Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=3)[N:16]=[C:15]([C:29]([F:32])([F:31])[F:30])[CH:14]=2)=[CH:9][C:8]=1[CH3:33])(=[O:5])=[O:4].[Cl:36]N1C(=O)CCC1=O.O>CN(C=O)C>[F:35][C:2]([F:1])([F:34])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[C:20]([F:28])[CH:19]=3)[N:16]=[C:15]([C:29]([F:30])([F:31])[F:32])[C:14]=2[Cl:36])=[CH:9][C:8]=1[CH3:33])(=[O:5])=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2c(Cl)c(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.4 %

Procedure:
To a stirred solution of 2-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl trifluoromethanesulfonate (0.185 g, 0.339 mmol) in DMF (2 mL) was added N-chlorosuccinimide (0.227 g, 1.70 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 72 hours. The reaction mixture was added water (20 mL) and extracted with ethyl acetate/hexane/ether=2/1/1 (20 mL×2). The organic layer was washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (4/1) to give the subtitle compound (0.117 g, 59.7% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]1)=O.[N-:15]=[N+:16]=[N-:17].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C.CCOC(C)=O>[CH3:1][N:2]1[C:3]([C@@H:5]2[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]2)=[N:17][N:16]=[N:15]1
Reactant: CNC(=O)[C@@H]1CCC[C@H](C(=O)OC)C1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@@H](c2nnnn2C)C1
Temperature: 0 °C
Yield: 67.6 %

Procedure:
(±)-cis-Methyl 3-(methylcarbamoyl)cyclohexanecarboxylate (460 mg, 2.309 mmol) was dissolved in Acetonitrile (5 mL) at 25° C. under nitrogen with stirring, then sodium azide (150 mg, 2.309 mmol) was added. Cooled to 0° C. then added trifluoromethanesulfonic anhydride (0.390 mL, 2.309 mmol) dropwise over 2 minutes. The reaction was a colorless solution. Stirred for 20 hours then added sat'd sodium bicarbonate and stirred for 15 minutes, then added a little EtOAc and concentrated in vacuo the acetonitrile. Added more EtOAc and separated the layers. The EtOAc layer was rinsed again with sat'd sodium bicarbonate then 1 time with brine. The EtOAc layer was dried over sodium sulfate and stripped to give of a colorless oil. Obtained (±)-cis-methyl 3-(1-methyl-1H-tetrazol-5-yl)cyclohexanecarboxylate (350 mg, 1.561 mmol, 68% yield) as a colorless oil for product. MS found: (M+H)+=225.00.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:19][C:20]1[CH:56]=[CH:55][CH:54]=[CH:53][C:21]=1[CH2:22][NH:23][C:24]([C@@H:26]1[C:30]([CH3:32])([CH3:31])[S:29][CH2:28][N:27]1[C:33](=[O:52])[C@@H:34]([OH:51])[C@@H:35]([NH:43][C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:56]=[CH:55][CH:54]=[CH:53][C:21]=1[CH2:22][NH:23][C:24]([C@@H:26]1[C:30]([CH3:32])([CH3:31])[S:29][CH2:28][N:27]1[C:33](=[O:52])[C@@H:34]([OH:51])[C@@H:35]([NH:43][C:44](=[O:50])[C@@H:45]([NH:46][C:5](=[O:7])[CH2:4][O:3][CH2:1][CH3:2])[CH:47]([CH3:49])[CH3:48])[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:25]
Reactant: CCOCC(=O)O
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Ethoxyacetic acid (28 μl), HOBt (41 mg), and HDC.HCl (63 mg) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 of Example 8 in DMF (5 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was recrystallized from ethyl acetate/n-hexane to obtain the title compound (153 mg).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1
Reactant: C[O-]
Reactant: CSc1nc2cccccc-2n1
Agent: [Na+]
Solvent: CO
Product: COc1nc2cccccc-2n1

Procedure:
First, 3 g of 2-methylthiocycloheptimidazole as synthesized according to Synthetic example 1 (c) with reference to the method disclosed in Bulletin of the Chemical Society of Japan, volume 33, No. 1, pages 56 to 58 (1960) was added to 50 ml of methanol, and 1 g of sodium methoxide was further added thereto. After reflux with heating for 10 hours, the solvent was distilled away, and 50 ml of benzene was added to the residue. The insoluble matters were filtered out, and the filtrate was concentrated. The resulting crystals were purified by silica gel column chromatography using ethyl acetate as a developing solvent.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][C:12]3=[N:13][O:14][N:15]=[C:11]3[CH:10]=2)O1.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH:25]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:24][CH2:23]2.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:13]1[O:14][N:15]=[C:11]2[CH:10]=[C:9]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[CH:25]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:24][CH2:23]4)[CH:17]=[CH:16][C:12]=12
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NC1CCc2cc(Oc3ccc4nonc4c3)ccc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (0.313 mmol, 77 mg), N-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (0.157 mmol, 40 mg), copper (II)acetate (0.157 mmol, 28.5 mg), triethylamine (0.783 mmol, 0.110 mL, 79 mg) and 4A molecular sieves (100 mg) in DCM (1 mL) was stirred at room temperature for 60 h. The reaction mixture was filtered through dicalite and the pad washed with MeOH before the filtrate was concentrated to dryness. The residue was purified by prep HPLC to give a brown film (32. mg, 5.5%). MS (ESI): m/z [M+H]+ 374.0
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[NH:24][NH2:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:20][CH:21]=1
Reactant: NNC(=O)Nc1ccc(Br)cc1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccc(Br)cc1

Procedure:
ninhydrin, 4-(4-bromophenyl)-semicarbazide hydrochloride
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[NH3:22].CO>ClCCl>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH2:22])=[C:4]([F:21])[C:5]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1cccc2ccccc12
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 1-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}naphthalene (0.96 g, 2.63 mmol) in dichloromethane (10 mL) was added 7N ammonia in methanol (20 mL, 140 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with dichloromethane to give the desired product (0.769 g, 87%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29-8.37 (m, 1H), 7.94-8.03 (m, 1H), 7.60-7.71 (m, 4H), 7.56 (t, 1H), 7.36 (t, 1H), 6.56 (d, 1H), 4.13 (s, 2H). ES MS: m/z 302 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([OH:29])=O)=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:70]([NH2:74])([CH3:73])([CH3:72])[CH3:71]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:18]([C:27]([NH:74][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:29])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2cc(C(=O)O)c(C(F)(F)F)nc2C1)Cc1cc(F)ccc1F
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product (33 mg, 0.061 mmol) from Example 3, Step B, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 12 mg, 0.063 mmol), 1-hydroxybenzotriazole (HOBt; 9 mg, 0.067 mmol) and N,N-diisopropylethyl amine (0.026 mL, 0.15 mmol) in 1.0 mL of dichloromethane was added tert-butylamine (0.011 mL, 0.100 mmol). The solution was stirred at room temperature for 18 h. The reaction mixture was subjected directly to flash chromatography (silica gel; 35 to 75% ethyl acetate/hexanes step-gradient elution) to afford the title compound as a white foam.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH3:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([S:7]([CH3:8])=[O:20])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CSc1nc(-c2ccccc2)c(C)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1sc(S(C)=O)nc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
6.56 g. of 5-methyl-2-methylthio-4-phenylthiazole pre-dissolved in 100 ml. of methylene chloride is cooled in an ice bath. The stirred solution is treated with 6.01 g. of m-chloroperoxybenzoic acid, added in portions over five minutes. After 30 minutes, the reaction is complete and the precipitated m-chlorobenzoic acid is filtered and the filtrate washed successively with a 10% solution of sodium sulfite, saturated aqueous sodium bicarbonate solution and water. After drying, concentration in vacuo and chromatography yields a white solid, m.p. 96°-97° C.
Reaction SMILES: [CH3:1][NH2:2].O.Cl[C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=[C:7]([Cl:15])[CH:6]=1>CC#N>[Cl:15][C:7]1[CH:6]=[C:5]([NH:2][CH3:1])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: CN
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Solvent: O
Solvent: CC#N
Product: CNc1cc(Cl)ncc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
40% Methylamine in water (0.847 mL, 9.78 mmol) was added slowly over 5 minutes at 0° C. to a solution of methyl 4,6-dichloronicotinate (0.40 g, 1.94 mmol) in MeCN (6 mL). The solution was stirred at 0° C. for 30 minutes then at room temperature for 2 hours. The reaction mixture was concentrated in vacuo onto silica gel. Gradient chromatography, eluting with 5% EtOAc:c-Hex over 5 column volume and 5-50% over 15 column volume, gave methyl 6-chloro-4-(methylamino)nicotinate (278 mg, 1.386 mmol, 71.4% yield) as a white solid.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@H:8]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]3)[CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(Cl)(Cl)Cl>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][C@H:8]2[CH2:9][CH2:10][C:11]3[C:6](=[C:5]4[C:14](=[CH:13][CH:12]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[O:7]2)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc4ncccc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: Fc1ccc2[nH]cc(C3=CCN(C[C@H]4CCc5ccc6ncccc6c5O4)CC3)c2c1
Yield: 56.6 %

Procedure:
A solution of (6R)-toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.17 g, 0.47 mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.20 g, 0.94 mmole) in anhydrous DMSO (25 mL) was stirred at 80° C. for 2 hours. The reaction mixture was then poured into chloroform (100 mL) and washed with water (3×40 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under vacuum. Column chromatography on silica gel (5% methanol/ethyl acetate) afforded 0.11 g (55%) of the title compound. The fumarate salt was prepared in ethyl acetate and isopropyl alcohol and had mp 210° C. and [α]25D=−60.03° (c=4.5, DMSO).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH3:20][Mg]Br.C(OCC)C>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][C:7]=1[CH:8]([OH:9])[CH3:20])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-ethyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde (0.793 g, 2.95 mmole) in THF (30 mL) at 0° C., is added a solution of methyl magnesium bromide in diethyl ether (3.0M, 2.0 mL, 0.60 mmole) dropwise. The reaction is stirred for 5 minutes and then warmed up to room temperature for 30 minutes. The reaction is quenched with NH4Cl(aq) (10 mL), partitioned between ethyl acetate (50 mL) and water (50 mL). Extracted the aqueous layer with ethyl acetate (2×50 mL). The combined organic is washed with brine (3×100 mL), dried over Na2SO4, filtered and concentrated to provide the titled compound as a white solid. The crude product is used for the next step without further purification. Mass [EI+] 286 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][C@H:22]([CH3:26])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].C(OC([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:39]([C@H:35]4[CH2:36][CH2:37][CH2:38][NH:34]4)=[O:40])[C@H:22]([CH3:26])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: C[C@@H]1CN(c2ccc3cnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3cnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a stirred solution of the crude 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-((R)-3-methylpiperazin-1-yl)-1H-indazole (0.078 g, 0.20 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.086 g, 0.40 mmol) in dichloromethane (1 mL) was added HATU (0.15 g, 0.40 mmol) and Et3N (0.10 mL, 0.72 mmol). The reaction mixture was stirred at room temperature for 30 min, followed by the addition with dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 30% ethyl acetate in hexanes) to afford the desired product (0.034 g, 0.058 mmol, 11% for 2 steps).
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([F:32])=[CH:14][C:15]([F:31])=[C:16]([C:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=2)[CH:17]=1)=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:11][C:12]1[C:13]([F:32])=[CH:14][C:15]([F:31])=[C:16]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]2)[CH:17]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(NC(=O)OCc3ccccc3)c(F)cc2F)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)c(F)cc2F)CC1
Reaction time: 72 h
Yield: 123.6 %

Procedure:
A mixture of tert-butyl 4-(5-{[(benzyloxy)carbonyl]amino}-2,4-difluorophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.60 g, 3.60 mmol) and 5% Pd/C (320 mg, 0.100 mmol) in ethyl acetate (25.0 mL) and methanol (25.0 mL) was hydrogenated at room temperature for 72 hours using hydrogen bomb (200 psi). The reaction mixture was filtered through Celite and washed with EtOAc/MeOH (1:1, 3×50 mL). The filtrate was concentrated in vacuo to afford tert-butyl 4-(5-amino-2,4-difluorophenyl)-1-piperidinecarboxylate (1.39 g, 100%). 1H NMR (400 MHz, CDCl3) δ 6.73 (t, 1H, J=10.6 Hz), 6.60-6.54 (dd, 1H, J=7.6, 6.57 Hz), 4.20 (br, 2H), 3.55 (s, 2H), 2.96-2.72 (m, 3H), 1.79-1.71 (m, 2H), 1.58-1.52 (m, 2H), 1.47 (s, 9H); ESMS m/e: 257.3 (M−56).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[S:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[C:6]([NH2:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(N)=O)cc1Sc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
A mixture of 4-amino-3-(2,4-difluorophenylthio)benzamide (0.82 g), methanesulfonyl chloride (0.64 g) and triethylamine (0.6 g) in dichloromethane (10 ml) was stirred for 2 hours at room temperature. The reaction mixture was evaporated. To the residue were added methanol (10 ml) and potassium hydroxide (0.6 g). The mixture was kept overnight and evporated. The residue was treated with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue obtained was recrystallized from ethanol to give 3-(2,4-difluorophenylthio)-4-(methanesulfonamido)benzamide (0.54 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(O)C.CCOCC>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cnc2cnc(Cl)cc2c1Cl
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1cnc2cnc(Cl)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To the above 600 mg of 4,6-dichloro-[1,7]naphthyridine-3-carbonitrile in 20 mL of absolute ethanol was added 1 mL of 3-bromoaniline. After refluxing the reaction under an inert atmosphere for 4 hours, the reaction mixture was cooled to ambient temperature, diluted with ether, and the product was filtered and washed with ether. Drying in vacuo yielded 790 mg of 4-(3-bromo-phenylamino)-6chloro-[1,7]naphthyridine-3-carbonitrile as an off-white solid: mp=220-223° C.; mass spectrum (m/e): M+H 359.0, 361.1.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.CS(O[CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:17]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.73 g, 0.0028 mol), tert-butyl 3-[(methylsulfonyl)oxy]-1-azetanecarboxylate (1.05 g, 0.0042 mol) and cesium carbonate (1.4 g, 0.0042 mol) in N,N-dimethylformamide (25 mL) were stirred at 70° C. under an atmosphere of nitrogen for 16 hours. The mixture was cooled to room temperature. Additional tert-butyl 3-[(methylsulfonyl)oxy]-1-azetanecarboxylate (0.35 g, 0.0014 mol) and cesium carbonate (0.46 g, 0.0014 mol) were added to the mixture. The mixture was stirred at 70° C. under an atmosphere of nitrogen for 16 hours. The solvent was removed under the reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with dichloromethane (3×70 mL). The combined organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure. The residue was triturated with dichloromethane (2×3 mL) to give tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.57 g, 0.0014 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 9.4 min. MS: MH+ 417
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:40])([CH3:39])[CH2:31][O:32]C1CCCCO1)([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:25])([CH3:24])[CH2:16][O:17]C1CCCCO1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)C>Cl.O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:39])([CH3:40])[CH2:31][OH:32])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:24])([CH3:25])[CH2:16][OH:17])[C:4]([O:3][CH2:1][CH3:2])=[O:41])[CH3:10]
Reactant: CCOC(=O)C(CCCCC(C)(C)COC1CCCCO1)(CCCCC(C)(C)COC1CCCCO1)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCCCC(C)(C)CO)(CCCCC(C)(C)CO)C(=O)OCC
Yield: 83.5 %

Procedure:
A solution of 2,2-bis[5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]malonic acid diethyl ester (2.92 g, 5.0 mmol) in concentrated hydrochloric acid (2.4 mL) and water (1.6 mL) was heated at reflux for 1 h. Ethanol (8.2 mL) was added and the reaction mixture was heated at reflux for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to afford 2,2-bis(6-hydroxy-5,5-dimethylhexyl)malonic acid diethyl ester (1.74 g, 84%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.13 (q, 4 H, J=7.2 Hz), 3.25 (s, 4 H), 2.42 (s, 2 H), 1.90-1.75 (m, 4 H), 1.30-1.12 (m, 18 H), 0.84 (s, 12 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 172.0, 71.7, 60.9, 57.4, 38.2, 34.9, 32.1, 24.8, 24.0, 23.7, 14.0. HRMS (LSIMS, gly): Calcd. for C23H45O6 (MH+): 417.3216, found: 417.3210.