Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[N+:16]([O-])([OH:18])=[O:17].O.[K+].[Br-]>C(O)(=O)C>[OH:1][C:2]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(=O)OC)c(O)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 88 %

Procedure:
Into a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, a condenser, and nitrogen inlet, dimethyl 4-hydroxyisophthalate (15.0 g, 71.4 mmol) was dissolved in acetic acid (150 mL). Nitric acid (10 ml) was then added dropwise. The mixture was warmed at 60° C. for 12 h. Then, the cool mixture was poured into water. The light yellow precipitate was collected, air-dried and recrystallized from ethanol to give 16.0 g (88% yield) of light yellow crystals: mp=74-76° C. Anal. Calcd. for C10H9NO7: C, 47.07%; H, 3.55%; N, 5.49%; O, 43.89%. Found: C, 47.75%; H, 4.01%; N, 5.44%; O, 43.51%: FT-IR (KBr, cm−1): 3076, 2992, 1722, 1690. Mass spectrum (m/e): 255 (M+, 100% relative abundance), 241, 237. 1H-NMR (DMSO-d6, ppm) δ 3.89 (s, 3H, CH3), 3.97 (s, 3H, CH3), 8.46-8.47 (d, 1H, Ar), 8.55-8.56 (d, 1H, Ar). 13C-NMR (CDCl3, ppm) δ 52.72, 53.38, 117.60, 120.19, 130.61, 135.31, 138.50, 156.13, 163.70, 166.87.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[P:6]([O:13]CC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>C(Cl)(Cl)Cl>[CH2:2]([P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:3][CH:4]=[CH2:5]
Reactant: CCOP(OCC)OCC
Reactant: C=CCCBr
Solvent: ClC(Cl)Cl
Product: C=CCCP(=O)(OCC)OCC
Temperature: 25 °C

Procedure:
1-bromo-3-butene (39.0 mmol) and triethyl phosphite (1 g, 6 mmol) were dissolved and reacted in CHCl3 (30 mL). Then, the reaction solution was refluxed for 12 hours, cooled to room temperature and filtered through a glass filter. Chloroform (CHCl3) was completely removed from the solution under vacuum to thereby give an oily compound as the title compound. The 1H NMR results of the compound thus obtained are given as follows.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([F:14])[CH:6]=1)=[O:4].[CH3:15][CH2:16][N:17](C(C)C)[CH:18](C)C.CNCCO>ClCCl.O>[F:14][C:7]1[CH:6]=[C:5]([CH:3]2[O:4][CH2:15][CH2:16][N:17]([CH3:18])[CH2:2]2)[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNCCO
Solvent: O
Solvent: ClCCl
Product: CN1CCOC(c2ccc([N+](=O)[O-])c(F)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-bromo-1-(3-fluoro-4-nitrophenyl)ethan-1-one E-1.17′″ (2.00 g; 7.63 mmol) is dissolved in dichloromethane (20 ml). DIPEA (1.4 ml; 8.00 mmol) and N-methyl ethanolamine (0.60 ml; 7.63 mmol) are added. The reaction mixture is stirred at 25° C. overnight. The reaction mixture is diluted with dichloromethane and water is added. The organic layer is separated and is dried with sodium sulfate and the solvent is removed under reduced pressure. The crude intermediate is dissolved in TFA (20 ml) and triethyl silane (8 mL) is added at 25° C. and then the reaction mixture is refluxed for 16 h. The reaction mixture is diluted with dichloromethane and the mixture is basified with saturated sodium hydrogencarbonate solution. The organic layer is separated and is dried with sodium sulfate and the solvent is removed under reduced pressure. The crude product is purified using normal phase chromatography (dichloromethane/methanol: 99:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:19].C(OC(=O)C)(=O)C.[CH3:27][C:28]1[S:29][CH:30]=[C:31]([CH:33]=O)[N:32]=1>O.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:19]=[CH:33][C:31]1[N:32]=[C:28]([CH3:27])[S:29][CH:30]=1
Reactant: Cc1nc(C=O)cs1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C=Cc2nc3ccccc3c(=O)n2-c2ccccc2Cl)cs1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
Anhydrous zinc chloride (0.136 g, 1.0 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (10 mL) was then added. To this mixture was added 3-(2-chloro-phenyl)-2-methyl-3H-quinazolin-4-one (0.135 g, 0.50 mmol), acetic anhydride (0.141 mL, 1.5 mmol), and 2-methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol). The reaction was refluxed for 3 hours, and was then allowed to cool to ambient temperature. Once the reaction had cooled to abient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The combined chloroform layers were washed with water and brine, dried over sodium sulfate and then concentrated to yield a waxy tan solid. This residue was triturated with ether, filtered and dried to afford 0.139 g (73%) of 3-(2-chloro-phenyl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[N:7]=1
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: NC(CO)CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Yield: 41.3 %

Procedure:
A solution of 4-Chloro-2-methylsulfinyl-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.90 g, 2.53 mmol) in dichloromethane (90 mL) was mixed with a solution of serinol (0.24 g, 2.66 mmol) in DMF (2.0 mL). The resultant mixture was stirred at room temperature for 1 hour before concentrated under vacuum. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (0.40 g, 42%): MS (ES) m/z 383 (M+H)+; 1H-NMR(CDCl3) δ 1.95 (s, br, 2H), 3.90 (m, br, 5H), 6.05 (m, br, 1H), 6.56 (d, J=9.6 Hz, 1H), 7.10 (m, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.94 (d, J=9.6 Hz, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27][CH2:28][CH2:29]CCC.C(Br)C=C>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:29][CH:28]=[CH2:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2csc3ccccc23)C1
Reactant: CCCCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCn1cc(C2=CCN(CCc3csc4ccccc34)CC2)c2ccccc21
Reaction time: 5.5 h

Procedure:
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (358 mg, 1 mmol) (obtained from example 29, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 330 min and allyl bromide (183 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Yellow semi-solid. Yield: 195 mg (48%); 399 (M+H); 1HNMR (400 MHz, CDCl3): δ 7.99˜7.87 (m, 3H); 7.42˜6.99 (m, 6H); 6.22˜6.21 (s, 1H); 5.22˜5.21 (d, J=1.3 Hz, 2H); 5.20˜5.19 (d, J=1.3 Hz, 2H); 4.71˜4.65 (d, 1.6 Hz, 2H); 3.49˜2.67 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1.C([O-])(=O)C.[NH4+:20]>C(O)C>[NH2:20][C:12]1[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2ccccc2Cl)C1
Yield: 88.4 %

Procedure:
A solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (2.5 g) and ammonium acetate (2.6 g) in ethanol (50 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crystals, which were recrystallized from ethyl acetate-hexane to give pale yellow crystals of 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.2 g).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41]([OH:43])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41](=[O:43])[N:2]([CH3:1])[C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CN[C@H](CN1CCCC1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Cc1ccccc1CNC(=O)OC(C)(C)C)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl-[1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl]-amine in acetonitrile (0.3 M) at 0° C. under nitrogen was added diisopropylethylamine (2.2 eq), 6a (1.1 eq) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (1.1 eq). The reaction was stirred at room temperature overnight. The acetonitrile was removed under reduced pressure. The remaining oil was partitioned between ethyl acetate and saturated sodium bicarbonate. The phases were separated and the organic phase was washed with saturated sodium bicarbonate (2×), brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (1-15% gradient methanol/dichloromethane) to afford the product. (65%) 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 9H), 6.21 (m, 1H), 5.62 (m, 1H), 4.31 (m, 2H), 3.95 (m, 1H), 3.71 (m, 1H), 3.05 (m, 1H), 2.82 (m, 5H), 2.55 (m, 2H), 1.85 (m, 5H), 1.46 (s, 9H). Mass Spectral Analysis m/z=452.3 (M+H)+ tR=4.92 min (96%)
Reaction SMILES: [C:1]1(=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:15]O>>[CH3:15][O:12][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][C:1]2=[O:14])=[CH:6][CH:7]=1)=[O:13]
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)C(=O)CCC2
Product: COC(=O)c1ccc2c(c1)C(=O)CCC2
Temperature: 0 °C
Yield: 48.6 %

Procedure:
Part A--A mixture of 1-tetralon-7-carboxylic acid (7.0 g, 0.037 mol) in methanol (13.6 mL, 10.8 g, 0.30 mol) with a catalytic amount of hydrochloriic acid (0.07 mL, 0.12 g, 0.0012 mol) was stirred at reflux over 5 hours. The cooled reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were backwashed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting solid was purified by flash chromatography using hexane:ethyl acetate::75:25. The resulting solid was triturated with hexane to give 1-tetralon-7-carboxylic acid methyl ester (3.61 g, 0.018 mol, 49%) as a yellow solid. mp=170-172° C.; 1H NMR (CDCl3) d 8.7 (s, 1H), 8.15 (d, 1H, J=8.1 Hz), 7.35 (d, 1H, J=8.1 Hz), 3.95 (s, 3H), 3.05 (d, 2H, J=6.1 Hz), 2.7 (t, 2H, J=6.4 Hz), 2.15 (quintet, 2H, J=6.2 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[CH2:23](Br)[C:24]#[CH:25].[OH-].[K+]>C(O)C.O>[CH2:25]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1)[C:24]#[CH:23]
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1
Reactant: C#CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCN1CCOC(C=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (300 mg) in ethanol were added propargyl bromide (2.0 g) and potassium hydroxide (570 mg) in water at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. After ethanol was distilled off, water was added to the residue, and the resultant mixture was extracted with chloroform. The chloroform extract was dried, evaporated and chromatographed to afford 5-(4-propargylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as crystalline material. M.P., 124°-125° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[NH2:13])=[CH:5][CH:4]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].CN1CCOCC1>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[NH:13][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1nccc2ccc(C(F)(F)F)cc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Nc1nccc2ccc(C(F)(F)F)cc12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 7-(trifluoromethyl)isoquinolin-1-amine (410 mg, 1.9 mmol), from above step E, and benzyl chloroformate (0.33 mL, 2.3 mmol) in DCM was treated with N-methylmorpholine (0.23 mL, 2.1 mmol) and stirred at room temperature for 18 h. Reaction mixture was diluted with DCM and washed with water and dried over Na2SO4. DCM was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [CH:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=O)[CH2:7][C@@H:6]1[OH:25])([CH3:3])[CH3:2].[C:26]1([CH3:37])[CH:31]=[CH:30][C:29]([S:32]([NH:35][NH2:36])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(O)C>C(Cl)Cl>[S:32]([NH:35][N:36]=[C:15]1[CH2:14][CH2:13][C@H:12]2[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:21]1([CH3:23])[C@H:8]([CH2:7][C@H:6]([OH:25])[C@@H:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH2:22]1)[CH2:9][CH2:10]3)([C:29]1[CH:28]=[CH:27][C:26]([CH3:37])=[CH:31][CH:30]=1)(=[O:33])=[O:34]
Reactant: CC(C)O[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OC(C)C)C[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 107.7 %

Procedure:
To a mixture of 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one (700 mg, 2.0 mmol) and p-toluenesulfonhydrazide (450 mg, 2.4 mmol) was added ethanol (2 mL) and the mixture obtained was heated to reflux for 12 h. Then the reaction mixture was dissolved in CH2Cl2 (150 mL) and washed with water (4×45mL). It was then dried over Na2SO4 and removal of the solvent in vacuo resulted in the crude 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one tosylhydrazone (1.113 g), which was used without further purification for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][N:21]=3)[C:7]=2[CH:27]=1)#[N:2].[Cl:28][CH2:29][C:30]#[C:31][CH2:32]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:32][C:31]#[C:30][CH2:29][Cl:28])[N:21]=3)[C:7]=2[CH:27]=1)#[N:2]
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Reactant: ClCC#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)n(CC#CCCl)n2)[C@@H]1O
Yield: 24.8 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (556 mg, 1.5 mmol) obtained in Example 8 and 1,4-dichloro-2-butyne (2.9 ml, 30 mmol) were dissolved in dimethylformamide (10 ml). Potassium carbonate (413 mg) was added and the mixture was reacted at 120° C. overnight. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (methanol:chloroform=1:30) to give 171 mg of crude (3S,4R)-6-cyano-4-[(1-(4-chloro-2-butyn-1-yl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino]-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol. The compound was dissolved in dimethylformamide (3 ml), added with diethylamine and stirred at 70° C. for 2.5 hours. Water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 71 mg of the title compound (38%).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:10]1(=[O:14])[CH2:13][CH2:12][CH2:11]1.O>C1COCC1>[Cl:9][C:3]1[C:2]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(Br)c(Cl)n1
Reactant: O=C1CCC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2(O)CCC2)c(Cl)n1
Temperature: -15 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A suspension of molecular sieves (4 Å) and 3-bromo-2-chloro-6-methylpyridine (CAN 185017-72-5, 5 g, 24.2 mmol) in THF (50 mL) was cooled to −15° C. 1.3 M isopropyl magnesium chloride lithium chloride complex solution in THF (19.6 mL, 25.4 mmol) was added within 30 min. Stirring was continued for 1 h at −15° C. Cyclobutanone (1.87 g, 2.00 mL, 26.6 mmol) was slowly added. Stirring was continued for 2 h at −15° C. and for further 2 h at 0° C. Water (2.5 mL) was added, the mixture was concentrated in vacuo, and poured onto sat. aqueous NH4Cl solution. The mixture was extracted with EtOAc (2×100 mL). The combined extracts were washed with ice water (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 140 g, heptane/EtOAc 0-40% in 120 min.) to give the title compound (3.33 g, 70%) as white solid, MS (ESI): m/e=198.1 [MH+].
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[NH2:18]>>[NH2:2][C:1]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: NNc1ccccn1
Product: Cc1ccc(-c2nn(-c3ccccn3)c(N)c2C(N)=O)cc1

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (4.64 mg, 2.0 mmol) and 2-hydrazinopyridine (218 mg, 2.0 mmol) following the procedure used for the compound of Example 12. The title compound was obtained as a white crystalline solid (350 mg) m.p. 244-247°. δH (d6DMSO) 8.46 (1H, dm, J 5.0 Hz), 7.97 (1H, ddd, J 8.4, 7.4, 1.9 Hz), 7.85 (1H, d, J 8.4 Hz), 7.68 (2H, br s), 7.47 (2H, d, J 8.1 Hz), 7.31 (2H, d, J 7.6 Hz), 7.29 (1H, signal obscured by overlapping d), 3.30 (2H, s) and 2.37 (3H, s). MS (ES+) 294 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][CH:37]=[N:36][C:35]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:35]6[N:36]=[CH:37][O:38][C:34]=6[CH3:33])[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ocnc1C1(N)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncoc5C)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methyloxazol-4-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Combiflash column chromatography (4 g flash column, CV 4.8 ml, 18 ml/min, max pressure 200 psi) using 0.5% Methanol/DCM. Yield: 0.045 g (17.6%) 1H NMR (400 MHz, DMSO-d6): δ 1.11-1.14 (m, 2H), 1.20-1.23 (m, 2H), 2.29 (s, 3H), 2.31 (s, 3H), 2.82 (d, 3H, J=4.4 Hz), 3.95 (s, 3H), 7.12 (s, 1H), 7.33 (dd, 1H, J=1.6, 8.4 Hz), 7.40 (apparent t, 2H, J=8.8 Hz), 7.49 (d, 1H, J=1.2 Hz), 7.60 (s, 1H), 7.72 (d, 1H, J=8.4 Hz), 7.97-8.01 (m, 2H), 8.04 (s, 1H), 8.46-8.48 (m, 1H), 8.67 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1O
Reactant: ClCCN1CCCC1
Agent: Cl
Product: COc1cc(Br)ccc1OCCN1CCCC1

Procedure:
The product was obtained analogously to Example 24.1a starting from 4-bromo-2-methoxyphenol and 1-(2-chloroethyl)pyrrolidine hydrochloride. Yield: 3.96 g (45% of theoretical); C13H19BrNO2 (M=300.192); calc.: molpeak (M+H)+: 300/302 (Br); found: molpeak (M+H)+: 300/302 (Br); HPLC-MS: 4.67 minutes (method A).