Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[Cl:41][C:42]1[CH:43]=[C:44]([CH2:49][S:50](Cl)(=[O:52])=[O:51])[CH:45]=[CH:46][C:47]=1[Cl:48]>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:40])=[CH:5][CH:6]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:50]([CH2:49][C:44]1[CH:45]=[CH:46][C:47]([Cl:48])=[C:42]([Cl:41])[CH:43]=1)(=[O:52])=[O:51])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: CN(CCc1c(CCNS(=O)(=O)Cc2ccc(Cl)c(Cl)c2)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12)c1ccc(C(=O)O)cc1
Yield: 87 %

Procedure:
The intermediate from Example 147 step 7 was treated with 3,4-dichlorophenylmethanesulfonylchloride according to the procedure in Example 87 step 2 to generate the desired product in 87% yield.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[C:31]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([CH2:43][NH2:44])[CH2:40][C@H:39]1[C:45]([N:47]1[CH2:51][CH2:50][S:49][CH2:48]1)=[O:46])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>CN(C=O)C>[C:31]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([CH2:43][NH:44][C:6]([C:4]2[N:3]=[CH:2][S:1][CH:5]=2)=[O:8])[CH2:40][C@H:39]1[C:45]([N:47]1[CH2:51][CH2:50][S:49][CH2:48]1)=[O:46])=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)c1cscn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cscn2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.3 %

Procedure:
To a solution of thiazole-4-carboxylic acid (2.25 g, 17.6 mmol) and HOBt (2.60 g, 19.2 mmol) in anhydrous DMF (80 mL) at 0° C. was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.69 g, 19.2 mmol) followed by the dropwise addition of a solution of Example 17D (5.07 g, 16 mmol) in anhydrous DMF (50 mL) over 10 minutes, after which anhydrous triethylamine (4.45 mL, 32 mmol) was added to the mixture via syringe. The mixture was allowed to stir for 12 hours at room temperature, concentrated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and H2O (30 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated to provide a yellow solid. The yellow solid was crystallized from ethyl acetate (30 mL). The white crystals were dried under vacuum at 40° C. for 12 hours to provide a white powder (4.8 g) as the titled compound. MS (ESI) m/e 427 (M+H)+, 425 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 1.41 (s, 5 H) 1.44 (s, 4 H), 1.66 (m, 1 H), 2.49 (m, 1 H), 2.59 (m, 1 H), 3.03 (m, 1 H), 3.13 (m, 1 H), 3.21 (m, 1 H), 3.48 (m, 2 H) 3.75 (m, 2 H) 3.85 (m, 1 H) 4.53 (m, 2 H) 4.66 (m, 1 H), 8.25 (s, 1 H), 8.99 (s, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)=[CH:3][CH:2]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=[N:16][NH:15][C:13]([C:12]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:8][C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][CH:11]=1)=[O:14]
Reactant: NNC(=O)c1cnc(-c2ccccn2)nc1-c1ccncc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cnc(-c2ccccn2)nc1-c1ccncc1

Procedure:
The title compound was prepared from 4-(pyridin-4-yl)-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid-hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 12.38 (s, 1H), 9.30 (s, 1H), 9.22 (s, 1H), 8.84 (m, 1H), 8.78 (d, J=6.0 Hz, 1H), 8.68 (d, J=6.0 Hz, 1H), 8.54 (m, 1H), 8.31 (s, 1H), 8.01 (m, 2H), 7.97 (s, 1H), 7.82 (m, 1H), 7.73 (m, 1H), 7.62 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[NH3:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:29])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reaction time: 18 h
Yield: 101.2 %

Procedure:
In a mixture of 3.0 g of concentrated ammonia water and 15 ml of tetrahydrofuran, a solution of 3.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl chloride in 20 ml of tetrahydrofuran was added dropwise, after the completion of the addition, continued to stir further for 18 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate, washed with 50 ml of water, dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 2.9 g of the aimed product as orange crystal.
Reaction SMILES: [C@@H:1]12[CH2:8][N:7]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:6][C@@H:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[CH2:34]([O:41][CH2:42][C:43](Cl)=[O:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[F:26][C:10]1[CH:11]=[C:12]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:13]=[CH:14][C:9]=1[N:7]1[CH2:8][C@@H:1]2[C@@H:5]([CH2:4][N:3]([C:43](=[O:44])[CH2:42][O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:2]2)[CH2:6]1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CNC[C@H]4C3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)COCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
(S)-N-[[3-[4-[cis-3-(Carbobenzyloxy)-3,7-ciazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (150 mg, 0.30 mmol), methylene chloride (5 mL), and methanol (10 mL) are combined with 10% palladium on carbon (30 mg) and placed under a hydrogen atmosphere (balloon) for 15 hours. The reaction is filtered through celite and concentrated in vacuo to give crude (S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. The crude amine is taken up in methylene chloride (15 mL), cooled to 0° C., and triethylamine (0.09 mL, 0.67 mmol) and benzyloxyacetyl chloride (0.06 mL, 0.40 mmol) are added. The reaction is warmed to ambient temperature, stirred 15 hours, and diluted with methylene chloride (100 mL). The organic phase is washed with water (2×50 mL) and saline (150 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (95/5). The appropriate fractions are combined (Rf =0.41, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, mp 138-140° C.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1)C.[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][CH:37]=C(F)[C:33]=1[C:34]#[N:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:7]=2)[C:33]=1[C:34]#[N:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1c(F)cccc1OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(3-Benzyloxy-4-nitrophenyl)-acetic acid ethyl ester (Step C) (1.90 g, 6.03 mmol) and 2-benzyloxy-6-fluorobenzonitrile (Step D) (2.74 g, 12.1 mmol) are dissolved in DMF (18 mL) and added dropwise to a suspension of Cs2CO3 (5.89 g, 18.1 mmol) in DMF (18 mL). The mixture is heated to 80° C. for 1.5 h, then stirred at 60° C. for 16 h. The mixture is diluted with EtOAc (350 mL) and extracted with 1N HCl (2×75 mL), followed by brine (75 mL). The organic phase is dried over Na2SO4 and concentrated. The residue is taken up in THF (18 mL), MeOH (18 mL) and 1N NaOH (36 mL). Decarboxylation is complete after 2 h, the reaction mixture is poured into ice water (100 mL) and acidified to pH ˜2 with 6N HCl. The mixture is extracted with EtOAc (2×200 mL) and the organic phase is washed with brine (75 mL), dried over Na2SO4 and concentrated to afford a brown oil. Purification by flash column (10-75% EtOAc/hexanes) affords 2-benzyloxy-6-(3-benzyloxy-4-nitrobenzyl)-benzonitrile as an off-white solid: MS (M+H)+=451.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[CH3:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH:28]([CH3:35])[CH3:27])[CH2:15][CH2:14]2)[C:10]=1[CH3:11]
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Reactant: CC(C)CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)CCCC(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (42 mg, 0.1 mmol), 5-methyl-hexanoic acid (0.12 mmol, 1.2 eq), HATU (0.12 mmol, 1.2 eq), and triethylamine (0.2 mmol, 2 eq) were dissolved in DMF (1 mL), and then stirred at room temperature for 1 hour. The crude was filtered and then purified via prep-LCMS 5-95% to provide Compound C121 as a white powder (28.2 mg, 57%). Exact mass calculated for C24H32FN3O5S 493.2, found LCMS (ESI) m/z 494.5 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc2cccnc2[nH]c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 91.7 %

Procedure:
1.50 g (6.9 mmol) of ethyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in N,N-dimethylformamide (30 mL), and 1.43 g (10.4 mmol) of potassium carbonate and 1.36 g (7.9 mmol) of benzyl bromide were added thereto. The resulting mixture was stirred for one whole day and night at room temperature. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The organic phase was dried, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=3:7 to 1:1), and thus 1.95 g (yield: 92%) of the title compound was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.ClC(O[C:47]1[CH:52]=[CH:51]C=[CH:49][CH:48]=1)=O>ClCCl>[C:32]1([C:35]2[CH:51]=[CH:52][CH:47]=[CH:48][CH:49]=2)[CH:33]=[CH:34][C:29]([S:26]([NH:25][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:13]3[C:6]4=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]4[N:4]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9 of Example 1, 1.55 g, 5.3 mmol) and triethylamine (0.80 mL, 5.8 mmol) in dichloromethane (26 mL) cooled in an ice bath was added dropwise phenyl chloroformate (0.69 mL, 5.5 mmol), and the mixture was stirred at ambient temperature. After 30 min, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (30 mL) and dichloromethane (30 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (30 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was recrystallized from dichloromethane/hexane to give 1.90 g (87%) of the title compound as pale brown crystals: 1H-NMR (CDCl3) δ 7.43-7.11 (9H, m), 6.91 (1H, s), 5.50 (1H, br.s), 3.57 (2H, pseudo q, J=6.9 Hz), 2.98 (2H, t, J=6.9 Hz), 2.83 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.52 (3H, s), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:41]=[CH:40][C:32]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH3:44])[N:15]=1)=[O:13])[CH3:2].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>C(Cl)Cl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:41]=[CH:40][C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH3:44])[N:15]=1)=[O:13])[CH3:10]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(C(=O)OC(C)(C)C)cc3OC)nc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(C(=O)O)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-({3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidin-9-yl}amino)-3-methoxybenzoate (0.450 g, 0.75 mmol) in DCM (6 mL), TFA (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The organic solvent was evaporated to dryness to give the title compound in quantitative yield.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:46])[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[C:6](=[O:24])[N:5]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])=[O:35].[CH3:47]I.O>CN(C=O)C>[CH3:3][C:4]1([CH3:46])[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:47])[C:17](=[O:19])[CH3:18])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[C:6](=[O:24])[N:5]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:41])([F:42])[F:43])=[O:35]
Reactant: CC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)c1ccc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Temperature: 23 °C
Yield: 72 %

Procedure:
NaH (to 60%) (6 mg, 0.16 mmole) is added under argon to a solution of N-[4-(4,4-dimethyl-2,5-dioxo-3-{9-[(4,4,5,5,5-pentafluoropentyl)sulphinyl]-nonyl}imidazolidin-1-yl)-2 (trifluoromethyl)phenyl]acetamide (100 mg, 0.15 mmole) (prepared according to Example 18) in anhydrous DMF (2 ml). A release of gas accompanies the change in colour of the reaction medium. Stirring is maintained for 1 hour at 23° C. before adding methyl iodide (10 μl, 0.16 mmole). After reaction for 1 hour the same quantity of sodium hydride and methyl iodide as previously are added, then the reaction mixture is again stirred for 3 hours at 23° C. The reaction medium is poured into water (25 ml) and extracted with AcOEt (2×25 ml). The organic phases are combined and washed successively with water (25 ml) and salt water (25 ml). After drying over Na2SO4, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent: CH2Cl2/MeOH: 95/5 to 90/10). The expected compound is obtained in the form of a colourless oil with a yield of 72% (72 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:18][CH:19]([NH2:21])[CH3:20].O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:19]([CH3:20])[CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CC(C)N
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)Nc1nc(Cl)nc2c1CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (172 mg, 0.65 mmol) in NMP (2 mL) was added propan-2-amine (115 mg, 1.95 mmol) dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water was added to precipitate out the product. The solid was filtered out, air-dried, and purified via Biotage (12 g, hexanes-70% EtOAc) to give 2-chloro-N-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (154 mg, 0.535 mmol, 82% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.30 (2H, t, J=7.5 Hz), 7.20-7.25 (1H, m), 7.15 (1H, d, J=1.5 Hz), 7.13 (1H, s), 4.53 (1H, d, J=7.3 Hz), 4.37-4.45 (1H, m), 4.23-4.28 (1H, m), 2.58-2.78 (3H, m), 2.10-2.17 (1H, m), 1.27-1.29 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:31]=[CH:30][C:10]([CH2:11][O:12][C:13]3[CH:14]=[C:15]4[N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][N:16]4[C:17](=[O:19])[N:18]=3)=[CH:9][C:8]=2[C:32]#[N:33])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:31]=[CH:30][C:10]([CH2:11][O:12][C:13]3[CH:14]=[C:15]4[NH:22][CH2:21][CH2:20][N:16]4[C:17](=[O:19])[N:18]=3)=[CH:9][C:8]=2[C:32]#[N:33])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(C#N)c1)nc2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3-cyanobenzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyri-midine-1(5H)-carboxylate (150 mg, 0.266 mmol) and TFA (5 ml, 64.9 mmol) in DCM (5 mL).
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[Cl:23][C:24]1[C:25]([NH:39][C:40](=O)[CH2:41][O:42][CH3:43])=[C:26]2[C:31](=[CH:32][C:33]=1[Cl:34])[N:30]=[C:29]([O:35][CH3:36])[C:28]([O:37][CH3:38])=[N:27]2>O1CCCC1>[Cl:23][C:24]1[C:25]([NH:39][C:40](=[S:10])[CH2:41][O:42][CH3:43])=[C:26]2[C:31](=[CH:32][C:33]=1[Cl:34])[N:30]=[C:29]([O:35][CH3:36])[C:28]([O:37][CH3:38])=[N:27]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCC(=O)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Solvent: C1CCOC1
Product: COCC(=S)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 166.7 %

Procedure:
2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (19.5 g, 48.2 mmol) was added to a solution of 6,7-dichloro-2,3-dimethoxy-5-methoxyacetamidoquinoxaline (27 g, 78 mmol) in tetrahydrofuran (480 mL) and the mixture was stirred for 18 hours at room temperature, then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using hexane:dichloromethane (1:1 changing to 1:4, by volume) as the eluent to give 6,7-dichloro-2,3-dimethoxy-5-methoxythioacetamidoquinoxaline (29.1 g, >100%) as a white solid, mp 198-200° C., containing a minor impurity.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.O.[CH:11](=[O:14])[CH2:12][CH3:13]>CO>[OH:14][CH:11]([C:7]1[O:8][C:2]([CH3:1])=[CH:3][C:4](=[O:5])[C:6]=1[OH:9])[CH2:12][CH3:13]
Reactant: Cc1cc(=O)c(O)co1
Reactant: CCC=O
Solvent: O
Solvent: CO
Product: CCC(O)c1oc(C)cc(=O)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.7 %

Procedure:
Allomaltol (12.6 g, 100 mmol, 1 eq.) was added to 100 ml water and the pH of the solution was adjusted to 10.5 using 50% aqueous sodium hydroxides. Propionaldehyde (8.7 g, 150 mmol, 1.5 eq.) dissolved in 50 ml methanol was slowly added dropwise over 1 hour and the solution allowed to stir at room temperature for 48 hours. After adjustment to pH 1 with 37% hydrochloric acid, the reaction mixture was evaporated to dryness and the residue taken up into 300 ml of dichloromethane. The organic layer was washed with water (150 ml), dried over anhydrous sodium sulphate, filtered and concentrated to yield the crude product. Recrystallisation from toluene afforded the pure product (14.5 g, 78.9%) as a white crystalline solid. m.p. 134-136° C. [lit. 132-135° C. Ellis (1993)].
Reaction SMILES: [OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]2)[OH:20])=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:4])[CH3:3].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[C:30]([O:20][C@H:19]1[CH2:21][CH2:22][C@@:23]2([CH3:24])[C:17](=[CH:16][CH2:15][C@@H:14]3[C@@H:25]2[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][C:2]([O:1][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH3:3])[CH3:4])[CH2:18]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C[C@H](CCCC(C)(C)OC(=O)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Heat 2.9 gm. (7.2 mmole) of 25-hydroxycholesterol with 2.1 ml. (18 mmole) of benzoyl chloride in 30 ml. of pyridine at 70°-80° C. for 4 hours. Add an additional 1.4 ml. (12 mmole) of benzoyl chloride and continue heating at 75°-80° C. for 1 hour. Pour the reaction mixture into ice-water mixture (b 1:1, 500 gm.) Stir for 1 hour, separate the precipitate and wash with ice-water. Recrystalize from acetone. Dissolve the crude product (3.8 gm.) in methylene chloride-hexane (3:2, 40 ml.) and pass the solution through a silica gel column (120 gm.). Elute the column with 800 ml. methylene chloride-hexane (5:1) followed by 800 ml. methylene chloridehexane (10:1). Combine the fractions and concentrate to a residue. Recrystalize from acetone to obtain the pure product (3.32 gm., m.p. 130°-132° C.).