Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([C:12](OCCC)=[O:13])[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)[CH2:2][CH2:3][CH3:4].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C(=O)OCCC)ccc1-c1cccc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1cc(CO)ccc1-c1cccc(OC)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a mixture of T13.1 (795 mg, 2230 μmol) and THF (10 mL) at 0° C. was added LAH (1.0 M solution in THF (3345 μL, 3345 μmol)). The reaction was stirred for one hour and then carefully diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then dried over sodium sulfate, filtered, and concentrated to provide T13.2 (530 mg, 83.0% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[NH2:32][CH2:33][CH2:34][OH:35]>C(#N)C>[OH:35][CH2:34][CH2:33][NH:32][C@H:14]1[CH2:15][CH2:16][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]=3[NH:22][C:23](=[O:31])[CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:8]=2)[CH2:13]1
Reactant: NCCO
Reactant: Cc1ccc2nc(N3CC[C@@H](OS(C)(=O)=O)C3)ccc2c1NC(=O)CC1CCCCC1
Solvent: CC#N
Product: Cc1ccc2nc(N3CC[C@H](NCCO)C3)ccc2c1NC(=O)CC1CCCCC1

Procedure:
Prepared according to the method of example 33(b), using N-[6-methyl-2-[(3R)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 86(a)) (0.16 g), 2-amino-ethanol (0.065 mL), and acetonitrile (4 mL). Purification (SiO2, 7M ammonia in methanol:methanol:dichloromethane 1:2:99 as eluant) gave the title compound (0.06 g).
Reaction SMILES: C([Cl:4])(=O)C.Cl.[CH2:6]([C:13]1[S:17][N:16]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[ClH:4].[CH2:6]([C:13]1[S:17][N:16]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:15][N:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N2CN=C(Cc3ccccc3)S2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(CC2=NCN(C3CCNCC3)S2)cc1
Reaction time: 0.17 h
Yield: 121.4 %

Procedure:
Acetyl chloride (0.2 mL, 2.8 mmol) was added to 2 mL of methanol and stirred for 10 min. This solution of HCl in methanol was added to 46 mg of 4-(5-benzyl-1,2,4-thiadiazol-2-yl)-1-t-butyoxycarbonyl-pieridine (step B) and stirred for 1 hr. The reaction mixture was concentrated and the residue was diluted with EtOAc and concentrated again to isolate 46 mg of the title compound which was sufficiently pure for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[C:11]([C:13](=[CH:22]OCC)[C:14]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])#[N:12]>C(O)C>[C:11]([C:13](=[CH:22][NH:4][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:5]=1[Cl:10])[C:14]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])#[N:12]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1c(Cl)cc(Cl)cc1Cl

Procedure:
2,4,6-Trichloroaniline (0.04 mol) is reacted with α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (0.04 mol) by heating at reflux in ethanol to yield α-cyano-β-(2,4,6-trichloroanilino)-N-ethoxycarbonylacrylamide, which is cyclized by heating at reflux in 1,2-dichlorobenzene to yield crude product which is chromatographed on silica eluting with chloroform/acetone (3/1) to 5-cyano-1-(2,4,6-trichlorophenyl)uracil, pale yellow crystals, m.p. 245°-247°.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CO>[F:29][C:28]([F:30])([F:31])[C:27]([C:24]1[CH:25]=[CH:26][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH2:12][C@@H:7]2[CH2:6][NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:22][CH:23]=1)([OH:33])[CH3:32]
Reactant: Nc1ccccc1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNc2ccccc2)cc1)C(F)(F)F
Temperature: 140 °C
Yield: 57.3 %

Procedure:
A 20-mL microwave vial was charged with ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (0.500 g, 0.946 mmol, Intermediate B), aniline (0.884 g, 9.46 mmol), and MeOH (8.0 mL). The vial was sealed and heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated and the crude product was purified by column chromatography (80 g, 2 to 5% 2M NH3 in MeOH/CH2Cl2) to afford 1,1,1-trifluoro-2-(4-((2S)-2-((phenylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.285 g) as a mixture of two isomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:27][C:28]1[N:33]=[CH:32][C:31]([O:1][C:2]2[CH:3]=[C:4]([C:8]34[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:12][CH2:13]3)[CH2:10][O:9]4)[CH:5]=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(Oc2cccc(C34CCC(CCOCC(=O)O)(CC3)CO4)c2)cn1

Procedure:
Example 115 was synthesized using the same 2-step protocol as for the syntheses of Examples 39-45 from intermediate phenol 7F, but with 6-methylpyridin-3-ylboronic acid. LCMS, [M−H]+=396.2. 1H NMR (500 MHz, DMSO-d6) δ=8.18 (br. s, 1H), 7.35-7.25 (m, 3H), 7.11 (d, J=7.3 Hz, 1H), 7.00 (br. s, 1H), 6.83 (d, J=7.6 Hz, 1H), 3.95 (s, 2H), 3.58-3.43 (m, 2H), 2.44 (s, 3H), 2.06-1.96 (m, 2H), 1.81-1.72 (m, 2H), 1.68-1.54 (m, 4H), 1.40-1.34 (m, 2H), 1.28-1.20 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([CH:9]1[CH2:13][C:12]([O:14]CC)=[CH:11][C:10]1=O)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(O)=O>C(O)C>[C:1]([O:5][C:6]([C:7]1[C:9]2[CH2:13][C:12](=[O:14])[CH2:11][C:10]=2[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=1)=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: NNCc1ccccc1
Reactant: CCOC1=CC(=O)C(C(=O)C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1nn(Cc2ccccc2)c2c1CC(=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of the intermediate from step A (2.15 g, 8.45 mmol) in ethanol (100 mL) was added benzyl hydrazine hydrochloride (1.8 g, 9.22 mmol) and HOAc (10 mL). The reaction mixture was stirred at room temperature for 16 hours and then refluxed at 70° C. for 30 minutes. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, saturated NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2) using 30% ethyl acetate-hexanes to give the desired product (1.64 g) a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:29].O>C(Cl)Cl>[Br:29][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(CCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(CCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of {3-[(5-chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.30 g, 0.78 mmol) in methylene chloride (5.0 mL) was added slowly a solution of boron tribromide in methylene chloride (2.3 mL, 2.3 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when water was added. The mixture was allowed to warm up to rt. Both aqueous layer (no product in it) and organic layer (containing small amounts of product, plus byproducts) were checked and discarded. The remaining solid residue was triturated with cold EtOAc and then filtered. The cake was washed with cold EtOAc and then H2O to give the desired product as a white powder (0.30 g, 89%). LCMS for C19H19BrClN4O (M+H)+: m/z=433.0, 435.0, 437.0. 1H NMR (400 MHz, CD3OD): δ 7.94 (s, 1H), 7.60 (s, 1H), 7.40 (m, 2H), 7.32 (m, 1H), 7.05 (m, 1H), 6.60 (m, 3H), 4.54 (s, 2H), 3.76 (t, J=6.4 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: SCc1ccccc1Cl
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl 2-chlorobenzylsulfide. The title compound was obtained in 74% yield following oxidation. 1HNMR (CDC13) δ 4.55 (2H, s), 6.66 (1H, d, JH,H=11.94), 7.20-7.65 (8H aromatic+1H ethylenic).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6]C[N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1.[BH4-].[Na+]>CO>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:1][C@H:2]2[CH2:7][CH2:6][N:4]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3]2)=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc(F)cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl (3S)-3-aminopiperidine-1-carboxylate (5 g) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (5.15 g, 26.8 mmol) were allowed to stir in methanol for 16 h at room temperature. Sodium borohydride (1.62 g, 26.8 mmol) was then added portionwise. The resulting solution was further stirred for 2 h at room temperature. The solvent was evaporated in vacuo, water was added, and the solution extracted with dichloromethane. The organic extracts were absorbed onto a methanol washed cationic ion exchange resin (Isolute™ SCX-2). The basic components were recovered from the column by elution with 7N ammonia in methanol. The resultant solution was concentrated in vacuo to yield the desired compound as an oil. This was further purified by column chromatography on silica gel, eluting with ethyl acetate/iso-hexane (0:100 to 40:60). The title compound was used in subsequent reactions without further purification. 1H NMR (300 MHz, CDCl3) δH: 7.37-7.28 (m, 2H), 7.24-7.20 (m, 1H), 3.80 (s, 2H), 3.52-3.48 (m, 2H), 3.32 (m, 3H), 3.12 (m, 1H), 2.08-2.0 (m, 1H), 1.75 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:7]([OH:9])=[O:8])[CH3:2]>[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: CCOc1cc(C(=O)O)ccc1N
Yield: 92.1 %

Procedure:
3-Ethoxy-4-nitrobenzoic acid (0.31 g) was treated with 5% palladium on charcoal under an atmosphere of hydrogen (1 bar) for 3 hours. The reaction mixture was filtered and the filtrate was evaporated to leave the product as a beige solid (0.245 g; MS: ES− (M−H) 180).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:12]1[CH:44]=[CH:43][C:15]([CH2:16][CH:17]([CH2:25][CH2:26][C@H:27]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=1)C1C=CC=CC=1>CO.[Pd]>[C:39]([O:38][C:36]([NH:35][C@@H:27]([CH2:26][CH2:25][CH:17]([CH2:16][C:15]1[CH:14]=[CH:13][C:12]([N:11]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:10][CH2:9][OH:8])=[CH:44][CH:43]=1)[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:37])([CH3:40])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(N(CCOCc2ccccc2)C(=O)OC(C)(C)C)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(N(CCO)C(=O)OC(C)(C)C)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 27 h
Yield: 94.9 %

Procedure:
Di-tert-butyl (5S)-2-(4-{[2-(benzyloxy)ethyl](tert-butoxycarbonyl)amino}benzyl)-5-[(tert-butoxycarbonyl)amino]hexanedioate (78 mg, 110 μmol) were dissolved in 10 ml methanol. Palladium (10% on charcoal) (15 mg) was added and the suspension was shaken under a hydrogen atmosphere for 27 h. The catalyst was filtered off, the residue was concentrated in vacuo to yield 65 mg (95%) of the product.
Reaction SMILES: [CH3:1][C:2]1([CH2:24][CH2:25][CH2:26][CH:27]([CH3:39])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[O:15][C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH3:17])[C:13]=2[CH3:16])[O:10]C(CCC)O[CH:7]3[CH2:21][CH2:22][CH3:23])[CH2:4][CH2:3]1>CC(O)=O.OS(O)(=O)=O.C(Cl)Cl.[Pd]>[CH2:7]([C:6]1[C:11]([OH:10])=[C:12]([CH3:17])[C:13]([CH3:16])=[C:14]2[C:5]=1[CH2:4][CH2:3][C@@:2]([CH3:1])([CH2:24][CH2:25][CH2:26][C@H:27]([CH3:39])[CH2:28][CH2:29][CH2:30][C@H:31]([CH3:38])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[O:15]2)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC1Oc2c(C)c(C)c3c(c2C(CCC)O1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O3
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1c(O)c(C)c(C)c2c1CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 105.3 %

Procedure:
A solution of 7,9,10-trimethyl-2,4-dipropyl-7-(4,8,12-trimethyl-tridecyl)-4,5,6,7-tetrahydro-1,3,8-trioxa-phenanthrene (Ex-1C-2) (180 mg of crude material form above) in AcOH (10 mL) and conc. H2SO4 (10 drops) was hydrogenated (H2, 50 psi, RT) with 5% Pd/C (20 mg of 50% w/w wet) at RT for 16 h. The reaction mixture was then filtered through celite. The celite was rinsed with DCM (2×2 mL). The DCM layer was concentrated by rotary evaporation to yield a light brown oil. The oil was dissolved in DCM (15 mL) and passed through a silica plug. The DCM was concentrated by rotary evaporation to yield (R,R,R)-5-butyl-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-6-ol (Ex-1C-3) as a cloudy yellow oil (165 mg, >100%), which was used directly without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[OH-].[K+:17]>CO>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:4][C:2](=[O:3])[C:1]([O-:6])=[O:5])=[CH:10][CH:9]=1.[K+:17]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=Cc1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of pyruvic acid and p-fluorobenzaldehyde (24.8 g) in methanol (20 ml) was cooled to 15° C. and treated with a solution of potassium hydroxide (16.8 g) in (50 ml) methanol. After 2/3 of the addition was complete, the cooling bath was removed and the temperature was allowed to rise to 40° C. A yellow precipitate appeared and was filtered after standing overnight. The solid was washed well with methanol and ether. The title compound (34.5 g) was used without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C-:28]#[N:29].[Na+]>CN(C)C=O>[C:28]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1)#[N:29]
Reactant: [C-]#N
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C#N)n3)c2)cc1

Procedure:
6-Cyano-4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine is prepared by the method of example 27 from 6-bromo-4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine (0.0745 mol), cuprous cyanide (0.296 mol), sodium cyanide (0.297 mol), and dimethylformamide (300 ml).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.[OH-].[Na+]>>[S:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9]1
Reactant: C1CNCCN1
Reactant: Clc1nsc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(N3CCNCC3)nsc2c1
Reaction time: 24 h
Yield: 91.1 %

Procedure:
A 4 L suction flask was charged with anhydrous piperazine (1582 g, 18.36 moles) followed by molten 3-chloro-1,2-benzisothiazole (Example 8, 622 g, 3.672 moles). The flask was stoppered with a wired-on rubber stopper and a short length of pressure tubing was wired-on to the side tube. The flask was evacuated (house vacuum) and the pressure tubing on the side arm clamped shut. The apparatus was then oven heated at 125° with occasional swirling as melting proceeded. After 24 hours at this temperature, the orange melt was quenched in 4.8 liter of cracked ice and water. One equivalent of 50% NaOH (293 g, 3.672 moles) was added in one portion. The mixture was extracted with methylene chloride and these extracts washed with water. Concentration in vacuo gave 734 g of crude product which was recrystallized from 1800 mL of boiling ethyl acetate to yield 548 g, 68%, m.p. 88°-90°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CC1C=CC(S(O[CH2:20][CH2:21][CH2:22][NH:23][C:24]2[C:25](=[O:41])[N:26]([C:37]([CH3:40])([CH3:39])[CH3:38])[S:27](=[O:36])(=[O:35])[C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=O)=O)=CC=1>>[C:37]([N:26]1[C:25](=[O:41])[C:24]([NH:23][CH2:22][CH2:21][CH2:20][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:27]1(=[O:35])=[O:36])([CH3:38])([CH3:39])[CH3:40]
Reactant: Oc1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccccc2Cl)=C(c2ccccc2)S1(=O)=O
Yield: 77 %

Procedure:
The title compound was prepared as described for Example 12 from 2-chlorophenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and the crude product was purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.085 g, 77%). 1H NMR (500 MHz CDCl3): δ 7.53-7.50 (m, 2H), 7.44-7.42 (m, 3H), 7.36 (dd, 1H), 7.19 (dt, 1H), 7.6.92 (dt, 1H), 6.83 (dd, 1H), 5.56 (t, 1H), 3.89 (t, 2H), 3.28 (m, 2H), 1.88-1.84 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 154.2, 135.3, 131.8, 130.6, 129.8, 128.8, 127.9, 125.2, 123.4, 122.1, 113.7, 107.4, 66.7, 61.7, 41.8, 29.2, 27.8; Mass Spectrum M+H+ 449.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.[OH-].[K+].[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl>C(O)(C)(C)C>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a mixture of 1.34 g (purity: 96.2%; 34.9 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (42.0 mL) was added 2.06 g (34.9 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for one hour. To the resultant solution was added dropwise the preliminarily prepared solution of 3.07 g (purity: 96.0%; 17.8 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (50.0 g) at 180° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 2 hours, the reaction mixture was cooled to room temperature, and pure water was added to the cooled mixture and stirred at room temperature for 30 minutes, and then an organic phase was separated. 1,2-Dichlorobenzene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and then an organic phase containing 2-cyclopropyl-6-methylphenol was separated, and then a 1 N aqueous hydrochloric acid solution and methanol were added to the resultant aqueous phase containing a potassium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 2.57 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 52%) and 29 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]=O)=[N:8][CH:9]=1.C(OP([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(OCC)=O)C.[H-].[Na+]>C1COCC1>[C:26]([O:25][C:23](=[O:24])[CH:22]=[CH:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([O:12][CH3:13])[O:2][CH3:1])=[CH:9][N:8]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: COC(OC)c1ccc(C=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc(C=CC(=O)OC(C)(C)C)nc1
Yield: 89.2 %

Procedure:
5-dimethoxymethyl-pyridine-2-carbaldehyde (355 mg, 1.97 mmol) was dissolved in THF (10 ml) and the resulting solution was added to a stirring mixture of tert-butyl diethylphosphonoacetate (547 mg, 2.169 mmol) and NaH (102 mg, 2.56 mmol, 60% oil dispersion) in THF (5 ml). After 15 minutes the reaction was quenched by addition of water and the resulting slurry was extracted with Et2O. The organic phase was dried over Na2SO4 and evaporated under vacuo. The crude product was purified by silica gel chromatography (petroleum ether/EtOAc 95:5) to give 491 mg of 3-(5-dimethoxymethyl-pyridin-2-yl)-acrylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.C1C(=O)N([I:19])C(=O)C1>CC#N>[Cl:1][C:2]1[C:7]([I:19])=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(Cl)nc(SC)n1
Solvent: CC#N
Product: COc1nc(SC)nc(Cl)c1I
Temperature: 25 °C

Procedure:
Compound 2 (10 g, 52.5 mmol) was dissolved in MeCN (150 mL) and NIS (14.2 g, 62.9 mmol) was added. The solution was heated to reflux for 5 h and cooled to room temperature. The solvent was evaporated and the residue was dissolved in EtOAc. The organics were washed with sat. NaHCO3 and sat. NaS2O3, dried (MgSO4), filtered and concentrated to give the title compound as a white solid. 1H NMR (CDCl3) δ 4.04 (s, 3H), 2.54 (s, 3H); LCMS 2.64 min, 317 (M+H).