Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:10][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: COc1cccc(C2CO2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cccc(C(O)COc2ccc(C=O)cc2)c1
Temperature: 78 °C
Yield: 122 %

Procedure:
To a stirring solution of 2-(3-methoxyphenyl)oxirane (5.60 g, 37.0 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (6.80 g, 5.60 mmol), 1M NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction mixture was allowed to cool to RT and extracted with EtOAc (2×150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed, eluting with 30-40% EtOAc/hexanes. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.86 g (18%) of the title compound as a clear colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.90 g (9%) the regioisomer as a nearly colorless oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1.S([CH2:28][N+:29]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+]>C(COC)OC.C(O)(C)(C)C>[C:28]([CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1)#[N:29]
Reactant: CC(CNS(=O)(=O)C(C)C)C1CCC(=O)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)C1CCC(C#N)CC1
Reaction time: 3 h

Procedure:
To a −15° C. solution of 1 eq. of N-[2-[4-oxocyclohexyl]propyl] 2-propanesulfonamide (see Preparation 2) and 1 eq. of tosylmethyl isocyanide in dimethoxyethane is added a solution of 2.8 eq. of potassium t-butoxide in t-butanol. The cooling bath is removed and the mixture is stirred for three hours. The mixture is then diluted with water and extracted three times with diethyl ether. The combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to provide the crude material. Chromatography (silica gel) of the crude material affords the purified title compound.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].Cl[C:8]1[C:9]2[NH:16][N:15]=[C:14]([CH3:17])[C:10]=2[N:11]=[CH:12][N:13]=1>O>[CH3:17][C:14]1[C:10]2[N:11]=[CH:12][N:13]=[C:8]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]=2[NH:16][N:15]=1
Reactant: Cc1n[nH]c2c(Cl)ncnc12
Reactant: CCCCCN
Solvent: O
Product: CCCCCNc1ncnc2c(C)n[nH]c12

Procedure:
When n-pentylamine (7 g) was added to 7-chloro-3-methylpyrazolo[4,3-d]pyrimidine (6.13 g, 36 mmol), an exothermic reaction took place and the mixture heated itself to boiling. The cooled reaction mixture was triturarted with water (100 ml). The crude product crystallized and was filtered, washed with water and air-dried to give a quantitative crude yield of slightly yellow crystals. Recrystallization from ether and treatment with charcoal afforded the product, yield 5.0 g (63%), m.p. 157.5°-158.5°. An additional 1.24 g was recovered from the mother liquor as the maleinate. Total yield, 73.6%.
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:7]=[N+:8]([O-])[CH:9]=[CH:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3]1.C[Si](C)(C)[C:21]#[N:22].CN(C)C(Cl)=O>ClCCl>[F:1][C:2]1([C:6]2[C:11]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]([C:21]#[N:22])=[N:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: [O-][n+]1ccc(OCC(F)(F)F)c(C2(F)CCC2)c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: N#Cc1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of 3-(1-fluorocyclobutyl)-1-oxido-4-(2,2,2-trifluoroethoxy)pyridin-1-ium (example 127b, 1.65 g, 6.22 mmol) in dichloromethane (25 ml) was added trimethylsilanecarbonitrile (945 mg, 1.19 ml, 9.33 mmol) and dimethylcarbamic chloride (833 μl, 8.71 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a separation funnel and extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (760 mg, 44%); MS (ESI, m/z): 275.5 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:28]([CH2:29][OH:30])[CH2:27][CH2:26][C@@:9]32[O:13][CH2:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])=[CH:10]3)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@@H:28]([CH2:29][OH:30])[CH2:27][CH2:26][C@@:9]32[O:13][CH2:12][C@H:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[CH2:10]3)=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccc(C#N)cc1C1=C[C@@]2(CC[C@H](CO)[C@H]2c2ccc(F)cc2)OC1
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1ccc(C#N)cc1[C@H]1CO[C@]2(CC[C@H](CO)[C@H]2c2ccc(F)cc2)C1

Procedure:
The title compound was prepared by hydrogenation of (5R, 6S, 7S)-6-(4-fluorophenyl)-3-(5-cyano-2-isopropoxy-phenyl)-1-oxaspiro[4.4]non-3-ene-7-methanol (78 mg) in methanol (4 mL) over 10% palladium-on-charcoal (20 mg) at 50 psi for 90 minutes. Purification was achieved by means of silica gel chromatography eluting with 10% acetone/methylene chloride; yield 35 mg.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]2[C:10](=[O:33])[CH2:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=3[CH2:30][CH2:31][CH3:32])([CH3:14])[O:13][C:8]=2[CH:7]=1.[OH-].[Li+]>O1CCCC1.O>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]2([CH3:14])[CH2:11][C:10](=[O:33])[C:9]3[CH:34]=[CH:35][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:7][C:8]=3[O:13]2)=[C:21]([CH2:30][CH2:31][CH3:32])[C:22]=1[OH:29])(=[O:28])[CH3:27]
Reactant: CCCc1c(OCCCCC2(C)CC(=O)c3ccc(OCC(=O)OC)cc3O2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCCC2(C)CC(=O)c3ccc(OCC(=O)O)cc3O2)ccc(C(C)=O)c1O
Yield: 97.9 %

Procedure:
Using the procedure of Example 24, the chromanone ester from Example 39 was saponified with lithium hydroxide in tetrahydrofuran-water giving rac.-[[2-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl]-3,4-dihydro-2-methyl-4-oxo-2H-1-benzopyran-7-yl]oxy]acetic acid in 97.9% yield, as a viscous, amber oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:25][CH2:26][C@@H:27]([C:38]([O:40]C(C)(C)C)=[O:39])[NH:28][C:29]2[S:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH3:2].FC(F)(F)C(O)=O.ClCCl.CO.O.C(O)(=O)C.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([C:3]1[C:4]([NH:25][CH2:26][C@@H:27]([C:38]([OH:40])=[O:39])[NH:28][C:29]2[S:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)[CH3:2]
Reactant: CCc1c(NC[C@H](Nc2nc3ccccc3s2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCc1c(NC[C@H](Nc2nc3ccccc3s2)C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Yield: 97 %

Procedure:
45 mg (0.073 mmole) of (1,1-dimethylethyl) 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(2-benzothiazolyl)alaninate in 10 ml of dichloromethane with 1 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2Cl2-MeOH—H2O—AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 60 mg (Yield=97% expressed as ditrifluoroacetate) of expected product is obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)OC1>O1CCOCC1.O.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>[CH3:44][N:43]1[C:39]([C:2]2[S:6][CH:5]=[C:4]([C:7]([NH:9][CH:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])[CH:3]=2)=[CH:40][CH:41]=[N:42]1
Reactant: CC(C)(C)OC(=O)NCC(NC(=O)c1csc(Br)c1)c1ccccc1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
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: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)c2ccccc2)cs1
Temperature: 80 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
To a solution of 1,1-dimethylethyl (2-{[(5-bromo-3-thienyl)carbonyl]amino}-2-phenylethyl)carbamate (250 mg, 0.588 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (325 mg, 2.35 mmol), tetrakistriphenylphosphine Pd(0) (34 mg, 29.4 μmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (126 mg, 0.647 mmol). The reaction mixture was heated to 80° C. in a sealed tube. After 5 h, additional tetrakistriphenylphosphine Pd(0) (34 mg, 29.4 μmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (126 mg, 0.647 mmol) were added. After 12 h, the reaction solution was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organics were dried (Na2SO4), concentrated under vacuum and purified on silica gel (1% MeOH in DCM) to give the title compound (250 mg, quant.) as an orange oil: LCMS (ES) m/z=427.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][C:25]1([CH3:42])[O:29][C@@H:28]([CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][O:26]1>>[CH3:24][C:25]1([CH3:42])[O:29][C@@H:28]([CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH2:27][O:26]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)O1

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and toluene-4-sulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH:13]3[CH2:17][CH2:16][C:15](=[O:18])[NH:14]3)C(=O)[NH:10][C:5]2=[N:4][CH:3]=1.BrC1C(N)=NC=C(Br)N=1.Cl.NCC1NC(=O)CC1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:10][C:5]1[C:6]([NH:8][CH2:12][CH:13]2[NH:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[N:7][C:2]([Br:1])=[CH:3][N:4]=1
Reactant: O=C1CCC(Cn2c(=O)[nH]c3ncc(Br)nc32)N1
Agent: Cl
Agent: NCC1CCC(=O)N1
Agent: Nc1ncc(Br)nc1Br
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1NCC1CCC(=O)N1

Procedure:
6-Bromo-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. 3,5-Dibromopyrazin-2-amine (253 mg, 1 mmol), 5-(aminomethyl)pyrrolidin-2-one hydrochloride (150 mg, 1 mmol), diisopropylethylamine (0.5 mL), and dimethylsulfoxide (2 mL) were heated in a Biotage Emrys Optimizer microwave reactor at 150° C. for 2 h to afford crude 5-((3-amino-6-bromopyrazin-2-ylamino)methyl)pyrrolidin-2-one. MS (ESI) m/z 286.0 [M]+, 288.0 [M+2]+. 1,1′-Carbonyldiimidazole (243 mg, 1.5 mmol) was added to the reaction mixture and the solution was heated again in a Biotage Emrys Optimizer microwave reactor at 150° C. for 10 min. The product was purified by reverse-phase semi-preparatory HPLC (10-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The product fractions were concentrated and then triturated with ether to give a white solid. MS (ESI) m/z 312.0 [M]+, 314.0 [M+2]+.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]1[O:10][CH2:9][CH2:8][NH:7][CH2:6]1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[ClH:15].[Cl:15][CH2:14][CH2:13][CH2:12][N:7]1[CH2:8][CH2:9][O:10][C@H:5]([CH2:4][O:3][CH3:2])[CH2:6]1
Reactant: ClCCCBr
Reactant: COC[C@@H]1CNCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H]1CN(CCCCl)CCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2S)-2-(methoxymethyl)morpholine hydrochloride (0.5 g), 1-bromo-3-chloropropane (1.47 ml) and potassium carbonate (2.06 g) in N,N-dimethylformamide (6 ml) was stirred at room temperature for 1 hour. After ethyl acetate and water were added to the mixture, the organic layer was separated, washed with water twice, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as an eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure. The resulting oil was treated with 4N hydrogen chloride in ethyl acetate to give (2S)-4-(3-chloropropyl)-2-(methoxymethyl)morpholine hydrochloride (0.44 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2[nH]c(C3CCNCC3)cc2-c2ccncc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reaction time: 8 h

Procedure:
A solution of 10.0 mg of the product of Example 4 was dissolved in 0.5 ml of pyridine and treated with 2.6 μL of acetic anhydride. The solution was stirred overnight and diluted with 5 ml water and was extracted with ethyl acetate (2×5 ml). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH2:9][C:10]2[N:15]=[C:14]([CH2:16]O)[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C(Cl)Cl>[Br:50][CH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][O:8][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:15]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 85.9 %

Procedure:
A solution of 6-(triphenylmethoxymethyl)pyridine-2-methanol (16.8 g, 44 mmol) in CH2Cl2 at 0° C. was treated with triphenylphosphine (17.3 g, 66 mmol) and carbon tetrabromide (17.5 g, 52.8 mmol), stirred at 0° C. for 2.5 h then concentrated in vacuo to approximately a quarter of the original volume. The resulting solution was filtered through a pad of silica, washed with hexane:EtOAc (1:1) and the filtrate concentrated in vacuo to give the title compound (16.8 g, 86%) as a cream solid; NMR δH (400 MHz, DMSO) 4.14 (2H, s), 4.61 (2H, s), 7.27-7.48 (16H, m), 7.68 (1H, d, J 7.5 Hz) and 7.90 (1H, t, J 7.5 Hz); Rf (Hexane:EtOAc (2:1))=0.84
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4].C1(OC2C=CC=CC=2)C=CC=CC=1>CCOCC>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1OC)C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(OC)cccc2c1=O

Procedure:
Ethyl 2-butyryl-3-(2-methoxyphenylamino)acrylate (15.50 g, 0.053 mol) was added in portions to boiling diphenyl ether (400 ml) and the mixture heated under reflux for 1.5 hours. After cooling, the solution was diluted with ether and petroleum ether, filtered, and the solid washed with petroleum ether to give 3-butyryl-8-methoxy-4-(1H)-quinolone as light grey crystals (13.46 g, 63.1%). m.p. 200°-202°.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:6]=[CH:7][S:8]([N:11]=[C:12](Cl)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)(=[O:10])=[O:9]>C1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:6]=[CH:7][S:8]([NH:11][C:12](=[NH:1])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)(=[O:10])=[O:9]
Reactant: N
Reactant: COc1ccc(C(Cl)=NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(C(=N)NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC
Yield: 96 %

Procedure:
Ammonia gas is bubbled through a solution of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzimidoyl chloride (8.7 g., 0.02 mole) in 100 ml. of dry benzene for a period of 1 hr. The solvent evaporated under reduced pressure and the solid residue stirred with 50 ml. of water and filtered affords 8.0 g. (96% yield) of N-(3,4-DICHLOROSTYRYLSULFONYL)-3,4-DIMETHOXYBENZAMIDINE, m.p. 205°-210° C. A sample crystallized from acetonitrile has a melting point of 208°-211° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([N+:18]([O-])=O)=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:21][C@H:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH3:23])[CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[NH2:18][C:17]1[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[CH:11][C:12]([NH:21][C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:23])=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c([N+](=O)[O-])cc1C#N)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)cc1C#N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (S)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]-5-nitrobenzonitrile (Method 32; 4.10 g, 10.1 mmol) and zinc dust (3.30 g, 50.4 mmol) in MeOH:THF (1:1, 100 ml) was slowly added saturated ammonium chloride (40 ml). The reaction mixture was stirred at 25° C. for 1 hr, to which was added saturated ammonium acetate solution (50 ml). The resulting mixture was stirred for another 30 min. The Zn dust was removed by filtration and washed with EtOAc (200 ml). The organic layer was separated, washed with brine (100 ml), dried over Na2SO4, and concentrated. The title compound was used directly for the next step without further purification. MS: Calcd: 376; Found: [M+H]+ 377.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13].C(N(CC)CC)C.CS([Cl:25])(=O)=O>C(Cl)Cl>[Cl:25][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(CO)ccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CCl)ccc2ccccc12
Temperature: 25 °C

Procedure:
To a mixture of 10.1 g of 2-hydroxymethyl-1-methylnaphthalene, 14.0 ml of triethylamine and 120 ml of methylene dichloride, cooled in an ice-salt bath was added dropwise 5.5 ml of methanesulfonyl chloride. The reaction mixture was allowed to warm to room temperature, washed with water, dried and concentrated in vacuo to obtain 8.4 g of 2-chloromethyl-1-methylnaphthalene as a waxy solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[O:12]C.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[O:20]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[OH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: COc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Oc1cc(C(F)(F)F)ccc1Oc1ccccc1
Temperature: 130 °C
Reaction time: 17 h
Yield: 51.8 %

Procedure:
A mixture of 4-fluoro-3-methoxybenzotrifluoride (5.26 g, 28.9 mmol), phenol (2.71 g, 28.8 mmol) and 325 mesh potassium carbonate (4.79 g, 34.7 mmol) in dry DMSO (50 mL) is heated to 130° C. and stirred for 17 hours under N2. The reaction is filtered, and the filtrate is acidified with 1 N HCl. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 15/1 hexanes/ethyl acetate to afford 3.79 g (49%) of the title compound (Rf=0.47 (4/1 hexanes/EtOAc) that is contaminated with starting 4-fluoro-3-methoxybenzotrifluoride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1([CH2:11][CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1([CH2:11][CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8]1)[CH2:6]/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CCC1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1CCC2(C/C(=N\C#N)c3cc(Br)ccc3O2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of 6-bromo-3′-ethylspiro[chroman-2,1′-cyclopentan]-4-one (226 mg, 0.73 mmol) in anhydrous DCM (5.7 mL) was added TiCl4 (1 M solution in DCM, 1.5 mL, 1.49 mmol) dropwise within 15 min at room temperature. The mixture was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (300 mg, 0.36 mL, 1.61 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (20 g) and extracted with DCM (3×20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-bromo-3′-ethylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide as light brown solid (225 mg), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH3:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.[C:29]([OH:32])(=[S:31])[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH3:22])[CH:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][S:31][C:29](=[O:32])[CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C(=O)OCC)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(O)=S
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45 °C

Procedure:
TEA (86 μL, 0.617 mmol) was added to a solution of 4-(2ethoxycarbonyl-1-methyl-allyl)-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.59 mmol) in thioacetic acid (2 mL) at 0° C. After stirring for 6 h more thioacetic acid (2 mL) was added and the mixture was stirred at 45° C. over night. EtOAc was added and the mixture was washed with water, saturated NaHCO3 and brine, dried and concentrated under reduced pressure. The crude was purified by flash chromatography (toluene/EtOAc, 5:1→1:1) to slightly unpure 4-(3-acetylsulfanyl-2-ethoxycarbonyl-1-methyl-propyl)-piperidine-1-carboxylic acid tert-butyl ester (0.17 g, 75%).