Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[Cl:7][C:8]1[N:13]=[C:12]([C:14]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:16])[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=1
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1)N1CCOCC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
Oxalyl chloride (0.38 mL, 4.5 mmol) and N,N-dimethylformamide (0.03 mL) were added to a suspension of 2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid (303 mg, 1.0 mmol) in dichloromethane (20 mL). The mixture was stirred at 20° C. for 3 h and then evaporated under reduced pressure. The residue was dissolved in dichloro-methane (25 mL) and the solution was stirred together morpholine (0.174 mL, 2.0 mmol) and saturated aqueous sodium hydrogencarbonate solution (8 mL) for 1 h at 20° C. The mixture was diluted with dichloromethane (25 mL), and the organic layer was washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-40% ethyl acetate as eluent to give the title compound (260 mg, 66%) as a white solid. MS ISP (m/e): 372.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.25 (d, 2H), 8.04 (s, 1H), 7.80 d, 2H), 3.83 (br s, 4H), 3.74 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=CCCCC)=[CH:10][CH:9]=1)=[O:6].O.I([O-])(=O)(=O)=[O:35].[Na+]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH:26]=1)[C:5]([NH:7][C:8]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]([CH:18]=[O:35])=[CH:10][CH:9]=1)=[O:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCC=Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)c2ccccc12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)c2ccccc12
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
To a stirred room temperature solution of 3-fluoro-N-(4-hex-1-enyl-naphthalen-1-yl)-5-morpholin-4-yl-benzamide (2.7 g, 6.25 mmol) THF (15 ml) and water (5 ml) is added osmium tetroxide (2.5% in t-butanol) (1000 and sodium periodate (6 g) in portions over 30 minutes. After 1.5 hours, the mixture is diluted with ethyl acetate (200 ml) and washed with water (2×100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 25-30% ethyl acetate in hexanes to give 3-fluoro-N-(4-formyl-naphthalen-1-yl)-5-morpholin-4-yl-benzamide as a tan powder (1.072 g). Mp: 204-5° C. 1H NMR 400 MHz (CDCl3) δ 10.3(s, 1H), 9.41(d, 1H, J=8.8 Hz), 8.47(d, 2H, J=7.6 Hz), 8.02(d, 1H, J=8 Hz), 7.92(d, 1H, J=8.4 Hz), 7.65-7.76(m, 2H), 7.31(s, 1H), 7.05(d, 1H, J=8 Hz), 6.79(d, 1H, J=11.6 Hz), 3.88(t, 4H, J=5.2 Hz), 3.27(t, 4H, J=5.2 Hz). MS: 379 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][CH:8]=[C:7]([C:14]([O:16]CC)=[O:15])[C:6]2=[O:19]>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]2=[O:19]
Reactant: CCOC(=O)c1c[nH]c2cc(C)c(OC)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(=O)c(C(=O)O)c[nH]c2cc1C
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Ethyl 6-methoxy-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate (25.5 g) was suspended in a 2 M aqueous sodium hydroxide solution (250 ml), and the mixture was heated under reflux for 4 hr. The reaction solution was cooled to room temperature, the aqueous layer was then washed with chloroform and was neutralized with dilute hydrochloric acid. The precipitated crystal was collected by filtration and was washed with water, isopropanol, and hexane in that order to give 6-methoxy-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (22.1 g, yield 98%).
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:9]([O:16][C:17]([C:19]2[N:24]3[C:25](=[O:38])[C@@H:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:23]3[S:22][CH2:21][C:20]=2[OH:39])=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CN(C)C=O.C(O)(=O)C>[C:3]1([CH:9]([O:16][C:17]([C@@H:19]2[N:24]3[C:25](=[O:38])[C@@H:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:23]3[S:22][CH2:21][CH:20]2[OH:39])=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
1.30 g of sodium borohydride are added in portions to a solution of 35.4 g of 3-hydroxy-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (crude product) in a mixture of 270 ml of dimethylformamide and 70 ml of glacial acetic acid in a stream of nitrogen while stirring and cooling with ice at approximately 15° to 20°. The reaction mixture is further stirred for one hour at room temperature, poured onto a mixture of ice and 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed successively with 2 N hydrochloric acid, water, saturated, aqueous sodium bicarbonate solution and saturated, aqueous sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is substantially freed from dimethylformamide under a high vacuum and recrystallised from ethyl acetate and a little diethyl ether. The title compound is obtained which has a melting point of 167°-170°; Rf~0.47 (silica gel; toluene/ethyl acetate 1:1); [α]D20 =+88°± 1° (in chloroform, c=0.526%); IR spectrum (in CH2Cl2): Absorption bands up to 3580; 3410; 1780; 1740; 1695; 1600; 1518; 1494 cm-1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][CH2:15][C@H:14]([NH:25]C(=O)OC(C)(C)C)[C:13]2=[O:33])[CH2:10][CH2:9]1>ClCCl>[NH2:25][C@H:14]1[CH2:15][CH2:16][CH2:17][C@@H:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:12]([CH2:11][CH:8]2[CH2:9][CH2:10]2)[C:13]1=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](c2ccccc2)N(CC2CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCC[C@@H](c2ccccc2)N(CC2CC2)C1=O
Reaction time: 1 h
Yield: 106.4 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution tert-butyl (3S,7S)-1-(cyclopropylmethyl)-2-oxo-7-phenylazepan-3-ylcarbamate (144.1 mg, 0.40 mmol) in dichloromethane (5 mL). After 1 h, the mixture was concentrated and aqueous saturated sodium bicarbonate was added. The mixture was extracted with dichloromethane (2×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound (110 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10].[Br:16][C:17]1[CH:24]=[C:21]([CH:22]=O)[C:20]([OH:25])=[CH:19][CH:18]=1>CC(C)=O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][C:8]([C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])=[CH:22][C:21]=2[CH:24]=1
Reactant: O=C(CBr)c1cccs1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1cc2cc(Br)ccc2o1)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (12.0 g, 0.087 mol) and subsequently 2-bromo-1-(thiophen-2-yl)ethanone (7.0 g, 0.034 mol; prepared as described in J. Med. Chem. 30, 1497 (1987)) were added to a stirred solution of 5-bromosalicylaldehyde (6.9 g, 0.034 mol) in acetone (150 mL). The mixture was stirred at ambient temperature for 30 min at first and then refluxed for 1 h. Solid mass was filtered off, washed with hot acetone (2×50 mL) and the filtrate was evaporated in vacuo. The residue (11.3 g) was crystallized from ethanol (15 mL) giving (5-bromobenzo[b]furan-2-yl)-(thiophen-2-yl)methanone. Yield: 8.0 g (77%). M.p. 84-86° C. RF (SiO2, hexane/ethyl acetate 3:1) 0.70.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[NH2:39][C:40]([CH3:55])([CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]([F:54])([F:53])[F:52])[C:41]#[N:42]>ClCCl.CN(C)C1C=CN=CC=1>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:39][C:40]([C:41]#[N:42])([CH3:55])[CH2:43][O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]([F:53])([F:54])[F:52])=[O:17])=[CH:13][CH:14]=1)(=[O:8])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CC(N)(C#N)COc1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C#N)(COc1ccccc1C(F)(F)F)NC(=O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
330 mg of benzophenone-4-carboxylic acid are dissolved in 6 ml of dichloromethane, then 283 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 18 mg of 4-dimethylaminopyridine and 222 mg of ethyldiisopropylamine are added, and stirred for 20 minutes at room temperature. 300 mg of 2-amino-2-methyl-3-(2-trifluoromethylphenoxy)-propionitrile are subsequently added, and the mixture stirred for a further 40 hours. Afterwards, the mixed solution is washed with an aqueous sodium bicarbonate solution, then with a 1 n hydrochloric acid solution and finally with a saturated sodium chloride solution. The organic phase is then separated, dried with sodium sulphate, filtered and concentrated by evaporation. After recrystallisation in diethylether, the residue yields 372 mg of the title compound with a melting point of 121-123° C.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[C:3]2=[CH:8][CH:9]=[CH:10][N:2]12.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Si:11]([O:7][C:4]1[C:3]2[N:2]([CH:10]=[CH:9][CH:8]=2)[N:1]=[CH:6][CH:5]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=c1cc[nH]n2cccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccnn2cccc12
Reaction time: 1 h

Procedure:
Pyrrolo[1,2-b]pyridazin-4(1H)-one (2.0 g, 14.9 mmol) and t-butyldimethylsilyl chloride (2.7 g, 17.9 mmol) were dissolved in anhydrous toluene under nitrogen atmosphere. After adding triethylamine (3.1 mL, 22.4 mmol), the mixture was stirred for 1 hour under reflux. Upon completion of the reaction, the produced solid was filtered and washed with a small volume of toluene. The filtrate was concentrated by distillation under reduced pressure. The resulting residue was subjected to the next step without further purification.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[F:17][CH:18]1[CH2:21][NH:20][CH2:19]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:13]([N:20]1[CH2:21][CH:18]([F:17])[CH2:19]1)=[O:15])[CH2:10][CH2:11][CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: FC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 110.1 %

Procedure:
A round-bottomed flask was charged with Boc-D-norvaline (300 mg, 1.38 mmol) and 3-fluoroazetidine hydrochloride (216 mg, 1.93 mmol). DMF (6 ml) was added followed by N,N-diisopropylethylamine (0.65 ml, 3.72 mmol) and HATU (578 mg, 1.52 mmol). The yellow reaction mixture was stirred at room temperature for 48 h the quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 417 mg of [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-carbamic acid tert-butyl ester as a light yellow solid.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([C@@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[C:22]2[CH3:34])=[CH:18][C:17]=1[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40]>>[C:2]([C:6]1[CH:7]=[C:8]([C@@H:12]([NH:14][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:19]2[CH:35]=[CH:36][C:16]([Cl:15])=[C:17]([CH:18]=2)[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:22]([CH3:34])=[C:23]3[CH3:33])=[O:31])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H](N)c1cccc(C(C)(C)C)c1
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl
Agent: Cl
Product: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)(C)C)c4)ccc32)ccc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride the (S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]2[O:15][CH:16]=[CH:17][C:6]=12)=[O:4].[OH-].[Na+].Cl>CO>[O:15]1[C:7]2=[N:8][C:9]3[C:14]([C:5]([C:3]([OH:4])=[O:2])=[C:6]2[CH:17]=[CH:16]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COC(=O)c1c2ccccc2nc2occc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c2ccccc2nc2occc12

Procedure:
A mixture of 1.0 g (4.3 mmol) Methyl-furo[2,3-b]quinoline-4-carboxylate 6, 12 ml methanol and 60 mL 1N NaOH was heated at reflux for 75 minutes. After cooling the solution was acidified with 4N HCl to pH ˜1-2, whereupon a solid precipitated. Then the reaction mixture was extracted with 200 mL diethylether. The organic layer was separated and extracted now with 150 mL of a sodium bicarbonate solution (5%), wich was acidified another time with 4N HCl to give the product 7 as a crystalline solid. The precipitate was filtered and dried under vacuum to give 760 mg of 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[N:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[N:10][C:11]([O:14][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cnc(O)nc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cnc(OC(=O)N(C)c3ccccc3)nc2)cc1
Yield: 78.3 %

Procedure:
A solution of 5-(4-methoxy-phenoxy)-pyrimidin-2-ol (0.44 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.22 g, 2.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.55 g, 79% yield) as an off-white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[CH:11]=1)[C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Br:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32]Br)[N:31]=1>C(#N)C>[Br:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32][O:1][N:2]=[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[CH:11]=2)[C:4]2[N:8]([CH3:9])[N:7]=[N:6][N:5]=2)[N:31]=1
Reactant: BrCc1csc(Br)n1
Reactant: CSc1cccc(C(=NO)c2nnnn2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CSc1cccc(C(=NOCc2csc(Br)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
To a stirred solution of N-hydroxy-1-[3-(methylsulfanyl)phenyl]-1-(1-methyl-1H-tetrazol-5-yl)methanimine (1.00 g, 3.73 mmol) in acetonitrile (60 mL), were added cesium carbonate (2.55 g, 7.83 mmol), potassium iodide (310 mg, 1.86 mmol) and 2-bromo-4-bromomethyl-thiazole (1.05 g, 4.10 mmol). The resulting suspension was stirred at 25° C. for 6 h. The suspension was filtered, the solids washed with ethyl acetate and dichloromethane and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL), washed with water, dried over MgSO4 concentrated in vacuo. Purification on silica gel afforded N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-[3-(methylsulfanyl)phenyl]-1-(1-methyl-1H-tetrazol-5-yl)methanimine as an oil that solidified on standing after 2 days [1.49 g, yield 94%; HPLC/MS: m/z=425 (M+H); logP(HCOOH)=3.55].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[C:4](Cl)[N:3]=1.Cl.[C@H:21]12[CH2:27][C@H:24]([NH:25][CH2:26]1)[CH2:23][N:22]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C.O>O1CCCC1>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:25]3[CH2:26][C@@H:21]4[CH2:27][C@H:24]3[CH2:23][N:22]4[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:5]=2)=[CH:9][C:10]=1[C:15]([F:18])([F:17])[F:16]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Nc1ncc(-c2cc(Cl)nc(Cl)n2)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(Cl)n1
Temperature: 75 °C
Yield: 55.6 %

Procedure:
To a solution of 5-(2,6-dichloropyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (300 mg, 0.84 mmol) in tetrahydrofuran (60 mL) was added (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate hydrochloride (197 mg, 0.84 mmol) and N-ethyl-N-isopropylpropan-2-amine (2 mL). The mixture was heated at 75° C. for 3 h. After cooling to room temperature, water (50 mL) was added to. The mixture was extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate, concentrated and purified by flash column chromatography (25% ethyl acetate in petroleum ether to 100% ethyl acetate) to provide (1S,4S)-tert-butyl 5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (220 mg, 48.1% yield). TLC (Thin layer chromatography) (petroleum ether (PE): ethyl acetate (EA)=3:1, Rf=0.3-0.4).
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:31])[CH:3]=1.[CH2:32]([OH:35])[C:33]#[CH:34]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:25]1([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([C:13]([C:12]3[C:7]([O:6][C:5]4[CH:28]=[C:29]([Cl:30])[C:2]([C:34]#[C:33][CH2:32][OH:35])=[CH:3][C:4]=4[Cl:31])=[N:8][CH:9]=[CH:10][CH:11]=3)=[O:14])[CH2:16][CH2:17]2)[CH2:27][CH2:26]1
Reactant: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1Oc1cc(Cl)c(C#CCO)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 100 °C
Yield: 52.2 %

Procedure:
To a degassed suspension of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (100 mg, 0.19 mmol, 1.0 equiv; Example 163) in triethylamine (0.8 mL) under Ar was added 2-propyn-1-ol (216 mg, 220 μL, 3.85 mmol, 20 equiv; [CAS RN 107-19-7]), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02 mmol, 0.1 equiv; [CAS RN 14221-01-3]) and copper(I) iodide (3.7 mg, 0.02 mmol, 0.1 equiv; [CAS RN 7681-65-4]). The reaction mixture was heated by microwave irradiation to 100° C. for 1 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 49 mg (52%) of the title compound as an off-white powder. MS (ISP): 494.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]=1[OH:14])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.[I-].[K+]>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]=1[O:14][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1)=[O:4]
Reactant: COC(=O)c1ccc2ccsc2c1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2ccsc2c1OCc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
200 mg 7-Hydroxy-benzo[b]thiophene-6-carboxylic acid methyl ester, 313 mg cesium carbonate, 230 mg of 1-bromomethyl-4-trifluoromethyl-benzene and 32 mg potassium iodide were dissolved in 1 ml of N,N-dimethylformamide and stirred for 3 h at 60° C. 10 ml of ethyl acetate and 10 ml of brine were added to the reaction. The organic layer was separated and washed again with 10 ml of brine. It was then dried over sodium sulphate, filtered and concentrated in vacuo to afford 325 mg of 7-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-6-carboxylic acid methyl ester.