Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[S:18][CH:19]=[C:20]([CH3:22])[CH:21]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:21]2[C:20]([CH3:22])=[CH:19][S:18][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C(=Cc1cc(C)cs1)CC(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(OC(C)=O)c2c(C)csc2c1
Yield: 58.3 %

Procedure:
Sodium acetate (90 g, 1.08 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(4-methylthien-2-yl)but-3-enoic acid (61 g, 0.24 mol) in 700 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 38.5 g (140 mmol, 58%) as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](=[S:28])[NH2:27])=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.Br[CH2:41][C:42](=O)[CH3:43].C(=O)([O-])O.[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]4[S:28][CH:41]=[C:42]([CH3:43])[N:27]=4)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=S)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(C)cs2)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 50.8 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenethioamide (0.46 g), 1-bromo-2-propanone (0.13 g) and ethanol (30 mL) was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(E)-2-(4-methyl-1,3-thiazol-2-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as pale-yellow crystals (0.25 g, yield 51%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 130-131° C.
Reaction SMILES: [ClH:1].[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:35]CC2C=CC=CC=2)=[C:26]([NH:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:27]=1)[OH:21].CO.C(OCC)(=O)C>CO.[Pd]>[ClH:1].[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:35])=[C:26]([NH:28][S:29]([CH:32]([CH3:33])[CH3:34])(=[O:31])=[O:30])[CH:27]=1)[OH:21]
Reactant: CC(C)S(=O)(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1O

Procedure:
According to the procedures described in Example 2, the compound of Example 53 (369 mg) was dissolved in 39.9 ml of methanol and subjected to a hydrogenolysis using 10% Pd—C (190 mg). The catalyst was filtered on celite at room temperature and washed with hot methanol. After the filtrate and the washed liquor were brought together, the solvent was distilled off under a reduced pressure, whereby the above-identified compound (267 mg) was obtained. Rf=0.27(methanol/ethyl acetate of 1/3).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1.[NH2:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[F:1][CH:2]([F:28])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:29][C@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CS(=O)(=O)c1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 2-difluoromethyl-1-[2-(methylsulfonyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (770 mg), tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (525 mg), potassium carbonate (390 mg), and N,N-dimethylacetamide (19 mL) was stirred in a microwave reactor at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and then poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to obtain tert-butyl (3S)-3-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl}amino)pyrrolidine-1-carboxylate (310 mg) as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>C1(C)C=CC=CC=1.CS(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:21][C:23]2[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1cc(N)ccc1Oc1ncccc1-c1ccncn1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2nc3ccccc3o2)ccc1Oc1ncccc1-c1ccncn1
Temperature: 100 °C

Procedure:
To 3-methyl-4-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (30 mg, 0.11 mmol) in toluene (2.0 mL) was added 2-chlorobenzo[d]oxazole (0.014 mL, 0.12 mmol). The resulting mixture was heated to 100° C. for 47 h. The mixture was diluted with DMSO and purified by Gilson reverse-phase HPLC. The product-containing fractions were combined, diluted with methylene chloride, and extracted with saturated sodium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield the title compound as a tan solid. MS m/z=396 [M+H]+. Calc'd for C23H17N6O2: 395.42.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>O>[Cl:17][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]#[N:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#CC(c1ccccc1)c1ccccc1
Solvent: O
Product: N#CC(Cl)(c1ccccc1)c1ccccc1
Yield: 91.7 %

Procedure:
A mixture of 25 g (0.13 m) of diphenylacetonitrile and 27 g (0.13 m) of phosphorus pentachloride is heated at 125° for 4 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent is evaporated to give 27 g of crude α-chlorodiphenylacetonitrile.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH2:21][CH3:22])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH2:21][CH3:22])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]([C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=2)=[CH:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCS(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCS(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 71.7 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (80 mg, 0.134 mmol), 4-methylsulfonyl phenylboronic acid (80 mg, 0.401 mmol) and dichlorobis(triphenylphosphine)palladium (II) (9.4 mg, 0.013 mmol) in dioxane (1 mL) was added an aqueous sodium carbonate solution (2 M, 0.2 mL, 0.4 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (10 mL), washed with a saturated aqueous sodium bicarbonate solution (2×3 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridine (56 mg, 72%) as a light yellow solid: LC/MS m/e calcd for C29H30N2O5S3 [M+H]+ 583.76, observed 583.2.
Reaction SMILES: [Li+].[OH-].O.[C:4]([NH:7][C@:8]1([CH:22]([CH2:24][CH3:25])[CH3:23])[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16]C)=[O:15])[C:9]1=[O:21])(=[O:6])[CH3:5].Cl>C1COCC1>[C:4]([NH:7][C@:8]1([CH:22]([CH2:24][CH3:25])[CH3:23])[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([OH:16])=[O:15])[C:9]1=[O:21])(=[O:6])[CH3:5]
Reactant: C=CC[C@@H](C(=O)OC)N1CC[C@](NC(C)=O)(C(C)CC)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)O)N1CC[C@](NC(C)=O)(C(C)CC)C1=O
Reaction time: 72 h
Yield: 88.2 %

Procedure:
Step L (7): A solution of LiOH/H2O (2M, 28 mg in 0.50 mL) was added to the diastereomer B, (S)-methyl 2-((S)-3-acetamido-3-sec-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate (122 mg, 0.39 mmol) from Step L (6) in THF (1.0 mL) at RT. The reaction was stirred for 3 days. The mixture was poured into 1N HCl and the aqueous layer was extracted with EtOAC. The combined organic layers were washed with brine, dried over NaSO4 and concentrated in vacuo to give 102 mg of the title compound as white solid. LC-MS (M+H)+=297.01.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:23][C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:23][C:13]2=[C:14]3[C:19](=[C:20]([I:24])[CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)NCC1Cc2ccc3[nH]c(=O)ccc3c2O1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC1Cc2cc(I)c3[nH]c(=O)ccc3c2O1
Reaction time: 2 h
Yield: 73.2 %

Procedure:
2-(t-Butoxycarbonyl)aminomethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (882 mg) and N-iodosuccinimide (756 mg) were dissolved in a solvent mixture (44 ml) of chloroform-methanol (5:1). After refluxing for 2.5 hours with heat, N-iodosuccinimide (756 mg) was added to the mixture, followed by further 2 hour refluxing with heat. Further, N-iodosuccinimide (400 mg) was added to the mixture, which was then refluxed for 1.5 hours with heat. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent=chloroform:methanol=200:1) to obtain 903 mg of 2-(t-butoxycarbonyl)aminomethyl-5-iodo -2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (73.2%). This compound was recrystallized from a solvent mixture of chloroform-n-hexane to obtain pale yellow powdery crystals (mp.: 173°-174° C.).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[N:10]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.O>CN1CCCC1=O>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: Nn1ccc2ccccc21
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1c(Cl)ncnc1Nn1ccc2ccccc21
Yield: 78.9 %

Procedure:
A solution of 8 g of 4,6-dichloro-5-pyrimidinamine, and 7 g of 1H-indol-1-amine, in 100 ml N-methyl-2-pyrrolidone was stirred at 130°-135° for seven hours, then cooled, stirred with water and extracted with ether. The organic extract was washed with water and saturated sodium chloride, dried (anhy. MgSO4), filtered and evaporated to 16 g of a residue. This was purified by flash chromatography (silica, 5% ethyl acetate/DCM) to give 10 g solid. This was combined with product obtained from other condensations and purified by HPLC (silica 5% ethyl acetate/DCM) to give 7 g oil. This oil was crystallized from ether-petroleum ether to give 2.2 g solid, 6-Chloro-N4 -(1H-indol-1-yl)-4,5-pyrimidinediamine, m.p. 175°-176°.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][OH:22]>>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][O:22][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CN(C)CCO
Product: CN(C)CCOC(=O)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
(2-Dimethylaminoethyl)-p-benzoylbenzoate was prepared from para-benzoylbenzoic acid chloride and 2-dimethylaminoethanol. The structure of the product was confirmed by the presence of carbonyl absorption bands in the infrared spectrum at 1670 and 1725 cm-1. When added at 4% by weight loading to the test solution described in Example 3, a cure rate of 40 ft./min./lamp was observed.
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])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=1[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: COc1cc2nccc(O)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC

Procedure:
M1 was prepared from 6,7-dimethoxyquinolin-4-ol and 1-fluoro-2-methyl-4-nitrobenzene following the general procedure reported in Preparative Example 1 Step 1-2. 1H NMR (400 MHz, d5-DMSO, 300K) δ 1.93 (s, 3H), 3.92 (s, 6H), 5.06 (br s, 2H), 6.24 (d, J=5.2 Hz, 1H), 6.48 (dd, J=8.4 Hz, J=2.5 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.53 (s, 1H), 8.40 (d, J=5.2 Hz, 1H). MS (ES) C19H19N2O3 requires: 310. Found: 311 (M+H)+.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]([OH:12])[CH:10]=[CH2:11].[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]#[N:16]>CCOCC>[Cl:13][C:14]([Cl:18])([Cl:17])[C:15](=[NH:16])[O:12][CH2:9][CH:10]=[CH2:11]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: C=CCOC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 80% sodium hydride (945 mg., 31.5 mmol.; washed twice with 25 ml. of hexane) in dry ether (30 ml.) was treated dropwise with a solution of 2-propen-1-ol (21.4 ml., 18.3 g., 315 mmol.), in dry ether (45 ml.), stirred for 20 minutes at room temperature under argon and then cooled to 0° C. (ice-salt bath). Trichloroacetonitrile (30 ml. or 42.3 g., 0.30 mole) was added over a period of 15 minutes and the brownish solution was stirred at 0° C. for 40 minutes, at 10° C. for 10 minutes and at room temperature for 10 minutes. The reaction mixture was concentrated to a syrup, treated with a solution of methanol (1.2 ml.) in pentane (30 ml.) and stirred vigorously for 5.0 minutes. The light brown precipitates were filtered off, washed with pentane (2×30 ml.) and the combined filtrates concentrated down to a light brown liquid. The liquid was re-dissolved in pentane (30 ml.), stirred for a few minutes, and the resulting suspension filtered, and the precipitates obtained washed with pentane (30 ml.), repeating the procedure at least one more time. The clear filtrate was concentrated and dried in vacuo to give 54.0 g. of title compound as a light red-colored liquid. This material was stored as a solution in hexane at 10° C.
Reaction SMILES: [Na+].[Na+].C([O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([O-:12])=[O:11])[C:8]=1[C:16]([O-:18])=[O:17])C.[Mn]([O-])(=O)(=O)=[O:20].[K+]>O>[C:6]([OH:5])(=[O:20])[C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=1[C:16]([OH:18])=[O:17]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCOCc1cccc(C(=O)[O-])c1C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc(C(=O)O)c1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
3-(Ethoxymethyl)phthalic acid disodium salt (3.7 mmol) from Example 2 was dissolved in water (40 ml). Potassium permanganate (7.5 mmol) was added and the resulting solution was stirred for 18 h at room temperature. The precipitate formed was filtered off and washed three times with hot water. The combined aqueous phase was evaporated under reduced pressure to approximately one third of the initial volume and cooled in an ice-bath. Concentrated HCl was added carefully for neutralization. The precipitated hemimellitic acid was collected on a glass filter, washed with water and dried (yield: 42%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])=[O:38])([CH3:35])([CH3:34])[CH3:33].[Cl:45][C:46]1[CH:47]=[C:48](O)[CH:49]=[N:50][C:51]=1[Cl:52]>C1COCC1>[Cl:45][C:46]1[CH:47]=[C:48]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:49]=[N:50][C:51]=1[Cl:52]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Oc1cnc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A solution of triphenylphosphine (2.6 g, 9.94 mmol) and diethyl azodicarboxylate (1.6 mL, 9.94 mmol) in THF (16 mL) was stirred at 0° C. for 15 minutes. 1-t-Butyloxycarbonyl-2-(S)-azetidinemethanol (1.55 g, 8.28 mmol, from step 7c above) and 5,6-dichloro-3-pyridinol (1.5 g, 9.1 mmol) were then added. The reaction mixture was allowed to warm slowly to room temperature and stir overnight. The solvent was removed, and the residue was redissolved in methylene chloride. The solution was washed with saturated aqueous K2CO3 and brine, dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; ethyl acetate:hexane, 1:5) to afford the 5,6-dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine (1.08 g): MS (CI/NH3) m/z 333 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.22-2.42 (m, 2H), 3.85-3.92 (m, 2H), 4.12 (dd, J=2.7, 10.1 Hz, 1H), 4.30-4.40 (m, 1H), 4.48-4.56 (m, 1H), 7.41 (d, J=2.8 Hz, 1H), 7.97 (d, J=2.8 Hz, 1H). To a solution of 5,6-dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)-pyridine (1.06 g, 3.11 mmol) in CH2Cl2 (10 mL) at 0° C. was added TFA (10 mL). The solution was allowed to warm to room temperature while stirring for 45 minutes. The volatile components were then removed under vacuum. The residue was treated with saturated K2CO3 solution, then extracted with methylene chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; MeOH/CHCl3/NH4OH, 1:10:0 to 1:10:0.05) to afford the free base of the title compound (475 mg, 64% yield): mp 59-60° C.; MS (CI/NH3) m/z 233 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ2.21-2.44 (m, 2H), 3.45 (m, 1H), 3.73 (dd, J=8.4, 15.8 Hz, 1H), 3.98-4.08 (m, 2H), 4.28 (m, 1H), 7.37 (d, J=2.8 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H). The base (336 mg) was slurried in ether and converted to the hydrochloride salt by treatment with saturated HCl in ether. Recrystallization from methanol/ether gave the title compound (317 mg, 81% yield): mp 181-182° C.; MS (CI/NH3) m/z 233 (M+H)+; 1H NMR (D2O, 300 MHz) δ2.65-2.74 (m, 2H), 4.03-4.21 (m, 2H), 4.44 (d, J=4.4 Hz, 1H), 4.95 (m, 1H), 7.79 (d, J=2.9 Hz, 1H), 8.13 (d, J=2.9 Hz, 1H). Anal. Calcd. for C9H11N2OCl2.1.0 HCl: C, 40.10; H, 4.11; N, 10.39. Found: C, 39.89; H, 4.08; N, 10.25.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].[H][H]>[Ni].C1(C)C=CC=CC=1>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CO)cc1
Yield: 90 %

Procedure:
A mixture of methyl 4-formylbenzoate (500 g, 3.05 mole), Raney nickel (25 g) and toluene (1000 mL) is heated in an autoclave between 60 and 75° C. under a hydrogen atmosphere at between 41 and 44 bars absolute for 3.5 hours. The hydrogen pressure then is released and the catalyst removed from the reaction mixture by filtration at 40° to 60° C. The toluene is removed by distillation and the product, methyl 4-(hydroxymethyl)benzoate obtained in a 90% yield, is used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])(C)(C)C.CCCCC.[CH2:21]([C:28]1([N:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([C:28]1([N:35]([CH3:36])[CH3:37])[CH2:33][CH2:32][C:31]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)([OH:34])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: Cn1ccc2ccccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN(C)C1(Cc2ccccc2)CCC(O)(c2cc3ccccc3n2C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A solution of N-methylindole (1.50 mg, 3.81 mmol) in dry THF (20 ml) was cooled to −5° C. under a stream of argon. Thereafter, tert-butyllithium (4.19 mmol, 2.47 ml of a 1.7 molar pentane solution) was added dropwise such that a reaction temperature of 0° C. was not exceeded during the addition. When the addition had ended the reaction mixture was stirred for a further two hours at 0° C. A solution of 4-benzyl-4-dimethylaminocyclohexanone (3.88 mg, 3.81 mmol) in dry THF (7 ml) was then added dropwise at 0° C. The mixture was stirred for 15 minutes at 0° C. and then for four hours at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase was extracted four times with methylene chloride (20 ml). The combined organic phases were dried over sodium sulfate and filtered and the solvent was removed in vacuo. Purification was carried out by means of flash chromatography over silica gel with cyclohexane/ethyl acetate (v/v=4:1). 456 mg 4-benzyl-4-dimethylamino-1-(1-methyl-1H-indol-2-yl) cyclohexanol with a melting point of 105-107° C. were obtained.