Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[NH:13][CH3:14].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[N:27]=[C:28]=S>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[NH:27][C:28]1[N:13]([CH3:14])[C:12]2[C:6]3[CH2:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]=3[C:4]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][C:2]=2[N:1]=1
Reactant: Fc1cccc(Cl)c1N=C=S
Reactant: CNc1c(N)cc(C(=O)OC)c2c1CC(C)(C)O2
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)n(C)c2c2c1OC(C)(C)C2
Yield: 56.3 %

Procedure:
The title compound was prepared following the procedure described for Step-1 of Intermediate-3 using methyl 5-amino-2,2-dimethyl-4-(methylamino)-2,3-dihydrobenzofuran-7-carboxylate (1.10 g, 4.4 mmol), 1-chloro-3-fluoro-2-isothiocyanatobenzene (Intermediate-14, 1.0 g, 5.3 mmol), N,N-di-isopropyl carbodimide (0.5 mL) and acetonitrile (3.0 mL) to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 1.46 (s, 6H), 3.34 (s, 2H), 3.53 (s, 3H), 3.72 (s, 3H), 7.00 (m, 1H), 7.06 (s, 1H), 7.17 (t, J=9.3 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 10.39 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O.C(OCC)(=O)C.C(OCC)C>CN(C)C=O>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([Br:13])=[C:4]([CH:3]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)c(Cl)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Methyl 3-amino-4-chlorobenzoate (Reference Compound No. 9, 12.0 g, 64.7 mmol) was dissolved in N,N-dimethylformamide (250 mL), and after cooling down to 0° C., N-bromosuccinimide (11.5 g, 64.6 mmol) was added thereto, and then the reaction mixture was stirred under argon atmosphere at room temperature for 30 minutes. Ethyl acetate (200 mL) and diethyl ether (200 mL) were added to the reaction mixture and then the whole was washed with 1% aqueous sodium hyposulfite solution (500 mL). The aqueous layer was extracted with ethyl acetate/diethylether (1/1) (200 mL). The combined organic layer was washed with water (400 mL, 4 times) and saturated brine (300 mL) successively, dried over anhydrous magnesium sulfate and then the solvent was removed under reduced pressure. The obtained residue was filtered with hexane (15 mL) to give the titled reference compound (15.74 g) as a pale brown solid. (Yield 92%)
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=3)=[CH:20][CH:21]=2)=[CH:26][CH:27]=1
Reactant: c1ccc(Nc2ccc3ccccc3c2)cc1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccc4ccccc4c3)cc2)cc1
Temperature: 80 °C
Yield: 60 %

Procedure:
A mixture of N-phenylnaphthalen-2-amine (Compound 20) (5.0 g, 22.8 mmol), 4,4′-dibromobiphenyl (17.8 g, 57 mmol), Pd(dppf)Cl2 (0.73 g, 1 mmol) and sodium tert-butoxide (2.4 g, 25 mmol) in toluene (250 mL) was degassed and heated at 80° C. overnight. The whole was poured into ethyl acetate (250 mL), washed with brine, dried over Na2SO4, loaded on silica gel and purified by flash column (hexanes to hexanes/dichloromethane 9:1). The desired fraction was collected, and concentrated. The resulting solid was filtered, and washed with methanol to give a white solid (Compound 21) (6.15 g, in 60% yield).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30][N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added triethylamine (0.35 mL) and naphthalene-2-carbaldehyde (97 mg). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature overnight, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (120 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([CH3:10])[N:5]=[C:4]([Cl:11])[CH:3]=1.[NH2:12][NH2:13]>CC(N(C)C)=O.CCOC(C)=O>[Cl:11][C:4]1[N:5]=[C:6]([CH3:10])[C:7]2[CH:8]=[N:12][NH:13][C:2]=2[CH:3]=1
Reactant: NN
Reactant: Cc1nc(Cl)cc(Cl)c1C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(Cl)cc2[nH]ncc12
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A solution of 4,6-dichloro-2-methylnicotinaldehyde (5.25 g, 23.48 mmol) in DMA (50 mL) was treated with hydrazine (7.37 mL, 235 mmol) at 0° C. The reaction was stirred for 15 min and then warmed to 80° C. for 2 h. The reaction was cooled and diluted with EtOAc and washed with water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give 6-chloro-4-methyl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C7H6ClN3 [M+1]+ 168. found 168.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:44]3[CH2:45][CH2:46][CH:41]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:42][CH2:43]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Product: O=C1c2c(-c3ccccc3)cc(N3CCC(N4CCCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
A mixture of 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (40.0 mg) and 4-(pyrrolidine-1-yl)piperidine (30.0 mg) was stirred at 150° C. for 3 hours. To the remaining product, water was added and the mixture was extracted with ethyl acetate. The extract was then washed with a saturated aqueous solution of sodium hydrogen carbonate and was dried on anhydrous sodium sulfate. The solvent was removed and the resulting residue was purified on a silica gel column chromatography (ethyl acetate:methanol=3:1) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (25.0 mg, 51%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:16][CH2:15][O:14][C:13]3=[O:17])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]([O:20]CC)=O.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:18]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])=[CH:8][CH:7]=3)=[O:20])=[CH:26][CH:25]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(N3CCOC3=O)cc2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(N3CCOC3=O)cc2c1O
Temperature: 185 °C

Procedure:
To a flask containing ethyl 4-hydroxy-6-(2-oxo-1,3-oxazolidin-3-yl)-3-quinolinecarboxylate (0.17 g) is added p-chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 185° C. over 1 hour. The reaction is cooled to room temperature and triturated with diethyl ether. The residue is adsorbed onto silica and chromatographed on silica eluting with 3% to 12% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.12 g of the title compound as a off-white solid.
Reaction SMILES: C([Mg]Br)C.[C:5]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[OH:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH2:23]=[O:24].C(N(CC)CC)C>C1COCC1.C1(C)C=CC=CC=1>[C:5]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([CH:23]=[O:24])[C:15]=1[OH:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:7])[CH3:6]
Reactant: COc1ccc(O)c(C(C)(C)c2ccccc2)c1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(C=O)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
Into a 1 liter reactor thoroughly purged with nitrogen, 43.5 ml of an ether solution containing 130.7 mmol of ethylmagnesium bromide and 70 ml of THF were introduced. To the reactor, a solution containing 30.16 g (124.5 mmol) of 2-cumyl-4-methoxyphenol diluted with 80 ml of a THF was dropwise added at 0° C. over a period of 30 minutes. Then, 500 ml of toluene was added, and the system was heated to 100° C. to distill off about 40 ml of a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to 15° C., 9.04 g (301.3 mmol) of paraformaldehyde and 24.8 ml (178.0 mmol) of triethylamine were added, followed by stirring at 90° C. for 15 minutes. The reaction solution was allowed to cool to room temperature and then quenched with 84 ml of 18% hydrochloric acid. The organic layer was washed with 400 ml of water, 200 ml of a sodium hydrogencarbonate aqueous solution and a sodium chloride aqueous solution (200 ml×2), and then concentrated. The resulting liquid was purified by silica gel column chromatography to obtain 27.27 g (yield: 81%) of 3-cumyl-5-methoxysalicylaldehyde.
Reaction SMILES: [CH2:1]([CH2:13][CH2:14][C:15](O)=[S:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)(=O)C(Cl)=O.C1C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O.CN(C)C(=O)C.C(N(CC)CC)C>[O:37]1[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][CH2:31][NH:30][C:15](=[S:16])[CH2:14][CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:35][CH2:36]1
Reactant: CCCCCCCCCCCCCCC(O)=S
Reactant: NCCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCC(=S)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8.23 Grams of 3-dodecylthiopropionic acid, 4.6 g of oxalyl chloride and 50 ml of benzene were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred for 24 hours at room temperature. After completion of the reaction, excess oxalyl chloride and benzene were distilled off under reduced pressure to prepare an acid chloride. The total of the resulting acid chloride was slowly added dropwise to 5.2 g of separately prepared N-(3-aminopropyl)morpholine, 3.7 g of triethylamine and 60 ml of N,N-dimethylacetamide which were charged in a flask. After completion of the addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was introduced into 300 ml of pure water and extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium chloride solution, and, then, chloroform was distilled off under reduced pressure and the residue was recrystallized from methanol to obtain 6.5 g of the desired product. m.p. 46° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:33]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:34])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CCC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclobutanecarbonyl chloride.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)[C:7]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:6][CH:5]=1.C1COCC1.O.[OH-].[Li+].Cl>O>[C:10]1([C:8]2[C:7]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:22])=[O:2])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
5-Cyclohex-1-enyl-6-(2,2,2-trifluoroethoxy)nicotinic acid methylester (0.03 g, 95.2 μmol) was combined with THF (0.3 mL) and water (0.15 mL) to give a light yellow solution. Lithium hydroxide hydrate (7.99 mg, 190 μmol) was added under argon. The reaction mixture was stirred at room temperature overnight, poured into 2 mL 2 M HCl and extracted with i-propyl acetate (2×20 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo to give the title compound (30 mg, quant) as white solid that was used in the subsequent reactions without further purification; MS (ESI) 300.2 (M−H)−.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1cccc(C2CCNCC2)c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)c1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-methoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 30% overall yield. mp 121°-123°. FDMS m/e=381 (M+ of free base). α[D]589 =-12.69 (c=0.53, methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[C:17]#[CH:18].C(#N)C>CC#N.CC#N.Cl[Pd]Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>[F:9][C:5]1[CH:4]=[CH:3][C:2]([C:18]#[C:17][CH2:16][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(Br)ccc1F
Reactant: C#CCOC1CCCCO1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C#CCOC2CCCCO2)ccc1F
Temperature: 85 °C
Reaction time: 10 h

Procedure:
A mixture of 5-bromo-2-fluorotoluene (10.0 g), cesium carbonate (45.0 g), 2-(2-propynyloxy)tetrahydropyran (11.2 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.51 g), bis(acetonitrile)palladium(II) dichloride (274 mg) and acetonitrile (300 ml) was stirred at 85° C. for 10 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90:10) to give the object product (8.08 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([F:18])([F:17])[F:16].[F:21][C:22]([F:33])([F:32])[C:23]([F:31])([F:30])[C:24]([F:29])([F:28])[C:25](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]2[NH:19][C:25]([C:24]([F:28])([F:29])[C:23]([F:30])([F:31])[C:22]([F:33])([F:32])[F:21])=[N:20][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2ccc(Cl)cc2C(F)(F)F)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Product: FC(F)(F)c1cc(Cl)ccc1-c1cc2[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc2cc1Cl
Yield: 68 %

Procedure:
A solution of 4-chloro-5-[4-chloro-2-(trifluoromethyl)phenyl]benzene-1,2-diamine (100 mg, 0.31 mmol, 1.00 equiv) in heptafluorobutanoic acid (5 ml) was stirred overnight at 80° C. in an oil bath and then quenched with ice-water (30 ml). The pH value of the solution was adjusted to 8 with saturated aqueous sodium carbonate and extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-[4-chloro-2-(trifluoromethyl)phenyl]-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a off-white solid (105.8 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:24][S:25]([CH2:28][S:29](Cl)(=[O:31])=[O:30])(=[O:27])=[O:26]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])(=[O:31])=[O:30])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)CS(=O)(=O)Cl
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (54 mg) in DCM (2 ml) and triethylamine (44 ul) was added methylsulfonylmethylsulfonyl chloride (45 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature overnight. Aqueous work-up and purification on silica gave 2-chloro-6-(4-methanesulfonylmethanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (35 mg).
Reaction SMILES: [C:1]1([CH:17]=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[OH:18][CH2:17][C:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ccc3cccc4ccc1c2c34
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1ccc2ccc3cccc4ccc1c2c34
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of pyrene carboxaldehyde (9.6 g, 42 mmol) in ethanol (50 mL) was added NaBH4 (2 g) and the mixture was stirred at room temperature for 6 hours. Water (100 mL) was added and the mixture was extracted with ether (2×50 mL). The organic layer was dried over MgSO4, and the solvent evaporated under reduced pressure to give a light-yellow solid which was recrystallized from ethyl acetate to afford prisms, m.p. 125°-126° C., yield: 8.3 g, 86%.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([O:30][CH2:31][CH3:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[S:17][CH:18]=2)=[CH:8][C:7]=1[CH3:29].[Li+].[OH-]>>[CH2:31]([O:30][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=3)[S:17][CH:18]=2)=[CH:8][C:7]=1[CH3:29])[C:3]([OH:33])=[O:2])[CH3:32]
Reactant: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(C(F)(F)F)cc3)n2)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(C(F)(F)F)cc3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], (2S)-2-ethoxy-3-{2-methyl-4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (2S)-2-ethoxy-3-{2-methyl-4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid as colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]([CH3:29])([CH3:28])[CH2:7][N:8]1[C:25](=[S:26])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:27])C.O>C(O)(C(F)(F)F)=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:15][C:16]3[CH:17]=[C:10]4[C:9](=[O:27])[N:8]([CH2:7][C:6]([CH3:28])([CH3:29])[CH2:5][C:4]([OH:30])=[O:3])[C:25](=[S:26])[N:11]4[C:12]=3[CH:13]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(C)(C)CN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC(=O)O)CN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Temperature: 90 °C
Yield: 83.4 %

Procedure:
Compound 10 (1.21 grams, 2.3 mmol) was dissolved in TFA (33 ml), water (11 ml) was added thereto, and the resulting mixture was heated at 90° C. for 16 hours. The product was filtered and washed with ethanol to give Compound 11 (800 mg, 83% yield) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl-].[Cl-].[Cl-].[Al+3].[C:14]1(=[O:24])[O:19][C:17](=[O:18])[C@H:16]2[CH2:20][CH:21]=[CH:22][CH2:23][C@@H:15]12>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:8][CH3:9])[C:14]([C@H:15]1[CH2:23][CH:22]=[CH:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:24]
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: COc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1Cl

Procedure:
0.5 mole of 2-chloroanisole was added slowly to a suspension of 0.5 mole aluminiumtrichloride in 1 l of dichloromethane at 0° C. After complete addition, cis-1,2,3,6-tetrahydrophthalic anhydride was added to the solution. After 8 hours of reflux the solution was poured into ice-cold water. The precipitate was filtered off, washed with water and diethyl ether and dried. M.p. 183-1 85° C.