Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:25]=[C:26]([CH2:29]O)[S:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:26]5[S:27][CH:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:25]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1nc(C(F)(F)F)cs1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (65.1 mg) and triphenylphosphine (140 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (26.5 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([OH:19])=O)=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH:43]([O:45][CH2:46][CH2:47][O:48][NH2:49])=[CH2:44].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH:43]([O:45][CH2:46][CH2:47][O:48][NH:49][C:17]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:20])=[CH:14][C:13](=[O:15])[N:12]([CH3:16])[CH:11]=1)=[O:19])=[CH2:44]
Reactant: C=COCCON
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1cn(C)c(=O)cc1Nc1ccc(Br)cc1F
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture or 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.120 g, 0.352 mmol), EDCl (0.10 g, 0.53 mmol), and HOBt (0.071 g, 0.53 mmol) in DMF (5 mL) was stirred for 3 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (0.071 mL, 0.70 mmol) was added followed by Et3N (0.098 mL, 0.70 mmol). After 2 hours, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHC3 solution and brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (3% MeOH in methylene chloride) gave 0.078 g (52%) clean desired product.
Reaction SMILES: [Na].[CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.C(Br)(C)C.[Na+:11].[Br-].[CH:13]([C:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>O1CCCC1>[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Na+:11].[CH:13]([C:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: C1=CCC=C1
Agent: CC(C)C1=CC=CC1
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)Br
Solvent: C1CCOC1
Product: c1cc[cH-]c1

Procedure:
Sodium cyclopentadienide is prepared by using 30 g of fine sodium beads (a two fold excess) and 50 ml of monomeric cyclopentadiene in 500 ml of tetrahydrofuran (THF). This solution is then transferred to another vessel (away from excess sodium) and stirred while adding 60 ml of isopropyl bromide from a dropping funnel. After completion the NaBr is allowed to settle. The slightly yellow solution containing isopropylcyclopentadiene is then transferred to a still pot for the separation of THF by fractional distillation. Pure isopropylcyclopentadiene thus produced is mixed with prepurified argon and passed downwardly through a vertical quartz tube 1/2 in o.d. which is heated electrically to 500°-600° C. by an electrical resistance heater in a tube furnace mounted vertically. Strontium metal chips are supported in the quartz tube by a platinum foil with many holes on it at a tube constriction. The product, which flows down the tube walls as a viscous liquid, is collected in a three-necked flask connected to the bottom end of the tube.
Reaction SMILES: [C:1]([O:23]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].CCN(CC)CC.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:21][O:20][C:18]([CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:23])=[O:19]
Reactant: COC(=O)CCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCCCCCC=CCCCCCCCC1=O
Yield: 53.8 %

Procedure:
Under an argon stream, CH2Cl2 solvent (0.5 ml) was placed in a two-necked flask beforehand, and thereto were added dropwise, at 0 to 5° C., a mixed solution of dimethyl cis-9-octadecenedioate (170 mg, 0.50 mmol) and Et3N (152 mg, 1.50 mmol) in CH2Cl2 (2.15 ml) and a solution of TiCl4 (159 μl 1.45 mmol) in CH2Cl2 (2.45 ml) at the same time over a period of about 1 hour by means of a microfeeder. The whole was further mixed at the same temperature for 15 minutes. Water was added to the reaction mixture and the resulting mixture was stirred and then extracted with ether. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the evaporation of the solvent under reduced pressure, the crude product was purified by silica gel chromatography (hexane/ethyl acetate=20/1→10/1) to obtain the aimed product (83 mg, 54%) and a by-product (34-membered ring; 21 mg, 14%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[C:6]([OH:25])[CH:5]=1.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:35]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[C:6]([O:25][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:35]=2[O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:5]=1
Reactant: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: CCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OC)c1
Yield: 92.7 %

Procedure:
A mixture of 1.5 g (4.1 mmol) of 3-hydroxy-5-(tetradecyloxy) benzoic acid methyl ester, 2.3 g (5.1 mmol) of 1-(6-bromohexyl)-2,3-bis(phenylmethoxy)benzene, 1.1 g (8.2 mmol) of potassium carbonate and 0.6 g (4.1 mmol) of sodium iodide in 50 ml of acetone and 15 ml of DMF was stirred at reflux under argon for 32 hours. After the usual workup, the crude product was crystallized from methylene chloride-methanol to give 2.8 g (93% yield, mp 56°-58°) of 3-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]-5-(tetradecyloxy) benzoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH2:16][CH3:17].N1C=CC=N[C:19]1=O.C[Mg]Br.C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH2:16][CH3:17])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[CH3:19]
Reactant: O=c1nccc[nH]1
Reactant: CCOc1cc2c(cc1Br)C(=O)CCC2(C)C
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cc2c(cc1Br)C(C)=CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-bromo-6-ethoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound A-4, 1.05 g, 3.53 mmol) in THF (12 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1])-pyrimidinone (2 mL) at 0° C. was added a solution of methylmagnesium bromide (3M in diethylether (3.53 mL, 10.59 mmol). The reaction was allowed to warm up to room temperature and was stirred at 50° C. overnight. The reaction was quenched with ice water and extracted with diethylether. The organic layer was washed successively with water, brine, dried over Na2SO4, and concentrated in vacuo. The crude material was then dissolved in benzene (20 mL). After catalytic amount of p-toluenesulfonic acid was added, the reaction was stirred at reflux for 2 h. The solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 1% ethyl acetate in hexane) to afford the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14]3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH:13]1[S:12][C:8]1[C:6]2[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SC3Cc4ccccc4C3)c2n1
Reactant: C1CNCCN1
Product: c1ccc2c(c1)CC(Sc1ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc13)C2

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2-indanyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 202°-205° C.) and piperazine.
Reaction SMILES: C([Li])(C)(C)C.[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:40][N:41](C)CCN(C)C.C1(N=C=O)C=CC=CC=1>O1CCCC1>[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:40]#[N:41])(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)[Si](C)(C)OCC(c1ccccc1)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Li]C(C)(C)C
Solvent: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(c1ccccc1)c1ccc2c(c1)cc(C#N)n2S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of tert-butyllithium (1.7 M in pentane, 3.42 mmol) was added at −78° C. to a mixture of 1-benzenesulfonyl-5-[2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethyl]-1H-indole CCLXVIII (865 mg, 1.71 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.51 mL, 3.42 mmol) in tetrahydrofuran (20 mL). The resulting mixture was stirred for 1 hour and then a solution of phenyl isocyanate (300 mg, 2.565 mmol) in tetrahydrofuran (2 mL) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 1.5 hour and at 0° C. for 1.5 hours. The reaction was then quenched by addition of a saturated aqueous solution of ammonium chloride. The resulting mixture was diluted with water and diethyl ether. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 10/90 to 20/80) to give 0.56 g (62% yield) of 1-benzenesulfonyl-5-[2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethyl]-1H-indole-2-carbonitrile CCLXIX.
Reaction SMILES: O.[NH2:2][NH2:3].CCO.Cl[C:8]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:9]=1[C:10](OC)=[O:11].Cl>O>[N+:18]([C:15]1[CH:14]=[C:9]2[C:8](=[CH:17][CH:16]=1)[NH:3][N:2]=[C:10]2[OH:11])([O-:20])=[O:19]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate (19 ml) was added to an EtOH (15 ml) solution containing methyl 2-chloro-5-nitrobenzoate (10 g), followed by stirring at 90° C. for 1 hour. The reaction solution was adjusted to room temperature. Water and concentrated hydrochloric acid (32 ml) were added dropwise to the reaction solution. A solid precipitate was collected by filtration and washed with water. A brown solid of 5-nitro-1H-indazol-3-ol (5.42 g) was thus obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC(O)C1C=C([N+]([O-])=O)C=CC=1OC>>[CH2:13]([O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][OH:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(O)c(CO)c1
Reactant: BrCc1ccccc1
Agent: COc1ccc([N+](=O)[O-])cc1C(O)OC
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(CO)c1
Yield: 84 %

Procedure:
This intermediate was prepared by alkylation of 2-hydroxymethyl-4-nitrophenol with benzyl bromide following the method described for preparation of 2-methoxy-5-nitrobenzaldehyde methyl hemiacetal in a yield of 84%: MP 81-83° C.; 1H NMR δ (DMSO-d6, 500 MHz) 8.26 (d, 1H, J=2.9 Hz H-6), 8.15 (dd, 1H, J=2.9 and 9.1 Hz, H-4), 7.46 (d, 2H, J=7.0, 2′,6′-Hs) 7.41 (dd, 2H, J=7.0 and 7.7, 3′,5′-Hs), 7.34 (d, 1H, J=7 Hz, 4′-H), 7.25 (d, 1H, J=9.1 Hz, 3-H), 5.4 (br, 1H, OH), 5.29 (s, 2H, CH2), 4.57 (s, 2H, CH2).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.Cl[C:30]1[NH:31][CH2:32][CH2:33][N:34]=1>CC(O)C>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:30]4[NH:34][CH2:33][CH2:32][N:31]=4)=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC1=NCCN1
Reactant: Nc1ccc(CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=S(=O)(c1ccccc1)N1CCC(Cc2ccc(NC3=NCCN3)cc2)CC1
Yield: 87.7 %

Procedure:
A mixture of 4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenylamine (0.28 g, 0.83 mmol) and 2-chloro-2-imidazoline sulfate (0.25 g, 1.25 mmol) in 2-propanol (20 mL) was heated under reflux for 30 minutes under nitrogen atmosphere. The reaction mixture was concentrated in vacuo. The residue was basified with 10% sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with cold water and brine, dried, and solvents removed in vacuo. The residue was chromatographed on neutral aluminum oxide, eluting with 1% methanovdichloromethane, to give 2-[4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenyl]amino-imidazoline (0.29 g, 89%) as a foam. Analysis for C21H26N4O2S.5H2O: Calc.: C, 61.89; H, 6.68; N, 13.75; Found: C, 62.00; H, 6.52; N, 13.85.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])(=[O:9])[CH3:8].O.[OH-].[Na+]>C(OCC)C.O1CCCC1>[OH:9][CH:7]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH2:12][OH:13])[CH3:8]
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(O)c1ccccc1CO

Procedure:
To a suspension of 12 g of lithium aluminium hydride in 50 ml of dry diethyl ether was added dropwise with stirring a solution of 25 g (152.4 mM) of 2-acetylbenzoic acid in 120 ml of dry tetrahydrofuran. After heating under reflux for 6 hours, the mixture was cooled and treated carefully with 12 ml of water, 12 ml of 10% sodium hydroxide solution and 24 ml of water. The solution was filtered, the filtrate was dried over magnesium sulphate, filtered and evaporated to yield the title compound as a colourless waxy solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH:7]=[CH:6][N:5]1[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=1.[CH3:39]I>CN(C=O)C>[CH3:39][N:32]([C:29]1[CH:28]=[CH:27][C:26]([N:5]2[CH:6]=[CH:7][C:8]([O:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[CH:9][C:4]2=[O:3])=[CH:31][CH:30]=1)[C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(NC(=O)C(C)(C)C)cc4)c(=O)c3)CC2)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(N(C)C(=O)C(C)(C)C)cc4)c(=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a stirring suspension of sodium hydride (9.1 mg, 0.23 mmol), N-(4-(2-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-1(2H)-yl)phenyl)pivalamide (15 mg, 0.030 mmol) in DMF (2 mL) was added Methyl iodide (10 μL, 0.16 mmol). The reaction was stirred at room temperature for 1.5 h. The reaction was quenched with H2O and extracted with EtOAc. The organic layer was concentrated in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 10 mg of the desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (s, 2H), 7.39-7.48 (m, 2H), 7.32-7.39 (m, 2H), 7.26 (d, J=2.01 Hz, 1H), 5.98-6.09 (m, 2H), 4.55-4.64 (m, 1H), 4.16-4.28 (m, 2H), 3.59-3.71 (m, 2H), 3.27 (s, 3H), 2.43 (t, J=7.40 Hz, 2H), 1.98-2.22 (m, 2H), 1.74-1.98 (m, 2H), 1.53-1.66 (m, 2H), 1.12 (s, 9 H), 0.96 (t, J=7.28 Hz, 3H). MS (ESI) 504 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:15]([N:16](COC)[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:34])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[Cl:34][C:13]1[CH:14]=[C:15]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=2)(=[O:19])=[O:18])[C:10]([C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH:7]=2)=[O:9])=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccnc(N)c1)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(NS(C)(=O)=O)c2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide (140 mg, 0.272 mmol) in pyridine (0.75 mL) was added methanesulfonyl chloride (0.042 mL, 0.544 mmol). The reaction was warmed to 50° C. and stirred 2.5 h. The resultant mixture was quenched with 10% HCl, diluted with EtOAc, and the organic layer washed with 10% HCl and saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to produce the desired sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[BH4-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2scnc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was slurried in dry methanol/tetrahydrofuran (1:10). The solution was cooled to 0° C. under nitrogen and sodium borohydride (1.1 eq) was added in four portions. The solution was stirred at 0° C. for 30 min. An additional 0.1 eq sodium borohydride was added if necessary. The solvent was removed under vacuum and the resulting residue was purified by silica gel chromatography isocratic 1:1 methylene chloride: ethylacetate. The resulting white solid of 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 was isolated.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:15]([O:17]CC)=[CH2:16])[C:12]=3[O:13][CH3:14])[N:8]=2)[CH2:3][CH2:2]1.O.[Br:24]N1C(=O)CCC1=O>O1CCCC1>[Br:24][CH2:17][C:15]([C:11]1[C:12]([O:13][CH3:14])=[C:6]2[O:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:8][C:7]2=[C:9]([C:21]#[N:22])[C:10]=1[CH3:20])=[O:16]
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(=O)CBr)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
2-Cyclopropyl-6-[1-(ethoxy)ethenyl]-7-methoxy-5-methyl-1,3-benzoxazole-4-carbonitrile (I-84) (2.58 g, 8.46 mmol) was dissolved in tetrahydrofuran (130 ml), water (7.7 ml) and N-bromosuccinimide (1.61 g, 8.89 mmol) were added all at a time, followed by stirring at room temperature for 1.5 hours. After the reaction, the solvent was evaporated away under reduced pressure, followed by dilution with ethyl acetate and by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography (covering) and eluted with a mixed solvent of n-hexane/ethyl acetate (2:1, v/v) to obtain the entitled compound (2.40 g, 81%) as a yellow white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[CH2:12][N:13]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)(=[NH:3])[NH2:2].[ClH:34].[C:35](=[NH:40])(OCC)[CH3:36].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:34].[ClH:34].[ClH:34].[C:35]([N:24]1[CH2:25][CH2:26][CH:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([N:13]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12]/[CH:11]=[CH:10]/[C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=3)=[CH:15][CH:16]=2)[CH2:22][CH2:23]1)(=[NH:40])[CH3:36]
Reactant: CCOC(=O)C(C)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(C)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47 %

Procedure:
To a solution of a mixture (544 mg) containing ethyl 2-[N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]amino]propionate in methanol (30 ml) were added ethyl acetimidate hydrochloride (360 mg) and triethylamine (0.81 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 25% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (468 mg, yield of two steps 47%) as a pale brown amorphous solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:23][CH:22]=[C:21]([C:24]([OH:26])=[O:25])[C:20]=1[CH2:27][CH2:28][OH:29])=O>>[OH:29][CH2:28][CH2:27][C:20]1[C:21]([C:24]([OH:26])=[O:25])=[CH:22][NH:23][C:19]=1[CH:17]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: O=Cc1[nH]cc(C(=O)O)c1CCO
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1[nH]cc(C(=O)O)c1CCO

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-4-(2-hydroxyethyl)-1H-pyrrole-3-carboxylic acid to give the title compound.