Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)C.[Cl:15]C=CCCCC.C=CCCCC>>[Cl:15][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC=CCCCCOC(C)=O
Reactant: CCCCC=CCl
Solvent: C=CCCCC
Product: CCCCC=CCCCCCl

Procedure:
FIG. 1B is a reaction diagram showing the second step of the synthesis of 5-decenyl acetate, in which 1-chloro-hexene is reacted with 1-hexene in the presence of Catalyst 823 to yield 1-chloro-5-decene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[C:5](\[CH3:8])/[CH2:6]O.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)[Cl:32]>>[CH3:1][O:2][C:3](=[O:9])/[CH:4]=[C:5](\[CH3:8])/[CH2:6][Cl:32]
Reactant: COC(=O)/C=C(\C)CO
Reactant: ClCCl
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)/C=C(\C)CCl
Reaction time: 2 h

Procedure:
To (E)-4-hydroxy-3-methyl-2-butenoic acid methyl ester (0.75 g, 5.76 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dibromotriphenylphosphorane (2.68 g, 6.34 mmol). The reaction is stirred at -15° C.-0° C. for two hours, quenched by addition of ice (10 ml), extracted with methylene chloride (2×10 ml), washed with saline (10 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (95/5). The appropriate fractions are combined and concentrated in vacuo to give (E)-4-chloro-3-methyl-2-butenoic acid methyl ester. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.06 g, 2.56 mmol) at ambient temperature followed by the addition of (E)-4-bromo-3-methyl-2-butenoic acid methyl ester (0.22 g, 1.16 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×20 ml). The extracts are combined, washed with saline (20 ml), dried over sodium sulfate, concentrated in uacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (80/20). The appropriate fractions are combined (Rf =0.43, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 134-136° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[C:34](B(O)O)=[C:33]([CH3:38])[O:32][N:31]=1.C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:19][CH:18]([O:17][C:16](=[O:21])[NH:15][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:34]3[C:30]([CH3:29])=[N:31][O:32][C:33]=3[CH3:38])[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:22])[CH2:6]1)[CH3:20]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(=O)N1c2ccc(Br)cc2C(NC(=O)OC(C)C)CC1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3c(C)noc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 38 %

Procedure:
A flask was charged with 1-methylethyl (1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol), potassium carbonate (74.9 mg, 0.542 mmol), 3,5-dimethyl-4-isoxazolylboronic acid (45.8 mg, 0.325 mmol), and tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) then filled with ethanol (1 mL) and toluene (1 mL) and the resulting mixture was refluxed under nitrogen for 20 h. tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) was then added and the mixture refluxed for 40 h then cooled to room temperature and partitioned between water (40 mL) and EtOAc (40 mL). The layers were separated and the aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 66% AcOEt in Hexanes) gave 1-methylethyl[(cis)-1-acetyl-6-(3,5-dimethyl-4-isoxazolyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (42 mg, 0.103 mmol, 38%) as a colourless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C[S:19][C:20]1C2C(=CC(C(N3CCOCC3)=O)=CC=2)N[CH:21]=1>>[CH2:20]([S:19][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:21]
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reactant: CSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Product: CCSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Synthesized from (1H-indol-6-yl)(morpholino)methanone (1.5 g, 6.52 mmol, 1.0 eq) in an analogous manner as described for 1b). Yield: 1.3 g. Mass spectroscopy: m/z: [M+H]+=291.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.[NH3:26]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:26])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:11][CH:12]=2)[CH:2]=1
Reactant: N
Reactant: COC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
Methyl 2-(4-(pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxylate (600 mg, 1.81 mmol) was added to ammonia in methanol (30 ml) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol, dried in vacuum. 550 mg 2-(4-(pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 96%. LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].O1CCCC1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:12]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1NCCN1C(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
8.6 parts by weight of imidazolid-2-one in 100 parts by volume of dry tetrahydrofurane were treated with 15.5 parts by weight of benzoyl chloride in 30 parts by volume of tetrahydrofurane over the course of 15 minutes, at 5°-10°C, and the mixture was subsequently stirred for 3 hours at 10°C. The solvent was stripped off, the residue was shaken with a mixture of chloroform and aqueous NaHCO3 solution for 15 minutes, the chloroform was separated off, the water was again extracted with chloroform and the combined organic phases were washed with water, dried over MgSO4 and evaporated. The residue was recrystallized from ethyl acetate/ether.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:3]([C:5]2[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)nn1C
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 94 %

Procedure:
As described for example 43, 2-methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (30 mg, 0.09 mmol) was converted using 4-aminotetrahydropyran instead of rac-3-aminotetrahydrofuran, to the title compound (34 mg, 94%) which was obtained as a colorless oil. MS: m/e=397.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=O.Cl.[NH2:21][OH:22].O>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[N:21][OH:22]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: ON=CC1=C(Cl)c2ccccc2OC1c1ccccc1

Procedure:
A solution of 27 g 4-chloro-3-formyl-flav-3-ene in 25 ml dimethylformamide is refluxed. To this solution one adds 7.7 g hydroxylamine hydrochloride dissolved in 60 ml dimethylformamide. After two hours reflux, the solution is cooled at room temperature before the addition of 400 ml water. The precipitate is formed, filtered, washed with water and dried. The solid is crystallized in diisopropylether. Pure 4-chloro-3-hydroxyiminomethyl-flav-3-ene is obtained as pale yellow crystals; m.p. 199°-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]1[CH2:26][CH2:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCC1

Procedure:
Ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in acetonitrile and K2CO3 (1.5 equiv.) and bromocyclobutane (2 equiv.) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:27])=[O:26])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), benzenesulfonyl chloride (20 mg, 0.113 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.I[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:44])=[CH:38][C:37]=1[CH3:51].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1>[CH3:51][C:37]1[CH:38]=[C:39]([C:43]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:44])[CH:40]=[C:41]([CH3:42])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(C(=O)N2CCOCC2)cc(C)c1I
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C(=O)N6CCOCC6)cc5C)ccc(F)c43)ccc21
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In a microwave vial, methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (75 mg), (4-iodo-3,5-dimethylphenyl)(morpholino)methanone (110 mg), K3PO4 (102 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (7 mg) are suspended in toluene (2 mL) and water (0.2 mL) and purged for 10 minutes with argon. Palladium-(II)-acetate (4 mg) are added, the vial is sealed and the mixture is stirred at 120° C. for 5 hours. After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→80:20) to give the title compound. Yield: 55 mg; LC (method 25): tR=1.38 min; Mass spectrum (ESI+): m/z=560 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH:18][CH3:19]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([N:18]([CH3:19])[CH3:17])=[O:10])[CH2:6]1
Reactant: CNC
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2Cl)C1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reaction time: 5 h

Procedure:
A stirred solution of 4.8 g (0.017 mole) of 3-(2,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 5.8 mL (0.05 mole) of 40% aqueous dimethylamine. After stirring for 5 h, the reaction mixture was diluted with 200 mL of water and the oil which separated was extracted into methylene chloride (3×30 mL). The combined extracts were dried (Whatman PS paper) and concentrated in vacuo, (5 g). The crude oil solidified on standing and was recrystallized from ligroin yielding 3.4 g (69.2%) of silver plate-like crystals, mp 62°-63° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[CH2:29][CH2:28][O:27][C:26]2=[C:30]([C:33](O)=[O:34])[S:31][CH:32]=[C:25]12>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:30]2[S:31][CH:32]=[C:25]3[C:26]=2[O:27][CH2:28][CH2:29][O:24]3)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1scc2c1OCCO2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2scc3c2OCCO3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-Dihydro-thieno[3,4-b][1,4]dioxine-5-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=496.3.
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](O)=[O:15])[CH2:6][CH2:5]2.C1N=[CH:22][N:21](C(N2C=NC=C2)=O)[CH:20]=1.C1COCC1>>[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]([N:21]([CH3:22])[CH3:20])=[O:15])[CH2:6][CH2:5]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N(C)C)O2
Yield: 73.9 %

Procedure:
Following the amide coupling procedure described in protocol A, 504 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.01 mmol), 361 mg CDI (2.23 mmol) and 1.1 mL of a 2.0 M solution of NN-dimethylamine in THF (2.2 mmol) produced 412 mg of 6-hydroxy-N,N,2,5,7,8-hexamethylchroman-2-carboxamide as amorphous powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1O)=[O:5])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.CO>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(O)CCCC1
Reactant: COc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCOC(=O)C1=C(c2ccccc2OC)CCCC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
Combine 2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (8.92 g, 29.5 mmol), 2-methoxyphenylboronic acid (5.0 g, 32.4 mmol), DMF (60.0 mL), methanol (20.0 mL), and sodium carbonate in water (40.0 g in 40 mL) at room temperature. Purge several times with nitrogen then add Pd(OAc)2 (72.0 mg, 1 mmol %) and 1,4-bis(diphenyl phosphino)butane (170.0 mg) and purge again with nitrogen. Stir at 70° C. under nitrogen for 5 hours then filter reaction wash with Methanol and ethyl acetate. Concentrate reaction mixture on rotovap and add ethyl acetate. Wash 5 times with brine and dry over anhydrous sodium sulfate. Concentrate and flash chromatograph using 5 to 40% ethyl acetate/hexanes eluent to yield the titled compound (3.98 g, 52%). TLC Rf=0.25 in 10% ethyl acetate/hexanes. 1H NMR (CDCl3): 7.2 (t, 1H, J=6.0 Hz), 6.9 (m, 3H),), 3.8 (m, 5H), 2.5 (m, 4H), 1.8 (m, 4H), 0.8 (t, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:6]1)[CH:2]=C.I([O-])(=O)(=O)=[O:25].[Na+].C(O)(C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:13]([CH2:12][O:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@H:5]([O:4][CH2:1][CH:2]=[O:25])[CH2:6]2)[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: C=CCO[C@H]1CCC[C@@H](OCc2cccc(C)c2C(=O)OC)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](OCC=O)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.0 g of methyl 2-((1R,3S)-3-allyloxycyclohexyloxymethyl)-6-methylbenzoate is dissolved in 30 ml of diethyl ether, and 2.0 g of sodium periodate, dissolved in 30 ml of water, are added. At 0° C., 2 ml of a solution of 2.5% by weight of osmium tetroxide and tert-butanol are added. The reaction mixture is stirred vigorously for three hours. The mixture is then cooled to 0° C., and 50 ml of a saturated sodium thiosulfate solution are added. The organic phase is removed. The aqueous phase is extracted three times with in each case 20 ml of diethyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 1.0 g of methyl 2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxymethyl]benzoate as a yellow oil C18H24O5 (320.39), MS(ESI): 321 (M+H+), Rf=0 23 (n-heptane:ethyl acetate=1:1).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:42])[CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:15]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(C)c2)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 157.9 %

Procedure:
To a solution of 3-butyl-4-[4-cyclohexyloxy-3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.094 mmol, 56.3 mg) in DCM (1 mL) was added formaldehyde solution in water (37%, 0.3 mmol, 0.022 mL), and 2 drops of acetic acid. Sodium triacetoxyborohydride (0.4 mmol, 89 mg, 95%) was added. The reaction mixture was stirred at room temperature for 2 h and partitioned between ethyl acetate (20 mL) and saturated aq. sodium bicarbonate solution (20 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel using 2 M ammonia in MeOH/DCM 1:19, dissolved in MeOH and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether and hexanes. The yellow solid was dried overnight under high vacuum to provide the title compound (42.8 mg). LCMS: m/z 505 [M+1] 1H NMR (400 MHz, CD3OD) δ 8.14 and 8.16 (1H, s), 8.00-8.01 (1H, m), 7.86 and 7.94 (1H, s), 7.75-7.79 (1H, m), 7.36-7.41 (1H, m), 7.26-7.30 (1H, s), 5.38-5.55 (1H, m), 4.57-4.62 (1H, m), 3.96 (3H, d), 3.14-3.70 (6H, m), 2.95 (3H, d), 1.81-2.58 (6H, m), 1.31-1.66 (12H, m), 0.81 (3H, t).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+]=[N-].O.NN>[Ni].CO>[NH2:1][C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](N=[N+]=[N-])C[C@@H]12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](N)C[C@@H]12

Procedure:
5.0 g 16α-azido-3-methoxy-estra-1,3,5(10)-triene-17β-ol, 100 ml methanol, 10 ml of 80% hydrazine hydrate and 4 spatula tips of Raney nickel are heated for 30 min on a water bath. Purification and recrystallization are performed as described for the purification of 16α-amino-3-methoxy-estra-1,3,5(10)-triene-17β-ol. Yield: 3.2 g (69%). F=158-161° C.; [α]D+41° (pyridine). IR: 3367 (NH). 3601 (OH);
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 4-chloro phenyl isocyanate (0.041 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 49 as a colorless solid (0.052 g, 42%). LCMS m/z (%)=463 (M+H+79Br, 35Cl, 41), 465 M+H+ (81Br 35Cl 88), 467 H+ (81 Br 37Cl, 21), 1H NMR (400 MHz, acetone-d6) δ: 8.30 (bs, 1H), 8.24 (bs, 1H), 7.685 (d, J=2.66 Hz, 1H), 7.577 (d, J=1.92 Hz, 2H), 7.74 (d, J=2.65, 1H), 7.292 (d, J=1.9 Hz, 2H), 7.280 (d, J=1.6 Hz, 1H), 7.135 (d, J=9.01 Hz, 1H), 4.256 (m, 1H), 3.811 (s, 3H), 1.447 (d, J=6.61 Hz, 3H), 1.288 (d, J=6.61 Hz, 3H).