Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(S(N[C:9](=O)[C:10]2[CH:15]=C(Cl)C(OCC3(C(F)(F)F)CCCC3)=CC=2F)(=O)=O)CCC1.Cl[C:31]1[C:32]([O:45][CH2:46][C:47]2([C:50]([F:53])([F:52])[F:51])[CH2:49][CH2:48]2)=[CH:33][C:34]([F:44])=[C:35]([CH:43]=1)[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37]>>[CH:15]1([C:31]2[C:32]([O:45][CH2:46][C:47]3([C:50]([F:53])([F:52])[F:51])[CH2:49][CH2:48]3)=[CH:33][C:34]([F:44])=[C:35]([CH:43]=2)[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37])[CH2:10][CH2:9]1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CC2)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CC2)cc1F
Yield: 19 %

Procedure:
Following the procedure as described in Example 165 and making variations as required to replace N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclopentyl)-methoxy)benzamide with 5-chloro-2-fluoro-N-(methylsulfonyl)-4-((1-(trifluoromethyl)-cyclopropyl)-methoxy)benzamide. Purification by reverse-phase preparative HPLC to yield the title compound (0.047 g, 19%): 1H NMR (300 MHz, DMSO-d6) 11.94 (br s, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.96 (d, J=12.9 Hz, 1H), 4.23 (s, 2H), 3.31 (s, 3H), 2.09-2.00 (m, 1H), 1.16-1.11 (m, 2H), 1.07-1.02 (m, 2H), 0.93-0.86 (m, 2H), 0.72-0.66 (m, 2H); MS (ES−) m/z 394.1 (M−1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([OH:13])[CH2:11][Cl:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Si:1]([O:8][CH2:9][CH:10]([O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH2:11][Cl:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](O)CCl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(CCl)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
(R)-(−)-1-(tert-Butyldimethylsilanyloxy)-3-chloropropan-2-ol (11.19 g) prepared in reference example 31 was dissolved in dichloromethane (20 ml), then 3,4-dihydro-2H-pyran (5.87 ml) and pyridinium p-toluenesulfonate (catalytic amount) were added, then the reaction mixture was stirred at a room temperature overnight. The reaction mixture was concentrated under a reduced pressure, the residue was purified by use of a silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1), there was obtained 1-(t-butyldimethylsilanyloxy)-3-chloro-2-(tetrahydropyran-2-yloxy)propane (14.14 g, yield: 92.0%) as colorless liquid product.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.[C:18](ON1C(=O)CCC1=O)(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(O)(=O)C>O>[C:18]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCCC[C@H](N)C(=O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Reaction time: 4 h
Yield: 86 %

Procedure:
To the solution of L-lysine (1 mmol) in water (2 ml) and triethylamine (0.27 ml, 2 mmol) 1 mmol of succinimidyl palmitate (suspended in 2 ml of acetone) was added at room temperature under stirring. Stirring of the reaction mixture was continued for 4h. Triethylamine was removed under reduced pressure, the precipitate was collected by filtration, washed with water and ethanol, crystallized from glacial acetic acid giving an 86% yield of the title compound. Analysis data are given in Table 2.
Reaction SMILES: N=C=N.C1C=CC2N(O)N=NC=2C=1.[Cl:14][C:15]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O.[NH2:25][CH2:26][C:27]1[C:28](=[N:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=2)[C:29]([NH2:32])=[N:30][N:31]=1>C(Cl)Cl.CN(C=O)C>[NH2:32][C:29]1[C:28](=[N:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=2)[C:27]([CH2:26][NH:25][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][C:22]([CH3:24])=[N:23][C:15]=2[Cl:14])=[N:31][N:30]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: NCC1=NN=C(N)C1=NNc1ccc(F)c(F)c1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC2=NN=C(N)C2=NNc2ccc(F)c(F)c2)c(Cl)n1
Reaction time: 16 h

Procedure:
To a 10 mL reaction vessel containing PS-carbodiimide (2 eq, 175 mg) and HOBt (1.7 eq, 20 mg) was added a solution of 2-chloro-6-methylnicotinic acid (1.5 eq, 0.12 mmol) in anhydrous CH2Cl2 (2 mL) and anhydrous DMF (0.2 mL). The reaction mixture was stirred at ambient temperature under argon for 30 minutes before a solution of 5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (20 mg, 0.079 mmol) in anhydrous DCM (3 mL) and anhydrous DMF (0.7 mL) was added. The reaction mixture was further stirred for approximately 16 hours before it was filtered, washed with DCM (3×3 mL) and concentrated under reduced pressure. The title compound was obtained as a yellow powder (yield 26%). MS (m/z, ES+): 406 (Cl35M+1, 20%), 408 (Cl37M+1, 10%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[C:34]([NH:33][CH:30]1[CH2:31][CH2:32][N:27]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:25])[C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:28][CH2:29]1)(=[O:36])[CH3:35]
Reactant: Cc1cc2nc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc(Cl)n2n1
Reactant: CC(=O)NC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: CC(=O)NC1CCN(c2cc(NC(=O)c3ccc(OC(F)(F)F)cc3)nc3cc(C)nn23)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
An orange solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(trifluoromethoxy)benzamide (14A, 69 mg, 0.186 mmol), N-(piperidin-4-yl)acetamide hydrochloride (40 mg, 0.279 mmol), and N,N-diisopropylethylamine (96 mg, 0.745 mmol) in DMF (1.8 mL) was stirred at 100° C. for 2 h, cooled to 80° C., and stirred overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, filtered, and then purified by preparatory HPLC (50-70% (1:1 MeOH/MeCN)/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (31.3 mg, 35%). 1H NMR (DMSO-d6) δ: 10.99 (s, 1H), 8.05-8.12 (m, 2H), 7.85 (d, J=7.6 Hz, 1H), 7.44 (dd, J=9.1, 1.0 Hz, 2H), 7.26 (s, 1H), 6.09 (d, J=0.5 Hz, 1H), 4.28 (d, J=12.4 Hz, 2H), 3.72-3.94 (m, 1H), 3.14 (t, J=11.0 Hz, 2H), 2.31 (s, 3H), 1.84 (dd, J=13.1, 3.0 Hz, 2H), 1.75 (s, 3H), 1.41-1.58 (m, 2H); ESI-MS: m/z 477.3 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[N:14]=[CH:13][NH:12][C:11]=2[CH:10]=1>>[CH:1]1([CH2:4][O:5][C:9]2[CH:18]=[N:17][C:16]3[C:15](=[O:19])[N:14]=[CH:13][NH:12][C:11]=3[CH:10]=2)[CH2:3][CH2:2]1
Reactant: O=c1nc[nH]c2cc(Cl)cnc12
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Product: O=c1nc[nH]c2cc(OCC3CC3)cnc12
Temperature: 25 °C
Yield: 11.9 %

Procedure:
To a glass microwave reaction vessel (2-5 ml) were charged with cyclopropylmethanol (3.1 ml, 38.6 mmol) and sodium hydride (60% dispersion in mineral oil) (416 mg, 17.35 mmol). The reaction mixture was stirred at RT for several min. Finally 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (350 mg, 1.928 mmol) (from intermediate 11, step 1 & 2) was added, and the mixture was heated in a Initiator microwave reactor at 140° C. for 10 min. Then it was quenched with water and sat. NH4Cl and extracted with EtOAc for five times. The organic extract was washed with brine and dried over MgSO4. The solution was filtered and concentrated to give the crude material as a mixture. It was washed with Et2O and the brown solid was collected by filtration to yield 7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4(1H)-one (50 mg, 0.230 mmol, 12% yield) as brown solid which was used for next step directly. MS m/z=218.1 (M+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: CCOC(=O)C(Br)CC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1ccccc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Phenol (28.5 g, 0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromobutyrate (0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:22][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([OH:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:30][C:26]3[C:27]([CH3:29])=[N:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)ccc1O
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)ccc1Oc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Temperature: 150 °C
Yield: 70.8 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.03 g, 3.27 mmol), 6-chloro-2-methyl-pyridin-3-ol (470 mg, 3.27 mmol), and potassium carbonate (903 mg, 6.53 mmol) in 15 mL DMF were heated in microwave for 1 hour at 150° C. The mixture was purified to give Compound C65 as a white solid (0.975 g, 71%). 1H NMR (CDCl3, 400 MHz) δ 0.92-0.94 (d, 6H), 1.74-1.82 (m, 2H), 1.95-2.02 (m, 2H), 2.19 (s, 3H), 2.47 (s, 3H), 3.39-3.45 (m, 2H), 3.74-3.79 (m, 2H), 4.91-4.97 (m, 1H), 5.33-5.36 (m, 1H), 7.21-7.23 (d, 1H), 7.36-7.38 (d, 1H), 8.19 (s, 1H). Exact mass calculated for C20H25ClN4O4 420.16, found 421.3 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]3[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]3)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:31]([O:30][C@@H:3]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]3[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]3)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:10][CH:11]=1)[CH2:2][Cl:1])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OC[C@H](COc2ccc(C(C)(C)c3ccc(OC[C@H](O)CCl)cc3)cc2)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H](CCl)COc1ccc(C(C)(C)c2ccc(OC[C@H]3COC(C)(C)O3)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of (S)-1-chloro-3-(4-(2-(4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (850 mg, 1.95 mmol) in anhydrous pyridine (6.0 mL) were successively added acetic anhydride (280 μL, 2.93 mmol) and catalytic amount of DMAP. After 3 h, the reaction mixture was quenched with an aqueous solution of sodium chloride and stirred for 15 min, and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and filtered. Solvents were evaporated, and the resulting crude material was used without further purification.
Reaction SMILES: [N:1]([CH:4]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:49][CH:48]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[NH2:1][CH:4]([C:47]1[CH:48]=[CH:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:51][CH:52]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(N=[N+]=[N-])c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(N)c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 62.2 %

Procedure:
To azido-bis[4-(12-docosoxydodecyloxy)phenyl]methane (72.0 mg, 58.7 μmol) were added toluene (2 ml), purified water (2 ml), and triphenylphosphine (29 mg, 110 μmol), and the mixture was vigorously stirred at 45° C. for 3 hours and 60° C. for 3.5 hours. The reaction mixture was cooled to room temperature, and 10% aqueous sodium hydrogen carbonate (2 ml) was added. After stirring for a while, toluene (8 ml) was added and the aqueous layer was discarded. The organic layer was washed with purified water (10 ml)×2. The organic layer was evaporated under reduced pressure, and the residue was crystallized from acetonitrile, and the obtained crystals were washed with purified water to give amino-bis[4-(12-docosoxydodecyloxy)phenyl]methane (44 mg, 36.5 μmol, 62%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu]>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 160 °C

Procedure:
A mixture of p-bromoacetophenone (3.98 g, 20 mmol), benzimidazole (4.72 g, 40 mmol), copper bronze (1.27 g, 20 mmol), anhydrous potassium carbonate (5.52 g, 40 mmol) and cuprous bromide (290 mg, 2 mmol) in dry N-methylpyrrolidinone (60 ml) was heated under nitrogen at 160° C. for 8 hours. Most of the solvent was removed by distillation under reduced pressure and the residue was diluted with dichloromethane (500 ml) and 2N sodium hydroxide (200 ml). The organic layer was washed with water (300 ml), dried (MgSO4) and concentrated to give a dark brown oil. Purification by flash chromatography (eluting with ethyl acetate gave 4'-(1-benzimidazolyl)acetophenone, 3.085 g as a pale yellow solid, m.p. 133°-135° C.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][N:25]=[C:24]([CH3:27])[C:23]=4[C:28]([O:30]C)=[O:29])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])C.[OH-].[Na+].[CH2:34]1COCC1>C(O)C.O>[CH2:1]([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][N:25]=[C:24]([CH3:27])[C:23]=4[C:28]([OH:30])=[O:29])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)=[O:6])[CH2:3][CH3:34]
Reactant: C1CCOC1
Reactant: COC(=O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OC(C)C)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the methyl ester from Step 5 (5.2 g, 12.4 mmol) in THF (100 mL) and ethanol (20 mL) was added a solution of sodium hydroxide (1.5 g, 37.2 mmol) in water (40 mL). The solution was stirred at room temperature 3 hours. ˜50 mL solvent evaporated and 200 mL water added. The product was precipitated out of solution with dilute hydrochloric acid to pH 2. The product was isolated by filtration to yield 4.6 grams of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][C:3]=1[CH3:22].[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:15])=[CH:4][C:3]=1[CH3:22]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: COCCOc1ncc(C(=O)O)cc1-c1ccc(Cl)c(C)c1
Product: COCCOc1ncc(C(=O)NCc2nc(C(F)(F)F)no2)cc1-c1ccc(Cl)c(C)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-methylphenyl)-6-(2-methoxyethoxy)nicotinic acid (example CG) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 469.0893 (M−H)−.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:12])[CH3:11])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:23]1[CH:24]=[C:25]([CH2:32][OH:33])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30]>C(#N)C>[OH:33][CH2:32][C:25]1[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([NH:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:12])[CH3:11])[CH2:7][CH2:8]2)[CH:24]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Reactant: CC(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CC[C@H](Nc2cc(CO)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(trans-4-aminocyclohexyl)acetamide hydrochloride (200 mg, 1.038 mmol) and DIPEA (0.494 mL, 2.83 mmol) in ACN (2 mL) was added (3-fluoro-4-nitrophenyl)methanol (161 mg, 0.944 mmol). The resulting mixture was stirred overnight at 80° C. After 16 hours, the reaction was concentrated and the residue purified by column chromatography, eluting with 0-10% MeOH in DCM, to provide N-(trans-4-(5-(hydroxymethyl)-2-nitrophenylamino)cyclohexyl)acetamide as a yellow powder (50 mg, 17.24% yield). MS, m/z (C15H21N3O4): calcd, 307.2. found, 308.1 [M+H].
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.6 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic-acid tert-butylamide (0.44 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (MeOH, dichloromethane) yielded the title compound as a white solid (0.11 g, 21%). MS (ISP) 532.0 [(M+H)+]; mp 262.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[CH2:35][O:36][CH3:37])[NH:29][C:28](=[O:39])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[CH2:35][O:36][CH3:37])[NH:29][C:28](=[O:39])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Product: COCC(=O)Nc1cc2c(cc1F)/C(=C/c1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CCC3)C(=O)N2
Yield: 60 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a obtained from step 1 of Example 7 as starting materials to obtain (Z)—N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 18 (47 mg, yield 60%) as a yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].O[C:35]1[CH:36]=[CH:37][C:38]2[CH2:44][CH2:43][CH2:42][C:41]([C:45]([O:47][CH3:48])=[O:46])=[CH:40][C:39]=2[CH:49]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:35]2[CH:36]=[CH:37][C:38]3[CH2:44][CH2:43][CH2:42][C:41]([C:45]([O:47][CH3:48])=[O:46])=[CH:40][C:39]=3[CH:49]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc2CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.4 %

Procedure:
To triphenylphosphine (2361 mg, 9.00 mmol), 1-tert-butoxycarbonyl-4-hydroxypiperidine (1812 mg, 9.00 mmol) and methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (655 mg, 3.00 mmol) dissolved in THF (15 ml) was added at 0° C. a solution of diisopropyl azodicarboxylate (1.772 ml, 9.00 mmol) in THF (2 ml), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography (silica gel: 70 g, ethyl acetate/hexane=1/9→1/7). The objective fractions were concentrated under reduced pressure to obtain methyl 2-[(1-tert-butoxycarbonylpiperidin-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (1270 mg).