Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:38][C@@H:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@@H:35]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:34]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([N+:55]([O-])=O)[CH:29]=3)[N:24]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>CCOC(C)=O.CO.[Ni]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:34][C@@H:35]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:36][C@@H:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:55])[CH:29]=3)[N:24]=2)[CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc([N+](=O)[O-])cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(N)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
2,3-Bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-6-nitro-quinoxaline (3) (0.159 g, 0.198 mmol) was dissolved in a mixture of EtOAc (3 mL) and MeOH (3 mL). The solution was heated to 60° C. and Raney Nickel (0.25 mL, 50% slurry in water) and hydrazine (0.5 mL, anhydrous) were added. Bubbling was observed. The mixture continued to stir for 15 minutes at 60° C. TLC (Rf: 0.05 compared to Rf: 0.3 for compound 245 in 1:1 hexanes/EtOAc) indicated complete reduction at this point. The mixture was passed through a plug of silica gel and concentrated to give a white powder. The solid was dissolved in EtOAc (30 mL), washed with water (2×20 mL) and brine (2×20 mL) via extraction, dried over MgSO4 and concentrated to give the desired product (246) as a white powder (0.135 g, 0.175 mmol, 88.3% yield). LC-MS (ESI): (exact mass: 771.46) m/e=772.6 [M+1]+.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[CH2:8][CH2:7]2.[Cl:18][C:19]1[S:20][C:21]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][C:23]=1[Cl:24]>>[Cl:24][C:23]1[CH:22]=[C:21]([S:25]([NH:14][C:12]2[S:13][C:9]3[CH2:8][CH2:7][C:6]4[C:15](=[CH:16][CH:17]=[C:4]([O:3][CH3:2])[CH:5]=4)[C:10]=3[N:11]=2)(=[O:27])=[O:26])[S:20][C:19]=1[Cl:18]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Agent: Br
Product: COc1ccc2c(c1)CCc1sc(NS(=O)(=O)c3cc(Cl)c(Cl)s3)nc1-2

Procedure:
The title compound was prepared from 7-methoxy-4,5-dihydronaphtho(1,2-D)(1,3)thiazol-2-amine hydrobromide (85 mg) and 2,3-dichlorothiophene-5-sulfonyl chloride (68 mg) as described in the synthetic METHOD B to give a white solid (16.4 mg) with purity >90%: MS (pos) m/z 447.3, 449.3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C@H:10]([CH3:11])[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH3:12].[Li].[O:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:12][C@H:6]1[CH2:7][CH2:8][CH2:9][C@@H:10]([CH3:11])[N:5]1[CH2:4][CH2:3][CH2:2][C:18]([C:17]1[CH:4]=[CH:3][CH:2]=[CH:15][CH:16]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)[OH:14]
Reactant: C[C@@H]1CCC[C@H](C)N1CCCCl
Reactant: C1CCOC1
Agent: [Li]
Product: C[C@@H]1CCC[C@H](C)N1CCCC(O)(c1ccccc1)c1ccccn1
Reaction time: 4 h

Procedure:
A solution of 18.9 g. of cis-1-(3-chloropropyl)-2,6-dimethylpiperidine in 50 ml. of tetrahydrofuran is added dropwise under a nitrogen atmosphere to a stirred mixture of 1.4 g. of lithium wire and 50 ml. of tetrahydrofuran over a period of 2 hours. After the addition is complete, the mixture is stirred another 4 hours under nitrogen, the excess lithium metal removed manually and a solution of 18.3 g. of 2-benzoylpyridine in 100 ml. of tetrahydrofuran is added dropwise with stirring over a period of 2 hours. The mixture is stirred for 16 hours, then treated with 5 ml. of water. The organic phase is decanted from the precipitated solid and evaporated at reduced pressure to about one-fourth its previous volume. This solution is poured into 400 ml. of water, the solution is acidified with acetic acid and washed with ether. The aqueous acid solution is basified with aqueous sodium hydroxide and extracted with ether. The ether extract is washed with water, dried and evaporated to give (+,-)-cis-α-[3-(2,6-dimethyl-1-piperidinyl)propyl]-α-phenyl-2-pyridinemethanol; m.p. (monohydrate) 100°-102° C. after crystallization from aqueous methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].[Br:18]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:18][C:7]1[C:2]([Cl:1])=[C:3]([C:16]#[N:17])[C:4](=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH:6]=1
Reactant: Cc1ccccc1-n1ccc(Cl)c(C#N)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step D of Example 1 (4.00 g) in N,N-dimethylformamide (33 mL) was added N-bromosuccinimide (3.49 g) at 50° C. The reaction mixture was heated at 50° C. for 6 hr, cooled to room temperature, and diluted with water. The resulting solid was collected by filtration, and washed with acetonitrile. The solid was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.30 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:34]([F:37])([F:36])[F:35])=[C:7]([NH:9][C:10]2[NH:14][C:13]3[CH:15]=[C:16]([O:32][CH3:33])[C:17]([C:19]([NH:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]4)=[O:20])=[CH:18][C:12]=3[N:11]=2)[CH:8]=1.[C:38]([O:42][C:43]([NH:45][CH:46]([C:50]([F:53])([F:52])[F:51])[C:47](O)=[O:48])=[O:44])([CH3:41])([CH3:40])[CH3:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[C:38]([O:42][C:43]([NH:45][CH:46]([C:50]([F:51])([F:52])[F:53])[C:47]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:34]([F:36])([F:37])[F:35])=[C:7]([NH:9][C:10]2[NH:14][C:13]3[CH:15]=[C:16]([O:32][CH3:33])[C:17]([C:19]([NH:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([C:28]([F:29])([F:30])[F:31])[CH2:24][CH2:23]4)=[O:20])=[CH:18][C:12]=3[N:11]=2)[CH:8]=1)=[O:48])=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(F)(F)F
Reactant: COc1cc2[nH]c(Nc3cc(CN)ccc3C(F)(F)F)nc2cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1cc2[nH]c(Nc3cc(CNC(=O)C(NC(=O)OC(C)(C)C)C(F)(F)F)ccc3C(F)(F)F)nc2cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared from 2-(5-aminomethyl-2-trifluoromethyl-phenylamino)-6-methoxy-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide and 2-tert.butoxycarbonylamino-3,3,3-trifluoro-propionic acid with TBTU, and TEA in THF_in analogy to example 3e.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:30](=[O:31])[CH:29]=[CH:28][C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=2[C:25]([F:37])([F:38])[F:24])=[CH:15][CH:16]=1
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1C(F)(F)F
Yield: 98.9 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2-trifluoromethylcinnamic acid (2.6 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (4.1 g, 99%) as an amorphous solid product.
Reaction SMILES: [CH:1](OCC)=[O:2].[CH:6]1([C@H:12]([NH2:14])[CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:6]1([C@H:12]([NH:14][CH:1]=[O:2])[CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC=O
Reactant: C[C@@H](N)C1CCCCC1
Product: C[C@@H](NC=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyl formate (1.2 mL, 15.0 mMol) was added to a round bottom flask containing (1R)-1-cyclohexyl-ethylamine Compound 17a (1.27 g, 10 mMol) at 0° C. and the mixture was stirred at r.t. for 15 hrs. Excess ethyl formate was removed in vacuo to obtain N-[(1R)-1-cyclohexyl-ethyl]-formamide Compound 17b (1.55 g) as a white solid, which was used in the next step without purification. MS m/z 156 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([O:35][CH3:36])[C:29]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[C:28]3[Cl:48])=[O:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]([C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([O:35][CH3:36])[C:29]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)=[C:28]3[Cl:48])([OH:24])[C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[CH2:22]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cn1ccnn1
Reactant: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -43 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (150 mg, 1.81 mmol) was added THF (15 mL) and the colorless homogeneous solution was cooled to −43° C. using a CH3CN—CO2 bath. n-BuLi (2.5M in hexanes, 0.7 mL, 1.75 mmol) was added drop wise via syringe which afforded an opaque mixture. The suspension was stirred at −40° C. for 30 min, then a THF solution of tert-butyl-3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate (430 mg, 0.8 mmol, in 2 mL THF, Intermediate 66: step b) was introduced at −40° C. The reaction mixture was allowed to warm gradually to room temperature over 45 min and then quenched with NH4Cl solution. The aqueous portion was extracted with EtOAc (3×30 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide an amber gum. Chromatography on silica gel (10% acetone-hexane increasing to 30% acetone) afforded the title compound (170 mg) as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.56-7.47 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.35 (dd, J=8.7, 2.1 Hz, 1H), 4.35 (s, 2H), 4.20 (t, J=8.8 Hz, 1H), 4.07 (s, 3H), 4.00 (dd, J=9.3, 5.6 Hz, 1H), 3.92 (dd, J=8.9, 5.7 Hz, 1H), 3.67 (s, 3H), 3.62 (t, J=8.8 Hz, 1H), 3.52-3.38 (m, 1H), 1.38 (s, 9H). MS (ESI): mass calcd. for C30H31ClF3N5O4: 618.06, m/z found 619.9 [M+H]+.
Reaction SMILES: C(N(C)[C:9]([Cl:11])=[O:10])C1C=CC=CC=1.[CH:13]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14]1.CC#N.O.CC#N>O>[C:17]1([N:16]([CH:13]2[CH2:15][CH2:14]2)[C:9]([Cl:11])=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(NC2CC2)cc1
Reactant: CN(Cc1ccccc1)C(=O)Cl
Solvent: CC#N
Solvent: O
Product: O=C(Cl)N(c1ccccc1)C1CC1

Procedure:
The title compound is prepared analogously as described for benzyl-methyl-carbamoyl chloride from cyclopropyl-phenyl-amine prepared according to 0 Synlett 2003, 14, 2139. MS (LC-MS): [M+H]+=196.2. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.44 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](=O)[CH2:14]Br)[CH3:10]>C1(C)C=CC=CC=1.O>[CH2:9]([O:11][C:12]([C:13]1[N:8]=[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]2[CH:14]=1)=[O:17])[CH3:10]
Reactant: Nc1cc(Br)ccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2ccc(Br)cc2n1
Temperature: 115 °C
Yield: 104.5 %

Procedure:
To a stirred solution of 4-Bromo-pyridin-2-ylamine (4 g, 23.12 mmol) in toluene (40 mL) is added 3-Bromo-2-oxo-propionic acid ethyl ester (4.5 g, 23.12 mmol). The reaction mixture is heated at 115° C. for 16 hours. Reaction mixture is cooled to 0° C. then diluted with water and extract with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo to afford the title compound (6.5 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.31 (t, J=7.2 Hz, 3H), 4.26-4.33 (q, J=7.2 Hz, 2H), 7.18-7.20 (dd, J1=1.92 Hz, J2=7.16 Hz, 1H), 7.98 (s, 1H), 8.53 (d, J=7.32 Hz, 1H), 8.57 (s, 1H). LC-MS (m/z): [M+H]=271.0.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:7][CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]=1[O:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])[CH3:4]>ClC(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[S:7][CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]=1[O:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: COC(=O)c1csc(C(C)=O)c1OC(=O)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1csc(C(=O)CBr)c1OC(=O)c1ccccc1
Temperature: 22.5 °C
Yield: 77 %

Procedure:
A solution of 1.28 mL of bromine in 24 mL of tetrachloromethane was added dropwise to a solution of 7.23 g of Compound 1C in 72 mL of tetrachloromethane over a period of 10 minutes and stirred at reflux. After a further 5 minutes at reflux, the mixture was cooled to 20-25° C. The precipitated solid was collected by filtration and washed with cold tetrachloromethane to yield 7 g (77%) of Compound 1D, melting at 115-118° C. The compound was contaminated with impurities 1B and methyl 2-(2,2-dibromoacetyl)-3-benzoyloxythiophene-4-carboxylate (2% and 6% mol. respectively, determined by 1H-NMR spectroscopy), but could be used without further purification in the next reaction step.
Reaction SMILES: [C:1]([O-])(O)=[O:2].[Na+].Cl.[NH2:7][C@@H:8]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]([O:11][CH3:12])=[O:10].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:13]1([C@H:8]([N:7]=[C:1]=[O:2])[C:9]([O:11][CH3:12])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)[C@@H](N)C1CCCCC1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](N=C=O)C1CCCCC1
Reaction time: 1 h

Procedure:
A 500 mL round-bottom flask was charged with saturated NaHCO3 (80 mL) and DCM (80 ml) and cooled in an ice bath with vigorous stirring. Methyl (2S)-amino(cyclohexyl)acetate hydrochloride (4.0 g, 19.26 mmol) was added followed by triphosgene (1.886 g, 6.36 mmol). The contents of the reaction flask were stirred for 1 hr with cooling, then poured into a reparatory funnel. The layers were separated, and the aqueous layers were extracted with 20 mL DCM. The combined organic portions were dried with anhydrous MgSO4, filtered and evaporated to give the title compound as a colorless oil. 1H NMR (CDCl3): δ 3.90 (d, J 4, 1H), 3.81 (s, 3H), 1.88-1.83 (m, 1H), 1.79-1.76 (m, 2H), 1.69-1.62 (m, 2H), 1.54-1.48 (m, 1H), 1.29-1.11 (m, 5H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc(Cl)cc1)CC2
Yield: 26 %

Procedure:
Prepared from 4-chloro-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform. Yield: 26% of theory, Melting point: 148°-153° C. (ether).
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.C(O[C:32](=[O:34])[CH3:33])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:4]([O:23][CH2:22][C@@H:21]([O:24][C:32](=[O:34])[CH3:33])[CH2:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][C@H:3]([O:27][C:18](=[O:19])[CH3:17])[CH2:2][Cl:1])=[CH:11][CH:10]=2)([CH3:14])[CH3:13])=[CH:26][CH:25]=1)(=[O:5])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(c1ccc(OC[C@H](O)CO)cc1)c1ccc(OC[C@H](O)CCl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](COc1ccc(C(C)(C)c2ccc(OC[C@@H](CCl)OC(C)=O)cc2)cc1)OC(C)=O
Reaction time: 14 h
Yield: 187.7 %

Procedure:
To a solution of (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (500 mg, 1.27 mmol) in anhydrous pyridine (6.0 mL) were successively added acetic anhydride (605 μL, 6.35 mmol) and a catalytic amount of DMAP. After 14 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 dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. Solvents were evaporated, and the resulting crude material was purified by silica gel flash chromatography (eluent: 2% methanol in dichloromethane) to provide the title compound (621 mg, 94%) as a sticky solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C[Si]([N:33]=[C:34]=[O:35])(C)C.O>ClCCl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])[CH2:23][C@H:24]3[CH2:28][CH2:27][N:26]([C:34]([NH2:33])=[O:35])[CH2:25]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: O
Product: NC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Yield: 99.9 %

Procedure:
The (R)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (20.0 mg, 47.2 μmol) obtained in Step 1 of Example 2 was dissolved in dichloromethane (1 mL), and trimethylsilyl isocyanate (25.0 μL, 188 μmol) was then added to the obtained solution. The obtained mixture was stirred for hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→20%) to obtain the captioned compound (22.0 mg, 99%) in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:19][C:20]1[C:21]([NH2:25])=[N:22][O:23][N:24]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:10](/[CH:11]=[N:12]/[O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4]([NH:25][C:21]1[C:20]([CH3:19])=[N:24][O:23][N:22]=1)=[O:6]
Reactant: Cc1nonc1N
Reactant: O=C(O)c1ccc(Cl)c(C=NOCC2CC2)c1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nonc1NC(=O)c1ccc(Cl)c(/C=N/OCC2CC2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
400 mg (1.39 mmol) of 2,4-dichloro-3-{[(cyclopropylmethoxy)imino]methyl}benzoic acid and 14418 mg (1.39 mmol) of 4-methyl-1,2,5-oxadiazole-3-amine were dissolved in 10 ml of CH2Cl2, 1.33 g (2.08 mmol) of propanephosphonic anhydride were added at 10-20° C. and the mixture was stirred at RT for 1 h. 700 mg of triethylamine and 34.6 mg (0.278 mmol) of DMAP were then added, and the mixture was stirred at RT for 2 days.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30].C(N(CC)CC)C.CN1CCCC1=O>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[N:23][C:2]([N:27]5[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCNC(=O)C3)cc1OCC2

Procedure:
A solution of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 (55.0 mg, 0.166 mmol), piperazin-2-one (0.110 g, 1.10 mmol) and triethylamine (0.275 mL, 1.97 mmol) in N-methylpyrrolidinone (3.00 mL, 31.1 mmol) was heated at 150° C. for 2d. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water and brine. The organic layer was dried Na2SO4, concentrated to give 325, analyzed by rHPLC. MS: (ESI+)=395.1. 1H NMR (400 MHz, DMSO) δ 8.55 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.6 Hz, 1H), 4.63-4.30 (m, 4H), 4.06 (d, J=8.0 Hz, 2H), 3.81-3.63 (m, 2H), 1.47 (d, J=6.6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(O)C.O.[OH-].[Na+]>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)Cc1ccc(-c2cccc(Cl)c2)nc1
Temperature: 67.5 °C

Procedure:
2-chloropyridine-5-acetic acid (0.2 gm, 1.21 mmole), 3-chlorophenylboronic acid (0.2 gm, 1.3 mmole) and 50% water wet 10% Palladium carbon (0.08 gm, 0.036 mmole Pd) were added to 10 ml of 5:1 water isopropanol mixture, then Na2CO3 (0.15 gm, 1.4 mmole) dissolved in 3 ml of water was added to the above mixture, the reaction was heated at 65-70° C. overnight, the reaction was cooled to room temperature, diluted with 20 ml of 70:15:1 i-PrOH/H2O/10% NaOH, filtered, the catalyst was washed with 20 ml×3 using the above mixture, the filtrate was dried under vacuum and crude mixture was used without any purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([F:21])[CH:3]=1.Cl.[NH2:23][OH:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:23][OH:24])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([F:21])[CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Reactant: NO
Agent: Cl
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Br)cc2F)cc1
Yield: 91 %

Procedure:
In a manner similar to that described for Example 4, Step (c), 4-(4′-bromo-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (1.05 g, 0.00300 mol) was allowed to react with hydroxylamine hydrochloride (0.256 g, 0.00368 mol) to give 1.00 g of 4-(4′-bromo-2′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a white solid; mp 163-164° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7](OC)=[O:8])([O-:3])=[O:2].O.[NH2:19][NH2:20]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([NH:19][NH2:20])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
A mixture of methyl 3-nitro-5-(trifluoromethyl)benzoate (20 g, 80 mmol) and hydrazine hydrate (5.56 mL, 96 mmol) in MeOH (100 mL) was stirred for 16 h at 25° C. Then the solvent was concentrated to yield an off white solid of 3-nitro-5-(trifluoromethyl)benzohydrazide (20 g, 72.2 mmol, 90% yield): 1H NMR (400 MHz, CD3OD) δ 8.89 (s, 1H), 8.65 (s, 1H), 8.50 (s, 1H); ES-LCMS m/z 250 (M+H).