Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:6]2[CH3:24])#[CH:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35](I)=[N:36][CH:37]=2)=[CH:28][CH:27]=1.N1CCCCC1>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:33]=[CH:34][C:35]([C:2]#[C:1][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:6]4[CH3:24])=[N:36][CH:37]=2)=[CH:30][CH:31]=1
Reactant: C#Cc1ccc2c(c1)c(C)c(C(=O)OCC)n2CCN1CCCC1
Reactant: Clc1ccc(-c2ccc(I)nc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C)c2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2n1CCN1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under an argon atmosphere 11 mg (0.02 mmol) Pd(PPh3)2Cl2 and 3 mg (0.02 mmol) CuI are added to a solution of 250 mg (0.77 mmol) ethyl 5-ethynyl-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole-2-carboxylate and 243 mg (0.77 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine in 1.52 mL (15.4 mmol) piperidine and 25 mL THF and the reaction mixture is stirred for 4 h at RT. It is diluted with water, extracted exhaustively with EtOAc, the combined organic phases are washed with water and saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified first by chromatography (silica gel, cyc/EtOAc 2:1) and then by HPLC.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][NH:26][CH2:25][CH2:24]4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].CCN(C(C)C)C(C)C.Cl[C:41]([O:43][CH3:44])=[O:42].[Li+].[OH-]>CN(C=O)C.O>[CH3:44][O:43][C:41]([N:26]1[CH2:25][CH2:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:19](=[O:20])[NH:18][C:15]3[NH:14][C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:7](=[O:8])[NH:6][C:2]5[NH:1][CH:5]=[CH:4][N:3]=5)[C:17]=4[N:16]=3)[CH:22]=2)[CH2:27]1)=[O:42]
Reactant: COC(=O)Cl
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCNC2
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)N1CCc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ccc2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 31 %

Procedure:
41 mg (0.08 mmol) of 1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide in 0.6 mL of DMF and 0.176 mL (1 mmol) of DIEA was treated with 0.024 mL (0.3 mmol) of methyl chloroformate and stirred at room temperature for 14 h. The reaction mixture was then treated with 0.15 mL of 2 N aq. LiOH. Water was added to the reaction mixture. The precipitated solid was collected by filtration and washed with water to yield 11.4 mg (0.0248 mmol, 31%) of 6-[4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-ylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid methyl ester. LCMS: 460 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)=[CH:3][C:4]=1[O:11][CH:12]([CH3:14])[CH3:13])([O-:10])=[O:9]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Yield: 74 %

Procedure:
A mixture of 10.0 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 5.78 g of 4-pyridylboronic acid, 12.2 g of sodium carbonate and 1.0 g of bis(triphenylphosphine)dichloropalladium, in 200 ml of dioxane and 35 ml of water, is heated at 110° C. (bath) for 9 h. The mixture is diluted with ethyl acetate and water. The aqueous phase is extracted twice with ethyl acetate and then with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under vacuum. The residue is purified on 330 g of silica, elution being carried out with ethyl acetate/heptane (1/1 to 4/1), so as to obtain 7.35 g of 4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine in the form of a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([I:34])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:35].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([I:34])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:35][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1

Procedure:
N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazolin-4-amine was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (1.0 g, 2.96 mmol), 5-chloro-7-iodo-1,3-benzodioxol-4-amine (0.97 g, 3.26 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 6.2 ml) in DMF (15 ml). The crude product was obtained as a pale bown solid (1.71 g, 97%) by quenching the reaction mixture with dilute aqueous ammonium chloride solution; Mass Spectrum: M+H+ 599/601.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[NH:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][OH:20])[CH2:14]1.C(N(CC)CC)C>C(#N)C>[N:4]1([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][C@H:15]([CH2:19][OH:20])[CH2:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: ClCCN1CCc2ccccc21
Reactant: OCC1CNCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1

Procedure:
A microwave vial was charged with 1-(chloroethyl)-indoline (compound 50; 724 mg, 4.00 mmol), hydroxymethylmorpholine (compound 54; 562 mg, 4.80 mmol), triethylamine (2.2 ml, 16.00 mmol) and acetonitrile (4 ml). The vial was irradiated with microwaves for 2 hrs at 100° C., 40 min at 120° C. and 1 hr at 110° C. The residue was purified by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2); and the product was isolated as an off-white solid (347 mg; 33%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C:15]#[N:16].[C:17](OC)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1>[OH:24][C:17]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[C:14]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([O:4][CH3:3])[CH:6]=2)[NH:10][CH:9]=1)[C:15]#[N:16]
Reactant: COC(=O)c1cccnc1
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(C(C#N)=C(O)c3cccnc3)c2c1
Temperature: 60 °C

Procedure:
To a suspension of NaH (780 mg, 80%, 26 mmol, 1.6 eq.) in anhydrous THF (50 mL) were added, under an argon atmosphere, (5-methoxy-1H-indol-3-yl)-acetonitrile (3 g, 16 mmol, 1.0 eq.) and, after 30 minutes stirring at room temperature, methyl nicotinate (2.9 g, 21 mmol, 1.3 eq.). The reaction mixture was heated in a sealed tube at 60° C. for 13 hours. The reaction was allowed to cool to room temperature and then, treated with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, and then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 96/4 to 95/5) to afford 3-hydroxy-2-(5-methoxy-1H-indol-3-yl)-3-(pyridin-3-yl)acrylonitrile as orange specks (2.5 g, 53%, E/Z ratio: 85/15).
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[C:6]1(C#C)[CH:11]=CC=[CH:8][CH:7]=1.O1CCCC1>CCCCCC>[Li:5][C:1]#[C:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:11][CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C#Cc1ccccc1
Reaction time: 0.67 h

Procedure:
2.5 ml. of a 1.2M solution of n-butyllithium in n-hexane were added dropwise to a solution of 0.33 ml. of phenylacetylene in 5 ml. of anhydrous tetrahydrofuran under an atmosphere of nitrogen with stirring at -20°C., and the reaction mixture was stirred at the same temperature for 40 minutes to give a lithio-phenylacetylene solution. The lithio-phenylacetylene solution thus obtained was added dropwise under an atmosphere of nitrogen with stirring at -78°C. to a solution of 1.05 g. of 1α,4α-diacetoxy-2α-(6-methoxycarbonylhex-cis-2-enyl)-3β-(6-methoxycarbonylhex-cis-2-enyl)-3β-(2-formyleth-trans-1-enyl)-cyclopentane (prepared as described in Procedure R) in 10 ml. of anhydrous tetrahydrofuran and the reaction mixture was stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The extracts were washed with an aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of benzene and ethyl acetate (5:1) as eluent to give 1.097 g. of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[N:7][NH:8][C:9]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([Cl:21])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][NH:8][C:9]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([Cl:21])=[CH:15][CH:14]=3)=[O:10])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C=NNC(=O)c2[nH]c3ccc(Cl)cc3c2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(CNNC(=O)c2[nH]c3ccc(Cl)cc3c2C)cc1
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 5-chloro-3-methyl-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide (7 mg, 0.022 mmol) in a mixture of methanol (8.5 mL) and water (1.5 mL) at 50° C. was added sodium borohydride (1.62 mg, 0.044 mmol). It was stirred for 4 h and the solution was evaporated. The residue was purified by column chromatography (silica gel, EtOAc/Hexane=4:1) to give 4 mg (56%) of the title compound. 1H NMR (CD3OD): 7.42 (s, 1H), 7.22−7.19 (m, 3H), 7.07−7.03 (m, 3H), (bs, 1H), 3.91 (s, 2H), 2.27 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][C:9]=2/[CH:11]=C\C(OCC)=O)[CH:4]=[CH:3][CH:2]=1.[O:18]=[O+][O-]>ClCCl.CO>[N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][C:9]=2[CH:11]=[O:18])[CH:4]=[CH:3][CH:2]=1
Reactant: O=[O+][O-]
Reactant: CCOC(=O)/C=C\c1cncc2cccnc12
Solvent: ClCCl
Solvent: CO
Product: O=Cc1cncc2cccnc12
Temperature: 25 °C

Procedure:
A solution of ethyl (2Z)-3-(1,6-naphthyridin-8-yl)prop-2-enoate (30 g) in dichloromethane (500 mL) and methanol (125 mL) was cooled to −78° C. and reacted with ozone until the color of the reaction mixture became light blue (˜3 h). The reaction was purged with nitrogen to remove the residual ozone. Methyl sulfide (60 mL) was then added, and the reaction was allowed to warm to room temperature and then concentrated. The resulting residue was dissolved in dichloromethane (300 mL), washed with water (100 mL) and saturated aqueous sodium bicarbonate (100 mL) and dried over sodium sulfate. The solvent was removed and product was slurried in heptane/ethyl acetate mixture (5:1). The solid was then filtered and dried under reduced pressure to provide the title compound: LCMS m/z 158.97 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 11.39 (s, 1 H), 9.09 (s, 1 H), 9.13 (m, 1 H), 9.07 (s, 1 H), 8.43 (d, J=8.3 Hz, 1 H), 7.78 (dd, J=8.7, 4.8 Hz, 1 H), 7.63 (dd, J=8.2, 4.2 Hz, 1 H), 7.34 (dd, J=8.7, 2.2 Hz, 1 H), 7.07 (m, 1 H), 3.55-3.53 (m, 1 H), 0.62-0.61 (m, 4 H).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[N:4][CH:5]=[CH:6][C:7]=1[I:8].[C:10]1(=[O:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[F:1][C:2]1[C:3]([N:11]2[CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]2=[O:19])=[N:4][CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1NCc2ccccc21
Reactant: Fc1c(I)ccnc1I
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1c2ccccc2CN1c1nccc(I)c1F
Temperature: 110 °C
Yield: 41 %

Procedure:
A mixture of 3-fluoro-2,4-diiodopyridine (300 mg, 0.860 mmol), isoindolin-1-one (114 mg, 0.860 mmol), copper (I) iodide (8.19 mg, 0.043 mmol), potassium carbonate (238 mg, 1.720 mmol) and N1,N2-dimethylethane-1,2-diamine (7.58 mg, 0.086 mmol) in 1,4-dioxane (5 mL) was heated at 110° C. in a sealed tube for 15 h. The mixture was cooled to rt, filtered through Celite and washed with DCM. The filtrate was concentrated and the residue was purified by column chromatography (eluting with a gradient from 80:20 hexane-EtOAc to EtOAc) to give 2-(3-fluoro-4-iodopyridin-2-yl)isoindolin-1-one (125 mg, 41%). 1H NMR (400 MHz, chloroform-d) δ 7.86-8.06 (2H, m), 7.41-7.71 (4H, m), 5.04 (2H, s). Mass spectrum m/z 354.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH:19]=3)[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:43]>O>[OH:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH2:30][CH2:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:35])([F:36])[F:37])=[O:43])[CH:19]=3)[C:7]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CO
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1cccc(OCCCCSCCCC(F)(F)C(F)(F)F)c1
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1cccc(OCCCCS(=O)CCCC(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[3-(4-(4,4,5,5,5-pentafluoropentylthio)butyloxy)phenyl]-2,3-dihydro-4H-benzopyran (72 mg, 0.12 mmol) was dissolved in methanol (5 ml) and water (1 ml), and NaIO4 (35 mg, 0.16 mmol) was added thereto. The reaction solution was stirred for 12 hours at room temperature and then extracted with ethyl acetate. The organic layer thus separated was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=2:1) to obtain 66 mg (yield: 89%) of the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:36]1[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[CH2:37]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:36]4[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[CH2:37]4)[CH:22]=[CH:23][CH:24]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)C1CNC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 149.8 %

Procedure:
To a solution of 3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylbenzaldehyde (D74) (120 mg), acetic acid (0.022 mL) and sodium acetate (31.9 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (90 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (137 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (D88) (226 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C26H29ClN2O3S requires 484. found 485.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:18][S:19]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][CH2:32]CS([O-])(=O)=O)(=[O:21])=[O:20]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:32][CH2:31][CH2:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CS(=O)(=O)Oc1ccccc1CCCCCS(=O)(=O)[O-]
Product: CCOC(=O)C(Cc1ccc(OCCCCc2ccccc2OS(C)(=O)=O)cc1)OCC

Procedure:
2-Ethoxy-3-{4-(4-(2-methanesulfonyloxyphenyl)butoxy]phenyl}propanoic acid ethyl ester was synthesized using the same method as in Example 1b from 2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) and 4-(2-methanesulfonyloxyphenyl)butylmethanesulfonate.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:12][CH2:13][CH2:14][OH:15].N1C=CC=CC=1>C(C(C)=O)C>[C:1]([O:15][CH2:14][CH2:13][Br:12])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: OCCBr
Solvent: CCC(C)=O
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)OCCBr
Yield: 86.9 %

Procedure:
35.3 g (0.212 mol) of cinnamic acid chloride and 100 mL of methyl ethyl ketone were placed in a reaction vessel and stirred under a nitrogen atmosphere. 28.2 g (0.225 mol) of 2-bromoethanol and 21 g of pyridine were dissolved in 100 mL of methyl ethyl ketone and added dropwise in the aforementioned reaction vessel. After completion of dropping, the solution was refluxed with stirring for 2 hours and cooled. Pyridine hydrochloride was precipitated, and then separated from the solution by filtration. The filtrate was concentrated and then dissolved in methylene chloride. The solution of methylene chloride was poured into a separating funnel and washed with water. Then the solution was dried with anhydrous sodium sulfate and concentrated. Thus 47 g of 2-bromoethyl cinnamate was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.S(Cl)(Cl)=O.[CH3:31]O>>[NH2:1][C:2]1[C:3]([C:24]([O:26][CH3:31])=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CO
Reactant: CC(C)n1cc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2)ccc1=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic acid (350 mg) in MeOH (7.0 ml), was added thionyl chloride (0.146 m) dropwise under ice-bath cooling. After 1 hour stirring at the same temperature, the mixture was allowed to warm to room temperature. The mixture was stirred for 6 hours and then refluxed with stirring for 15 hours. After cooling, the solvent was removed under reduced pressure. Water was poured into the residue and the pH of the mixture was adjusted to 10 with 1N aq. NaOH. A precipitate was isolated by filtration, washed with water, and dried in vacuo to give methyl 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylate (244 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl-].[NH4+].[F:9][C:10]([F:35])([F:34])[C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][CH:33]=1)[CH2:14][NH:15][C:16]1[C:17]2[C:22]([N:23]=[C:24]3[C:29]=1[C:28](=[O:30])[CH2:27][CH2:26][CH2:25]3)=[CH:21][CH:20]=[CH:19][CH:18]=2>C1COCC1>[F:34][C:10]([F:9])([F:35])[C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][CH:33]=1)[CH2:14][NH:15][C:16]1[C:17]2[C:22]([N:23]=[C:24]3[C:29]=1[CH:28]([OH:30])[CH2:27][CH2:26][CH2:25]3)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: O=C1CCCc2nc3ccccc3c(NCc3cccc(C(F)(F)F)c3)c21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3cccc(C(F)(F)F)c3)c21
Yield: 80.4 %

Procedure:
In 100 ml dry THF was dissolved in 3.86 g of 3,4-dihydro-9-(3-trifluoromethylbenzyl)aminoacridin-1(2H)-one. The solution was stirred mechanically under nitrogen and cooled in ice. To it was added 5.2 ml of 1M LiAlH4 in THF dropwise. After stirring an additional 0.5 hour, the reaction was complete. It was neutralized with 1 ml of saturated ammonium chloride and the salts were filtered off. The THF filtrate was evaporated to an oil which solidified upon trituration with pentane. The solid was recrystallized from 1:1 dichloromethane/pentane to yield 3.12 g of solid, mp 154°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([F:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][N:21]=1.COC(=O)C(=CC1C=CC(F)=CC=1)CC(O)=O>>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([F:15])=[C:13]([O:16][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:27])=[O:28])=[CH:22][N:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Br)nc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(O)c1F
Agent: COC(=O)C(=Cc1ccc(F)cc1)CC(=O)O
Product: CCS(=O)(=O)c1ccc(Oc2c(F)c(CC(=O)OC)cc3ccc(F)cc23)nc1
Yield: 47.9 %

Procedure:
Starting with (3,6-difluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (25 mg, 0.099 mmol) and 2-bromo-5-ethanesulfonyl-pyridine (28 mg, 0.112 mmol), using a method analogous to the one described for the methyl ester of example 1-1, [4-(5-ethanesulfonyl-pyridin-2-yloxy)-3,6-difluoro-naphthalen-2-yl]-acetic acid methyl ester (20 mg, 48%) was obtained as a white solid, which was used in the next step without further purification.