Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][N:17]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].CN(C1C=CC=CN=1)C.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1.C(OCC)(=O)C>[C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][N:17]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
To a solution of 2-amino-N-benzylisonicotinamide (0.23 g, 0.43 mmol), dimethylaminopyridine (0.01 g, 0.08 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol) in tetrahydrofuran (10 mL) at 0° C. was added benzoyl chloride (0.12 mL, 1.00 mmol). The resulting solution was warmed to ambient temperature and stirred for 18 hours, diluted with ethyl acetate (30 mL), washed with water (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 2-benzamido-N-benzylisonicotinamide (0.02 g, 15%): mp 174-176° C.; 1H NMR (300 MHz, CDCl3) δ 8.86 (br s, 1H), 8.72 (s, 1H), 8.38 (d, J=5.1 Hz, 1H), 7.91-7.82 (m, 2H), 7.60-7.32 (m, 9H), 6.73 (br s, 1H), 4.64 (d, J=5.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.9, 165.0, 151.9, 148.3, 144.4, 137.4, 133.5, 132.7, 129.0, 128.8, 128.0, 127.8, 127.2, 118.6, 110.5, 44.3; MS (ES+) m/z 332.5 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]#[C:15][Si](C)(C)C)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].CO.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:14]([C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[CH:15]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
Methyl 3-nitro-5-[(trimethylsilyl)ethynyl]benzoate (7.9 g, 28 mmol) was dissolved in THF (90 mL) and methanol (90 mL) and then potassium carbonate (2.0 g, 14 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with 1 N HCl, and the solvent was removed in vacuo. The aqueous residue was extracted with ethyl acetate twice. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated to give a solid. The solid was washed with ether to give the desired product (4 g, 68%). LCMS for C10H8NO4 (M+H)+: m/z=206.0.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].C(=O)([O-])[O-].[K+].[K+].[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(COC)OC.[Cu](I)I>[O:12]=[C:7]1[C:6]2[NH:13][CH:14]=[CH:15][C:5]=2[C:4]2[CH:3]=[C:2]([S:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:11]=[CH:10][C:9]=2[NH:8]1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Reactant: Sc1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=c1[nH]c2ccc(Sc3ccccc3)cc2c2cc[nH]c12
Temperature: 90 °C
Yield: 28.7 %

Procedure:
In a sealed tube, a suspension of 152 mg (0.4 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 209) and 110 mg (0.8 mmol) of potassium carbonate in dimethoxyethane (0.6 mL) is purged with an argon stream before adding 15 mg (0.08 mmol) of copper iodide and 86 mg (0.6 mmol) of thiophenol. The reaction mixture is heated at 90° C. for 5 to 6 days then filtered on celite and rinsed with dichloromethane, then methanol. The filtrate is evaporated and the residue obtained is purified by chromatography on silica (eluent dichloromethane/methanol 96/4 then 9/1) to give 42 mg (29%) of 4-oxo-8-phenylsulfanyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[C:5]2=[N:6][CH:7]=1.C[N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=O>NCC1CC1>[CH:36]1([CH2:37][NH:33][C:13]2[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:8]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:9]=3)[N:12]=2)[CH2:34][CH2:35]1
Reactant: CN1CCCC1=O
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(I)c21
Agent: NCC1CC1
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(NCC3CC3)c21
Temperature: 150 °C

Procedure:
200 mg (0.206 mmol, approx. 55% purity) of the compound obtained in example 21A was dissolved in 1-methyl-2-pyrrolidone (4 ml) in a reaction vessel suitable for a microwave and 1 ml of aminomethylcyclopropane was added. Then it was sealed with a corresponding septum and it was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 64 mg of the title compound was obtained (65% of theor.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.[CH3:19][NH:20][CH2:21][CH2:22][OH:23].CCN(CC)CC>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:20]([CH2:21][CH2:22][OH:23])[CH3:19])=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CNCCO
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(CCO)C(=O)c1cc2nccc(Cl)c2s1
Yield: 49.2 %

Procedure:
This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (1.0 g, 4.68 mmole) by treatment with thionyl chloride followed by reaction of the resultant acyl chloride with 2-(methylamino)ethanol (0.414 ml, 5.15 mmole) and Et3N (0.718 ml, 5.15 mmole), in a manner as previously described for example 9d to give a pale brown solid (0.624 g, 49% yield). 1H NMR (400 MHz, CDCl3) δ8.61 (1H, d, J=4.8 Hz), 7.80 (1H, s), 7.33 (1H, d, J=4.8 Hz), 3.92 (2H, m), 3.76 (2H, t, J=5.1 Hz), 3.37 (3H, s), 3.19 (1H, s); ESIMS (MH+): 259.10.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:25][CH:26]=1)[NH:24][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[C:2]2[CH3:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
An amount of 3.6 g (0.015 mole) of 2-bromo-propiophenone and 6 g (0.03 mole) of 4-benzyloxy-aniline were refluxed for two hours in 15 ml of triethylamine. The mixture was evaporated to dryness, and the residue was heated for two hours to 180° C. After cooling, the residue was mixed with 10% hydrochloric acid and extracted with chloroform. The extracts were dried over sodium sulfate, filtered, and evaporated. The residue obtained was purified by column chromatography on silicagel with toluene as solvent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])CCC.C([O:18][B:19](OCC)[O:20]CC)C.Cl>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([B:19]([OH:20])[OH:18])=[CH:7][C:6]=2[CH:10]=1
Reactant: Fc1ccc2occc2c1
Reactant: CCOB(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cc(F)ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a nitrogen atmosphere, to a solution of 2.0 g of 5-fluorobenzofuran in 150 ml tetrahydrofuran was added 18.5 ml of a 1.59 M solution of n-butyllithium in n-hexane at −78° C., and the mixture was stirred at the same temperature for 10 minutes and at 0° C. for further 10 minutes. At −78° C., 3.7 ml of triethoxyborane was added, and the mixture was stirred for 2 hours while elevating to 0° C. 30 ml of 1 N hydrochloric acid was added, stirred at room temperature for 1 hour, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1), to give 525 mg of the title compound as colorless crystals.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:19])[CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[OH:2][CH2:3][CH:4]([CH3:19])[CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1
Reactant: COC(=O)C(C)CCOc1ccc2c(c1)NC(=O)CC2
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(CO)CCOc1ccc2c(c1)NC(=O)CC2
Yield: 51.9 %

Procedure:
6 g of 2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyric acid methyl ester was added dropwise to a tetrahydrofuran (200 ml) suspension of 1.6 g of lithium aluminum hydride while being stirred under ice-cooling and stirred at the same temperature for 2 hours. While being stirred under ice-cooling, saturated Rochelle salt aqueous solution was added, which was extracted with diethyl ether and, after washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1), and 2.8 g of 7-(4-hydroxy-3-methylbutoxy)-3,4-dihydro-1H-quinolin-2-one was obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]=[C:5]([CH3:11])[C:4]=2[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][NH:6][CH:5]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC1=NCCc2sc(C)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cc2c(s1)CCNC2C
Yield: 14 %

Procedure:
In close analogy to the procedure described above, 2,4-Dimethyl-6,7-dihydro-thieno[3,2-c]pyridine is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: C(O[CH:4]([O:17]CC)[CH2:5][CH2:6][N:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:8]([NH2:10])=[O:9])C.C1C=CC2N(O)N=NC=2C=1.[Cl:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([S:41]([CH2:44][C@@H:45]([OH:49])[C:46](O)=[O:47])(=[O:43])=[O:42])[CH:35]=[CH:34]2.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([S:41]([CH2:44][C@@H:45]([OH:49])[C:46]([N:14]1[CH2:13][CH2:12][CH:11]([N:7]3[CH2:6][CH2:5][CH:4]([OH:17])[NH:10][C:8]3=[O:9])[CH2:16][CH2:15]1)=[O:47])(=[O:42])=[O:43])[CH:35]=[CH:34]2
Reactant: CCOC(CCN(C(N)=O)C1CCNCC1)OCC
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCC(O)NC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of N-(3,3-diethoxypropyl)-N-piperidin-4-yl urea (7.79 g) obtained in Example 46a), HOBt (4.81 g) and (2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropionic acid (9.88 g) in DMF (200 mL) was added WSC (6.02 g) at room temperature. The mixture was stirred at room temperature overnight, and DMF was distilled off under reduced pressure. The residue was diluted with chloroform, washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (from ethyl acetate to ethyl acetate/ethanol=97/3) to obtain the title compound (9.41 g, 52%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([Cl:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([Cl:12])[C:5]2[O:9][C:8]([N:18]3[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1c(Cl)cc2nc(S)oc2c1Cl
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cc2nc(N3CCN(C)CC3)oc2c1Cl

Procedure:
5,7-Dichloro-6-methyl-2-mercaptobenzoxazole (200 mg) was dissolved in chloroform (20 ml), N-methylpiperazine (0.94 ml) was added dropwise to the solution and then the mixture was stirred with heating for 29 hours. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5,7-dichloro-6-methyl-2-(4-methyl-1-piperazinyl)benzoxazole (163 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[N:5][C:4]=1[CH3:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[S:7][C:3]=1[CH2:2][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=3)=[N:5][C:4]=2[CH3:20])[CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: COc1cc(-c2nc(C)c(CCl)s2)cc(OC)c1OC
Product: COc1cc(-c2nc(C)c(CN3CCN(Cc4sc(-c5cc(OC)c(OC)c(OC)c5)nc4C)CC3)s2)cc(OC)c1OC

Procedure:
5-Chloromethyl-4-methyl-2-(3,4,5-trimethoxy-phenyl)thiazole (104 mg) and piperazine (13 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:19]([S:21]([CH2:24][CH2:25]O)(=[O:23])=[O:22])[CH3:20].CC1C=CC(S([O-])(=O)=O)=CC=1>CN(C)C=O>[CH2:19]([S:21]([CH2:24][CH2:25][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)(=[O:23])=[O:22])[CH3:20]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CCS(=O)(=O)CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCN1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 96 h
Yield: 812.7 %

Procedure:
To a solution of 6.6 g (0.03 mole) of 1-piperazinecarboxylic acid, phenylmethyl ester in 100 ml of N,N-dimethylformamide was added, in portions, 1.44 g (0.03 mole) of a 50% sodium hydride suspension in mineral oil. The mixture was heated at 50° for 1 hr and allowed to cool slightly. To it was added dropwise a solution of 8.8 g (0.003 mole) of 2-(ethylsulfonyl)ethanol, 4-methylbenzenesulfonate in 30 ml of N,N-dimethylformamide. The mixture was heated at 50° for 1 hr, allowed to cool, concentrated under vacuum to one-half the original volume, allowed to stand for four days and then concentrated to a paste. The paste was diluted with ether and the suspension filtered to remove insoluble salts. The filtrate was concentrated and chromatographed over 250 g of silica gel with 1 l each of the following solutions of methanol in ethyl acetate: 1.5%, 3% and 15%. That portion of the eluent containing the product, Rf(silica--10 % methanol/ethyl acetate)=0.7, was concentrated to dryness under vacuum to afford 8.3 g (81%) of the desired product as an oil. The IR and NMR spectra were consistent with the assigned structure.
Reaction SMILES: [K+].[CH3:2][O:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([S-:13])[S:12][C:8]=2[C:7]=1[F:16])=[O:5].[K].S[C:19]1SC2C(N=1)=NC=C(C(OCC)=O)C=2>>[F:16][C:7]1[C:8]2[S:12][C:11]([S:13][CH3:19])=[N:10][C:9]=2[CH:14]=[CH:15][C:6]=1[C:4]([O:3][CH3:2])=[O:5]
Reactant: COC(=O)c1ccc2nc([S-])sc2c1F
Reactant: CCOC(=O)c1cnc2nc(S)sc2c1
Agent: [K+]
Agent: [K]
Product: COC(=O)c1ccc2nc(SC)sc2c1F

Procedure:
Methyl 7-fluoro-2-(methylthio)benzo[d]thiazole-6-carboxylate was synthesized as a clear oil (400 mg, 29%) using a procedure analogous to that described in Step 2 of Example 114, substituting 6-(methoxycarbonyl)-7-fluorobenzo[d]thiazole-2-thiolate potassium salt from the previous step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt used in Example 114. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (m, 1H), 7.77 (d, J=8.6 Hz, 1H), 3.89 (s, 3H), 2.85 (s, 3H); LCMS (ESI) m/z 258 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:28])=[C:16]([C@:18]2([CH3:27])[CH2:23][S:22](=[O:25])(=[O:24])[CH2:21][C:20]([NH2:26])=[N:19]2)[CH:17]=1>>[NH2:26][C:20]1[CH2:21][S:22](=[O:24])(=[O:25])[CH2:23][C@:18]([C:16]2[CH:17]=[C:12]([NH:11][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:13]=[CH:14][C:15]=2[F:28])([CH3:27])[N:19]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)CC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)CS(=O)(=O)CC(N)=N1
Yield: 46 %

Procedure:
Prepared from 5-chloropicolinic acid (73.5 mg, 466 μmol, Eq: 1.1) and (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (115 mg, 424 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (80 mg, 195 μmol, 45.9% yield) as a light yellow solid. MS (ISP): m/z=411.4 [(M+H)+] and 413.2 [(M+2+H)+].
Reaction SMILES: CO[C:3]([C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[O:6]1)=[O:4].O.[NH2:31][NH2:32]>CO>[CH:25]1([NH:24][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[C:21]=2[N:22]=[CH:23][N:15]3[C@H:7]2[C@@H:8]3[O:9][C:10]([CH3:14])([CH3:13])[O:11][C@@H:12]3[C@@H:5]([C:3]([NH:31][NH2:32])=[O:4])[O:6]2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NN
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: CO
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)NN)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Temperature: 25 °C

Procedure:
A mixture of (3aS,4S,6R,6aR)-6-(6-cyclopentylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid methyl ester (0.48 g) and hydrazine hydrate (0.29 ml) in methanol (10 ml) was heated at reflux for 28 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue evaporated twice with dichloromethane (2×20 ml) to give the title compound as a white solid (0.49 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CN([CH:30]=[O:31])C>O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:22]([CH3:24])[CH3:23])[C:14]=2[CH:30]=[O:31])=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 3 °C
Reaction time: 1.5 h

Procedure:
5.77 g (78.96 mmol) of DMF are weighed into a 100 ml three-necked round-bottomed flask, equipped with a magnetic stirrer, thermometer, dropping funnel, reflux condenser and nitrogen delivery line, and cooled, with stirring, to 3° C. 12.11 g (78.96 mmol) of phosphorus oxychloride are then slowly added dropwise so that the internal temperature does not exceed 10° C. The reaction mixture is then heated to 80° C. and 10 g (39.48 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, dissolved in 10 ml of DMF, are added dropwise in the course of 30 min. Stirring is subsequently carried out for 1.5 hours at that temperature. Cooling and dilution with 10 ml of DMF are then carried out. The reaction mixture is transferred into a dropping funnel and, with stirring, slowly added dropwise at 40° C. to 10 g (0.25 mol) of sodium hydroxide in 200 ml of water. The aqueous phase is extracted four times with 50 ml of toluene and the combined organic phases are washed six times with 100 ml of water. Subsequently, 10 g of silica gel are added, the mixture is stirred for 1 hour and filtration is carried out, followed by washing three times with 50 ml of toluene and concentration by evaporation. 10.17 g of a brown oil are obtained, which is dissolved in 100 ml of hexane under reflux. 10 g of silica gel are added, and filtration is carried out while hot, followed by washing three times with 50 ml of hot hexane. The filtrate is concentrated by evaporation and the residue is recrystallised from 94% ethanol. Slightly beige crystals having a melting point of from 89.5 to 91° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:8]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:7][C:6]=12.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>>[F:12][CH:11]([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:6]2[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(Br)cnn12
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 88.5 %

Procedure:
Prepared from 3-bromo-7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (18.6 g, 45 mmol) and commercially available trimethylsilylacetylene (11.1 mL, 80 mmol) as described in example C.1, step 3a to give 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (16.3 g, 99%) as an orange-solid. MS (ISP) 410.1 [(M+H)+].
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (6.70 g, 28.2 mmol) in CH2Cl2 (100 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-chloro-4-((E)-2-nitro-vinyl)-benzene (4.97 g, 27.1 mmol) and trifluoroacetic acid (0.31 g, 2.7 mmol) in CH2Cl2 (150 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 6.75 g (79%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1>>[OH:19][C:3]1[CH:2]=[C:11]([C:6]2[CH:5]=[C:17]3[C:12](=[CH:8][CH:7]=2)[C:13]([C:25]2[CH:26]=[N:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:14]([OH:18])[CH:15]=[CH:16]3)[CH:10]=[CH:9][CH:4]=1
Reactant: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1
Reactant: COc1ccc(OB(O)O)cn1
Product: COc1ccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)cn1
Reaction time: 3 h
Yield: 84 %

Procedure:
The compound is prepared by the reaction of 1-bromo-6-(3-hydroxyphenyl)-naphthalene-2-ol (100 mg, 0.32 mmol, 1 eq) with 6-methoxypyridin-3-ylboric acid (48.6 mg, 0.32 mmol, 1 eq) according to method A in 3 h. Purification by column chromatography with hexane/ethyl acetate 8/2 yields the desired compound in a yield of 84%, 92 mg.