Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=1[NH:10][C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[NH:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(OCC)C>[CH2:1]([C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=1[NH:10][C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[N:20]([CH3:21])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1Cc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)N(C)[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A solution of (±) trans 1-(2-benzylanilino)-2-methylaminoindane (Example 2)(0.66 g, 2.0 mmol) in dry diethyl ether (25 ml) was treated with triethylamine (0.55 ml, 4.0 mmol) and ethyl chloroformate (0.21 ml, 2.2 mmol). After stirring at room temperature for 1 h, the reaction was concentrated in vacuo and the residue was partitioned between chloroform (25 ml) and water (25 ml). The organic layer was washed with water (3×25 ml) followed by brine (25 ml), and then concentrated in vacuo to give a brown oil (0.73 g) which crystallised on cooling and was used in the next stage without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H][H]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [H][H]
Reactant: CCOC(=O)CC/C=C/c1ccccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCCCc1ccccc1OC
Yield: 99.2 %

Procedure:
To a solution of ethyl (4E)-5-(2-methoxyphenyl)-4-pentenoate (3.40 g, 14.5 mmol) in a mixture of EtOAc and MeOH (40.0/10.0 mL), Pd/C (palladium on carbon 10%, 0.700 g) was added in small portions to avoid fire. The reaction mixture was then stirred for overnight at room temperature under 300 psi of hydrogen. After the pressure was released, the mixture was filtered through Celite and the Celite was washed with EtOAc (3×50 mL). The filtrate was concentrated in vacuo to afford crude product as a light yellow oil (3.40 g 100%), which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[OH:39][CH2:40][CH2:41][NH2:42]>>[OH:39][CH2:40][CH2:41][NH:42][CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1
Reactant: NCCO
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCNCCO)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 2-hydroxyethylamine were converted to the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17].[C:18]([OH:21])(=[O:20])[CH3:19].O>CCOCC.C([O-])(=O)C.[Ag+]>[C:18]([O:21][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17])(=[O:20])[CH3:19]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCl)C2
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)C2
Temperature: 105 °C
Reaction time: 16 h

Procedure:
2-(2-Chloroethyl)-6,7-dichloro-2,3-dihydro-5-methoxy-1H-inden-1-one (18.14 gm, 0.0619 mole), silver acetate (22.74 gm, 0.136 mole), acetic acid (225 ml) and water (2 ml) was stirred and heated at 105° C. internal temperature for 9 hours, then at ambient temperature for 16 hours. The mixture was diluted with ether, filtered and the solid washed with ethyl acetate. The combined filtrate and washing was evaporated in vacuo and the reside suspended in water then extracted first with a mixture of ether and tetrahydrofuran, then with methylene chloride and finally with ethyl acetate. The combined organic extracts were washed with water, then with brine and finally dried over MgSO4. The solvents were removed by evaporation in vacuo to give 12.9 g of residual solid. The solid was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 8.1 g of product, m.p. 134°-136° C.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1)[C:12]([O:14][CH3:15])=[O:13].O=[C:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>ClCCl>[N:28]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30][C:25]2([O:8][C:9]3[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:16]=[CH:17][C:18]=3[N:19]3[CH:23]=[CH:22][CH:21]=[C:20]23)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(-n2cccc2)c(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1cccn1-2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Trifluoroacetic acid (3.15 g, 2.13 mL, 27.6 mmol) was added dropwise to a solution of methyl 3-hydroxy-4-pyrrol-1-yl-benzoate (3.00 g, 13.8 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.00 g, 15.2 mmol) in dichloromethane (60 mL) and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with water and 1N NaOH. The organics were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 0-30% EtOAc in Hexanes. The pure fractions were combined and concentrated to give 1′-tert-butyl 7-methyl spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′,7-dicarboxylate. ESI-MS m/z calc. 398.4. found 399.5 (M+1)+. Retention time: 2.13 minutes (3 min run).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[O:12][N:11]=[C:10]([C:13]([O:15]CC)=[O:14])[CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[O:12][N:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(CN2CCOCC2)on1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(CN2CCOCC2)on1

Procedure:
The title compound was prepared from ethyl 5-(morpholinomethyl)isoxazole-3-carboxylate (0.2 g, 0.85 mmol) and sodium hydroxide solution (2 mL) using the method of Example 225(b). Yield 0.25 g. 1H NMR (400 MHz; D2O): δ 3.46 (m, 4H), 3.99 (m, 4H), 4.72 (s, 2H), 7.10 (m, 1H).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1.[H][H]>CO.O.[Pt]=O>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=2)[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CC(C)Oc1cc(-c2cc[n+](C)cc2)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Agent: [I-]
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc(C2CCN(C)CC2)ccc1N
Yield: 96.7 %

Procedure:
A solution of 10 g of 1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in 280 ml of methanol is hydrogenated in an autoclave on 2.9 g of platinum oxide hydrate, at a hydrogen pressure of 15 bar and at ambient temperature for 4 h. The catalyst is removed by filtration on Clarcel and the mixture is concentrated under vacuum. The residue is taken up in 200 ml of ethyl acetate and washed with 200 ml of 1M sodium hydroxide and then with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated under vacuum, so as to obtain 6.0 g of 4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19](/[C:23](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]\S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.Cl.CO>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(Br)ccc1F
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
tert-Butyllithium (3.68 mL, 5.89 mmol) was added dropwise to THF (10 mL) at −100° C. under an argon atmosphere. A solution of 4-bromo-1-fluoro-2-methoxybenzene (0.604 g, 2.95 mmol) in THF (5 ml) was added dropwise followed by the addition of (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1 g, 2.46 mmol) in THF (5 ml). The resulting reaction mixture was left on the thawing cooling bath for 30 min then the cooling bath was removed and the mixture was stirred at r.t. for 1 h. Hydrogen chloride-methanol solution (11.78 mL, 14.73 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated and purified on a silica gel column eluting with 0-10% 0.1 M NH3 in MeOH in DCM to afford 0.98 g (93%) of the title compound. MS (ES+) m/z 429, 431 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[C@H:10]([NH:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=O)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[CH3:19][O:18][C:16](=[O:17])[NH:15][C@H:10]1[C@@H:11]([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COC(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N[C@@H]1CNCC[C@@H]1C

Procedure:
A solution of racemic cis 3-methoxycarbonylamino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 7.35 mmol) in 4 M HCl in dioxane (40 mL) was stirred at ambient temperature for 1 hour then concentrated under vacuum. The resulting residue was azeotroped with DCM to afford 1.7 g (quant.) of racemic cis (4-methyl-piperidin-3-yl)-carbamic acid methyl ester hydrochloride. LCMS (Method I, ESI): RT=0.34 min, m+H=173.4.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:37]=[CH:36][C:15]([CH:16]=[CH:17][CH2:18][NH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][C:32]=3[CH:33]=[CH:34][CH:35]=2)(=[O:25])=[O:24])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[CH:17][CH2:18][N:19]([CH2:20][CH2:21][NH:22][S:23]([C:26]2[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][C:32]=3[CH:33]=[CH:34][CH:35]=2)(=[O:24])=[O:25])[CH:1]=[O:3])=[CH:36][CH:37]=1
Reactant: O=CO
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: O=CN(CC=Cc1ccc(Cl)cc1)CCNS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C

Procedure:
3 ml of formic acid and 3 ml of acetic anhydride were mixed and stirred at a room temperature, and to the mixture was added 1.41 g of the product of Example 172, and the mixture was stirred for one hour. The reaction mixture was added to 50 ml of ethyl acetate and 30 ml of saturated sodium carbonate aqueous solution with ice, and the mixture was stirred, and after foaming was terminated, the ethyl acetate layer was sequentially washed twice with water and once with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate, filtered and evaporated under a reduced pressure. The resulting residue was purified on a silica gel column (silica gel 60 g, eluant: 2% methanol in chloroform), to obtain 1.49 g of the title compound as a mixture of two isomers (3:2) in a colorless amorphous form.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH:12]([CH3:17])[CH2:13][C:14](O)=[O:15])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.O.[NH2:20][NH2:21]>C(O)C>[CH3:1][C:2]1[C:10]([C:11]2[CH:12]([CH3:17])[CH2:13][C:14](=[O:15])[NH:20][N:21]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: NN
Reactant: Cc1nn2ccccc2c1C(=O)C(C)CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1nn2ccccc2c1C1=NNC(=O)CC1C
Yield: 75.1 %

Procedure:
The compound (2.76 g) of Example 17 and hydrazine monohydrate (0.90 g) were dissolved into ethanol (30 ml), and the solution was refluxed for 3 hours under heat. The reaction liquor was submitted to distillation under reduced pressure, and the residue was purified by means of silica gel column chromatography (developing solvent, methylene chloride:ethanol=10:1) to obtain aimed product (2.04 g) as colorless powder. When recrystallizing from isopropyl ether, this gave colorless prismatic crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.O[CH2:9][CH:10]([CH2:12]O)O>>[N:4]1[C:3]2[C:2](=[N:1][CH:9]=[CH:10][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OCC(O)CO
Reactant: Nc1cccnc1
Product: c1cnc2cccnc2c1

Procedure:
Thus 3-amino pyridine III may be condensed with a glycerol of formula IV to give the ##STR3## 1,5-naphthyridine of formula V which is reduced e.g. by hydrogenation over platinum oxide, to the 1,2,3,4-tetrahydro-1,5-naphthyridine of formula (VI). In formula IV, V and VI, R1, R2 and R3 are as defined in connection with formula I.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:24]2[C:23](=[O:29])[CH2:22][C@@:21]2([CH3:30])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C:18](=[O:20])[CH3:19])[CH2:9]1.[C:31](=[O:38])([O:35][CH2:36][CH3:37])OCC.[OH-].[Na+]>C(O)C>[CH2:36]([O:35][C:31]([CH2:19][C:18](=[O:20])[C@@H:17]1[C@:21]2([CH3:30])[C@H:14]([C@H:13]3[C@H:24]([C:23](=[O:29])[CH2:22]2)[C@:25]2([CH3:28])[C@H:10]([CH2:9][C@H:8]([OH:7])[CH2:27][CH2:26]2)[CH2:11][CH2:12]3)[CH2:15][CH2:16]1)=[O:38])[CH3:37]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CCOC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
3α-(Tetrahydropyran-2ξ- yloxy)-5α-pregnane-11,20-dione (0.9 g) in boiling diethyl carbonate (12 ml) under nitrogen was treated with 1 drop of ethanol and then sodium hydroxide (0.17 g). The mixture was refluxed for 20 minutes, then cooled and the excess sodium hydride was destroyed with ethanol. The reaction mixture was partitioned between water and ether. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue (1.0 g) was purified by preparative t.l.c. to give the ester (0.59 g) This ester in ethanol (5 ml) was treated with 2N hydrochloric acid (0.5 ml) and after ca 6 hours the reaction mixture was partitioned between water and ether. The organic layer was washed with water, dried (MgS04) and evaporated. The residue (0.6 g) was subjected to preparative t.l.c. (ethyl acetate/petrol 1:2). The more polar fraction (0.29 g) gave after crystallisation from ispropyl ether the title compound (0.08 g), m.p. 120-121°, [α]D + 120.5°, λmax. 249 nm. (ε 4,250).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([CH3:13])[CH:10]([OH:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:15]>CN(C=O)C>[CH3:15][O:12][CH:10]([CH3:11])[CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:13]
Reactant: CI
Reactant: CC(O)C(C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)C(C)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A 2 L reaction flask was charged with NaH (32 g, 0.79 mol) in oil dispersion (60%) and DMF (500 mL) under N2. The mixture was heated to 40° C. 3-Phenyl-butan-2-ol (100 g, 0.66 mol) was fed to the mixture over 1 hour. The reaction mixture was aged for 1 hour at 40° C. Iodomethane (113 g, 0.79 mol) was then fed into the reaction mixture over 2 hours. The reaction mixture was further aged for 8 hours, and quenched subsequently with saturated NH4Cl solution (300 mL). The layers were separated. The organic layer was washed with saturated NaHCO3 (300 mL) and brine (300 mL) to provide a crude product, which was purified by distillation to afford (2-methoxy-1-methylpropyl)-benzene (101 g, 61% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:45][CH3:46])[C:41]=1[O:42][CH2:43][CH3:44])[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:36](=[O:37])[C:35]4[CH:34]=[C:33]([O:32][CH3:31])[C:41]([O:42][CH2:43][CH3:44])=[C:40]([O:45][CH3:46])[CH:39]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1
Reactant: CCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCNCC1)=C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1c(OC)cc(C(=O)N2CCN(C(=O)C3=Cc4cc(OC)c(OC)cc4CCC3)CC2)cc1OC
Temperature: 0 °C
Yield: 45.2 %

Procedure:
To a mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine (1.2 g), triethylamine (0.5 g) and methylene chloride (20 ml) is added dropwise, with stirring under ice-cooling, a solution of 3,5-dimethoxy-4-ethoxybenzoyl chloride (1.0 g) in methylene chloride (20 ml). The reaction mixture is then stirred for one hour at room temperature, and then poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (hexane:ethyl acetate:acetone=1:2:1) to afford 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,5-dimethoxy-4-ethoxy-benzoyl)piperazine (0.9 g). This product is recrystallized from ethyl acetatehexane to give colorless needles, m.p. 171°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH3:20])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.CO>CN1CCCC1=O>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH3:20])[C:8]2[N:9]=[C:10]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cn1c(=O)c(Oc2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cn1c(=O)c(Oc2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(2,6-dichlorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 12—Step A–B, (replacing methyl 2-fluorophenoxyacetate with methyl 2,6-dichlorophenoxyacetate) 0.35 g, 1 mmol) and 4-fluoroaniline (0.284 mL, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the crude product which was purified by column chromatography (SiO2, CH2Cl2/MeOH—95/5). The column fractions were combined and concentrated under reduced pressure to provide the free amine. This was suspended in ethyl acetate (1–2 mL) and hydrochloric acid in ether (1M, 1.2 eq) was added. Isolation of the solid via filtration and drying provided 0.131 g of the hydrochloride salt (Mass spec. M+1=430, MP=248.2–249.1° C.).
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]([F:26])([F:25])[F:27])[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(OCC(F)(F)F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(OCC(F)(F)F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(2,2,2-trifluoroethoxy)phenyl)-carbamoyl)benzylthio)propanoate (200 mg, 0.27 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 68 mg (37%) of a light yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.61 (s, 1H), 9.57-9.54 (m, 1H), 8.99-8.98 (m, 1H), 8.49-8.41 (m, 2H), 7.89-7.79 (m, 10H), 7.30-7.26 (m, 1H), 4.92-4.84 (dd, J=18 Hz, 9 Hz, 2H), 4.65-4.63 (d, J=5.4 Hz, 2H), 3.89 (s, 2H), 2.63-2.59 (m, 4H). MS (ES, m/z): 692 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([N:30]1[CH2:35][CH2:34][C@H:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37]2)[C@H:32]([CH2:45]O)[CH2:31]1)[CH3:29].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH2:28]([N:30]1[CH2:35][CH2:34][C@H:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37]2)[C@H:32]([CH2:45][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:31]1)[CH3:29]
Reactant: Oc1ccc(F)cc1
Reactant: CCN1CC[C@H](N2CCc3ccccc32)[C@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCN1CC[C@H](N2CCc3ccccc32)[C@H](COc2ccc(F)cc2)C1
Reaction time: 8 h
Yield: 24.5 %

Procedure:
Under a nitrogen gas stream, 4-fluorophenol (168 mg) and triphenyiphosphine (420 mg) were added to a solution of cis-1-(1-ethyl-3-hydroxymethylpiperidin-4-yl)indoline (300 mg) in tetrahydrofuran (4 ml). After cooling the resultant mixture to −10° C., diethyl azodicarboxylate (278 mg) was gradually added dropwise thereinto. Then the resultant mixture was gradually warmed to room temperature and stirred at the same temperature overnight. After adding water (40 ml), the reaction mixture was extracted with ether (40 ml) for three times. The organic phase was washed successively with a saturated aqueous solution (40 ml) of sodium bicarbonate and a 1 N aqueous solution (40 ml) of sodium hydroxide, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia Chemical Ltd. NH-DM2035, hexane/ethyl acetate system) to give the title compound (100 mg) as a colorless oil (yield: 25%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.CS[C:27]1[S:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[N+:31]=1[CH3:32].C(N(CC)CC)C>CO>[CH3:32][N:31]1[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[S:28](=[C:6]2[C:5](=[O:7])[N:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:3][CH:2]2[CH3:1])[CH2:27]1
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CSc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1NN(c2ccccc2)C(=O)C1=S1CN(C)c2ccccc21
Reaction time: 1 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.74 g, 0.01 mol) was mixed with 3.68 g (0.01 mol) 2-methylthio-3-methylbenzothiazolium tosylate in 25 ml methanol. Triethylamine (1.01 g, 0.01 mol) was added. The mixture was stirred for one hour, then filtered and washed with methanol. After drying the yield was 2.46 g (78%), mp 159°-162° C., λmax=375 (ε=25,000).