Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:11][C:12](Cl)=[O:13].C(N(CC)CC)C.[NH2:22][C:23]1[CH:44]=[CH:43][C:26]([C:27]([N:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH2:33][N:32]3[CH:40]=[CH:41][CH:42]=[C:31]3[CH2:30]2)=[O:28])=[CH:25][CH:24]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH:42]1[CH:41]=[CH:40][N:32]2[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N:29]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:12](=[O:13])[CH2:11][C:3]4[S:4][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=5[C:2]=4[CH3:1])=[CH:44][CH:43]=3)=[O:28])[CH2:30][C:31]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1c(CC(=O)Cl)sc2ccccc12
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CC(=O)Nc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)sc2ccccc12
Reaction time: 0.05 h
Yield: 39.5 %

Procedure:
To a stirred solution of 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. An additional 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride, 0.346 g of triethylamine and 30 mg of dimethylaminopyridine is added and stirring continued for an additional 18 hours. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.320 g of the desired product as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([P:37](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>ClCCl>[C:31]1([P:37]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([C:6]([N:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH2:12][N:11]4[CH:19]=[CH:20][CH:21]=[C:10]4[CH2:9]3)=[O:7])=[CH:4][CH:3]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(NP(=O)(c2ccccc2)c2ccccc2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine 0.060 g of triethylamine and 0.12 g of diphenylphosphinyl chloride in 2 ml of dichloromethane is stirred at room temperature for 2 hours and then 1N NaOH is added. The mixture is extracted with ethyl acetate and the extract washed with brine and dried (Na2SO4). The solvent is removed and the residue triturated with ether-hexane to give 0.16 g of a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]=O)=[CH:30][CH:29]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39][C:40](=[O:42])[CH3:41])(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[CH3:50][O:51][NH2:52]>C(O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]=[N:52][O:51][CH3:50])=[CH:30][CH:29]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39][C:40](=[O:42])[CH3:41])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C#N)cc1
Temperature: 80 °C
Yield: 57.8 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-cyano-3-(4-(2-oxoethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (100.0 mg, 0.17 mmol) in ethanol (4 mL) under nitrogen atmosphere, was added pyridine (0.07 mL, 0.86 mmol) and O-methylhydroxylamine hydrochloride (28.7 mg, 0.34 mmol). The reaction mixture was heated at 80° C. for 2 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was diluted with ethyl acetate (40 mL). The organic layer was separated, washed with 5% HCl (10 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:49 EtOAc:Pet Ether) to afford title compound (60 mg, 43%) as solid.
Reaction SMILES: [Li][CH2:2]CCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CI.[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][C:31]2=O>C1COCC1>[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][C:31]2=[CH2:2]
Reactant: [Li]CCCC
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CI
Solvent: C1CCOC1
Product: C=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of n-BuLi (2.5 M, 3.80 mL) was added to a mixture of PPh3.MeI. (4.092 g, 10.13 mmol) in THF at −10. The mixture was stirred for 1 h at the same temperature, and then 6-bromo-2-phenylchroman-4-one (2 g, 6.62 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 h. The resulting mixture was concentrated and purified by column chromatography to give 6-bromo-4-methylene-2-phenylchroman (400 mg, 20%). 1H-NMR (CDCl3): 2.76 (m, 2H), 4.90 (d, 1H), 5.01 (m, 1H), 5.48 (d, 1H), 6.76 (d, 1H), 7.31 (m, 6H), 7.62 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[N:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[N:14][CH:15]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)[C@H]1CCN(c2ccc(Br)cn2)C1
Temperature: 25 °C
Yield: 50 %

Procedure:
Heat a mixture of dimethyl-pyrrolidin-3-(S)-yl-amine (3.0 g, 26.3 mmoL), 5-bromo-2-fluoro-pyridine (4.62 g, 26.3 mmol), potassium carbonate (7.98 g, 57.8 mmol) in acetonitrile (91 mL) at 80° C. overnight. Allow the mixture to cool to RT, filter with CH2Cl2, and concentrate. Purify the crude material by flash chromatograph, eluting with 5% MeOH (2N NH3)/CH2Cl2 to give 3.55 g (50%) of the title compound. LC-MS/ES m/z (81Br) 272.3 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][C:19]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[CH3:18][C:19]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Cc1ccc(CBr)c(C)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: Cc1ccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)c(C)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,4-dimethylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[NH2:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>O>[OH:18][CH:15]([CH2:16][OH:17])[CH2:14][NH:13][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: NCC(O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(NCC(O)CO)c2ccccc2n1
Temperature: 160 °C

Procedure:
A mixture of 4-chloro-2-methylquinoline (50 g) and 3-amino-1,2-propandiol (51 g) was heated at 160° C. for 1 hour. The mixture while still hot was poured into 700 ml of water. The mixture was saturated with potassium carbonate and cooled in an ice bath, whereupon the product crystallized. It was filtered and recrystallized from ethanol. The yield was 55 g, mp 167°-168° C.
Reaction SMILES: C(O)=O.[CH2:4]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([NH:18]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[CH2:4]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([NH2:18])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(CN2CCCCC(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Solvent: O=CO
Solvent: ClCCl
Product: NC1CCCCN(Cc2ccccc2)C1
Yield: 72.8 %

Procedure:
Formic acid (0.25 ml, 6.63 mmol) was added dropwise to a solution of 1-benzyl-N-trityl-3-azepanamine (300 mg, 0.672 mmol) in methylene chloride (7 ml) under ice-cooling and stirred under ice-cooling for 3.5 hours. After the reaction mixture was concentrated, the residue was diluted with ether and washed with 1N-hydrochloric acid. After extraction, a 1N-aqueous sodium hydroxide solution was added to the aqueous layer under ice-cooling to make the aqueous layer basic, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate and then concentrated to obtain 1-benzyl-3-azepanamine (100 mg, 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(N(CC)CC)C>C(#N)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1c[nH]nn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cn2ccnn2)cc1
Temperature: 25 °C

Procedure:
4-Nitrobenzylbromide (25.4 g, 0.12mol) was added to a solution of 1H-1,2,3-triazole (8.12 g, 0.12 mol) and triethylamine (11.88 g, 0.12 mol) in anhydrous acetonitrile. The mixture was refluxed for 1 h, cooled to room temperature and the precipitated NEt3. HBr filtered off. The solvent was removed under vacuum and the residue chromatographed through silica gel eluting with CH2Cl2 (100) to CH2Cl2 /MeOH (95.5) to give 2-products. The more polar product was identified as the title-1-isomer (13 g, 54%); mp 114°-116° C. δ (250 MHz, CDCl3) 5.72 (2H, s, CH2), 7.38 (2H, d, J=9 Hz, Ar--H), 7.64 (1H, s, Ar--H), 7.78 (1H, s, Ar--H), 8.18 (2H, d, J=9 Hz, Ar--H). The less polar, minor isomer was identified as the 2-alkylation product (2.25 g, 9%), mp 112°-113° C. δ (250 MHz, CDCl3) 5.72 (2H, s, CH2), 7.40 (2H, d, J=9 Hz, Ar--H), 7.66 (2H, s, Ar--H), 8.18 (2H, d, J=9 Hz, Ar--H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](COCC[Si](C)(C)C)[N:13]=[C:12]2[NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:30]2[CH:38]=[CH:39][C:40]([CH2:42][OH:43])=[CH:41][C:29]=2[N:28]=1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:26][C:27]1[N:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:30]2[CH:38]=[CH:39][C:40]([CH2:42][OH:43])=[CH:41][C:29]=2[N:28]=1
Reactant: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(CO)ccc3n1-c1ccccc1)nn2COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: COc1ccncc1-c1ccc2[nH]nc(Nc3nc4cc(CO)ccc4n3-c3ccccc3)c2c1
Temperature: 100 °C

Procedure:
A mixture of (2-(5-(4-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1-phenyl-1H-benzo[d]imidazol-5-yl)methanol (0.024 g, 0.000040 mol) and 0.03 M HCl (1 mL,) in ethanol (3 mL) was heated at 100° C. for 2 hours. The reaction was concentrated and the residue was dissolved in DMSO and purified by HPLC.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: Cc1ncc(-c2ccc(C(F)(F)F)cc2)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cnc(CBr)nc2)cc1
Temperature: 75 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
0.31 g (1.3 mmol) of 2-methyl-5-(4-trifluoromethyl-phenyl)-pyrimidine, 0.255 g (1.43 mmol) of N-bromosuccinimide and 0.15 g (0.91 mmol) of 2,2′-azobis-(2-methyl-propionitril) were dissolved in 5 ml of carbon tetrachloride and the mixture was stirred at 75° C. Two portions of 0.13 g (0.73 mmol) of N-bromosuccinimide and of 0.075 g (0.046 mmol) of 2,2′-azobis-(2-methyl-propionitril) were added to the reaction mixture, after 4 and 8 hours, respectively, and heating was continued for additional 16 hours. After cooling to ambient temperature, the mixture was chromatographed on silicagel with dichloromethane as eluent. 0.145 g of the title compound was obtained as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH2:17][C:18]([OH:20])=O)[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]1=2.[NH2:26][CH2:27][C:28]1[N:29]=[C:30]([NH:33][C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[S:31][CH:32]=1>>[CH2:37]([NH:36][C:34]([NH:33][C:30]1[S:31][CH:32]=[C:28]([CH2:27][NH:26][C:18](=[O:20])[CH2:17][N:8]2[C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:25])[C:6]3[CH:24]=[CH:23][CH:22]=[CH:21][C:7]2=3)[N:29]=1)=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)CN1c2ccccc2C(=O)N(CC(=O)O)c2ccccc21
Reactant: NCc1csc(NC(=O)NCc2ccccc2)n1
Product: COC(=O)CN1c2ccccc2C(=O)N(CC(=O)NCc2csc(NC(=O)NCc3ccccc3)n2)c2ccccc21

Procedure:
Preparation took place in analogy to I.B.23 by reacting [5-(2-methoxy-2-oxoethyl)-11-oxo-5,11-dihydro-10H-dibenzo[b,e]-[1,4]diazepin-10-yl]acetic acid 37c with N-[4-(aminomethyl)1,3-thiazol-2-yl]-N′-benzylurea (hydrochloride) (38). Chromatography on silica gel (CH2Cl2/CH3OH 2→10%) afforded 0.45 g; ESI-MS [M+H+]=585.25.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:39]=[CH:38][C:25]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:23]=1>>[CH2:1]([N:8]([CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1)[C:35](=[O:36])[CH2:34][N:31]1[CH2:32][CH2:33][CH:28]([C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:39][CH:38]=2)[CH2:29][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNCc2ccccc2)nc2c1COCC2
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2ccccc2)Cc2nc3c(c(=O)[nH]2)COCC3)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (17.7 mg) from 2-((benzylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C29H31FN4O4 518.58. found 519.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.98 (br. s., 2H) 7.28-7.52 (m, 1H) 7.21 (d, J=7.58 Hz, 4H) 4.66 (d, J=8.08 Hz, 2H) 4.60 (br. s., 1H) 4.48 (br. s., 2H) 3.85-4.08 (m, 5H) 3.81 (br. s., 2H) 3.42 (d, J=7.07 Hz, 2H) 3.28 (br. s., 2H) 2.70 (d, J=15.66 Hz, 2H) 2.06-2.36 (m, 3H) 1.17-1.41 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:32])([F:33])[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccccc3C(F)(F)F)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: ClC1C=CC(C2(C)C(C3C=CC(Cl)=CC=3)(C)N([C:21](Cl)=[O:22])C(C3C=CC(C(F)(F)F)=CC=3OCC)=N2)=CC=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][N:50]([CH:21]=[O:22])[CH2:49][CH2:48]1)(=[O:42])=[O:43]
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CS(=O)(=O)CCCN1CCN(C=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the racemic rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone. Chiral separation of the enantiomers by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C35H40N4O4SF3Cl2 [(M+H)+] 739.2094, observed 739.2094.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:14]N1C(=O)CCC1=O.C([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH:1]1([NH:6][C:7]2[C:12]([I:14])=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc(NC2CCCC2)n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(I)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a stirred solution of compound 315 (25.5 g, 143 mmol) in DMF (120 mL) was added N-iodosuccinimide (32 g, 143 mmol) in two portions at rt. The resulting mixture was stirred at rt for 2 h. Upon workup, the mixture was poured into ice and saturated Na2CO3 aqueous solution with some sodium sulfite and extracted with ethyl acetate (2×). The combined organics were washed with saturated Na2CO3 aqueous solution (3×), dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM) to give compound 243 (39 g, 73% yield in 2 steps). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.89 (1 H, s), 6.18 (2 H, s), 5.63 (1 H, d, J=7.6 Hz), 4.30 (1 H, sxt, J=7.4 Hz), 1.84-1.96 (2 H, m), 1.61-1.74 (2 H, m), 1.42-1.58 (4 H, m). LCMS-ESI (POS), M/Z, M+1: Found 305.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10]([N:12]([CH2:15][CH2:16][N:17]=[C:18]=[S:19])[CH2:13][CH3:14])[CH3:11]>>[CH2:10]([N:12]([CH2:13][CH3:14])[CH2:15][CH2:16][NH:17][C:18]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[S:19])[CH3:11]
Reactant: NCCN1CCCCC1
Reactant: CCN(CC)CCN=C=S
Product: CCN(CC)CCNC(=S)NCCN1CCCCC1

Procedure:
By the general method described in Example 1, 1-(2-aminoethyl)-piperidine is reacted with diethylaminoethyl isothiocyanate to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@:26]1([CH2:30][N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)[C@H:28]([CH3:29])[O:27]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[N:11][N:10]([C@H:28]([CH3:29])[C@:26]([C:20]3[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=3[F:18])([OH:27])[CH2:30][N:31]3[CH:35]=[N:34][CH:33]=[N:32]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Fc1ccc(-c2cn[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: C[C@@H](n1cc(-c2ccc(F)cc2)cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a suspension of 4-(4-fluorophenyl)-1H-pyrazole (0.12 g) in N,N-dimethylformamide (5 ml) were added calcium carbonate (0.15 g) and 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (0.204 g). While argon gas was provided, stirring was conducted at room temperature for 20 min prior to the irradiation of microwaves thereto at 180° C. for 15 min for reaction. After the reaction was terminated, the solution was diluted in ethyl acetate (10 ml) and washed with a saturated ammonium chloride solution (10 ml) and then with brine (10 ml). The washed organic layer thus formed was dried over anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The residue was separated through silica gel chromatography to give the title compound (Yield 56%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].N>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Clc1cncc2ccccc12
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2cncc(Cl)c12
Reaction time: 2 h
Yield: 69.4 %

Procedure:
Intermediate 88 (375 mg) was dissolved in concentrated sulfuric acid (2 ml), then added with potassium nitrate (260 mg) with ice cooling and stirred for 2 hours. The reaction mixture was added with 28% aqueous ammonia (10 ml) and extracted twice with ethyl acetate (15 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (332 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2cccc(F)c2)cc1
Yield: 85.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.059 g (85%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4-carboxamide as a white solid.