Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH:23][C:31](=[O:33])[CH3:32])=[CH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) (1.5 g, 0.005 mol), triethylamine (0.76 mL, 0.0054 mol) and N,N-dimethylaminopyridine (catalytic amount) in 50 mL of dichloromethane is cooled to 0° C. and acetyl chloride (0.42 mL, 0.006 mol) is added dropwise. The cold bath is removed and the solution is stirred at room temperature for 1 hour. The reaction is quenched with saturated aqueous sodium bicarbonate, the organic layer is washed with water and dried (sodium sulfate), and the solvent is removed under reduced pressure. The residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound, containing 0.35 mol of water; mp 158.5°-159.5° C.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:16]([O-:18])=[O:17])=[CH:10][C:11]=2I)[CH2:6]1)=O.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl.CO>CCOCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].ClCCl.O.O.C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:11]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][NH:5][CH2:6]2
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(N1CCc2c(I)cc([N+](=O)[O-])cc2C1)C(F)(F)F
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1cc2c(c(-c3ccccc3Cl)c1)CCNC2
Temperature: 25 °C

Procedure:
2,2,2-Trifluoro-1-(5-iodo-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (0.8 g, 2 mmoles) and 2-chlorophenyl boronic acid (0.31 g, 2 mmoles) were stirred with an acetonitrile water mixture (50:50, 28 mls). Anhydrous potassium carbonate (0.55 g, 4 mmoles) was then added under a stream of nitrogen. To this solution was then added palladium tetra(triphenyl phosphine) (tetrakis, 0.12 g, catalytic) and the solution heated (95° C.) for three hours. The reaction mixture was cooled to room temperature and water (10 mls) added followed by dichloromethane (3×60 mls), the combined dichloromethane extracts were washed with brine (20 mls) and dried over magnesium sulphate. The solution was then filtered and evaporated to leave an orange gum which was then dissolved in ether (20 mls) to which was added HCl/MeOH (4M) dropwise to afford a beige precipitate which was collected and dried (0.62 g, 95%, 90% pure).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([N:14]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl-].[P+]=O.[BH4-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][C@H:12]1[C:31]2[CH:30]=[C:29]([O:32][CH3:33])[C:28]([O:34][CH3:35])=[CH:27][C:26]=2[CH2:25][CH2:24][CH2:23][N:14]1[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: COc1ccc(CCCN(C(=O)Cc2ccc(OC)c(OC)c2)[C@@H](C)c2ccccc2)cc1OC
Agent: O=[P+]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CC#N
Product: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCCN2[C@@H](C)c2ccccc2)cc1OC
Temperature: 25 °C
Yield: 20.1 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-N-(1-(S)-phenyl-ethyl)-acetamide (7.0 g, 14.65 mmol) and phosphorus oxide chloride (13.4 ml, 146.5 mmol) in anhydrous acetonitrile, (160 ml) was heated at reflux for 6.5 h, under nitrogen. After cooling to RT, the volatiles were removed under vacuum and the resulting oil was dissolved in anhydrous methanol before evaporation to dryness (repeated twice). The resulting brown oil was dissolved again in anhydrous methanol (122 ml) and cooled at −78° C., under nitrogen. Then, sodium borohydride (3.02 g, 79.99 mmol) was added portionwise in 5 h to the reaction mixture kept at −78° C. The reaction was quenched by dropwise addition of aqueous 1N HCl (8 ml) and the mixture was allowed to warm to RT before the solvent was removed under vacuum and water (175 ml) was added. After extraction with CH2Cl2 (4×150 ml), the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under vacuum. The resulting crude oil was purified by flash chromatography (CH2Cl2/CH3OH: 36/1) giving the pure diastereoisomer 1-(S)-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2-(1-(S)-phenyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow oil (1.36 g, 20%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1>[C:3]([C:5]1[CH:6]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(-c2cccs2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cccs2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of 2-(3-methoxycarbonylphenyl)thiophene (1.29 g) in methanol (15 ml) and tetrahydrofuran (5 ml) was added an aqueous solution of sodium hydroxide (1N, 8.87 ml) followed by stirring for 2 hours at 60° C. To the mixture was added hydrochloric acid (1N, 10 ml). The resulting precipitate was collected by filtration and dried to give 2-(3-carboxyphenyl)thiophene (1.13 g, 93.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:15]([NH:22][C:23](=[O:43])[CH2:24][NH:25][C:26](=[O:42])[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[NH:35][CH2:36][CH:37]([OH:40])[CH2:38][N:39]=3)[CH:30]=[C:29]([OH:41])[CH:28]=2)[CH2:16][C:17]([O:19]CC)=[O:18])[CH:5]=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:15]([NH:22][C:23](=[O:43])[CH2:24][NH:25][C:26](=[O:42])[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[NH:39][CH2:38][CH:37]([OH:40])[CH2:36][N:35]=3)[CH:30]=[C:29]([OH:41])[CH:28]=2)[CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C(C)(O)C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC(O)(c1cc(Cl)cc([C@H](CC(=O)O)NC(=O)CNC(=O)c2cc(O)cc(NC3=NCC(O)CN3)c2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of (3S)-ethyl 3-(3-chloro-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (from step 2 above) (0.968 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (8 mL) was added lithium hydroxide monohydrate (203.1 mg, 4.84 mmol) and the reaction mixture was stirred at room temperature overnight (15 h). The solvent was evaporated in vacuo to afford a yellow-orange viscous residue. The residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL). The DCM layer was removed and discarded after analyzed by LC-MS. The aqueous layer was neutralized with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA to afford the desired product, after lyophilization, as a colorless lyophilized powder (439.2 mg). LC-MS analysis of the solid shows the desired product: (3S)-3-(3-chloro-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid's mass: m/z 602 (35ClM+H) and m/z 604 (37ClM+H); Calcd for C25H27ClF3N5O7: 601.96. 1H NMR (400 MHz, DMSO-d6): δ 1.69 (s, 3H), 2.72 (d, J=7.0 Hz, 2H), 3.16 (d, J=12.8 Hz, 2H), 3.33 (d, J=12.7 Hz, 2H), 3.87 (d, J=5.3 Hz, 2H), 4.08 (s, 1H), 5.21 (appq, 1H), 5.45 (brs, 1H), 6.74 (brs, 1H), 6.79 (brs, 1H), 7.12 (dt/m, 2H), 7.41 (s, 1H), 7.49 (brs, 2H), 8.14 (brs, 2H), 8.58 (dd/m, 1H), 8.63 (brt, 1H), 9.67 (brs, 1H), 10.03 (brs, 1H), 12.40 (brs, 1H). 1H NMR spectrum of the sample was consistent with the structure of the desired titled product.
Reaction SMILES: C(O[C:6]([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.C[NH:47][CH2:48][CH2:49]C#N>>[C:48]([CH2:49][CH2:39][N:8]([CH3:6])[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])#[N:47]
Reactant: CNCCC#N
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C)CCC#N)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (150 mg) described in Example 769 and 3-methylaminopropionitrile (90 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (26 mg) was obtained.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)[C@@H](C1C=CC=CC=1)CN>CC(CC(C)=O)C>[C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)[C@H](CN)c1ccccc1
Solvent: CC(=O)CC(C)C
Product: C[C@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 35 °C
Reaction time: 5 h
Yield: 68.9 %

Procedure:
(±)-2-(3-Benzoylphenyl)propionic acid (12.7 g, 50 mmol) was added to MIBK (70 ml) and dissolved with heating to 35° C. Then, (S)-(+)-3-methyl-2-phenylbutylamine (5.24 g, 32 mmol) was added dropwise with stirring. After completing the addition, the reaction solution was stirred at 35° C. to 40° C. for one hour, followed by at room temperature for 5 hours and then at 10° C. for 2 hours. Then, the crystal precipitated was filtered, and the filter cake was washed with cold MIBK (30 ml) and dried to give a diastereomer salt (8.76 g) of (S)-(+)-2-(3-benzoylphenyl)propionic acid with (S)-(+)-3-methyl-2-phenylbutylamine. The yield of the product based on (S)-(+)-2-(3-benzoylphenyl)propionic acid contained in the starting material was 84%.
Reaction SMILES: CN.[CH2:3]([N:6]([CH2:10][C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[N:12]=1)[CH2:7][CH2:8][CH3:9])[CH2:4][CH3:5]>C(O)C>[NH2:17][CH2:16][C:13]1[N:12]=[C:11]([CH2:10][N:6]([CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH3:5])[O:15][N:14]=1
Reactant: CCCN(CCC)Cc1nc(CN2C(=O)c3ccccc3C2=O)no1
Agent: CN
Solvent: CCO
Product: CCCN(CCC)Cc1nc(CN)no1
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
400 ml of methylamine (33% in ethanol) were added dropwise to a solution of 38 g (111 mmol) of 2-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-ylmethyl)-2,3-dihydro-1H-isoindol-1,3-dione in 300 ml of ethanol. The mixture was stirred at 70° for 1.5 hours and subsequently evaporated. The residue was triturated in methylene chloride and filtered off. The filtrate was concentrated and chromatographed (silica gel, methylene chloride/methanol 19:1). There were obtained 15.6 g (66%) of (3-aminomethyl-1,2,4-oxadiazol-5-ylmethyl)-dipropyl-amine as a yellow oil, Rf=0.25 (silica gel, methylene chloride/methanol 9:1).
Reaction SMILES: O.[ClH:2].[CH3:3][N:4]1[CH:8]=[C:7]([CH2:9]O)[N:6]=[N:5]1>S(Cl)(Cl)=O>[ClH:2].[Cl:2][CH2:9][C:7]1[N:6]=[N:5][N:4]([CH3:3])[CH:8]=1
Reactant: Cn1cc(CO)nn1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cn1cc(CCl)nn1
Reaction time: 0.08 h

Procedure:
To thionyl chloride (20 ml) under nitrogen, cooled by an ice bath, was added (1-methyl-1H-[1,2,3]triazol-4-yl)methanol hydrochloride monohydrate (1.996 g, 11.9 mmol). The mixture was stirred for 5 min before removing the cooling bath and heating at reflux for 30 min. The excess thionyl chloride was evaporated in vacuo and the residue was triturated with diethyl ether. The resulting solid was collected by filtration, washed with diethyl ether and dried under vacuum at 60° C. to give the title compound as a white solid: 1H NMR (360 MHz, DMSO-d6) δ 4.04 (3H, s), 4.81 (2H, s), 8.13 (1H, s).
Reaction SMILES: N1(CCO[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[CH2:21][CH2:22][C:23]5[NH:24][C:25](=[O:28])[CH:26]=[CH:27][C:18]([C:19]=54)=[CH:17][N:16]=3)=[CH:11][CH:10]=2)CCCC1.OCCC1C=CC([C:38]2[N:43]3[CH2:44]CC4NC(=O)C=C[C:41]([C:42]=43)=CN=2)=CC=1.CNC.N.C(Cl)(Cl)Cl.[K+].[Br-]>>[CH3:38][N:43]([CH3:44])[CH2:42][CH2:41][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]3[CH2:21][CH2:22][C:23]4[NH:24][C:25](=[O:28])[CH:26]=[CH:27][C:18]([C:19]=43)=[CH:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: O=C1C=CC2=CN=C(c3ccc(CCO)cc3)N3CCC(=C23)N1
Reactant: O=C1C=CC2=CN=C(c3ccc(OCCN4CCCC4)cc3)N3CCC(=C23)N1
Agent: CNC
Agent: N
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CN(C)CCc1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Yield: 26 %

Procedure:
The product was prepared following the procedure used for 1-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Example 123) from 1-[4-(2-hydroxy-ethyl)-phenyl]-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Example 127) and methanolic dimethylamine heating to 85° C. overnight to give a 26% yield (2 steps) of a yellow solid: mp >98° C. (dec); Rf=0.08 (7% methanolic ammonia/CHCl3); IR (KBr) 1653, 1479, 1381, 1307 cm−1; 1H NMR (DMSO-d6) δ 2.21 (s, 6H), 2.50-2.56 (m, 2H), 2.79-2.84 (m, 2H), 3.52-3.53 (m, 2H), 4.44-4.46 (m, 2H), 7.34 (t, 1H, J=7.8 Hz), 7.43 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz), 7.84-7.90 (m, 2H), 8.39-8.43 (m, 1H). HRMS calcd for C20H23N4O 335.1872 (M+H), found 335.1865. Anal. (C20H22N4O) C, H, N.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]([N:18]([C:20]2[C:21]([Cl:40])=[C:22]([C:36]([Cl:39])=[CH:37][CH:38]=2)[CH2:23][O:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[C:32]([CH3:35])[CH:31]=[CH:30]3)[CH3:19])=[O:17])=[O:13])=[CH:6][CH:5]=1)([OH:3])=O.[NH2:41][C:42]1[CH:47]=[N:46][CH:45]=[CH:44][N:43]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:40][C:21]1[C:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]2[CH:8]=[N:9][C:4]([C:1](=[O:3])[NH:41][C:42]3[CH:47]=[N:46][CH:45]=[CH:44][N:43]=3)=[CH:5][CH:6]=2)=[CH:38][CH:37]=[C:36]([Cl:39])[C:22]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[C:32]([CH3:35])[CH:31]=[CH:30]2
Reactant: Nc1cnccn1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)Nc5cnccn5)nc4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 18.5 %

Procedure:
To a mixture of 8-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)-acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), 2-aminopyrazine (19.7 mg) and N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (43 mg) and 1-hydroxybenzotriazole (35 mg), and the mixture was stirred for 36 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride--methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(2-pyrazinylcarbamoyl)-pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methylquinoline (21 mg) as an amorphous powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23]C)[O:7][C:8]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:9]=1[C:10]#[N:11])([CH3:3])[CH3:2].B(Br)(Br)Br>ClCCl>[CH:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[OH:23])[O:7][C:8]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:9]=1[C:10]#[N:11])([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C#N)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C#N)c1Oc1ccc(O)c(C(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a cooled (−78° C.), stirred solution of 2-(3-isopropyl-4-methoxy-phenoxy)-3-methyl-5-nitrobenzonitrile (308 mg) in dichloromethane (5 mL) was added boron tribromide (0.31 mL) dropwise. The reaction was allowed to warm to RT and stirred for 1 h, quenched with water and stirred for 20 min. The reaction was extracted with ethyl acetate, the organic phase washed with water, saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo. Flash chromatography (20% ethyl acetate/hexanes) on silica gel afforded 2-(3-isopropyl-4-hydroxy-phenoxy)-3-methyl-5-nitrobenzonitrile as a yellow oil (215 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([NH:7][C:8]([CH3:13])([C:10](O)=[O:11])[CH3:9])=[O:6])[CH3:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.O.S(O)(O)(=O)=O.O[NH:64][C:65]([NH2:67])=[NH:66]>CN(C=O)C>[C:2]([O:4][C:5](=[O:6])[NH:7][C:8]([C:10]1[O:11][N:66]=[C:65]([NH2:67])[N:64]=1)([CH3:13])[CH3:9])([CH3:14])([CH3:3])[CH3:1]
Reactant: N=C(N)NO
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C)(C)c1nc(N)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a colorless solution of N-[(1,1-dimethylethoxy)carbonyl]-2-methyl-alanine (CAN 30992-29-1; 1.0 g, 4.92 mmol) in DMF (24 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (3.07 g, 5.9 mmol) and DIEA (1.72 mL, 4.9 mmol), and the resulting pale yellow solution was stirred under argon for 30 minutes at room temperature. This mixture was added dropwise over 40 minutes to a suspension of hydroxyguanidine sulfate monohydrate (3.93 g, 14.8 mmol), DIEA (2.6 mL, 7.4 mmol), and molecular sieves (4 Å, 2 g) in DMF (35 mL) under argon, the temperature not exceeding 25° C. Once addition was complete another 2 g of molecular sieves was added and the reaction mixture (pale yellow suspension) was stirred for 1.5 hours under argon at room temperature then stirred at 130° C. for 20 hours. After cooling to room temperature the mixture was filtered through Celite®. The filtrate was concentrated in vacuo (HV pump) and the residue was stirred vigorously with 2-methoxy-2-methylpropane (40 mL) and 1N NaOH (40 mL) for 20 h. Phases were separated; the aqueous phase was washed with 2-methoxy-2-methylpropane (2×10 mL). Combined organic extracts were washed with water, then dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 50 g, 0% to 100% EtOAc in hexanes) to give the title compound (106 mg, 8.9%), which was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:21]#[N:22])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1)[CH:7]=2.Cl.[NH+]1C=CC=CC=1.Cl>>[OH:2][C:3]1[CH:4]=[C:5]([C:21]#[N:22])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)[CH:7]=2
Reactant: COc1cccc(-c2ccc3cc(OC)cc(C#N)c3c2)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1cc(O)cc2ccc(-c3cccc(O)c3)cc12
Yield: 63.4 %

Procedure:
3-Methoxy-7-(3-methoxyphenyl)-1-naphthonitrile (100 mg, 0.35 mmol, 1 eq) and pyridinium hydrochloride (492 mg, 4.3 mmol, 12.2 eq) are boiled under reflux for 3 h. After cooling the reaction mixture, it is acidified with 1 N HCl, the resulting precipitate is filtered and dissolved in a small amount of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. The residue formed is the desired product (yield 64%, 58 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][NH:21][CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][N:21]([C:38](=[O:40])[CH3:39])[CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4nsc5ccccc54)CC3)n1-2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3nsc4ccccc43)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-1-(4-benzo[d]isothiazol-3-yl-cyclohexyl)-8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (35 mg, 0.080 mmol) and triethylamine (0.022 ml, 0.16 mmol) in dichloromethane (0.8 ml) was added acetyl chloride (0.011 ml, 0.16 mmol) at room temperature. Stirring for 20 h was followed by partitioning between water (20 ml) and ethyl acetate (25 ml). The layers were separated. The organic layer was washed with two 25 ml-portions of water. The organic layer was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (26 mg, 68%) as white solid. MS m/e: 478 ([M+H]+)
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13]>ClCCl.C(OCC)(=O)C.CCCCCC>[CH:1]([NH:4][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])(=[O:22])=[O:23])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 96.3 %

Procedure:
Isopropylamine (11.07 g, 68.85 mmol) and triethylamine (13 ml, 93 mmol) were dissolved in dichloromethane (50 ml) and the mixture was stirred under ice-cooling. Thereto was added 2-nitrobenzenesulfonyl chloride (10.11 g, 45.62 mmol), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate-hexane=1:1 mixed solvent, and the organic layer was washed with diluted hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the solution was concentrated under reduced pressure and the obtained solid was washed with hexane and air-dried to give the title compound (10.73 g, yield 96%) as a colorless solid.