Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH2:19][C@@H:20]([C@H:46]([OH:48])[CH3:47])[CH2:21][O:22][C:23]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:61]([N:64]([CH:78]([CH3:80])[CH3:79])[P:65](N(C(C)C)C(C)C)[O:66][CH2:67][CH2:68][C:69]#[N:70])([CH3:63])[CH3:62]>ClCCl>[CH:78]([N:64]([CH:61]([CH3:63])[CH3:62])[P:65]([O:66][CH2:67][CH2:68][C:69]#[N:70])[O:48][C@H:46]([CH3:47])[C@H:20]([CH2:19][N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][CH:17]=[N:18][C:10]=2[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][O:22][C:23]([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:80])[CH3:79]
Reactant: COc1ccc(C(OC[C@@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 20 h
Yield: 93.1 %

Procedure:
To a stirred solution of 14 (0.9 g, 1.4 mmol) in 20 ml of anhydrous dichloromethane was added diisopropylammonium tetrazolide (0.25 g) followed by 0.5 g (1.66 mmol) of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite. In about 5 hrs another 0.04 g of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite was added. The reaction was allowed to proceed for total 20 hrs and then concentrated. The resultant semi-solid was portioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude phosphoramidite was precipitated twice by re-dissolving in small (˜5-10 ml) amount of ethyl acetate, diluting with hexane (100 ml), allowing to settle as an oil and decanting the liquid. Drying in vacuo afforded 1.1 g (93%) of 15 as a white amorphous solid. 31P NMR (DMSO-d6): δ 147.11, 146.16.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CO.O>[CH:19]1([CH2:18][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(OCC2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4′-hydroxyacetophenone (10.6 g, 77.7 mmol) in 600 mL MeOH and 15 mL H2O at room temperature was added Cs2CO3 (25.6 g, 1.01 eq). The reaction mixture immediately turned yellow and was then stirred for 40 min. The MEOH was removed in vacuo, and the remaining H2O was removed azetropically with 5×100 mL toluene. The resulting yellow solid was suspended in DMF (450 mL) and treated with (bromomethyl)cyclohexane (13.0 mL, 1.2 eq). The reaction mixture was heated to 90° C. and stirred overnight. The reaction mixture was then cooled to room temperature, poured into 500 mL of ice water and extracted with Et2O. The Et2O extract was dried over MgSO4 and concentrated in vacuo to a yellow oil, which smelled of the starting bromide. The bromide was distilled off at 50° C. under high vacuum until the bottoms reached a constant weight (13.96 g, 77%). This oil solidified to a white solid upon standing. 1H NMR (300 MHz CDCl3): 7.91 (2H, d, J=8.9 Hz), 6.90 (2H, d, J=8.8 Hz), 3.81 (2H, d, J=6.1 Hz), 2.55 (3H, s), 1.8 (6H, m), 1.2 (3H, m), 1.1 (2H, m).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[N+:32]([C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)([O-:34])=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([O:12][C:11](=[O:13])/[CH:10]=[CH:9]/[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:2][CH:3]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)/C=C/C=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
As in Example 115, a solution of (E)-5,5-bis[(1,1'-biphenyl)-4-yl]-2,4-pentadienoic acid (0.673 g) and 4-nitrophenol (0.256 g) in dichloromethane (7 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.345 g). The mixture was stirred at room temperature for 1.5 hours. The usual work up furnished 0.88 g of (E)-5,5-bis[(1,1'-biphenyl)-4-yl]-2,4-pentadienoic acid 4-nitrophenyl ester.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=1[F:32])#[N:16]>>[F:32][C:24]1[C:25]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1[C:17]([C:15]#[N:16])=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1-c1cccc(B(O)O)c1F
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C(F)(F)F)cnn23)c1F
Yield: 15 %

Procedure:
7-Bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine was coupled with 2′-cyano-2-fluorobiphenyl-3-boronic acid as described in Example 3, step f, to give 21 mg (15%) of the title compound: mp 167-168° C.; 1H NMR (360 MHz, CDCl3) δ 7.47-7.60 (4H, m), 7.73 (1H, dd, J 1.4, 7.7 Hz), 7.84 (1H, dd, J 0.7, 7.0 Hz), 8.26-8.30 (1H, m), 8.69 (1H, d, J 2.8 Hz), 8.83 (1H, s); MS (ES+) m/z 384 [M+H]+. Anal. Found: C, 59.14; H, 2.75; N, 18.01%. Required for C19H9F4N5.0.2H2O: C, 58.98; H, 2.45; N, 18.10%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[C:24]1([O:30]C)C=CC=CC=1.C(N1CCC(C(Cl)=O)CC1)(=O)C>C(=S)=S>[OH:30][CH2:24][CH2:2][CH2:1][N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1
Reactant: COc1ccccc1
Reactant: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)cc1
Agent: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)C2CCN(CCCO)CC2)cc1
Yield: 60 %

Procedure:
1-Acetyl-4-(4-methoxybenzoyl)piperidine. To a suspension of aluminum trichloride (3.40 g, 25.7 mmol) in CS2 (15 mL) were added anisole (1.90 mL, 17.6 mmol) and, portionwise, N-acetylisonipecotoyl chloride (2.40 g, 11.7 mmol). After the addition was complete, the mixture was refluxed for 1 h. The solvent was decanted and the red residue was dissolved in 5% HCl (50 mL) and was extracted with EtOAc (4×30 mL). The combined organic phase was dried and was concentrated under reduced pressure to afford the title compound as a colorless solid (1.8 g, 60%):mp 102-105° C.; 1H NMR (CDCl3) d 1.50-1.75 (m, 1H), 1.70-2.00 (m, 3H), 2.10 (s, 3H), 2.70-2.90 (m, 1H), 3.15-3.30 (m, 1H), 3.40-3.53 (m, 1H), 3.86 (s, 3H), 3.85-4.00 (m, 1H), 4.56 (d, J=13.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.92 (d, J=9.0 Hz, 2H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]([CH3:21])[CH2:7][C@H:8]([CH3:20])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)=[O:10].C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.[NH4+]>C1COCC1>[NH2:17][C:13]1[CH:12]=[C:11]([C@@:9]([OH:10])([CH2:1][CH3:2])[C@@H:8]([CH3:20])[CH2:7][N:6]([CH3:21])[CH3:5])[CH:16]=[CH:15][CH:14]=1
Reactant: CC[Mg]Br
Reactant: C[C@@H](CN(C)C)C(=O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)([O-])O
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC[C@](O)(c1cccc(N)c1)[C@@H](C)CN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
726 ml of ethylmagnesium bromide (1M in THF; 0.726 mol) are added under a nitrogen flow into a 2-liter four-neck flask, provided with mechanical stirrer, thermometer and dropping funnel. A solution of (S)-3-(dimethylamino)-2-methyl-1-(3-nitro-phenyl)-propan-1-one (50 g, 0.242 mol) in 50 ml of THF are dripped maintaining the temperature between 15-30° C. The reaction is stirred at room temperature for 3 hours. It is cooled to about 10° C. and toluene (200 ml) and slowly a 20% ammonium hydrogen sulphate solution (200 ml) are added. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The organic phase is concentrated under vacuum almost to oily residue. Then toluene (200 ml), 30% sodium metabisulfite solution (300 ml) are added. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The aqueous phase is washed 2 times with 200 ml of toluene. The organic phases are eliminated while Cert-butylmethylether (200 ml) is added to the aqueous phase. The pH of the mixture is brought to 11-12 with 28% sodium hydroxide. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The aqueous phase is eliminated while the organic phase is concentrated under vacuum to oily residue which solidifies by cooling. 35 g of a yellowish solid with a 95% HPLC purity are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].ClC1C2C(=CC=CC=2)N=CC=1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22][CH:21]=1.[H-].[Na+]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]=[CH:21][N:22]=1
Reactant: Nc1ccccc1O
Reactant: c1ccc2ncncc2c1
Agent: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ccccc1Oc1ncnc2ccccc12

Procedure:
Alternatively, the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative may be produced by reacting an aminophenol derivative with the 4-chloroquinoline derivative or corresponding quinazoline derivative in a suitable solvent, for example, dimethyl sulfoxide, in the presence of a base, for example, sodium hydride. Alternatively, the 4-(aminophenoxy)quinazoline derivative may also be produced by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the solution to a two-phase reaction with a solution of the 4-chloroquinazoline derivative in a suitable organic solvent, for example, ethyl methyl ketone, in the presence of a phase transfer catalyst, for example, tetra-n-butylammonium chloride, or in the absence of the catalyst.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([NH2:18])=[C:13]([CH3:19])[CH:12]=1)[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH2:20]([C:22]([CH3:24])=O)[CH3:21]>[Pt].C1(C)C=CC=CC=1>[CH:20]([NH:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:1]([CH2:2][CH3:3])[CH3:11])=[C:4]([CH3:10])[CH:3]=2)=[CH:12][C:13]=1[CH3:19])([CH2:22][CH3:24])[CH3:21]
Reactant: CCC(C)=O
Reactant: Cc1cc(Cc2cc(C)c(N)c(C)c2)cc(C)c1N
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CCC(C)Nc1c(C)cc(Cc2cc(C)c(NC(C)CC)c(C)c2)cc1C
Temperature: 22 °C
Reaction time: 4.5 h
Yield: 96 %

Procedure:
4,4′-Methylenebis(2,6-dimethylbenzeneamine) (1.25 g), methyl ethyl ketone (15 g), Pt(S)/C (0.10 g), and toluene (40.0 g) were charged into reactor. The reactor was purged 3 times with 110 psig (8.60×105 Pa) of H2 at 22° C. The reaction mixture was then stirred at 22° C. under 110 psig (8.60×105 Pa) of H2 for 4.5 hours. GC (conditions: 100° C./5 minutes/10° C.-minute/270° C.) showed 35% conversion of 4,4′-methylenebis(2,6-dimethylbenzeneamine). The reaction mixture was then stirred for 4 hours at 60° C., after which GC showed 79.5% conversion of 4,4′-methylenebis(2,6-dimethylbenzeneamine). The reaction mixture was then stirred for 11 hours at 130° C., after which GC showed 100% conversion of 4,4′-methylenebis(2,6-dimethylbenzeneamine), and a 96% yield of N,N′-di-sec-butyl-4,4′-methylenebis(2,6-dimethylbenzeneamine); the remaining 4% was determined to be N-sec-butyl-4,4′-methylenebis(2,6-dimethylbenzeneamine). The product was observed to be water-white in color, and the structure of the product was confirmed by GC-MS.
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.[CH:27](N(C(C)C)CC)(C)C.CNCCC>C(#N)C>[CH3:4][N:5]([CH2:6][CH2:7][CH3:27])[C:8](/[N:10]=[C:11]1\[S:12][C:13]([CH3:26])=[CH:14][N:15]\1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=1)=[O:9]
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: CCN(C(C)C)C(C)C
Agent: CCCNC
Agent: [I-]
Solvent: CC#N
Product: CCCN(C)C(=O)/N=c1\sc(C)cn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (50 mg, 0.10 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylethylamine (28 μL, 0.13 mmol) dissolved in acetonitrile (0.6 mL). Then, to the solution was added N-methylpropan-1-amine (8 mg, 0.11 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: CO[N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=[O:6].[ClH:13].[H][H]>CO.O>[ClH:13].[NH2:3][CH:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: CON=C(C(=O)O)c1csnn1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(C(=O)O)c1csnn1
Reaction time: 1 h

Procedure:
A solution of 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (mixture of syn- and anti-isomers) (500 mg) [prepared by the method described in Belgian Pat. No. 859384 (1978)] in a mixture of methanol (10 cm3) and water (2.3 cm3) was treated with 1N hydrochloric acid (2.7 cm3) and hydrogenated under 50 psi of hydrogen with 5% rhodium-on-charcoal (500 mg) for one hour. A further portion of catalyst (500 mg) was added and hydrogenation continued for one hour. After filtration the filtrate was evaporated to dryness in vacuo and the residue triturated with ether to give the title compound as an off-white solid, (490 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:23][O:24][CH3:25])[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH:13]2[CH2:14][N:11]([CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:23][O:24][CH3:25])[CH2:12]2)=[CH:21][CH:20]=1
Reactant: COC[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@@H](N)CCN1CC(Oc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-carbamic acid tert-butyl ester (0.87 g, 2.26 mmol) in dichloromethane (7 ml) is treated with trifluoroacetic acid (2 ml), and stirred at ambient temperature for 18 hours. The solvent is evaporated and the residue taken up in water, made alkali with 4.0 M aqueous sodium hydroxide solution and extracted into dichloromethane. The organic phase is dried over MgSO4 and evaporated to afford (S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propylamine. [MH]+ 285.20
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([F:17])[CH:5]=1)[CH3:3].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30](O)=[O:31])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CCOC(OC(OCC)=O)=O>CN(C=O)C>[F:17][C:6]1[CH:5]=[C:4]([CH:2]([NH:1][C:30](=[O:31])[C:29]#[C:28][C:25]2[CH:26]=[CH:27][C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:23][CH:24]=2)[CH3:3])[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: C=Cc1cc(C(C)N)cc(F)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(C#CC(=O)O)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: C=Cc1cc(C(C)NC(=O)C#Cc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 85.1 %

Procedure:
N-[4-(1-Amino-ethyl)-2-fluoro-6-vinylphenyl]methanesulfonamide (0.03 mmol, 10.0 mg), (4-tert-butylphenyl)propynoic acid (step 2 of Example 11, 0.03 mmol, 6.52 mg), DEPC (0.03 mmol, 5.46 μl), and TEA (0.06 mmol, 8.36 μl) were added into DMF. The mixture was stirred for 12 hr. The reaction mixture was purified according to Example 12 to give a title product (11.3 mg, 95.09%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].[Cl:18][CH2:19][C:20](=O)[CH2:21]Cl>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:21]=[C:20]([CH2:19][Cl:18])[N:8]=2)[CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: FC(F)(F)c1cc(-c2nc(CCl)co2)cc(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 353A using 3,5-bis-(trifluoromethyl)benzamide and 1,3-dichloro-2-propanone: 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 2H), 7.96 (s, 1H), 7.80 (s, 1H), 4.59 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH2:37]2)(=[O:33])=[O:32].N1CCCCC1>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])/[C:37]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1])(=[O:32])=[O:33]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Temperature: 25 °C
Yield: 79 %

Procedure:
3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c (75 mg, 0.262 mmol) and 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (84 mg, 0.236 mmol) were dissolved in 2.5 ml of ethanol, and added with 42 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2-oxoindolin-3-yl idene)methyl)-3-methyl-5-(2-(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 66 (117 mg, yield 79.6%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([OH:27])=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1.Cl.[NH2:29][C@H:30]([C:35]([NH2:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33]>>[NH2:37][C:35]([C@@H:30]([NH:29][C:25]([C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)=[O:27])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:36]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1)C(N)=O

Procedure:
The title compound was prepared from the product of example 148 step (i) (0.15 g) and (S)-leucinamide hydrochloride (0.07 g) according to the method of example 115, step (i). Yield 0.04 g as a solid.
Reaction SMILES: Cl[CH:2]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=1>>[CH:18]1([CH:2]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ClC(c1nn(-c2ccccc2)c2ccccc12)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2nn(-c3ccccc3)c3ccccc23)C2CCCCC2)cc1
Yield: 12.4 %

Procedure:
Using 3-[chloro(cyclohexyl)methyl]-1-phenyl-1H-indazole (397 mg) synthesized in Example A14(4) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (305 mg) synthesized in Example 2(2) and in the same manner as in Example A7(3), the title object compound (76.9 mg, 12%) was obtained as a pale-yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:40])[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]2[CH:16]=[C:17]([C:21]([N:23]([CH:37]([CH3:39])[CH3:38])[C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=[O:22])[C:18]([CH3:20])=[CH:19][C:5]=2[O:4]1.[CH2:41]([N:43]=[C:44]=[O:45])[CH3:42]>O1CCCC1>[CH2:41]([NH:43][C:44]([O:1][CH2:2][C:3]1([CH3:40])[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]2[CH:16]=[C:17]([C:21]([N:23]([CH:37]([CH3:38])[CH3:39])[C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:25]3)=[O:22])[C:18]([CH3:20])=[CH:19][C:5]=2[O:4]1)=[O:45])[CH3:42]
Reactant: COCCCCN1C(=O)C(C)(CO)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)OCC1(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2N(CCCCOC)C1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
To a solution of tert-butyl (3R)-3-[{[2-(hydroxymethyl)-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (66 mg) in tetrahydrofuran (1 ml) was added ethyl isocyanate (83 mg), and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (65 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:10])([CH3:9])[C:7]#[N:8].[NH2:11][OH:12]>CCO>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:10])([CH3:9])[C:7]([NH:11][OH:12])=[NH:8]
Reactant: CC(C)(C#N)COCCCl
Reactant: NO
Solvent: CCO
Product: CC(C)(COCCCl)C(=N)NO
Reaction time: 18 h

Procedure:
3-(2-Chloroethoxy)-2,2-dimethylpropanenitrile (6.1 g, 37.7 mmol) was placed together with 50% aqueous hydroxylamine (3.1 g, 37.7 mmol) in 60 mL EtOH and warmed at 75-80 C with stirring for 18 h. The solution was concentrated and then concentrated further with EtOH and vacuum dried to leave (9.4 g, ˜80% pure) of the title compound as a gum. 1H NMR (300 MHz, CDCl3) δ: 1.17 (s, 6H), 3.40 (s, 2H), 3.58-3.73 (m, 4H), 5.16 (s, 2H). LC/MS (M+H): 195.