Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].Cl.[CH3:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][C:3]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[CH3:7])[CH2:12][CH2:13]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)CCN1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CCN1CCN(C(=O)CBr)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 13.3 %

Procedure:
Bromoacetyl bromide (0.52 ml, 6.0 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperazine hydro-chloride from Example E4 (1.5 g, 5.7 mmol) in dichloromethane (20 ml) and triethylamine (3.57 ml, 25.6 mmol) at 0° C. The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (220 mg, 13%).
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([OH:20])[CH:18]=[CH2:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:24][C:25]1([CH3:35])[CH:27]([CH:28]=[C:29]([Cl:31])[Cl:30])[CH:26]1[C:32](Cl)=[O:33]>C1C=CC=CC=1>[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([O:20][C:32]([CH:26]1[CH:27]([CH:28]=[C:29]([Cl:30])[Cl:31])[C:25]1([CH3:35])[CH3:24])=[O:33])[CH:18]=[CH2:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C=CC(OC(=O)C1C(C=C(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g of pyridine in 10 ml of benzene is added dropwise at 5° C. to a solution of 8 g of 3-phenoxy-α-vinyl-benzyl alcohol in 30 ml of benzene, and at 10° C. is subsequently added 8 g of 2,2-dimethyl-3-(dichlorovinyl)-cyclopropanecarboxylic acid chloride. The reaction mixture is stirred for two hours at room temperature and is then allowed to stand for 12 hours. In further processing, the reaction mixture is diluted with ice water, the organic phase is extracted 3 times with 100 ml of 3% HCl solution each time and 3 times with 100 ml of 3% sodium bicarbonate solution each time; it is dried over sodium sulfate, and the benzene is distilled off. There is obtained the compound of the formula ##STR7## as colourless oil have a refractive index of nD40 =1.5710. (isomeric mixture 40% cis and 60% trans compound)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:30])[CH2:17][CH2:16][C:15]([CH2:28][NH2:29])([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[F:30][C:12]1([F:11])[CH2:13][CH2:14][C:15]([CH2:28][NH:29][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=2)[CH2:16][CH2:17]1
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=413.2, tR (minutes, Method D)=0.74
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[N:23][N:22]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:26]([C:24]1[S:25][C:21]([C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[Cl:13])=[N:22][N:23]=1)(=[O:28])=[O:27])[CH3:4]
Reactant: O=S(=O)(Cl)c1nnc(-c2cc(Cl)ccc2Cl)s1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2cc(Cl)ccc2Cl)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(2,5-Dichlorophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 8.27 (s, 1H), 7.80 (d, 1H), 7.75 (d, 1H), 4.03 (q, 2H), 3.35 (s, 2H), 3.21 (t, 2H), 2.71 (t, 2H), 1.15 (t, 3H).
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[C:15]([OH:16])=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=1)=O>CO>[OH:16][C:15]1[C:6]([C:4]([NH2:1])=[O:3])=[CH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: N
Reactant: COC(=O)c1cc2c(cc1O)CCCC2
Solvent: CO
Product: NC(=O)c1cc2c(cc1O)CCCC2
Temperature: 100 °C

Procedure:
To 300 ml of methanol saturated with ammonia gas at 0° C. was added 122 g of 3-hydroxy-5,6,7,8-tetrahydro-2-naphthoic acid methyl ester, and the mixture was maintained in an autoclave at 100° C. for 5 hours. After cooling, the precipitating solid was filtered off, washed with a small amount of methanol, and dried, giving 96 g of a pale yellow crystal having the following physical properties.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:24])[C:10]([S:22][CH3:23])=[CH:11][CH:12]=[C:13](N(C)C)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.C([OH:28])C>>[OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:24])[C:10]([S:22][CH3:23])=[CH:11][CH:12]=[C:13]([OH:28])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCO
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(O)c(O)c1)N(C)C
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SC)C(=O)c1ccc(O)c(O)c1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
The procedure is as in Example 4, starting with ethyl 6-(3,4-dihydroxyphenyl)-2-dimethylamino-5-methylthio-6-oxo-2,4-hexadienoate (1.9 g) and 1N aqueous hydrochloric acid solution (10.8 cc) in ethanol (10.8 cc). The mixture is heated to boiling for 5 minutes, and then cooled to a temperature in the region of 20° C. After purification by crystallization in isopropyl ether (100 cc), ethyl 6-(3,4-dihydroxyphenyl)-2-hydroxy-5-methylthio-6-oxo-2,4-hexadienoate (0.6 g), m.p. 156° C., is obtained.
Reaction SMILES: [OH:1][C:2]1([CH2:10][NH2:11])[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[NH2:12][C:13]1[C:21]([Cl:22])=[CH:20][C:16]([C:17](N)=[O:18])=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([I:31])[CH:26]=2)[CH:14]=1>>[NH2:12][C:13]1[C:21]([Cl:22])=[CH:20][C:16]([C:17]([NH:11][CH2:10][C:2]2([OH:1])[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[O:18])=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([I:31])[CH:26]=2)[CH:14]=1
Reactant: NC(=O)c1cc(Cl)c(N)cc1OCc1cccc(I)c1
Reactant: NCC1(O)CN2CCC1CC2
Product: Nc1cc(OCc2cccc(I)c2)c(C(=O)NCC2(O)CN3CCC2CC3)cc1Cl

Procedure:
Following the procedure of Example 2, the title compound is prepared from 3-hydroxy-1-azabicyclo[2.2.2]oct-3-ylmethanamine and 4-amino-5-chloro-2-[(3-iodophenyl)methoxy]benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][CH2:34][O:35][CH3:36])[CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][O:35][CH3:36])[CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: COCCn1cc(C(=O)Oc2ccccc2)cn1
Product: COCCn1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1-(2-methoxy-ethyl)-1H-pyrazole-4-carboxylic acid phenyl ester, the title compound was obtained as light yellow crystals 43% yield). MS: m/e=418(M+H+), mp 191-193° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].N1C2C(=CC=CC=2)[CH:17]=N1.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: c1ccc2[nH]ncc2c1
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylic acid, [Marfat, A., et al., “Indazole Derivatives and Their Use as Inhibitors of Phosphodiesterase Type IV and the Production of Tumor Necrosis Factor TNF, U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2Cl2 was added 1.5 g (7.8 mmol) of EDCl—nHCl. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 mL of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. 1H-NMR (CDCl3) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73 (apparent q, 9.0 Hz, 2H), 3.94 (s, 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl[C:6]1[N:7]=[C:8]([NH:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2[S:14][CH:13]=[C:12]([CH3:15])[C:10]=2[N:11]=1>O>[CH2:1]([NH:4][C:6]1[N:7]=[C:8]([NH:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2[S:14][CH:13]=[C:12]([CH3:15])[C:10]=2[N:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: Cc1csc2c(NCC(C)(C)C)nc(Cl)nc12
Solvent: O
Product: C=CCNc1nc(NCC(C)(C)C)c2scc(C)c2n1
Temperature: 140 °C
Yield: 63.1 %

Procedure:
In 2.28 g (40.0 mmol) of allylamine was dissolved 250 mg (0.9 mmol) of 2-chloro-7-methyl-4-neopentylaminothieno[3,2-d]pyrimidine, and the resulting solution was heated in a sealed tube at 140° C. for 24 hours. After the reaction mixture was cooled, 100 ml of water was added thereto, followed by extraction with ethyl acetate (20 ml×3). The organic layer was washed with 20 ml of water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane=1/4) to give 165 mg (yield: 61.3%) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:20]#[N:21])=[CH:15][CH:14]=1.C1C[O:30]CC1.C(=O)(O)[O-].[Na+]>Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:20]([NH2:21])=[O:30])=[CH:17][CH:18]=1
Reactant: C1CCOC1
Reactant: N#CC(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: NC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2 g (5.8 mmol) of the compound from Example II are suspended in 6 ml of concentrated hydrochloric acid, and the suspension is stirred at 40° C. overnight. After cooling to room temperature, THF is added until solution is complete, and the solution is neutralised with sodium bicarbonate solution. The organic phase is separated off, dried with sodium sulphate and concentrated to a small volume in vacuo. Separation is carried out by column chromatography (silica gel 60, mobile phase: dichloromethane/ethyl acetate/glacial acetic acid 80/15/15).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1.[F:17][C:18]([F:27])([F:26])C1C=C(O)C=CC=1>>[F:17][C:18]([F:27])([F:26])[C:4]1[CH:3]=[CH:14][C:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2o1
Product: O=C(O)c1cc2ccc(C(F)(F)F)cc2o1

Procedure:
93 mg of 6-(trifluoromethyl)benzofuran-2-carboxylic acid were prepared as described for 5-(trifluoromethyl)benzofuran-2-carboxylic acid, using 3-(trifluoromethyl)phenol instead of 4-(trifluoromethyl)phenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: NC(=O)c1ccc(Br)cn1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3ccc(C(N)=O)nc3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
5-methoxybenzofuran boronic acid (1.2 mmol), 5-bromopyridine-2-carboxamide (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 μL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor, filtered, and the precipitate was washed with water and EtOAc and dried under vacuum to afford the title compound (75 mg). 1H NMR δ ppm 9.10 (d, 1 H) 8.34 (dd, 1 H) 8.21 (br. s., 1 H) 8.00 (d, 1 H) 7.52-7.72 (m, 3 H) 7.25 (d, 1 H) 7.00 (dd, 1 H) 3.82 (s, 3H); MS m/z 269 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:60](O)(=[O:63])[CH2:61][OH:62]>C(Cl)Cl>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:61](=[O:62])[CH2:60][OH:63])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: O=C(O)CO
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)CO)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (0.010 g, 0.024 mmol), DIPEA (0.00918 g, 0.071 mmol), TBTU (0.0228 g, 0.071 mmol) in DCM (2 mL) was added Glycolic acid (0.00360 g, 0.0474 mmol) at 0° C. The mixture was stirred for 1 h. The reaction mixture was directly loaded onto Prep TLC for purification (silica gel, eluting with 4% MeOH in DCM) to afford the title compound as a yellow solid. 1H-NMR (CD3OD, 400 MHz): δ=1.88 (d, J=6.8 Hz, 3H), 2.53 (d, J=17.2 Hz, 2H), 3.63 (t, J=5.8 Hz, 1H), 3.83 (t, J=5.8 Hz, 1H), 4.12 (d, J=2.0 Hz, 1H), 4.26 (s, 2H), 4.30 (s, 1H), 6.29 (d, 1H), 6.49 (q, J=6.7 Hz, 1H), 7.15-7.25 (m, 1H), 7.39 (dd, J=9.0, 4.9 Hz, 1H), 7.64 (d, J=10.4 Hz, 1H), 8.20 (s, 1H). MS (ES+): m/z 480.01 (MH+, 35Cl, 37Cl), 481.96 (MH+, 37Cl, 37Cl). HPLC: tR=2.76 min (polar—5 min, ZQ3).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:38])[CH:10]([O:14][C:15]1[CH:37]=[CH:36][C:18]2[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]=2[CH:16]=1)[CH:22]=[C:21]([C:27]1[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=1)[N:20]=3)[CH2:11][CH2:12]Br>C1COCC1.O>[CH3:7][O:8][C:9]([C:10]1([O:14][C:15]2[CH:37]=[CH:36][C:18]3[C:19]4[N:23]([CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH:22]=[C:21]([C:27]2[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=2)[N:20]=4)[CH2:12][CH2:11]1)=[O:38]
Reactant: COC(=O)C(CCBr)Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(Oc2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
Potassium tertbutoxide (611 mg, 5.45 mmol) was added to a solution of 4-bromo-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]butyric acid methyl ester (2.5 g, 4.96 mmol) in THF (20 mL) and the mixture was stirred at RT for 30 min. The crude reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, then dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-7% MeOH in DCM) affording 1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropanecarboxylic acid methyl ester (1.4 g, 67%). 1H NMR (CDCl3, 400 MHz): δ 8.42 (1H, d, J=8.98 Hz), 7.56 (1H, s), 6.75 (1H, dd, J=8.97, 2.58 Hz), 6.58 (1H, d, J=2.55 Hz), 5.97-5.82 (1H, m), 4.50-4.35 (4H, m), 3.74 (3H, s), 2.40 (3H, s), 1.67-1.60 (2H, m), 1.55 (6H, d, J=6.52 Hz), 1.38-1.31 (2H, m)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18](Br)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>>[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1cn(Cc2ccc(-c3ccsc3)nc2)cn1

Procedure:
Synthesized using 3-thiophenylboronic acid (206 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Brown solid. Yield: 144 mg, 0.61 mmol, 73%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.15 (s, 2H), 6.91 (t, J=1.3 Hz, 1H), 7.12 (s, 1H), 7.40 (dd, J=5.0, 3.2 Hz, 1H), 7.45 (dd, J=8.2, 2.2 Hz, 1H), 7.58 (s, 1H), 7.60 (dd, J=8.2, 0.6 Hz, 1H), 7.64 (dd, J=5.0, 1.3 Hz, 1H), 7.91 (dd, J=3.2, 1.3 Hz, 1H), 8.51 (dd, J=2.2, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 119.0, 120.3, 124.4, 126.1, 126.5, 129.6, 130.3, 135.7, 137.3, 141.4, 148.6, 153.8; MS (ESI): m/z=242.03 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[Mg]Br.Br[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([CH3:20])[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Pd](Cl)Cl>[CH3:20][C:14]1[CH:13]=[C:12]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: Cc1ccc(C)c([Mg]Br)c1
Reactant: Cc1cc(Br)ccc1C#N
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C)c(-c2ccc(C#N)c(C)c2)c1
Yield: 90 %

Procedure:
2,5-dimethylphenylmagnesium bromide (84 g, 20% solution in tetrahydrofuran) is added dropwise over five hours to a refluxing solution of 4-bromo-2-methylbenzonitrile (16 g), palladium (II) chloride (0.57 g) and triphenylphosphine (1.7 g) in tetrahydrofuran (100 ml). [HPLC: yield 90-95%]. After cooling to room temperature tetrahydrofuran is removed under vacuum. The residue is taken up in toluene/water (1:1) (200 ml) and filtered. The aqueous phase is separated off, and the solvent removed by distillation. The crude product is recrystallised from ethanol to give 3,2',5'-trimethylbiphenyl-4-carbonitrile as a solid, m.pt. 96-97° C. 1H NMR (CDCl3): 2.19(s,3H), 2.34(s,3H), 2.58(s,3H), 6.99(s,1H), 7.08-7.25(m,3H), 7.62(d,1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1cc2c(cc1O)CCC2
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4c(cc3C(C)=O)CCC4)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
1-(6-Hydroxyindan-5-yl)-ethanone (275 mg), 4-chloro-6,7-dimethoxyquinoline (173 mg), and 4-dimethylaminopyridine (286 mg) were suspended in o-dichlorobenzene (5 ml) to prepare a suspension which was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (37 mg, yield 13%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](S)=[CH:9][C:8]=1[CH3:14])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[C:23](C)(C)[C:24](OCC)=[O:25]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:24](=[O:25])[CH3:23])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(C)=O)cc1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 159 %

Procedure:
To intermediate 4 (710 mg, 1.81 mmol) in DMF (50 mL) was added the K2CO3 (275 mg, 1.99 mmol) followed by the ethyl 2-bromo-2-methylpropanate (280 μL, 1.91 mmol; Aldrich) and the reaction heated to 80° C. After 18 h, the reaction cooled to rt and the solvent removed in vacuo. The residue treated with water (200 mL), extracted 3×50 mL CH2Cl2, dried over Na2SO4, filtered and the solvent removed under vaccum. The residue was chromatographed (CH2Cl2/MeOH: 99/1). To afford 680 mg (77%) of Intermediate 5 as a clear oil. 1H NMR(CDCl3): δ 7.95 (d, 2H), 7.60 (d, 2H), 7.15 (d, 2H), 6.75 (d, 2H), 6.05 (t, 1H), 4.45 (d, 2H), 4.15 (q, 2H), 2.65 (s, 3H), 1.50 (s, 6H), 1.20 (t, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: C1COCCN1
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
3-Fluoronitrobenzene (10 g, 71 mmol) was dissolved in acetonitrile (100 mL). Morpholine (30 mL, 350 mmol) was added and the mixture was reacted 18 h at 150° C./80 psi in a pressure reactor. The reaction was cooled to room temperature, concentrated under vacuum and 5 g of the total mixture was purified by column chromatography on silica eluted with CH2Cl2. The product (3.6 g) was isolated as a bright yellow oil.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[S:29][C:28]=2[C:38]([O:40][CH3:41])=[O:39])[C:18]([CH:20]2[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(OCC)(=O)C>[Pd].CO>[CH3:41][O:40][C:38]([C:28]1[S:29][C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:31][C:27]=1[N:17]([C:18]([CH:20]1[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:39]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
To a solution of 4-[(2-Methoxycarbonyl-5-phenyl-thiophen-3-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-piperidine-1-carboxylic acid benzyl ester (506 mg, 0.88 mmol) in a 6:1 mixture of ethyl acetate and methanol (7 ml) was added the 10% palladium on charcoal (103 mg, 0.097 mmol). The resulting reaction mixture was placed under H2 atmosphere (25 psi), stirred at room temperature for 3 days, and then filtered on celite and evaporated to dryness. The crude product was purified by flash chromatography (100/90/16/1 CH2Cl2/CHCl3/MeOH/Et3N) to give 287 mg (74%) of 3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.