Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:11]1.Cl>CCOCC.O1CCCC1>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:11]1
Reactant: O=C(O)CC1CCCC(=O)C1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)CC1CCCC(O)(c2ccccc2)C1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 80 mmol of phenyl magnesium bromide (from 24.2 ml of a 3.3 M solution of phenyl magnesium bromide in ether) in 100 ml of tetrahydrofuran at 10° C. was slowly added 5.0 g (32.1 mmol) of 3-oxocyclohexane-1-acetic acid (prepared by the method of Bartlett and Woods, J.A.C.S. 62, 2933 (1960)) in 25 ml of tetrahydrofuran. The reaction was stirred 1 hr. longer at 25° and then added to 250 ml 1 N hydrochloric acid and 250 ml ether. The organic extract was extracted with 150 ml of 1 N sodium hydroxide. The base extract was reacidified with 200 ml of 1 N hydrochloric acid and extracted with 300 ml of ether. This ether extract was dried over magnesium sulfate and evaporated to an oil. Crystallization from ether gave 3.25 g (43%) of the title compound, MP, 152°, as a pure diastereomer. The mother liquor (4.0 g, 53%) was pure by PMR analysis and contained the other diastereomer. Crystallization of the mother liquor in cyclohexane followed by several recrystallizations gave the other diastereomer of the title compound, MP, 114°-115°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:18])=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCCc1cc(NC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 71 %

Procedure:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[CH3:21][O:20][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:19]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccccc2c1OCCO[Si](C)(C)C(C)(C)C
Yield: 94.6 %

Procedure:
To 5.2 g cesium carbonate and 1.6 g methyl 1-hydroxy-2-naphthoate in 10 ml abs. DMF was added 1.9 g (2-bromethoxy)-tert.butyldimethylsilane and the mixture was reacted for 4 h at 60-80° C. The reaction was poured unto ice and extracted with ethyl acetate twice. The combined organic layers were washed with aqueous sat. sodium hydrogen carbonate solution and brine, dried over magnesium sulphate and concentrated in vacuo to yield 2.7 g of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-naphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][O:5][C:6]1[CH:10]=[C:9]([N:11]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[S:8][C:7]=1[C:20]([O:22]C)=O.[NH3:29]>CO>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][O:5][C:6]1[CH:10]=[C:9]([N:11]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[S:8][C:7]=1[C:20]([NH2:29])=[O:22]
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1c(Cl)cccc1Cl
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1c(Cl)cccc1Cl

Procedure:
In a similar manner as described for example 38, 123.1 mg of methyl 3-[(2,6-dichlorobenzyl)oxy]-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 15 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][CH:11]([OH:16])[CH2:12]2.[C:19](O)(=[O:21])[CH3:20]>>[C:19]([O:16][CH:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:17][CH3:18])[CH2:12]1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: CCC(CCCCC1CCC2CC(O)CC12)OC
Product: CCC(CCCCC1CCC2CC(OC(C)=O)CC12)OC

Procedure:
The procedure followed is the same as that described in Example 24 substituting 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]-7octanol {octahydro-4-(5-methoxyheptyl)-2-pentalenol} (1.0 g, 4.0 mmoles), and glacial acetic acid (7 ml). The product is kugelrohred under reduced pressure leaving a clear, colorless oil (0.7 g, 2.5 mmoles).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].C(N(CC)CC)C.[N:25]1[C:34]2[C:29](=[CH:30][C:31]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>CC#N.CCOC(C)=O>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:25]=[CH:26][CH:27]=[CH:28]3)(=[O:36])=[O:37])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1ccc2ncccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4ncccc4c3)C2=O)c1
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
3-(3-(S)-Amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.32 g, 1.26 mmol) is suspended in 15 mL of CH3CN. To the solution is added triethylamine (0.384 g, 3.78 mmol) followed by quinoline-6-sulfonyl chloride (0.25 g, 0.99 mmol). After stirring for 1.5 hours, the solution is diluted with EtOAc and washed with 0.1 N aqueous HCl, water and saturated NaCl solution. The organic layer is dried over Na2SO4, filtered and concentrated. The crude residue is purified by column chromatography (4% MeOH/CH2Cl2) to afford the title compound (0.146 g, 0.36 mmol) and as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: Oc1cccc(F)c1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(Cc3cccc(F)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 70 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 104°-105° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-fluorophenol. The yield was 70% of theory.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CC(C)=O.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[N:13]1([CH2:12][CH2:11][O:4][C:1](=[S:3])[CH3:2])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: ClCCN1CCCCC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=S)OCCN1CCCCC1
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
Potassium thioacetate (1.8 g, 16.35 mmol) was added to acetone (50 ml) and then stirred for 10 minutes under argon atmosphere. 1-(2-Chloroethyl)piperidine (1.61 g, 10.40 mmol) was added dropwise thereto and stirred for 18 hours under argon atmosphere at room temperature. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer thus separated was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with flash column chromatography (dichloromethane:ethyl acetate=19:1) to obtain 0.71 g (yield: 35%) of the title compound as a red oil.
Reaction SMILES: BrBr.[NH2:3][C:4]1[CH:5]=[C:6]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)[C:7]([F:11])=[CH:8][C:9]=1[Cl:10].[S-:23][C:24]#[N:25].[Na+].O>C(O)(=O)C>[NH2:25][C:24]1[S:23][C:5]2[C:6]([C:12]3[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=3)=[C:7]([F:11])[CH:8]=[C:9]([Cl:10])[C:4]=2[N:3]=1
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2c(Cl)cc(F)c(-c3ncc(C(F)(F)F)cc3Cl)c2s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 13 %

Procedure:
At about 20° C., a solution of 37 g (234 mmol) of bromine in 10 ml of glacial acetic acid was added over a period of 10 minutes to a solution of 38 g (117 mmol) of 2-(3-amino-4-chloro-6-fluorophenyl)-3-chloro-5-trifluoromethylpyridine and 38 g (468 mmol) of sodium thiocyanate in 500 ml of glacial acetic acid. The reaction mixture was subsequently stirred at room temperature for 10 hours and then poured into 2 l of water. The product was then extracted with 3×500 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and (finally concentrated. The crude product was purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate =4:1→1:1). Yield: 13%; m.p.: 230-235° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Br[CH2:21][C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1.[NH4+].[Cl-]>C1CCCCC1.C1COCC1>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([CH2:21][CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9]3=[O:14])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C1C(Cc2ccc3c(c2)OCO3)CCCN1Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1-Benzyl-piperidin-2-one (4.8 g, 25.4 mmol) in abs. THF (200 ml) is cooled to −70° C.; sec.-BuLi (23.4 ml of a 1.3 M solution in cyclohexane; 30.4 mmol) is added dropwise under an Ar atmosphere and the mixture is stirred at −70° C. for 30 min. A solution of 5-bromomethyl-benzo[1,3]dioxole (see Harrowven et al., Tetrahedron (2001), 57(29), 4447) (8.0 g, 37.2 mmol) in abs. THF (80 ml) is added dropwise, stirring is continued at −70° C. for 3 h, then at rt for 15 h. sat. aq. NH4Cl solution is added, the organic layer is separated, dried over Na2SO4 and evaporated. The oily residue is purified by MPLC (140 g silica gel, eluent cyclohexane, then cyclohexane:AcOEt 7:3) to give 3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidin-2-one as a yellow oil. Preparative resolution using a Chiralpak AD 5×50 cm/20 μm column (Daicel Chiral Technologies, Inc., Exton USA; a chiral stationary phase); eluent hexane: isopropanol 90:10; flow 80 ml/min; UV detection (210 nM) gives (−)-3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidin-2-one ([α]Drt=−61.1° (c=0.5, EtOH)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH:12]=[O:13].[Mn]([O-])(=O)(=O)=[O:15].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([OH:15])=[O:13]
Reactant: Cn1cc(C=O)c2cc(F)ccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1cc(C(=O)O)c2cc(F)ccc21
Temperature: 0 °C
Yield: 64.1 %

Procedure:
In acetone (50 ml) was dissolved 5-fluoro-1-methylindole-3-carbaldehyde (1.33 g, 7.52 mmol). To the resulting solution was added dropwise an 1N aqueous solution of potassium permanganate (7.15 ml, 7.15 mmol) under stirring at 0° C. After stirring at room temperature for 18 hours, another 1N aqueous solution of potassium permanganate (4.0 ml, 4.0 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through Celite. After washing with water, the filtrate was added with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 5-fluoro-1-methylindole-3-carboxylic acid (885 mg, 61%) as a white crystalline powder.
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Zn+].Br[C:10]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[C:14]([F:22])[C:11]=1[C:12]#[N:13].O>C1COCC1.CN(C=O)C.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>[F:22][C:14]1[C:11]([C:12]#[N:13])=[C:10]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(F)c(C#N)c(Br)c1OC
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c(C#N)c(-c2ccccn2)c1OC
Temperature: 98 °C
Yield: 94.5 %

Procedure:
A mixture of pyridyl zinc chloride (max 31.5 mmol, prepared from 2-bromopyridine by bromine to magnesium to zinc exchange) in THF (30 ml) and 2-bromo-6-fluoro-3,4-dimethoxybenzonitrile (prepared according to step (d), 3.30 g, 12.7 mmol) in DMF (75 ml) was charged with tetrakis(triphenylphosphine)palladium(0) (0.59 g, 0.51 mmol), warmed to 98° C. and maintained at this temperature for 15 hours. After this time, the reaction mixture was cooled to room temperature and water (300 ml) added. The resulting mixture was extracted with ethyl acetate (3×150 ml), and the combined organics dried over MgSO4 before being concentrated in vacuo. The crude product was purified on silica gel (eluting with hexane/ethyl acetate [7/3 followed by 1/1] to give 3.1 g of the title product (93%).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C(O[B:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]1)(C)C.[C-:19]#[C-].[Li+].[Li+].Cl>C1COCC1>[CH3:16][C:13]1([CH3:15])[C:12]([CH3:17])([CH3:18])[O:11][B:10]([C:5]#[C:4][CH2:3][CH2:2][CH3:19])[O:14]1
Reactant: [C-]#[C-]
Reactant: [Li]CCCC
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC#CB1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of IIc′ (5 mL, 51 mmol) in dry THF (25 mL) at −78° C. was added n-BuLi (2.5 M in n-hexane, 22.4 mL, 56 mmol). Another flask was charged with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.4 mL, 51 mmol) in dry THF (50 mL) under argon atmosphere, and the reaction mixture was cooled to −78° C. The lithium acetylide from the first flask, which was cooled to −78° C., was slowly added to the second by a double-ended needle. The mixture was stirred at −78° C. for 2 hours, after which anhydrous HCl (56 mmol) was added. Then, reaction mixture was warmed to room temperature. After removal of the precipitated LiCl by filtration and removal of solvents under reduced pressure, the residue was purified by distillation (115-125° C./15 mbar) to afford IIIc (6.3 g, 64%) as an oil.
Reaction SMILES: C(O)(=O)/C=C/[C:4](O)=[O:5].[N:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[NH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21](C2C3N=C(N)N(CC4N=CSC=4)C=3C=CC=2)[CH2:20][CH2:19]1.N1(C2CCCNC2)CCC([NH:46][C:47]2[N:51]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=3)[C:50]3[CH:60]=[CH:61][CH:62]=[CH:63][C:49]=3[N:48]=2)CC1>>[F:59][C:56]1[CH:57]=[CH:58][C:53]([CH2:52][N:51]2[C:50]3[CH:60]=[CH:61][C:62]([O:5][CH3:4])=[CH:63][C:49]=3[N:48]=[C:47]2[NH:46][CH:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][NH:15][C:10]3[N:9]=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:23][CH2:22]2)=[CH:54][CH:55]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(C4CCCNC4)CC3)nc3ccccc32)cc1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: Nc1nc2c(C3CCN(CCNc4ncccn4)CC3)cccc2n1Cc1cscn1
Product: COc1ccc2c(c1)nc(NC1CCN(CCNc3ncccn3)CC1)n2Cc1ccc(F)cc1

Procedure:
N-[[1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]-1-(4-thiazolylmethyl)-1H-benzimidazol-2-amine (E)-2-butenedioate (1:2); mp. 173.9° C. (compound 72);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9](O)[CH2:8][CH2:7][CH2:6]2.P(Cl)(Cl)(Cl)=O.[C:21]([O-])(=[O:23])C.[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH:21]=[O:23])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(O)CCC2
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)CCC(C=O)=C2
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
A solution of 6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-ol (208 mg, 1 mmol) in dry DMF (5 mL) was cooled in an ice bath and phosphoryl chloride (0.2 mL, 2.3 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 3 hours, then cooled and treated with a cold saturated aqueous solution of sodium acetate (2 mL) and stirred at room temperature for 10 min. Water was added and the mixture was extracted with DCM. The combined organic phase was washed with brine and dried over sodium sulfate. The solvent was then removed under reduced pressure to afford 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbaldehyde as white solid (160 mg, 46%). LC-MS (ES-API); rt 8.23 min; m/z calculated for C13H14O3 [M+H]+ 219.1, found 219.0.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CO
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1N

Procedure:
18 g (99 mmol) of the compound from Example 1 b) are stirred under reflux in 200 ml of methanol with 20 ml of thionyl chloride for 48 h. The reaction solution is evaporated in a rotary evaporator, the residue is taken up in 400 ml of satd. Na2CO3 solution, the solution is extracted 3 times with EA, and the combined organic phases are washed with dilute Na2CO3 solution and satd. NaCl solution, dried over Na2SO4 and concentrated. Chromatography on SiO2 with EA/Hep 9:1 and 7:3 yields 11.5 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[C:10]([CH3:18])[C:11]([OH:17])=[CH:12][CH:13]=3)[O:8][CH:7]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[CH3:28][C:29](CC(O)=O)=[O:30]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[C:10]([CH3:18])[C:11]([O:17][C:29](=[O:30])[CH3:28])=[CH:12][CH:13]=3)[O:8][CH:7]=2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)ccc2c(=O)c(-c3ccc(O)cc3)coc12
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1
Temperature: 107.5 °C
Yield: 84 %

Procedure:
A mixture of 4′,7-dihydroxy-8-methylisoflavone (2.9 g, 10.8 mmol), acetic anhydride (18 ml) and pyridine (3 ml) was heated on an oil bath at 105-110° C. for 1 h. After cooling the mixture to room temperature, it was stirred for a further 30 min during which time the diacetate crystallised from the solution. The product was filtered, washed thoroughly with water and recrystallised from ethyl acetate to yield 4′,7-diacetoxy-8-methylisoflavone as colourless prisms (3.2 g, 84%). 1H NMR (CDCl3): δ 2.31 (s, 3H, CH3), 2.32, 2.39 (each s, 3H, OCOCH3), 7.13 (d, 1H, J 9.0 Hz, H6), 7.17 (d, 2H, J 8.7 Hz, ArH), 7.59 (d, 2H, J 8.7 Hz, ArH), 8.07 (s, 1H, H2), 8.19 (d, 1H, J 8.7 Hz, H5).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CN(C)C=O.[BH4-].[Na+].[Cl:21][CH2:22][CH2:23]CBr>O.CC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][CH2:23][CH2:22][Cl:21])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: ClCCCBr
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)=O
Product: Nc1ccc(SCCCCl)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
6 G. of 2-nitro-4-thiocyanatoaniline in 30 ml. of dimethylformamide is treated under nitrogen with 1.2 g. of sodium borohydride at 20° to 30°. After 11/2 hours 15 ml. of acetone is added, followed 2 hours later by 10 g. of 3-chloropropylbromide. The mixture is left at 20°-25° for 16 hours, then diluted with water. The oily product is extracted into chloroform and passed through a silica column. 2-Nitro-4-(3-chloropropylthio)aniline is isolated by evaporation of the solvent.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([S:8]([OH:11])(=[O:10])=[O:9])[CH2:4][C:5]([OH:7])=[O:6].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[CH:13]1>CC(N(C)C)=O>[C:5]([CH2:4][CH:3]([S:8]([OH:11])(=[O:9])=[O:10])[CH2:2][NH:1][C:12](=[O:18])/[CH:13]=[CH:14]\[C:15]([OH:17])=[O:16])([OH:7])=[O:6]
Reactant: O=C1C=CC(=O)O1
Reactant: NCC(CC(=O)O)S(=O)(=O)O
Solvent: CC(=O)N(C)C
Product: O=C(O)/C=C\C(=O)NCC(CC(=O)O)S(=O)(=O)O
Yield: 86.9 %

Procedure:
To the solution of 4-amino-3-sulfobutanoic acid (˜2.50 g, 13.66 mmol) in 100 ml of DMA was added maleic anhydride (1.48 g, 15.10 mmol) and the mixture was stirred over night, evaporated, purified on C-18 column (2×30 cm) eluted with 1% HAc in water and crystallized with MeOH/Acetone/toluene to afford 3.34 g (83%) of (Z)-4-(3-carboxy-2-sulfopropylamino)-4-oxobut-2-enoic acid. 1H NMR (CD3OD) 6.33 (d, 1H, J=12.6 Hz), 6.10 (d, 1H, J=12.6 Hz), 3.64 (dd, 1H, J=5.8, 14.0 Hz), 3.54 (m, 1H), 3.30 (m, 1H), 2.78 (dd, 1H, J=4.9, 16.8 Hz), 2.39 (m, 1H); 13C NMR 173.52, 168.68, 167.98, 135.59, 127.79, 57.31, 40.56, 34.52; ESI MS m/z− 279.7 (M−H).
Reaction SMILES: [O:1]1[CH:5]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH:4]2[O:3][CH2:2]1.[ClH:16]>ClCCl.C(O)(C)C>[ClH:16].[O:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC2OCOC2C1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: C1OC2CNCC2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
tert-Butyl tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (19.77 g) was dissolved in dichloromethane (500 mL) and cooled in an ice bath. Cold (from the fridge) HCl in isopropanol (150 mL; 5N) solution was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated off and the residue triturated under ether. The precipitate was collected by filtration, washed with ether and dried to give tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole hydrochloride (13.18 g; 95%) as a beige solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26].[CH3:29][N:30]1[N:34]=[N:33][C:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)=[N:31]1>>[CH3:28][O:27][C:25]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13](=[O:14])[C:4]=1[CH2:3][NH:2][C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([C:32]3[N:33]=[N:34][N:30]([CH3:29])[N:31]=3)=[CH:36][CH:37]=1)=[CH:11][CH:10]=[C:9]([C:15]([F:16])([F:17])[F:18])[N:8]=2)=[O:26]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Reactant: Cn1nnc(-c2ccc(C(=O)O)cc2)n1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc(-c3nnn(C)n3)cc2)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1

Procedure:
3-{[4-(2-Methyl-2H-tetrazol-5-yl)-benzoylamino]-methyl}-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]-naphthyridine-2-carboxylic acid methyl ester was prepared starting from intermediate J and 4-(2-methyl-2H-tetrazol-5-yl)-benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.91 (d, J=8.15 Hz, 1H) 8.71 (br. s., 1H) 8.07-8.17 (m, 2H) 7.90-8.03 (m, 3H) 7.52-7.62 (m, 3H) 7.39-7.50 (m, 2H) 4.48 (d, J=4.83 Hz, 2H) 4.44 (s, 3H) 3.41 (s, 3H). LCMS calcd. for C27H20F3N7O4 [(M+H)+] 563.1, obsd. 564.1.