Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:17])[C:5]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:9][C:6]=2[O:7][CH:8]=1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O>C(O)(=O)C>[CH:2]([C:3]1[C:4](=[O:17])[C:5]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:9][C:6]=2[O:7][CH:8]=1)=[O:1]
Reactant: O=c1c(CO)coc2cc3c(cc12)CCCC3
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1coc2cc3c(cc2c1=O)CCCC3
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.3 g (0.01 mole) of 3-(hydroxymethyl)-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-4-one and 15 ml of glacial acetic acid is added to a solution of 2.98 g (0.01 mole) of sodium dichromate dihydrate in 15 ml of glacial acetic acid, keeping the temperature at about 50°C. with mild cooling. After 15 minutes, the reaction is heated at 60°C. for 15 minutes, water (100 ml) is added and the mixture is heated at 50°C. for 5 minutes. The separated solid is filtered, washed with water and dried; wt. 1.6 g (70%); mp 120°-123°C. Purification is effected by dissolving in methylene chloride and filtering through a layer of silica gel. The pure aldehyde is obtained by removal of solvent from the filtrate; mp 128°-130°C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:10][CH3:11]>ClCCl>[CH2:9]([N:12]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH3:15])[CH2:10][CH3:11]
Reactant: CCCNCCC
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Product: CCCN(CCC)Cc1ccccc1
Reaction time: 3 h

Procedure:
Benzaldehyde (0.404 cm3, 4.0 mmol), di-n-propylamine (0.548 cm3, 4.0 mmol) and [Ir(COD)(dppb)][PF6] (0.070 g, 2 mol %) in dichloromethane were treated as stated above under approx 1 bar H2 at approx. 20° C. for 3 hrs. The yield of N,N-di-n-propylbenzylamine obtained was 39.6%.
Reaction SMILES: N[C:2]1C(N)=NC=CN=1.C[O:10][C:11]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[CH:23])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].OC1C=C(O)C=CC=1C(OC)=O.C(Cl)C#C>>[OH:10][C:11]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[CH:23])[CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH3:2])=[O:14]
Reactant: C#CCOc1ccc(C(=O)O)c(OC)c1
Reactant: Nc1nccnc1N
Agent: C#CCCl
Agent: COC(=O)c1ccc(O)cc1O
Product: C#CCOc1ccc(C(=O)OC)c(O)c1

Procedure:
A mixture of 11 g of 2,3-diaminopyrazine (IIa), 20.6 g of 2-methoxy-4-propargyloxybenzoic acid [m.p. 142°; obtainable by reacting methyl 2,4-dihydroxybenzoate with propargyl chloride to give methyl 2-hydroxy-4-propargyloxybenzoate (m.p. 100°), reacting the latter with methyl iodide to give methyl 2-methoxy-4-propargyloxybenzoate (m.p. 88°), and hydrolysing the latter] and 300 ml of POCl3 is boiled for 2 hours. The mixture is evaporated to dryness, ice-water is added to the residue, and the mixture is rendered alkaline with K2CO3 solution. The precipitated 2-(2-methoxy-4-propargyloxyphenyl)-1,3,4,7-tetraazaindene is filtered off. M.p. 189°-190°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11])[CH3:2].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([NH:24][C:25](=O)[O:26]C)[N:17]=1.C[Al](C)C>>[CH2:1]([O:3][C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[S:10]([NH:13][C:25]([NH:24][C:18]1[N:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[N:19]=1)=[O:26])(=[O:11])=[O:12])[CH3:2]
Reactant: CCOc1sc(C)nc1S(N)(=O)=O
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Agent: C[Al](C)C
Product: CCOc1sc(C)nc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Yield: 49.7 %

Procedure:
By employing the procedure described in Example 2, the reaction of 1.33 g of 5-ethoxy-2-methyl-4-thiazolesulfonamide with 1.4 g of methyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate in the presence of 3.3 ml of a 2.0M solution of trimethylaluminum, there was obtained 1.2 g of the title compound, m.p. 140°-143°. IR: 1710 cm-1 (C=O).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)=[O:23].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:26][CH:25]=1)=[O:23]
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Reactant: Nc1ccc(C(=O)c2ccccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(c1ccc(NC(=O)C(O)(C(F)F)C(F)F)cc1)c1ccccn1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmoles) in dimethylacetamide (10 mL) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution was stirred at -10° C. for approximately 30 mins. 4-(2-Pyridylcarbonyl)aniline (0.58 g, 2.5 mmoles) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water, sodium bicarbonate solution added to give a pH of 7 and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water, brine, dried (Na2SO4), decolorized (charcoal), and evaporated. The crude solid was dissolved in ether, clarified by filtration, and evaporated to give a yellow orange gum. Crystallization from methylene chloride/hexane gave the title compound (0.35 g, 35%) as a tan solid; mp 158°-161° C. 1H-NMR (300 MHz, d6 -DMSO); 6.48(t, J=54.12 Hz, 2H, HCF2), 7.67(t, J=6.18 Hz, 1H, ArH), 7.91-8.10 (m, 7H, ArH, OH), 8.73 (d, J=7.35 Hz, 1H, ArH), 10.40 (s, 1H, NH). MS(CI),CH4 : 357(M+H, 100%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)n(-c2ccccc2)n1

Procedure:
192 mg (94%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-(3,4-dichlorophenyl)piperazine (95 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[Cl:11][C:4]1[CH:3]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)c3c(n2)CCC3)CC1
Yield: 19.2 %

Procedure:
Following general procedure B1, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol) was reacted with tert-butyl piperazine-1-carboxylate (0.223 g, 1.2 mmol) to afford the title compound (0.052 g, 19%) as a yellow solid. MW=337.84. 1H NMR (CDCl3, 500 MHz) δ 6.39 (s, 1H), 3.56-3.50 (m, 4H), 3.49-3.44 (m, 4H), 2.92 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.08 (quin, J=7.5 Hz, 2H), 1.48 (s, 9H); APCI MS m/z 338[M+H]+.
Reaction SMILES: [CH:1]1([C:4]([NH:10]S(C(C)(C)C)=O)([CH3:9])[CH2:5][C:6]([NH2:8])=[O:7])[CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:10][C:4]([CH:1]1[CH2:3][CH2:2]1)([CH3:9])[CH2:5][C:6]([NH2:8])=[O:7]
Reactant: CC(CC(N)=O)(NS(=O)C(C)(C)C)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(N)(CC(N)=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 3-cyclopropyl-3-(1,1-dimethylethylsulfinamido)butanamide (442 mg, 1.79 mmol) in methanol (8 ml) was added a 4.0M solution of hydrochloric acid in dioxane (1.35 ml, 5.38 mmol) and the reaction mixture was stirred at room temperature for 1 h. Volatiles were removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of dichloromethane/(solution of 3% aq. NH3 in methanol) to yield the title compound (213 mg, 83%); MS (ESI, m/z): 143.1 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13](OCC)=O)=[O:9])=[CH:6][C:5]([C:18]2[CH:23]=[CH:22]N=[CH:20][CH:19]=2)=[N:4][NH:3]1.[CH2:24]([O:31][C:32]1C=CC(C2CC(C(O)=O)C(=O)NN=2)=CC=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.[Cl:58][C:59]1[CH:66]=[C:65]([Cl:67])C=C[C:60]=1CN.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:67][C:65]1[CH:66]=[C:59]([Cl:58])[CH:60]=[CH:13][C:12]=1[CH2:11][NH:10][C:8]([C:7]1[C:2](=[O:1])[NH:3][N:4]=[C:5]([C:18]2[CH:19]=[CH:20][C:32]([O:31][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)[CH:6]=1)=[O:9]
Reactant: CCOC(=O)CCNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: O=C(O)C1CC(c2ccc(OCc3ccccc3)cc2)=NNC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]c1=O

Procedure:
Working as in example 13 for the preparation of ethyl 3-[(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carbonyl)amino]propionate, but starting with 1 g of 6-[4-(benzyloxy)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid, 100 cm3 of N,N-dimethylformamide, 0.523 g of 1-hydroxybenzotriazole, 0.56 cm3 of 2,4-dichlorobenzylamine, 1.1 cm3 of N,N-diisopropylethylamine and 1.47 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 1.02 g of N-(2,4-dichlorobenzyl)-3-oxo-6-[4-(benzyloxy)phenyl]-2,3-dihydropyridazine-4-carboxamide were obtained in the form of a yellow solid melting at 225° C.
Reaction SMILES: C([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH2:18])=[O:17])[NH:8][C:7]1=[O:19])(=O)C.[OH-].[Na+].Cl>C(O)C>[SH:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH2:18])=[O:17])[NH:8][C:7]1=[O:19]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(N)=O)NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)[C@H]1CCCCCC[C@H](CS)C(=O)N1
Reaction time: 1 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxamide (0.16 g, 0.56 mmol) is dissolved in ethanol (5.0 mL). An aqueous solution of 1N sodium hydroxide (0.60 mL, 0.60 mmol) is added, and the reaction is stirred for 1 hour. The reaction is acidified with 1N hydrochloric acid to a pH of about 3, and the solvent is evaporated. The residue is partitioned between ethyl acetate and water, and the aqueous layer is extracted several times with ethyl acetate. The combined organic layers are dried (Na2SO4), and the solvent is evaporated to give trans 3-mercaptomethyl-2-oxo-1-azacyclodecane-10-carboxamide, m.p. 185°-192° C.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:8][C:7]=2[CH:31]=1.Cl.N1C=C(CN2C3C=CC=CC=3CN([C:50](C3C4C(=CC=CC=4)C=CC=3)=[O:51])CC2)N=C1>CO>[ClH:1].[ClH:1].[OH:51][CH2:50][C:4]1[CH:3]=[CH:31][C:7]2[CH2:8][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[C:6]=2[CH:5]=1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccccc2C1
Agent: Cl
Solvent: CO
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2cc(CO)ccc2C1

Procedure:
Example 274 was prepared as an off white solid from Compound B as described for Compound F of Example 41, with chromatography using 5% MeOH/0.5% NH4OH/methylene chloride, and Compound D of Example 1, with purification by prep HPLC before formation of the HCl salt.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH2:6]([C:8]([CH2:10][CH3:11])=[O:9])[CH3:7]>>[CH3:1][Si:2]([CH3:5])([CH3:4])[O:9][C:8]([CH2:10][CH3:11])=[CH:6][CH3:7]
Reactant: CCC(=O)CC
Reactant: C[Si](C)(C)Cl
Product: CC=C(CC)O[Si](C)(C)C

Procedure:
From reaction between diethylketone and trimethylchlorosilane to form 3-trimethylsilyloxy-2-pentene (1.2.4.17). This product was reacted with 1-fluoro-pyridinium triflate (1.2.4.5) to obtain 2-fluoro-3-pentanone (1.2.4.9). After bromination with pyridinium bromide followed by reduction using diborane 2-fluoro-4-bromopentane-3-ol (1.2.4.18) was obtained. Reaction of this product with sodium methylate yielded the title compound (1.2.4.16).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:21]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:27]=[C:26]([C:37]3[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=3)[N:25]=2)([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:21]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:27]=[C:26]([C:37]3[CH:38]=[CH:39][C:40]([NH:41][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:42][CH:43]=3)[N:25]=2)([CH3:22])[CH3:23])(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Phenyl chloroformate (0.482 mL, 3.83 mmol) was added dropwise to 4-[4-[2-(4-fluorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.8 g, 3.83 mmol) and sodium bicarbonate (0.482 g, 5.74 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to give crude product which was triturated with diethyl ether to give the desired material as a white solid (2.26 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.CN(C)C=O.C(O)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:29][C:27]1[CH:26]=[CH:25][C:24]([O:32][CH3:33])=[C:23]([C:10]2[C:9]([CH2:8][O:7][C:6]3[CH:34]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:35])=[C:18]3[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]3[CH3:19])=[CH:12][CH:11]=2)[CH:28]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N)cc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(2-methoxy-5-nitrophenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 6-27, 18.8 mg, 0.0392 mmol) and tin chloride (II) (23.0 mg, 0.121 mmol) was suspended in mixed solvent of anhydrous N,N-dimethylformamide (0.25 ml) and anhydrous ethanol (0.5 mL), and stirred at 80° C. overnight. After cooling down, the reaction mixture was diluted with ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution was added thereto until the pH became 9. After the precipitate was filtered, the filtrate was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (8.2 mg) as a brown solid. (Yield 47%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:10])[C:7]=1[CH:8]=[O:9].[H-].[Na+].I[CH2:14][C:15]([NH2:17])=[O:16]>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:10][CH2:14][C:15]([NH2:17])=[O:16]
Reactant: NC(=O)CI
Reactant: O=Cc1c(O)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)COc1cccc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
3.1 1.0 g of 6-chlorosalicylaldehyde 9 is dissolved in 30 ml of DMF, 0.26 g of NaH (60% suspension in paraffin oil) is carefully added with cooling, and the mixture is stirred at RT for 45 min. 1.30 g of 2-iodoacetamide 2 are then added, and the reaction mixture is stirred overnight. The mixture is subsequently subjected to conventional work-up, giving 1.28 g (90%) of 2-(3-chloro-2-formylphenoxy)acetamide 10; MS-EI (M+)=213.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:19]([Zn]CC)[CH3:20].CCCCCC>O1CCCC1.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>[CH2:19]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:20]
Reactant: CC[Zn]CC
Reactant: Cc1csc(Nc2nccc3ccc(Cl)nc23)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc2ccnc(Nc3nc(C)cs3)c2n1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a solution of (2-chloro-[1,7]naphthyridin-8-yl)-(4-methyl-thiazol-2-yl)-amine (0.055 g, 0.20 mmol) in 2 ml dry tetrahydrofuran (purged with argon) were subsequently added tetrakis(triphenylphosphine)palladium (0.011 g, 0.0095 mmol) and a 1.0 M solution of diethylzinc in n-hexane (0.4 ml, 0.4 mmol). The reaction mixture was heated at reflux for 1 h. Cooling to room temperature was followed by quenching with saturated aqueous ammonium chloride solution at 0-5° C. The aquous layer was basified to pH 12 with 1 M aqueous sodium hydroxide solution and extracted with three portions of methyl-tert.-butyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. Flash-chromatography gave the title compound (0.015 g, 28%) as light yellow solid, MS m/e (%): 271 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=O)[CH3:5].[NH:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:11]=2[CH:10]=[N:9]1.CI>O>[CH3:5][N:4]1[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:11]=2[CH:16]=[N:8]1.[CH3:3][N:9]1[CH:10]=[C:11]2[C:16]([CH:15]=[CH:14][CH:13]=[C:12]2[C:17]([O:19][CH3:20])=[O:18])=[N:8]1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cccc2c1cnn2C
Product: COC(=O)c1cccc2nn(C)cc12
Reaction time: 0.33 h

Procedure:
To a mixture of sodium hydride (522 mg) and DMF (30 ml) was added methyl 1H-indazole-4-carboxylate (2.0 g) under ice-cooling, followed by stirring for 20 minutes. To the reaction mixture was added methyl iodide (1.41 ml), followed by stirring under ice-cooling for 30 minutes, and further at room temperature for 1 hour. The reaction mixture was ice-cooled, and water (100 ml) was added thereto, followed by stirring for 15 minutes. The insolubles were removed by filtration and the filtrate was extracted with ethyl acetate (80 ml). The organic layer was washed with a saturated sodium bicarbonate solution and saturated brine in this order and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) to obtain methyl 1-methyl-1H-indazole-4-carboxylate (900 mg) as a pale yellow solid and methyl 2-methyl-2H-indazole-4-carboxylate (600 mg) as a pale red oil.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27]C)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].N>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: N
Product: NC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
Compound 20 was prepared in a manner similar to that of compound 16 using ammonia instead of methylamine, MS 377.25 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[N:4]=[C:5]([S:27][CH3:28])[C:6](=[N:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9](OC)[C:8]=1[F:17].FC1C=C(OC)C(OC)=CC=1[CH:33]=[O:34]>>[CH3:1][O:2][C:3](=[O:29])[N:4]=[C:5]([S:27][CH3:28])[C:6](=[N:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:34][CH3:33])=[CH:9][C:8]=1[F:17]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OC)c1F
Reactant: COc1cc(F)c(C=O)cc1OC
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)c(OC)cc1F

Procedure:
The same procedure was carried out as in Example (2a) to (2e), except that 2-fluoro-4,5-dimethoxybenzaldehyde was used instead of the 2-fluoro-3,5-dimethoxybenzaldehyde in Example (2a), to give [2-(4-Cyanophenylimino)-2-(2-fluoro-4,5-dimethoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=C)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:12]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C=Cc1ccc(C#N)c(F)c1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(CO)cc1F

Procedure:
Into a cooled solution (−78° C.) of 2-fluoro-4-vinylbenzonitrile (1.3 g, 8.8 mmol; see step (i) above) in 40 mL of CH2Cl2 and 5 mL of methanol was bubbled ozone (50 L/h, 29 g/m3) for 30 min. Argon was subsequently bubbled through to remove excess ozone. Sodium borohydride (0.67 g, 0.018 mol) was added and the cooling bath was removed. The mixture was stirred and allowed to react for 1 h. The mixture was evaporated and 2M HCl was added. The mixture was extracted twice with diethyl ether and the combined ether fraction was dried (Na2SO4) and evaporated. The crude product crystallised. Yield: 1.1 g (81%).