Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:20][C:12]=3[C:11]=2[CH:10]([CH2:25][Cl:26])[CH2:9]1)=O)(C)(C)C.[N+:27]([O-])([O-:29])=[O:28].[K+].N>OS(O)(=O)=O>[Cl:26][CH2:25][CH:10]1[C:11]2[C:12]3[C:20]([N+:27]([O-:29])=[O:28])=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][C:13]=3[CH:14]=[CH:15][C:16]=2[NH:8][CH2:9]1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1ccc2c3c(ccc2c1)N(C(=O)OC(C)(C)C)CC3CCl
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])c2c3c(ccc2c1)NCC3CCl
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 13.3 %

Procedure:
Powdered 150 (900 mg, 2.39 mmol) was added to stirred conc. H2SO4 (6 mL) at 0° C. and the mixture was warned to room temperature for 15 nm. The resulting solution was cooled to −5° C. and treated dropwise with a solution of KNO3 (266 mg, 2.63 mmol) in conc. H2SO4 (1.5 mL). The mixture was stirred at −5° C. for a further 5 min, then poured into ice/water and neutralized with dilute aqueous NH3. The resulting solid was chromatographed on silica gel, eluting with CH2Cl2 to give crude methyl 1-(chloromethyl)-9-nitro-1,2-dihydro-3H-benzo[e]indole-7-carboxylate (151) (102 mg, 13%) as an orange-brown solid; 1H NMR [(CD3)2SO] δ 8.66 (d, J=1.7 Hz, 1H), 8.30 (d, J=1.7 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.25 (s, 1H), 7.18 (d, J=8.8 Hz, 1H), δ 3.92-3.83 (m, 4H), 3.74-3.67 (m, 1H), 3.63 (dd, J=10.6, 2.3 Hz, 1H), 3.39-3.28 (m, 2 H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:13][OH:14])[CH2:8][CH2:7][CH2:6]2)=[CH2:2].C(N(C(C)C)CC)(C)C.[Si](Cl)(C)(C)C.[Li]N1C(C)(C)CCCC1(C)C.[C:40]1([C:46]2[C:50]([C:51]([F:54])([F:53])[F:52])=[C:49]([C:55](OC)=[O:56])[O:48][N:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[C:40]1([C:46]2[C:50]([C:51]([F:54])([F:52])[F:53])=[C:49]([C:55]3([OH:56])[O:14][N:13]=[C:9]4[C:10]5[C:5]([CH2:6][CH2:7][CH:8]34)=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:12][CH:11]=5)[O:48][N:47]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: C=Cc1ccc2c(c1)CCCC2=NO
Reactant: COC(=O)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: C[Si](C)(C)Cl
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)CCC1C2=NOC1(O)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a stirred solution of 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (I-1, 4.03 g, 21.50 mmol) and diisopropylethylamine (6.83 mL, 39.1 mmol) in anhydrous THF (50 mL) was added TMS-Cl (2.75 mL, 21.50 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min. The previously prepared LiTMP solution was added dropwise at −78° C. under nitrogen. After the mixture was stirred at the same temperature for 30 min, a solution of methyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate (I-3, 5.3 g, 19.54 mmol) in anhydrous THF (10 mL) was added dropwise at −78° C. The solution was stirred at −78° C. for 30 min and then warmed to 0° C. over 30 min. The reaction was quenched with saturated aqueous ammonium chloride solution (25 mL) and water (20 mL). The mixture was mixed with EtOAc (50 mL), stirred at room temperature for 30 min and filtered through a pad of celite. The filtrate was separated. The aqueous layer was extracted with EtOAc (2×25 mL). The combined organic solutions were washed with brine (50 mL), dried over sodium sulfate and concentrated to give a liquid. Flash chromatography purification (330 g silica gel column, 15-30% ethyl acetate in hexanes) afforded 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol (5 g, 11.73 mmol, 60.0% yield) as a yellow solid. The compound had an HPLC retention time=3.74 min (condition C); LC/MS M+1=426.9.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:18])[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:7][CH:6]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:50]COC)([C:46]([F:49])([F:48])[F:47])[C:42]([F:45])([F:44])[F:43])=[CH:37][C:36]=2/[CH:54]=[CH:55]\[CH3:56])[C@H:31]([CH3:57])[CH2:30]1)=[O:28].Cl.C(OCC)(=O)C>CN(C)C=O.C(OCC)(=O)C.O>[F:48][C:46]([F:47])([F:49])[C:41]([C:38]1[CH:39]=[CH:40][C:35]([N:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[CH2:26][N:13]3[C:12](=[O:17])[C@:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[CH:10][CH:9]=4)([CH3:18])[NH:15][C:14]3=[O:16])[CH2:30][CH:31]2[CH3:57])=[C:36](/[CH:54]=[CH:55]\[CH3:56])[CH:37]=1)([OH:50])[C:42]([F:45])([F:44])[F:43]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: C/C=C\c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)C[C@H]1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)N[C@](C)(c3ccc(OC(C)C)cc3)C2=O)CC1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
5-[4-(1-Methylethoxy)phenyl]-5-methylimidazolidine-2,4-dione (7.7 mg, 0.0311 mmol) was dissolved in N,N-dimethylformamide (500 μL), added potassium carbonate (8.6 mg, 0.0622 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 5 minutes. Then, under ice-cold conditions, (R,Z)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-(prop-1-en-1-yl)phenyl}-3-methylpiperazin-1-yl)ethanone (17 mg, 0.0311 mmol) was added, and stirred at room temperature for 18 hours. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained crude product was dissolved in ethyl acetate (1.0 mL), added a solution of 4N-hydrochloric acid-ethyl acetate (1.0 mg), and stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added water and a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and (R,Z)-3-(2-{4-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(prop-1-en-1-yl)phenyl]-3-methylpiperazin-1-yl}-2-oxoethyl)-5-[4-(1-methylethoxy)phenyl]-5-methylimidazolidine-2,4-dione (17.4 mg (yield 83%)) was obtained as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17]C(NC(N)=O)(C)C)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=C2CC(C)(C)C)[CH2:3][CH2:2]1.CO>[C].[Pd].O1CCCC1>[NH2:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[CH:10][C:9]=1[NH:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)NC(N)=O)ccc2n1CC1CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.4 %

Procedure:
A mixture of N-(cyclopropylmethyl)-4-(methylsulfonyl)-2-nitroaniline (Step A, 9.32 g, 34.2 mmol), 10% palladium carbon (950 mg), methanol (250 mL) and tetrahydrofuran (250 mL) was stirred at room temperature for 3 h under hydrogen atmosphere. The resulting mixture was filtered through a pad of celite. The filtrate was concentrated to afford the crude product (9.16 g) as brown viscous oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][N:36]=1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:39]([C:38]3[CH:37]=[N:36][C:35]([OH:34])=[CH:43][CH:42]=3)=[O:40])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: O=C(O)c1ccc(O)nc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)c3ccc(O)nc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and 6-hydroxynicotinic acid as a colorless oil (95%). HPLC, Rt: 4.86 min (Purity: 88%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Temperature: 110 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Into a 250-mL round-bottom flask, was placed 1-(bromomethyl)-4-nitrobenzene (15 g, 69.77 mmol, 1.00 equiv), triethyl phosphite (70 mL). The resulting solution was stirred for 2 h at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:1). This resulted in 17 g (89%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].[OH-].[Na+:25]>>[CH3:1][C:2](=[CH:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O-:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].[Na+:25]
Reactant: CC(=Cc1ccc(Cl)cc1)C(=O)Nc1cccc(CC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=Cc1ccc(Cl)cc1)C(=O)Nc1cccc(CC(=O)[O-])c1

Procedure:
330 Milligrams of 3-(α-methyl-4'-chlorocinnamoylamino)phenylacetic acid were dissolved in an alcohol and an equivalent amount of sodium hydroxide was added to the solution. The solution was warmed for 30 minutes and then concentrated under reduced pressure. Ether was added to the residual liquid to precipitate crystals which were then collected by filtration to obtain sodium 3-(α-methyl-4'-chlorocinnamoylamino)phenylacetate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26].N1C=CC=CC=1>C(OCC)C>[C:24]([O:21][C:19]1[CH:20]=[C:15]([N:5]2[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=[C:4]2[O:3][CH2:1][CH3:2])[C:16]([F:23])=[CH:17][C:18]=1[Cl:22])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)Cl
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(=O)C(C)C)c(Cl)cc1F

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone and isobutyryl chloride with pyridine in diethyl ether there is obtained {5-[2-ethoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-2-chloro-4-fluorophenyl} isobutyrate, 1NMR (CDCl3, 400 MHz): 7.38 ppm (d,1H), 7.13 ppm (d,1H), 6.58 ppm (s,1H), 4.50 ppm (m,2H), 2.87 ppm (m,1H), 1.35 ppm (d,3H), 1.34 ppm (d,3H), 1.31 ppm (t,3H);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([N:25]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([CH2:14][CH3:15])[C:9]#[C:10][C:11]([NH2:13])=O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([N:25]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([CH2:14][CH3:15])[C:9]#[C:10][C:11]#[N:13])=[CH:4][CH:3]=1
Reactant: CCC(C#CC(N)=O)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCC(C#CC#N)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from step C (20 mg, 0.036 mmol, enantiomer A) in pyridine (5 mL) was added POCl3 (0.05 mL). The mixture was stirred at RT for 2 h. The residue was purified by Combiflash (Mobile phase: MeOH/H2O (0.08% of NH4HCO3) to obtain the title compound. LC/MS m/z=564.0 [M+Na]+.
Reaction SMILES: C(OC([N:8]([CH2:16][CH2:17][CH2:18][N:19]1[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:22][S:21][C:20]1=[N:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[O:39][CH3:40])[CH2:9][CH2:10][C:11](OCC)=[O:12])=O)(C)(C)C.ClC1C=CC(N=C2N(CCCNCCO)C(C3C=CC(F)=CC=3)=CS2)=C(OC)C=1.Cl>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([N:31]=[C:20]2[N:19]([CH2:18][CH2:17][CH2:16][NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:23]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[CH:22][S:21]2)=[C:33]([O:39][CH3:40])[CH:34]=1
Reactant: CCOC(=O)CCN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Agent: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCNCCO
Agent: Cl
Product: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCNCCCO

Procedure:
The compound (1.3 g) obtained in the above (1) was treated in a similar manner to in Example 321 (2), (3) to give the title compound (889 mg) as hydrochloride.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]([N:15]=[N:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]=[N:30][CH:31]([C:35]([NH:37][C:38]4[CH:43]=[CH:42][C:41](C)=[CH:40][C:39]=4[CH3:45])=[O:36])[C:32]([CH3:34])=[O:33])=[C:25]([Cl:46])[CH:24]=3)=[CH:19][C:18]=2[Cl:47])[C:12]([CH3:14])=[O:13])=[O:10])=[C:4]([CH3:48])[CH:3]=1.CC(C(C)=O)C(NC1C=CC=CC=1)=O>>[CH3:45][C:39]1[C:38]([NH:37][C:35]([CH:31]([N:30]=[N:29][C:26]2[CH:27]=[CH:28][C:23]([C:20]3[CH:21]=[CH:22][C:17]([N:16]=[N:15][CH:11]([C:9]([NH:8][C:5]4[C:4]([CH3:48])=[CH:3][CH:2]=[CH:7][CH:6]=4)=[O:10])[C:12]([CH3:14])=[O:13])=[C:18]([Cl:47])[CH:19]=3)=[CH:24][C:25]=2[Cl:46])[C:32]([CH3:34])=[O:33])=[O:36])=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(=O)C(N=Nc1ccc(-c2ccc(N=NC(C(C)=O)C(=O)Nc3ccc(C)cc3C)c(Cl)c2)cc1Cl)C(=O)Nc1ccc(C)cc1C
Agent: CC(=O)C(C)C(=O)Nc1ccccc1
Product: CC(=O)C(N=Nc1ccc(-c2ccc(N=NC(C(C)=O)C(=O)Nc3ccccc3C)c(Cl)c2)cc1Cl)C(=O)Nc1ccccc1C

Procedure:
The pigment suspension was prepared similarly to C.I. Pigment Yellow 13 by coupling of 28 g of tetrazotized 3,3'-dichlorobenzidene with 44.3 g of 2-methylacetoacetanilide.
Reaction SMILES: C(N)CCC.[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH3:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:24]([CH2:27][CH3:28])([O-:26])=[O:25]>C(O)(=O)C>[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:27]([N+:24]([O-:26])=[O:25])[CH3:28])=[CH:16][C:15]=1[O:22][CH3:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[N+](=O)[O-]
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Solvent: CC(=O)O
Solvent: CCCCN
Product: COc1cc(C=C(C)[N+](=O)[O-])ccc1OCc1ccccc1
Yield: 18 %

Procedure:
4.02 g (55.0 mmol) of butylamine was added dropwise to a mixture of 12.1 g (50.0 mmol) of 4-benzyloxy-3-methoxybenzaldehyde, 5.63 g (75.0 mmol) of nitroethane and 120 ml of acetic acid and refluxed for 5 hours by heating. The reaction mixture was cooled and extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:1) to give 2.70 g of 1-benzyloxy-2-methoxy-4-(2-nitropropenyl)benzene.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([S:56]([NH:59][CH3:60])(=[O:58])=[O:57])[CH:44]=[CH:45][C:46]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([S:56]([NH:59][CH3:60])(=[O:58])=[O:57])[CH:44]=[CH:45][C:46]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: CNS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNS(=O)(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c(OC)c1
Yield: 80.4 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with 3-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (72 mg, 0.22 mmol), sodium carbonate (23 mg, 0.22 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (21 mg, 0.03 mmol) in 1,2-dimethoxyethane (1.60 ml) and water (0.40 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 46 mg (73% yield) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[O:4]1.[H-].[Na+].[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:23]([O:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11][CH2:12]2)[O:4]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CCN2CCC3(CC2)OCC(COCc2ccccc2)O3)cc1
Temperature: 58 °C
Yield: 84 %

Procedure:
2-hydroxymethyl-8-phenethyl-1,4-dioxa-8-azaspiro[4,5]decane (compound 1, 50 gm, 0.18 mole) was dissolved in toluene (250 ml) at room temperature. 10 gm of 60% of sodium hydride in toluene (300 ml) was added to the above solution until the effervescence ceased. 2 gram of phase transfer catalyst tetrabutylammonium bromide (TBAB) was added. Benzyl chloride, 23 gm was then added drop wise to the above reaction mass and the reaction was maintained at 58° C. for 15 hrs. The reaction mass was poured into water and organic layer was separated. Toluene was removed under reduced pressure to get a thick reddish brown liquid. The yield is 84%.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:52]C(OC(C)(C)C)=O)[C:14](=[O:51])[NH:15][C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:19]([O:25][S:26](=[O:47])(=[O:46])[NH:27][C:28](=[O:45])[CH2:29][C:30]2[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][C:33]([CH:39]([CH3:41])[CH3:40])=[CH:32][C:31]=2[CH:42]([CH3:44])[CH3:43])=[C:18]([CH:48]([CH3:50])[CH3:49])[CH:17]=1)(C)(C)C>CO>[ClH:1].[ClH:1].[NH2:52][C@@H:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])[C:14]([NH:15][C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:19]([O:25][S:26](=[O:46])(=[O:47])[NH:27][C:28](=[O:45])[CH2:29][C:30]2[C:31]([CH:42]([CH3:43])[CH3:44])=[CH:32][C:33]([CH:39]([CH3:40])[CH3:41])=[CH:34][C:35]=2[CH:36]([CH3:37])[CH3:38])=[C:18]([CH:48]([CH3:50])[CH3:49])[CH:17]=1)=[O:51]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2C(C)C)c(C(C)C)c1
Agent: Cl
Solvent: CO
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(NC(=O)[C@@H](N)CCCCN)cc2C(C)C)c(C(C)C)c1
Yield: 96 %

Procedure:
HCl (g) was bubbled through a solution of (S)-[5-tert-butoxycarbonylamino-5-(3,5-diisopropyl-4-{[(2,4,6-triisopropyl-phenyl)-acetyl]sulfamoyloxy}-phenylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester (1.08 g, 1.3 mmol) in 150 mL methanol for 30 minutes. The reaction was concentrated, and the resulting foam was triturated with 5% dichloromethane/hexanes to give 0.88 g (96%) of the title compound as a tan solid; mp 172-179° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>CN(C=O)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]
Reactant: O=C(CCl)N1CCCC1
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (200 mg, 0.33 mmol, 1.00 equiv, 50%) in DMF (5 mL) was added potassium carbonate (91.1 mg, 0.66 mmol, 2.00 equiv) and 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (73.5 mg, 0.50 mmol, 1.50 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. The solids were filtered out and the filtrate was concentrated under vacuum. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH3HCO3 and CH3CN (5.0% CH3CN up to 50.0% in 11 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The fractions containing product were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]-1-(pyrrolidin-1-yl)ethan-1-one (40 mg) as a white solid. MS (ES, m/z): 414 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 5.97 (d, 1H), 4.02-4.04 (m, 1H), 3.49 (t, 2H), 3.35 (t, 2H), 3.21 (s, 2H), 3.09 (t, 2H), 2.95 (t, 2H), 2.39-2.51 (m, 3H), 2.25 (s, 3H), 1.95-2.03 (m, 2H), 1.69-1.88 (m, 6H), 1.33-1.51 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:41]([O:48][C:49]1[CH:50]=[C:51]2[C:56](=[CH:57][CH:58]=1)[CH:55]=[C:54]([C:59]1[N:64]=[C:63]([NH:65][C:66]3[CH:71]=[CH:70][C:69]([NH2:72])=[CH:68][CH:67]=3)[N:62]3[N:73]=[CH:74][CH:75]=[C:61]3[CH:60]=1)[CH:53]=[CH:52]2)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:72][C:69]2[CH:70]=[CH:71][C:66]([NH:65][C:63]3[N:62]4[N:73]=[CH:74][CH:75]=[C:61]4[CH:60]=[C:59]([C:54]4[CH:53]=[CH:52][C:51]5[C:56](=[CH:57][CH:58]=[C:49]([O:48][CH2:41][C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[CH:50]=5)[CH:55]=4)[N:64]=3)=[CH:67][CH:68]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Nc2nc(-c3ccc4cc(OCc5ccccc5)ccc4c3)cc3ccnn23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc5cc(OCc6ccccc6)ccc5c4)cc4ccnn34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (251 mg) and N-hydroxy-benzotriazole (HOBt)(153 mg) in DMF (10 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(575 mg) and triethylamine (0.416 ml). The mixture is stirred for 0.5 h at ambient temperature. To this solution is added N-[5-(6-benzyloxy-naphthalen-2-yl)-pyrazolo[1,5-c]pyrimidin-7-yl]-benzene-1,4-diamine (compound B2)(0.38 g). After completion of the reaction the mixture is evaporated at high vacuum and the residue is treated with methanol. The resulting solid is filtered and dried. A colorless solid (0.523 g) is obtained in 91% yield.