Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1>CN1CCCC1=O.O>[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:2]2[CH:3]=[C:4]([N:21]([CH:31]3[CH2:33][CH2:32]3)[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:37][CH2:36]1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Temperature: 120 °C

Procedure:
6-chloro-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (9 g, 18.6 mmol) was combined with trans-1,4-diaminocyclohexane (31.9 g, 279 mmol) in N-methyl-2-pyrrolidinone (50 mL) and heated at 80° C. for 16 hours and at 120° C. for 6 hrs. The reaction was cooled to room temperature, and water (200 mL) was added, and the solid collected via Buchner filtration. The crude product was purified with silica gel chromatography using a stepwise gradient of 10% methanol/chloroform to 25% methanol/chloroform/1% triethylamine to isolated foamy solid. The solid was suspended in water (400 mL) and collected with Buchner filtration (2×50 mL water wash) and dried for 16 hrs under reduced pressure to afford 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (10.2 g, 18.18 mmol, 98% yield) as a off white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.77 minutes. [M+H]=561.16.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[O:25][C:22]2=[N:23][CH:24]=1>C1COCC1.CCOC(C)=O>[Br:8][C:27]1[C:21]2[C:22](=[N:23][CH:24]=[C:19]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:10]=3[Cl:9])[C:14]([OH:16])=[O:15])[CH:20]=2)[O:25][C:26]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
NBS (29.0 mg, 0.163 mmol) was added to a stirring solution of 4-chloro-3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (50 mg, 0.136 mmol) in THF (4.5 mL) at room temperature. It was allowed to stir for 1 hour. An additional portion of NBS (29 mg, 0.16 mmol) was added it was allowed to stir for 1 hour after which another portion of NBS (29 mg, 0.16 mmol) was added and the reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 10% NaHSO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with DCM to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-chlorobenzoic acid (57 mg, 0.128 mmol, 94% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.48 (1H, d, J=2.14 Hz), 8.19-8.24 (2H, m), 8.17 (1H, d, J=2.14 Hz), 7.99-8.05 (2H, m), 7.79 (1H, d, J=8.24 Hz), 7.46-7.52 (2H, m). LC-MS retention time: 1.29 min; m/z (MH+): 447. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14]C.C([Li])CCC.CCC(=O)CC>O.C1COCC1>[C:1]([C:5]1[CH:9]=[CH:8][C:7](=[C:12]([CH2:13][CH3:14])[CH2:11][CH3:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC
Reactant: CC(C)(C)C1=CC=CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCC(=O)CC
Solvent: O
Product: CCC(CC)=C1C=CC(C(C)(C)C)=C1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a THF solution of 1.53 g (13 mmol) of tert-butylcyclopentadiene, 9.0 ml (14 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 1.7 ml (16 mmol) of 3-pentanone was further added at −78° C., followed by stirring at room temperature for 2 days. To the reaction solution, water was added. The mixture was subjected to extraction with ether, then the solvent was distilled off, and the residue was subjected to column chromatography (silica gel, developing solvent: hexane) to obtain 1.50 g of a yellow liquid (yield: 63%) The analyzed values are given below.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([CH2:27][C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])(=O)C.[NH4+]>C(O)C>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:32]([C:31]3[CH:30]=[CH:29][C:28]([CH2:27][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:35][CH:34]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol), 4-morpholin-4-ylmethyl-benzaldehyde (26.7 mg, 0.130 mmol) and ammonium acetate (59.4 mg, 0.771 mmol) were heated in ethanol (5 mL) at 70° C. for 18 hours. The reaction mixture was concentrated and the product was purified by reverse phase chromatography (Gilson) to afford, following neutralization with saturated sodium bicarbonate solution and filtration, the title compound 35 mg (57%). mp: 217-219° C., 1H NMR (300 MHz, DMSO-d6): 13.27 (s, 1H), 8.10 (d, J=9 Hz, 2H), 8.03 (s, 1H), 7.76 (s, 1H), 7.48 (d, J=8 Hz, 2H), 7.22 (s, 1H), 7.16 (d, J=8 Hz, 1H), 6.41 (br s, 1H), 6.37 (br s, 1H), 5.23 (t, J=8 Hz, 1H), 3.59 (br s, 4H), 3.53 (s, 2H), 2.89 (s, 1H), 2.78 (s, 1H), 2.39 (br s, 4H), 2.25 (d, J=8 Hz, 1H), 1.90 (s, 1 h), 1.39 (d, J=8 Hz, 1H). MS: 523, 525 (M+H), HPLC: 1.82 min (G method).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][N:6]([O:18][CH3:19])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])[O:12][C:11](C)(C)[O:10]1>CO>[CH3:11][O:12][C:13](=[O:14])[C:9]([OH:10])=[CH:8][C:7](=[O:17])[N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([F:23])=[C:2]([F:1])[CH:3]=1)[O:18][CH3:19]
Reactant: CON(Cc1ccc(F)c(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(F)c1)OC
Yield: 53 %

Procedure:
N-(3,4-Difluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (53% yield); mp 76–77° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.72 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.45 (1H, s, CH), 7.05–7.19 (3H, m, aromatics). Anal. calcd for C13H13F2NO5: C, 51.83; H, 4.35; N, 4.65. Found: C, 51.78; H, 4.28; N, 4.53.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][NH:5][C:6]([C:8]1[C:13]([O:14]CC2C=CC=CC=2)=[CH:12][C:11]([O:22]CC2C=CC=CC=2)=[CH:10][N:9]=1)=[O:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:30])[CH2:4][NH:5][C:6]([C:8]1[C:13]([OH:14])=[CH:12][C:11]([OH:22])=[CH:10][N:9]=1)=[O:7]
Reactant: COC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CNC(=O)c1ncc(O)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester (3.50 g, 8.62 mmol) in MeOH (100 mL) is added 10% Pd/C (0.350 g, 0.862 mmol) and the reaction mixture stirred under an atmosphere of H2 at room temperature for 16 hours. The suspension is filtered through Celite™ and the filtrate concentrated under reduced pressure. The crude material is purified over silica (MeOH:CH2Cl2 gradient 1% to 5%) to afford 1.95 g (quantitative yield) of the desired compound as an off-white solid. 1H NMR (250 MHz, MeOD) δ ppm 7.62 (1H, d, J=2.4 Hz), 6.53 (1H, d, J=2.4 Hz), 4.04 (2H, s), 3.64 (3H, s). HPLC-MS: m/z 227 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH3:35])=[CH:18][CH:17]=1
Reactant: COc1ccccc1CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccccc1COC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 117.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-methoxyphenyl)methanol (36 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (91 mg, yield 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.[C:20]1([S:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[NH:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:28]=[S@:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:27])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)CS(=N)(=O)c1ccccc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of 5-bromonicotinic acid (343 mg, 1.66 mmol) in anhydrous DMF (5.5 μL) was added N,N-diisopropylethylamine (0.58 mL, 3.32 mmol) and ethyl (S-phenylsulfonimidoyl)acetate (415 mg, 1.83 mmol) followed by the final addition of (benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophophate (0.81 g, 1.83 mmol). The reaction mixture was stirred at room temperature for 20 min, and then partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was separated and washed once with brine and dried over anhydrous Na2SO4. The organic layer was concentrated and the residue purified by chromatography (silica gel, gradient elution (5:1 Hexane/EtOAc to 3:1 Hexane/EtOAc). The product containing fractions were concentrated to give the title compound as a white solid (230 mg, 34%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([C:16]([OH:18])=O)[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=O)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>C(O)(=O)C>[OH:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:20]2[C:16](=[O:18])[C:9]3=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:15][CH:14]=[C:10]3[C:11]2=[O:13])=[CH:24][CH:25]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CCCCCOc1ccc(C(=O)O)c(C(=O)O)c1
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCOc1ccc2c(c1)C(=O)N(CCc1ccc(O)cc1)C2=O
Temperature: 96 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
The crude product of 4-pentyloxyphthalic acid was dissolved in acetic acid (20 ml), and tyramine hydrochloride (2.74 g, 20 mmol) was added. The mixture was stirred at 96° C. for 4 hours, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=6/1) to give N-2-(4-hydroxyphenyl)ethyl-4-pentyloxyphthalimide (2.6 g, 9.4 mmol, 88%) as colorless crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH3:25])[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>ClC(Cl)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH3:25])[C:33](=[O:35])[CH3:34])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CNc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)N(C)c1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-methyl-amine was diluted to 0.20 M with anhydrous dichloroethane, then delivered to an 8 mL vial via pipette (0.20 mmol). To the amine solution was added base (0.4 M triethylamine in dichloroethane, 0.40 mmol). Acetyl chloride was diluted to 0.20 M with dichloroethane, and added at rt (0.2 mmol). The reaction was shaken overnight at 50° C., then evaluated by MS. Polyamine scavenging resin was added (0.5 mmol). The solution was shaken overnight at rt, then filtered into an 8 mL vial. The reaction was concentrated using an HT-12 GeneVac, then purified by HPLC (30×100 mm ODS-A C(18) 5u column). N-{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-N-methyl-acetamide was isolated in 100% purity @ 254 nm, LCMS (APCI): 479 [M+H]+.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)=O)CCC.[CH3:29][NH2:30]>CO>[CH3:29][NH:30][C:6]([C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]([F:28])[C:17]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[C:18]([F:20])[CH:19]=2)[CH2:9]1)=[O:5]
Reactant: CN
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Yield: 85 %

Procedure:
To a stirred solution of (5R)-3-[3,5-Difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid butyl ester (EXAMPLE 76, Step 5, 132 mg) in MeOH (1 mL) is added MeNH2 (2 mL, 4.0 mmol, 2.0 M solution in MeOH). The reaction mixture is then heated at 40–50° C. until all of the solid disappears. Solvent is removed and the residue is dissolved in 20% MeOH/CH2Cl2 and purified by silica gel chromatography (10% MeOH/CH2Cl2) to give the title compound as a yellow solid (100 mg, 76%), 1H NMR (300 MHz, DMSO) δ 8.40 (m, 1H), 7.52–7.38 (m, 3H), 5.08 (dd, 1H), 5.00 (d, 1H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.78 (t, 2H), 2.65 (d, 3H); MS for C16H15F2N3O4 m/z 352.5 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6](O)([C:17]([F:20])([F:19])[F:18])[CH2:7][CH:8]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]1([CH3:16])[CH3:15]>O>[CH3:15][C:9]1([CH3:16])[CH:8](/[CH:7]=[C:6](\[CH3:5])/[C:17]([F:18])([F:19])[F:20])[CH:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1C(CC(C)(O)C(F)(F)F)C1(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)C1C(/C=C(\C)C(F)(F)F)C1(C)C

Procedure:
160 ml of thionyl chloride were added at 0° C. to 80.5 g of methyl 2,2-dimethyl-3-(2-methyl-2-hydroxy-3,3,3-trifluoropropylcyclopropane carboxylate of Stage C. The mixture was refluxed for 48 hours, cooled, poured into ice-cooled water and extracted with isopropyl ether. The organic phases were washed with water and after drying over magnesium sulfate and evaporation to dryness, the crude product was chromatographed on silica with a hexane-AcOEt mixture (9-1), then rechromatographed with a hexane--acetone mixture (99-1) to obtain 22.02 g of the starting alcohol, 11.71 g of the exo+Z isomer mixture and 23.31 g of the expected product.
Reaction SMILES: C([O:4][C:5]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:26][C:27](=[O:29])[CH3:28])[CH2:13][CH2:12]4)[CH2:9][C:8](=O)[C:7]=2[CH:6]=1)(=O)C.Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[C:27]([O:26][C@H:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C:20]1[CH:21]=[C:22]([O:23][CH2:24][CH3:25])[C:5]([OH:4])=[CH:6][C:7]=1[C:8](=[N:32][OH:33])[CH2:9]3)(=[O:29])[CH3:28]
Reactant: CCOc1cc2c(cc1OC(C)=O)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1cc2c(cc1O)C(=NO)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Temperature: 100 °C
Yield: 102 %

Procedure:
A solution of 3,17,β-diacetoxy-2-ethoxy-estra-1,3,5(10)-triene-6-one (5, 800 mg, 1.93 mmol) in pyridine (12 ml) was treated with hydroxylamine hydrochloride (1.07 g, 15.4 mmol). The resulting mixture was stirred and heated at 100° C. for 30 min. The mixture was cooled to room temperature and then poured into ice/water mixture (150 ml). The compound was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with sodium bicarbonate (100 ml), water (2×100 ml) and brine (2×100 ml), dried over sodium sulfate, and evaporated to dryness. Chromatography of the residue on silica gel using 30% ethyl acetate in hexane gave the title compound (763 mg, 89%), which was crystallized from ethyl acetate/hexane to afford title compound 27 as yellowish crystals: mp 226-227° C. 1H NMR (CDCl3) δ7.55 (s, 1 H). 6.78 (s, 1 H), 4.75 (t, J=8.5 Hz, 1 H), 4.19 (q, J=6.9 Hz, 2 H), 3.15 (dd, J=4.3 and 12 Hz, 1 H), 1.2-2.40 (m, 18 H), 0.85 (s, 3 H); CIMS (isobutane) m/z (rel intensity) 388 (MH+, 100), 372 (MH—H2O, 10), 328 (75); Anal. Calcd for C22H29O5N: C, 68.20; H, 7.54; N, 3.61. Found: C, 68.04; H, 7.62; N, 3.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1/[CH:5]=[CH:13]/[C:14]([C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1)=[O:15]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2,4-dimethoxybenzaldehyde (1 g, 6.00 mmol) and 3,4,5-trimethoxyacetophenone (1.27 g, 6.00 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (1 ml). The mixture was stirred for 24 hours at room temperature, acidified with 2N HCl and extracted with ethyl acetate (3×30 ml). The combined organic phase was dried over anhydrous MgSO4, filtered, and the solvent evaporated in vacuo. The product was purified by recrystallisation from ethanol to afford the title compound as a pale yellow solid, 1.67 g (78%). 1H-NMR (CDCl3) δ 8.0 (1H, d), 7.5 (1H, d), 7.4 (1H, d), 7.2 (2H, s), 6.6 (1H, dd), 6.5 (1H, d), 3.9 (9H, d), 3.85 (3H, s), 3.83 (3H, s). Mass Spectrum (FAB) m/e 359 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([OH:11])[CH2:7][CH2:6]1.[H-].[Na+].I[CH3:16]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][CH3:16])[CH2:7][CH2:6]1
Reactant: COC(=O)C[C@H]1CC[C@@H](O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1CC[C@@H](OC)CC1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
Cis (4-Hydroxy-cyclohexyl)-acetic acid methyl ester (500 mg, 2.90 mmol) were dissolved in 1.5 ml DMF and cooled to 0-5° C. Sodium hydride (190 mg, 4.35 mmol, 55%) and iodomethane (3.62 ml, 23.2 mmol) were added and the reaction mixture stirred for 4 hours at 0-5° C. The reaction mixture was quenched with saturated NaHCO3-solution and extracted with dichloromethane. The organic extract was washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product (561 mg, quant.) was obtained as a colourless oil and used without any further purification for the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:28])[CH:22]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>CO>[F:28][C:23]1[CH:22]=[C:21]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:30][CH3:29])=[CH:6][CH:7]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: CCC(=C(c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1)c1ccccc1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(OCCNC)cc1)c1ccc(O)c(F)c1)c1ccccc1
Temperature: 85 °C
Yield: 59 %

Procedure:
To a stirred solution of 4-(1-(4-(2-chloroethoxy)phenyl)-2-phenylbut-1-enyl)-2-fluorophenol in 5 mL MeOH was added 2 mL CH3NH2 (30% aq) and heated at 85° C. overnight. The mixture was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (CH2Cl2/MeOH(NH3 gas)=10/1) to give the desired product (59% yield, Z/E=1/1 as a white solid. m/z=392[M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(OCc1ccccc1)Oc1ccc(C(=O)O)cc1
Reaction time: 24 h
Yield: 100.1 %

Procedure:
To an aqueous solution of 55 m moles (7.6 g) of 4-hydroxybenzoic acid and 65 m moles (2.6 g) of sodium hydroxide in 200 ml of water, 65 m moles (10.6 g) of carbobenzoxychloride was added dropwise at 0° C. After 24 hours, the precipitate was washed with water, filtered, and dried, then purified by column chromatography to obtain 15.0 g of 4-carbobenzoxyoxybenzoic acid [m.p. 181.9°-183.1° C⟧ (yield:99%)