Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([N+:13]([O-])=O)([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[H][H]>CCO.[Ni]>[NH2:13][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH2:11][OH:12])[CH2:9][OH:10]
Reactant: O=[N+]([O-])C(CO)(CO)c1cccc(Br)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: NC(CO)(CO)c1cccc(Br)c1

Procedure:
A solution of 2-(3-bromo-phenyl)-2-nitro-propane-1,3-diol (6.79 g, 24.59 mmol) in 100 ml of EtOH was hydrogenated in the presence of 5 g of Raney-Ni. When the take-up of hydrogen had ceased, the mixture was filtered through Celite, and the filtrate was chromatographed on silica gel (EtOAc/MeOH/25% aqueous NH3, 5%) to give the title compound in the form of a colourless solid. TLC (EtOAc/MeOH/25% aqueous NH3, 5%): Rf=0.24; HPLC: RtH2=2.354 min; 1H-NMR (400 MHz, CD3OD): 7.73 (s, 1H), 7.50 (d, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 3.79 (d, 2H), 3.72 (d, 2H); MS: 246, 248 [(M+H)+].
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[NH:5][C:6]([NH:8][C:9]1[S:10][C:11](=[S:14])[NH:12][N:13]=1)=[O:7].[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[S:14]=[C:11]1[S:10][C:9]([NH:8][C:6]([NH:5][C@@H:4]([CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[C:3]([NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:7])=[N:13][NH:12]1
Reactant: COC(=O)[C@H](CC1CCCCC1)NC(=O)Nc1n[nH]c(=S)s1
Reactant: NCCc1ccccc1
Product: O=C(Nc1n[nH]c(=S)s1)N[C@@H](CC1CCCCC1)C(=O)NCCc1ccccc1

Procedure:
Following the general procedure outlined in EXAMPLE 5, and making non-critical variations but starting with N-[[(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]-β-cyclohexyl-L-alanine methyl ester (prepared similarly to that described in EXAMPLE 1) and phenethylamine, the title compound is obtained (mp 199°-200° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[N:7]([CH3:10])[CH:8]=[N:9][C:5]=2[CH:4]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].COCCO.[ClH:33]>C(O)(C)C>[ClH:33].[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[N:7]([CH3:10])[C:8]([N:25]3[CH2:26][CH2:27][N:22]([C:20]([C:16]4[O:15][CH:19]=[CH:18][CH:17]=4)=[O:21])[CH2:23][CH2:24]3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1cc2ncn(C)c2cc1OC
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: COCCO
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)n(C)c2cc1OC

Procedure:
3.50 g. 2-chloro. 5,6-dimethoxy-1-methyl benzimidazole [(J. Org. Chem. USSR 1 1466), (1965)] 7.00 g N-(2-furoyl) piperazine, and 25 ml 2-methoxyethanol were reacted as described in Example I. The product was converted to its hydrochloride by dissolving in isopropyl alcohol and acidifying with a solution of HCl gas in isopropyl alcohol. Yield: 3.99 g product, mp 212°-215° C decomp.
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C@H:18]1[CH2:27][CH2:26][C:25]2[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=2[CH2:19]1)=O)C.C(O[C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54](O)=O)=[CH:50][CH:49]=2)[CH2:44][CH2:43]1)=O)(C)(C)C>>[OH:3][CH2:4][CH2:6][N:7]([CH2:54][C:51]1[CH:50]=[CH:49][C:48]([CH:45]2[CH2:44][CH2:43][N:42]([CH3:40])[CH2:47][CH2:46]2)=[CH:53][CH:52]=1)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C@H:18]1[CH2:27][CH2:26][C:25]2[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=2[CH2:19]1
Reactant: CCOC(=O)CNc1cc(OC)c(OC)cc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Product: COc1cc([C@H]2CCc3cc(O)ccc3C2)c(N(CCO)Cc2ccc(C3CCN(C)CC3)cc2)cc1OC
Yield: 36.4 %

Procedure:
Synthesized from pivalic acid (S)-6-[2-(ethoxycarbonylmethylamino)-4,5-dimethoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (90 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (88 mg) according to an analogous synthetic method to the above-mentioned Preparation Example 86 and Example 337, the title compound (37 mg) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1.[OH-].[K+].C(O)C.Cl>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(NCCc2cccs2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCc2cccs2)cc1

Procedure:
A mixture of 29.7 g. of crude ethyl 4-[2-(2-thienyl)ethylamino]benzoate, 29 g. of potassium hydroxide and 200 ml. of 95% ethanol is refluxed for 3 hours. The solution is diluted with 100 ml. of water and adjusted to pH 6 with concentrated hydrochloric acid. The mixture is cooled, filtered and the solid washed with ethanol-water (1:1) to give a solid. The solid is heated with 200 ml. of ethanol, filtered and the filtrate concentrated. Purification gives the product, m.p. 163°-165° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH:22]2[CH2:36][C:25]3=[C:26]4[C:31](=[N:32][CH:33]=[C:24]3[O:23]2)[CH:30]=[CH:29][C:28]([O:34][CH3:35])=[N:27]4)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:35][O:34][C:28]1[CH:29]=[CH:30][C:31]2[C:26]([N:27]=1)=[C:25]1[CH2:36][CH:22]([CH2:21][C@H:18]3[CH2:19][CH2:20][C@H:15]([NH2:14])[CH2:16][CH2:17]3)[O:23][C:24]1=[CH:33][N:32]=2
Reactant: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)O3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](N)CC1)O3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (821 μL, 10.56 mmol, 15.0 eq) is added at 0° C. to a stirred solution of [trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (300 mg, 0.70 mmol, 1.0 eq) in dichloromethane (12 mL). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and water (10 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexylamine as an orange viscous oil (190 mg, 82% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:27])[CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(=O)C1CNCC(c2ccc(CC)cc2)C1
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
10.0 g (36.0 mmol) of ethyl 5-(4-ethylphenyl)piperidine-3-carboxylate and 7.0 g (46.8 mmol, 1.3 eq.) of morpholine-4-carbonyl chloride were reacted according to the General Method 3A. Yield: 12.0 g (89% of theory)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].ClC1C=CC=C(C(OO)=[O:24])C=1>C(OCC)(=O)C>[O-:24][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)CCc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1cccc[n+]1[O-]
Yield: 80.6 %

Procedure:
tert-Butyl 3-(2-pyridyl)propanoate (1.0 g, 5.0 mmol) was dissolved in ethyl acetate (5 ml), and 3-chloroperbenzoic acid (ca. 70%, 1.3 g, 5.2 mmol) was added thereto. The reaction mixture was subjected to a silica gel (50 g) column chromatography and eluted with ethyl acetate-ethanol (5:1, v/v) to give the titled compound (0.9 g, 80%). 1H-NMR (CDCl3) δ: 1.41 (9H, s), 2.76 (2H, t, J=7.1 Hz), 3.17 (2H, t, J=7.1 Hz), 7.15-7.32 (3H, m), 8.24 (1H, d, J=5.7 Hz).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][C:6]=1[F:14].[Al+3].[Cl-].[Cl-].[Cl-].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)=[O:10])=[CH:7][C:6]=1[F:14]
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(OCCBr)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OCCBr)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.2 %

Procedure:
To a solution of 4-(2-bromoethoxy)-3-fluorobenzoyl chloride (1.07 g, 3.80 mmol) and anhydrous AlCl3 (1.01 g, 7.60 mmol) in dry dichloromethane (18 mL) was added anisole (822 mg, 7.60 mmol) in 2 mL dichloromethane at 0° C. After stirring at rt for 6 h, the mixture was poured into 3 N HCl, and extracted with dichloromethane. The extract was washed with sat. NaHCO3 and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 5/1) to give 1.05 g (77%) of the subtitle compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.8 Hz, 2H), 7.58 (d, J=11.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.03 (dd, J=8.0 Hz, 8.4 Hz, 1H), 6.98 (d, J=9.2 Hz, 2H), 4.44 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.70 (t, J=6.4 Hz, 2H).
Reaction SMILES: [C:1]([C:6]1[CH:46]=[C:45]([C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])[CH:44]=[CH:43][C:7]=1[O:8][CH:9]([CH2:41][CH3:42])[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:40])=[C:17]([CH:39]=1)[NH:18][C:19]1[CH:23]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)[C:22](=[O:29])[N:21]([C:30]2[C:35]([Cl:36])=[CH:34][C:33]([Cl:37])=[CH:32][C:31]=2[Cl:38])[N:20]=1)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:52](OC(C)=C)(=[O:54])[CH3:53].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:6]1[CH:46]=[C:45]([C:47]([CH2:50][CH3:51])([CH3:48])[CH3:49])[CH:44]=[CH:43][C:7]=1[O:8][CH:9]([CH2:41][CH3:42])[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:40])=[C:17]([CH:39]=1)[NH:18][C:19]1[C:23]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[C:22]([O:29][C:52](=[O:54])[CH3:53])[N:21]([C:30]2[C:35]([Cl:36])=[CH:34][C:33]([Cl:37])=[CH:32][C:31]=2[Cl:38])[N:20]=1)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(C)OC(C)=O
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2n2cccn2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(Nc2nn(-c3c(Cl)cc(Cl)cc3Cl)c(OC(C)=O)c2-n2cccn2)c1

Procedure:
34 g of 3-{5-[2-(2,4-di-tert-amylphenoxy)butyramido]-2-chloroanilino}-1-(2,4,6-trichlorophenyl)-4-(1-pyrazolyl)-5-oxo-2-pyrazoline (prepared by the method described in German Patent Application (OLS) No. 2,536,191), 25 g of isopropenyl acetate and 0.5 g of p-toluenesulfonic acid were added to 250 ml of benzene and the mixture was refluxed for 5 hours. After the reaction, the reaction mixture was condensated under reduced pressure. Upon crystallization of the residue from a solvent mixture of benzene and hexane, 23 g of Coupler (2) was obtained. The melting point of the coupler was 102° to 108° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>C(Cl)(Cl)Cl>[CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: O=CN1CCNCC1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C=O)CC3)ncc2c1=O
Yield: 83 %

Procedure:
A mixture of 8.4 g of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine, 6.9 g of formylpiperazine and 160 cm3 of chloroform is heated under reflux for 1 hour. After cooling, the solution is washed with water and dried and the solvent is evaporated. The oily residue crystallises on being taken up to 100 cm3 of isopropyl ether. The solid is filtered off and recrystallised from 50 cm3 of ethanol and yields 8.9 g (82%) of 2-(4'-Formylpiperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine which melts in two stages; melting point 195°C, solidification, followed by m.p. 204°C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Yield: 41.7 %

Procedure:
Using the procedure described in Example 161C, 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (2.00 g, 9.3 mmol) was reacted with phenyl chloroformate (1.6 g, 10.2 mmol) and K2CO3 (1.7 g, 12.1 mmol) in THF (20 mL), which was purified by silica gel chromatography (0-50% EtOAc/hexane) to afford phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate as solid (1.3 g, 42%). 1H NMR (300 MHz, DMSO-d6) δ 10.0 (s, 1H), 7.55 (m, 4H), 7.40 (m, 3H), 7.08-7.23 (m, 3H), 6.37 (s, 1H), 1.3 (s, 9H); LC-MS (ESI) m/z 336 (M+H)+.
Reaction SMILES: [N:1]1([C:5]([C@@H:7]2[CH2:12][C@H:11]([N:13]([C:18]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]4[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:22]=4[N:21]=3)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[N:1]1([C:5]([C@H:7]2[CH2:8][NH:9][CH2:10][C@@H:11]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]4[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:22]=4[N:21]=3)=[O:19])[CH2:12]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCC3)CN(C(=O)OC(C)(C)C)C2)nc2cc(F)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCC3)C2)nc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
tert-Butyl (3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (80 mg) was dissolved in trifluoroacetic acid (3 ml), and the mixture was stirred at room temperature for 1 hr. Aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (42 mg).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:44])[NH:6][C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]=[CH:23][N:24]([CH2:26][CH2:27][N:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)[CH:25]=5)[S:20][C:13]=34)=[C:9]([F:43])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]=[CH:23][N:24]([CH2:26][CH2:27][N:28]6[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]6)[CH:25]=5)[S:20][C:13]=34)=[C:9]([F:43])[CH:8]=2)=[O:44])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2cnc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4cn(CCN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of 307 (1.4 g, 2.25 mmol) in DCM (30 ml) was added TEA (2 mL) and the reaction mixture was stirred for 1 h. More TFA (3 mL) was added and the reaction mixture was stirred for an additional 3 h then concentrated, diluted with water and 1M NaOH to pH 11. The solid was collected by filtration, rinsed with water and dried. The residue was purified by Biotage (SNAP 80 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 35/65 over 30 CV), to afford the title compound 308 (870 mg, 1.67 mmol, 74% yield) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.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>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([NH:8][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:7])=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccc(N)cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(N)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-amino-(S)-α-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 518 (M+H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:18]([OH:20])=[O:19].[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([CH2:43]O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[C:30]([O:34][C:35]([N:37]1[CH2:38][CH2:39][C:40]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([CH2:43][O:19][C:18](=[O:20])[C:17]2[CH:16]=[C:15]([C:14]([F:28])([F:29])[F:13])[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=2)[CH2:41][CH2:42]1)=[O:36])([CH3:31])([CH3:32])[CH3:33]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (897 mg) was added to a stirred solution of 3,5-bis(trifluoromethyl) benzoic acid (292 mg) and 4-dimethylaminopyridine (483 mg) in dry dimethylformamide (20 ml). The resulting solution was stirred for 30 minutes then the compound of step (a) above (1.0 g) was added. The resulting solution was stirred at room temperature for 19 hours. At this time the reaction was diluted with water (200 ml) and extracted into ethyl acetate. The organic layers were separated, washed with water, brine, and dried over MgSO4. Filtration and removal of solvent under reduced pressure afforded a yellow oil. Purification by chromatography on silica gel (20% ethyl acetate/n-hexane) afforded the product as a clear oil. 1H NMR (360 MHz, CDCl3) δ 1.4 (9H, s), 1.95 (2H, m), 2.3 (2H, m), 3.03 (2H, m), 3.8 (2H, m), 4.35 (2H, s), 7.0-7.2 (5H, m), 8.01 (1H, s), 8.25 (2H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:23]1([CH2:22][CH2:21][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:10][C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[N:8][C:7](=[O:17])[C:6]=3[CH:18]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCCc1ccccc1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCCCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), 1-bromo-3-phenylpropane (0.86 g, 4.3 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 20 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.48 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N+:13]1[CH:21]=[C:20]2[N:15](C(=O)[NH:17][CH2:18][CH2:19]2)[CH:14]=1.O.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.O1CCOCC1>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:29][CH:30]=1.[CH3:12][N:13]1[CH:21]=[C:20]([CH2:19][CH2:18][NH2:17])[N:15]=[CH:14]1
Reactant: C[n+]1cc2n(c1)C(=O)NCC2
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc(CCN)c1
Temperature: 90 °C

Procedure:
A mixture of 2-methyl-5-oxo-5,6,7,8-tetrahydroimidazo[1,5-c]pyrimidin-2-ium 4-methylbenzenesulfonate (625.1 g), 4-methylbenzenesulfonic acid hydrate (406.6 g), 1,4-dioxan (9.38 litres) and water (625 ml) was heated at reflux (ca. 90° C.) for 2.5 h. when the reaction was complete by nmr. The reaction mixture was concentrated by distillation at atmospheric pressure collecting 7.03 litres. The concentrate was allowed to cool to ca. 77° C., and IMS-G (1.56 litres) was added. The resulting bright solution was allowed to cool and was seeded with [2-(1-methyl-1H-imidazol-4-yl)ethyl]amine bis(4-methylbenzenesulfonate) (0.625 g) at ca. 54° C. The suspension was allowed to cool to ca. 22° C. and aged for 40 min. The solid was filtered off and washed successively with 1,4-dioxan-IMS (3:1, 1.25 litres), and then 1,4-dioxan (2×1.25 litres), pulled dry and dried in vacuo at ca. 50° C. to yield the title compound, 866.3 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[C:5]([C:13]#[C:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:4]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].[Li]CCCC>>[CH3:20][N:21]([O:22][CH3:23])[C:7](=[O:9])[C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:13]#[C:14][CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CNOC
Reactant: COC(=O)c1ccc(OC)cc1C#CCC(C)C
Agent: Cl
Agent: [Li]CCCC
Product: COc1ccc(C(=O)N(C)OC)c(C#CCC(C)C)c1
Yield: 85 %

Procedure:
Treatment of methyl 4-(methyloxy)-2-(4-methyl-1-pentyn-1-yl)benzoate (102) (0.76 g, 3.09 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 0.72 g (85%) of the title compound (103) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.02 (d, J=6.6 Hz, 6H), 1.80-1.95 (m, 1H), 2.28 (d, J=6.6 Hz, 2H), 3.28 (br s, 3H), 3.59 (br s, 3H), 3.80 (s, 3H), 6.84 (dd, J1=8.6 Hz, J2=2.5 Hz, 1H), 6.94 (d, J=2.6 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H). LCMS (ESI): m/z 276 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][CH:15]([NH:17][C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:16].C(N=C=NCCCN(C)C)C>>[CH3:16][CH:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:25][CH2:26][N:27]([C:11]([C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=3[CH:5]=2)=[O:13])[CH2:28][CH2:29]1)[CH3:14]
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(Br)ccc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-bromoindole-2-carboxylic acid (0.51 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.47 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.49 g), the title compound is obtained, mp 229°-230°.