Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH:13]=O)=[CH:11][C:10]2[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6][C:5]=2[N:4]=1.[C:17]1([C@H:23]2[C@@H:28]([NH2:29])[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:29][C@H:28]1[CH2:27][CH2:26][CH2:25][NH:24][C@H:23]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1nc2c(cc1C=O)N(C)C(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1nc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
The 2-methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridine-3-carbaldehyde prepared in step 5 (0.35 g; 1.4 mmol) was dissolved in 20 ml of dichloroethane. To this was added 250 mg (1.1 mmol) of 2-(S)-phenyl-piperidin-3(S)-ylamine and 0.4 ml (2.8 mmol) of triethylamine, and the mixture was stirred for 60 minutes at room temperature. To this mixture was added 0.7 g (3.3 mmol) of sodium triacetoxyborohydride, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and stirred at room temperature for 30 minutes. The pH of the mixture was adjusted to 8.5 with Na2CO3. The organic layer was separated from the water layer. An additional 20 ml of water was added to the organic layer. The pH of the mixture was adjusted to 2 with 1N HCl and extracted with ethyl acetate. The pH of the water layer was adjusted to 7.5 with sodium bicarbonate and extracted with ethyl acetate. The pH=7.5 ethyl acetate extracts were combined, dried (Na2SO4), and evaporated to yield 300 mg of 6-methoxy-1-methyl-7-[(2(S)-phenyl-piperidin-3(S)-ylamino)-methyl]-3,4-dihydro-1H-[1,5]naphthyridin-2-one. 1H NMR (CDCl3) δ 7.2–7.4 (m, 5H), 6.85 (s, 1H), 3.90 (s, 1H), 3.85 (s, 3H), 3.60,3.38 (d,d 2H), 3.30 (d, 1H), 3.10 (s, 3H), 3.0 (s, 1H), 2.90 (m, 2H), 2.80 (m, 2H), 2.66 (m, 2H), 2.0–2.2 (m, 3H), 1.9 (m, 1H), 1.6 (m, 1H), 1.45 (m, 1H). Mass spectrum: m/e=381.1 (p+1). TLC: Rf=0.5; (5:1 chloroform/methanol).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:14][CH:15]1[CH2:19][CH2:18][CH:17]([CH3:20])[NH:16]1.[Cl-].[NH4+]>>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:16]2[CH:17]([CH3:20])[CH2:18][CH2:19][CH:15]2[CH3:14])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC1CCC(C)N1
Reactant: CC#CCOc1ncnc(Cl)c1F
Agent: [Cl-]
Agent: [NH4+]
Product: CC#CCOc1ncnc(N2C(C)CCC2C)c1F
Reaction time: 18 h
Yield: 95.2 %

Procedure:
0.2 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine and 0.30 g of 2,5-dimethylpyrrolidine were mixed and left for 18 hours at room temperature. Into the reaction mixture was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.25 g of 4-(2-butynyloxy)-5-fluoro-6-(2,5-dimethyl-1-pyrrolidinyl)pyrimidine (hereinafter, referred to as Compound (6)).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH:26]=[CH2:27].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.Cl>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH:26]=[CH2:27])=[O:11]
Reactant: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1N
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO200687543, 2.27 g, 11.8 mmol) and Ethyl (3S,4R)-4-amino-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 18, 2.7 g, 11.8 mmol) in dichloromethane (180 mL) was added HOBt (1.85 g, 11.8 mM) and N-methylmorpholine (3.8 mL, 35.43 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (4.07 g, 21.3 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight, treated by the addition of 2 N HCl (120 mL) and the resulting layers were evaporated. The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica gel, 35% ethylacetate in pet ether) to afforded 3.5 g (73.6%) as brown solid. NMR (400 MHz, DMSO-d6): δ 1.24 (t, 3H), 1.62 (m, 2H), 2.16 (s, 3H), 2.97 (m, 2H), 3.53 (m, 2H), 3.97 (m, 4H), 4.15 (q, 2H), 4.21 (m, 1H), 5.13 (d, 1H), 5.23 (d, 1H), 5.87 (m, 1H), 7.10 (d, 1H), 12.10 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][S:26]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27].CC(C)([O-])C.[K+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]([CH2:25][S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
A solution of 1-benzyl-4-(4-nitrophenoxy)piperidine (3.00 g, 9.60 mmol) and 1-chloromethanesulfonyl-naphthalene (2.35 g, 9.76 mmol) in THF was chilled in an ice bath, treated dropwise with 1.0 M potassium tert-butoxide in THF (20 mL, 20 mmol), stirred at ambient temperature for 1 hour, 20 minutes under nitrogen, poured into water and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 40-80% ethyl acetate in hexane to give 1-benzyl-4-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-piperidine as a brown gum/foam, 2.36 g (47.6% yield), Mass spectrum (+EI, [M+H]+) m/z 517. 1HNMR (500 MHz, DMSO-d6): δ8.44-8.47 (m, 1H), 8.28 (d, 1H, J=8.17 Hz), 8.06-8.09 (m, 1H), 7.91-7.96 (m, 2H), 7.59-7.68 (m, 3H), 7.20-7.32 (m, 5H), 7.03 (dd, 1H, J=9.15 Hz and 2.80 Hz), 6.62 (d, 1H, J=2.81 Hz), 5.24 (s, 2H), 4.07-4.10 (m, 1H), 3.44 (s, 2H), 2.49-2.53 (m, 2H), 2.05-2.09 (m, 2H), 1.65-1.69 (m, 2H), 1.38-1.46 ppm (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(Cl)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-chlorobenzenesulfonyl chloride according to METHOD A, giving 0.47 g (65%) of a pink powder: MS (electrospray, [M−H]−) m/z 359.1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[C:29]([OH:31])=O)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:32][OH:33]>>[OH:33][NH:32][C:29]([C@H:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[NH:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:15][CH:16]=1)(=[O:22])=[O:21])=[O:31]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@@H]3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 43 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 321.4 mg (0.73 mmol) of (1S,2R)-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid with hydroxylamine provided 139.5 mg of (1S,2R)-N-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide with 43% yield. MS: 456.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][CH3:34])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:30][CH2:31][NH:32][CH2:33][CH3:34])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCN(CCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1)C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCNCCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
In chloroform (1.8 ml) was dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(2-(N-(t-butoxycarbonyl)-N-ethylamino)ethyloxyimino)quinazoline (V-16, 54 mg), and trifluoroacetic acid (1.8 ml) was added, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated, and diluted with ethyl acetate. The mixture was sequentially washed with aqueous saturated sodium bicarbonate solution, water, and aqueous sodium chlorite solution, and dried over magnesium sulfate. After concentration, the crystalline residue was washed with a mixture of dichloromethane-hexane (1:4) to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(2-(N-ethylamino)ethyloxyimino)quinazoline (V-17, 28 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([OH:27])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][N:22]=4)[CH:18]=3)[NH:13][C:12](=[O:35])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=4)([OH:27])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][N:22]=4)[CH:18]=3)[N:13]([CH2:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)[C:12](=[O:35])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cn1cnnc1C(O)(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnnc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 6.3 %

Procedure:
NaH 60% in oil (0.0023 mol) was added at room temperature to a mixture of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2(1H)-quinolinone (0.0021 mol), obtained in Example B32, in DMF (10 ml). The mixture was stirred for 30 minutes. 4-(Bromomethyl)-benzonitrile (0.0023 mol) was added. The mixture was stirred at room temperature for 18 hours, then at 80° C. for 2 hours, then overnight, cooled and poured out into ice water. The precipitate was filtered, taken up in DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.8 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0 to 90/10; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.1 g) was purified by column chromatography over kromasil (eluent: CH3CN/H2O 60/40; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.078 g (6%) of 4-[[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2-oxo-1(2H)-quinolinyl]methyl]-benzonitrile, mp. 185° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:23])[NH:17][C@H:18]([C:20](F)=[O:21])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][C@H:18]([C:20](=[O:21])[NH:7][CH2:8][CH2:9][SH:10])[CH3:19])([CH3:12])([CH3:13])[CH3:14]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)F
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 25 mL round-bottom flask charged with a solution of sodium bicarbonate (148.1 mg, 1.76 mmol) in 8.6 mL water was added 2-aminoethanethiol hydrochloride (107.5 mg, 0.95 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25c (163.5 mg, 0.86 mmol) in 8.6 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 108.0 mg (51% from 24c) of clean 26c as a colorless oil.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:25][N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[CH3:26])[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccncc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccncc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 51.9 %

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (4-methylpyridin-3-yl)boronic acid (206 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 6 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→0:1) to give the title compound as a colorless oil (yield 230 mg, 52%).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH:11]([Cl:13])[CH3:12])=[O:9].[C:14]([O:19][CH2:20][CH2:21][OH:22])(=[O:18])[C:15]([CH3:17])=[CH2:16]>ClCCl>[C:8](=[O:9])([O:22][CH2:21][CH2:20][O:19][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])[O:10][CH:11]([Cl:13])[CH3:12]
Reactant: C=C(C)C(=O)OCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCOC(=O)OC(C)Cl
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of 1-chloroethyl chloroformate (1.20 ml, 11.00 mmol) and 2-hydroxyethyl methacrylate (1.22 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. under a dry N2 atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2×10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure to give 1.76 g (74%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.85 (3 H, d, J=6 Hz, CH3 --CH), 1.96 (3 H,d, J= 2 Hz, CH3 --C=), 5.55 (1 H, m, CH=), 6.10 (1 H, m, CH=), 6.38 (1 H, k, J=6 Hz, CH--CH3).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:19]1([CH2:22][C:23]([NH2:31])([CH3:30])[C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][C:23]([NH:31][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([CH3:30])[C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 66e) as starting materials and the racemate was isolated (43 mg, 32%) as a colorless oil. The racemate was separated into its enantiomers by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first enantiomer collected and isolated as a colorless oil; MS (ESI, m/z): 425.5 (M+H+). The collected enantiomer shows levorotation properties according to the observed optical activity measured during preparative chiral HPLC.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8]([CH3:21])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:10].[CH3:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>C(O)C>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([CH:8]([CH3:21])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)=[O:10])[CH2:30][CH2:29]2)=[CH:34][CH:35]=1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: COc1ccc(C(=O)C(C)Br)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=O)C(C)N2CCC(Cc3ccc(C)cc3)CC2)cc1OC

Procedure:
5.4 g (0.05 mol) of sodium carbonate are added to a mixture of 13.65 g (0.05 mol) of 2-bromo-3',4'-dimethoxypropiophenone and 9.46 g (0.05 mol) of 4-(4-methylbenzyl)-piperidine in 50 ml of ethanol and the mixture is heated under reflux for 3 hours. It is then evaporated to dryness and the residue is passed through a column of silica using acetone as the eluant. This gives an oil, which is used as such.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]O)[CH:27]=1)[CH3:17]>>[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]([F:1])[CH:7]=2)[CH:27]=1)[CH3:17]
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: CCc1cccc(CC)c1-c1cccc(CO)c1
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(CC)cccc3CC)c2)cc1F
Yield: 80 %

Procedure:
The title compound was synthesized in the same manner as in Example 277 from ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate and (2′,6′-diethylbiphenyl-3-yl)methanol. a yellow oily substance (yield 80%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9](=O)[CH3:10])=[C:6]([Cl:12])[N:5]=[CH:4][N:3]=1.[CH3:13][NH:14][NH2:15].C([O-])(=O)C.[Na+]>CC#N>[Cl:12][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[N:14]([CH3:13])[N:15]=[C:9]([CH3:10])[CH2:8][C:7]=12
Reactant: CC(=O)Cc1c(Cl)ncnc1Cl
Reactant: CNN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1=NN(C)c2ncnc(Cl)c2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 122 %

Procedure:
To a stirred solution of 1-(4,6-dichloropyrimidin-5-yl)propan-2-one (940 mg) in dry MeCN (10 mL), methyl hydrazine (232 mg) and sodium acetate (715 mg) were added. The reaction mixture was stirred at room temperature for 24 hours before being quenched with water (100 mL). Aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure gave crude 5-chloro-1,3-dimethyl-1,4-dihydropyridazino[3,4-d]pyrimidine (1.1 g) as white solid which was used as was. 1H NMR (DMSO-d6): δ 2.06 (s, 3H), 3.2 (s, 3H), 3.55 (s, 2H), 8.33 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:6][CH:7]=3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCN4CCCC4)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3[4-(2-bromo-ethoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, pyrrolidine, potassium carbonate, potassium iodide and 5% aqueous acetonitrile at 75° C. essentially as described above in Example 13, except that the column is eluted with 10% methanol in ethyl acetate. Purity by LC/MS=99%, [M+H]+=327.
Reaction SMILES: [F:1][C:2]1[C:3]([C:12]#[C:13][Si](C)(C)C)=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[C:12]([C:3]1[C:2]([F:1])=[CH:9][CH:8]=[C:5]([C:6]#[N:7])[C:4]=1[C:10]#[N:11])#[CH:13]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1c(F)ccc(C#N)c1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a solution of 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (Example 40C) (0.302 g, 1.246 mmol) in anhyd THF (5 mL) was added a solution of TBAF in THF (1.246 mL, 1.246 mmol), dropwise. The resulting black mixture was stirred at rt under N2 for 5 min. The mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 3-ethynyl-4-fluorophthalonitrile (0.0635 g, 30% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J=8.7, 4.7 Hz, 1H), 7.49 (dd, J=8.7, 8.0 Hz, 1H), 3.86 (s, 1H); MS (GCMS EI) m/z 170 ([M]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](OC)[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]2[C:18]([N:19]=1)=[N:17][CH:16]=[CH:15][N:14]=2.C([O-])(=O)/C=C/[C:23]([O-])=[O:24]>>[CH3:1][O:2][C:3]1[C:8]([O:24][CH3:23])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:13]([N:12]=1)=[N:14][CH:15]=[CH:16][N:17]=2
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: COc1ccc(-c2nc3nccnc3[nH]2)c(OC)c1
Product: COc1cccc(-c2nc3nccnc3[nH]2)c1OC

Procedure:
2-(2,4-dimethoxyphenyl)-1,3,4,7-tetraazaindene, m.p. 210°-215°; fumarate, m.p. 265° (decomposition)