Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11]=2[N:12]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:11]=3[N:12]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: Sc1nc2c(ccc3ccccc32)o1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1CCN(c2nc3c(ccc4ccccc43)o2)CC1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (498 mg) was dissolved in anhydrous toluene (8 ml), the resulting solution was mixed with 2-mercaptonaphtho[1,2-d]oxazole (400 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 2 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (2.2 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-piperazinyl)naphtho[1,2-d]oxazole (94.9 mg).
Reaction SMILES: FC(F)(F)S([O:6][C@@H:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=O)=O.O[CH:17]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])=[CH:25][CH:24]=2)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]1>>[CH2:11]([O:10][C:8]([C@H:7]([O:6][CH:17]1[CH:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])=[CH:27][CH:28]=2)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]1)[CH3:13])=[O:9])[CH3:12]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)[C@@H](C)OC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Example 35c, 0.32 ml of ethyl 2(S)-trifluoromethanesulphonyloxypropionate and 0.734 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate are reacted. The title compound is obtained as a colourless oil. Rf=0.19 (1:3 EtOAc-heptane); Rt=5.93.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([O:25]CC)=O)[O:20][N:19]=2)=[CH:4][CH:3]=1.[NH2:28][NH2:29].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH:28][NH2:29])=[O:25])[O:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a solution of ethyl 3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate (10.5 mmol, 4.0 g) in MeOH (50 mL) was cooled to 0° C., and 99% NH2NH2.H2O (62.8 mmol, 3.2 g) was then added dropwise. In the period of addition, lots of white precipitate was generated, kept stirring for 15 mins, the white solid was collected by filtration. The white solid was dispersed into MeOH again, sonicated for 10 mins, filtered, to give the final product (3.3 g, 86.0%). m/e+=369 (M+H+). 1H NMR (400 MHz, in DMSO-d6): δ 10.9-10.5 (1H, D, brd, NH), δ 8.44-8.42 (1H, D, d, J=6.8 Hz, ArH), δ 7.87-7.85 (2H, D, dd, J=6.4, 1.6 Hz, ArH), δ 7.67-7.64 (1H, D, d, J=9.2 Hz, ArH), δ 7.56-7.54 (2H, D, dd, J=6.4, 1.6 Hz, ArH), δ 7.38-7.25 (1H, D, m, ArH), δ 5.01-4.75 (2H, D, brd, NH2), δ 4.75 (2H, D, s, CH2).
Reaction SMILES: C1([Si:7]([CH3:16])([CH3:15])[CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)C=CC=CC=1.[C:17]([NH:19][C:20]([NH2:22])=[NH:21])#[N:18]>>[NH2:21][C:20]1[N:19]=[C:17]([NH2:18])[C:9]2[CH:8]([SiH:7]([CH3:15])[CH3:16])[CH:13]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:12][CH2:11][C:10]=2[N:22]=1
Reactant: C[Si](C)(c1ccccc1)C1CCC(=O)CC1
Reactant: N#CNC(=N)N
Product: C[SiH](C)C1c2c(N)nc(N)nc2CCC1c1ccccc1

Procedure:
When the bridging group n is --Si(CH3)2 --, the Grignard reagent of 8-bromo-1,4-dioxaspiro[4.5]decane is reacted with, for example, chlorodimethylphenylsilane, affording 8-phenyldimethylsilyl-1,4-dioxaspiro[4.5]decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, yielding the corresponding 4-(phenyldimethylsilyl)cyclohexanone. The cyclohexanone is then reacted with cyanoguanidine, affording the target 2,4-diamino-6-phenyldimethylsilyl-5,6,7,8-tetrahydroquinazoline. Example 14 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:33].O>C1COCC1>[CH3:33][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)=[O:9]
Reactant: CI
Reactant: O=C(Nc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-phenyl-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (100 mg, 0.252 mmol, example 9 (step 3) in THF (1 mL) was added sodium hydride (12 mg, 0.505 mmol) slowly. The resulting mixture was stirred at RT for 15 min and iodomethane (16 μL, 0.252 mmol) was added. The mixture was stirred at RT for 16 h. Then, H2O (2 mL) was added and the mixture was extracted with EtOAc (2×2 mL). The combined organic extracted were dried over MgSO4 and concentrated. The residue was then dissolved in DMSO (1 mL) and the solution mixture was purified by preparative HPLC (10%-400% of MeCN (0.1% TFA)/H2O (0.1% TFA) to give the title compound as an off-white solid. MS (ESI, positive ion) m/z: 411 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]1[CH:60]=[C:59]([S:61](Cl)(=[O:63])=[O:62])[N:58]=[CH:57]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:61]([C:59]2[N:58]=[CH:57][N:56]([CH3:55])[CH:60]=2)(=[O:63])=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 17 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-methyl-1H-imidazole-4-sulfonyl chloride as starting materials in 17% yield. LCMS for C28H31ClN9O3S (M+H)+: m/z=608.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[F:26][C:27]([F:34])([F:33])[CH2:28][S:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)(=[O:31])=[O:30]
Reactant: Cn1cc(-c2cc(N)ccc2OC2CCOCC2)c2cc[nH]c2c1=O
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc(NS(=O)(=O)CC(F)(F)F)ccc2OC2CCOCC2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.7 %

Procedure:
To a solution of Example 99b (43.2 mg, 0.127 mmol) in dichloromethane (2 mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.015 mL, 0.140 mmol) and triethylamine (0.053 mL, 0.382 mmol). The mixture was stirred for 18 hours at ambient temperature. The reaction mixture was concentrated and the residue was purified by flash column chromatography (silica gel, 0.5-5% methanol in dichloromethane) to provide the title compound (20.8 mg, 33.7% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), 10.16 (s, 1H), 7.25-7.32 (m, 3H), 7.14-7.20 (m, 2H), 6.18-6.24 (m, 1H), 4.36-4.55 (m, 3H), 3.52-3.68 (m, 5H), 3.33-3.45 (m, 2H), 1.79-1.94 (m, 2H), 1.39-1.57 (m, 2H). MS (ESI+) m/z 486.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)([CH3:5])[CH2:3][OH:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:5][C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)([CH3:1])[CH2:3][O:4][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1
Reactant: CC(C)(CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC(C)(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 34.6 %

Procedure:
305 mg of 2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanol dissolved in 15 ml THF were treated with 338 mg of triphenylphosphine, 196 mg of methyl 4-hydroxybenzoate and 0.21 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was partitioned in 100 ml of 1:1 ethyl acetate/sat. aq. sodium chloride solution. The phases were separated and the organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting oil was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes), giving 160 mg of methyl 4-[2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoate as a colorless oil. The ester (160 mg), dissolved in 4 ml THF/0.8 ml H2O, was treated with 50 mg of lithium hydroxide hydrate. The mixture was heated at 60° C. for two hours. The mixture was acidified to pH 2 with 1N hydrochloric acid then partitioned in 10 ml ethyl acetate/10 ml sat. aq. sodium chloride solution. The phases were separated and the organic phase was dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by preparation tlc (SiO2, 40% ethyl acetate/hexanes), giving a white foam. 1H NMR (CDCl3): 8.03 (d, J=8.8 Hz, 2H), 7.35 (d, J=2.1 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.4, 2.1 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 3.96 (s, 2H), 1.67 (s, 4H), 1.46 (s, 6H), 1.27 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[OH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([N:15]2[CH2:16][CH2:17][C:12]([OH:11])([CH3:18])[CH2:13][CH2:14]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: CC1(O)CCNCC1
Solvent: CC(=O)N(C)C
Product: CC1(O)CCN(c2cc(N)ncc2C#N)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 6-amino-4-chloronicotinonitrile (intermediate 16, 31.6 mg, 0.206 mmol) and 4-hydroxy-4-methylpiperidine (47.4 mg, 0.412 mmol) in DMA (0.75 ml) was heated to 100° C. and stirred for 1 h. The resulting brown solution was heated to 120° C. and stirred for 18 h.
Reaction SMILES: C(OC(N(CC([O-])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](CO)[N:10]=1)=O)(C)(C)C.FC1C=CC([S:28]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[S:40][CH:41]=[CH:42][N:43]=3)=[CH:35][CH:34]=2)(=[O:30])=[O:29])=CC=1>>[S:40]1[CH:41]=[CH:42][N:43]=[C:39]1[C:36]1[CH:35]=[CH:34][C:33]([CH2:32][NH:31][S:28]([C:12]2[CH:11]=[N:10][CH:9]=[CH:14][CH:13]=2)(=[O:30])=[O:29])=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)[O-])c1cccc(CO)n1
Reactant: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1ccc(F)cc1
Product: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl([tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate (101 mg, 0.298 mmol) obtained in Reference Example 3-(b), and using 4-fluoro-N-[4-(thiazol-2-yl)benzyl]benzenesulfonamide (105 mg, 0.301 mmol) obtained in Reference Example 6 in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide to afford the title compound (181 mg) as a white foam. (Yield: 91%)
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].CCN(CC)CC.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:15][O:14][C:12]([C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:8]=[C:9]([CH3:11])[CH:10]=2)[C:2]=1[NH:1][C:30](=[O:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)c1cnc2cc(C)nn2c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc2cc(C)nn2c1NC(=O)Cc1ccccc1
Temperature: 80 °C

Procedure:
A 250 mL round-bottomed flask containing methyl 7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (1.10 g, 5.0 mmol, 1 eq.), CH2Cl2 (40 mL), and Et3N (2.04 g, 20 mmol, 4 eq.) was added slowly phenylacetyl chloride (6.16 g, 40 mmol, 8 eq.). Then the mixture was heated at 80° C. for 4 h. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (40 mL) and water (25 mL). The aqueous phase was extracted with CH2Cl2 (2×15 mL). The combined organic solution was dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography using MeOH and CH2Cl2 as the mobile phases to furnish Compound (20-1) as a yellowish solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:11](Br)[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([N:25]([CH:43]([CH:45]([CH3:47])[CH3:46])[CH3:44])[C:26]1[CH:31]=[C:30](B2OCC(C)(C)CO2)[CH:29]=[CH:28][C:27]=1[N+:40]([O-:42])=[O:41])#[N:24]>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:11]([C:30]2[CH:29]=[CH:28][C:27]([N+:40]([O-:42])=[O:41])=[C:26]([N:25]([CH:43]([CH:45]([CH3:47])[CH3:46])[CH3:44])[C:23]#[N:24])[CH:31]=2)[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Reactant: CC(C)C(C)N(C#N)c1cc(B2OCC(C)(C)CO2)ccc1[N+](=O)[O-]
Product: Cc1nc(-c2ccc([N+](=O)[O-])c(N(C#N)C(C)C(C)C)c2)c(-c2ccc(F)cc2F)n1Cc1ccccc1

Procedure:
Beginning with 1-benzyl-2-methyl-4-bromo-5-(2,4-difluorophenyl)-1H-imidazole and N-[cyano]N-[3-methylbut-2-yl]2-nitro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)aniline, the title compound is prepared essentially as described in Preparation 35.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl)([O-])=O.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)C>C(O)(=O)C>[N+:10]([C:6]1[C:5]2[C:4](=[N:1][N:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=2)[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2nn(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 17.7 %

Procedure:
A solution of 40.6 grams of 2,6-dinitrochlorobenzene, 21.6 grams phenylhydrazine and 350 milliliters of 95% ethanol is heated at the reflux temperature for 22 hours. Then the solvent is evaporated to yield a dark oil. To the oil is added 70 milliliters of acetic acid and the mixture is heated to reflux for 6 hours. After cooling to room temperature, the crude product is collected by filtration, washed with petroleum ether and then washed with hot methanol to yield 8.5 grams (18%) of product m.p. 155°-156° C. The analytical sample is recrystallized from methanol, m.p. 155°-156° C.
Reaction SMILES: [N:1]1[P:6](Cl)(Cl)=[N:5][P:4](Cl)(Cl)=[N:3][P:2]=1(Cl)Cl.[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH2:13]([O:17][P:2]1([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=[P:4]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=[P:6]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:1]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCO
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Solvent: c1ccncc1
Product: CCCCOP1(OCCCC)=NP(OCCCC)(OCCCC)=NP(OCCCC)(OCCCC)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a chilled solution (0°-5° C.) of triphosphonitrilic chloride (0.018 mole) in 26 ml of pyridine, butanol (0.34 mole) was added. The mixture was stirred at room temperature overnight, diluted with petroleum ether and washed with dilute HCl, NaHCO3, and water successively. After removal of solvent, the product IIa was obtained in a yield of 90%. Found (and calcd. for C24H54N3O6P3 /M.W. 574): C 47.32 (50.25); H 9.00 (9.49); and N 7.71 (7.33).
Reaction SMILES: ClN1C(=O)CCC1=O.Cl[CH2:10][Cl:11].[CH2:12]([N:14]1[C:19](=[O:20])C=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]1[NH:25][C:26]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36])[CH3:13].[Cl-].[NH4+]>CCOCC>[Cl:11][C:10]1[C:19](=[O:20])[N:14]([CH2:12][CH3:13])[C:15]([NH:25][C:26]2[C:27]([F:36])=[C:28]([F:35])[C:29]([F:34])=[C:30]([F:33])[C:31]=2[F:32])=[N:16][C:17]=1[C:21]([F:22])([F:24])[F:23]
Reactant: CCn1c(Nc2c(F)c(F)c(F)c(F)c2F)nc(C(F)(F)F)cc1=O
Reactant: ClCCl
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCn1c(Nc2c(F)c(F)c(F)c(F)c2F)nc(C(F)(F)F)c(Cl)c1=O
Reaction time: 24 h

Procedure:
N-Chlorosuccinimide (0.61 g, 5.15 mmol) was added at room temperature to dichloromethane (15 ml) solution of 3-ethyl-2-(2,3,4,5,6-pentafluorophenyl)amino-6-trifluoromethyl-4(3H)-pyrimidinone (1.28 g, 3.42 mmol), followed by stirring at the same temperature for 24 hours. After completion of the reaction, ether (20 ml) and saturated ammonium chloride aqueous solution (10 ml) were added to the reaction solution to separate the organic layer, and the aqueous layer was extracted with ether (10 ml×2). The organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. By purifying the thus obtained crude product by a silica gel column chromatography (hexane:ethyl acetate=3:1˜1:1), white solid of 5-chloro-3-ethyl-2-(2,3,4,5,6-pentafluorophenyl) amino-6-trifluoromethyl-4 (3H)-pyrimidinone [Compound No. 17] was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])=[CH:4][C:3]=1[F:22].N1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]>C(Cl)Cl>[F:22][C:3]1[CH:4]=[C:5]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH:6]=[CH:7][C:2]=1[NH:1][C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]
Reactant: COC(=O)c1ccc(Sc2ccc(N)c(F)c2)c([N+](=O)[O-])c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)c(F)c2)c([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
The product of Example 96B (2.0 g, 6.2 mmol) and pyridine (0.55 mL, 6.8 mmol) in CH2Cl2 (20 mL) was reacted with 2,2,2-trichloroethyl chloroformate (0.92 mL, 6.5 mmol) dropwise at 5° C. The mixture was stirred at 5° C. for 30 minutes and concentrated. The residue was diluted with water (50 mL). The resulting crystals were collected by filtration, washed with water and i-Pr2O, and dried at room temperature in vacuum overnight to give the title compound as pale yellow crystals (2.9 g, 93%).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reaction time: 72 h
Yield: 87.1 %

Procedure:
7-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (1.5 g, 3.9 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (1.5 g, 20% wt). The mixture was shaken on a Parr Shaker under H2(g) atmosphere (60 PSI) for 3 days. The mixture was filtered through celite and evaporated to give 1.0 g of material as a yellow solid (87%), which was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:13]1[CH2:18][CH2:17][CH:16]2[S:19][C:20](=[O:22])[CH:21]=[C:15]2[CH2:14]1)[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[C:30]([O:33][C:34]1[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:36](Cl)=[O:37])(=[O:32])[CH3:31].C([O-])(O)=O.[Na+]>O1CCCC1>[C:30]([O:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([O:22][C:20]1[S:19][C:16]2[CH2:17][CH2:18][N:13]([C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([O:11][CH3:12])=[O:10])[CH2:14][C:15]=2[CH:21]=1)=[O:37])(=[O:32])[CH3:31]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1CCC2SC(=O)C=C2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sc(OC(=O)c3ccccc3OC(C)=O)cc2C1
Reaction time: 0.17 h
Yield: 56 %

Procedure:
338 mg of (2S)-methyl 2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate (IV-1) was dissolved in 15 ml of tetrahydrofuran, 0.83 ml of triethylamine was added dropwise and stirred for 10 minutes, and then 600 mg of acetylsalicylic chloride was added and stirred at room temperature for 24 hrs. The reaction solution was poured into saturated aqueous NaHCO3 solution (20 ml), extracted with ethyl acetate (50 ml×3), concentrated, evaporated, and subjected to flash column chromatography (petroleum ether:ethyl acetate=5:1), to obtain (S)-methyl 2-(2-(2-acetoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5 (4H)-yl)-2-(2-chlorophenyl)-acetate (I-5) (280 mg). Yield: 56%, ee=96.1% (chiral HPLC analysis conditions: Chiralpak IC 4.6 mm×250 mm; column temperature: 25° C.; mobile phase: 85% n-hexane/15% tetrahydrofuran/0.1% diethylamine; flow rate: 0.5 ml/min; and detection wavelength: UV 254 nm), [α]D20=+14.00° (c 0.50, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 2.79-2.81 (m, 2H), 2.90-2.93 (m, 2H), 3.54-3.66 (m, 2H), 3.72 (s, 3H), 4.93 (s, 1H), 6.37 (s, 1H), 7.14-7.36 (m, 4H), 7.39-8.15 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 20.93, 24.93, 48.04, 50.12, 52.12, 67.65, 112.61, 117.34, 118.97, 121.66, 124.09, 126.14, 127.12, 129.35, 129.45, 129.79, 129.92, 130.71, 132.12, 133.54, 134.71, 135.73, 149.32, 151.12, 161.32, 169.47, 171.17; ESI-MS m/z 500 [M+H]+, 522 [M+Na]+; HRMS Calcd for C25H23NO6SCl [M+H]+ m/z 500.0931. found 500.0935.