Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:19]([NH2:21])[CH3:20])=[C:10]([C:13]3[C:14]([CH3:18])=[N:15][NH:16][CH:17]=3)[CH:11]=2)[CH:6]=[CH:5]1.Cl[C:23]1[C:28]([C:29]#[N:30])=[C:27]([CH3:31])[N:26]=[C:25]([S:32][CH3:33])[N:24]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:31][C:27]1[C:28]([C:29]#[N:30])=[C:23]([NH:21][C@H:19]([C:9]2[N:8]=[C:7]3[CH:6]=[CH:5][N:4]([CH3:3])[C:12]3=[CH:11][C:10]=2[C:13]2[C:14]([CH3:18])=[N:15][NH:16][CH:17]=2)[CH3:20])[N:24]=[C:25]([S:32][CH3:33])[N:26]=1
Reactant: Cc1n[nH]cc1-c1cc2c(ccn2C)nc1[C@H](C)N
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSc1nc(C)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2c[nH]nc2C)n1

Procedure:
A solution of (S)-1-(1-methyl-6-(3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine dihydrochloride (200 mg, 0.609 mmol), 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carbonitrile (182 mg, 0.914 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.318 mL, 1.83 mmol) in acetonitrile (5 mL) was heated in a microwave reactor at 120° C. for 2 hours. The mixture was then concentrated. The residue was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by column chromatography eluting with 20-80% EtOAc in hexane over 60 minutes to give the title compound. ESI-MS m/z [M+H]+ calc'd for C21H22N8S, 419; found 419.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[N:12]=[C:13]([NH2:19])[S:14][C:15]=1[C:16]([OH:18])=[O:17].[H-].[Na+].Cl>O1CCCC1.CN(C)C(=O)C>[CH3:10][C:11]1[N:12]=[C:13]([NH:19][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=2)[S:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: Cc1nc(N)sc1C(=O)O
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2nc(C)c(C(=O)O)s2)n1
Reaction time: 3 h
Yield: 87.3 %

Procedure:
In a reaction flask, 49.49 g 4,6-dichloro-2-methylpyrimidine (0.303 mol), 40.00 g methyl 2-aminothiazol-5-carboxylic acid (0.253 mol), and 200 ml N,N-dimethylacetamide were charged, the temperature was brought to −5° C. and 18.20 g sodium hydride (0.455 mol) in 90 ml tetrahydrofuran were added dropwise and the reaction mixture was kept under these conditions for about three hours. At the end of the reaction, 250 ml of a solution of hydrochloric acid 2N were added, the temperature was brought to the room value, the formed solid was filtered and washed with water (4×200 ml) and dried in oven under vacuum at a temperature of 55° C. for about eight hours, to give 62.89 g methyl 2-(6-chloro-2-methylpyrimidin-4-yl-amino)thiazol-5-carboxylic acid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=O>>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(F)ccc1Br
Product: O=c1cc(N2CCN(Cc3cc(F)ccc3Br)CC2)nc[nH]1

Procedure:
6-[4-(2-Bromo-5-fluoro-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-bromo-5-fluorobenzaldehyde. Mass spectrum (ES) MH+=367.
Reaction SMILES: NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(F)=CC=3F)=CC=2Cl)=O)C=1.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:46][CH3:47])=[C:32]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][C:37]=2[Cl:45])=[O:35])[CH:33]=1>>[NH2:42][C:39]1[CH:40]=[CH:41][C:36]([C:34]([C:32]2[CH:33]=[C:28]([Br:27])[CH:29]=[CH:30][C:31]=2[O:46][CH3:47])=[O:35])=[C:37]([Cl:45])[CH:38]=1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: COc1ccc(Br)cc1C(=O)c1ccc(N)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 404, using compound 423 (16.1 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 20:80 to 45:55 as the eluent to afford the title compound as yellow solid.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][CH2:13][C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=3[NH:21][C:22]([O:24][CH3:25])=[O:23])[C:6]2=[N:5][C:4]=1[CH3:26])=[O:2].[BH4-].[Na+]>CO.Cl>[OH:2][CH2:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][CH2:13][C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=3[NH:21][C:22]([O:24][CH3:25])=[O:23])[C:6]2=[N:5][C:4]=1[CH3:26]
Reactant: COC(=O)Nc1cccc(C)c1CNc1cccn2c(C=O)c(C)nc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Nc1cccc(C)c1CNc1cccn2c(CO)c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
2 g of 3-formyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methylimidazo[1,2-a]pyridine are suspended in 30 ml of methanol at RT, 0.2 g of sodium borohydride is added in portions, and the mixture is stirred at RT for 1 h. Subsequently, half the solvent is stripped off in vacuo, the residue is poured into ice-water, and the mixture is neutralized with a few drops of dilute hydrochloric acid and extracted four times with ethyl acetate. The collected organic phases are washed with water and dried over sodium sulfate. The solvent is stripped off in vacuo. The remaining yellowish residue completely crystallizes after some time. Recrystallization from ethyl acetate results in 1.3 g of the title compound of m.p. 170°-172° C.
Reaction SMILES: [NH4+].[OH-:2].[CH3:3][C:4]1[CH:9]=[C:8]2[C:10]([CH:24]([CH3:26])[CH3:25])=[C:11]([OH:23])[C:12](/[C:14](=[CH:15]\NC3C=CC=CC=3)/[C:7]2=[C:6]([OH:27])[C:5]=1[C:28]1[C:33]([OH:34])=[C:32]2[C:35]([CH:44]=[O:45])=[C:36]([OH:43])[C:37]([OH:42])=[C:38]([CH:39]([CH3:41])[CH3:40])[C:31]2=[CH:30][C:29]=1[CH3:46])=[O:13]>CO>[CH3:3][C:4]1[C:5]([C:28]2[C:29]([CH3:46])=[CH:30][C:31]3[C:38]([CH:39]([CH3:41])[CH3:40])=[C:37]([OH:42])[C:36]([OH:43])=[C:35]([CH:44]=[O:45])[C:32]=3[C:33]=2[OH:34])=[C:6]([OH:27])[C:7]2=[C:14]([CH:15]=[O:2])[C:12]([OH:13])=[C:11]([OH:23])[C:10]([CH:24]([CH3:26])[CH3:25])=[C:8]2[CH:9]=1
Reactant: [OH-]
Reactant: Cc1cc2c(c(O)c1-c1c(C)cc3c(C(C)C)c(O)c(O)c(C=O)c3c1O)/C(=C/Nc1ccccc1)C(=O)C(O)=C2C(C)C
Agent: [NH4+]
Solvent: CO
Product: Cc1cc2c(C(C)C)c(O)c(O)c(C=O)c2c(O)c1-c1c(C)cc2c(C(C)C)c(O)c(O)c(C=O)c2c1O

Procedure:
The mass spectrometer was a Micromass Quattro Ultima LC/MS/MS detector by Waters, and contained a triple quadrupole mass spectrometer with negative electrospray ionization. Because the HPLC did not provide the correct ionization matrix for negative electrospray ionization of the dianilino-gossypol, 0.6% NH4OH in methanol was introduced past the HPLC column at a flow rate of 0.05 mL/minute. Post-column mixing of the NH4OH in MeOH with the HPLC eluant was achieved using a mixing T-connection. In MS/MS mode, the first quadrupole was used to select 667.3 as the mass to charge ratio that represented the negative ion of dianilino-gossypol. In the second quadrupole, the 667.3 mass to charge ratio was fragmented in a collision cell. The third quadrupole was used to select the fragment ion, monoanilino-gossypol, which had a mass to charge ratio of 574.2 as a result of the loss of an aniline. Detection of the second fragment ion provides improved specificity and increased signal to noise ratios.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.ClCCl>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:15][C:10]([S:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:24])[CH3:23])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCCNS(=O)(=O)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCCCNS(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Biphenyl-4-sulfonic acid (4-amino-butyl)amide (1 g) was suspended in a mixture of acetic anhydride (45 mL) and pyridine (15 mL) and stirred at 80° C. for 4 hours. The solution was left to stir overnight and then poured into ice water. The aqueous mixture was extracted with dichloromethane, dried (Na2SO4) and evaporated to give a brown oil. The oil was redissolved in dichloromethane and the title compound precipitated as a white solid by addition of a small amount of petrol. δC (CDCl3, 62.9 MHz): 23.2, 26.6, 26.8, 39.1, 42.9, 127.3, 127.6, 127.8, 128.5, 129.1, 138.4, 139.3, 145.6 and 170.9.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[C:24]([OH:26])[C:23]([C:27]([OH:29])=[O:28])=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[O:12])[CH3:10])=O)(C)(C)C.N1C=CC=[CH:32][CH:31]=1.C(OC(=O)CC)(=O)CC>CO>[C:6]([NH:8][C@H:9]([C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:25]=[C:24]([OH:26])[C:23]([C:27]([OH:29])=[O:28])=[CH:22][N:21]=2)=[CH:18][CH:19]=1)=[O:12])[CH3:10])(=[O:5])[CH2:31][CH3:32]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: c1ccncc1
Agent: CCC(=O)OC(=O)CC
Solvent: CO
Product: CCC(=O)N[C@@H](C)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: 25 °C

Procedure:
A suspension of 1.90 g (6.3 mmol) of the above pyrimidine acid and 20 ml of pyridine is stirred at room temperature and 5 ml of propionic anhydride is added. After stirring 1 hr at room temperature, methanol (10 ml) is added and the mixture evaporated to a syrup in vacuo. Water is added to the residue, the pH is adjusted to 2.3 with dilute HCl, and the product filtered. After washing with water and drying gives 1.93 g of 2-[4-(N-propionyl-L-alanylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid; mp 247°-248° C. [α]D25 -81° (cl, pH 7).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>CN(C)C=O>[Cl:23][CH2:24][C:25]([N:13]1[CH2:14][CH2:15][CH2:16][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)=[O:26]
Reactant: O=[N+]([O-])c1ccc(N2CCCNCC2)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCl)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
22.1 g (0.1 mol) of 1-(4-nitrophenyl)[1,4]diazepane, 8.3 g (0.06 mol) of potassium carbonate and 120 ml of dimethylformamide were mixed together in a reactor. 8.3 ml (0.11 mol) of chloroacetyl chloride were added to this stirred suspension, while maintaining the temperature between 15 and 25° C. After stirring for about ten hours at room temperature, 400 g of slightly hydrochloric ice-cold water were added to the mixture: a yellow gum crystallized. After filtering off by suction, washing with water and drying under vacuum over phosphorus pentoxide, 22.4 g of yellow crystals were obtained (yield=75%).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:10]([Si](C)(C)C)=[N+:11]=[N-:12].Cl>C(OCC)C>[CH3:9][C:8]1[N:10]=[N:11][NH:12][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC#Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: Cc1nn[nH]c1-c1ccccc1
Temperature: 155 °C

Procedure:
##STR7## 1-Phenyl-1-propyne (2.52 g) and azidotrimethylsilane (2.48 g, Me3SiN3) were sealed into a heavy-walled glass reactor at -70° C. and 0.5 mm Hg. The mixture was heated 11 days at 155° C., cooled, dissolved in diethyl ether (Et2O), and stirred briefly with 5 percent HCl. After washing with a small amount of NaHCO3 solution, the Et2O solution was evaported to give 3.06 g (89%) cream white solid, mp 173.5-174.0 whose NMR spectrum and elemental analysis confirm its structure.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])C.[NH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[N:16]=1>>[CH3:21][C:17]1[N:16]=[C:15]([NH:14][C:4]([C:6]2[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([CH3:13])[N:7]=2)=[O:5])[CH:20]=[CH:19][N:18]=1
Reactant: Cc1nccc(N)n1
Reactant: CCOC(=O)c1cc(Br)cc(C)n1
Product: Cc1cc(Br)cc(C(=O)Nc2ccnc(C)n2)n1

Procedure:
The tide compound, white solid, MS (ISP): m/e=307.1, 309.2 (M+H)+, was prepared from 4-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 1. Step 5 was performed using 4-Amino-2-methylpyrimidine instead of 2-Amino-4-methylthiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]=[O:18].C[Mg+].[Br-].[CH2:22](OCC)C>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)[S:4][C:3]=1[CH:17]([OH:18])[CH3:22]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Reaction time: 2 h

Procedure:
To a solution of 3-methyl-5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (0.130 g, 0.481 mmole) in THF (5 mL), is injected 3.0 M MeMgBr in ethyl ether (0.27 mL, 0.810 mmole) dropwise. The reaction is stirred for 2 hours. The reaction is quenched with saturated NH4Cl(aq) (10 mL), then the aqueous solution is extracted with ethyl acetate (3×15 mL). The combined organic solution is washed with brine (3×50 mL), dried over Na2SO4 and concentrated. The crude product is purified on a silica gel column, eluting with 0-20% ethyl acetate in hexane and concentrated to provide the titled compound as yellow solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:16]([CH:17]=1)[CH2:15][CH2:14][O:13][C:12]1[C:7]2=[CH:8][C:9]([C:19]#[C:20][C:21]2([OH:30])[CH2:24][CH:23]([C:25](OCC)=[O:26])[CH2:22]2)=[C:10]([F:18])[CH:11]=1)(=[O:3])[NH2:2].CC(C[AlH]CC(C)C)C>O1CCCC1>[F:18][C:10]1[C:9]([C:19]#[C:20][C:21]2([OH:30])[CH2:22][CH:23]([CH2:25][OH:26])[CH2:24]2)=[CH:8][C:7]2[C:6]3[N:16]([CH2:15][CH2:14][O:13][C:12]=2[CH:11]=1)[CH:17]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3
Reactant: CCOC(=O)C1CC(O)(C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CC(CO)C3)c(F)cc1OCC2
Temperature: -70 °C
Reaction time: 4 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of ethyl 3-(2-[4-carbamoyl-12-fluoro-9-oxa-3,6-diazatricyclo[8.4.0.0[2,6]]tetradeca-1(14),2,4,10,12-pentaen-13-yl]ethynyl)-3-hydroxycyclobutane-1-carboxylate (140 mg, 0.34 mmol, 1.00 equiv) in tetrahydrofuran (5 mL). Then added DIBAL-H (1.0M in THF, 7 mL, 2.00 equiv) dropwise with stirring at −70° C. The resulting solution was stirred for 4 h at −70° C. The reaction was then quenched by the addition of 2 mL of 10% sodium potassium tartrate. The solids were filtered out. The mixture was diluted with 40 mL of ethyl acetate, and washed with 20 mL of brine, dried over sodium sulfate. Filtered and concentrated, the residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-016(Waters)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH4CO3 and CH3CN (10% CH3CN up to 29% in 13 min); Detector, uv 254/220 nm. This resulted in 25 mg (20%) of 8-Fluoro-9-(1-hydroxy-3-hydroxymethyl-cyclobutylethynyl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a white solid. (single undetermined diastereomer). LC-MS: (ES, m/z):372[M+H]+ 1H-NMR: (400 MHz, DMSO-d6, ppm) δ 8.602 (d, 1H), 7.785 (s, 1H), 7.596 (s, 1H), 7.142 (s, 1H), 7.033 (d, 1H), 5.907 (s, 1H), 4.559-4.410 (m, 4H), 3.422 (t, 2H), 2.449 (t, 2H), 2.238-2.100 (m, 1H), 2.029 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)Cc1ccc(Nc2nc3ccc(F)cc3s2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Nc2nc3ccc(F)cc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
Methyl (3-chloro-4-(6-fluoro-2-benzothiazolyl)aminophenyl)acetate (158 mg, 0.45 mmol) was dissolved in THF (3 ml). To the resulting solution was added 0.5N NaOH (3.0 ml, 1.50 mmol), and the resulting mixture was stirred at room temperature for 18 hours. The mixture was poured in ice-1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (3-chloro-4-(6-fluoro-2-benzothiazolyl)aminophenyl)acetic acid (127 mg, 84%) as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:11]([O:13][C:14](=[O:15])[C:8]3[C:9]=2[C:4]2[C:5]([C:16]([O:18][C:19](=[O:20])[C:3]=2[CH:2]=1)=[O:17])=[CH:6][CH:7]=3)=[O:12].[CH2:21]([NH2:24])[C:22]#[CH:23]>CN(C=O)C>[CH2:21]([N:24]=[C:14]([C:8]1[C:9]2[C:10]([C:11]([OH:13])=[O:12])=[CH:1][CH:2]=[C:3]([C:19]([OH:18])=[O:20])[C:4]=2[C:5]([C:16](=[N:24][CH2:21][C:22]#[CH:23])[OH:17])=[CH:6][CH:7]=1)[OH:15])[C:22]#[CH:23]
Reactant: C#CCN
Reactant: O=C1OC(=O)c2ccc3c4c(ccc1c24)C(=O)OC3=O
Solvent: CN(C)C=O
Product: C#CCN=C(O)c1ccc(C(O)=NCC#C)c2c(C(=O)O)ccc(C(=O)O)c12
Temperature: 135 °C
Reaction time: 5 h

Procedure:
In a 250-ml round-bottom flask, equipped with a mechanical stirrer was placed 10.3541 g. (0.036 mole) of 1,4,5,8-naphthalene tetracarboxylic acid dianhydride in 100 ml DMF and the system purged with nitrogen. To this solution was added 4.9310 g. (0.089 mole) of propargyl amine, causing the temperature to rise to 46° C. Then heating was begun and continued at 135° C. for 5 hours. Then the apparatus was fitted with a distillation head and approximately 2 ml of distillate were removed over a one-hour period by heating at 135° C. After cooling, the solid material was isolated by filtration, washed with DMF and vacuum-dried to give a tan solid, 9.0084 g. (68.3%), recrystallization from DMAC gave 4.5840 g. of the diimide whose infrared spectrum was identical to that of Example 2(a).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[CH2:28]([N:30]([CH3:40])[CH2:31][C:32]1[N:33]=[C:34]([N+:37]([O-])=O)[NH:35][CH:36]=1)[CH3:29].CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[CH2:28]([N:30]([CH2:31][C:32]1[N:33]=[C:34]([NH:37][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[F:27])=[CH:14][CH:15]=2)=[O:3])[NH:35][CH:36]=1)[CH3:40])[CH3:29]
Reactant: CCN(C)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCN(C)Cc1c[nH]c(NC(=O)c2ccc(-c3c(F)c(OC)cc(OC)c3F)c3nccnc23)n1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1) and stirring the reaction mixture for 3 h at 70° C. Ethyl-methyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 157.1) instead of 2-nitroimidazole was used in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. Title compound: ESI-MS: 483.9 [M+H]+; TLC: Rf=0.10 (DCM/MeOH, 9:1).
Reaction SMILES: [CH2:1]([C@H:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:44][C:32]1[N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:25][CH:26]=2)[C:39]2[C:34]([C:33]=1[CH3:43])=[CH:35][C:36]([C:40](=[O:41])[NH:10][C@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][CH3:2])=[CH:37][CH:38]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC[C@H](N)c1ccccc1
Product: CC[C@H](NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (S)-α-ethylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:32][NH:31][C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:28][CH:29]=1)=[NH:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)CN(Cc1ccc(C#N)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 97 %

Procedure:
Prepared using General Procedure 19. To a stirred solution of tert-butyl 2-(N-(4-cyanobenzyl)-4-nitrobenzamido)acetate INT-56 (11.5 g, 29.2 mmol) and TEA (10.2 mL, 73.0 mmol) in DMF (50 mL) was added hydroxylamine hydrochloride (5.07 g, 73.0 mmol). After 24 h the reaction mixture was poured onto water (200 mL) and NaHCO3 (200 mL) and extracted into EA (2×250 mL). The organics were washed with brine (3×200 mL), dried over MgSO4 and concentrated in vacuo, evaporating from hexanes, to provide 12.1 g (97%) of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-nitrobenzamido)acetate INT-57 as an off-white powder. LCMS-ESI (m/z) calculated for C21H24N4O6: 428; found 429 [M+H]+, tR=1.42 min (Method 10).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=1.[OH-].[Na+]>CC#N.O>[Cl:11][C:12]1[N:13]=[C:14]([NH:19][CH3:20])[N:15]=[C:16]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]2)[N:17]=1
Reactant: CNc1nc(Cl)nc(Cl)n1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)O)CC2)n1
Reaction time: 3 h

Procedure:
Commercially available cis-4-aminocyclohexanecarboxylic acid (17.46 mmol) was added to the above crude solution of 4,6-dichloro-N-methyl-1,3,5-triazin-2-amine in CH3CN:H2O (1:1, 28.6 mL). The reaction mixture was stirred at room temperature to 40° C. for 3 hours while the pH was maintained between 9 and 10 with addition of a NaOH solution. LCMS analysis showed the complete consumption of 4,6-dichloro-N-methyl-1,3,5-triazin-2-amine. The crude product was used in the next step. MS (ES+): m/e 286.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([NH2:7])=O.C(N(CC)CC)C.S(=O)(=O)=O>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]#[N:7]
Reactant: NC(=O)c1cc(F)cc(F)c1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)cc(F)c1
Temperature: 89 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A suspension of 10 mmol of 3,5-difluorobenzamide and 25 mmol of triethylamine-sulphur trioxide in 30 ml of triethylamine was stirred at 89° C. for 1 hour. The working up was effected as described under Example 1a). Yield: 85.7% of theory.