Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:22][C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[N:11]=1)[CH3:2].CN(C=O)C.[H-].[Na+].[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>O>[CH2:30]([O:32][CH2:33][N:22]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]2[N:11]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[S:3][CH2:1][CH3:2])[CH3:31]
Reactant: CCOCCl
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCn1c(-c2ccccc2SCC)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (270 mg) and DMF (10 ml), 60% of sodium hydride (in oil) (80 mg) and chloromethyl ethyl ether (118 μl) were sequentially added under ice-cooling. The mixture was heated to room temperature, and stirred for 5 hours. Into the reaction mixture, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 180 mg of 3-ethoxymethyl-2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 33) and 70 mg of 1-ethoxymethyl-2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-1H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 34)).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[CH3:23][C:24]1[N:25]=[N:26][N:27]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[CH:28]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:31]2[CH2:32][CH2:33][CH:29]([N:27]3[CH:28]=[C:24]([CH3:23])[N:25]=[N:26]3)[CH2:30]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Cc1cn(C2CCNC2)nn1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1cn(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Yield: 46.5 %

Procedure:
5-Amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (298 mg, 1 mmol) was reacted with 470 mg (2.5 mmol) of 3-(4-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride in the presence of 380 mg (2.5 mmol) of DBU in 20 ml of dry acetonitrile for two days under reflux conditions and the atmosphere of nitrogen. The yellow suspension was then evaporated to dryness and to the residue water was added. The yellow solid was filtered and crystallized repeatedly (3x) with acetonitrile to free the product from the unreacted starting material. After drying, 200 mg of the desired product was obtained, m.p. 271°-272.5° C. 1H NMR (TFA) δ: 9.15 (s, 1H), 8.4 (s, 1H), 5.8-5.6 (m, 1H), 4.8-4.05 (m, 5H), 3.0-2.7 (m, 2H), 2.67 (s, 3H), 1.65-1.2 (m, 4H). Anal. calcd. for C20H20F2N6O3.1/2 H2O: C, 54.67; H, 4.82; N, 19.12. Found: C, 54.91; H, 4.69; N, 18.76.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[S:15]([CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21])([OH:18])(=[O:17])=[O:16].C(=O)(O)[O-].[Na+]>CC(C)=O.O>[S:15]([CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12)=[O:21])([OH:18])(=[O:17])=[O:16]
Reactant: O=C(Cl)C(c1ccccc1)S(=O)(=O)O
Reactant: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(c3ccccc3)S(=O)(=O)O)C(=O)N12

Procedure:
The α-sulfo-acylamido-3-halo-cephem compounds of the Formula I wherein Q is a sulfo group (-SO3H) are prepared by following the acylation procedures employed for the preparation of α-sulfobenzylpenicillins described by U.S. Pat. No. 3,660,379 and in the J. Med. Chem., 15 (11), 11-5 (1972); ibid, p. 1108. For example, 7-amino-3-chloro-3-cephem-4-carboxylic acid is reacted with α-sulfophenylacetyl chloride in a mixture of acetone and water containing an excess of sodium bicarbonate to yield 7-(α-sulfophenylacetamido)-3-chloro-3-cephem-4-carboxylic acid. Examples of α-sulfoacylamido-3-halo-cephems of the present invention are,
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[NH:26]2)=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2>CC#N>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][C:25](=[O:29])[NH:26]4)=[CH:21][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: O=c1ccc2ccc(O)cc2[nH]1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=c1ccc2ccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cc2[nH]1

Procedure:
The title compound was prepared analogous to the methods used in Example 32(e) using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.50 g, 1.9 mmol), 7-hydroxy-1H-quinolin-2-one (0.37 g, 2.3 mmol, prepared according to Synthesis 1997, 87–90) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL, 2.3 mmol, Aldrich) in CH3CN (40 mL). Purification by flash chromatography (0→2.5% MeOH/CH2Cl2) afforded the title compound as an off-white powder. Mp 288° C. MS (ESI, pos. ion) m/z: 384 (M+1).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[S:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([C:24](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([CH:8]([OH:9])[C@H:6]2[S:7][C@@H:1]([N:10]3[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]3=[O:12])[C@H:2]([OH:3])[C@@H:4]2[OH:5])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]2[CH:40]=[CH:41][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=c1ccn([C@@H]2S[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: c1ccncc1
Product: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2S[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Compound 13 (2 g, 7.754 mmol) was dissolved in dry pyridine (20 mL), 4,4′-dimethoxytrityl chloride (2.9 g, 8.53 mmol) was added and the mixture stirred at room temperature overnight. The reaction was quenched with methanol and taken up in ethyl acetate (200 mL). The ethyl acetate solution was washed twice with saturated sodium bicarbonate solution, once with water, once with brine, and dried over anhydrous sodium sulfate. The solvents were removed under reduced pressure and the residue purified by flash chromatography (7% methanol in dichloromethane). The desired fractions were pooled and concentrated to give Compound 14 (3.0 g) in 80% yield. The structure of Compound 14 was confirmed by 1H NMR & ESMS.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of phenylboronic acid (5.12 g, 42 mmol), 2-bromophenol (3.55 g, 21 mmol), Cu(OAc)2 (7.63 g, 42 mmol), pyridine (8 ml, 103 mmol) and 4 Å molecular sieves (2.1 g) in CH2Cl2 was stirred at r.t. overnight. The mixture was diluted with CH2Cl2, filtered through celite, washed with 1M NaOH, brine and dried. Removal of solvent gave 1-bromo-2-phenoxybenzene, crystals (1.40 g, 27%). LRMS (ESI+): 248 (M+1). 1-Bromo-2-phenoxybenzene was coupled to piperazine using the Buchwald chemistry described in preparation 1A to afford the title compound. LRMS (ESI+) 255 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8](Cl)(Cl)Cl)[NH:5][C:6]=1[Cl:7].[NH3:12]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:8]#[N:12])[NH:5][C:6]=1[Cl:7]
Reactant: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Reactant: N
Solvent: CCO
Product: N#Cc1nc(Cl)c(Cl)[nH]1
Yield: 90 %

Procedure:
25.4 g (0.1 mol) of 4,5-dichloro-2-trichloromethyl-imidazole were introduced in small portions into 200 ml of ethanol saturated with ammonia, whilst cooling with ice and stirring vigorously. The mixture was stirred for a further 30 minutes at 50° C., the constituents which had not dissolved were then filtered off and the filtrate was evaporated under reduced pressure. The combined residues were dissolved in hot water. On acidifying the solution with dilute hydrochloride acid, the reaction product precipitated out. This was filtered off, washed with water and dried. In this way 14.6 g (90% of theory) of 4,5-dichloro-2-cyano-imidazole were obtained and after recrystallisation from toluene this had a melting point of 187°-189° C.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([C:10]2[CH:15]=[C:14]3[O:16][CH2:17][O:18][C:13]3=[CH:12][C:11]=2[CH:19]([CH3:24])[C:20](OC)=[O:21])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:28][NH2:29]>COCCO>[CH2:17]1[O:16][C:14]2=[CH:15][C:10]3[C:8]([C:7]4[CH:25]=[CH:26][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[N:29][NH:28][C:20](=[O:21])[CH:19]([CH3:24])[C:11]=3[CH:12]=[C:13]2[O:18]1
Reactant: NN
Reactant: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1)OCO2
Solvent: O
Solvent: COCCO
Product: CC1C(=O)NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc21)OCO3

Procedure:
A mixture of methyl 2-(2-(4-nitrobenzoyl)-4,5-methylenedioxyphenyl)propionate (211 mg, 0.59 mmol), hydrazine hydrate (0.15 mL, 2.4 mmol), and 2-methoxyethanol (6 mL) was heated to reflux for 72 h. The solvent was removed in vacuo and the crude product was purified by chromatography to yield 7,8-methylenedioxy-5-methyl-1-(4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one which was treated with excess amount of hydrazine and Raney Ni for 1 h. The reaction was then allowed to settled and liquid phase was decanted. The solvent was then removed and residue obtained was purified by chromatography (10% acetone in CH2Cl2) to yield the product (5 mg). 1H NMR (CDCl3) 8.44 (s, 1H), 7.43 (d, J=8.7, 2H), 6.86 (s, 1H), 6.68 (d, J=8.7, 2H), 6.65 (s, 1H), 6.04 (s, 1H), 6.00 (s, 1H), 4.83 (b, 2H), 3.29 (q, J=6.8, 1H), 1.59 (d, J=6.8, 3H).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:15]Br>ClCCl>[Br:15][C:3]1[C:4]2=[N:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=[C:9]2[O:1][CH:2]=1
Reactant: BrBr
Reactant: CCOC(=O)c1ccc2occc2n1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2occ(Br)c2n1
Reaction time: 3.5 h
Yield: 35.4 %

Procedure:
To a solution of ethyl furo[3,2-b]pyridine-5-carboxylate (0.30 g, 1.57 mmol) in dichloromethane (5 mL) was added dropwise bromine (7.82 mL, 157 mmol) at room temperature, and the resulting mixture was stirred for 3.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). To this solution was added dropwise a 1 M potassium hydroxide ethanol solution (10 mL) at 0° C., and the resulting mixture was stirred at room temperature for 5 min. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=17/3-1/1) to give the title compound (0.15 g, yield 36%) as colorless crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:35])[C:27]([C:30](=[O:34])[CH:31](Br)[CH3:32])([CH3:29])[OH:28]>C(#N)C>[CH3:24][O:25][C:26](=[O:35])[C:27]([C:30](=[O:34])[CH:31]([O:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:12][CH:13]=1)[CH3:32])([CH3:29])[OH:28]
Reactant: COC(=O)C(C)(O)C(=O)C(C)Br
Reactant: Oc1ccc(Oc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(O)C(=O)C(C)Oc1ccc(Oc2nc3ccccc3s2)cc1
Yield: 84.8 %

Procedure:
48.6 g of 4-(2-benzthiazolyloxy)-phenol, 33.1 g of potassium carbonate and 50.2 g of 2-bromopropionyl-lactic acid methyl ester in 250 cc of acetonitrile are refluxed for 8 hours. After cooling the salt precipitate is filtered off and the acetonitrile is distilled off. The residue is fraction-distilled, yielding 68 g (82.5% of theory) of 2-[4-(2-benzthiazolyloxy)-phenoxy]-propionyl-lactic acid methyl ester, b.p. 218° to 220° C./0.01 mbar. ##STR11##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH:16]1[CH2:15][CH2:14][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:18][CH2:17]1
Reactant: NCCCN
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: NCCCNC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 9 h

Procedure:
The starting material is prepared as follows: To the ice cooled stirred solution of 62.5 ml of 1,3-diaminopropane in 100 ml of ethanol, 30 g of 1-benzyl-4-piperidone are added dropwise. The mixture is hydrogenated over 2 g of pre-reduced platinum oxide at 50° and 2.7 atm. for 9 hours. After theoretical hydrogen-uptake the catalyst is filtered off, the filtrate evaporated, the residue distilled and the fraction boiling at 145°-160°/0.2 mmHg collected, to yield the 4-(3-aminopropylamino)-1-benzylpiperidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([OH:14])[CH2:10]2)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1CC(O)C2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C2CCC1CC(OS(C)(=O)=O)C2
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.250 g, 6.28 mmol) in dichloromethane (62 mL) was added triethylamine (1.40 mL, 10.0 mmol) and methanesulfonyl chloride (0.722 mL, 9.38 mmol) dropwise. The solution was stirred 2 hrs, washed with sodium bicarbonate, dried over MgSO4, filtered, and concentrated. The crude oil (1.74 g) was taken on with no purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.1 Hz, 3H), 2.04 (m, 6H), 2.18 (m, 2H), 3.02 (s, 3H), 4.14 (q, J=7.1 Hz, 2H), 4.29 (m, 2H), 5.02 (m, 1H); MS (ESI+Q1MS) m/z 278 [M+H]+
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCCC1>[CH2:9]([O:11][C:12](=[O:19])[CH:13]([CH2:27][C:26]1[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: -62 °C

Procedure:
21.4 g of lithium diisopropyl amide was added to 210 ml anhydrous tetrahydrofuran in a stream of nitrogen in a dry 3-necked flask with a drying tube and dropping funnel with pressure compensation. Next, 58.0 g of malonic acid diethyl ester in 100 ml anhydrous tetrahydrofuran was added dropwise at room temperature in 40 minutes. After 30 minutes the reaction solution was cooled to -62° C. and 39.1 g of 4-nitrobenzyl bromide in tetrahydrofuran was slowly added dropwise with vigorous agitation, followed by agitation for a further hour at -62° C., after which the precipitate was filtered cold. The filtrate was concentrated in a rotary evaporator, and the residue was dissolved in 300 ml ethanol at 65° C. and separated from the insoluble residue. 34.7 g of faintly yellowish crystals were obtained after cooling.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.C(N(CC)CC)C>O1CCCC1>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([CH:2]=[CH:3][C:4]2=[O:12])=[CH:9][CH:8]=1
Reactant: O=C1CC(Br)c2ccc(Cl)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=Cc2ccc(Cl)cc21
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
13.4 kg 3-Bromo-6-chloro-indan-1-one (A; for references on this material, see: Bøgesø EP 35363 A1 19810909 and Kehler, Juhl, Püschl, WO 2008025361; each herein incorporated by reference in its entirety) was dissolved in tetrahydrofuran (170.8 L), and the solution was cooled to 0-5° C. (Scheme 9). Triethylamine (9.1 L) was added over 0.5 h. The mixture was stirred at 0-5° C. for 5 hours before an additional portion of triethylamine (2.48 L) was added over 0.5 hour, and stirring was continued for 2 hours. The mixture was filtered, and the filtrate was concentrated to 30 L before n-heptane (102 L) was added. The volume was reduced to 60 L. More n-heptane (203 L) was added, and the mixture was stirred for 1 hour. Silica gel (17.2 kg) was added. The mixture was filtered, and the residual solid was washed with n-heptane (100 L). The combined filtrates were concentrated to 30 L and stirred at 0-5° C. for 1 hour. The mixture was centrifuged, and the residual solid was dried to afford 6-chloro-inden-1-one (compound B; 2.42 kg) sufficiently pure for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][O:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:15]/[CH2:14][C:13]([CH3:18])([CH3:17])[CH2:12][O:11][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COCC(C)(C)CC=O
Solvent: ClCCl
Product: COCC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Yield: 100.1 %

Procedure:
Step E In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.3 g, 2.3 mmol) was reacted with 4-methoxy-3,3-dimethyl-butyraldehyde (0.3 g, 2.3 mmol) in CH2Cl2 at room temperature for 18 h to give [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.56 g, 100%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][S:14]2(=[O:19])=[O:18])=[C:9]([F:20])[CH:8]=1)[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O>[O:19]=[S:14]1(=[O:18])[CH2:15][CH2:16][CH2:17][N:13]1[C:10]1[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[C:4]([OH:21])=[O:3])=[CH:8][C:9]=1[F:20]
Reactant: CCOC(=O)C(C)c1ccc(N2CCCS2(=O)=O)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(N2CCCS2(=O)=O)c(F)c1
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
2-[4-(1,1-Dioxo-[1,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid ethyl ester (448 mg, 1.42 mmol) was dissolved in a 2:1 mix of THF/water (2.8 mL+1.4 mL) and stirred for 15 min. 3 equivalents of LiOH (98 mg, 4.26 mmol), which is also dissolved in a 2:1 THF/water mix (1 mL+0.5 mL), are added to this solution. The reaction mixture was stirred overnight under reflux. While cooling, the aqueous phase is set to pH 1 using 4 N aq. HCl and repeatedly extracted with ethyl acetate (3×10 mL). The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to afford 2-[4-(1,1-dioxo-[1,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid (350 mg, 86%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:21]=[CH:20][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([N+:11]([O-:13])=[O:12])[O:10][C:6]=2[CH:5]=1.[CH2:22](I)[CH3:23].O>C(COC)OC>[CH2:22]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([N+:11]([O-:13])=[O:12])[O:10][C:6]=2[CH:5]=1)[CH3:23]
Reactant: O=[N+]([O-])c1oc2cc(O)ccc2c1-c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1

Procedure:
To a suspension of 0.34 g (0.008 mole) of sodium hydride in 45 ml of glyme is added dropwise a solution of 2.0 g (0.008 mole) of 6-hydroxy-2-nitro-3-phenylbenzofuran in 20 ml of glyme. To this suspension is added 16 g (0.010 mole) of ethyl iodide and the mixture is heated to its reflux temperature and maintained at reflux for 5 hours. After cooling to 25° C. an additional 0.1 g of sodium hydride and 5 ml of ethyl iodide are added and the mixture is refluxed for about three hours. The mixture is poured into water and extracted with diethyl ether. The extracts are washed with water and saturated sodium chloride solution and dried. Concentration of the extracts provides a residue which is recrystallized from aqueous ethanol to provide yellow needles of 6-ethoxy-2-nitro-3-phenylbenzofuran, m.p. 109°-111° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1>CS(C)=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:18])([F:20])[F:19])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: OC1CCNCC1
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCC(O)CC2)cc1C(F)(F)F

Procedure:
2.5 g of 4-hydroxypiperidine and 4.7 g of 4-fluoro-2-(trifluromethyl)-benzonitrile were reacted 5 h at 95° C. in DMSO to form 4-(4-hydroxypiperidin-1-yl)-2-(trifluoromethyl)-benzonitrile which, after aqueous work-up and isolation was disolved in 10 ml DMF was reacted at 5° C. with 250 mg of NaH (60% w/w) for 30 min. Then at 0° C., 2 g of 4,6-dichloropyrimidine were added to the mixture, stirred 30 min at room temperature to form 4-{4-[(6-chloropyrimidin-4-yl)oxy]piperidin-1-yl}-2-(trifluoromethyl)-benzonitrile. 115 mg of isolated by aqueous work-up and isolation by column chromatography were reacted with 138 mg of 1-[4-(trifluoromethyl)-phenyl]piperazine in presence of 117 mg of CsCO3, 7 mg of Pd(OAc)2, 21 mg of RuPhos in 2 ml of tert-BuOH at 85° C. over night to provide compound No. 23 after isolation by aqueous workup and column chromatography.