Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C(OC3C=CC(C4C=CC=CC=4C4N=NNN=4)=CC=3)=C(C(OC(OC(=O)CC)C(C)C)=O)C3C(=CC=CC=3)N=2)CC1.[CH:44]1([C:47]2[C:56]([O:57][C:58]3[CH:63]=[CH:62][C:61]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[C:70]4[N:71]=[N:72][N:73]([C:75]([C:88]5[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=5)([C:82]5[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=5)[C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)[N:74]=4)=[CH:60][CH:59]=3)=[C:55]([C:94]([OH:96])=[O:95])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:48]=2)[CH2:46][CH2:45]1.[CH3:97][C:98]([CH3:108])([CH3:107])[C:99]([O:101][CH:102](Cl)[CH:103]([CH3:105])[CH3:104])=[O:100].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.C(OCC)(=O)C>[CH:44]1([C:47]2[C:56]([O:57][C:58]3[CH:59]=[CH:60][C:61]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[C:70]4[N:71]=[N:72][N:73]([C:75]([C:88]5[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=5)([C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)[C:82]5[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=5)[N:74]=4)=[CH:62][CH:63]=3)=[C:55]([C:94]([O:96][CH:102]([O:101][C:99](=[O:100])[C:98]([CH3:97])([CH3:108])[CH3:107])[CH:103]([CH3:105])[CH3:104])=[O:95])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:48]=2)[CH2:45][CH2:46]1
Reactant: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12
Reactant: CC(C)C(Cl)OC(=O)C(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCC(=O)OC(OC(=O)c1c(Oc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c(C2CC2)nc2ccccc12)C(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(OC(=O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12)OC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of the title A compound of Example 28, 2-cyclopropyl-3-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]oxy]-4-quinolinecarboxylic acid (1.55 mmol), the title B compound of Example 16, 2,2-dimethylpropanoic acid, 1-chloro-2-methylpropyl ester (1.09 g, 6.65 mmol), potassium carbonate (521 mg, 3.77 mmol), potassium iodide (375 mg, 2.26 mmol), and 18-crown-6 (100 mg, 0.378 mmol) in dimethylformamide (3.7 mL) was heated at 90° C. for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (75 mL) and filtered. The organic filtrate was rinsed with aq. 5% sodium bisulfite and brine, dried (magnesium sulfate), and concentrated in vacuo to give a crude product (2 g). Flash chromatography on silica gel (60 g) eluted with 1 column volume of hexanes followed by 1.8 L of 12:1, then 900 mL of 8:1, hexanes:ethyl acetate yielded the title compound (950 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]=[C:16]=[O:17].C([Li])CCC>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:16]([NH:15][C:9]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:8]=2[Cl:7])=[O:17])=[CH:5][N:6]=1
Reactant: Cc1cccc(Cl)c1N=C=O
Reactant: Clc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(Cl)s1

Procedure:
The first step of the process involves reacting 2-chlorothiazole with 2-chloro-6-methylphenylisocyanate in the presence of n-butyl lithium in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide. The second step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide with 4-methoxybenzylchloride in the presence of sodium hydride in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The third step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with 4-amino-6-chloro-2-methylpyrimidine in the presence of sodium hydride in tetrahydrofuran at reflux temperature to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The fourth step involves reacting N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with trifluoromethanesulfonic acid and trifluoroacetic acid in dichloromethane to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[F:6][C:7]([F:24])([F:23])[C:8]1[CH:9]=[C:10](/[CH:14]=[N:15]/[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:12][CH:13]=1>>[CH3:1][S:2]([CH2:5][CH:14]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:24])([F:23])[F:6])[CH:9]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)/N=C/c1cccc(C(F)(F)F)c1
Reactant: CS(C)(=O)=O
Product: CC(C)(C)OC(=O)NC(CS(C)(=O)=O)c1cccc(C(F)(F)F)c1

Procedure:
From 1.50 g (15.9 mmol) of (methylsulphonyl)methane and 1.45 g (5.31 mmol) of the compound from Example 11A, using the same process as for Example 117A, 535 mg (27% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:3])[CH3:2].[N:10]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[N:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13]>C1(C)C=CC=CC=1>[CH:15]([O:14][C:12]([N:11]([C:4]1([C:1](=[O:3])[CH3:2])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[NH:10][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: CC(=O)C1CCCC1=O
Solvent: Cc1ccccc1
Product: CC(=O)C1(N(NC(=O)OC(C)C)C(=O)OC(C)C)CCCC1=O
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a solution of 2-acetyl-cyclopentanone (13.9 mg, 0.11 mol) and (R,R)-trans-1-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(N,N-dimethylamino)cyclohexyl]thiourea (4.1 mg, 0.01 mmol) in toluene (1 mL) was added diisopropyl azodicarboxylate (21.5 μL, 0.10 mmol) at −78° C. After stirring for 18 hr, the reaction mixture was concentrated. The residue was purified by silica gel column (hexane/ethyl acetate=3/1) to give the title compound (31.8 mg, yield: 97%, optical purity: 77% ee). Colorless oil
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:30])(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:25]4[CH2:26][CH2:27][CH2:28][S:24]4(=[O:30])=[O:29])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nn3)CC2)c(C)c1
Yield: 37.2 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and isothiazolidine 1,1-dioxide (66 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (70 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12])[C:7]=1[NH2:8].[CH:16](Cl)(Cl)Cl.CCOCC>C(O)=O>[CH3:13][CH:10]([CH2:11][CH3:12])[CH2:9][N:6]1[C:7]2[N:8]=[CH:16][NH:1][C:2]=2[C:3](=[O:15])[NH:4][C:5]1=[O:14]
Reactant: ClC(Cl)Cl
Reactant: CCC(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Solvent: O=CO
Solvent: CCOCC
Product: CCC(C)Cn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
17.3 g of 5,6-diamino-1-(2-methyl-1-butyl)-2,4-(1H,3H)-pyrimidinedione (XXXXII) was refluxed in 30 ml of formic acid for 2 h. 20 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 17.0 g. The amide was refluxed in 50 ml of 2N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 400 ml of ethanol. Yield 10 g (XXXXI) NMR (see Table I).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].O.O.[OH-].[Li+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=3)[N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Yield: 99 %

Procedure:
To a solution of ethyl 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate (0.16 g, 0.39 mmol) in tetrahydrofuran (8 mL), and water (2 mL) was added lithium hydroxide monohydrate (0.08 g, 1.99 mmol) at ambient temperature. The resulting reaction mixture was heated to reflux for 17 hours. The organic solvent was removed in vacuo and the residue was neutralized to pH 4˜5 with 10% hydrochloric acid. The resulting precipitate was filtered and dried to afford the title compound in 99% yield (0.15 g): MS (ES+) m/z 385.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=[C:22]([CH3:30])[N:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH:29][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:24][CH:23]=[C:22]([CH3:30])[N:21]=1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: Cc1ccc(OCCN)c(C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(OCCNc2nc(Nc3cc(C)[nH]n3)cc(C)c2C#N)c(C)n1
Temperature: 100 °C
Reaction time: 27 h
Yield: 5.5 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(2,6-dimethylpyridin-3-yloxy)ethylamine hydrochloride (584 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(2,6-dimethylpyridin-3-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile dihydrochloride (30 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25](OC)=[O:26])=[C:11]2[C:16](=[CH:17][CH:18]=1)[C@@H:15]([OH:19])[C@H:14]([NH:20][CH:21]1[CH2:24][CH2:23][CH2:22]1)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:25][OH:26])=[C:11]2[C:16](=[CH:17][CH:18]=1)[C@@H:15]([OH:19])[C@H:14]([NH:20][CH:21]1[CH2:24][CH2:23][CH2:22]1)[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(OCc2ccccc2)ccc2c1CC[C@@H](NC1CCC1)[C@@H]2O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1c(OCc2ccccc2)ccc2c1CC[C@@H](NC1CCC1)[C@@H]2O

Procedure:
In 20 ml. of anhydrous tetrahydrofuran is dissolved 535 mg. of trans-6-benzyloxy-2-cyclobutylamino-1-hydroxy-5-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene and with the addition of 200 mg. of lithium aluminum hydride, the solution is refluxed in a current of molecular nitrogen for 4 hours. After cooling, a 20 % solution of sodium hydroxide is added, followed by extraction with ethyl acetate. The ethyl acetate layer is washed with water, dried and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate. The procedure provides trans-6-benzyloxy-2-cyclobutylamino-1-hydroxy-5-hydroxymethyl-1,2,3,4-tetrahydronaphthalene as colorless platelets melting at 156°-158° C. Yield 377 mg.
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>>[O:27]1[C:19]2[CH:18]=[CH:17][C:22](/[CH:23]=[CH:1]/[C:2]3[O:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:3]=3)=[CH:21][C:20]=2[O:25][CH2:26]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: Cc1cc(OCc2ccccc2)cc(=O)o1
Product: O=c1cc(OCc2ccccc2)cc(/C=C/c2ccc3c(c2)OCO3)o1
Yield: 39 %

Procedure:
6-methyl-4-(phenylmethoxy)-2H-pyran-2-one (known) was reacted with piperonal in accordance with Method C described above under II to form E-6-[2-(1,3-benzodioxol -5-yl)ethenyl]-4-(phenylmethoxy)-2H-pyran-2-one: C21H16O5; yield 39%, melting point 150 to 152° C. (acetone). This condensation product was hydrogenated in accordance with Method A described above under I. For cleaning purposes the product was taken up in ethyl acetate, was extracted therefrom with 2 N potassium hydroxide solution and was precipitated from the latter by acidification: C14H12O5; yield 67%, melting point 200 to 201° C. (isopropanol/water).
Reaction SMILES: [CH2:1](Cl)Cl.C[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16][CH2:17][C:18](=[O:23])[CH2:19][C:20]([O-:22])=[O:21])[CH:10]=[CH:9]2.B(Br)(Br)Br>CO>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16][CH2:17][C:18](=[O:23])[CH2:19][C:20]([O:22][CH3:1])=[O:21])[CH:10]=[CH:9]2
Reactant: COc1ccc2cc(SCC(=O)CC(=O)[O-])ccc2c1
Reactant: ClCCl
Agent: BrB(Br)Br
Solvent: CO
Product: COC(=O)CC(=O)CSc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dry methylene chloride solution of 102.8 mg (0.34 mmol) of 4-(6-methoxy-2-naphthylthio)-3-oxobutanoate was cooled to -78° C., one hundred (100) μl (0.97 mmol) of boron tribromide was added, and the reaction was carried out from -78° C. to room temperature for 2 hours. Then dry methanol (3 ml) was added, and the mixture was stirred over one day and night at room temperature. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the desired sulfideketone derivative was obtained by silica gel column chromatography. Yield: 81.8 mg (83%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH3:25]I>>[CH3:25][N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=1
Reactant: O=c1nc(Nc2ccc(C(F)(F)F)cc2)sc2ncccc12
Reactant: CI
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc(C(F)(F)F)cc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 646 mg of 2-(4-trifluoromethylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 18 mg of lithium hydride and 0.13 ml of methyl iodide were used. As a result, 565 mg of 3-methyl-2-[(4-trifluoromethylphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 25 mg of 2-[N-methyl-N-(4-trifluoromethylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (76 mg, 91%), MS (ISP) m/z=336.4 [(M+H)+], mp 245.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:20])[C:17]([OH:19])=O)[C:3]=12.[C:21]1([C:27](=[N:34][C:35]#[N:36])[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].O>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:20])[C:17]([N:31]3[CH2:30][CH2:29][N:28]([C:27](=[N:34][C:35]#[N:36])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:33][CH2:32]3)=[O:19])[C:3]=12
Reactant: O=C(O)C(=O)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Reactant: N#CN=C(c1ccccc1)N1CCNCC1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#CN=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3c(-n4ccnn4)ncc(F)c23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 3 %

Procedure:
2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (100 mg), (phenyl(piperazin-1-yl)methylene)cyanamide (77 mg), DEPBT (108 mg) and iPr2NEt (0.2 ml) were combined in DMF (2 ml). The reaction mixture was stirred at room temperature for 17 hours before diluted with 10% Na2CO3 in water (5 ml). The aqueous solution was extracted with EtOAc (3×20 ml). The organic layer was combined, dried over MgSO4 and concentrated. The residue was tritarated with MeOH (5 ml) and the resultant solid was collected by filtration to give ((4-(2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperazin-1-yl)(phenyl)methylene)cyanamide (5 mg).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:23]([NH:25][C@H:26]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][CH:29]=1)=[O:24])[CH2:17][O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(NCC)C>CN(C)C=O>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:23]([NH:25][C@H:26]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:30][CH:29]=1)=[O:24])[CH2:17][O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)OC[C@H](NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C

Procedure:
93.0 g (about 102 mmol) of Fmoc-D-Trp-Ser(tBu)-Tyr(tBu)-OtBu are dissolved in 500 ml of dimethylformamide. 114.5 ml of diethylamine are added to this while stirring, reaction is allowed to take place at room temperature for 10 minutes, and the mixture is concentrated under high vacuum. The residue is triturated 3 times with petroleum ether and twice with diethyl ether. The diethyl ether is removed by distillation and then partition between ethyl acetate and water is carried out. The ethyl acetate is, after drying over Na2SO4, removed by distillation, and the residue is triturated twice with diethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27]Br.[NH4+].[Cl-]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:27][CH2:26][CH2:25]2)=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:19])([F:20])[F:21])([O-:3])=[O:2]
Reactant: BrCCCBr
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])c(OCC(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.7 %

Procedure:
Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (3 g, 9.7 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.514 g, 10.7 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,3-dibromopropane (1.03 mL, 9.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (900 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:23][CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([CH2:12][N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:24])([OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)CC1(O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Epoxide (32) (46 g, 216 mmol) was dissolved in dioxane (300 ml). Benzyl methylamine (75 ml, 583 mmol) was added and the mixture was stirred at reflux for 90 h. TLC analysis revealed complete conversion. The mixture was evaporated to dryness. The excess of benzyl methylamine was removed by evaporation in vacuo (0.05 mbar, 80° C.). Yield: 69.3 g of aminoalcohol (35) (96%) as an orange oil.
Reaction SMILES: [CH:1]([CH:4]1[CH:9]([C:10]#[N:11])[CH2:8][CH:7]2[CH2:12][CH:5]1[C:6]2([CH3:14])[CH3:13])([CH3:3])[CH3:2].C(C1C(CN2C(=O)C(CC3C=CN=CC=3)(CC3C=CN=CC=3)NC2=CC(C2C=CC(C#N)=CC=2)=O)CC2CC1C2(C)C)(C)C.[N-]=[C:60]=[S:61]>>[CH:1]([CH:4]1[CH:9]([CH2:10][N:11]=[C:60]=[S:61])[CH2:8][CH:7]2[CH2:12][CH:5]1[C:6]2([CH3:14])[CH3:13])([CH3:3])[CH3:2]
Reactant: [N-]=C=S
Reactant: CC(C)C1C(C#N)CC2CC1C2(C)C
Agent: CC(C)C1C(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Product: CC(C)C1C(CN=C=S)CC2CC1C2(C)C

Procedure:
The same procedure that was used in example 1 was followed except that 2-isopropyl-3-isothiocyanatomethyl-6,6-dimethyl-bicyclo[3.1.1]heptane was used in the place of (+)-3-pinanemethyl isothiocyanate in step D to give the titled compound as a tan solid. 2-Isopropyl-3-isothiocyanatomethyl-6,6-dimethyl-bicyclo[3.1.1]heptane was prepared by reduction of 2-isopropyl-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carbonitrile to the requisite amine following the procedure in step C of example 42 and subsequent conversion to the isothiocyanate using step A of example 15: C.I. m/z 588 [M+1]; 1H NMR (CDCl3)δ 10.45 (br s, 1H), 8.42-8.46 (m, 4H), 7.82 (d, J=8.1 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 7.13 (m, 2H), 7.07 (m, 2H), 5.22 (s, 1H), 3.32 (dd, J=11.2, 13.9 Hz, 1H), 3.24 (d, J=13.1 Hz, 2H), 3.01-3.10 (m, 2H), 2.92 (dd, J=3.1, 13.9 Hz, 1H), 1.96 (m, 1H), 1.76 (m, 1H), 1.59-1.70 (m, 3H), 1.32 (m, 1H), 1.24 (m, 1H), 1.14 (s, 3H), 1.05 (d, 10.2 Hz, 1H), 0.86 (d, J=6.6 Hz, 3H), 0.78 (d, J=6.9 Hz, 3H), 0.70 (s, 3H), 0.50 (m, 1H).