Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][NH:7][S:6]1(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(OCC)(=O)C.CCCCCC>[C:1]([N:5]1[CH2:9][CH2:8][N:7]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[S:6]1(=[O:10])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1CCNS1(=O)=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)N1CCN(Cc2ccc([N+](=O)[O-])cc2)S1(=O)=O
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield from 2-tert-butyl-1,2,5-thiadiazolidine-1,1-dioxide [M. Preiss, Chem. Ber., 1978, 111, 1915] and 4-nitrobenzyl bromide following the procedure described for Example 1 (Method B, Step 1); mp 113° C. (ethyl acetate-hexane, 60:40); δH (360 MHz, CDCl3) 8.21 (2H, d, J=8.7 Hz, Ar--H), 7.58 (2H, d, J=8.7 Hz, Ar--H), 4.24 (2H, s, Ar--CH2 --), 3.40 (2H, t, J=6.2 Hz, --CH2 --), 3.17 (2H, t, J=6.2 Hz, --CH2 --), 1.44 (9H, t-Bu); m/z (EI) 313 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[O:9][C:10]=2[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:29][N:30]=1
Reactant: COCCN(C)c1ncc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2Br)oc1C(F)(F)F
Product: COCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3Br)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyrimidine-2,5-diamine. LCMS calcd for C19H17BrF3N5O3 (m/e) 500, obsd 501 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH3:28][S:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH2:7]1)(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc(N)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc(NS(C)(=O)=O)c2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl [(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (659 mg) in CH2Cl2 (6.6 mL) was added pyridine (274 uL) and methanesulfonyl chloride (193 uL), which was stirred at room temperature for 20 hours. To the resultant was added H2O. The mixture was extracted with 1-butanol. The organic phase was washed brine, dried Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-{3-[(methylsulfonyl)amino]benzyl)-3-pyrrolidinyl]carbamate (845 mg) as pale yellow amorphous.
Reaction SMILES: ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[C:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:22]=1.Cl.[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH2:42])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH:42][C:25]1[C:24]([N+:28]([O-:30])=[O:29])=[C:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:22]=[C:21]([Cl:20])[N:26]=1)[CH3:38]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CCOC(=O)CNc1nc(Cl)nc(C(=O)OCC)c1[N+](=O)[O-]

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and glycine ethyl ester hydrochloride salt were reacted to yield N-(2-chloro-6-ethoxycarbonyl-5-nitro-4-pyrimidinyl)glycine Ethyl Ester. 1H NMR (CDCl3): δ 8.87 (bs, 1H), 4.48 (q, 2H, J=7.2 Hz), 4.39 (d, 2H, J=5.1 Hz), 1.40 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=7.2 Hz); LCMS: ret. time: 28.27 min.; purity: 97%; MS (m/e): 332 (M+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:15][CH2:17][CH2:22][CH2:21][C@H:20]1[CH2:19][NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCc1ccccc1)[C@@H]1CCCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC[C@@H]1CCCCN1Cc1ccccc1
Temperature: -78 °C
Yield: 89 %

Procedure:
To a solution of 230 mL (0.23 mmol) of 1M lithium aluminum hydride in THF was added over 20 min a solution of (S)-N-benzylpiperidine-2-carboxamide in 150 mL of THF. The mixture was refluxed for 5 h, diluted with 500 ml of THF, cooled to -78° C. and quenched with a solution of 48 mL 1N aqueous sodium hydroxide in 200 mL THF. The resulting slurry was filtered through a Celite® pad and concentrated at reduced pressure to yield (S)-N-benzyl-2-aminomethylpiperidine (10.9 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([OH:15])[CH:14]=3)[C:6]=2[N:5]([CH2:16][CH2:17][CH3:18])[CH2:4][C:3]=1[CH3:19].[OH-].[Na+].Cl[C:23]([F:28])([F:27])C(O)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH:23]([F:28])[F:27])[CH:14]=3)[C:6]=2[N:5]([CH2:16][CH2:17][CH3:18])[CH2:4][C:3]=1[CH3:19]
Reactant: O=C(O)C(F)(F)Cl
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(O)C=C1C=N2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC(F)F)C=C1C=N2
Temperature: 150 °C

Procedure:
5.51 g (0.02 mol) 4-chloro-3-methyl-1-propyl-9H-imidazo[1,5-a]pyrido[3,2-e]pyrazin-8-ol (Intermediate A25) and 2 g (0.05 mol) sodium hydroxide were dissolved in 20 ml dimethylformamide. After 10 min stirring 2.53 ml (0.03 mol) chlorodifluoroacetic acid was added dropwise. The mixture was heated 5 h at 150° C. bath temperature with stirring. After cooling the product was extracted with ethyl acetate (200 ml, 300 ml), the combined organic phases were washed with water (2×100 ml), the organic phase was dried over sodium sulfate, filtered off, and evaporated to dryness.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:4]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][C@H:41]1[C:46]([OH:48])=[O:47]>>[CH2:38]([O:37][C:35]([C:4]1[CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]2[CH:22]=[C:23]([C:31]([F:32])([F:34])[F:33])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=2)[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]=1[CH2:2][N:40]1[CH2:45][CH2:44][O:43][CH2:42][C@H:41]1[C:46]([OH:48])=[O:47])=[O:36])[CH3:39]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)[C@@H]1COCCN1
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 58 %

Procedure:
Ethyl 6-(bromomethyl)-4-(5-fluoro-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.37 g, 5.3 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.69 g, 5.3 mmol) according to the procedure described in Example 1, Step C to give the title compound as a yellow solid (2.11 g, 58%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:32]1([C:37]2[CH:38]=[C:39]([CH:42]=[CH:43][N:44]=2)[CH:40]=O)[CH2:36][CH2:35][CH2:34][CH2:33]1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:40][C:39]4[CH:42]=[CH:43][N:44]=[C:37]([N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:38]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: O=Cc1ccnc(N2CCCC2)c1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4ccnc(N5CCCC5)c4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 2-pyrrolidin-1-ylisonicotinaldehyde (14 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH:13]1[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]1)[C:6](=[O:12])[NH:7]2.C(Cl)(=O)OC(Cl)C>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:6](=[O:12])[NH:7]2
Reactant: O=C1Nc2cccc(Cl)c2CN1C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C1Nc2cccc(Cl)c2CN1C1CCNCC1
Temperature: 0 °C

Procedure:
An ice-cold solution of 6.3 g (0.0177 mol) of 5-chloro-3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-quinazolinone (prepared analogously to Example A4e)) in 50 ml of dichloromethane was mixed dropwise with 3.34 g (0.0234 mol) of α-chloroethyl chlorocarbonate whilst maintaining a reaction temperature of 0° C., after which the mixture was allowed to come back slowly to room temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in 50 ml of methanol and refluxed for 4 hours. After cooling, the colourless precipitate formed was suction filtered. Yield: 2.0 g (42.5% of theory).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][Se:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-].C(NCC)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>CC(OC)(C)C.[Cu].CN(C=O)C>[Br:7][C:6]1[C:2]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])=[CH:3][Se:4][CH:5]=1
Reactant: Brc1c[se]cc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: C[Si](C)(C)C#Cc1c[se]cc1Br
Temperature: 90 °C
Yield: 79.5 %

Procedure:
To a pressure vessel purged with N2 was added 3,4-dibromo-selenophene (3.69 g, 12.77 mmol), DMF (10.0 mL), triphenylphosphine (0.669 g, 2.55 mmol), copper(l) iodide (0.161 g, 0.843 mmol), diethylamine (dried over KOH, 20.0 mL, 191.55 mmol), (trimethylsilyl)acetylene (0.910 mL, 6.39 mmol), and palladium dichloride-bis-triphenylphosphine (0.592 g, 0.843 mmol). The reaction vessel was sealed and the mixture heated to 90° C. for 1 h. Upon cooling to room temperature, the reaction mixture was diluted with MTBE (100.0 mL) and was washed with 0.1 M HCl (3×50.0 mL). The combined aqueous layers were extracted with MTBE (50.0 mL). The combined MTBE extracts were quenched with saturated sodium bicarbonate (50.0 mL), dried over magnesium sulfate, and concentrated to an oil. The crude oil was purified by column chromatography (silica gel, cyclohexane) to provide (4-Bromo-selenophen-3-ylethynyl)-trimethyl-silane (1.55 g, 5.08 mmol, 79.5 mol %): 500 MHz 1H NMR (CDCl3) δ 8.15 (d, J =2.9 Hz, 1 H), 7.58 (d, J =2.9 Hz, 1 H), 0.26 (S, 9h); 125 MHz 13C NMR (CDCl3) δ 135.4, 127.0, 126.4, 114.1, 99.8, 96.8, 0.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1Br)[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[C:21]1[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)cc(OC)c1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(C(=O)OC)cc(OC)c1-c1cnn(C)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Methyl 3-ethoxy-4-bromo-5-methoxybenzoate (300 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg) were dissolved in DME in a nitrogen atmosphere, and potassium phosphate (661 mg) and 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride-CH2Cl2 complex (85 mg) were added to it at room temperature and degassed. The reaction liquid was stirred overnight at 90° C., then cooled to room temperature, water was added to it, and filtered through Celite. The filtrate was extracted with chloroform, washed with saturated saline water, and dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 40/60) to obtain the title compound as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([CH2:16][C:17]([N:19]([CH3:28])[N:20]=[C:21]([CH3:27])[C:22]([O:24]CC)=O)=[O:18])=[C:10]([CH2:29][CH3:30])[CH:9]=1>O1CCCC1.C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:29][CH3:30])[C:11]([C:16]2[C:17](=[O:18])[N:19]([CH3:28])[N:20]=[C:21]([CH3:27])[C:22]=2[OH:24])=[C:12]([CH2:14][CH3:15])[CH:13]=1
Reactant: CCOC(=O)C(C)=NN(C)C(=O)Cc1c(CC)cc(Cl)cc1CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(Cl)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Reaction time: 0.17 h
Yield: 14.6 %

Procedure:
A solution of 0.55 g of potassium tert-butoxide in 20 mL of tetrahydrofuran was stirred at 36 to 38° C. under nitrogen atmosphere. To the solution was added dropwise a solution of 0.79 g of ethyl 2-[2-(4-chloro-2,6-diethylphenylacetyl)-2-methylhydrazono]propanoate (compound VI-2) in 15 mL of toluene over about 20 minutes. The mixture was further stirred at the same temperature for 10 minutes. Then, the reaction mixture was concentrated under reduced pressure. To the residue was added 20 mL of ice water, followed by extraction with tert-butyl methyl ether (20 mL×2). An aqueous layer was acidified by an addition of 0.6 g of 35% hydrochloric acid, followed by extraction with ethyl acetate (20 mL×2). The ethyl acetate extracts were combined, washed with an aqueous saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate:hexane=1:4) to give 0.1 g of a solid. The solid was washed with an ethyl acetate-hexane mixture solvent (1:10) and air dried to give 0.07 g of the title compound as a white powder.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:18])=[C:11]([F:17])[C:12]=3[C:14]#[C:15][CH3:16])[C:7](=[O:19])[C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:18])=[C:11]([F:17])[C:12]=3[C:14]#[C:15][CH3:16])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 81.9 %

Procedure:
1.4 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propin-1-yl)-3-quinolinecarboxylate are refluxed for 1 hour in a mixture of 20 ml of glacial acetic acid, 1.5 ml of water and 0.5 ml of concentrated sulphuric acid. The mixture is treated with approx. 10 ml of water, and the solid which has precipitated is then isolated and dried. In this manner, 1.05 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propin-1-yl)-3-quinolinecarboxylic acid are obtained (82% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].[N+](=[CH2:21])=[N-].O.O.[Sn](Cl)Cl>CN(C)C=O.CO.CCOCC>[NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[O:9][CH3:21])[CH:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: C=[N+]=[N-]
Agent: Cl[Sn]Cl
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc(C(N)=O)c1N

Procedure:
5-Amino-1-β-D-ribofuranosylimidazole-4-carboxamide (5.2 g, 20 mmol) was dissolved in 40 ml hot dimethylformamide and diluted with 70 ml methanol containing 35 mg tin(II) chloride dihydrate. A solution of 0.1 mol of diazomethane in 200 ml of ether was added in portions over 45 min. After each addition, 20 mg of tin(II) chloride dihydrate was added. The resulting mixture was filtered and evaporated to give a syrup. The syrup was dissolved in 25 ml of methanol and upon cooling yielded crystalline 5-amino-1-(2-O-methyl-β-D-ribofuranosyl)imidazole-4-carboxamide which was collected by filtration and dried. Yield was 1.2 g, melting point 114°-117° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[CH2:15]O)=[N:7][C:6]=2[CH:20]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[CH2:15][Br:22])=[N:7][C:6]=2[CH:20]=1
Reactant: OCc1cccc(OCc2nc3cc(F)ccc3s2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc2sc(COc3cccc(CBr)c3)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.9 %

Procedure:
To a solution of 1.04 g of 3-(5-fluorobenzothiazol-2-ylmethoxy)benzyl alcohol (Preparation L) in 60 ml of dry tetrahydrofuran was added 2.38 g of carbontetrabromide and 1.89 g of triphenylphosphine and the reaction stirred under nitrogen at room temperature for 1.5 hours. The reaction mixture was filtered, treated with 100 ml of water and extracted with ethyl acetate. The extracts were washed with water and a brine solution and dried over sodium sulfate. The solvent was removed and the residual brown solid chromatographed on 200 g of silica gel using from 5-10% ethyl acetate--95-90% hexane (v:v). The fractions containing the product were combined and concentrated to give 910 mg of the titled product, m.p. 99°-100° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:43])[C:7]([CH3:42])([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:41]=[CH:40][S:39][CH:38]=2)[CH:32]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)C.C(OC(=O)C(C)(OC1C=CC=CC=1)CC1C=CC(OCCC2N=C(C3CCCCC3)OC=2C)=CC=1)C>C(O)C>[CH:24]1([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][C:7]([CH3:42])([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:41]=[CH:40][S:39][CH:38]=5)[CH:32]=4)[C:6]([OH:43])=[O:5])=[CH:14][CH:13]=3)[N:19]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1cccc(-c2ccsc2)c1
Agent: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2cccc(-c3ccsc3)c2)C(=O)O)cc1
Temperature: 25 °C

Procedure:
5N NaOH (0.5 mL) was added to a solution of 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(3-thiophen-3-yl-phenoxy)-propionic acid ethyl ester and 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy-]-phenyl}-2-methyl-2-phenoxy-propionic acid ethyl ester in ethanol (4 mL). The resultant mixture was refluxed under an atmosphere of nitrogen for 2 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo, diluted with 1N HCl, and extracted with CH2Cl2. The organic layer was dried through a Varian ChemElut cartridge, concentrated in vacuo, and purified by LCMS. 1H NMR (400 MHz, CDCl3): δ 7.39-7.26 (m, 5H), 7.17 (d, 2H, J=8.60 Hz), 7.11-7.10 (m, 1H), 6.82-6.80 (m, 1H), 6.78 (d, 2H, J=8.60 Hz), 4.11 (t, 2H, J=6.26 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.13 (d, 1H, J=14.08 Hz), 2.93 (t, 2H, J=6.26 Hz), 2.87-2.81 (m, 1H), 2.28 (s, 3H), 1.99 (d, 2H, J=12.51 Hz), 1.77 (d, 2H, J=12.51), 1.67 (d, 2H, J=12.51), 1.57-1.46 (m, 2H), 1.45 (s, 3H), 1.37-1.19 (m, 2H). MS [ES+] m/z exact mass calcd for C32H36NO5S 546.2314, found 546.2308.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH2:22][CH2:21][C:15]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].FC(F)(F)C(C1C=CC(N2CCC3(CCN(S(C4C=CC=CC=4C(F)(F)F)(=O)=O)CC3)C2=O)=CC=1)O.[F:61][C:62]([F:74])([F:73])[C:63]([C:66]1[CH:71]=[CH:70][C:69](I)=[CH:68][CH:67]=1)([OH:65])[CH3:64]>>[F:61][C:62]([F:73])([F:74])[C:63]([C:66]1[CH:67]=[CH:68][C:69]([N:18]2[CH2:17][CH2:16][C:15]3([CH2:21][CH2:22][N:12]([S:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:23])[F:24])(=[O:11])=[O:10])[CH2:13][CH2:14]3)[C:19]2=[O:20])=[CH:70][CH:71]=1)([OH:65])[CH3:64]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2
Reactant: CC(O)(c1ccc(I)cc1)C(F)(F)F
Agent: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2
Product: CC(O)(c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4C(F)(F)F)CC3)C2=O)cc1)C(F)(F)F

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(2-trifluoromethyl-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one, product of example 166 A) and 1,1,1-trifluoro-2-(4-iodo-phenyl)-propan-2-ol). White crystalline solid. MS (ESI): 551.1 (MH+).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:27])[CH2:26][CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[N:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCC(F)(F)C2)ncn1

Procedure:
100 mg (0.8 mmol) of the compound from Example 12A, 57 mg (0.4 mmol) of 3,3-difluoropyrrolidine hydrochloride and 174 μl (129 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine were initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 30 min. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 13 mg (12% of theory)