Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:31]([O:33]C)=[O:32])=[C:26]2[C:30]=1[O:29][CH2:28][CH2:27]2.Cl>C(O)C.O>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:31]([OH:33])=[O:32])=[C:26]5[C:30]=4[O:29][CH2:28][CH2:27]5)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: COC(=O)c1ccc(N)c2c1CCO2
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
(7S)-2-Chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one 41f (300 mg, 1.70 mmol) and methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate 1g (543 mg, 1.80 mmol) were dissolved in 34 mL of the mixture solvent of ethanol and water (V/V=1:2.4) followed by the addition of 0.4 mL of concentrated hydrochloric acid and heated to reflux for 16 hours. The reaction solution was cooled down to room temperature, put into the refrigerator for 1 hour and filtered. The filter cake was washed with water (50 mL) and dissolved in 20 mL of the mixture solvent of water and 1 M lithium hydroxide (V/V=1:1), extracted with ethyl acetate (50 mL×2), the aqueous phase was added dropwise with 1 M hydrochloric acid to adjust pH to 2 resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-[[(7S)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 41g (0.45 g, yield: 62.0%) as a white solid.
Reaction SMILES: Br.Br.[NH:3]1[CH2:6][CH:5]([NH:7][C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)[CH:9]=2)[CH2:4]1.[C:23](O)(=[O:32])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:23]([N:3]1[CH2:6][CH:5]([NH:7][C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)[CH:9]=2)[CH2:4]1)(=[O:32])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CNc1cc(-c2c[nH]c(=O)c(NC3CNC3)c2)ccn1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1cc(-c2c[nH]c(=O)c(NC3CN(C(=O)/C=C/c4ccccc4)C3)c2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
A solution of 5-(azetidin-3-ylamino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one di-hydrobromide (80.0 mg, 0.185 mmol) in DMF (1 mL) was added cinnamic acid (60 mg, 0.41 mmol), HATU (105 mg, 0.277 mmol), and DIPEA (120 mg, 0.924 mmol). The reaction mixture was stirred at RT under nitrogen for 16 h. The residue was purified by Prep HPLC (ethyl acetate/hexane) to afford (E)-5-((1-cinnamoylazetidin-3-yl)amino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one (41 mg, 55%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 11.25 (s, 1H), 8.11 (d, J=5.4 Hz, 1H), 7.69 (d, J=15.6 Hz, 1H), 7.52 (dd, J=6.7, 3.0 Hz, 2H), 7.37 (dd, J=5.0, 2.0 Hz, 3H), 7.09 (d, J=2.2 Hz, 1H), 6.63 (dd, J=5.4, 1.6 Hz, 1H), 6.48 (d, J=15.6 Hz, 1H), 6.38 (d, J=1.9 Hz, 2H), 5.48 (d, J=6.6 Hz, 1H), 4.80-4.65 (m, 2H), 4.63-4.50 (m, 1H), 4.46-4.32 (m, 1H), 4.26-4.05 (m, 2H), 2.98 (d, J=4.8 Hz, 3H); MS (ES) m/z 402 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.O1CCCC1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:24])=[O:23])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc2[nH]ncc2c1)c1ccccc1
Yield: 58.5 %

Procedure:
N-(1H-Indazol-5-yl)benzenesulfonamide can be obtained as described in Example 1 from 0.5 g of 5-amino-1H-indazole, 25 ml of tetrahydrofuran, 1.05 ml of triethylamine and 0.73 g of benzenesulfonyl chloride. 0.6 g of N-(1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of a cream solid melting at 179° C. (analysis C13H11N3O2S % calculated C, 57.13; H, 4.06; N, 15.37; O, 11.71; S, 11.73. % found C, 56.90; H, 4.24; N, 14.21; S, 10.67).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:7].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH3:33])[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:32][O:31][C:27]1[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=[C:25]([CH3:33])[C:26]=1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:7]
Reactant: CCOC(=O)CCCCCCCCC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(OC)c1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Under cooling with ice, aluminum chloride (4.08 parts) was added in small portions to a mixed solution of ethyl 9-chloroformylnonanoate (3.52 parts) and 3,4,5-trimethoxytoluene(formulaVII wherein R=H3CO, X=H, Y=H3CO) (2.21 parts) in nitrobenzene (20 volume parts). The mixture was stirred at 0° C. for 16 hours and, then, at room temperature for 1.5 hours. The reaction mixture was rendered acidic with dilute hydrochloric acid and extracted with diethyl ether. By a procedure similar to that described in Example 1 (2), the extract was hydrolyzed and subjected to column chromatography on silicic acid. The fraction eluted by benzenediethyl ether (9:1) yielded 9-(2',3',4'-trimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1 wherein R=H3CO, X=H, Y=OCH3, n=8, in the free form) (1.82 part). From the fraction eluted by benzene-diethyl ether (5.7:1), there was obtained 9-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1, R=H3CO, X=H, Y=OH, n=8, in the free form) (0.67 part) as colorless needles melting at 75°-76.5° C.
Reaction SMILES: C(N1CCN(C2C=CC(N)=CC=2)CC1)CC(C)C.[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20].C(Cl)Cl>CCO.[Pd]>[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: CC(C)CCN1CCN(c2ccc(N)cc2)CC1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 3 h
Yield: 86.4 %

Procedure:
Using the method described above for the synthesis of 4-(4-isopentylpiperazin-1-yl)aniline, treatment of 1-isopropyl-4-(4-nitrophenyl)piperazine (11.0 g, 40.1 mmol) with H2 and 10% Pd/C (1.0 g) at RT in EtOH (150 mL) for 24 h, followed by the addition of DCM (100 mL) to the reaction mixture and stirring for a further 3 h, provided crude 4-(4-isopropylpiperazin-1-yl)aniline (7.6 g, 86% recovery, 99% purity as determined by LC/MS analysis @ UV 254 nm detection). The crude product is used in the next step without further purification. LCMS-ESI (m/z): calcd for C13H21N3, 219; [M+H]+ found, 220.
Reaction SMILES: C[C:2]([OH:15])([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].O.O.[OH-].[Li+]>CO.O1CCCC1>[OH:15][CH:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: CC(O)(C(=O)O)C(C)(C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)C(O)C(=O)O
Temperature: 62.5 °C
Reaction time: 16 h

Procedure:
According to general procedure, methyl 2-hydroxy-3-methyl-3-phenylbutanoic acid (0.27 g, 1.3 mmol, from Reference Example 37) is dissolved in methanol (6 mL) and tetrahydrofuran (6 mL). To this solution is added water (3 mL) and lithium hydroxide monohydrate (0.12 g, 2.9 mmol), and the resulting mixture is stirred at 60-65° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 2 M aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a light pink oil, which solidified under vacuum (0.25 g, 100%). TOF MS (ES−): (M−H)=193.0
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C([O-])([O-])=O.[Ca+2].C(Cl)(Cl)(Cl)Cl.[C:35](Cl)(Cl)=[S:36]>O.C(Cl)Cl>[N:13]([C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[C:35]=[S:36]
Reactant: S=C(Cl)Cl
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2ccccc2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt, 42, (726 mg, 1.79 mmol) and CaCO3 (716 mg, 7.16 mmol) in H2O (2 mL) is added CCl4 (3 mL) followed by thiophosgene (0.28 mL, 3.58 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2Cl2 and water. The layers are separated and the aqueous layer extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue which is purified over silica (CH2Cl2) to afford 480 mg (73%) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=8.7 Hz, 2H), 7.97-7.99 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 7.15 (d, J=0.9 Hz, 1H), 5.40-5.95 (m, 1H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H), 3.46 (dd, J=13.8 and 6.0 Hz).
Reaction SMILES: C([Li])CCC.C(OCC)C.Br[C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.CN(OC)[C:24](=[O:28])[CH2:25][CH2:26][CH3:27]>C1COCC1>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[CH:13]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: CCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(=O)c1cnc2ccccc2c1
Temperature: 0 °C
Yield: 58.1 %

Procedure:
In a dry 3-necked flask under argon at -50° C., n-butyl lithium (0.0025 M, 0.021 ml) was added to 150 ml diethylether. Then 4.16 grams 3-bromoquinoline in 2 ml THF was added dropwise while stirring and maintaining the temperature at -60° C. to -55° C. The solution was stirred for 30 minutes, and 2.3 grams N-methyl-N-methoxybutanamide were then added dropwise at -50° C. and the solution was stirred an additional 30 minutes The solution was then allowed to warm to 0° C. and stirred for one hour. The reaction was quenched with a saturated solution of ammonium chloride and the THF layer separated, washed with brine, separated, and dried over magnesium sulfate. Filtration through diatomaceous earth, followed by concentration and subsequent thin layer chromatography (35% ethylacetate/65% CH2Cl2) gave a total yield of 2.03 g (51%) of the title compound.
Reaction SMILES: CN(C)C1C=CC=CC=1.Cl.[CH3:11][CH:12]1[CH:17]=[C:16]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[N:15]2[C:26](=[O:29])[CH:27]([NH2:28])[C@H:14]2[S:13]1.[C:30]([CH2:32][C:33](O)=[O:34])#[N:31].C1(N=C=NC2CCCCC2)CCCCC1.Cl>ClCCl.C(N(CC)CC)C>[CH3:11][CH:12]1[CH:17]=[C:16]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:23])[Cl:24])=[O:19])[N:15]2[C:26](=[O:29])[CH:27]([NH:28][C:33](=[O:34])[CH2:32][C:30]#[N:31])[C@H:14]2[S:13]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CC#N)[C@H]2S1
Yield: 84.9 %

Procedure:
A solution of triethylamine (0.9 g) and dimethylaniline (0.15 g) in dichloromethane (20 ml) was added under stirring and ice-cooling to a suspension of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.82 g) in dried dichloromethane (80 ml). To the mixture were added cyanoacetic acid (0.85 g) and dicyclohexylcarbodiimide (2.25 g), and the mixture was stirred for 1 hour under ice-cooling. To the mixture was added 5% hydrochloric acid (50 ml), and the mixture was stirred for 30 minutes, after which the organic layer was separated, washed in turn with 5% hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. The solvent was distilled off to give colorless powder of 2,2,2-trichloroethyl 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylate (3.5 g), mp 160° to 165° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2ccc(Cl)cc2C(=O)O)cc1

Procedure:
5-Chloro-2-(4-methoxyphenylamino)benzoic acid [X; R=5-Cl, OR°=4-OCH3, R"=H] was prepared from 2,5-dichlorobenzoic acid and p-methoxyaniline according to the procedure of Example 1A, part (a), and obtained as a light green solid, m.p. 188°-189° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:57]=[CH:58][C:59]([C:62]([F:65])([F:63])[F:64])=[CH:60][CH:61]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(C(F)(F)F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 101 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give 110 mg colorless viscous oil (71%). MS (ISP) 479.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][OH:9].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.O>CN(C)C=O>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: OCCc1ccsc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
A mixture of 2-(2-bromothiophen-3-yl)ethanol (4.5 g, 21.8 mmol), tert-butylchloro-dimethylsilane (3.16 g, 24.0 mmol) and imidazole (1.63 g, 24.0 mmol) in N,N-dimethylformamide (40 mL) was stirred at rt for 24 h. 100 mL of water was added and the mixture was extracted with diethyl ether (3×00 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the product purified by flash chromatography eluting with ethyl acetate/hexane (1:20) to give the title compound as an oil (5.9 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[F:12][C:13]1[CH:14]=[C:15]([OH:23])[CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20]>>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[O:23][C:15]1[CH:16]=[CH:17][C:18]([C:19]([F:20])([F:21])[F:22])=[C:13]([F:12])[CH:14]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(C(F)(F)F)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccc(C(F)(F)F)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-fluoro-4-(trifluoromethyl)phenol.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3](O)=O.[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.Cl.[NH2:49]CCC(OCC)=O>N1C=CC=CC=1>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[N:49]=[C:17]([OH:18])[C:16]2[C:15](=[C:23]([O:24][CH3:25])[CH:22]=[CH:21][CH:20]=2)[N:14]=1
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C(O)C(F)(F)c1ccc(F)cn1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: COc1cccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid from Example 33 step A (1 g, 5.23 mmol) and 2-amino-3-methoxybenzoic acid (875 mg, 5.23 mmol) in pyridine (15 mL) was added triphenyl phosphite (1.51 mL, 5.75 mmol) and the mixture was heated in a microwave synthesizer at 150° C. for 10 min. The mixture was allowed to cool to rt and then ethyl 3-aminopropanoate hydrochloride (883 mg, 5.75 mmol) was added. The mixture was heated in a microwave synthesizer at 190° C. for 4 min and then concentrated under reduced pressure. THF (10 mL) and sodium ethoxide (21% in EtOH, 4 mL) were added, and the mixture was stirred at 60° C. for 0.5 h. The mixture was allowed to cool and concentrated under reduced pressure. The residue was dissolved in water and the pH was adjusted to <4 by addition of 4 N HCl. The precipitate was collected by filtration, washed with water, and dried on the funnel to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxyquinazolin-4-ol (1.19 g, 71%). LC-MS (ESI) m/z 322 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].IC.[C:20](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:2][C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([O:10][CH3:20])=[O:9])([CH3:4])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of 5.50 g (23.5 mmoles) of 3,5-di-t-butylbenzoic acid in 25 ml of dry dimethylformamide was added 5.01 g (35.3 mmoles) of iodomethane, and then 6.49 g of anhydrous potassium carbonate. After stirring at room temperature for 2 hours, water was added, the mixture was extracted three times with diethyl ether, the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to give 5.68 g of the title compound as a crystalline solid, m.p. 52.0°-52.5° C. The structural assignment was supported by 1H NMR.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:21](=[CH:22][C:11]3=4)[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:9]2=[O:29])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[O:13]1[CH2:14][C:10]2([C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:8][C:9]2=[O:29])[C:11]2[CH:22]=[C:21]3[C:16](=[CH:15][C:12]1=2)[CH2:17][CH2:18][CH2:19][CH2:20]3
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCCC3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCCC3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1-(diphenylmethyl)-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1H)-one was obtained (80%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 7.33-7.19 (m, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 6.68 (s, 1H), 6.49 (s, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 2.76-2.72 (m, 2H), 2.58-2.56 (m, 2H), 1.71 (t, J=3.2 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ180.5, 158.7, 140.4, 139.0, 132.9, 130.2, 128.8, 126.0, 124.1, 123.6, 123.3, 110.3, 110.2, 79.6, 58.6, 30.0, 29.0, 23.2, 23.0; MS (ES+) m/z 292.0 (M+1).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[N:34]=[CH:35][N:36]([CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH:37]=2)[CH:28]=1>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:42][CH2:41][CH2:40][CH2:39][CH2:38][N:36]5[CH:37]=[C:33]([C:29]6[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=6)[N:34]=[CH:35]5)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Reactant: NCCCCn1cnc(-c2cccnc2)c1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(NCCCCn4cnc(-c5cccnc5)c4)cc3)cc2s1)C1CC1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (50 mg, 127.4 μmol) and 4-(4-pyrid-3-ylimidazol-1-yl)butylamine (110.2 mg, 0.51 mmol) in 0.5 ml of NMP is heated at 150° C. by microwave for 8 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 36 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic 2-(cyclo-propanecarbonylamino)benzothiazol-6-yl ester (beige-colored solid).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:22][Si](Cl)(C)C>CO>[CH3:22][O:20][C:19](=[O:21])[C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:10][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: C[Si](C)(C)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C

Procedure:
The title compound is prepared by the procedure of Example 7 using 0.50 g of L-leucine-L-phenylalanine, 10 ml of methyl alcohol and 0.536 ml of trimethylsilyl chloride to give 0.53 g of the desired product.