Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:41]4[CH2:40][CH2:39][N:38]([CH:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)[CH2:43][CH2:42]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCN(C2CCN(C)CC2)CC1
Temperature: 105 °C
Yield: 69.6 %

Procedure:
Following the procedure of Example 11, a mixture of 220 mg (0.5 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile, 290 mg (1.6 mmol) of 1-(1-methylpiperidin-4-yl)piperazine in 1.2 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 20 hours to yield the crude product. Purification by silica gel chromatography (gradient 9:1 methylene chloride/methanol to 85:15 methylene chloride/methanol) gives 210 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-methoxy-7-[4-(1-methyl piperidin-4-yl)piperazin-1-yl]quinoline-3-carbonitrile as a beige solid, mp 220-226° C. (shrinks at 205° C.).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(-c2ccc(Cl)cc2)c1
Yield: 120.4 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromopyridine (280 mg, 0.79 mmol) and 4-chlorophenylboronic acid (246 mg, 1.57 mmol, Lancaster Chemical Co.) in toluene (10 mL) was added Pd(0) (30 mg) and Na2CO3 (2.5 mL of a 2 M solution), and the mixture was heated at reflux for 6 h. The solvent was removed under vacuum, and the residue was chromatographed (silica gel; EtOAc/hexane, 1:5 to 1:2) to afford the title compound (370 mg, >100% yield): 1H NMR (CDCl3, 300 MHz) δ 1.47 (s, 9H), 1.80-2.10 (m, 3H), 3.30-3.49 (m, 2H), 3.90-4.30 (m, 3H), 7.40-7.60 (m, 5H), 8.31 (s, 1H), 8.42 (s, 1H); MS (CI/NH3) m/z 389 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].Cl[C:15]([O:17][CH3:18])=[O:16].Cl>O.CCOCC>[CH3:18][O:17][C:15]([NH:1][C@@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4])=[O:16]
Reactant: COC(=O)Cl
Reactant: C=CC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C=CC[C@H](NC(=O)OC)C(=O)O
Temperature: 0 °C
Reaction time: 20 h
Yield: 83.1 %

Procedure:
A mixture of (S)-2-aminopent-4-enoic acid (1.0 g, 8.69 mmol) and NaHCO3 (2.26 mg, 26.9 mmol) in H2O (40 mL) was cooled to 0° C. A mixture of methyl chloroformate (740 μL, 9.55 mmol) dissolved in Et2O (4 mL) was slowly added to the aqueous mixture and stirred for 20 hours coming to ambient temperature. Mixture was adjusted to pH 3.0 with HCl (conc). The mixture was extracted with EtOAc and then dried (MgSO4), filtered and concentrated to afford 1.25 g (83%) of the title compound. MS (ESI) m/z 174 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])=O.[CH2:21]([NH2:24])[CH2:22][CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[N+:18]([C:17]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:4][C:3]=1[CH2:1][NH:24][CH2:21][CH2:22][CH3:23])([O-:20])=[O:19]
Reactant: CCCN
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(C=O)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
The following reaction was completed under N2. A mixture of 3-(3-formyl-4-nitro-phenoxy)-benzonitrile (0.056 mol) and propylamine (0.059 mol) in DCE (450 ml) was stirred at room temperature, then NaBH(OAc)3 (0.063 mol) was added. The reaction mixture was stirred overnight at room temperature. A saturated NaHCO3 solution was added and the layers were separated. The organic layer was dried, filtered off and the solvent was evaporated. The residue was purified over silica gel filter (eluent: CH2Cl2/CH3OH 99/1). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: C(C1C=CC(CC(C2CCCCC2)C(N[C@@H:15]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:16]([NH:18][C@@H:19]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([NH2:29])=[NH:28])[C:20]([NH2:22])=[O:21])=[O:17])=O)=CC=1)(=N)N.C(C1C=CC([CH2:51][CH:52]([CH:66]2[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]2)[C:53]([NH:55][C@@H:56]([CH:60]2[CH2:65][CH2:64][CH2:63][CH2:62]C2)[C:57]([OH:59])=[O:58])=[O:54])=CC=1)(=N)N.Cl.Cl.N[C@@H](CCC[NH:82][C:83](N)=[NH:84])C(N)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[C:57]([OH:59])(=[O:58])[CH3:56].[C:83]([C:64]1[CH:65]=[CH:60][C:56]([N:55]([C:53](=[O:54])[CH:52]([CH:66]2[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71]2)[CH3:51])[CH:34]2[CH2:33][CH2:32][CH2:31][CH:30]([CH2:15][C:16]([NH:18][C@@H:19]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([NH2:29])=[NH:28])[C:20]([NH2:22])=[O:21])=[O:17])[CH2:35]2)=[CH:62][CH:63]=1)(=[NH:82])[NH2:84]
Reactant: N=C(N)c1ccc(CC(C(=O)N[C@H](C(=O)O)C2CCCCC2)C2CCCCC2)cc1
Reactant: N=C(N)NCCC[C@H](N)C(N)=O
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C1CCCCC1)C1CCCCC1)C(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(=O)O
Product: CC(C(=O)N(c1ccc(C(=N)N)cc1)C1CCCC(CC(=O)N[C@@H](CCCNC(=N)N)C(N)=O)C1)C1CCCCC1
Yield: 46 %

Procedure:
2-(S)-{2-(S)-[3-(4-Carbamimidoyl-phenyl)-2-cyclohexyl-propionylamino]-2-cyclohexyl-acetylamino}-5-guanidino-pentanoic acid amide acid salt, less polar diastereomer, was prepared from (S)-[3-(4-carbamimidoyl-phenyl)-2-cyclohexyl-propionylamino]-cyclohexyl-acetic acid (less polar diastereomer, example 1 h), 2-(S)-amino-5-guanidino-pentanoic acid amide dihydrochloride. HATU, and collidine in dimethylformamide as described in example 3 to yield 46% of the desired product. MS m/z: 569.5 (M+H)+, 285.4 (M+2H)2+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:15])=[CH:12][C:13]=1[F:14])(=[O:8])=[O:7])(C)(C)C.C1CCN2C(=NCCC2)CC1.FC(F)(F)C(O)=[O:30].[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:50](=[O:51])[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:43][C:42]2=[O:52])=[CH:37][CH:36]=1.C(#N)C>C(O)(C(F)(F)F)=O>[O:52]=[C:42]1[N:41]([C:38]2[CH:39]=[CH:40][C:35]([NH:34][C:1]([NH:5][S:6]([C:9]3[S:10][C:11]([Cl:15])=[CH:12][C:13]=3[F:14])(=[O:8])=[O:7])=[O:30])=[CH:36][CH:37]=2)[C:50](=[O:51])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[NH:43]1
Reactant: Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1)NS(=O)(=O)c1sc(Cl)cc1F
Reaction time: 1 h
Yield: 31.8 %

Procedure:
A 19 mg-sample (0.07 mmol) of (tert-butyl)[(5-chloro-3-fluoro(2-thienyl))sulfonyl]amine was dissolved in neat TFA and stirred for 1 h, concentrated in vacuo and used directly in the next transformation. This sample was dissolved in 150 uL of DCM and 21 mg (0.084 mmol) of DSC was added followed by 21 μL (0.14 mmol) of DBU. This solution was stirred for 18 h, 26 mg (0.07) of 3-(4-aminophenyl)-1,3-dihydroquinazoline-2,4-dione trifluoroacetate salt was added plus 150 μL of dry acetonitrile and refluxed for 2 h. This material was then purified on RP-HPLC to afford 11 mg (34%) of the desired product. ES-MS: M+H+=495 (Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:3]=12.[CH2:15]([Br:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[Br-:22].[CH2:15]([N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:8][C:4]=12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccnc2c1-c1ccccc1C2
Solvent: CC(C)=O
Product: Cc1cc[n+](Cc2ccccc2)c2c1-c1ccccc1C2
Product: [Br-]
Temperature: 25 °C

Procedure:
A mixture of 4-methyl-9H-indeno[2,1-b]pyridine (0.64 g) and benzyl bromide (0.42 mL) in acetone (5 mL) is stirred at reflux temperature for 4 h. After cooling to room temperature, the precipitate is separated by filtration, washed with little diethyl ether, and dried to give the title compound as a beige solid. Yield: 0.93 g (75% of theory); LC (method 1): tR=2.49 min; Mass spectrum (ESI+): m/z=272 [M-Br]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH:7](Br)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[C:27]([CH3:28])=[C:26]([C:29]([O:31][CH3:32])=[O:30])[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[C:14]([OH:33])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:32][O:31][C:29]([C:26]1[S:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=3[O:33][CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])[CH3:8])[C:20]=2[C:27]=1[CH3:28])=[O:30]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)OC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Bromopropionic acid tert-butyl-ester (1.4 g) was added to methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (Intermediate III) (2.00 g) and cesium carbonate (4.8 g) in ACN (50 ml) and stirred at 60° C. for 2 hours. The mixture was diluted with water, filtrated and washed with water.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:8]1C=[CH:12][CH:11]=[CH:10][C:9]=1CBr)=[N:5][O:6][CH3:7].[C:17]([O-:20])(=O)[CH3:18].[K+].[CH3:22][NH2:23]>C1COCC1.O>[CH3:22][NH:23][C:3](=[O:2])[C:4]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:18]=1[CH2:17][OH:20])=[N:5][O:6][CH3:7]
Reactant: CN
Reactant: CC(=O)[O-]
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1CO
Temperature: 25 °C
Yield: 67.6 %

Procedure:
Methyl-2-(2-bromomethylphenyl)-2-methoxyiminoacetate (2.00 g) and potassium acetate (1.37 g) were suspended in THF, and the suspension was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, and 30 % methanolic methylamine (5.4 g) was added thereto. The resultant mixture was stirred for 10 hours, diluted with water and neutralized, followed by extraction with ethyl acetate. The solvent was dried and distilled off, and the residue was purified by silica gel column chromatography, whereby there was obtained (E) N-methyl-2-(2-hydroxymethylphenyl)-2-methoxyiminoacetamide (1.05 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Cc2ccc(C#N)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(Cc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 26-3 (0.391 g, 1.75 mmol) in methylene chloride (6 ml) cooled in an ice-bath in a 3-necked round bottom flask equipped with a nitrogen inlet and rubber septum was added 1.0M boron tribromide in methylene chloride (3.9 ml, 3.9 mmol) via syringe. The resulting mixture was stirred 18 h while warming to ambient temperature. Water (7 ml) was added and the mixture was extracted with ether (35 ml). The organic fraction was washed with brine (10 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1:5 increasing to 1:3), to give product 26-4 as a white solid, mp: 163°-164° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:11]Br>C(O)(=O)C>[Br:11][C:7]1[C:8]([OH:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c(O)cc1F
Temperature: 45 °C
Reaction time: 26 h
Yield: 81.2 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzaldehyde (2.16 g, 15.4 mmol) in acetic acid (70 mL) was added a solution of bromine (2.71 g, 17.0 mmol) in acetic acid (10 mL), and the mixture was stirred at 45° C. for 26 hr. The reaction mixture was concentrated under reduced pressure, brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (2.74 g, yield 81%) as colorless crystals.
Reaction SMILES: [CH3:1]/[C:2](/[O-:7])=[CH:3]/[C:4]([CH3:6])=[O:5].[Na+].[I-].[Na+].[CH:11]([CH:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=C.[CH3:21]C(C)=O>>[CH:13]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:21][CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:5])[CH3:6])=[CH2:11]
Reactant: CC(C)=O
Reactant: CC(=O)/C=C(/C)[O-]
Reactant: C=CC(Cl)c1ccccc1
Agent: [I-]
Agent: [Na+]
Product: C=Cc1cccc(CC(C(C)=O)C(C)=O)c1
Temperature: 25 °C

Procedure:
To 308 g of sodium acetylacetonate and 30 g of sodium iodide in 100 mL acetone (dried over 3A molecular sieves) was added dropwise 282 ml vinylbenzyl chloride (70% Meta, 30% Para), in 600 ml acetone. An ice bath was used to keep the pot temperature below 50° during the addition. The solution was maintained at 45°-50° C. until NMR samples showed no residual vinylbenzyl chloride (about 1 hour). The pot was then cooled to room temperature and placed in the refrigerator overnight. The sodium chloride was then filtered and the acetone removed at room temperature under reduced pressure. The crude product was then added to an excess of toluene (800 ml) to precipitate any remaining sodium salts. The solution was again filtered and the toluene was removed at temperatures below 50° C. under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](Cl)([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13].[C:30](=[O:33])(O)[O-:31].[Na+]>O>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:30]([O:31][CH2:15][CH:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:33])[CH:10]=1)[C:5]([OH:7])=[O:6])([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13]
Reactant: Nc1cc(N)cc(C(=O)O)c1
Reactant: O=C([O-])O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc(C(=O)O)c1)OCC1c2ccccc2-c2ccccc21

Procedure:
The compound was synthesised from 3,5-diaminobenzoic acid and Fmoc-chloride using sodium bicarbonate as base in a mixture of water and a suitable organic solvent. NMR analytical data were in accordance with the structure.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([CH:39]2[CH2:40][CH2:41][O:42][CH2:43][CH2:44]2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(C2CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(C2CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.12 g), sodium hydrogen carbonate (0.19 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-6-oxo-4-propyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.12 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL). N,N′-carbonyldiimidazole (0.06 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.08 g, 62%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:17])[CH:6]2[O:15][CH3:16].[Li]CCCC.[CH2:23]1[O:25][CH2:24]1.O>C1COCC1>[C:11]([C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][CH:5]([CH3:17])[CH:6]2[O:15][CH3:16])=[C:2]([CH2:23][CH2:24][OH:25])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CO1
Reactant: COC1c2cc(C(C)(C)C)cc(Br)c2CC1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC1c2cc(C(C)(C)C)cc(CCO)c2CC1C
Temperature: -110 °C
Reaction time: 0.67 h

Procedure:
To a solution of 40.0 g (134.5 mmol) of 4-bromo-6-tert-butyl-1-methoxy-2-methylindane in 250 ml of THF 107.7 ml of 2.5 M (269 mmol) n-BuLi in hexanes was added for 20 min at −80° C. This mixture was stirred for 40 min at this temperature, cooled to −110° C., and 11.85 g (269.15 mmol) of ethylene oxide was added by one portion at vigorous stirring. The resulting mixture was stirred for 12 h at room temperature, and then 10 ml of water was added. The organic layer was separated and evaporated to dryness. To the residue 200 ml of water was added, and the crude product was extracted with 3×100 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography using short column with Silica Gel 60 (40-63 um, d 110 mm, l 90 mm; eluent: hexanes/ether=20/1). Yield 27.58 g (78%) of a ca. 1 to 2 mixture of two diastereomers.
Reaction SMILES: O=C1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)=[CH:7][CH:8]=2)[NH:3]1.NC1C=C(Br)C=CC=1C#N.B([O-])[O-]>>[NH2:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)NC(=O)NC3)CC1
Agent: N#Cc1ccc(Br)cc1N
Agent: [O-]B[O-]
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)c(N)c2)CC1
Yield: 62 %

Procedure:
Following the same procedure adopted for the synthesis of 22, the reaction of nitrile 11 with boronic ester 21 afforded the title compound 24 as an off-white solid (62%). IR (KBr) νmax, cm−1: 3421, 3318 (NH2), 3072 (Ar—H), 2247 (CN), 1691 (C═O), 1616, 1510, 1412 (C═C). 1H-NMR (500 MHz, CDCl3) δ=1.49 (s, 9H, (CH3)3C); 1.71 (br, s, 2H, CH2); 2.45 (br. s, 2H, CH2); 3.61 (m, 2H, CH2); 4.07 (s, 2H CH2); 4.43 (br. s, 2H, NH2); 6.10 (br. s, 1H, CH); 6.71 (d, J=2.2 Hz, 1H, H-2); 6.75 (dd, 1H, J=2.3, 8.6 Hz, H-6); 7.33 (d, J=8.5 Hz, 1H, H-5); 8.01 (br. s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=27.35 (CH2), 28.47 (CH3)3C), 29.73 (CH2), 41.96 (CH2), 79.91 (CH3)3C), 94.63 (aromatic-C), 115.12 (aromatic-C), 117.69 (CN), 133.67 (aromatic-C), 147.42 (aromatic-C), 150.47 (aromatic-C), 155.33 (C═O). Calculated (%) for C17H21N3O2 (299.16); C: 68.20, H: 7.07, N: 14.04. found (%); C: 68.16, H: 7.13, N: 13.97.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:25]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:33])=[O:32])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)C1CCCCC1
Reaction time: 0.08 h

Procedure:
To a 50 ml round-bottom flask equipped with a stir bar, was added 5-bromo-2-chloropyridin-3-amine (0.250 g, 1 mmol) while under inert atmosphere. The solid was dissolved in THF (10 ml, 122 mmol), then sodium bis(trimethylsilyl)amide (0.650 g, 3 mmol) was added to the mixture and allowed to stir 5 minutes. Then cyclohexanesulfonyl chloride (0.5 ml, 4 mmol) was added into the mixture. The mixture was allowed to stir overnight, while under inert atmosphere. The progress of the reaction was monitored by LC/MS, which showed product and a small amount of bis-sulfone material in the mixture. The mixture was diluted with DCM and water. The organic layer was extracted with DCM (3×25 ml). Combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was dissolved in methanol (5 ml), then potassium carbonate (0.250 g) was added to the mixture with stirring. After 20 minutes, the progress of the de-sulfonylation reaction was monitored by LC/MS, which showed mostly desired product. The mixture was filtered and concentrated in vacuo. The crude was purified by ISCO silica-gel chromatography, in a gradient of 1-15% ethyl acetate/hexanes. This gave N-(5-bromo-2-chloropyridin-3-yl)cyclohexanesulfonamide (0.140 g, 33% yield) as an off-white amorphous solid. MS (ESI pos. ion) m/z: 354 (MH+). Calc'd exact mass for C11H14BrClN2O2S: 353. 1H NMR (400 MHz, chloroform-d): 1.15-1.35 (m, 2H), 1.52-1.66 (m, 1H), 1.70 (d, J=4.52 Hz, 1H), 1.73 (s, 1H), 1.76-1.86 (m, 1H), 1.92 (d, J=11.54 Hz, 1H), 2.11-2.22 (m, 2H), 2.96-3.05 (m, 1H), 6.70 (s, 1H), 8.15-8.22 (m, 2H).