Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:6](C=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[O:8].Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=[N:39]C=1.N1N(C2C(C(O)=O)=NC=CC=2)N=CC=1>>[N:28]1[N:27]([C:5]2[C:6]([C:7]([NH:9][C@H:10]3[CH2:14][CH2:13][CH2:12][C@@H:11]3[NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=3)=[O:8])=[N:39][CH:2]=[CH:3][CH:4]=2)[N:31]=[CH:30][CH:29]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Agent: Cl
Agent: O=C(O)c1ncccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for 5-chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 97) from (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 50 mg, 0.20 mmol) and 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 39 mg, 0.20 mmol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1.N(OC(C)(C)C)=O.O>C1COCC1>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(Cl)nc2ccc(Oc3ccc(F)cc3F)cc12
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(Oc2ccc3nc(Cl)ncc3c2)c(F)c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
Compound (1G) (21 g, 0.07 mol) was dissolved in THF (200 mL) and the solution added dropwise to a solution of t-butyl nitrite (16.5 mL, 0.14 mol) in THF (100 mL). The mixture was heated to reflux for 4 h, and after cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (2×100 mL). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The crude product was purified by chromatography (silica gel, hexane: EtOAc, 4:1) giving 9.05 g of 2-chloro-6-(2,4-difluoro-phenoxy)-quinazoline (1H).
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:29])[C@H:9]([CH:26]([CH3:28])C)[NH:10][C:11](=[O:25])[C@H:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH:13]C(OC(C)(C)C)=O)CCCCC.ON1C2C=CC=CC=2N=N1.Cl.CNC(=O)[C@H](CC1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH3:56])=[CH:49][CH:48]=1)N.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C=O>[CH3:1][NH:7][C:8](=[O:29])[C@H:9]([CH2:26][C:28]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH3:56])=[CH:49][CH:48]=1)[NH:10][C:11](=[O:25])[C@H:12]([CH2:21][CH:22]([CH3:23])[CH3:24])[NH2:13]
Reactant: CCCCCCNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)C
Reactant: CCCOc1ccc(C[C@H](N)C(=O)NC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCOc1ccc(C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)NC)cc1
Temperature: 20 °C

Procedure:
N-Tertiary butyloxycarbonyl-O-propyl-L-tyrosine N-methyl amide (370 mg, 1.1 mM) in dichloromethane (8 ml) was treated with trifluoroacetic acid (2 ml) at 20° C. for 2 h. The solvent was removed in vacuo and the residue redissolved in ether saturated with hydrogen chloride and this procedure repeated twice more to afford O-propyl-L-tyrosine-N-methyl amide hydrochloride (1.1 mM) which was used directly in the next step. N-(3-N-(Benzyloxycarbonyl)amino-1-(R)-methoxycarbonylpropyl)-L-leucine hydrochloride (prepared as described in Example 1) (416 mg, 1 mM) in dichloromethane (10 ml) and dimethyl formamide (2 ml) was treated with 1-hydroxybenzotriazole (159 mg, 1.04 mM), O-propyl-L-tyrosine-N-methyl amide hydrochloride (1.1 mM), N-methyl morpholine (315 mg, 3.3 mM) and N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (200 mg, 1.04 mM) at 0° C. The reaction mixture was stirred continuously as it was allowed to warm to 20° C. over 16 h. The reaction was diluted with dichloromethane (30 ml) and washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous citric acid (1M) dried over anhydrous sodium sulphate and concentrated in vacuo to afford N-(3-N-Benzyloxycarbonyl)amino-1-(R)-methoxycarbonylpropyl)-L-leucyl-O-propyl-L-tyrosine-N-methyl amide (0.22 g, 0.36 mM) which crystallised from ethyl acetate/hexane as needles m.p. 135°-140° C. (Found: C,62.8; H,7.8; N,9.2. C32H46N4O7 +0.5 H2O requires: C,63.2; H,7.8; N,9.2%); δ(CDCl3) 0.86 (6H,d,d,J=4 Hz J=4 Hz (CH3)2C); 1.02 (3H,t,J=7 Hz CH3CH2); 1.1-1.98 (9H,m,CH,CH2,CH2,CH2CH2); 2.74 (3H,d,J=4 Hz CH3NH); 2.86-3.48, (5H,m,CH2CH2,CH); 3.64 (3H,s,OCH3); 3.86 (2H,t,J=6 Hz,CH2O); 4.58 (1H,m,NHCHCO); 5.06 (2H,s,CH2C6H5); 5.14 (1H,m,NH) 6.54 (1H,m,NH); 6.76, and 7.06 (4 H,each d, each J=8 Hz,C6H4); 7.32 (5H,m,C6H5); 7.42 (1H,m,NH).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1ccnc(Cl)c1
Reactant: O=C1CCCCN1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(N2CCCCC2=O)c1
Temperature: 130 °C
Yield: 21.2 %

Procedure:
A mixture of N-benzyl-2-chloroisonicotinamide (0.30 g, 1.22 mmol), piperidin-2-one (0.12 g, 1.22 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.03 g, 0.05 mmol), palladium acetate (0.01 g, 0.05 mmol) and sodium tert-butoxide (0.12 g, 1.22 mmol) in toluene (10 mL) was heated at 130° C. for 36 hours under nitrogen atmosphere and concentrated in vacuo to dryness. The residue was dissolved in dichloromethane (50 mL) and washed with water (30 mL). The separated organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with 65-75% ethyl acetate in petroleum ether to give N-benzyl-2-(2-oxopiperidin-1-yl)isonicotinamide as a colorless solid (0.08 g, 21%): MS (ES+) m/z 310.1 (M+1).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCNCC3)cnc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCN(S(C)(=O)=O)CC3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Piperidin-4-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.073 g, 0.158 mmol) was suspended in DCM (1 mL) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) was added. Methanesulfonyl chloride (0.015 mL, 0.19 mmol) was added and the resulting solution stirred at RT overnight. The solvent was evaporated. The remaining semi-solid was purified by SiO2 chromatography (12 g SiO2, DCM/MeOH 0-4% MeOH). Obtained 0.065 g of 1-(1-methanesulfonyl-piperidin-4-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as an off-white solid (88% yield).
Reaction SMILES: [CH3:1][SiH:2]([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].C(O)C.[CH2:12]([O:16][CH2:17][CH:18]=[CH2:19])[CH:13]1[O:15][CH2:14]1>C(O)(=O)C>[CH2:12]([O:16][CH2:17][CH2:18][CH2:19][Si:2]([CH3:1])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5])[CH:13]1[O:15][CH2:14]1
Reactant: CCO[SiH](C)OCC
Reactant: C=CCOCC1CO1
Solvent: CC(=O)O
Solvent: CCO
Product: CCO[Si](C)(CCCOCC1CO1)OCC
Temperature: 85 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Again, to the apparatus of Example 3 were pressure charged 49.6 lb [22.5 kg] (168.2 mol) of methyldiethoxysilane from a 10 gallon Pope can. After addition of the 20.0 g of CPA ethanol solution (15 ppm Pt) and 21.0 ml (460 ppm) of acetic acid through the handhole, the reactor was kept under nitrogen purge, sealed and heated to 85° C. Allyl glycidyl ether (50.6 lb [23 kg], 20 mole % excess or 210.8 mol) was added through a line to the mixture in the reactor from a pressurized can. The AGE was added at a rate that kept the reaction temperature between 85 and 95° C. After two hours, the addition was complete and the hydrosilation lites were stripped. The crude product was vacuum distilled at 104-121° C. (3-7 mm Hg) to yield 75.5 pounds (31.23 kg) of γ-glycidoxypropylmethyldiethoxysilane with an average purity of 99.0%. This represents a conversion of 82.3%. Again present were the silane scrambled products γ-glycidoxy-propyldimethyl(ethoxy) silane (0.39% by GC) and γ-glycidoxypropyltriethoxysilane (0.27% by GC).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.Cl.[CH3:25]N(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:25][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][NH:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)NC(CNc1ncccc1N)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(CNc1ncccc1N)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 66.6 %

Procedure:
A solution of (2S) 2-tert-Butoxycarbonylamino-3-(3-aminopyridin-2-ylamino)-propionic acid (360 mg, 1.21 mmol) and MeOH (59 mg, 1.82 mmol) in anhydrous CH2Cl2 (20 ml) was treated with 4-dimethylaminopyridine (DMAP, 163 mg, 1.33 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (280 mg, 1.45 mmol). The reaction was stirred for 18 h, diluted with EtOAc (150 ml), washed with water (2×), sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4 and concentrated in vacuo. Chromatography (flash, SiO2, 0 to 5% MeOH/CH2Cl2) gave 250 mg (67%) of the title compound as a light tan solid.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:27][C:28]([NH:39][CH2:40][CH:41]([OH:57])[CH2:42][O:43][C:44]1[C:49]2[C:50]3[C:55]([NH:56][C:48]=2[CH:47]=[CH:46][CH:45]=1)=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[N+:37]=[N-:38])=[CH:32][CH:31]=1)[CH3:29].[CH3:58][C:59]1[C@@H:76]([O:77][C:78]([C@H:80]([OH:97])[C@@H:81]([NH:88][C:89]([C:91]2[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=2)=[O:90])[C:82]2[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=2)=[O:79])[CH2:75][C@:71]2([OH:98])[C:72]([CH3:74])([CH3:73])[C:60]=1[C@@H:61]([O:116][C:117]([CH3:119])=[O:118])[C:62]([C@@:64]1([CH3:115])[C@H:69]([C@@H:70]2[O:99][C:100]([C:102]2[CH:103]=[CH:104][CH:105]=[CH:106][CH:107]=2)=[O:101])[C@:68]2([O:110][C:111]([CH3:113])=[O:112])[CH2:108][O:109][C@@H:67]2[CH2:66][C@@H:65]1[OH:114])=[O:63].N12CCCN=C1CCCCC2>O1CCCC1>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:29][C:28]([NH:39][CH2:40][CH:41]([OH:57])[CH2:42][O:43][C:44]1[C:49]2[C:50]3[C:55]([NH:56][C:48]=2[CH:47]=[CH:46][CH:45]=1)=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[N+:37]=[N-:38])=[CH:32][CH:31]=1)[CH3:27].[CH3:58][C:59]1[C@@H:76]([O:77][C:78]([C@H:80]([OH:97])[C@@H:81]([NH:88][C:89]([C:91]2[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=2)=[O:90])[C:82]2[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=2)=[O:79])[CH2:75][C@:71]2([OH:98])[C:72]([CH3:73])([CH3:74])[C:60]=1[C@@H:61]([O:116][C:117]([CH3:119])=[O:118])[C:62]([C@@:64]1([CH3:115])[C@H:69]([C@@H:70]2[O:99][C:100]([C:102]2[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=2)=[O:101])[C@:68]2([O:110][C:111]([CH3:113])=[O:112])[CH2:108][O:109][C@@H:67]2[CH2:66][C@@H:65]1[OH:114])=[O:63]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: CC(C)(NCC(O)COc1cccc2[nH]c3ccccc3c12)c1ccc(N=[N+]=[N-])cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
8 (0.50 g, 0.37 mmol) was treated with 1% of 1,8-Diazabicyclo[5.4.0]undec-7-en (DBU) in Tetrahydrofuran (THF) (10 mL) for 45 seconds at room temperature and the product was precipitated by 1 M HCl in diethyl ether (500 mL). Then it was purified on a silica gel column using chloroform/methanol (7:1) to afford 9 (350 mg, 84%) as a white powder. ESI-MS (5 kV, MeOH): m/z (%)=1116.1 (100) [M+H]+; HPLC (230 nm): >95%.
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)(=[O:6])=[O:5])[CH3:2].[S-:21][C:22]#[N:23].[K+].BrBr.[ClH:27]>C(O)(=O)C.C(O)C>[ClH:27].[CH2:1]([NH:3][S:4]([CH2:7][CH2:8][N:9]1[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][C:11]=2[S:21][C:22]1=[NH:23])(=[O:5])=[O:6])[CH3:2]
Reactant: CCNS(=O)(=O)CCNc1ccc(OC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCNS(=O)(=O)CCn1c(=N)sc2cc(OC(F)(F)F)ccc21

Procedure:
The procedure is as in Example 3, starting with N-ethyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide (6.1 g), potassium thiocyanate (7.6 g) and bromine (3.6 g) in acetic acid (60 cc). After 18 hours at a temperature in the region of 20° C., neutralization with 30% strength sodium hydroxide and extraction with ethyl acetate, a crude product is obtained, which product is converted to a hydrochloride by adding 4.2N ethereal hydrogen chloride (5 cc) in ethanol (30 cc) and recrystallized in absolute ethanol (50 cc). N-Ethyl-2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanesulphonamide hydrochloride (3.0 g), m.p. 240° C., is thereby obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:18]([NH:26][C:27]1[CH:36]=[C:35](Br)[CH:34]=[CH:33][C:28]=1[C:29]([O:31]C)=[O:30])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C(=O)C>[C:18]([NH:26][C:27]1[CH:36]=[C:35]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:34]=[CH:33][C:28]=1[C:29]([OH:31])=[O:30])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)c1
Temperature: 90 °C
Reaction time: 11 h
Yield: 24.7 %

Procedure:
36 mg of 3-methoxyphenylboronic acid, 55 mg of sodium carbonate and 30 mg polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of methyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 11 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.2 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and one solvent was evaporated under reduced pressure, 1.0 mL of 1.0 mol/L aqueous sodium hydroxide and 2.0 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour. 0.6 mol/L hydrochloric acid was added to the reaction mixture and a solid substance was separated by filtration to obtain 18 mg of 2-(benzamido)-4-(3-methoxyphenyl)benzoic acid as white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:30])[C:11]3[C:16]4[N:17]=[C:18]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:19]=[C:20]([O:21][CH2:22][CH3:23])[C:15]=4[S:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH2:31]([O:35]C1C=CC(O)=CC=1)[CH2:32][CH2:33][CH3:34].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:31]([O:35][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:30])[C:11]3[C:16]4[N:17]=[C:18]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:19]=[C:20]([O:21][CH2:22][CH3:23])[C:15]=4[S:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(O)cc1
Reactant: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(Br)cc3)nc(C)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2nc(C)c3c(n2)sc2c(OCC)nc(N4CCNCC4)nc23)cc1
Temperature: 180 °C

Procedure:
100 mg (0.21 mmol) 7-(4-bromophenyl)-4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine, 51 mg (0.31 mmol) 4-n-butoxyphenol, 134 mg (0.41 mmol) Cs2CO3, 1 μl (5 mole %) ethyl acetate and 1.5 mg (5 mole %) CuBr were suspended in 5 ml absolute toluene and heated in a microwave oven at 180° C. for 17 h. Thereafter, the solvent was removed and the residue was purified by means of flash chromatography. 4 mg (3%) of the title substance is obtained. ESI-MS [m/z]: 571
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:22])=O)=[CH:17][CH:18]=3)[CH2:13][O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH2:40])[CH3:36].O>C1COCC1>[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH:40][C:20]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[C:11](=[C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]1=[O:1])[O:12][CH2:13]2)=[O:22])[CH3:36]
Reactant: O=C1Nc2ccccc2C1=C1OCc2cc(C(=O)O)ccc21
Reactant: CCN(CC)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
A mixture of 1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-carboxylic acid (100 mg, 0.34 mmol) and 1,1′-carbonyldiimidazole (100 mg, 0.62 mmol) in THF (10 ml) was stirred at room temperature for 16 hours. N,N-diethylethylenediamine (0.25 ml, 1.76 mmol) was added. The mixture was stirred for 15 minutes and poured into water (100 ml). The precipitates were filtered, washed with water and dried under vacuum to give the title compound as a yellow powder (99 mg, 74%).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:11])[CH2:4][CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:17]([S:31](Cl)(=[O:33])=[O:32])=[CH:16]2.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])[C:17]([S:31]([N:9]1[CH2:8][CH2:7][NH:6][CH:5]([CH2:4][CH:3]([CH3:11])[CH3:2])[CH2:10]1)(=[O:33])=[O:32])=[CH:16]2
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(C)CC1CNCCN1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a methylene chloride solution (150 ml) of 2-(2-methylpropyl)piperazine hydrochloride (1.50 g) were added 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (2.72 g) and triethylamine (2.91 ml). The resulting mixture was stirred at room temperature for 13 hours. Distilled water and methylene chloride were added and the water layer was extracted three times. The organic layers were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:20), whereby the title compound (2.69 g) was obtained as a brown oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:28])[N:14]([CH3:27])[N:15]=[C:16]([OH:26])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].[H-].[Na+].[CH3:31][O:32][CH2:33]Cl>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:28])[N:14]([CH3:27])[N:15]=[C:16]([O:26][CH2:31][O:32][CH3:33])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(O)nn(C)c1=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(OCOC)nn(C)c1=O
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-hydroxy-5-benzyloxy-2-methyl-3(2H)-pyridazinone (120 mg, 0.317 mmol) in dry DMF (2 ml) was added 60% sodium hydride (20 mg, 0.50 mmol) at 5° C. under nitrogen atmosphere. The mixture was stirred for 5 minutes, and then 80% chloromethyl methyl ether (0.04 ml, 0.47 mmol) was added. After ice-bath was removed, the mixture was stirred at room temperature for further 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic layer was washed with water 2 times, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 115 mg of Compound (I-7-1) as oil (yield: 85%).
Reaction SMILES: CC(C)([O-])C.[K+].CN(C=O)C.[N+:12]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C@H:21]([CH2:24][OH:25])[O:20][C:19]=2[CH:26]=1)([O-:14])=[O:13].ClC1C=CC(O[CH2:33][C:34]#[N:35])=CC=1>CC(OC)(C)C>[OH:25][CH2:24][C@H:21]1[CH2:22][O:23][C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[C:26]([CH2:33][C:34]#[N:35])[C:19]=2[O:20]1
Reactant: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CO)CO2
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: N#CCc1c([N+](=O)[O-])ccc2c1O[C@@H](CO)CO2
Yield: 60 %

Procedure:
A 5 L 3-necked flask equipped with a mechanical stirrer is charged with solid potassium t-butoxide (103.00 g, 0.918 mol) and DMF (1900 mL). The stirred solution is cooled until the internal temperature is 0° C., and a DMF (1100 mL) solution containing [(2S)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (47.33 g, 0.224 mol) and (4-chlorophenoxy)acetonitrile (39.05 g, 0.233 mol) is added over 45 min. The reaction is quenched with 1 N HCl (1 L) and the volatiles are removed by rotary evaporation (˜3 L removed). The residue is dissolved in water (2 L) and extracted with EtOAc (3×600 mL). The combined extracts are washed with water (2×300 mL), 1 N NaOH (3×400 mL) and brine (300 mL), and evaporated to give an orange/brown solid. The solid is suspended with stirring in MTBE (300 mL) for 30 min. The solid is collected by vacuum filtration, washed with MTBE (50 mL) and then suction dried giving the title compound (33.60 g, 60%) as a tan solid. LCMS (Standard Method): 2.14 min, 251 (M+H)+. 1H NMR (300 MHz, CDCl2) δ 7.77 (d, J=9.2 Hz, 1H), 7.00 (d, J=9.2 Hz, 1H), 4.48-4.37 (m, 2H). 4.28-3.91 (series of m, 5H), 2.32 (br s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH3:6])[CH2:3][CH2:2]1.FC(F)(F)S([O-])(=O)=O.[N:15]1([S:20](N2C=C[NH+](C)C2)(=[O:22])=[O:21])[CH:19]=[CH:18][N:17]=[CH:16]1>>[CH:1]1([CH2:4][N:5]([CH3:6])[S:20]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)(=[O:22])=[O:21])[CH2:3][CH2:2]1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Reactant: CNCC1CC1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(CC1CC1)S(=O)(=O)n1ccnc1

Procedure:
Imidazole-1-sulfonic acid cyclopropylmethyl-methyl-amide was prepared in accordance with step A of the general method described in example 76 from cyclopropylmethyl-methylamine and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=216.5 (M+H+).