Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[S:40]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41]1>C1COCC1.O.[Na+].[Cl-]>[CH3:3][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:47][CH2:46][CH2:45][C:42]2[CH:43]=[CH:44][S:40][CH:41]=2)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:7])([CH3:1])[CH3:4]
Reactant: NCCc1ccsc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCCc2ccsc2)c1F
Reaction time: 8 h
Yield: 109.8 %

Procedure:
Tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (1.84 g, 3.71 mmol) was dissolved in THF (5 mL). To this solution was added triethylamine (0.62 mL, 4.4482 mmol), followed by [2-(3-thienyl)ethyl]amine (0.470 g, 3.70 mmol) which was semi-suspended in THF (15 mL). The reaction was left to stir overnight, then diluted with water and saturated NaCl. The aqueous layer was extracted with ethyl acetate. The organics were dried (MgSO4) and concentrated to produce tris(1,1-dimethylethyl)2-(2-chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate as an orange oil (2.389 g). LCMS: (M+H)+=588.3.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1.Cl.C(=O)([O-])[O-].[NH4+:47].[NH4+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:47])[NH2:41])=[CH:36][CH:35]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-5-[N-(2-ethoxycarbonylethyl)-quinoline-8-sulphonylamino]-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>CN(C=O)C>[NH2:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Br:1])=[C:12]([C:17]([F:20])([F:18])[F:19])[CH:11]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1cc(C(F)(F)F)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.7 %

Procedure:
A solution of N-bromosuccinimide (1.0 g, 5.6 mmol) dissolved in DMF (3 mL) was slowly added to a mixture of 3-amino-4-chlorobenzotrifluoride (1 g, 5 mmol) dissolved in DMF (2 mL) and the reaction mixture was stirred at RT for 20 min, concentrated, and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography (eluted with 100% hexanes) to produce the title intermediate as a reddish colored oil (970 mg, 70% yield). (m/z): [M+H]+ calcd for C7H4BrClF3N, 273.92, 275.92 found 276.2.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9](O)=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.C1C=CC2N(O)[N:20]=[N:19]C=2C=1.CCN=C=NCCCN(C)C.Cl.NN.C1CCCCC=1>C(#N)C>[OH:12][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:8]/[C:9]([NH:19][NH2:20])=[O:10])=[CH:1][CH:2]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: C1=CCCCC1
Solvent: CC#N
Product: NNC(=O)/C=C/c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a stirred solution of p-coumaric acid (3.28 g, 20 mmol) in anhydrous acetonitrile (40 mL) was added HOBt (3.24 g, 24 mmol) and EDC.HCl (4.6 g, 24 mmol) at room temperature, and the mixture was stirred at room temperature for 2 h. The resulting yellow suspension was cooled with an ice-bath, and an ice-cold solution of hydrazine (1.25 mL, 40 mmol) and cyclohexene (0.61 mL, 6 mmol) in acetonitrile (30 mL) was added in one portion. The mixture was stirred at 0° C. for 20 min and followed by an additional 1 h at room temperature. The resulting yellow suspension was filtered off, and the solid was washed with MeOH (3×30 mL), H2O (2×30 mL), saturated NaHCO3 (2×30 mL), H2O (2×20 mL) and EtOAc (2×20 mL) successively, and finally air-dried, obtaining 133 (1.3 g, 36% yield), with its identity verified by 1H NMR (300 MHz, DMSO-d6).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:12][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.81-mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (522 mg, 86%).
Reaction SMILES: C([O:4][CH:5]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:17])(=O)C.C(OCC(CO)O)(=O)CCCCCCCCCCCCCCC(C)C.C(OCCCCCC)(=O)CCCCCCCCCCC>>[OH:4][CH:5]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:17]
Reactant: CCCCCCC(CCCCCCCCCCC(=O)OCC(CC)CCCC)OC(C)=O
Agent: CC(C)CCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: CCCCCCCCCCCC(=O)OCCCCCC
Product: CCCCCCC(O)CCCCCCCCCCC(=O)OCC(CC)CCCC

Procedure:
2-ethylhexyl 12-acetoxystearate (Compound 9) glyceryl isostearate (Compound 10) hexyl laurate (Compound 11).
Reaction SMILES: [OH-:1].[Na+].Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH:15]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1.[BH4-].[Na+]>C(O)C.O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:1])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH:15]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: O=C(Cc1ccc(Cl)cc1)CN1CCC(O)CC1c1ccc(Cl)cc1
Reactant: [OH-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CCN(CCC(O)c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)C1
Temperature: 50 °C
Yield: 100.4 %

Procedure:
To a solution containing 1.2 g (0.03 mol) of sodium hydroxide in 50 ml of an 50% by volume ethanol/water mixture, 12.41 g (0.03 mol) of 1-(4-chlorophenyl)-3-[4-hydroxy-(4-chlorophenyl)-1-piperidyl]propanone hydrochloride and then, over 1 hour 1.17 g of sodium borohydride are added. The suspension is heated at a temperature of 50° C. for 2 hours. After cooling down, the reaction mixture is filtered and washed with water to give 11.45 g of product, m.p.: 129°-132° C. After recrystallization of the latter product from 215 ml of acetonitrile, 9.1 g of title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[CH:10]1.Br[CH2:20][CH2:21][CH3:22].[H-].[Na+]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:20][CH2:21][CH3:22])[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[CH:10]1
Reactant: CCCBr
Reactant: Cc1cn(Nc2ccncc2Cl)c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: CCCN(c1ccncc1Cl)n1cc(C)c2ccccc21

Procedure:
The title compound was prepared from N-(3-chloro-4-pyridinyl)-3-methyl-1H-indol-1-amine and 1-bromopropane with the aid of NaH in substantially the same manner as in Example 4, m.p. 68°-70°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:5])[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[SH:35]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:35][C:29]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=2[Cl:27])[CH2:8][C@H:7]1[CH2:16][O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(S)c(Cl)c1
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1COCc1ccc(OC)cc1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(F)cc2Cl)C[C@H]1COCc1ccc(OC)cc1

Procedure:
The title compound was prepared in analogy to example 68 step 8 using (1R,2R,4R)-4-methanesulfonyloxy-2-(4-methoxy-benzyloxymethyl)-cyclopentanecarboxylic acid ethyl ester (example 153 step 6) and 2-chloro-4-fluorothiophenol. Yellow oil (95%). MS (EI): 452 (M)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[N:17][C:18]([NH:21][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ncc(Br)cn1
Product: O=C(Nc1ncc(Br)cn1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 5-Bromo-pyrimidin-2-ylamine to produce N-(5-Bromo-pyrimidin-2-yl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:13]=1[C:14]([OH:16])=[O:15])=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1.C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCNc1cccc([N+](=O)[O-])c1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCNc1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred solution of 2-(2-tert-butoxycarbonylamino-ethylamino)-6-nitro-benzoic acid (0.22 g, 0.00068 mol) in THF at 0° C. was added 4N HCl in dioxane (0.68 mL). The reaction was stirred at 0° C. for 2 h then warmed to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-(2-amino-ethylamino)-6-nitro-benzoic acid (0.12, 76% yield). 1H NMR (400 MHz, CDCl3) δ 11.6 (s, 1H), 7.57 (t, 1H, J=7.6 Hz), 7.05 (d, 1H, J=7.8 Hz), 6.80 (d, 1H, J=7.8 Hz), 4.0 (broad s, 3H), 3.63 (m, 2H), 3.07 (m, 2H); MS (m/e) 226 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[CH:14][O:13][C:12]=1[NH:16][C:17](=O)[CH2:18][CH2:19][CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)CO>[CH2:1]([N:8]1[C:9](=[O:10])[C:11]2[CH:15]=[CH:14][O:13][C:12]=2[N:16]=[C:17]1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1occc1C(=O)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: CCCc1nc2occc2c(=O)n1Cc1ccccc1
Temperature: 130 °C

Procedure:
A mixture of N-benzyl-2-(butyrylamino)-3-furamide (1-2, 1 equiv) and sodium hydroxide (0.1 equiv) in ethylene glycol is heated at 130° C. for 5 h. The reaction mixture is allowed to cool, then partitioned between a half-saturated aqueous sodium chloride solution and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by flash column (hexanes initially, grading to 100% ethyl acetate) to provide 3-benzyl-2-propylfuro[2,3-d]pyrimidin-4(3H)-one (1-3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([CH3:30])[C:26]([F:28])([F:29])[F:27])[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)C(F)(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC(C)C(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
190 mg (purity 92%, 0.36 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluor-4-methylpentanoate (mixture of racemic diastereomers) were hydrolysed with TFA according to General Method 6A. The crude product was reacted in the next step without further purification. Yield: 129 mg
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([F:9])[CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:23])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[F:9][CH:6]1[CH2:5][N:4]([C:10]([C:12]2[N:13]=[C:14]([CH3:23])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[CH:3]([CH2:2][NH:1][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[N:24]=[CH:25][CH:26]=[CH:27]3)=[O:35])[CH2:8][CH2:7]1
Reactant: Cc1nc(C(=O)N2CC(F)CCC2CN)c(-c2ccccc2)s1
Reactant: O=C(O)c1cccc2cccnc12
Product: Cc1nc(C(=O)N2CC(F)CCC2CNC(=O)c2cccc3cccnc23)c(-c2ccccc2)s1

Procedure:
The final product N-((5-fluoro-1-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared by following general procedure A using (2-(aminomethyl)-5-fluoropiperidin-1-yl)(2-methyl-5-phenylthiazol-4-yl)methanone and quinoline-8-carboxylic acid. The NMR of desired product indicated the presence of two rotamers in 1/2 ratio. 1H NMR (DMSO-d6, 400 MHz) δ 11.02-10.99 (m, 0.33H), 10.73-10.70 (m, 0.67H), 9.05-9.03 (m, 0.33H), 8.98-8.97 (m, 0.67H), 8.62-8.59 (m, 1.33H), 8.52-8.50 (M, 0.67 h), 8.24-8.19 (m, 1H), 7.81-7.74 (m, 1.33H), 7.72-7.68 (m, 0.67H), 7.47-7.43 (m, 0.67H), 7.34-7.32 (m, 2.33H), 7.19-7.10 (m, 2H), 5.08-4.67 (m, 2H) 3.98-3.34 (m, 4H), 2.65 (s, 1H), 2.23 (s, 2H), 2.12-1.69 (m, 2.67H), 1.41-1.39 (m, 1.33H). MS (ESI) 489 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]2[CH:31]=[C:30]([N:32]3[C:36]4=[N:37][CH:38]=[CH:39][C:40]([C:41]5[CH:42]=[N:43][C:44]6[C:49]([CH:50]=5)=[CH:48][CH:47]=[CH:46][CH:45]=6)=[C:35]4[C:34]([CH3:51])=[CH:33]3)[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1>ClCCl>[C:1]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]2[CH:31]=[C:30]([N:32]3[C:36]4=[N:37][CH:38]=[CH:39][C:40]([C:41]5[CH:42]=[N:43][C:44]6[C:49]([CH:50]=5)=[CH:48][CH:47]=[CH:46][CH:45]=6)=[C:35]4[C:34]([CH3:51])=[CH:33]3)[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](N)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](Nc2cc(-n3cc(C)c4c(-c5cnc6ccccc6c5)ccnc43)ccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (0.012 mL) and triethylamine (0.021 mL) were added to a solution of compound (61) (0.050 g) prepared in Example 61 in dichloromethane (10 mL), followed by stirring at room temperature for 1 hr. The solvent was distilled away under reduced pressure, and water was added to the residue. The precipitate was collected by filtration, washed by sprinkling water and ether, and dried under reduced pressure to obtain compound (62) (0.043 g, 78%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:23][N:24]([CH3:27])C=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:4][CH2:5][C:6]4[CH:7]=[N:8][N:24]([CH3:27])[CH:23]=4)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1cc(CCN2CCC(c3c[nH]c4cc(Cl)ccc34)CC2)cn1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a mixture of 2.0 gm (8.5 mMol) 6-chloro-3-(piperidin-4-yl)-1H-indole and 2.25 gm (21 mMol) sodium carbonate in 20 mL dimethylformamide was added a solution of 1.74 gm (8.4 mMol) 1-methyl-4-(2-methanesulfonyloxy)ethyl-1H-pyrazole in a minimal volume of dimethylformamide. The resultant mixture was heated at 100° C. for 18 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was separated and washed first with water and then with saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. This residue was subjected to silica gel chromatography, eluting with dichloromethane containing 5% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give 1.74 gm (59.8%) of 6-chloro-3-(1-(2-(1-methylpyrazol-4-yl)ethyl)piperidin-4-yl)-1H-indole as a yellow foam. The oxalate salt was formed and crystallized from methanol to provide the title compound as yellow crystals.
Reaction SMILES: BrBr.Br[C:4]1[C:12](OC)=[C:11](OC)[C:10](OC)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[OH-].[Na+].O>C(O)C.[Cu]>[C:6]([OH:8])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:4]=1
Reactant: COc1cc(C(=O)O)c(Br)c(OC)c1OC
Agent: [Cu]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
A mixture of 1,2,3-Trimethoxybenzene (1.48 g) and 2-hydroxy-3,4,5-trimethoxybenzoic acid (2.00 g) is stirred in 40 ml of ≈9% solution of P2O5 in methanesulfonic acid at room temperature in a stoppered flask for 4 hours. The 2-hydroxy-3,4,5-trimethoxybenzoic acid was obtained by the method of Mayer and Fikentscher (Mayer and Fikentscher (1956) Chem. Ber. 89:511) from 3,4,5-trimethoxybenzoic acid by bromination and then copper-catalyzed replacement of bromine (by OH) of 2-bromo-3,4,5-trimethoxybenzoic acid. The resultant orange mixture is poured onto crushed ice (500 ml) producing an unfilterable gummy precipitate. This crude product is then subjected to base-catalyzed ring closure by heating in a beaker in 100 ml of 40% ethanol and 10 ml of 10N NaOH just below boiling point. As the mixture reaches 80° C., a white flocculent product appears. The temperature is maintained just below the boiling point and the volume is kept constant by addition of water. After 5 hours, the supernatant is bright yellow and a mass of the precipitate has formed. Heating is continued for 4 more hours. Cooling, filtering (by suction) and washing with water afforded 1.37 g of analytically pure 2,3,4,5,6-pentainethoxyxanthone (yield approximately 45% relative to benzoic acid). This base-catalyzed ring closure is illustrated below:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][N:26]([C:30](=[O:37])[CH2:31][CH:32]5[CH2:36][CH2:35][NH:34][CH2:33]5)[CH2:27]4)=[CH:22][CH:21]=3)[N:17]=[C:16]([NH2:38])[N:15]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C>C(#N)C>[NH2:38][C:16]1[N:17]=[C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][N:26]([C:30](=[O:37])[CH2:31][CH:32]4[CH2:36][CH2:35][N:34]([C:2]([O:4][CH3:5])=[O:3])[CH2:33]4)[CH2:27]3)=[CH:22][CH:21]=2)[CH:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH3:7])[CH2:13][CH2:12]2)[N:15]=1
Reactant: COC(=O)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNC3)CC4)nc(N)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)N1CCC(CC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (2.1 uL, 0.028 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-[2-(pyrrolidin-3-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (0.013 mL, 0.092 mmol) in acetonitrile (0.5 mL). The reaction mixture was stirred at r.t. for 30 min The mixture was purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=494.3.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:25])(=[O:24])[NH:11][CH2:12][C:13]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]2)[CH:5]=1.[OH-].[Na+]>C1COCC1>[C:20]([O:19][C:17]([C:13]1([CH2:12][NH:11][S:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:26])=[O:2])(=[O:25])=[O:24])[CH2:14][CH2:15][CH2:16]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1cccc(S(=O)(=O)NCC2(C(=O)OC(C)(C)C)CCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)O)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(1-tert-butoxycarbonyl-cyclobutylmethyl)-sulfamoyl]-benzoic acid methyl ester (step 3) (1.87 g, 4.88 mmol) in THF (25 ml) was treated with 2M NaOH (aq) (24.38 ml, 48.8 mmol) and stirred at RT for 2 h. The reaction mixture was partitioned between diethyl ether and water. The aqueous portion was separated and acidified to pH 1 with 2N HCl, and extracted with EtOAc, and the combined organic portions were washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title product; 1H NMR (400 MHz, CDCl3) δ 8.64 (1H, s), 8.33 (1H, d), 8.12 (1H, d), 7.67 (1H, t), 5.40 (1H, t), 3.24 (2H, d), 2.38 (2H, m), 1.97 (4H, m), 1.48 (9H, s). LC-MS Rt 1.13 mins; 314.1 [M+H]+ (-tBu), Method 2minLC_v003.
Reaction SMILES: C(NC(NC1C=CC([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[N:21]([CH3:22])[N:20]=[CH:19][C:17]=3[N:18]=2)=CC=1)=O)C.[N+:30]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[CH3:29][C@H:24]1[CH2:25][O:26][CH2:27][CH2:28][N:23]1[C:15]1[C:16]2[N:21]([CH3:22])[N:20]=[CH:19][C:17]=2[N:18]=[C:13]([C:36]2[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:38][CH:37]=2)[N:14]=1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3c(cnn3C)n2)cc1
Product: C[C@H]1COCCN1c1nc(-c2ccc([N+](=O)[O-])cc2)nc2cnn(C)c12

Procedure:
This compound was prepared in an analogous fashion to (S)-1-ethyl-3-(4-(1-methyl-7-(3-methylmorpholino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)urea, using 4-nitrophenylboronic acid pinacol ester as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 8.62 (d, J=9.0 Hz, 2H), 8.32 (d, J=9.0 Hz, 2H), 8.22 (s, 1H), 4.27 to 4.17 (m, 4H), 4.08 to 3.95 (m, 2H), 3.93 to 3.82 (m, 1H), 3.79 to 3.67 (m, 2H), 3.60 to 3.50 (m, 1H), 1.38 (d, J=6.6 Hz, 3H).