Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].CS[C:18](SC)=[C:19]1[C:28](=[O:29])[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:30][CH2:31][CH2:32][CH3:33])[C:20]1=[O:34]>C1(C)C=CC=CC=1>[CH2:30]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][N:23]=2)[C:28]([OH:29])=[C:19]([C:18]2[NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=3[S:7](=[O:8])(=[O:9])[N:10]=2)[C:20]1=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Reactant: CCCCN1C(=O)C(=C(SC)SC)C(=O)c2cccnc21
Solvent: Cc1ccccc1
Product: CCCCn1c(=O)c(C2=NS(=O)(=O)c3c(COCOC)csc3N2)c(O)c2cccnc21
Yield: 55.4 %

Procedure:
The product of Example 309G (110 mg, 0.43 mmol) and the product of Example 315B (140.6 mg, 0.43 mmol) were reacted in toluene (5 mL) at 100° C. for 3 hours. The reaction was concentrated under reduced pressure and the residue was purified by chromatography on silica gel using a Biotage-12 m column eluting with 1:99 methanol:dichloromethane to give the title compound as a white solid (114 mg, 54.6%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz,CDCCl3) δ ppm 1.00 (t, J=7.35 Hz, 3 H), 1.46 (m, 2 H), 1.74 (m, 2 H), 3.45 (s, 3 H), 4.56 (m, 2 H), 4.80 (s, 2 H), 4.84 (s, 2 H), 7.09 (s, 1 H), 7.26 (s, 1 H), 7.36 (dd, J=8.09, 4.41 Hz, 1 H), 8.57 (dd, J=8.09, 1.84 Hz, 1 H), 8.81 (dd, J=4.78, 1.84 Hz, 1 H), 15.06 (s, 1 H), 15.11 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Product: N#Cc1c(NCCN2CCOCC2)nc(N)nc1-c1cccs1

Procedure:
From 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile and 4-(2-aminoethyl)morpholine in dioxane. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:10][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=Cc1cc(I)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(I)cc2C=O)CC1
Temperature: 60 °C
Yield: 83.9 %

Procedure:
To a solution of 5-iodosalicylaldehyde (3 g, 12.1 mmol) (Aldrich) in N,N-dimethylformamide (20 mL) was added anhydrous K2CO3 (5 g, 36.3 mmol), and 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (5.4 g, 18.1 mmol, ASTATECH). The reaction mixture was heated at 60° C. for 18 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated to give crude 4-(2-formyl-4-iodo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (Yield 4.38 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)[CH:38]=[CH2:39]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCOC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 494 (0.06 g, 0.16 mmol) was suspended in dry CH2Cl2 (1.5 mL) under an argon atmosphere in a screw cap vessel. K2CO3 (0.044 g, 0.32 mmol) was added followed by allyl chloroformate (0.034 mL, 0.032 mmol). The suspension was stirred for 48 h at room temperature. Work up as described in the preparation of compound 277. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 5:95→30:70 as the eluent. This afforded the title compound as yellow oil. 13C NMR (CDCl3) δ 195.8, 159.1 (dd), 155.5 (dd), 153.2, 147.7, 139.6, 135.4, 135.2, 133.6, 132.9, 132.3, 132.0, 129.3, 124.4 (dd), 124.2 (dd), 121.3, 119.7, 118.3, 116.3, 112.8, 111.6 (dd), 105.0 (dd), 65.9, 19.7
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCCN1CCCC1=O
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCN1CCCC1=O)O2
Yield: 79.8 %

Procedure:
Following the amide coupling procedure described in protocol A, 499 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 357 mg CDI (2.2 mmol) and 569 mg 1-(3-aminopropyl)pyrrolidin-2-one (4.0 mmol) yielded 598 mg of 6-hydroxy-2,5,7,8-tetramethyl-N-(3-(2-oxopyrrolidin-1-yl)propyl)chroman-2-carboxamide as a white powder.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH2:1]([NH:8][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C1CCCCCO1
Reactant: CCCCCCCN
Product: CCCCCCCNC(=O)CCCCCO
Temperature: 100 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
A mixture of n-heptylamine (1.21 g, 10.5 mmols) and 6-hexanolactone (1.14 g, 10 mmols) was stirred at 100° C. for 3 hours, and then crystallized from ether-hexane to obtain 1.77 g (yield 78%) of N-heptyl-6-hydroxyhexaneamide as colorless crystal.
Reaction SMILES: N[CH:2]1[CH2:6][C@@:5]([CH:26]([CH3:28])[CH3:27])([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:8])[CH:4]=[CH:3]1.[O:29]=C(C(OCC)=O)C(OCC)=O.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:22]([O:21][C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=1[CH2:10][NH:9][C:7]([C@:5]1([CH:26]([CH3:28])[CH3:27])[CH2:6][C:2](=[O:29])[CH:3]=[CH:4]1)=[O:8])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(N)C1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of (1S)-4-amino-N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]1-isopropylcyclopent-2-ene-1-carboxamide (35 g, 88 mmol) and diethyl oxomalonate (31 g, 176 mmol) in toluene (350 mL) was refluxed until no more starting material left as judged by HPLC. The reaction mixture was cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (27 g, 176 mmol) was added. The reaction mixture was then warmed to r.t. and stirred at this temperature for 1 hr before being quenched with 1M HCl and vigorously stirred for 1 hr. The reaction mixture was diluted with EtOAc and the two layers were separated. The aqueous phase was then extracted with EtOAc (5×). The organics were combined, dried over sodium sulfate and evaporated to dryness. The crude was purified by column chromatography on silica gel eluting with hexane:EtOAc (11:1) to yield 32 g of (1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-4-oxocyclopent-2-ene-1-carboxamide as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([F:38])=[C:28](B2OCC(C)(C)CO2)[CH:29]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([F:38])=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:25]=1
Reactant: CC1(C)COB(c2cc(Cl)ccc2F)OC1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cc(Cl)ccc4F)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-(5-chloro-2-fluorophenyl)-5,5-dimethyl-[1,3,2]dioxaborinane were coupled in the same way as in Example 30 to give 2-[3-(5′-chloro-2,2′-difluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (6 mg, 3%): m/z (ES+) 417 [MH+].
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][CH2:9][CH:10]=[CH2:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.[Li]CCCC>C1(C)C=CC=CC=1.C1COCC1>[CH2:8]([C:3]1[C:2]([B:12]([OH:17])[OH:13])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:9][CH:10]=[CH2:11]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=CCCc1ncccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCCc1ncccc1B(O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a stirring solution of 3-bromo-2-(but-3-en-1-yl)pyridine (Ref. Zhang, Z; Dwoskin, L. and Crooks, P. Tetrahedron Lett. 2011, 52, 2667-2669, 550 mg, 2.59 mmol) and triisopropyl borate (0.775 mL, 3.37 mmol) in toluene (4 mL) and THF (1 mL) cooled to −78° C. was added 2.5 M n-BuLi (1.349 mL, 3.37 mmol) over the course of 15 min. During this time period, the reaction color changed from yellow to orange. The reaction was stirred at −78° C. for 2 h then warmed to 0° C. for 15 min. It was then quenched with 2 N HCl (5 mL) and stirred for 10 min. The solution became a slurry (pH was found to be 3). It was then diluted with ether, the ether layer was discared. The aqueous layer was adjusted pH=7-8. A white cloud was formed. It was then extracted with EtOAc, the organic layer was dried over MgSO4, filtered and concentrated to obtain 450 mg (98%) of the desired product as a white foam. LCMS (M+1)=178.1.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:3]=1[O:4][C@@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].[Cl:16]C1C=CC(O)=CC=1C>>[Cl:16][C:13]1[CH:14]=[CH:2][C:3]([O:4][C@@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7])=[CH:11][C:12]=1[CH3:15]
Reactant: Cc1cc(O)ccc1Cl
Reactant: COC(=O)[C@H](C)Oc1cc(C)ccc1Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(C)c1

Procedure:
The title compound was prepared following the same general protocol as described for the synthesis of the (S)-methyl 2-(2-chloro-5-methylphenoxy)propanoate (Step 1, Example 55), using the 4-chloro-3-methylphenol instead of the 2-chloro-5-methylphenol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14].[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:22](=[O:24])[CH3:23])=[CH:27][CH:28]=2)=[C:6]([C:13]([F:15])([F:16])[F:14])[CH:7]=1)#[N:10]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)c(C(F)(F)F)c1
Product: CC(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)cc2C(F)(F)F)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-3-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (APCI) m/z 446 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[O:27]1[CH:32]2[CH:28]1[CH2:29][O:30][CH2:31]2>CN(C)C=O>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:32]2[CH:28]([OH:27])[CH2:29][O:30][CH2:31]2)[CH:11]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1O
Reactant: C1OCC2OC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1COCC1O
Temperature: 120 °C
Yield: 27.1 %

Procedure:
400 mg (1.2 mmol) of N-(3,5-dichloropyridin-4-yl)-3-hydroxy-4-methoxybenzamide (starting compound A16) and 540 mg (3.85 mmol) of potassium carbonate are stirred under a nitrogen atmosphere at RT for 1 h in 5 ml of dimethylformamide. The mixture is heated to 120° C. and 115 mg (1.3 mmol) of 3,4-epoxytetrahydrofuran are added to the reaction mixture 4×at an interval of 6 h in each case. The mixture is concentrated, 50 ml of water are added, it is acidified with 2 N HCl and extracted with 3×50 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, concentrated and the residue is chromatographed on silica gel [toluene/ethyl acetate=1:2]. The product-containing fractions are concentrated and the residue is crystallized from diethyl ether. 130 mg of the title compound of m.p. 183-185° C. are obtained.
Reaction SMILES: [CH3:1][NH:2]C[C@H](C1C=CC=CN=1)O.Cl[CH2:13][C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15]>>[CH3:1][NH:2][CH2:13][C@H:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[OH:15]
Reactant: O=C(CCl)c1cccnc1
Reactant: CNC[C@@H](O)c1ccccn1
Product: CNC[C@@H](O)c1cccnc1

Procedure:
As described for the preparation of (1R)-2-(methylamino)-1-pyridin-2-ylethanol (Preparations 68-69), 3-chloroacetylpyridine (Chem. Ber. 1951, 84, 147-149) is converted to the title compound, isolated as a pale yellow amorphous solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[S:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:20]([C:34]([F:37])([F:36])[F:35])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:39]>C(O)C>[ClH:39].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[S:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[C:20]([C:34]([F:37])([F:35])[F:36])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: Cc1ccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)s1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 48-4 (710 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (480 mg) as a white powder.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.[H-].[Na+].[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][N:20]=[CH:19]1.O>C1COCC1>[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[CH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:25][CH:24]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C(=Cc1ccc(-n2ccnc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.6 %

Procedure:
1.0 g of diethylbenzylphosphonate were dissolved in 50 ml of dry THF under nitrogen gas flow. To this solution, were added 0.21 g of 60% NaH while cooling the solution with ice, and the resultant solution was then stirred for 2 hours at room temperature. After cooling the whole solution with ice, 0.75 g of 4-(imidazole-1-yl)benzaldehyde were added thereto and stirred for 48 hours at room temperature. The solution reacted was condensed under reduced pressure, added with water, and extracted with chloroform. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, for which chloroform is used for the developer, thereby affording 0.5 g of 4-(imidazole-1-yl)stilbene.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2].[CH2:20](O)[CH2:21][CH2:22][OH:23]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([C:6]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:23][CH2:22][CH2:21][CH2:20][O:7]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: CCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C2(c3ccccc3)OCCCO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A suspension of 3-ethyl-4-nitro-benzophenone (11f) (20.0 g, 78.4 mmol), 1,3-propandiol (7.15 g, 94.0 mmol), p-toluenesulfonic acid monohydrate (50 mg) in toluene (300 mL) was refluxed using a Dean-Stark-trap for 24 hours. The Dean-Stark-trap was then replaced by a Soxhlet-extractor filled with molecular sieve and the mixture was refluxed for an additional 48 hours to achieve complete conversion. The reaction mixture was then cooled to ambient temperature, washed with an aqueous, saturated solution of NaHCO3 and concentrated in vacuo until crystallization started. The suspension was cooled for 0.5 hours in an ice bath and after which the crystalline product was filtered, washed with a small volume of hexane and air dried to give 22.48 g (72 mmol, 91.5%) compound 17 as yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:17](O)=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)=[O:9])=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)(=[O:24])=[O:23].P(Cl)(Cl)([Cl:36])=O>>[Cl:36][C:17]1[C:18]2[C:10]([C:8]([C:7]3[C:2]([F:1])=[C:3]([NH:21][S:22]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:4]=[CH:5][C:6]=3[F:20])=[O:9])=[CH:11][NH:12][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(O)c34)c2F)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(Cl)c34)c2F)cc1
Temperature: 100 °C
Yield: 87.8 %

Procedure:
To N-[2,4-difluoro-3-(4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-propyl-benzenesulfonamide (P-1030, 239 mg, 0.506 mmol), phosphoryl chloride (4.0 mL, 43 mmol) is added and the suspension is heated in an oil bath at 100° C. for one hour. The reaction is allowed to cool, then poured onto ice. The resulting solid is collected by vacuum filtration and dried to provide the desired compound (P-1030, 218 mg). MS (ESI) [M+H+]+=490.9.
Reaction SMILES: C([O:8][CH2:9][C:10]1[NH:19][C:18](=[O:20])[C:17]2[C:12](=[CH:13][C:14]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=4)[C:15]=3[CH:16]=2)[N:11]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][CH2:9][C:10]1[NH:19][C:18](=[O:20])[C:17]2[C:12](=[CH:13][C:14]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[CH:27][CH:26]=4)[C:15]=3[CH:16]=2)[N:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc4nc(COCc5ccccc5)[nH]c(=O)c4cc32)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc4nc(CO)[nH]c(=O)c4cc32)cc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
To a solution of tert-butyl 4-{N-[(6RS)-2-benzyloxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]amino}benzoate (1.40 g, 2.8 mmol) in EtOH (150 ml) was added 10% Pd/C (0.665 g). The mixture was stirred at 45° C. for 3 h, then more catalyst (0.200 g) was added and stirring was continued at 50° C. for 6 h. The catalyst was removed by filtration, washed with EtOH, and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography, on elution with 8% methanol in ethyl acetate, gave a white solid (0.679 g, 60%); mp 265-266° C.; 1H-NMR (250 MHz, DMSO-d6, TMS) 1.52 (s, 9H, C(CH3)3), 1.88, 2.57 (2×m, 1H each, 7-CH), 2.90-3.17 (m, 2H, 8-CH2), 4.38 (d, J=6.0 Hz, 2H 2-CH2OH), 5.17 (m, 1H, 6-CH), 5.54 (t, J=6.1 Hz, 1H, CH2OH), 6.79 (d, J=8.8 Hz, 2H, 3′,5′-ArH), 6.91 (d, J=7.8 Hz, N10—H), 7.51, 7.91 (2×s, 1H each, 5-H and 9-H), 7.68 (d, J=8.8 Hz, 2H, 2′,6′-ArH), 11.83 (s, 1H, CONH); MS (ESI, m/z) 408 [M+H)+, 65%], 352 [(M-tBu)+, 100%], 215 (60%); Found: C, 67.41; H, 6.20; N, 10.17; C23H25N3O4 requires C, 67.80; H, 6.18; N, 10.31%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[Cu][C:18]#[N:19]>CN1CCCC1>[N:12]1([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:18]#[N:19])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH3:11])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CCCC(c1ccc(Br)cc1)n1ccnc1
Reactant: N#C[Cu]
Agent: CN1CCCC1
Product: CCCC(c1ccc(C#N)cc1)n1ccnc1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
2.79 g of 1-[1-(4-bromophenyl)-butyl]-imidazole and 1.8 g of copper(I) cyanide are heated in 5 ml of N-methylpyrrolidine for 4 hours at 180° C. under a protecting gas atmosphere (argon). After cooling, it is precipitated in 50 ml of ammonia solution, stirred for 15 more minutes at room temperature and extracted with ethyl acetate. After concentration by evaporation in a vacuum 1.95 g of dark oil is obtained. This oil is distilled on a bulb tube in a vacuum; boiling point 200°-215° C./0.05 mbar. The resulting distillate is recrystallized from ethanol/petroleum ether. 1.54 g of 4-[1-(1-imidazolyl)-butyl]-benzonitrile with a melting point of 63°-71° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@@H:9]([CH:10]=[CH:11][C:12]4=[O:21])[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@@H:9]([CH2:10][CH2:11][C:12]4=[O:21])[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)C=C[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
0.5 g. of 3-methoxy-14α-estra-1,3,5(10), 8,15-pentaen-17-one in 25 ml. of ethanol is reduced catalytically with 50 mg. of 5% palladium-on-charcoal until a molar equivalent of hydrogen is taken up. The catalyst is filtered off and the filtrate evaporated to dryness to yield the known 3-methoxyestra-1,3,5 (10),8-tetraen-17-one which can be converted into estrone methyl ether by procedures outlined in Chemistry & Industry (London), 1022 (1960) or into 19-nor-Δ4 -steroids using the procedure of, for example, U.S. Pat. No. 3,318,922.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]1([N:24]2[C:28]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[CH:27][C:26]([CH:34]=O)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:34][C:26]2[CH:27]=[C:28]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:25]=2)[CH2:13][CH2:14]1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Product: Cc1cccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)c1C
Yield: 77.9 %

Procedure:
Compound 19 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.