Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[N:10][CH:11]=1.[CH3:21]O>>[OH:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([O:17][CH3:21])=[O:16])=[N:8][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1cccc(-c2ncc(O)cn2)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(-c2ncc(O)cn2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
32.7 ml (445 mmol) of thionyl chloride are added to a suspension of 88.0 g (366 mmol) of 3-(5-hydroxypyrimidin-2-yl)benzoic acid in 1.4 l of methanol, and the mixture is heated at 80° C. for 2 hours. 20 ml (276 mmol) of thionyl chloride and, after 2 hours, a further 10 ml (138 mmol) of thionyl chloride are then added. After each addition, the reaction mixture is stirred at 80° C. for 2 hours. The reaction mixture is concentrated to a volume of about 300 ml in vacuo. The resultant precipitate is filtered off and dried in vacuo: methyl 3-(5-hydroxypyrimidin-2-yl)benzoate as brownish crystals; m.p. 219-223° C., ESI 231 (M+H); HPLC: Rt=3.87 min (method C).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:16][C:17](=[O:19])[CH3:18])[CH:11]=[N:10][C:9]=3[NH:8][C:6]2=[O:7])[CH2:3][CH2:2]1.[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:16][C:17](=[O:19])[CH3:18])[CH:11]=[N:10][C:9]=3[N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:2][CH2:3]1
Reactant: BrC1CCCC1
Reactant: CC(=O)Cn1cnc2[nH]c(=O)n(CC3CC3)c(=O)c21
Product: CC(=O)Cn1cnc2c1c(=O)n(CC1CC1)c(=O)n2C1CCCC1

Procedure:
The title compound was prepared from 1-cyclopropylmethyl-7-(2-oxopropyl)xanthine and cyclopentylbromide in an analogous procedure to that of Example 19. The product was obtained as a crystalline solid; m.p. 155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:10]=O)=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][CH3:21].[OH-].[Na+].C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH2:10][N:20]([CH3:21])[CH3:19])=[CH:4][CH:3]=1
Reactant: O=CC=C(c1ccc(Cl)cc1)c1cccnc1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)CC=C(c1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
To 0.25 g (1 mmol) crude 3-(4-chlorophenyl)-3-(3-pyridyl)-2-propenal, in a flask, was added in the following order: 0.73 g (9 mmol) dimethylamine hydrochloride, 10 ml methanol, 0.24 g (6 mmol) sodium hydroxide, 0.094 g (1.5 mmol) sodium cyanoborohydride and 5 g molecular sieves (3 Å). The mixture was stirred at room temperature under nitrogen for 3 days and then 100 ml methanol were added. After filtration the methanol was evaporated and the residue dissolved in a hydrochloric solution at pH 4.9 and washed with ether twice. The aqueous solution was made alkaline, extracted twice with ether and dried over MgSO4. Evaporation gave 0.18 g (66%) of pure title compound as an isomeric mixture having an approximate Z/E ratio of 54/46 (NMR).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:28])[CH:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:10])([CH3:9])[CH3:8].Cl[C:30]1[S:34][N:33]=[C:32]([CH3:35])[N:31]=1>O1CCCC1>[C:7]([O:11][C:12](=[O:28])[C:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])([C:30]1[S:34][N:33]=[C:32]([CH3:35])[N:31]=1)[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])([CH3:9])([CH3:8])[CH3:10]
Reactant: Cc1nsc(Cl)n1
Reactant: CC(C)(C)OC(=O)C(CCCCCC#N)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nsc(C(CCCCCC#N)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 42 %

Procedure:
Potassium tert-butoxide (14.6 g, 0.13 mol) followed by 2-(5-cyanopentyl)malonic acid di-tert-butyl ester (2021050) (32.3 g, 0.1 mol) was added portionwise to stirred tetrahydrofuran (150 mL). 5-Chloro-3-methyl-1,2,4-thiadiazole (2009380) (13.5 g, 0.10 mol) was then added to the slurry and the mixture was heated at reflux overnight before being quenched with water (150 mL) and extracted with dichloromethane (3×200 mL). The combined organic fractions were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (6:1 hexane/ethyl acetate) to afford 2-(5-cyanopentyl)-2-(3-methyl[1,2,4]thiadiazol-5-yl)malonic acid di-tert-butyl ester (2021051) (17.2 g, 42%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=1>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[C:2]([NH:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=2[F:28])(=[O:26])=[O:25])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: CN(C)C(=O)CCSc1ccc(Cl)cc1N
Solvent: c1ccncc1
Product: CN(C)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Yield: 74.3 %

Procedure:
Following General Procedure B, the title compound (476 mg, 75%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide (364 mg, 1.42 mmol) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride (325 mg, 1.42 mmol) in pyridine (5 ml).
Reaction SMILES: [CH:1]1([C@@H:4]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[N:5]2[CH2:10][CH2:9][C@:8]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:22])[CH2:3][CH2:2]1.BrC1C=CC([C@H](C2CC2)N2CC[C@](CC(O)(C)C)(C3C=CC=CC=3)OC2=O)=CC=1.Cl[C:68]1[N:69]=[N:70][C:71]([CH3:74])=[CH:72][CH:73]=1>>[CH:1]1([C@@H:4]([C:23]2[CH:28]=[CH:27][C:26]([C:68]3[N:69]=[N:70][C:71]([CH3:74])=[CH:72][CH:73]=3)=[CH:25][CH:24]=2)[N:5]2[CH2:10][CH2:9][C@:8]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:7][C:6]2=[O:22])[CH2:2][CH2:3]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Reactant: Cc1ccc(Cl)nn1
Agent: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(Br)cc2)C2CC2)C(=O)O1
Product: Cc1ccc(-c2ccc([C@H](C3CC3)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from 3-{(S)-cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one {prepared in analogy to the intermediate in Example 3 from 3-[(S)-(4-bromo-phenyl)-cyclopropyl-methyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one} and 3-chloro-6-methyl-pyridazine following a procedure analogous to that described in Example 3. LC-MS (Method 1): tR=3.39 min; Mass spectrum (ESI+): m/z=472 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(CCl)cc1
Product: CCOP(=O)(Cc1ccc(OC)cc1)OCC

Procedure:
p-Methoxybenzyl chloride was reacted with triethyl phosphite as described in Example 2.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[N:16]1(C(N)=O)[CH2:20]CC[CH2:17]1>>[CH3:17][N:16]([CH3:20])[C:13](=[O:15])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(C(=O)C2CC2)cc1
Reactant: NC(=O)N1CCCC1
Product: CN(C)C(=O)Cc1ccc(C(=O)C2CC2)cc1

Procedure:
(4-cyclopropanecarbonyl-phenyl)-acetic acid, pyrrolidineamide;
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:32]([CH3:43])[CH:31]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]=3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>ClCCCl>[CH3:43][C:32]1[CH:31]=[C:30]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]3[NH:15][C:14]4[C:9]([C:8]=3[CH:7]=2)=[CH:10][CH:11]=[C:12]([C:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=2)[CH:13]=4)[CH:35]=[CH:34][C:33]=1[CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)ccc4c3c2)ccc1CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(C5=CCNCC5)ccc4c3c2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(8-carbamoyl-6-(3-methyl-4-(morpholinomethyl)phenyl)-9H-carbazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate 484 (3 mg, 5.17 μmol) was mixed with TFA (0.2 mL, 2.60 mmol) in 1,2-Dichloroethane (0.4 mL). The mixture was stirred at r.t. for 1 hr. The mixture was concentrated to give the titled product as TFA salt. MS (ESI) m/z 481.07 (M+H)+. 1H NMR (MeOD-d4) δ ppm 8.60 (d, 1H, J=1.8), 8.27 (d, 1H, J=1.8), 8.21 (d, 1H, J=8.2), 7.87 (s, 1H), 7.82 (dd, 1H, J=7.9, 1.5), 7.75 (d, 1H, J=1.3), 7.63 (d, 1H, J=7.9), 7.43 (dd, 1H, J=8.2, 1.5), 6.31 (bs, 1H), 4.51 (s, 2H), 4.1-3.85 (m, 6H), 3.56 (t, 2H, J=6.1), 3.47-3.2 (m, 4H), 2.98 (bs, 2H), 2.63 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](/[C:21]([OH:23])=[O:22])\[CH3:20])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([CH3:29])[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2].[CH:31]1(Br)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](\[CH3:20])/[C:21]([O:23][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([CH3:29])[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)O
Reactant: BrC1CCCCC1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)OC1CCCCC1

Procedure:
From Compound A and cyclohexyl bromide stirring for 20 h at 40°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:27]=[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CCCCCCCCC(=N)NO
Solvent: Cc1ccccc1
Product: CCCCCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Reaction time: 1.25 h

Procedure:
To a solution of 0.59 g (2.84 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 6 mL of toluene, 0.503 g (3.1 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 5 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxynonanimidamide (compound of example 47; 1.0 g, 3.8 mmol) diluted with 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: OB(O)c1ccc(F)cc1F
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccc(F)cc2F)s1
Yield: 33 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and 2,4-difluorophenylboronic acid (9 mg, 0.06 mmol). The title compound was obtained in 33% yield (6.9 mg). MS (ESI+) calcd mass for C17H11F2N5O2S2 419.032222, found 419.032372.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[CH:15]=[C:14](/[C:16](/[C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[C:25]([O:31][CH3:32])[N:24]=2)=[CH:17]\[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=[CH:12][C:11]=1[OH:33].O>CN(C)C=O>[Cl:9][C:10]1[CH:15]=[C:14](/[C:16](/[C:23]2[N:24]=[C:25]([O:31][CH3:32])[C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=2)=[CH:17]\[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH:13]=[CH:12][C:11]=1[O:33][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: CCc1ccc(/C(=C/C2CCCC2)c2ccc(O)c(Cl)c2)nc1OC
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(/C(=C/C2CCCC2)c2ccc(OC)c(Cl)c2)nc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
Potassium carbonate (188 mg) and methyl iodide (73 μL) were sequentially added to a solution of 2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenol (163 mg) in N,N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for four hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→2:1) to give 6-[(E)-1-(3-chloro-4-methoxyphenyl)-2-cyclopentylethenyl]-3-ethyl-2-methoxypyridine as a yellow oil (131 mg, 77%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:8][C:7]([SH:9])=[N:6][N:5]=1)[CH3:2].[H-].[Na+].Cl[C:13]1[C:14]([C:19]#[N:20])=[N:15][CH:16]=[CH:17][N:18]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:3][C:4]1[S:8][C:7]([S:9][C:13]2[C:14]([C:19]#[N:20])=[N:15][CH:16]=[CH:17][N:18]=2)=[N:6][N:5]=1)[CH3:2]
Reactant: CCSc1nnc(S)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedure described in Example 1 by using 5-(ethylthio)-1,3,4-thiadiazole-2-thiol (592 mg, 3.33 mmol), NaH (60% dispersion in mineral oil, 146 mg, 3.66 mmol), and 3-chloropyrazine-2-carbonitrile (422 mg, 3.02 mmol) in DMF and benzene (8 ml, 1/1) by stirring at 90° C. under nitrogen atmosphere overnight.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10](O)[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:14])([O-])=O.OP(O)(O)=O>C1COCC1.[Pd]>[CH2:10]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:13][CH3:14])[C:4]=1[NH2:1])[CH3:11]
Reactant: COc1cccc(C(C)O)c1[N+](=O)[O-]
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Product: CCc1cccc(OC)c1N
Reaction time: 8 h
Yield: 42.9 %

Procedure:
The compound of Example 27B (310 mg) was dissolved in 10 mL of THF; 1.5 mL of H3PO4 was added, followed by 50 mg of 10% palladium-on-charcoal. The resultant mixture was purged with nitrogen, then placed under a balloon of hydrogen, and stirred overnight. Bicarb was added carefully, and the mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc; the organic extracts were washed with bicarb and brine, and were concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1:1 ether/hexanes, to give 102 mg (43% yield) of the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19][Cl:20])=[CH:12][CH:11]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:20][CH2:19][CH2:18][C:17]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[C:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][OH:3])=[CH:15][CH:14]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)COCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCOCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Yield: 68 %

Procedure:
{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-acetic acid ethyl ester was dissolved in tetrahydrofuran at room temperature under nitrogen atmosphere. Lithium aluminium hydride was added to the solution in small portions until the reduction reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution. The product was extracted into toluene, which was dried and evaporated in vacuo. The residue was purified with flash chromatography with toluene/triethyl amine (9.5:0.5) as eluent. Yield 68%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[CH:7][C:6]=2[CH:12]=1.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][C:6]=2[CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc2cc(F)ccc2o1
Solvent: Cc1ccccc1
Product: Fc1ccc2oc(CBr)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Compound 14 (150 mg, 0.90 mmol) was dissolved in toluene (10 mL) and the solution was cooled to 0° C. PBr3 (102 μL, 1.08 mmol) was added dropwise over 15 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 15 (150 mg, 72%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 7.43 (1H, d, J=7.60 Hz, H-7), 7.21 (1H, t, J=8.10, H-4), 7.06 (1H, t, J=8.90, H-4), 6.75 (1H, s, H-3), 4.60 (2H, s, 2-CH2). 13C NMR CDEPT 135, (500 MHz, CDCl3): δ: 113.08 (C-7), 112.08 (C-6), 106.87 (C-4), 106.34 (C-3), 60.42 (CH2—Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][C:9]1[C:10]([CH3:33])=[C:11]([C:18]([C:20]2[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=2)[C:25]([O:27][CH3:28])=[O:26])=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)=[O:7].[CH3:37]I>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([N:8]([CH3:37])[C:9]1[C:10]([CH3:33])=[C:11]([C:18]([C:20]2[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=2)[C:25]([O:27][CH3:28])=[O:26])=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)=[O:7]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(NC(=O)c3cccc(OC)c3)c3ccccn23)ccc1[N+](=O)[O-]
Reactant: CI
Product: COC(=O)c1cc(C(=O)c2c(C)c(N(C)C(=O)c3cccc(OC)c3)c3ccccn23)ccc1[N+](=O)[O-]
Yield: 84 %

Procedure:
This compound is prepared according to the protocol described in the example above by methylating 1.9 g (3.9 mmol) of methyl 5-({1-[(3-methoxybenzoyl)amino]-2-methylindolizin-3-yl}carbonyl)-2-nitrobenzoate with methyl iodide. 1.85 g of a red solid are obtained.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C:12]1[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C@@H:15]([OH:36])[CH2:14][CH:13]=1)(=O)C.[OH-].[K+]>ClCCl>[CH2:29]([O:28][C:24]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([OH:36])[CH2:14][CH:13]=4)[C@H:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[CH2:27][C:26]=2[CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3C1=CC[C@@H]2O
Yield: 94.2 %

Procedure:
2.16 g of 7α-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14-tetraen-17β-ol is saponified with 38 ml of 1N methanolic potassium hydroxide solution overnight at room temperature. The reaction mixture is poured into ice-cold saturated common salt solution, the precipitate is suctioned off, taken up in dichloromethane, washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. 1.86 g of 3-benzyloxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),14-tetraen-17β-ol is obtained as foam.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[CH3:12][O:13][C:14](=O)[O:15]C.Cl>O1CCCC1.CCCCCC>[CH3:3][C:4]1([CH3:11])[CH2:9][CH:8]([C:14]([O:13][CH3:12])=[O:15])[C:7](=[O:10])[CH2:6][CH2:5]1
Reactant: COC(=O)OC
Reactant: CC1(C)CCC(=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C1CC(C)(C)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of hexane-washed NaH (0.72 g, 60%, 18 mmol) in tetrahydrofuran (30 mL) was added a solution of 4,4-dimethylcyclohexanone (2.0 g, 15.6 mmol) in tetrahydrofuran (20 mL). The suspension was stirred at room temperature for 30 minutes. Then dimethylcarbonate (6.31 mL, 75 mmol) was added dropwise by syringe. The mixture was heated to reflux for four hours. The mixture was acidified with 5% HCl and extracted with dichloromethane (100 mL×3) and washed with water, brine, and dried over Na2SO4. After concentration, the crude product was loaded on a column and eluted with 10% ethyl acetate in hexane to give title compound.
Reaction SMILES: [CH2:1]([C:8]1([OH:31])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32][S:33]([OH:36])(=[O:35])=[O:34]>CO>[CH2:1]([C:8]1([OH:31])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[O:18])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:33]([O-:36])([O-:35])(=[O:34])=[O:32]
Reactant: O=S(=O)(O)O
Agent: Cc1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)c2ccccc2n1
Solvent: CO
Product: O=S(=O)([O-])[O-]
Temperature: -2 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea (21.36 kg) in CH3OH (178 L) is added aqueous H2SO4 (6 L, 9.91%) during 10 min. The clear solution is filtered and further aqueous H2SO4 (33.8 L, 1.07 M) is added during 45 min. The solution is cooled to −2° C. during 1.5 h and stirred at −5 to −9° C. for 1 h. The formed precipitate is filtered, washed with cooled CH3OH (−5° C., 54 L) and dried under a stream of nitrogen provide 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I sulfate as a non-defined hydrate. A slurry of the so obtained salt in H2O (16.2% w/w) is stirred for 3 days at 25° C. Filtration and drying at 30° C. under a wet stream of nitrogen (50% RH) provides the title compound.