Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([CH:33]=2)[C:31]#[N:32])O1>>[C:31]([C:30]1[CH:33]=[C:26]([C:2]2[CH:7]=[N:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=2)[CH:27]=[N:28][CH:29]=1)#[N:32]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cn1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cncc(C#N)c2)cn1
Yield: 49 %

Procedure:
Prepared in a similar manner to Example 23 from 2-(5-bromopyridin-2-yl)-N-isobutyl-2-methylpropanamide (example 42a) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile. Yield 49%. 1H NMR (400 MHz, acetonitrile-d6): δ 0.80-0.81 (d, 6H), 1.63 (s, 6H), 1.71-1.77 (m, 1H), 2.97-3.00 (t, 2H), 7.01 (bs, 1H), 7.59-7.62 (d, 1H), 8.18-8.21 (dd, 1H), 8.59-8.60 (t, 1H), 8.99 (d, 1H), 9.20-9.21 (d, 1H); MS+H (323).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][S:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O.[NH2:31][C@@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[OH:38].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH:38][C@H:33]1[CH2:34][CH2:35][CH2:36][CH2:37][C@H:32]1[NH:31][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[N:27][C:19]=1[O:18][C:17]1[CH:28]=[CH:29][CH:30]=[C:15]([S:14][CH3:13])[CH:16]=1
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Reactant: N[C@@H]1CCCC[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncccc2C(=O)N[C@@H]2CCCC[C@@H]2O)c1
Reaction time: 18 h
Yield: 48.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) was added to a solution of 2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.765 mmol), (1S,2R)-2-aminocyclohexanol hydroformate [8151/194/1] (128 mg, 0.765 mmol), 1-hydroxybenzotriazole (114 mg, 0.842 mmol) and triethylamine (430□l, 3.10 mmol) in dimethylformamide (5 ml) under nitrogen at room temperature. The reaction was stirred for 18 h and partitioned between diethyl ether (25 ml) and water (25 ml). The organic phase was washed with brine (30 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate: cyclohexane (35:65 to 50:50) to give an off-white solid which was purified by flash column chromatography using ethyl acetate:cyclohexane (50:50 as eluant) to give N-[(1R,2S)-2-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (133 mg) as a gum.
Reaction SMILES: O.[CH3:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[C:13](Cl)([Cl:15])=[S:14]>Cl>[CH3:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][C:13]([Cl:15])=[S:14]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1NC(=S)Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.25 l of water are added to a solution of 130 mmol (20 g) of 2-methyl-5-nitroaniline in 375 ml of concentrated hydrochloric acid. At a temperature of 0° C., 162 mmol (19 g) of thiophosgene are poured in in one go. The reaction mixture is stirred vigorously for 24 hours at ambient temperature. The precipitate formed is filtered off and then taken up in diethyl ether. The organic phase is washed with water, dried over magnesium sulphate and concentrated to yield the expected product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3c(F)cccc3F)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Nc1ccc(S(=O)(=O)N2CCN(c3c(F)cccc3F)CC2)cc1

Procedure:
In the manner given in Example 5B, 1-[(p-nitrophenyl)sulfonyl]-4-(2,6-difluorophenyl)piperazine is reduced with titanium trichloride to give 1-[(p-aminophenyl)sulfonyl]-4-(2,6-difluorophenyl)piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[CH2:10]([NH2:12])[CH3:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:12][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: BrCc1ccc(Br)cc1
Product: CCNCc1ccc(Br)cc1
Yield: 75.9 %

Procedure:
Following the procedure outlined for Example 488, 1-bromo-4-(bromomethyl)benzene (2.0 g, 8.0 mmol) was reacted with ethanamine (720 mg, 16 mmol) to afford the desired product (1.3 g, 75%) as a brown solid: ESI MS m/z 215 [C9H12BrN+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([NH:20][CH2:21][OH:22])=[O:19])=[C:16]([CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(Cl)=O.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:27])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([NH:20][CH2:21][O:22][CH2:9][C:26]([F:29])([F:28])[F:27])=[O:19])=[C:16]([CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCO
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCOCC(F)(F)F
Yield: 119.3 %

Procedure:
In a solution of 1.70 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-(hydroxymethyl)benzoic acid amide in 20 mL of dichloromethane, 0.68 g of thionyl chloride was added at room temperature with stirring, and stirred at the same temperature for 2 hours. Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in 10 mL of tetrahydrofuran. 1.50 g of 2,2,2-trifluoroethanol was added dropwise in a suspension of 0.33 g of 60% oily sodium hydride in 30 mL of tetrahydrofuran under cooling with ice and with stirring, and stirred at the same temperature for 10 minutes. Then, in this reaction mixture, the tetrahydrofuran solution of benzoic acid chloride prepared above was added dropwise under cooling with ice and with stirring. After the completion of the addition dropwise, it was continued to stir at room temperature for 1 hour. After the completion of the reaction, 50 mL of water was added in the reaction mixture, extracted with ethyl acetate (70 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 1.20 g of the aimed product as colorless resinous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH:24]=[N:23][C:22]([NH2:25])=[N:21]1>>[Cl:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH:24]=[N:23][C:22]([NH:25][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:21]1
Reactant: Nc1ncn(Cc2ccccc2Cl)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(Cc4ccccc4Cl)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(2-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless solid (Yield=11%). MS ISP (m/e): 390.3 (100) [(M+H)+].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(=O)OCC)=S)=[N:18][CH:19]=2)=[O:8])=[CH:5][C:4]([CH3:33])=[N:3]1.[Cl-].O[NH3+].C([N:40](CC)C(C)C)(C)C.C(O)C>O.CO>[NH2:23][C:21]1[N:20]=[C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=4)=[O:8])[CH:11]=3)=[CH:19][N:18]2[N:40]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(C)c(NC(=O)c3cc(C)nn3C)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: O
Solvent: CO
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)nn4c3)ccc2C)n(C)n1
Yield: 75.4 %

Procedure:
A mixture of N-{5-[(6-aminopyridin-3-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (214 mg, 0.634 mmol), ethyl isothiocyanatoformate (108 mg, 0.824 mmol) and DMSO (5 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl) carbonyl]amino}-4-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (280 mg, 94%) as a white solid. A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (270 mg, 0.576 mmol) thus-obtained, hydroxylammonium chloride (280 mg, 4.03 mmol), N,N-diisopropylethylamine (502 μL, 2.88 mmol), ethanol (10 mL) and methanol (10 mL) was stirred at 80° C. for 8 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (164 mg, 75%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[S:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:30][NH:31][C:32]([NH:34][OH:35])=[NH:33].[ClH:36]>C(O)C>[ClH:36].[OH:35][NH:34][C:32]([NH:31][N:30]=[C:10]1[CH2:9][CH:8]([C:13]2[S:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)=[NH:33]
Reactant: N=C(NN)NO
Reactant: Cc1ccc(C2CC(=O)c3c(C)ccnc3C2)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C2CC(=NNC(=N)NO)c3c(C)ccnc3C2)s1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-7-(5-methyl-2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (257 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (285 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (10 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (1 ml), and the mixture was concentrated under reduced pressure. The residue in ethanol (1 ml) was stirred at room temperature for 15 hours to give crystals, which were filtered and dried to give 5-(1-hydroxyguanidin-3-yl)imino-4-methyl-7-(5-methyl-2-thienyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 98) (163 mg) as pale yellow crystals.
Reaction SMILES: [NH:1]1[C:10](N)=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[N:4][C:2]1=S>C(O)CC.[Ni]>[N:1]1[CH:10]=[C:9]2[C:5](=[N:6][CH:7]=[N:8]2)[NH:4][CH:2]=1
Reactant: Nc1[nH]c(=S)nc2nc[nH]c12
Agent: [Ni]
Solvent: CCCO
Product: c1nc2cnc[nH]c-2n1
Yield: 59 %

Procedure:
4.39 g (I1 mmoles) of thioisoguanine and 7.10 g (121 mmoles) of neutral Raney-nickel are refluxed in 50 ml of 1-propanol for 4.5 hours. The nickel was filtered off and the filtrate evaporated to dryness. The residue (3.79 g/93.8%) was dissolved in 20 ml of chloroform and 0.4 ml methanol and filtered through 24 g of silicagel in a column also with 2% methanol. The combined fractions were washed with 1N NaOH and the organic phase evaporated to dryness. The residue (2.69 g/66.6%) was dissolved in 30 ml of dichloromethane and 0.6 ml methanol and again filtered through 30 g of silicagel. A total of 1.86 g (46.0%) of 3H-purine was isolated, which was dissolved in 20 ml of methanol, treated with 5.4 ml of 1N methanolic HCl, and evaporated in vacuo to dryness. Crystallization and recrystallization from dichloromethane and ethyl acetate gave 1.75 g (39.4%) of 3H-purine hydrochloride with mp 170-85° C.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]CC)=O.[N:8]([CH2:11][CH2:12][S:13]([O:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[C:9]=[S:10].N(CCS(O)(=O)=O)=C=S.C(N(CC)CC)C>ClCCCl>[O:5]=[C:3]1[CH2:2][S:1][C:9](=[S:10])[N:8]1[CH2:11][CH2:12][S:13]([O:16][CH2:17][CH3:18])(=[O:15])=[O:14]
Reactant: CCOS(=O)(=O)CCN=C=S
Reactant: CCOC(=O)CS
Agent: O=S(=O)(O)CCN=C=S
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOS(=O)(=O)CCN1C(=O)CSC1=S

Procedure:
Ethyl 2-mercaptoacetate (I-A) and ethyl 2-isothiocyanato-ethanesulfonate (I-B) or 2-isothiocyanato-ethanesulfonic acid, alternatively, are dissolved in 1,2-dichloroethane and triethylamine is added. The product ethyl 2-(4-oxo-2-thioxothiazolidin-3-yl)-ethanesulfonate (1-C) can be isolated after e.g. 1 h of stirring and subsequent solvent removement.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([O:20][CH2:21][O:22][CH3:23])=[C:6]([CH:19]=1)[C:7]([C:9]1[C:14]([O:15][CH2:16][O:17][CH3:18])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].[CH3:25][NH:26][CH3:27]>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:26]([CH3:27])[CH3:25])=[CH:4][C:5]([O:20][CH2:21][O:22][CH3:23])=[C:6]([CH:19]=1)[C:7]([C:9]1[C:14]([O:15][CH2:16][O:17][CH3:18])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: COCOc1cc(F)c(Cl)cc1C(=O)c1ncccc1OCOC
Reactant: CNC
Solvent: CN(C)C=O
Product: COCOc1cc(N(C)C)c(Cl)cc1C(=O)c1ncccc1OCOC

Procedure:
A mixture of 2-(5-chloro-4-fluoro-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine (1.98 g), a 50% aqueous solution of dimethylamine (20 ml) and DMF (50 ml) was stirred overnight at room temperature. The reaction mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous saline solution, successively, which was then dried (anhydrous magnesium sulfate). The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography (ethyl acetate/hexane) to afford 2-(5-chloro-4-dimethylamino-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine (1.82 g) (Compound F-3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH3:30])([CH3:29])[O:21][C:20]1=[O:31]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH3:29])([CH3:30])[O:21][C:20]2=[O:31])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)OC(=O)C(N)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)OC(C)(C)c2ccccc21

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine and 4-amino-1,1-dimethyl-3-isochromanone, the title compound could be prepared.
Reaction SMILES: [NH2:1][C:2](=[N:11][OH:12])[C:3](=[N:6][O:7][CH:8]([CH3:10])[CH3:9])[C:4]#[N:5].NC(=NOC(C)C)C(=N[O:19]C(C)C)C#N.OO.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CS(C)=O.CO>[NH2:1][C:2](=[N:11][OH:12])[C:3](=[N:6][O:7][CH:8]([CH3:9])[CH3:10])[C:4]([NH2:5])=[O:19]
Reactant: CC(C)ON=C(N)C(C#N)=NOC(C)C
Reactant: CC(C)ON=C(C#N)C(N)=NO
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)ON=C(C(N)=O)C(N)=NO
Reaction time: 4 h
Yield: 63 %

Procedure:
To a mixed solution of methanol (1.5 ml) and dimethyl sulfoxide (0.5 ml), of 0.50 g (2.94 mM) of the 3-amino-3-hydroxyimino-2-isopropoxyiminopropionitrile obtained in (1) of Example 1 were added, at room temperature, 0.73 g (6.4 mM) of a 30% aqueous hydrogen peroxide solution and 0.02 g (0.14 mM) of potassium carbonate. Stirring was conducted at room temperature for 4 hours. Excessive hydrogen peroxide was treated with an aqueous sodium thiosulfate solution. The solvent was distilled off under reduced pressure. Water was added to the residue and extraction with ethyl acetate was conducted. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered to remove inorganic matter. The solvent was distilled off under reduced pressure. The resulting crude crystal was washed with a 1:2 mixed solution of diisopropyl ether and n-hexane to obtain 0.35 g (yield: 63%) of the title compound.
Reaction SMILES: C([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:18](\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[CH2:19][CH2:20][Cl:21])=[CH:13][CH:12]=1)(=O)C(C)(C)C.CO.O.[OH-].[Na+]>C1COCC1>[CH:25]1[CH:26]=[CH:27][C:22](/[C:18](/[CH2:19][CH2:20][Cl:21])=[C:17](\[C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][OH:7])=[CH:12][CH:13]=2)/[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)C(=O)OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.4 %

Procedure:
(Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl pivalate (1 g, 2.16 mmol) was dissolved in THF (8 ml) followed by addition of MeOH (1 ml) and water (1 ml). Sodium hydroxide (0.1 g, 2.5 mmol) was added in one portion and the reaction was stirred at room temperature for 12 h. After completion of the reaction the mixture was partitioned between water (20 ml) and EtOAc (20 ml). Organic phase was washed with water (20 ml) and brine (20 ml), dried (Na2SO4), filtered and concentrated. The residue was crystallized from i-PrOH yielding ospemifene (0.29 g, 35%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.37 (2H, t, J=8 Hz, ArH), 7.29 (3H, t, J=7.2 Hz, ArH), 7.20 (2H, t, J=7.6 Hz, ArH), 7.16-7.13 (3H, m, ArH), 6.80 (2H, d, J=8.8 Hz, ArH), 6.57 (2H, d, J=8.8 Hz, ArH), 3.94 (2H, t, J=4.4 Hz, ArOCH2CH2OH), 3.87 (2H, m, ArOCH2CH2OH), 3.42 (2H, t, J=7.2 Hz, ClCH2CH2), 2.92 (2H, t, J=7.2 Hz, ClCH2CH2), 1.95 (1H, t, J=6.4 Hz, OH). 13C-NMR (100 MHz, CDCl3) δ (ppm): 157.2, 143.2, 142.1, 141.3, 2×135.7, 132.2, 130.0, 129.8, 128.8, 128.7, 127.4, 127.0, 113.9, 69.3, 61.8, 43.3, 39.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].N#N.CC(C)([O-])C.[Na+].ClP(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)=[CH:4][CH:3]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccc(C2OCCO2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(Cl)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(N(c2ccccc2)c2ccc(C3OCCO3)cc2)cc1

Procedure:
48.8 g (213 mmol) of 2-(4-bromophenyl)-1,3-dioxolane and 48 g (213 mmol) of (4-tert-butylphenyl)phenylamine are initially introduced in 750 ml of toluene, and the solution is saturated with N2 for about 30 min. 29.2 g (304 mmol) of sodium tert-butoxide are subsequently added in small portions, followed by 760 mg (4.2 mmol) of chlorobis-t-butylphosphine and 485 mg (2.1 mmol) of Pd(OAc)2. The mixture is refluxed for 3 h with monitoring by TLC.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])C)[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN(C4(C(OC)=O)CC4)C3=O)=CC=2)=CC=1.[Cl:58]C1C=CC(C(Cl)=O)=CC=1>>[Cl:58][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([C:26]5([C:27]([O:29][CH3:30])=[O:28])[CH2:33][CH2:31]5)[C:22]4=[O:25])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[O:8])=[CH:7][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CC1
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)CC1
Yield: 95 %

Procedure:
The compound of example 587 was prepared analogous to compound of example 97 by reaction of compound of example 584 with 4-chloro benzoyl chloride.
Reaction SMILES: [OH-].[Na+].[N:3]1[NH:4][N:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[CH:7]=1.Cl>C(O)C>[N:3]1[NH:4][N:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=1
Reactant: COC(=O)CCCOc1cn[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1cn[nH]n1
Temperature: 60 °C
Yield: 100.7 %

Procedure:
Add 1N sodium hydroxide (2.32 mL; 2.0 equiv; 2.32 mmoles) to a solution of methyl 4-(2H-triazol-4-yloxy)butanoate (0.215 g; 1.0 equiv; 1.16 mmoles) in ethanol (1 mL) and heat the mixture to 60° C. for 16 hours. Add 1N hydrochloric acid (2.32 mL; 2.0 equiv; 2.32 mmoles) and concentrate to afford 4-(2H-triazol-4-yloxy)butanoic acid (0.20 g; 100%). Use without further purification in the next step: MS (m/z): 170(M−1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:8][NH:7][CH2:6]1)=[O:4].[C:30]1([CH:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37](O)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C=C2C(N(O)N=NC2=CC=1)=O.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[C:40]1([CH:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:37]([N:7]2[CH2:8][C@H:9]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][C:15]3[N:19]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[CH:18]=[N:17][CH:16]=3)[CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]2)=[O:38])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)[C@@H]1CNC[C@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)C1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)CN(C(=O)C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
cis-3-Methoxycarbonyl-5-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine (86.8 mg, 0.219 mmol) (EXAMPLE 2, Step A) diphenyl acetic acid (302 mg, 1.42 mmol), HOOBT (54.3 mg, 0.328 mmol), EDC (63 mg, 0.328 mmol), and Et3N (392 uL, 5.34 mmol) were dissolved in DMF (4 mL) and stirred at ambient temperature for 5 days. The solution was concentrated, the residue was taken up in EtOAc, washed with sat. NaHCO3 solution, water, and brine. The organics were dried (MgSO4), concentrated, and chromatographed (silica gel, 0.5-2% MeOH/CH2Cl2 with NH4OH) to give the title compound. FAB MS=590 (M+1)