Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:22]([N:26]([CH2:30][CH2:31]Cl)[CH2:27][CH2:28]Cl)[CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:31][CH2:30][N:26]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28]1)=[O:21])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OCCC(C)C)cc1
Reactant: CCCCN(CCCl)CCCl
Product: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CC1

Procedure:
1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester (6.2 g, 20 mmol) and butyl-bis-(2-chloro-ethyl)-amine (5.2 g, 22 mmol). Yield 7 g (79%); yellow oil; MS: 440 (M+H)+
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:16][CH:15]=2)[CH2:11][C:12]1=[O:17])(=[O:20])[CH3:19]
Reactant: CCCCCC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)OC(C)=O
Product: CCCCCC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O

Procedure:
Prepared from 5-hexanoyl-2-indolinone and acetic anhydride
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:32]([O:36][C:37]([NH:39][C@@H:40]([CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[C:41]([OH:43])=O)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C@:51]12([CH3:61])[C:57]([CH3:59])([CH3:58])[CH:54]([CH2:55][CH2:56]1)[CH2:53][CH:52]2[NH2:60]>CN(C=O)C>[C:32]([O:36][C:37](=[O:38])[NH:39][C@H:40]([C:41](=[O:43])[NH:60][C@H:52]1[CH2:53][C@@H:54]2[C:57]([CH3:59])([CH3:58])[C@@:51]1([CH3:61])[CH2:56][CH2:55]2)[CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CC1(C)C2CC[C@@]1(C)C(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@H]1C[C@H]2CC[C@]1(C)C2(C)C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
3.53 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.4 mmol, 1.0 equiv.), 1.25 g of 1-hydroxybenzotriazole (9.2 mmol, 0.5 equiv.) and 7.3 ml of Hünig's base were added to a solution of 5.0 g of (S)-2-tert-butoxycarbonylamino-3-cyclohexylpropionic acid (Boc-Cha-OH, 18.4 mmol, 1.0 equiv.) in DMF (60 ml) at 0° C. under argon, and the mixture was stirred for 30 min. Then 2.83 g of (R)-(+)-bornylamine (18.4 mmol, 1.0 equiv.) and 3.7 ml of Hünig's base were added, and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with NaHCO3 (saturated, aq.) and extracted three times with ethyl acetate. The combined organic phases were washed twice with water and dried over Na2SO4 and concentrated. Purification by flash chromatography on silica gel with heptane/ethyl acetate mixtures as eluent afforded 6.58 g (88% yield) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][OH:66])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:57][CH:58]5[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][OH:66])[CH2:60][CH2:59]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(CCO)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino piperidine 1-ethanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-2.07 (m, 12 H) 2.38 (t, J=6.32 Hz, 2 H) 2.89 (d, J=11.37 Hz, 2 H) 3.27-3.34 (s, 3 H) 3.49 (q, J=6.06 Hz, 2 H) 3.65-3.83 (m, 1 H) 3.93 (s, 2 H) 3.97-4.14 (m, 2 H) 4.37 (t, J=5.31 Hz, 1 H) 4.76 (t, J=7.83 Hz, 1 H) 7.48 (d, J=8.0 Hz, 1 H), 7.49 (br. s., 1 H) 7.96 (s, 1 H) 8.12 (d, J=7.83 Hz, 1 H)), 8.26 (s, 1 H) 8.27 (d, J=8.0 Hz, 1 H). [M+H] calculated for C28H37F2N7O4, 574; found 574.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.O1CCCC1.[CH3:26][NH2:27]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:27][CH3:26])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CN
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reaction time: 0.25 h

Procedure:
A suspension of 14.3g (0.05 mol) of 7-chloro-5-phenyl-1,2,3,5-tetrahydro-4H-1,5-benzodiazepin-2,4-dione in 1l of tetrahydrofuran and 200 ml of benzene was saturated with methylamine. A solution of 11.5 g (0.06 mol) of titanium tetrachloride in 200 ml of benzene was added at 0° through a dropping funnel. After stirring at 0° to 10° for 15 min, the mixture was heated to reflux for 1 1/2 hrs. It was then partitioned between water and benzene. The benzene layer was separated, dried and evaporated. Crystallization of the residue form methylene chloride/hexane yielded the above-named product, mp 215°-217°.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([C:18](OCC)=[O:19])=[C:14]3[C:23](OCC)=[O:24])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:32][NH2:33]>C(O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][N:13]3[C:14]4[C:23](=[O:24])[NH:32][NH:33][C:18](=[O:19])[C:15]=4[CH:16]=[CH:17]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1ccn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C(=O)OCC
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccc3c(=O)[nH][nH]c(=O)c32)cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
In ethanol (70 ml) was dissolved 1-[4-(4-chlorobenzoyl)benzyl]-2,3-diethoxycarbonylpyrrole (3.31 g) followed by addition of anhydrous hydrazine (10.54 g) and the mixture was refluxed for 3 hours. The solvent was then distilled off under reduced pressure and the resulting crystals were suspended in water (150 ml) and, after addition of concentrated hydrochloric acid (30 ml), stirred at 85° C. for 30 minutes. The crystals were rinsed with water, methanol and ether serially and dried under reduced pressure to provide 1.46 g (yield 81%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6]2[CH:13]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:10][C:7]=2[S:8][CH:9]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH2:21]1>C(O)(=O)C>[CH3:26][C@H:24]1[CH2:23][N:22]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=2)[CH2:21][C@@H:20]([CH3:19])[N:25]1[S:14]([C:12]1[CH:11]=[CH:10][C:7]2[S:8][CH:9]=[C:5]([CH2:4][C:3]([OH:2])=[O:18])[C:6]=2[CH:13]=1)(=[O:16])=[O:15]
Reactant: COC(=O)Cc1csc2ccc(S(=O)(=O)Cl)cc12
Reactant: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1
Solvent: CC(=O)O
Product: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1ccc2scc(CC(=O)O)c2c1

Procedure:
{5-|cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl|-benzo|b|thiophen-3-yl}-acetic acid: The compound {5-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-acetic acid was synthesized according to the procedure in Example 37 using (5-chlorosulfonyl-benzo[b]thiophen-3-yl)-acetic acid methyl ester and cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine from Example 95, Step 1. 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.96 (d, 1H), 7.88-7.80 (m, 2H), 7.57 (d, 2H), 7.28 (d, 2H), 4.60-4.50 (m, 2H), 4.36 (s, 2H), 3.97 (s, 2H), 3.38-3.28 (m, 2H), 2.74-2.64 (m, 2H), 1.55 (d, 6H); LCMS 542.9 (M+1)+.
Reaction SMILES: CO[C:3](=[O:33])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([OH:30])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=C(C)O[N:15]=2)=[CH:10][CH:9]=1.C[O:35][C:36]([C:38]1[S:39][CH:40]=[CH:41][C:42]=1[NH:43][NH2:44])=[O:37].COC(=O)N=C(SC)C(C1C=C(OC)C=C(O)C=1F)=NC1C=CC(C2N=[C:61]([CH3:63])[O:60]N=2)=CC=1.COC(C1SC=NC=1NN)=O>>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C@@H:6]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH2:63][CH2:61][OH:60])[CH:21]=2)[C:5]2[NH:4][C:3](=[O:33])[N:43]([C:42]3[CH:41]=[CH:40][S:39][C:38]=3[C:36]([OH:35])=[O:37])[N:44]=2)=[CH:13][CH:12]=1)(=[NH:18])[NH2:15]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Reactant: COC(=O)c1sccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(O)c(OC)c(OC)c1
Agent: COC(=O)c1scnc1NN
Product: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)cc(OCCO)c1OC

Procedure:
The same procedure was carried out as in Example 167, except that {2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (159a)) and 3-hydrazinothiophene-2-carboxylic acid methyl ester were used instead of respectively the [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester and 4-hydrazinothiazole-5-carboxylic acid methyl ester, to give the first eluting enantiomer of the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH3:20])([CH3:19])[S:17](=[O:18])[C@H:13]12)(=[O:10])[CH3:9].[Cl:36]N1C(=O)CCC1=O>O>[CH3:19][C:16](=[CH2:20])[CH:15]([N:14]1[C:34](=[O:35])[CH:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:13]1[S:17]([Cl:36])=[O:18])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(C)(C)S(=O)[C@H]12
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(C)=O)C1S(=O)Cl

Procedure:
Toluene (500 ml.) was heated in equipment containing a Dean-Stark water trap to azeotropically remove any moisture which may be present. To the resulting dried toluene was added 1.0 gms. (2.4 mmol.) of p-nitrobenzyl 6-acetamido-2,2-dimethylpenam-3-carboxylate-1-oxide. The resulting mixture was refluxed again using a Dean-Stark water trap to remove any additional amounts of water which may be present. The mixture then was cooled, and 400 mg. (2.9 mmol) of N-chlorosuccinimide were added. The mixture then was refluxed for 1 hour. A sample of the reaction mixture was withdrawn, and the solvent was removed. The product which was obtain was consistent by nmr analysis with the structure of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(O)(=O)C.[H][H]>C1COCC1.[Pd].C([O-])([O-])=O.[Ca+2]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH:12]=[CH:13][C:14](=[O:17])[CH2:15][CH2:16]2)=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C=CN(c2ccc([N+](=O)[O-])cc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccc(N2C=CC(=O)CC2)c(F)c1

Procedure:
In a 500 ml Parr bottle, 1-(2-fluoro-4-nitrophenyl)-2,3-dihydro-1H-pyridin-4-one (Step 3, 35 g, 148.3 mmol), Pd/CaCO3 (3.5 g, 10 wt %) and acetic acid (17 ml, 297 mmol) are combined in THF (350 ml). The mixture is hydrogenated at 40° C. under 15 psi hydrogen for 6 h at which time the reaction is complete by HPLC. The reaction mixture is filtered through a GF/F filter and the catalyst cake washed with THF (350 ml). The filtrate is partitioned between 500 ml of NaHCO3 and 500 ml of ethyl acetate. The organic layer is washed again with 500 ml of NaHCO3. The organic layer is separated and dried over MgSO4. The mixture is filtered, and the filtrate is concentrated under reduced pressure to afford 29.0 g (95% recovery) of the title compound, MS (ESI−) for C11H11FN2O m/z 205.0 (M−H)−; 1H NMR (MeOD) δ 7.37 (d, 1H), 7.02 (t, 1H), 6.47 (m, 3H), 5.07 (d, 1H), 3.84 (t, 2H), 2.58 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[O:22]=[C:23]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[CH2:24][CH2:25][C:26](O)=[O:27].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:26](=[O:27])[CH2:25][CH2:24][C:23](=[O:22])[C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)CCC(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCC(=O)c1cccs1)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 55.8 %

Procedure:
(S)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl amine (0.200 gm, 0.00068 moles) was taken up in 1:1 THF-water mixture (20 ml). To this was added 4-oxo-4 (2-thienyl)butanoic acid (0.125 gm, 0.00068 moles) and HOBt (0.091 gm, 0.00068 moles). The resulting mixture was cooled to 0° C. and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.142 gm, 0.00074 moles) was added and the resulting mixture was allowed to warm to room temp and then stirred for 24 hr. The reaction mixture was concentrated, 15 ml of saturated sodium bicarbonate was added, stirred for 15 min and then extracted with ethyl acetate. The ethyl acetate layer was separated and the solvent evaporated off. The residue was chromatographed over silica gel (100-200 mesh, 20 gm). The column was eluted with mixture of ethyl acetate:hexane, and finally with ethyl acetate. The combined fractions were concentrated to give the title compound (0.175 gm, 56%) as a white solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC(C)C)=O.[NH2:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].Cl>C(Cl)Cl.CN1CCOCC1.O>[O:25]=[C:24]1[C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([F:32])([F:33])[F:34])[C:22]=2[N:21]=[C:10]([CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[O:12]1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCc1nc2c(C(F)(F)F)cccc2c(=O)o1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A mixture of 17.5 g of N-BOC glycine, 100 ml of methylene chloride and 13.7 ml of N-methyl-morpholine was cooled to -20° C. and a solution of 13 ml of isobutyl chloroformate in 50 ml of methylene chloride was added. After stirring for 30 minutes at -20° C., a solution of 10.25 g of 2-amino-3-trifluoromethyl benzoic acid [prepared by the process of J. Med. Chem., Vol. 16 (2) 101,6 (1973)] in 5.49 ml of N-methyl-morpholine and 120 ml of methylene chloride was added thereto and after stirring for 20 hours at ambient temperature, the mixuture was poured into 500 ml of water and 150 ml of 2N hydrochloric acid. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and concentrated under reduced pressure to dryness. The residue was triturated with 50 ml of methanol and the mixture was frozen, separated, washed with methanol and dried under reduced pressure at 50° C. to obtain 11 g of 1,1-dimethylethyl [(4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl)-methyl]-carbamate melting at 176° C.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:8]2=[O:22])([O-:4])=[O:3].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:35][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:36][CH3:37])[N:27]=[CH:26][N:25]=[C:24]2[N:19]1[CH2:18][CH2:17][CH:16]([N:9]2[C:8](=[O:22])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[NH:11][C:10]2=[O:15])[CH2:21][CH2:20]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)n1C1CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Temperature: 80 °C
Yield: 84.7 %

Procedure:
In 150 ml of DMF was dissolved 3.0 g (8.09 mmol) of 1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide, and 1.7 g (8.09 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 1.1 g (24 mmol) of potassium carbonate were added to the solution, followed by heating at 80° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with an aqueous solution of sodium chloride and dried. After the solvent was distilled off, ethanol and ether were added to the residue. The precipitated crystals were collected by filtration and washed with ether to give 3.28 g (yield: 85%) of Compound 24 as white crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27].[CH3:31][CH:32]([CH3:36])[C:33](O)=[O:34]>>[C:33]([NH:25][S:22]([C:20]1[S:21][C:17]([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:28])[C:2]([CH3:1])([CH3:29])[CH3:30])=[C:7]([CH3:27])[CH:8]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:26])(=[O:24])=[O:23])(=[O:34])[CH:32]([CH3:36])[CH3:31]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Reactant: CC(C)C(=O)O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)NC(=O)C(C)C)s1
Yield: 56 %

Procedure:
Using a procedure analogous to Example 163, 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide and 2-methylpropionic acid give the title compound (56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[O:5][CH2:6]/[C:7](/[F:18])=[CH:8]\[CH2:9][NH:10]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:31]>>[ClH:31].[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[O:5][CH2:6]/[C:7](/[F:18])=[CH:8]\[CH2:9][NH2:10]
Reactant: CC(C)(C)OC(=O)NC/C=C(/F)COc1ccc(F)c(F)c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NC/C=C(/F)COc1ccc(F)c(F)c1
Reaction time: 2 h

Procedure:
To a stirred solution of (E)-tert-butyl 4-(3,4-difluorophenoxy)-3-fluorobut-2-enylcarbamate (0.061 g, 0.19 mmol [synthesized from (E)-tert-butyl 3-fluoro-4-hydroxybut-2-enylcarbamate and 3,4-difluorophenol following procedure F]) in CH2Cl2 (4.5 mL) at room temperature was added trifluoroacetic acid (0.5 mL). The reaction mixture was allowed to stir for 2 h until no further starting material remained by thin layer chromatography analysis. The solvent was then removed under reduced pressure and the residue taken up in diethyl ether (20 mL) and water (30 mL), and the pH adjusted to ˜pH 1 by addition of 0.1 M HCl (aq.). The aqueous layer was extracted with a further portion of diethyl ether (10 mL) before addition of 2 M NaOH solution to bring the pH up to ˜pH 12. The alkaline layer was extracted with diethyl ether (2×20 mL) and the organics combined and washed with brine (10 mL), dried over MgSO4, filtered and solvent removed under reduced pressure to afford the amine as a clear oil (0.061 g). This product was dissolved in diethyl ether and treated dropwise with HCl (2 M solution in diethyl ether; 0.4 mL) which resulted in the formation of a colorless precipitate. After standing for 20 minutes the precipitate was filtered, washed with diethyl ether (2×2 mL) and dried under vacuum to yield (E)-4-(3,4-difluorophenoxy)-3-fluorobut-2-en-1-amine hydrochloride (0.030 g, 62%) as a fine colorless powder; m.p.=139-140° C.; 1H-NMR (200 MHz, CD3OD): δppm: 3.70 (2H, d, J 7.4 Hz), 4.76 (2H, d, J 18.2 Hz), 5.54 (1H, dt, J 18.1, 8.3 Hz), 6.74-6.83 (1H, m), 6.90-7.01 (1H, m), 7.20 (1H, q, J 19.2).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[CH:21]=1)(=O)[NH2:2].COC(OC)[N:25]([CH3:27])C.Cl.[F:31][C:32]([F:37])([F:36])[CH2:33][NH:34]N>C(O)(=O)C>[F:31][C:32]([F:37])([F:36])[CH2:33][N:34]1[C:1]([C:4]2[N:5]=[C:6]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=4[O:10][CH2:9][CH2:8][N:7]3[CH:21]=2)=[N:2][CH:27]=[N:25]1
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(C(N)=O)nc1-2
Reactant: NNCC(F)(F)F
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Yield: 65 %

Procedure:
Alternatively, and following the procedure for 184, methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate was reacted with 1,1-dimethoxy-N,N-dimethylmethanamine, followed by treatment of trifluoroethylhydrazine hydrochloride in acetic acid to provide 185 (65% yield). 1H NMR (400 MHz, DMSO) δ 8.51 (d, J=8.4, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.71 (dd, J=8.4, 1.7, 1H), 7.58 (d, J=1.6, 1H), 5.89 (q, J=8.8, 2H), 4.65-4.45 (m, 5H), 3.87 (s, 3H), 3.58-3.37 (m, 7H)
Reaction SMILES: C([N:3](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[F:25][C:26]1[C:31]([O:32][CH2:33][CH2:34][F:35])=[CH:30][C:29]([O:36][CH3:37])=[CH:28][C:27]=1[CH:38]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[N:65]=[C:64]([CH3:66])[O:63][N:62]=2)=[CH:57][CH:56]=1)[C:39]1[NH:43][C:42](=[O:44])[N:41]([C:45]2[N:50]=[C:49](C(O)=O)[CH:48]=[CH:47][CH:46]=2)[N:40]=1>O1CCOCC1>[NH2:3][C:49]1[N:50]=[C:45]([N:41]2[C:42](=[O:44])[NH:43][C:39]([CH:38]([C:27]3[CH:28]=[C:29]([O:36][CH3:37])[CH:30]=[C:31]([O:32][CH2:33][CH2:34][F:35])[C:26]=3[F:25])[NH:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]4[N:65]=[C:64]([CH3:66])[O:63][N:62]=4)=[CH:57][CH:56]=3)=[N:40]2)[CH:46]=[CH:47][CH:48]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(OCCF)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3cccc(C(=O)O)n3)c(=O)[nH]2)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(OCCF)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3cccc(N)n3)c(=O)[nH]2)c1
Temperature: 80 °C

Procedure:
After adding 41 μl of triethylamine and 63 μl of diphenylphosphorylazide to a solution of 81 mg of 6-(3-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)pyridine-2-carboxylic acid in 4 ml of 1,4-dioxane under a nitrogen atmosphere, the mixture was heated for 20 hours at 80° C. After cooling, the reaction mixture was filtered and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (33 mg) as a white solid.