°. A solution of diphenylmethyl 7β-(2-thienylacetamido)-3-vinylceph-3-em-4-carboxylate (5.16 g., 10 mmole) in methylene dichloride (70 ml.), cooled to 0°, was added and the mixture stirred for 20 minutes. The solution was run into a vigorously stirred mixture of methanol (10 ml.) in methylene dichloride (50 ml.) and the resulting solution washed with aqueous sodium bicarbonate and water, and dried and evaporated in vacuo. The residual gum, in a small volume of chloroform, was run onto a column (7 × 4 cm.) of Kieselgel (0.02 to 0.5 mm.), and the column eluted with chloroform (2 × 100 ml.), then chloroform:ethyl acetate = 1:1 (3 × 100 ml.). The first chloroform fraction and the last chloroform : ethyl acetate fraction were discarded and the other fractions combined and evaporated in vacuo. The residue was triturated with ether to give the amine (2.7 g., 69%) as small needles, m.p 157°-160° (decomp), [α]D - 155.4° (CHCl3), λmax. 296.5 nm. (ε, 12,400), νmax. (CHBr3) 3460 and 3390 (NH), 1780 (β-lactam), 1730 (CO2R) and 910 cm.-1 (CH=CH2), τ (CDCl3) 2.65 (Ph), 3.02 (CH Ph2), 33.09 (CH=CH2, dd, J 11 and 18 Hz.), 4.64 and 4.82 (CH=CH2, two d, J 18 and 11 Hz. resp.), 5.09 (C(7) -H, d, J 5 Hz.), 5.32 (C(6) -H, d, J 5 Hz.), 6.35 (C(2) -CH2, AB-q J 18 Hz), and 8.21 (NH2); (DMSO-d6) 2.60 (Ph), 3.03 (CH Ph2), 3.28 (CH = CH2, dd J 11 and 17 Hz.), 4.40 and 4.76 (CH=CH2, two d, J 17 and 11 Hz. resp.), 4.91 (C(7) -H, d, J 5 Hz.), 5.12 (C(6) -H, d, J 5 Hz), 6.09 and 6.45 (C(2) -CH2, AB-q J 18 Hz.) and 7.62 (NH2) (Found: C, 66.2; H, 5.1; N, 6.8; S, 8.1. C22H20N2O3S requires C, 67..3; , H, 5.15; N, 7.15; S, 8.2%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]([S:22]([NH:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[C:27]=2[CH3:32])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.C(N(CC)CC)C.ON1C2N=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[CH3:31][C:28]1[C:27]([CH3:32])=[C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][CH:13]=[CH:14][N:15]=3)=[CH:10][C:5]=2[CH2:4][N:3]([CH3:2])[C:38](=[O:40])[C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:42][CH:41]=2)(=[O:24])=[O:23])[O:30][N:29]=1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(O)c1ccc(F)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide, monohydrochloride (100 mg, 0.21 mmol, prepared as described in Step (A) of Example 28) and 4-fluorobenzoic acid (29.5 mg, 0.21 mmol) in 0.3 ml of CH2Cl2, triethylamine (43 mg, 0.42 mmol) and 1-hydroxy-7-azabenzotriazole (31.6 mg, 0.23 mmol) were added and followed by 1,3-diisopropylcarbodiimide (29.3 mg, 0.23 mmol). The reaction was stirred at room temperature for 3 hrs and concentrated. The residue was purified by preparative HPLC on an ODS S10 O column using 31% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 69% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (60 mg, 51%) as a white solid, m.p. 125°-135° C. (amorphous).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[C:7]([CH3:13])[CH:6]=1)(=[O:3])[CH3:2].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:13])[C:8]([Br:12])=[C:9]([CH2:11][Br:14])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cc(C)c(Br)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(C)c(Br)c(CBr)c1
Temperature: 75 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
A suspension of 4-bromo-3,5-dimethylphenyl acetate (12.1 g, 49.8 mmol), N-bromosuccinimide (9.79 g, 55.0 mmol) and 2,2′-azobisisobutyronitrile (82.1 mg, 0.500 mmol) in carbon tetrachloride (100 mL) was stirred at 75° C. for 5 hr under nitrogen atmosphere. The reaction mixture was ice-cooled, and concentrated under reduced pressure. The residue was diluted with diethyl ether, the insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was-purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75) to give the title compound (11.7 g, yield 73%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:18][S:19]([O:9][CH2:8][CH:6]1[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]1)(=[O:21])=[O:20]
Reactant: CC1(C)CC(CO)CCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(COS(C)(=O)=O)CCO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)methanol (2.54 g) was dissolved in dry DCM (40 mL) and triethylamine (4.9 mL) was added with stirring. The solution was cooled (ice bath) under nitrogen and methanesulphonyl chloride (1.77 mL) was added dropwise over 5 mins. The mixture was allowed to warm slowly to room temperature as the ice bath melted and was left for 16 h. The mixture was shaken with saturated sodium bicarbonate solution and the aqueous layer was extracted with DCM (×2). The combined organics were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound (3.93 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[N:14]1([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C1CCCNCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(N2CCCCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 41.9 %

Procedure:
3 g (14.7 mmol) of 2-chloro-3,5-dinitropyridine, 10 ml of THF and 30 mmol of azepane were placed in a round-bottomed flask. The mixture was maintained at 60° C. for 15 hours with stirring and was then poured into an ice-water mixture with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 1.64 g of yellow powder were obtained.
Reaction SMILES: O([C@:3]12[CH2:20][C@@H:19](O)[CH2:18][CH2:17][C@:16]1([CH3:22])[C@@H:15]1[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C:10](=[O:23])[CH2:9][CH2:8]3)[CH:5]=[CH:4]2)O.[CH2:24](O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)C1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:24][C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C@@H:3]([CH2:4][CH2:5][C@@H:6]3[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:23])[CH2:20]1
Reactant: [H][H]
Reactant: C[C@]12CC[C@H](OCc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CC[C@H]3[C@@H](C=C[C@@]4(OO)C[C@@H](O)CC[C@]34C)[C@@H]1CCC2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 80 %

Procedure:
Firstly an example of catalytic hydrogenation for the synthesis of 5α-androstanes from androst-5-enes is the synthesis of 3β-methyl-5α-androstan-17-one 2 from 3β-methylandrost-5-en-17-one 1. 3β-Methylandrost-5-en-17-one 1 (400 mg), prepared as described previously was dissolved in glacial acetic acid (80 ml). Palladium on carbon (10%, 100 mg) was added and the solution maintained under an atmosphere of hydrogen. When hydrogen uptake ceased, the solution was filtered through celite and evaporated to give solid which was recrystallized from methanol to yield 3β-methyl-5α-androstan-17-one, 2, (320 mg, 80% yield). MP 107°-108° C., 1H NMR (CDCl3) δ0.86 (d, 3H, J-5Hz, methyl at C-3), 0.85 (s, 3H, C-19 Me), 0.79 (s, 3H, C-18 Me).
Reaction SMILES: C(O[BH-](O[C:11](=O)[CH3:12])OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[CH3:24][C:25]([CH3:27])=O.[OH-].[Na+]>C1COCC1.O.C(O)(=O)C>[CH:25]([N:20]([C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([O:16][CH3:15])[CH:18]=1)[C:12]1[CH:11]=[CH:22][CH:23]=[CH:17][CH:18]=1)([CH3:27])[CH3:24]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)=O
Reactant: COc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cccc(N(c2ccccc2)C(C)C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 133.1 %

Procedure:
Sodium triacetoxyborohydride (27.9 g, 134 mmol) is added portion wise over 45 minutes to a 0° C. solution of 3-methoxyaniline (12.5 g, 101 mmol) in THF (100 mL), acetone (7.82 mL, 106 mmol) and acetic acid (5.9 mL) and the resultant mixture is allowed to attain RT overnight. The reaction mixture is cooled to 0° C. and then water (50 mL) is added slowly followed by 50% aqueous sodium hydroxide solution (20 mL) and the resultant mixture stirred for 1.5 h. The organics were removed and the residual aqueous phase diluted with water (30 mL) and extracted into ethyl acetate (3×50 mL). The combined organics were washed with water (2×100 mL), brine (50 mL), dried (MgSO4), and concentrated in vacuo to afford N-Isopropyl-N-(3-methoxy-phenyl) aniline (16.22 g) as a brown oil which is used without further purification: 1H NMR (300 MHz, CDCl3) δ7.13 (t, 1H, J=8.0), 7.01 (dt, 2H, J=9.7, 1.9), 6.19 (s, 1H), 3.80 (s, 3H), 3.62 (m, 1H, J=6.8), 1.06 (d, 6H, J=6.8).
Reaction SMILES: C(OC([C:6]1([CH:14]=[O:15])[S:13][C:12]2[CH:11]=[CH:10][NH:9][C:8]=2[CH2:7]1)=O)C.[O-]S([O-])(=O)=O.[Mg+2].[C:22]([O:25]CC)(=[O:24])C>>[CH:14]([C:6]1[S:13][C:12]2[CH:11]=[C:10]([C:22]([OH:25])=[O:24])[NH:9][C:8]=2[CH:7]=1)=[O:15]
Reactant: CCOC(=O)C1(C=O)Cc2[nH]ccc2S1
Reactant: CCOC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: O=Cc1cc2[nH]c(C(=O)O)cc2s1

Procedure:
2-Formyl-4H-thieno[3,2-b]pyrrole-carboxylic acid ethyl ester (see, for example, Gale, W. W. et al., J. Org. Chem., 29: 2160-2165 (1964)) was hydrolyzed according to Procedure F (50° C. overnight; acidified aqueous phase extracted with ethyl acetate; combined organic phases dried over MgSO4, concentrated).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]2.CN1CCOCC1.[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:27]=[C:23]1[CH2:22][CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:26]=[CH:25][C:24]1=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
Trifluoro-methanesulfonic anhydride (14.35 mL, 77.3 mmol) was added to a CH2Cl2 (150 mL) solution of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (11.40 g, 70.3 mmol), N-methylmorpholine (8.5 mL, 77.3 mmol) and DMAP (130 mg, 1 mmol) in 5 min at −80° C. The mixture was warmed to 0° C. in 1 h then poured into a cold solution of saturated NH4Cl. The mixture was diluted with CH2Cl2 (400 mL), washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo to provide the crude compound which was purified by column chromatography (silica, 0 to 60% CH2Cl2 in hexane) to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1
Product: COC(=O)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1

Procedure:
Compound (3) was esterified with methyl alcohol to provide (4).
Reaction SMILES: Cl[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:3]([C:9]([O:11]CC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH:29][CH3:30])=[CH:24][CH:23]=1)#[N:21]>C1(C)C=CC=CC=1>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:9](=[O:11])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:29]2[CH3:30])=[CH:26][CH:27]=1)#[N:21]
Reactant: CNNc1ccc(C#N)cc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Yield: 26.2 %

Procedure:
4.7 g of the title compound was prepared as colorless crystals from 14.6 g of ethyl 3-chloro-2-ethoxycarbonyl-3-phenyl-acrylate, 11.0 g of 1-(4-cyanophenyl)-2-methyl-hydrazine and toluene in the same manner as in Reference Example 5.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([F:27])[CH:17]=1)[C:10]([CH3:29])([CH3:28])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:27][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:28])([CH3:29])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N3CCCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A mixture of 2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.18 g, 0.45 mmol), lithium hydroxide hydrate (0.19 g, 4.5 mmol), water (1 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 60%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C22H25FN2O2 (M+H)+: 369.5, observed: 369.2.
Reaction SMILES: [CH:1]([O-:6])([O-])[O:2][CH2:3][CH3:4].[F:7][C:8]1[CH:21]=[C:20]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)[C:19]([F:27])=[CH:18][C:9]=1[C:10]([CH2:12][C:13](OCC)=O)=[O:11].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C(OC(=O)C)(=O)C>[CH:28]1([NH:31][CH:13]=[C:12]([C:10](=[O:11])[C:9]2[CH:18]=[C:19]([F:27])[C:20]([N:22]3[CH:23]=[CH:24][CH:25]=[CH:26]3)=[CH:21][C:8]=2[F:7])[C:1]([O:2][CH2:3][CH3:4])=[O:6])[CH2:30][CH2:29]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(-n2cccc2)cc1F
Reactant: CCOC([O-])[O-]
Reactant: NC1CC1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(-n2cccc2)cc1F
Reaction time: 1 h
Yield: 36.1 %

Procedure:
1 g (0.0068 mol) of ethyl orthoformate is added to a solution of 1.1 g (0.00315 mol) of ethyl 2,5-difluoro-4-(pyrrol-1-yl)benzoylacetate in 3 ml of acetic anhydride and the mixture is refluxed for 3 hours. It is evaporated to dryness, the residue is dissolved in 10 ml of ethanol, 0.3 ml (0.0034 mol) of cyclopropylamine is added and the mixture is left at room temperature for 1 hour. It is evaporated to dryness and the oily residue is extracted with 3×30 ml of boiling hexane. The hexane fractions are concentrated to 20 ml and left for 12 hours at 5° C. to give 0.41 g of crystals melting at 90°-2° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1I.N.[CH3:16][N:17]1CCCC1=O>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Cc1cc(-n2cncn2)cc(I)c1N
Reactant: CN1CCCC1=O
Agent: N
Product: Cc1cc(-n2cncn2)cc(C#N)c1N

Procedure:
A mixture of 1-(4-amino-3-iodo-5-methyl-phenyl)-1,2,4-triazole (14.23 g) and cuprous cyanide (5.94 g) was heated at 120° in N-methylpyrrolidone (32 cm3) for 2.5 hours. The cooled mixture was poured into ammonia solution (100 cm3 ; S.G. 0.880) and the resulting solution was extracted with chloroform:methanol, 19:1 (3×150 cm3). The combined and dried (MgSO4) organic extracts were filtered and evaporated in vacuo (0.5 mm) to afford an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:methanol, 19:1. Combination and evaporation of appropriate fractions gave an oil which crystallised on trituration with ether to give the title compound, m.p. 231°-3° (2.8 g).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:18]([NH2:20])=O)[C:12](=[CH:16][CH:17]=1)[C:13]([NH2:15])=O)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].P(Cl)(Cl)(Cl)=O.Cl>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:18]#[N:20])[C:12](=[CH:16][CH:17]=1)[C:13]#[N:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(C(N)=O)c(C(N)=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(=O)Nc1ccc(C#N)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a suspension of 7.0 g (25.1 mmol) 4-ethoxalylaminophthalamide in 75 ml dry pyridine was gradually added 4.1 ml (44.8 mmol) phosphorus oxychloride. Stirring was continued at 25° C. for 30 min. The reaction mixture was poured into 300 ml ice-cooled 4N hydrochloric acid to give 4.7 g (77%) of 4-ethoxalylaminopthalonitrile. M.p. 193.7° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:12][C:13]([C:15]1[S:37][C:18]2[N:19]=[C:20]([S:35][CH3:36])[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][S:30]([CH:33]=[CH2:34])(=[O:32])=[O:31])[CH:24]=3)[C:17]=2[C:16]=1[NH2:38])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([NH:12][C:13]([C:15]1[S:37][C:18]2[N:19]=[C:20]([S:35][CH3:36])[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][S:30]([CH2:33][CH2:34][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)(=[O:31])=[O:32])[CH:24]=3)[C:17]=2[C:16]=1[NH2:38])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CN1CCNCC1
Reactant: C=CS(=O)(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Product: CSc1nc(-c2cccc(NS(=O)(=O)CCN3CCN(C)CC3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
Reaction of N-methyl piperazine (184 μl) with tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 10, 87 mg) was performed according to the method described in example 11. The title compound was first purified by chromatography on silica gel with hept/EtOAc=3/2 (v/v) as eluent and then by HPLC using a Luna C-18 column with the following gradient: CH3CN/0.1% aq. TFA=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and 0.1% aq TFA.