Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:30][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:6]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:5][N:4]=2)=[CH:27][CH:26]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1
Reactant: OCc1ccc(F)cc1
Product: Fc1ccc(COc2ncc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)n2)cc1

Procedure:
2-Methylthio-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 4-fluorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(4-fluorobenzyloxy)-4-(4-chloro-phenyl)-5-(2,4-dichlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=459 (M+30 1); Rt=4.80 min; 1H-NMR 500 MHz (CDCl3): δ 5.58 (s, 2H), 7.05-7.15 (m, 3H), 7.23-7.30 (m, 3H), 7.39 (d, J=9 Hz, 2H), 7.41-7.49 (m, 1H), 7.50-7.58 (m, 2H), 8.48 (s, 1H).
Reaction SMILES: [C:1]([N:4]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18](Br)=[CH:19][C:20]([CH3:22])=[CH:21][C:6]1=2)(=[O:3])[CH3:2].[C:39]([N:42](CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)[CH:43]1CCCN(C(OC(C)C)=O)C2C=C(Cl)C(N(C)C)=CC1=2)(=O)C>>[C:1]([N:4]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18]([N:42]([CH3:43])[CH3:39])=[CH:19][C:20]([CH3:22])=[CH:21][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(N(C)C)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Br)cc(C)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1cc(C)cc2N(C)C

Procedure:
This compound prepared utilizing the same methodology described in Example 51 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl 5-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-9-bromo-7-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylate following the procedure of Example 51 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-chloro-7-dimethylamino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. CI MS 574 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[C:17]3[C:12](=[C:13]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-4-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 486.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([OH:10])=O)=[C:3]1[CH3:11].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C(=O)C.O>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:4]5[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[C:3]=5[CH3:11])=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Cc1cc(C(=O)O)c(C)n1C
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(C)n(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
To a solution of 1,2,5-trimethylpyrrole-3-carboxylic acid (142 mg, 0.93 mmol) in tetrahydrofuran (4.0 mL) were added N,N-dimethylformamide (20 μL, 0.26 mmol) and oxalyl chloride (108 μL, 1.24 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and triethylamine (259 μL, 1.86 mmol) in N,N-dimethylacetamide (4.0 mL), and the mixture was stirred at 50° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3→ethyl acetate alone), washed with hexane/ethyl acetate and filtrated to give the title compound (68 mg, 24%) as a white powder.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3([C:25]([OH:27])=O)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:15]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH:43]1[CH2:47][CH2:46][C:45]2([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=3[C:49](=[O:56])[O:48]2)[CH2:44]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3([C:25]([N:43]4[CH2:47][CH2:46][C@@:45]5([C:51]6[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=6[C:49](=[O:56])[O:48]5)[CH2:44]4)=[O:27])[CH2:23][CH2:24]3)=[CH:20][CH:21]=2)[N:15]=1
Reactant: O=C1OC2(CCNC2)c2ccccc21
Reactant: Nc1nc(-c2ccc(C3(C(=O)O)CC3)cc2)cs1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)cs1
Reaction time: 5 h

Procedure:
N,N-Diisopropylethylamine (50 μL, 0.3 mmol) was added to a mixture of 1-[4-(2-amino-1,3-thiazol-4-yl)phenyl]cyclopropanecarboxylic acid (26.0 mg, 0.1 mmol), (1S)-(+)-10-camphorsulfonic acid-3H-spiro-[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (42.1 mg, 0.01 mmol) and BOP (57.0 mg, 0.13 mmol) in DMF (0.5 mL) at room temperature, and the reaction mixture was stirred for about 5 hours (the completion of the reaction was determined by HPLC). The crude product was purified by prep-HPLC. LC-MS: 432.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
EX-1A) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (50 g, 0.24 mol) and N-bromosuccinimide (42.75 g, 0.24 mol) in 100 mL of carbon tetaachloride under nitrogen was added 2,2′-azobisisobutyronitrile (0.71 g, 0.004 mol). The resultant mixture was refluxed for 2 h, then cooled to room temperature and quenched with 300 mL of water. The organic layer was collected, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 66.0 g (96%) of the desired crude 3-(1,1,2,2-tetrafluoroethoxy)bromomethylbenzene product as a yellow oil. 1H NMR indicates that this oil is a mixture of products: 7% dibrominated, 67% monobrominated, and 20% starting material. The crude product was used without further purification. ESMS m/z=287 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:15]=[C:14]([C:16]4[S:17][C:18]5[C:24]([C:25]6[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=6)=[C:23]([C@H:32]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=5[N:20]=4)[CH:13]=[CH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:44][C:45]([F:58])([F:57])I1C2C=CC=CC=2C(C)(C)O1.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(=S)=S>[C:39]([O:38][C@@H:32]([C:23]1[C:22]([CH3:43])=[CH:21][C:19]2[N:20]=[C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[N:1]([C:45]([F:58])([F:57])[F:44])[N:2]=[CH:3]5)[CH:15]=3)[S:17][C:18]=2[C:24]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5[nH]ncc5c4)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: S=C=S
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5C(F)(F)F)c4)c3)sc2c1-c1ccc(Cl)cc1

Procedure:
To a solution of (S)-ethyl 2-(2-(2-(1H-indazol-5-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (40 mg, 0.065 mmol) in CS2 (1.5 mL), was added 1-Trifluoromethyl-3,3-dimethyl-1,2-benziodoxole (64 mg, 0.195 mmol), bis(trifluoromethane)sulfonimide (27 mg, 0.0975 mmol). The reaction mixture was heated at 60° C. in sealed microwave vial for 1d. The reaction mixture was washed by saturated NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down, purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C35H30ClF3N4O3S: 679.2 (M+H+); found: 679.2.
Reaction SMILES: Br[C:2]1[C:12]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH3:19])[N:3]=1.[C-:20]#[N:21].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC>C(#N)C.O>[C:20]([C:2]1[C:12]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH3:19])[N:3]=1)#[N:21]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc(NC(CC)CC)c(Br)nc1C
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc(NC(CC)CC)c(C#N)nc1C
Temperature: 88 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of ethyl 6-bromo-2-methyl-5-(pentan-3-ylamino)nicotinate (1.202 g, 3.65 mmol) in acetonitrile (30 ml) was added sodium cyanide (0.357 g, 7.3 mmol), tributyltin chloride (1.306 g, 4.015 mmol) and Pd(dpppf)3 (0.298 g, 0.365 mmol). The reaction mixture was stirred at 88° C. overnight. The reaction mixture was diluted with water (100 ml), then extracted with ethyl acetate (3×100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and brine. After evaporation of solvent, ethyl 6-cyano-2-methyl-5-(pentan-3-ylamino)nicotinate (0.59 g, 59% yield) was obtained by column chromatography. 1H NMR (400 MHz, CDCl3): 7.56 (s, 1H), 4.50 (q, J=6.8 Hz, 2H), 4.35 (br, s, 1H), 3.40 a9m, 1H), 2.64 (s, 3H), 1.80-1.50 (m, 4H), 1.42 (t, J=6.8 Hz, 3H), 1.0 (t, 6H). MS (EI) for C15H21N3O2: 276.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[C:51]([CH3:55])=[CH:52][CH:53]=[CH:54][C:49]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1c(C)cccc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cccc(C)c2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.44 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.25 g of N-[2-(2-hydroxy-6-methylphenyl)ethyl]acetamide are reacted. The title compound is obtained as a colourless oil. Rf=0.50 (EtOAc); Rt=5.77.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>C(Cl)Cl.CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2c(NC(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
2,6Dichlorophenyl isocyanate (0.075 g) was added to a solution of 4amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline (0.093 g) in a mixture of methylene chloride (2 ml) and DMF (0.1 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The resultant solid was isolated, redissolved in a 20:1 mixture of methylene chloride and methanol and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride, methanol and a 1% aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound as a white solid (0.029 g); NMR Spectrum: (DMSOd6) 1.3-1.4 (m, 2H), 1.7-1.8 (m, 4H), 1.85 (t, 1H), 2.1 (s, 3H), 2.8 (d, 2H), 3.9 (s, 3H), 4.0 (br d, 2H), 7.3 (br s, 1H), 7.4 (d, 1H), 7.5 (s, 1H), 7.6 (s, 1H), 8.0 (br s, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 490, 492 and 494.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[NH2:10][C:11]([C@@H:13]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:14]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[NH2:10][C:11]([C@@H:13]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[F:9])=[CH:20][CH:19]=2)[N:14]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:12]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(N)=O)CC[C@H]1c1ccc(O)cc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](C(N)=O)CC[C@H]1c1ccc(OCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
1-(Bromomethyl)-2-fluorobenzene (30 μl, 0.244 mmol) was added to a solution of 1,1-dimethylethyl (2S,5S)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate (D14, 50 mg, 0.163 mmol) and potassium carbonate (34 mg, 0.244 mmol) in acetonitrile (0.5 ml). The mixture was stirred overnight at room temperature. Then ethyl acetate (20 mL) and water (10 mL) were added. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (7:3 to 6:4) to afford the title compound (65 mg, 97%); Rf (cyclohexane:ethyl acetate=7:3): 0.19; MS: (ES/+) m/z: 437 [M+Na+], C23H27FN2O4 requires 414; Rt (HPLC): 5.28 min; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.54-7.44 (m, 1H), 7.40-7.27 (m, 2H), 7.24-7.11 (m, 2H), 7.06-6.98 (m, 2H), 6.96-6.79 (m, 3H), 5.10-5.00 (m, 2H), 4.91 and 4.81 (d, d, 1H), 4.29 and 4.24 (d, d, 1H), 2.35-2.18 (m, 1H), 2.17-1.97 (m, 1H), 1.78-1.62 (m, 1H), 1.58-1.43 (m, 1H), 1.28 and 1.03 (s, s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][C@@:8]2([CH3:28])[N:12]3[C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:9]2=[O:27])=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]([NH2:56])([C:44](=[O:55])[NH:45][C:46]2([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)[CH2:48][CH2:47]2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]([NH:56][C:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=4)([CH3:28])[C:9](=[O:27])[N:10]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=4)[C:11]3=[N:15][CH:14]=2)=[O:18])([C:44](=[O:55])[NH:45][C:46]2([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)[CH2:48][CH2:47]2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)NC2(c3ccccn3)CC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)(C(=O)NC2(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.2 %

Procedure:
To a mixture of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (80 mg, 0.18 mmol) and 4-amino-4-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (74 mg, 0.20 mmol) in DMF (1 mL) was added HATU (76 mg, 0.19 mmol) and diisopropylethylamine (47 mg, 0.36 mmol). The reaction was stirred at room temperature for 7 h. After addition of water (10 mL) the mixture was extracted with EtOAc (2×15 mL). The organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the remaining residue was purified via reverse phase HPLC to afford 4-{[(R)-5-(4-cyanobenzyl)-7-(3,5-dichlorophenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-4-(1-pyridin-2-yl-cyclopropyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (140 mg), m/z 784.9 [M+1]+.
Reaction SMILES: [CH2:1]([C:5]([NH:16][C:17]([C:19]1[N:23]2[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH2:29][C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])[C:22]2=[N:21][C:20]=1[CH3:38])=[O:18])([C:11](OCC)=[O:12])[C:6](OCC)=[O:7])[CH2:2][CH2:3][CH3:4].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>C(O)C.O.C(OCC)(=O)C>[F:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[CH2:29][O:28][C:27]1[C:22]2[N:23]([C:19]([C:17]([NH:16][C:5]([CH2:6][OH:7])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:11][OH:12])=[O:18])=[C:20]([CH3:38])[N:21]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCCCC(NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCC(CO)(CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a mixture of 68 mg of diethyl butyl[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]malonate in 1.4 ml of ethanol was added a solution of 35 mg of calcium chloride in 0.34 ml of water. Subsequently, 24 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring for 1 hour under ice-cooling and at room temperature for 4 hours. Further, 2 ml of ethanol, a solution of 35 mg of calcium chloride in 0.34 ml of water, and 24 mg of sodium borohydride were added thereto followed by stirring at room temperature for 15 hours. Further, a solution of 35 mg of calcium chloride in 0.34 ml of water and 24 mg of sodium borohydride were added thereto, followed by stirring at room temperature for 15 hours. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 32 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1-hydroxy-2-(hydroxymethyl)hexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:12]([C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:30][NH2:31]>CO>[OH:29][C:26]1[CH:27]=[CH:28][C:23](/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:31][CH3:30])=[CH:6][CH:7]=2)=[C:12](/[C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)\[CH2:13][CH3:14])=[CH:24][CH:25]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccn(C)c(=O)c1
Reactant: CN
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccn(C)c(=O)c1
Temperature: 85 °C

Procedure:
To a stirred solution of 4-(1-(4-(2-chloroethoxy)phenyl)-1-(4-hydroxyphenyl)-but-1-en-2-yl)-1-methylpyridin-2(1H)-one (30 mg, 1.0 eq) in 10 mL MeOH was added 5 mL 30% CH3NH2 (aq), and the mixture was then heated at 85° C. for 36 h. Then the solvent was removed in vacuo, water was added to the residue and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (3 mg, Z-isomer), E-isomer (2 mg), and Z/E mixture (230 mg, 49% yield) as well. 1H NMR (400 MHz, CDCl3) δ 6.96-6.98 (m, 3H), 6.84 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 6.57 (d, J=8.8 Hz, 2H), 6.47 (d, J=2.0 Hz, 1H), 5.78 (dd, J=6.8 Hz, 2.0 Hz, 1H), 3.98 (t, J=5.2 Hz, 2H), 3.47 (s, 3H), 2.96 (t, J=5.2 Hz, 2H), 2.52 (s, 3H), 2.36-2.38 (m, 2H), 0.92 (t, J=7.2 Hz, 3H); m/z=405[M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([OH:21])=O)[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:21])[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1
Reactant: C1COCCN1
Reactant: Cc1nnc2n1-c1sc(CC(=O)O)cc1C(c1ccccc1Cl)=NC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1sc(CC(=O)N3CCOCC3)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
Here, [4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-methane carboxylic acid (20 g, 0.054 mol), tetrahydrofuran (500 ml) and 1,1'-carbonyldiimidazole (10 g) are stirred for 1 hour at ambient temperature and the solution, now clear, is mixed with morpholine (0.06 mol, 5.2 g). After stirring overnight at ambient temperature, evaporation, taking up in methylene chloride, washing with sodium bicarbonate solution and filtering through a column of SiO2, the title compound (9.4 g), m.p. 143°-144° C., is obtained by recrystallization from ethyl acetate.