Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[C:32]([CH3:34])([CH3:33])[O:31]C(C)(C)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2].O.Cl>CCO>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[C:32]([CH3:34])([OH:31])[CH3:33])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC(C)(C)OC2(C)C)ns1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)C(C)(C)O)ns1
Yield: 92.9 %

Procedure:
To a mixture of (S)—N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine (0.134 g, 0.255 mmol) in EtOH (5 ml) and water (0.227 ml, 0.255 mmol) was added concentrated HCl (0.0531 ml, 0.637 mmol) and the reaction heated at reflux for 5 hours. The reaction was concentrated to a residue that was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The combined organic layers were dried over Na2SO4, filtered and concentrated to give (S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-2-methylpropane-1,2-diol (0.115 g, 92.9% yield) as a white solid. Mass Spectrum (apci) m/z=468.1 (M+H−H2O).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]#[N:12].[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]1[NH:15][CH2:14][CH2:13][N:12]=1
Reactant: Cc1ccc(F)c(CC#N)c1F
Reactant: NCCN
Product: Cc1ccc(F)c(CC2=NCCN2)c1F

Procedure:
2-(2,6-Difluoro-3-methyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2,6-difluoro-3-methyl-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): colourless powder; MS (ISP): 210.1 ((M+H)+.).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:10])=[C:6]([CH2:8]O)[N:7]=1)[CH3:2].S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:13][CH2:8][C:6]1[N:7]=[C:3]([CH2:1][CH3:2])[S:4][C:5]=1[CH3:10]
Reactant: CCc1nc(CO)c(C)s1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1nc(CCl)c(C)s1
Yield: 84.7 %

Procedure:
To a solution of (2-ethyl-5-methyl-1,3-thiazol-4-yl)methanol (3.7 g) in toluene (200 mL) was added thionyl chloride (8.5 g) at room temperature, and the mixture was heated under reflux for 30 min. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (10:90-25:75, v/v) to give 4-chloromethyl-2-ethyl-5-methyl-1,3-thiazole as a yellow oil (3.5 g, yield 84%). NMR (CDCl3) δ: 1.35 (3H, t, J=7.6 Hz), 2.44 (3H, s), 2.95 (2H, q, J=7.6 Hz), 4.63 (2H, s).
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:38][OH:39].Cl>N1C=CC=CC=1>[OH:39][N:38]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: NO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NO)c4ccccc4)ccc32)cc1
Temperature: 0 °C

Procedure:
A solution of the compound obtained in Step A of Example 31 (500 mg) and hydroxylamine hydrochloride (137 mg) in 10 ml of pyridine is heated at reflux for 3 hours. The reaction mixture is hydrolysed using 100 ml of ice-cold water and is acidified using 6N HCl. The precipitate obtained is then filtered off, washed with water and then with petroleum ether and purified on silica gel (eluant AcOEt/PE 2/8) to yield the title compound in the form of a white powder.
Reaction SMILES: Cl[Si:2]([CH3:16])([CH3:15])[Si:3]([CH:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]1[CH3:14])([CH3:5])[CH3:4].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>CCOCC>[C:17]([NH:21][Si:2]([CH3:16])([CH3:15])[Si:3]([CH:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]1[CH3:14])([CH3:5])[CH3:4])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC1=C(C)C([Si](C)(C)[Si](C)(C)Cl)C(C)=C1C
Reactant: CC(C)(C)N
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)[Si](C)(C)NC(C)(C)C)C(C)=C1C
Temperature: 25 °C

Procedure:
To a solution of 3.000 g (11.0 mmol) 1-chloro-2-(tetramethylcyclopentadienyl)-1,1,2,2-tetramethyldisilane in 50 mL ether was added 2.422 g (33.1 mmol) tert-butylamine. Precipitate formed rapidly. The slurry was stirred for several days at room temperature, then was gently heated to drive the reaction to completion. The solvent was removed, the residue was extracted with pentane, the amine hydrochloride was filtered and the pentane was removed under reduced pressure to give the product as a yellow oil. The yield was 3.150 (92.5%). Mass spec: m/e 309. 1H NMR (C6D6) δ 2.75 (s, 1H), 1.95 (s, 6H), 1.82 (s, 6H),1.08 (s, 9H), 0.51 (s, 1H), 0.24 (s, 6H), 0.16 (s, 6H); 13C NMR (C6D6) δ 135.2, 134.4, 55.2, 50.3, 34.1, 14.9 11.6, 3.3, -1.4.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][P:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25](Cl)=[CH:24][N:23]=3)=[C:17](OC)[CH:16]=2)(=[O:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH:44]([O-])=[O:45].[NH4+]>[Pd]>[CH3:44][O:45][C:15]1([P:11]2(=[O:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:16]=[CH:17][C:18]([NH:21][C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[CH:25]=[CH:24][N:23]=2)=[CH:19][CH2:20]1
Reactant: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Product: COC1(P2(=O)CCNCC2)C=CC(Nc2nccc(Nc3ccccc3S(=O)(=O)C(C)C)n2)=CC1
Yield: 42 %

Procedure:
A flask was charged with N2-[4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-5-chloro-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine (40.0 mg, 0.0625 mmol) and 10% Pd—C (40.0 mg). The flask was evacuated and filled with nitrogen. Anhydrous methanol (2 mL) was added to the flask and the flask was equipped with a reflux condenser with a nitrogen inlet. Ammonium formate (31.5 mg, 0.500 mmol) was added in one portion at room temperature. The resulting mixture was stirred at reflux for 3 h. The reaction was filtered through a Celite pad and the Celite was washed with 2×5 mL methanol. The combined filtrate and washing was evaporated in vacuo. The crude residue was purified by prep-HPLC to afford the final compound (13.6 mg, 42% yield). MS/ES+: m/z=516.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[C:35](Cl)(=[O:37])[CH3:36]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:35](=[O:37])[CH3:36])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1.Cl[CH2:14][CH2:15][CH2:16][C:17]#[N:18]>C(OCC)C.C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:17]2[CH2:16][CH2:15][CH2:14][N:18]=2)=[CH:7][CH:6]=1
Reactant: N#CCCCCl
Reactant: ClCc1ccc(Cl)cc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Clc1ccc(CC2=NCCC2)cc1
Reaction time: 0.75 h

Procedure:
Magnesium turnings (4.04 g, 168 mmol) are introduced into diethyl ether abs. (10 ml), and the formation of the Grignard reagent is started with a crystal of iodine and 4-chlorobenzyl chloride (2.2 ml, 2.7 g, 16.8 mmol). The remaining amount of 4-chlorobenzyl chloride (19 ml, 24 g, 148.7 mmol), dissolved in diethyl ether abs. (150 ml), is added dropwise (45 min) such that the mixture boils vigorously. After addition is complete, the mixture is refluxed by heating for a further 1.5 h. A solution of 4-chlorobutyronitrile (16.6 g, 160 mmol) in diethyl ether abs. (150 ml) is added dropwise to the solution of the 4-chlorobenzyl Grignard reagent prepared in this way (45 min), the mixture is stirred for a further 45 min after the addition, toluene abs. (200 ml) is added and diethyl ether is distilled off over a bridge until a temperature of 95° C. is reached in the bottom (2.5 h). The mixture is cooled in an ice bath and dil. HCl (10%) is added at 25-30° C. until a pH of 2-3 is reached in the depositing aqueous phase. The toluene/ether phase is separated and extracted 3 times with HCl (10%, 150 ml). The collected HCl phase is washed again with toluene (100 ml) and then rendered alkaline (pH 9-10) with NaOH (32%). The depositing oily pyrroline phase is taken up in diethyl ether (300 ml), dried over K2CO3 and concentrated. The concentrated ether phase (to 50%-55% product content) is used without further purification.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Li+].Cl.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[C:35]([NH2:36])=[CH:34][NH:33][N:32]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.O.O.CN(C=O)C>[NH:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:22]=[C:23]1[C:31]1[C:35]([NH:36][C:3](=[O:18])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:34][NH:33][N:32]=1
Reactant: COC(=O)c1ccccc1OCCN1CCCC1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)c1ccccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.3 %

Procedure:
2-(2-Pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester (125 mg, 0.50 mmol) and lithium hydroxide (21 mg, 0.50 mmol) were dissolved in THF/H2O (1:1, 2 ml) and the mixture stirred at ambient temperature for 20 h. The reaction mixture was reduced in vacuo and azeotroped with toluene (3×5 ml) to give a white solid, which was dissolved in water (1 ml) and acidified with 2 M aqueous HCl (1 ml). The resulting solution was reduced in vacuo and azeotroped with toluene (3×5 ml) to give a pale yellow gel, which was combined with 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.50 mmol), EDC (116 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) and stirred at ambient temperature in DMF (3 ml) for 20 h. The reaction mixture was reduced in vacuo and purified by flash column chromatography [SiO2, CH2Cl2/MeOH (95:5, 87.5:12.5) then 120 DMAW] to give N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzamide (63 mg, 30%) as a pale pink solid. (LC/MS: Rt 2.08, [M+H]+ 417.11).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:34][CH3:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:22]>>[CH2:34]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:32][CH2:33]1)[CH3:35]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)CCCCC1CCNCC1
Product: CCN(CC)CCCCC1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 43 %

Procedure:
Prepared analogously to Example 1 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[4-(diethylamino)butyl]piperidine in a yield of 43% of theory.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]=[CH:19][NH:20][C:21](=[O:23])[CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(#N)C>[Pd].C(O)C>[N:14]1([C:17]2[N:18]=[CH:19][NH:20][C:21](=[O:23])[CH:22]=2)[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCN(c2cc(=O)[nH]cn2)CC1
Agent: [Pd]
Solvent: CC#N
Solvent: CCO
Product: O=c1cc(N2CCNCC2)nc[nH]1
Reaction time: 6 h
Yield: 63.7 %

Procedure:
A mixture of 4-(6-oxo-1,6-dihydro-pyrimidin-4-yl)-piperazine-1-carboxylic acid benzyl ester (Intermediate 3; 2.00 g, 7.14 mmol) and a catalytic amount of 10% palladium on carbon in ethanol (300 mL) was hydrogenated at atmospheric temperature and pressure. The starting material is not readily soluble in ethanol so it is clearly visible. After 6 h, the amount of starting material was significantly reduced. Hydrogenation was continued overnight, and a large amount of solid was present. Acetonitrile (300 mL) was added and the mixture was heated to dissolve the solid. The catalyst was filtered off using Celite, and the solvent was evaporated from the filtrate to give 6-piperazin-1-yl-3H-pyrimidin-4-one (820 mg, 64%) as a white solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:18]([OH:20])=[O:19].[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([CH2:43]O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[C:30]([O:34][C:35]([N:37]1[CH2:38][CH2:39][C:40]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([CH2:43][O:19][C:18](=[O:20])[C:17]2[CH:16]=[C:15]([C:14]([F:28])([F:29])[F:13])[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=2)[CH2:41][CH2:42]1)=[O:36])([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (897 mg) was added to a stirred solution of 3,5-bis(trifluoromethyl) benzoic acid (292 mg) and 4-dimethylaminopyridine (483 mg) in dry dimethylformamide (20 ml). The resulting solution was stirred for 30 minutes then the compound of step (a) above (1.0 g) was added. The resulting solution was stirred at room temperature for 19 hours. At this time the reaction was diluted with water (200 ml) and extracted into ethyl acetate. The organic layers were separated, washed with water, brine, and dried over MgSO4. Filtration and removal of solvent under reduced pressure afforded a yellow oil. Purification by chromatography on silica gel (20% ethyl acetate/n-hexane) afforded the product as a clear oil. 1H NMR (360 MHz, CDCl3) δ 1.4 (9H, s), 1.95 (2H, m), 2.3 (2H, m), 3.03 (2H, m), 3.8 (2H, m), 4.35 (2H, s), 7.0-7.2 (5H, m), 8.01 (1H, s), 8.25 (2H, s).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16]>C1COCC1>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:16][C:15]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[Cl:13])[CH3:11])[N:5]=1)[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cc(C)c(N)c(Cl)c1
Solvent: C1CCOC1
Product: CC(=Nc1c(C)cc(C)cc1Cl)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 22 °C
Yield: 74.7 %

Procedure:
To a solution of 2,6-diacetylpyridine (35 g, 0.21 mol) in THF (1.21) was added 2-chloro-4,6-dimethylaniline (76.7 g, 2.3 eq) and Sicapent (45 g). The reaction mixture was refluxed overnight. Then additional 2-chloro-4,6-dimethylaniline (25 g, 0.7 eq) and Sicapent (25 g) were added and once again refluxed overnight. The suspension was cooled to 22° C., filtered and washed with two times THF (75 ml). The mother liquor was concentrated (90%) and methanol was added to precipitate the product, which was washed two times with methanol (50 ml) and dried under high vacuum. 68.8 g of a yellow powder was isolated (y=73.1%)
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:30])[CH2:24][C:25](OCC)=[O:26])[CH2:19][CH2:18]2)[N:4]=1.[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>CS(C)=O>[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:30])[CH2:24][C:25]([NH:35][CH2:31][CH2:32][CH2:33][CH3:34])=[O:26])[CH2:19][CH2:18]2)[N:4]=1
Reactant: CCCCN
Reactant: CCOC(=O)CC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Product: CCCCNC(=O)CC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 140 °C
Yield: 53 %

Procedure:
A mixture of 4 g of the compound prepared in Example 18 and 30 ml of n-butylamine in 10 ml DMSO is warmed at 140° C. for 20 h in a closed flask. The solution is evaporated under vacuum, the oily residue is treated with 200 ml H2O and extracted with CHCl3 (3×50 ml). The vitrous residue, obtained by evaporating the organic phase, is dissolved in 40 ml EtOH 95%, the solution is added with 10 ml KOH 0.3N and warmed to reflux for 30'. The residue obtained by evaporation of the solution is purified by flash chromatography on SiO2 column eluting with a CHCl3 /MeOH gradient from 100:3 to 100:10. The crude product, obtained by evaporating the fractions containing the pure compound, is dissolved in 75 ml EtOH, the solution acidified with HCl in EtOH 4N and the hydrochloride is collected by filtration, crystallized from EtOH 90% giving 2.5 g (53%) of the wanted compound; m.p.: 260°-262° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH2:7].Cl.[CH3:14][NH:15][O:16][CH3:17].CN1CCOCC1>C1(C)C=CC=CC=1.ClCCl.O>[CH2:5]([O:8][CH2:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])[CH:6]=[CH2:7]
Reactant: CNOC
Reactant: C=CCOCC(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Solvent: O=S(Cl)Cl
Product: C=CCOCC(=O)N(C)OC
Temperature: 65 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
Thionyl chloride (1.5 L) is added in one portion to a solution of 2-(allyloxy)acetic acid (2.2 Kg, 18.9 mol) in toluene (3.0 L), and the mixture is heated at 65° C. under a nitrogen atmosphere for 1 h. The mixture is cooled to room temperature and is added to a solution of N,O-dimethylhydroxylamine hydrochloride (2.1 Kg, 21.5 mol) and N-methyl morpholine (6.5 L, 59.2 mol) in dichloromethane (19 L) at 5° C. The reaction mixture is stirred at 25° C. for 16 h. Water is added, and the reaction mixture is extracted with dichloromethane. The combined organic phase is collected and washed with 1 M HCl (6 L), dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with ethyl acetate in hexanes to afford the title compound (1.49 Kg, 50%). ES/MS m/e: 160 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[C:12]([O:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22])(=[O:16])[C:13]([CH3:15])=[CH2:14]>CC(C)=O>[OH:11][C:4]1[CH:3]=[C:2]([NH:1][C:21]([NH:20][CH2:19][CH2:18][O:17][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:22])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: C=C(C)C(=O)OCCN=C=O
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc(C(=O)O)c(O)c1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
15.3 g (0.1 mol) 4-amino-2-hydroxy-benzoic acid was dissolved in 100 ml acetone. 17.06 g (0.11 mol) 2-isocyanatoethyl methacrylate was dissolved in 15 ml acetone and added dropwise to the 4-amino-2-hydroxy-benzoic acid solution. The temperature rose to 32° C. during the addition. The reaction was allowed to continue for two hours at room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in a mixture 200 ml acetone and 50 ml methanol. The solution was added to 1 l water while stirring. 2-hydroxy-4-{3-[2-(2-methyl-acryloyloxy)-ethyl]-ureido}-benzoic acid precipitated from the medium and was isolated by filtration. 2-hydroxy-4-{3-[2-(2-methyl-acryloyloxy)-ethyl]-ureido}-benzoic acid was washed twice with 150 ml water and dried. 28.5 g (92.5%) of 2-hydroxy-4-{3-[2-(2-methyl-acryloyloxy)-ethyl]-ureido}-benzoic acid was isolated (melting point: 208-210° C.)
Reaction SMILES: [CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([OH:19])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C:6]1=[CH:5][CH2:4][C:3]2=[O:20].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([O:19][C:21](=[O:23])[CH3:22])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C:6]1=[CH:5][CH2:4][C:3]2=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC=C12
Reaction time: 4 h

Procedure:
Mix 13β-methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17one with pyridine (3 cc) and acetic anhydride (1 cc) and keep at room temperature for 4 hours. Add ethanol (1 cc) and remove low-boiling material under reduced pressure (0.1 mm) to leave a red gum which crystallizes from a mixture of ethyl acetate and light petroleum. Recrystallize from methanol to obtain crystals of 13β-methyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one, melting partially at 161°-166° with resolidification at about 220° and finally melting at 260°-265° (decomp.); infrared absorption peaks at 5.75 μ and 8.27 μ, with absence of an absorption band due to a hydroxy group; ultraviolet absorption peak at 307.5 mμ (ε24,000).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:9][CH3:10])[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1.CO.COC1CCSCC=1.OC1C(O)=[C:29]([O:32][CH3:33])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>CC1C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH3:33][O:32][C:29]1[C:1]2[O:2][C:3]3([O:9][C:10]=2[C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=1)[CH2:8][CH2:7][S:6][CH2:5][CH2:4]3
Reactant: COC1(OC)CCSCC1
Reactant: COc1ccc(C(=O)O)c(O)c1O
Agent: COC1=CCSCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C(=O)O)c2c1OC1(CCSCC1)O2
Temperature: 145 °C
Yield: 60.4 %

Procedure:
P-Toluenesulfonic acid (97 mg, 0.51 mmol) was added to 4,4-dimethoxytetrahydro-(4H)-thiopyran (20.7 g, 128 mmol) and the mixture was heated to 145° C. and kept at that temperature until approximately one equivalent of methanol (5.17 mL, 128 mmol) was distilled off. The mixture was then cooled to 130° C. and distillation under reduced pressure afforded 10.1 g of a 5:3 mixture of 5,6-dihydro-4-methoxy-(2H)-thiopyran [1H NMR (DMSO) δ 4.87 (m, 1H), 3.44 (s, 3H), 3.15 (dt, 2H), 2.72 (t, 2H), 2.22 (m, 2H)] and 4,4-dimethoxytetrahydro-(4H)-thiopyran. Without further purification the mixture was added to 2,3-dihydroxy-4-methoxybenzoic acid (2.00 g, 10.9 mmol) and the suspension was exposed to microwave heating (180° C., one hour) in a sealed reaction vessel. Ethyl acetate (100 mL) was added and the organic phase was first washed with 0.5 M HCl (40 mL) and then extracted with saturated aqueous NaHCO3 (2×30 mL). The aqueous phase was washed with Et2O (2×40 mL), acidified to pH=1 with concentrated HCl and extracted with dichloromethane (2×30 mL). The organic phase was dried over MgSO4. Evaporation under reduced pressure afforded 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylic acid (1.86 g, 61%). 13C NMR (DMSO) δ 164.9, 148.2, 146.6, 134.5, 123.8, 118.0, 107.2, 106.9, 56.1, 35.9, 25.4.