Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][NH:7][CH:8]=O)=[CH:4][C:3]=1[CH3:12].P(Cl)(Cl)(Cl)=O.O.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N+:7]#[C-:8])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(CNC=O)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: [C-]#[N+]Cc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 114.1 %

Procedure:
To a solution of N-(4-bromo-3-methyl-benzyl)-formamide (Example 10.2) (4.3 g) in dichloromethane (70 ml) was added a solution of phosphorus oxychloride (2.8 g) in dichloromethane (15 ml) at 0-5° C. The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured onto a mixture of ice and water (400 ml), and sodium hydrogen carbonate (saturated) (100 ml) and ethyl acetate (250 ml) were added. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated to give 1-bromo-4-isocyanomethyl-2-methyl-benzene (4.52 g) as a brown oil. 1H-NMR (400 MHz, CDCl3): 7.54 (m, 1H), 7.22 (s, 1H), 7.03 (m, 1H), 4.57 (s, 2H), 2.42 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].[Cl:37][C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[N:43]=1.ClC1C=CC(=O)NN=1>>[CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[N:43]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].[Cl:37][C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[N:43]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Agent: Cn1nc(Cl)ccc1=O
Agent: O=c1ccc(Cl)n[nH]1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)n2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 6-chloro-2-methylpyridazin-3(2H)-one following a procedure analogous to that described in Example 1 Step 3. 6-chloro-2-methylpyridazin-3(2H)-one was prepared from 6-chloropyridazin-3-(2H)-one following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.138 min, m/z=471.3; 1H NMR (CDCl3) 1.28 (s, 3H), 1.41 (s, 3H), 1.49 (m, 3H), 2.1 (s, 2H), 2.2 (m, 1H), 2.42 (m, 2H), 2.85 (m, 1H), 3.78 (s, 3H), 6.92 (m, 3H), 7.31 (m, 5H), 7.43 (d, 2H), 7.50 (d, 1H), 7.35 (m, 8H)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]#[C:11][CH2:12][OH:13])[C:4]=2[CH2:3][CH2:2]1>N1C=CC=CC=1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](/[CH:10]=[CH:11]\[CH2:12][OH:13])[C:4]=2[CH2:3][CH2:2]1
Reactant: OCC#Cc1cccc2c1CCO2
Agent: [Pd]
Solvent: c1ccncc1
Product: OC/C=C\c1cccc2c1CCO2
Yield: 100.7 %

Procedure:
A mixture of 3-(2,3-dihydrobenzofuran-4-yl)prop-2-yn-1-ol (6.2 mmol) and Pd/C (300 mg) in 20 mL of pyridine was shaken under an atmosphere of H2 (10 psi) until no starting material remained (8 h). The crude reaction mixture was filtered to remove the catalyst and the catalyst was washed with ether. The filtrate was concentrated in vacuo to provide 1.1 g of the desired product as a yellow oil (quantitative yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:22][O:23][C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:21]
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Reactant: COC(=O)C(C)(C)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cn1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 40 h
Yield: 40.3 %

Procedure:
To a stirred solution of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.17 mmol), 3-Hydroxy-2,2-dimethyl-propionic acid methyl ester (0.026 mL, 0.20 mmol) and triphenylphosphine (53 mg, 0.20 mmol) in dry THF (1.5 mL) is added diisopropyl azodicarboxylate (0.041 mL, 0.20 mmol) in a drop wise manner. The mixture is stirred at room temperature for 40 hrs. Then the solvent is removed under vacuum and the residue is purified by two preparative TLC's (first one is developed with 30% EtOAc in Hexanes, second one is developed with 1% MeOH in CH2Cl2) to give 28 mg (41%) of 2,2-Dimethyl-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2=[O:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][OH:35])[CH2:33][O:32][CH2:31]1>C(#N)C>[OH:35][CH2:34][C:30]1([CH2:29][O:1][C:2]2[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=2[C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH2:33][O:32][CH2:31]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)COC2)c1OC
Temperature: 70 °C

Procedure:
To a stirring solution of 4-(2-Hydroxy-3,4-dimethoxy-phenyl)-indan-1-one (Compound 303) (500 mg, 1.76 mmol) in acetonitrile, were added potassium carbonate (728 mg, 5.28 mmol) and (3-Bromomethyl-oxetan-3-yl)-methanol (764 mg, 4.28 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) afforded 4-(2-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-3,4-dimethoxyphenyl)-indan-1-one (Compound 104) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[N:11]=[N:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8]2)[S:4][C:3]=1[C:18]([OH:20])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:51]([NH2:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C)C=O.ClCCl>[CH2:51]([NH:58][C:18]([C:3]1[S:4][C:5]([N:7]2[N:11]=[N:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8]2)=[CH:6][C:2]=1[CH3:1])=[O:20])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(-n2nnc(-c3ccccc3)n2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-n2nnc(-c3ccccc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
To a solution of 3-methyl-5-(5-phenyl-2H-tetrazol-2-yl)thiophene-2-carboxylic acid (0.12 g, 0.40 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (0.65 g, 0.48 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.09 g, 0.48 mmol), N,N-diisopropylethylamine (0.21 mL, 1.20 mmol) and benzylamine (0.05 mL, 0.48 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid in 10% yield (0.02 g): mp 155-158° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.23-8.19 (m, 2H), 7.53-7.51 (m, 4H), 7.39-7.35 (m, 5H), 6.09 (br s, 1H), 4.65 (d, J=6.0, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.4, 161.9, 140.1, 137.6, 130.9, 129.1, 129.0, 128.9, 128.8, 127.9, 127.8, 127.1, 126.4, 122.7, 44.3, 16.2; MS (ES+) m/z 376.3 (M+1).
Reaction SMILES: Br[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1)=[N+:17]=[N-:18]
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(N=[N+]=[N-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (6.73 g, 25.29 mmoles), title B compound, in dry N,N-dimethylformamide (100 mL) was treated with sodium azide (3.79 g, 50.57 mmoles) and stirred at room temperature under argon for four hours. The reaction mixture was partitioned between 100 mL ethyl acetate and 200 mL distilled water. The organic layer was separated and the aqueous layer was extracted with 100 mL of ethyl acetate. The combined organics were washed successively with distilled water, saturated sodium bicarbonate solution, brine and dried over magnesium sulfate. The solvent was evaporated under vacuum to obtain an orange gum (5.62 g) which was triturated with penme to provide the title compound (4.50 g, 78%) as an off-white solid, m.p. 63°-64° C.
Reaction SMILES: [P:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O:29]=O>CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Co+2]>[P:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:29]
Reactant: O=O
Reactant: CCCCCCCCOP(OCCCCCCCC)OCCCCCCCC
Agent: [Co+2]
Agent: CCCCC(CC)C(=O)[O-]
Product: CCCCCCCCOP(=O)(OCCCCCCCC)OCCCCCCCC
Yield: 91 %

Procedure:
A mixture of 0.2 g. of cobalt octoate and 70 g. of trioctyl phosphite is warmed in vacuo (10 mm.) at 30°C while oxygen is added over a period of six hours. The mixture is stirred throughout this period by means of a magnetic stirrer. The product is washed with an aqueous alkaline solution to remove the cobalt catalyst, having a 91% yield of trioctyl phosphate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][C:12]1[C:13]([N+:18]([O-:20])=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=1)(=O)=O.C(=O)(O)[O-].[Na+].C(Cl)Cl>CS(C)=O>[N:1]([CH2:10][CH2:11][C:12]1[C:13]([N+:18]([O-:20])=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCc1cccnc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCc1cccnc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
Sodium azide (1.16 g, 17.8 mmol) was added to a solution of 3-(2-methansulfonyloxyethyl)-2-nitropyridine (0.44 g, 1.78 mmol) in dimethyl sulfoxide (5 mL), then stirred overnight at 50° C. The reaction was cooled and worked up with saturated sodium bicarbonate and methylene chloride. The organic phase was dried over sodium sulfate. This material was chromatographed (silica gel, 0-50% ethyl acetate in hexane, gradient elution) to produce the title compound (0.190 g) as a yellow oil. MS 194 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH3:31])[CH:21]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)(C)(C)C>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:19][C:20]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:39])[F:40])[CH3:31])[CH:21]=3)[CH:3]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1sc(N)cc1O[C@H](C)c1ccccc1C(F)(F)F
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 80 °C
Yield: 79.6 %

Procedure:
A mixture of 1-[(3-chloro-4-nitrophenyl)methyl]-4-methylpiperazine (0.313 g, 1.16 mmol), methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (0.401 g, 1.16 mmol), K2CO3 (0.401 g, 2.90 mmol), X-Phos (0.0587 g, 0.12 mmol), tris(benzylideneacetone)dipalladium(0) (0.0531 g, 0.06 mmol) and tert-butanol (4.6 mL) in a sealed tube was heated at 80° C. for 18 h. The crude reaction mixture was filtered through celite, washing with toluene and then purified by flash column chromatography (EtOAc:MeOH:NEt3) to give the title compound (0.534 g, 70%) as a red amorphous solid.
Reaction SMILES: FC(F)(S(O[C:17]1[CH:18]=[C:19]2[C@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:36]#[C:37][C:38]([O:41][CH3:42])([CH3:40])[CH3:39])[CH:28]=3)[O:23][C:20]2=[CH:21][CH:22]=1)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:51]1[CH:56]=[CH:55][N:54]=[N:53][CH:52]=1)CCC>[Cu]I.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.CN(C=O)C>[CH3:42][O:41][C:38]([CH3:40])([CH3:39])[C:37]#[C:36][C:27]1[CH:28]=[C:29]2[C@@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:19]3[C:20](=[CH:21][CH:22]=[C:17]([C:51]4[CH:56]=[CH:55][N:54]=[N:53][CH:52]=4)[CH:18]=3)[O:23][C:24]2=[N:25][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: COC(C)(C)C#Cc1cnc2c(c1)[C@@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc1O2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@@]1(COC(N)=N1)c1cc(-c3ccnnc3)ccc1O2

Procedure:
A vial was charged with (R)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (102 mg, 0.158 mmol), copper(i) iodide (3.01 mg, 0.016 mmol), tetrakis(triphenylphosphine)palladium (18.24 mg, 0.016 mmol), and lithium chloride (10.96 mg, 1.579 mmol). The vial was purged with Ar (g), then DMF (790 μL) and 4-(tributylstannyl)pyridazine (146 μL, 0.474 mmol) were added in sequence. The vial was sealed and placed in a 110° C. oil bath for 4 hours. The mixture loaded onto a 2-g SCX-2 column and eluted 4× with methanol to remove impurities. The product was then eluted with 2M ammonia in methanol. The filtrate was evaporated, and the residue was chromatographed on a 40-g Redi-Sep column, eluting with 0-100% EtOAc/Hexane, then with 0-10% MeOH/DCM. The resulting material was still impure, so the material was dissolved in methanol and purified by reverse-phase HPLC (15-80% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution with the aid of methanol and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (R)-3-(3-methoxy-3-methylbut-1-ynyl)-7-(pyridazin-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH3:5][CH2:6][C@@H:7]([CH:32]([CH3:34])[CH3:33])/[CH:8]=[CH:9]/[C@H:10]([C@@H:12]1[C@@:16]2([CH3:31])[CH2:17][CH2:18][C@@H:19]3[C@@:24]4([CH3:30])[CH2:25][CH2:26][C@H:27]([OH:29])[CH2:28][C:23]4=[CH:22][CH2:21][C@H:20]3[C@@H:15]2[CH2:14][CH2:13]1)[CH3:11].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:3][C:1]([O:29][C@H:27]1[CH2:26][CH2:25][C@@:24]2([CH3:30])[C:23](=[CH:22][CH2:21][C@@H:20]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:31])[C@H:15]3[CH2:14][CH2:13][C@@H:12]2[C@H:10]([CH3:11])/[CH:9]=[CH:8]/[C@H:7]([CH:32]([CH3:33])[CH3:34])[CH2:6][CH3:5])[CH2:28]1)=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC[C@H](/C=C/[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC[C@H](/C=C/[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)Cl)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Temperature: -10 °C
Reaction time: 24 h

Procedure:
10 ml of a 20% phosgene solution in toluene are added to a solution, cooled to -10° C., of 4.12 g of stigmasterol in 40 ml of methylene chloride. The mixture is reacted overnight and then cooled to -10° C. After adding 0.7 ml of triethylamine in 10 ml of methylene chloride the reaction is continued for 24 hours. The mixture is neutralized with 0.7 ml of triethylamine in 10 ml of methylene chloride and the (E)-stigmasta-5,22-dien-3β-yl chloroformate is isolated.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C[O:13][CH:14](OC)[CH2:15][CH2:16][CH2:17][CH:18]=O>CCOC(C)=O.CCCCCC>[N+:1](/[C:4](/[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:18]/[CH2:17][CH2:16][CH2:15][CH:14]=[O:13])([O-:3])=[O:2]
Reactant: COC(CCCC=O)OC
Reactant: O=[N+]([O-])CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCC/C=C(\Cc1ccccc1)[N+](=O)[O-]
Yield: 39.9 %

Procedure:
Prepared according to the general procedure B from 1-(2-nitroethyl)benzene 112e (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.49 g, 40% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([NH:8][C:9]([NH2:11])=S)[CH:7]=1.O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.[OH-].[K+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([NH:8][C:9]#[N:11])[CH:7]=1
Reactant: NC(=S)Nc1cc(F)ccc1N1CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CNc1cc(F)ccc1N1CCOCC1

Procedure:
A mixture of 1-(5-fluoro-2-morpholinophenyl)thiourea (5.1 g) suspended in water (36.5 ml), lead acetate trihydrate (7.95 g) in water (36 ml) and potassium hydroxide (11.45 g) in water (32 ml) was heated under reflux for 25 minutes to give N-(5-fluoro-2-morpholinophenyl)cyanamide as a white solid (m.p. 168°-170° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH2:24].CCN(CC)CC.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:11]([F:13])([F:14])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH:24][C:35]([NH:34][CH2:32][CH3:33])=[O:36]
Reactant: CCN=C=O
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added Et3N (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[CH:4][N+:3]=1[O-].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:20]>S(=O)(=O)(O)O>[OH:20][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(OCC(F)(F)C(F)F)cc[n+]([O-])c1C
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=S(=O)(O)O
Product: Cc1c(OCC(F)(F)C(F)F)ccnc1CO
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Concentrated sulfuric acid (two drops) was added to a solution of 2,3-dimethyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine-1-oxide (2.6 g) in acetic anydride (8 ml). The mixture was stirred at 110° C. for 4 hours, which was then concentrated. The residue was dissolved in methanol (20 ml), to which was added sodium hydroxide (1.2 g) dissolved in water (5 ml). The mixture was stirred at room temperature for 30 minutes, which was concentrated. To the residue was added water, and the mixture was subjected to extraction with ethyl acetate. The extract was dried on magnesium sulfate, followed by removal of the solvent by evaporation. The residue was chromatographed on a column of silica gel (50 g), eluted with chloroform-methanol (10:1), and recrystallized from isopropyl ether to yield 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine as yellow crystals, m.p. 67°-68° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C.C(COC)OC.O>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2ccccc2c1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: COc1ccc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
To a flask charged with 1-bromo-2-methoxynaphthalene (20.0 g, 84.4 mmol), phenylboronic acid (11.3 g, 92.8 mmol), palladium acetate (0.10 g, 0.46 mmol), triphenylphosphine (0.85 g, 2.78 mmol) and potassium phosphate (40.9 g, 177.9 mmol), added was mixture of water (60 mL) and dimethoxyethane (120 mL), and the resultant mixture was heated under reflux for 6 hours. After cooling the mixture to ambient temperature, aqueous ammonium chloride solution (150 mL) and diethyl ether (200 mL) were injected thereto. The organic layer was isolated, and the residue was extracted with diethyl ether. The combined organic layer was dried over magnesium sulfate and evaporated to remove the volatile substances. Purification via silica gel column chromatography (n-hexane) gave 2-methoxy-1-phenylnaphthalene (13.0 g, yield: 66%) as colorless liquid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13](Br)[CH:14]=1.[CH3:17][O-:18].[Na+]>CO>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13]([O:18][CH3:17])[CH:14]=1
Reactant: C[O-]
Reactant: CN1CCC[C@H]1COc1cc(Br)c[n+]([O-])c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC[C@@H]2CCCN2C)c[n+]([O-])c1

Procedure:
A sample of the compound from step 98a above is reacted with sodium methoxide in methanol according to standard procedures. The reaction is quenched with water, the product is extracted, then purified by chromatography on silica gel.