Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][C:7]1[C:20]2[O:19][C:18]3[C:13](=[CH:14][C:15]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=3)[C:12](=[O:25])[C:11]=2[CH:10]=[CH:9][C:8]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][C:7]1[C:20]2[O:19][C:18]3[C:13](=[CH:14][C:15]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=3)[C:12](=[O:25])[C:11]=2[CH:10]=[CH:9][C:8]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCc1c(OCCCCC=Cc2ccc(OC)cc2)ccc2c(=O)c3cc(C(=O)OC)ccc3oc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1c(OCCCCCCc2ccc(OC)cc2)ccc2c(=O)c3cc(C(=O)OC)ccc3oc12
Yield: 91.7 %

Procedure:
A solution of 630 mg of 7-methoxycarbonyl-3-{[6-(4-methoxyphenyl)-5-hexenyl]oxy}-9-oxo-9H-xanthene-4-propanic acid ethyl ester in ethyl acetate was hydrogenated in the presence of 10 mg of 5% palladium on carbon. After hydrogen uptake ceased, the solution was filtered, concentrated in vacuo, and the residue crystallized from ethyl acetate/hexane to provide 580 mg of the desired subtitle intermediate, m.p. 108°-109° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:3][N:4]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N3CCCC3)c2c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 4-chloro-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), prepared as described in example 45, in DMF (25 ml) was stirred under dry N2 at room temperature, and dropwise added with pyrrolidine. The mixture was heated at 100° C. for 20 hours, then concentrated and partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a solid which was crystallised from ethyl acetate (25 ml) to give 0.77 g of the title compound (yield: 71%). m.p.: 170-172° C.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CCc2ccccc2C1
Product: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Acetyl-1,2,3,4-tetrahydroisoquinoline (180 gm., 1.03 m.) was added slowly to 800 gms. (6.9 m.) of chlorosulfonic acid and stirred at -50° C. The solution was stirred at 25° C. for two days, poured onto crushed ice and extracted with ethyl acetate. The extract was washed, dried over anhydrous sodium sulfate and evaporated to yield crude N-acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.[C:14]([NH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)(=[O:34])[CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=[CH:31][CH2:32][CH3:33].CCN(CC)CC.[CH:51]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH:60]([CH3:62])[CH3:61])[C:55]=1[N:63]=[C:64]=[O:65])([CH3:53])[CH3:52]>C1COCC1>[C:14]([NH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:64]([NH:63][C:55]2[C:54]([CH:51]([CH3:52])[CH3:53])=[CH:59][CH:58]=[CH:57][C:56]=2[CH:60]([CH3:62])[CH3:61])=[O:65])=[CH:38][CH:37]=1)(=[O:34])[CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=[CH:31][CH2:32][CH3:33]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)Nc1ccc(CN)cc1
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)Nc1ccc(CNC(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 87.7 %

Procedure:
This compound was subjected to TLC analysis [silica gel plate, developing solvent:CHCl3 -MeOH-H2O (90:10:1)]. As a result, a single spot was obtained by the detection with iodine and a 0.2% ninhydrin reagent. The obtained 4-(N-5,8,11,14,17-eicosapentaenoylamino)benzylamine (813 mg, 2 mmol) and Et3N (204 mg, 2 mmol) were dissolved in anhydrous THF (10 ml), and 2,6-diisopropylphenyl isocyanate (406 mg, 2 mmol) was added. The mixture was reacted for about 2 hours under cooling in a nitrogen stream, and concentrated under reduced pressure. The obtained concentrate was dissolved in a small amount of CHCl3 and applied to an SiO2 (800 g) column activated with CHCl3 in advance, which was followed by elution with CHCl3 (600 ml) and CHCl3 -MeOH (98:2, 800 ml) in this order. The objective fractions were recovered from the obtained eluate fractions based on TLC analysis as an index, and concentrated to give the objective compound (1.07 g, yield 88%).
Reaction SMILES: Br[C:2]1[C:3]([Cl:19])=[C:4]([O:9][C:10]2[C:15]([F:16])=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=2[Cl:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:20]([Zn]C#N)#[N:21]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:3]1[C:4]([O:9][C:10]2[C:11]([Cl:18])=[CH:12][CH:13]=[C:14]([CH3:17])[C:15]=2[F:16])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[C:20]#[N:21]
Reactant: N#C[Zn]C#N
Reactant: Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2Cl)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2Cl)c1F
Temperature: 120 °C
Yield: 117.7 %

Procedure:
2-[(3-bromo-2,5-dichlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (2.0 g, 5.20 mmol) was combined with dicyanozinc (0.305 g, 2.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.601 g, 0.520 mmol) and heated at 120° C. for 60 min in a microwave reactor under an inert atmosphere. The reaction mixture was diluted with EtOAc, washed four times with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 120 g silica eluted successively with 100% hexanes followed by 0 to 10% EtOAc/hexanes to give 2,5-dichloro-3-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile (1.01 g, 3.06 mmol, 58.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (d, J=2.20 Hz, 1H), 7.31-7.47 (m, 2H), 7.24 (d, J=1.83 Hz, 1H), 2.29 (d, J=1.74 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH:19]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:19]2[CH2:25][CH2:24][C:23](=[O:26])[NH:22][CH2:21][CH2:20]2)=[O:9])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCNCCN1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Temperature: 0 °C

Procedure:
A solution of 20.00 g (109.52 mmol) of (E)-3-chlorocinnamic acid in 500 ml of dichloromethane was treated at RT with 6 drops of DMF. 10.08 ml (115.00 mmol) of oxalyl chloride in 60 ml dichloromethane were added dropwise and stirring was continued for 3 h30. The solution was evaporated, redissolved in 400 ml of dichloromethane, cooled (0° C.) and treated with a solution of 12.50 g (109.52 mmol) of [1,4]diazepan-5-one and 30.49 ml (219.05 mmol) of triethylamine in 190 ml of dichloromethane. The reaction was warmed up over night to RT and then evaporated. The precipitate was suspended in 90 ml of water, stirred 30 min, and filtered, washed with water to give, after drying under reduced pressure overnight, 28.03 g (92%) of the titled compound as a off-white powder. MS: 278.9 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]([C:19](OCC)=[O:20])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:26][CH2:27][CH2:28][NH2:29]>O>[ClH:1].[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:29][CH2:28][CH2:27][OH:26])=[O:20])=[CH:24][CH:25]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(CN2CCN(c3ccc(Cl)nn3)CC2)cc1
Reactant: NCCO
Solvent: O
Product: Cl
Product: O=C(NCCO)c1ccc(CN2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
A mixture of 16.7 parts of ethyl 4-[[4-(6-chloro-3-pyridazinyl)-1-piperazinyl]methyl]benzoate and 11.3 pats of 2-hydroxyethanamine was stirred for 4 hours at 140° C. After cooling, the reaction mixture was stirred into water. The precipitated product was filtered off, washed with 2,2'-oxybispropane and converted into the hydrochloride salt in 2-propanol. The salt was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried at 70° C., yielding 9.7 parts (51.1%) of 4-[[4-(6-chloro -3-pyridazinyl)-1-piperazinyl]methyl]-N-(2-hydroxyethyl)benzamide monohydrochloride; mp.>260° C. (decomp.) (comp. 167).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.CO[C:12]1[CH:20]=[CH:19][N:18]=[C:17]2[C:13]=1[CH:14]=CN2.[Cl:21][C:22]1[CH:30]=[CH:29][N:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[Cl:21][C:22]1[CH:30]=[CH:29][N:28]=[C:27]2[NH:26][CH:25]=[C:24]([CH2:14][C:13]3[CH:12]=[CH:20][C:19]([NH:7][CH2:6][C:5]4[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:18][CH:17]=3)[C:23]=12
Reactant: NCc1ccc(Cl)cc1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: COc1ccnc2[nH]ccc12
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4nccc(Cl)c34)cn2)cc1

Procedure:
was prepared following the protocol of Scheme 12, substituting 4-trifluoro-benzylamine with 4-chloro-benzylamine in Step 1 and 4-methoxy-7-azaindole with 4-chloro-7-azaindole (24, prepared as described in Example 11) in Step 4. MS (ESI) [M+H+]+=381.1 and 383.0.
Reaction SMILES: CC([OH:5])(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.CS(N)(=O)=O.[CH3:69][O:70][N:71]([CH3:77])[C:72](=[O:76])[C:73]([CH3:75])=[CH2:74].[OH2:78]>>[OH:78][C@@:73]([CH3:75])([CH2:74][OH:5])[C:72]([N:71]([O:70][CH3:69])[CH3:77])=[O:76]
Reactant: CC(C)(C)O
Reactant: C=C(C)C(=O)N(C)OC
Reactant: O
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Product: CON(C)C(=O)[C@@](C)(O)CO
Temperature: 25 °C
Yield: 118 %

Procedure:
A round bottom flask was charged with tBuOH (850 mL), water (850 mL), Ad-Mix-β (230 g, 166 mmol) and methanesulfonamide (15.8 g, 166 mmol). The mixture was stirred at ambient temperature until both phases were clear (about 5 minutes) and then cooled to 0° C., after which orange salts precipitated. N-methoxy-N-methylmethacrylamide (21.5 g, 166 mmol) was added and the heterogeneous slurry was stirred vigorously at 0° C. for 2 hours and warmed to ambient temperature and stirred for 24 hours. The reaction was quenched by the slow, portionwise addition of sodium bisulfite (223 g) and stirred for 1 hour. The reaction mixture was extracted with EtOAc (3×300 mL), dried over sodium sulfate, filtered and concentrated to afford (S)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196 mmol, 118% yield) as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1.[C:21](Cl)(=[O:23])[CH3:22]>C1COCC1.O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: Brc1ccc(C2CCNC2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 117.8 %

Procedure:
Triethylamine (192 mg, 1.9 mmol) was added to a suspension of 3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76 mmol) in anhydrous THF (5 mL). The mixture was stirred at room temperature for 5 minutes and then treated with acetyl chloride (66 mg, 0.84 mmol). The reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give 1-[3-(4-bromophenyl)pyrrolidin-1-yl]ethanone (0.24 g, quantitative yield) as an oil which was used directly in the next step. MS (ES+) 267.9 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:19]1([N:25]=[C:26]=[S:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[S:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: S=C=Nc1ccccc1
Solvent: ClCCl
Product: S=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccccc1
Yield: 29.7 %

Procedure:
1-(3-Aminopropyl)-4-(4-chlorobenzyl)piperazine (5.36 g; 20 mmole) was reacted with phenyl isothiocyanate 2.82 g; 21 mmole) in methylene chloride (35 ml) in the manner described in Example 17. The crude product was isolated and chromatographed on silica gel in analogous manner. The product crystallized from ethanol to yield the title compound (2.39 g; 30% yield) as an off-white crystalline solid, m.p. 155°-156° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([Cl:32])=[CH:27][CH:26]=2)=[O:22])=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:21]([NH:20][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH2:14][C@H:9]1[NH2:8])=[O:22])=[CH:31]2
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](N)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(5-chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine (200 mg) was dissolved in dichloromethane (6 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure to obtain (1S,2R,4S)-N1-[(5-chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine trifluoroacetate.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[Cl-].[Cl-].[O:47]=[C:48]1[N:56]([CH:57]2[CH2:62][CH2:61][NH2+:60][CH2:59][CH2:58]2)[C:55]2[C:50](=[NH+:51][CH:52]=[N:53][CH:54]=2)[NH:49]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:60]2[CH2:61][CH2:62][CH:57]([N:56]3[C:55]4[C:50](=[N:51][CH:52]=[N:53][CH:54]=4)[NH:49][C:48]3=[O:47])[CH2:58][CH2:59]2)=[O:34])[CH2:18][CH2:17]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=c1[nH]c2[nH+]cncc2n1C1CC[NH2+]CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)N1CCC(n2c(=O)[nH]c3ncncc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
Triethylamine (94 μL, 0.673 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (94 mg, 0.224 mmol) and 4-nitrophenyl chloroformate (45 mg, 0.224 mmol) in tetrahydrofuran (3 mL) at 0° C. After 1 h, 8-oxo-7-piperidinium-4-yl-8,9-dihydro-7H-purin-3-ium dichloride (66 mg, 0.224 mmol) and triethylamine (94 μL, 0.673 mmol) were added and the mixture allowed to warm to ambient temperature. After 1 h, saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (76 mg). MS 591.2214 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][C:12]1[C:17]2[NH:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([C:14]1[CH:13]=[C:12]([CH3:11])[C:17]2[NH:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1)=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cccc(Br)c2)cc2oc(=O)[nH]c12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.08 g (9.48 mmol) 3-bromo-benzoic acid chloride, 1.41 g (9.48 mmol) 4-methyl-3H-benzoxazol-2-one and 5.33 g (40.0 mmol) aluminium trichloride were heated to 125° C. with stirring for 1.5 h. Then the mixture was mixed with ice water and the grease precipitated was separated from the solvent by decanting. The residue was dissolved in EtOAc, evaporated down and a little MeOH was triturated. The precipitate formed was suction filtered, washed with diethyl ether and dried i. vac.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:25](O)=[O:26].C[N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.O1CCOCC1>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][CH:19]([CH3:24])[C:20]([F:21])([F:22])[F:23])=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:25]([NH2:29])=[O:26]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC(C)C(F)(F)F)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3OC(C)C(F)(F)F)c12
Temperature: 25 °C

Procedure:
5-Methyl-4-(2-(1,1,1-trifluoropropan-2yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (278 mg), HATU (320 mg) and Hünig's Base (144 μl) were dissolved in DMF (6.5 ml) at 0° C. The reaction was stirred for 30 minutes after this time NH3 in dioxane (0.5 M; 5.3 ml) was added. The reaction was allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was extracted with dichloromethane and water. The organic layer was separated, dried and evaporated. The crude product was purified by chromatography (silica/dichloromethane: methanol: NH3 90:10:1).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(O[N:29]1[N:37]=NC2C=CC=C[C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CNN>CN(C=O)C.C(Cl)CCl>[CH:1]1([NH:6][C:7]2[C:12]([C:13]([N:29]([CH3:30])[NH2:37])=[O:15])=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)O)cnc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNN
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCCC3)c(C(=O)N(C)N)cnc21
Reaction time: 0.25 h

Procedure:
Intermediate 3 (0.10 g) was dissolved in DMF (2 ml) and treated with HBTU (0.136 g) and DIPEA (0.116 g). A separate portion of Intermediate 3 (0.10 g) was dissolved in DMF (2 ml) and treated with EDC (0.096 g) and HOBT (0.058 g). The resultant suspensions were both stirred under nitrogen for 15 min, then methyl hydrazine (0.017 g) added to each and stirring continued under nitrogen for 18 h. The mixtures were independently concentrated in vacuo and the residues partitioned between DCM and water. The organic layers were concentrated and each applied to an SPE cartridge (aminopropyl, 2 g) which was eluted with methanol, followed by 10% ammonia in methanol. The two portions of Intermediate 7 thus afforded were combined (0.16 g). LCMS showed MH+=303; TRET=2.22 min.
Reaction SMILES: [N:1]1([CH2:10][C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>C1COCC1>[N:1]1([CH:10]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=2)[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CON(C)C(=O)Cn1nnc2ccccc21
Reactant: Clc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CON(C)C(=O)C(Cc1ccc(Cl)cc1)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 2.0 g (9 mmol) of 2-(1H-1,2,3-benzotriazol-1-yl)-N-methoxy-N-methylacetamide in 15 mL anhydrous THF at −78° C., 10 mL (10 mmol) of 1M lithium bis(trimethylsilyl)amide was added dropwise. After stirring for 25 min, a solution of 2.06 g (10 mmol) of 4-chlorobenzyl bromide in 2 mL anhydrous THF was added. The resulting reaction mixture was allowed to warm to RT and stirred for 6 h. This reaction was quenched, diluted with 75 mL EtOAc and washed 3 times with 10 mL each of brine, After drying the organic phase solvent removal afforded a crude product which was purified on silica gel using 40% EtOAc in hexane as solvent to afford the desired product as a solid. 1H NMR: (CDCl3): δ 3.2 (s, 3H), 3.34 (s, 3H), 3.52 (m, 1H), 3.7 (m, 1H), 6.32 (t, 1H), 6.9-8.2 (m, 8H).