Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Cl:36][C:37]1[C:38]2[CH:48]=[CH:47][CH:46]=[CH:45][C:39]=2[S:40][C:41]=1[C:42](Cl)=[O:43]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:42]([C:41]2[S:40][C:39]3[CH:45]=[CH:46][CH:47]=[CH:48][C:38]=3[C:37]=2[Cl:36])=[O:43])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(NCc2cccc(-c3ccncc3)c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(N(Cc2cccc(-c3ccncc3)c2)C(=O)c2sc3ccccc3c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of 18 (410 mg, 1.1 mmol) and Et3N (280 μL, 2.0 mmol) in CH2Cl2 (10 mL) was added 3-chlorobenzo[b]thiophene-2-carbonyl chloride 12 (278 mg, 1.2 mmol), and the reaction mixture was stirred at room temperature for 0.5 h. The solvent was removed and the residue was purified by a flash chromatography on silica gel (acetone/PE=5:1) to give the desired product 19 (587 mg) in 96% yield; 1H-NMR (400 MHz, CDCl3): 8.65 (br, 2H), 7.20-8.20 (m, 10H), 3.70-5.00 (m, 4H), 3.20-3.40 (br, 1H), 1.75-2.20 (m, 4H), 1.42-1.75 (br, 2H), 1.38 (s, 9H), 0.90-1.30 (br, 2H); 13C NMR (100 MHz, CDCl3): 163.7, 155.1, 150.2, 148.1, 147.7, 139.2, 138.4, 137.2, 135.6, 130.0, 129.3, 127.6, 126.5, 126.2, 125.5, 122.7, 122.5, 121.6, 119.0, 79.2, 58.7, 48.5, 45.1, 32.1, 30.5, 29.7, 29.3, 28.3; HRMS (EI) calcd for C32H34ClN3O3S (M+) 575.2009; found 575.2018.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:18])[C:5]([Br:19])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl>[Br:19][C:5]1[C:6]([CH3:18])=[C:7]([C:2]([NH:1][S:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: Cc1c(Br)ccc(N)c1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Br)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1

Procedure:
A mixture of Example 126B (760 mg, 2.1 mmol), 4-fluorobenzenesulfonyl chloride (600 mg, 3.1 mmol), dichloromethane (10 mL), and pyridine (0.69 mL, 8.5 mmol) was stirred for 18 hours, diluted with dichloromethane (100 mL), washed with 0.5M HCl (2×100 mL) and brine, dried (Na2SO4), filtered, concentrated and purified on a Biotage silica gel cartridge (40 g) eluted with 50-75% dichloromethane/hexanes to provide the desired product. MS (ESI(+) lm/e 478, 480 (M+H)+, 495, 497 (M+NH4)+, 500, 502 (M+Na)+; (ESI(−)) m/e 476, 478 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.73 (m, 2H), 7.62 (d, 1H), 7.40 (m, 7H), 6.85 (d, 1H), 5.25 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:32](O)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:33])[CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Product: O=C(c1ccccc1-c1cccc(Cl)c1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 3′-chloro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C27H23ClN4O, 454.95; m/z found, 455.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11](C#N)([CH3:13])[CH2:12][CH:7]2[CH2:6]1)=[O:4].[C:17](=[O:20])([O-])[O-:18].[K+].[K+]>Cl.O>[CH3:1][N:2]([CH3:16])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH3:13])([C:17]([OH:18])=[O:20])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)N1CC2CC(C)(C#N)CC2C1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CN(C)C(=O)N1CC2CC(C)(C(=O)O)CC2C1
Temperature: 50 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
5-Cyano-5-methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12b (6.99 g, 31.6 mmol) was dissolved in 90 mL of hydrochloric acid (36%). The reaction mixture was heated at 50° C. in an oil bath and stirred for 48 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction mixture was diluted with 100 mL of water. Upon cooling by an ice-water bath, the mixture was adjusted to pH 6 with potassium carbonate and extracted with ethyl acetate (1500 mL×3) and dichloromethane (150 mL×3) successively. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 2-dimethylcarbamoyl-5-methyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 12c (7.0 g, yield 92%) as a yellow liquid, which was directly used in the next step.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=3[S:22][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]=4[S:22][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1ccc(F)c(Cl)c1
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCCNC4)cc1Cl
Yield: 82 %

Procedure:
The title compound was synthesized in analogy to Example 12A from tert-butyl 4-chloro-5,6,7,9-tetrahydro-8H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepine-8-carboxylate from Example 80A (349 mg, 0.40 mmol) and 3-chloro-4-fluoroaniline (61 mg, 0.42 mmol) to yield 169 mg (68% purity, 82% yield), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([C:23](Cl)=[O:24])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].Cl>ClCCCl>[C:14]([N:17]1[CH2:18][CH2:19][CH:20]([C:23](=[O:24])[C:7]2[CH:6]=[CH:5][C:4]([O:8][CH3:9])=[CH:3][C:2]=2[F:1])[CH2:21][CH2:22]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)c(F)c1
Reaction time: 1 h

Procedure:
A mixture of 155 parts of 1-fluoro-3-methoxybenzene, 75 parts of aluminium chloride and 650 parts of 1,2-dichloroethane is stirred and 113 parts of 1-acetyl-4-piperidinecarbonyl chloride are added portionwise. Upon completion, stirring is continued for 1 hour at 40°-50° C. The reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by high pressure liquid-chromatography over silica gel using a mixture of trichloromethane, hexane and methanol (47.5:47.5:5 by volume) as eluent. The first fraction (A-isomer) is collected and the eluent is evaporated, yielding 1-acetyl-4-(2-fluoro-4-methoxybenzoyl)-piperidine. The second fraction (B-isomer) is collected and the eluent is evaporated, yielding 40 parts (25%) of 1-acetyl-4-(4-fluoro-2-hydroxybenzoyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[OH:28]O>>[Cl:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:28])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2cc3c(cc2Cl)NC(=O)OC3(C)C)cc1
Product: Cc1ccc(S(=O)CCCCOc2cc3c(cc2Cl)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 7-chloro-6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1.[OH:17][CH2:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][C:22]=2[CH:23]=1>C(#N)C>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:26]=[CH:27][C:21]3[O:20][C:19]([CH2:18][OH:17])=[CH:23][C:22]=3[CH:24]=2)[CH2:33][CH2:32]1
Reactant: COc1ccc2[nH]cc(CCCCCl)c2c1
Reactant: OCc1cc2cc(N3CCNCC3)ccc2o1
Solvent: CC#N
Product: COc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(CO)cc5c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1.8 g of 3-(4-chlorobutyl)-5-methoxyindole [obtainable by diazotization of p-methoxyaniline, reaction with ethyl cyclohexanone-2-carboxylate according to Japp-Klingemann to give 4-(2-carbethoxyindol-3-yl)butyric acid, alkaline hydrolysis, decarboxylation, reduction with LiAlH4 and reaction with SOCl2 ] and 1.9 g of 1-(2-hydroxymethylbenzofuran-5-yl)piperazine [obtainable by reaction of N,N-bis(2-chloroethyl)amine with 2-hydroxymethyl-5-aminobenzofuran] are dissolved in 200 ml of acetonitrile and the mixture is stirred at room temperature for 10 hours. Customary working up gives 1-[4-(5-methoxyindol-3-yl)butyl]-4-(2-hydroxymethylbenzofuran-5-yl)piperazine, m.p. 159°.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[N:18]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([C:14]2[N:18]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3cccc(Oc4ccccc4)c3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc(-c3cccc(Oc4ccccc4)c3)no2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A mixture of methyl 4-[3-(3-phenoxyphenyl)-1,2,4-oxadiazol-5-yl]benzoate (1.69 g), 1 M aqueous sodium hydroxide solution (10 ml), methanol (15 ml) and tetrahydrofuran (15 ml) was stirred at 60° C. for 1 hr. After cooling, 1 M hydrochloric acid was added to acidify the reaction mixture. The crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give 4-[3-(3-phenoxyphenyl)-1,2,4-oxadiazol-5-yl]benzoic acid (1.35 g, yield 83%) as colorless crystals. melting point: 292–293° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][NH2:12])[CH2:9][NH2:10].Cl>>[C:3]1([CH:8]([CH2:9][NH2:10])[CH2:11][NH2:12])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: NCC(CN)c1ccccc1Cl
Agent: Cl
Product: NCC(CN)c1ccccc1

Procedure:
2-(2-chlorophenyl)1,3-propanediamine, bp 87°-92° C./0.05 mm (di HCl salt, mp 253°-257° C.);
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[N:27]1[C:35]2[C:30](=[CH:31][C:32]([OH:36])=[CH:33][CH:34]=2)[C:29]([C:37]([F:40])([F:39])[F:38])=[N:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[N:27]1[C:35]2[C:30](=[CH:31][C:32]([O:36][CH2:2][C:3]3[CH:4]=[N:5][C:6]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=4)=[N:7][CH:8]=3)=[CH:33][CH:34]=2)[C:29]([C:37]([F:40])([F:38])[F:39])=[N:28]1
Reactant: FC(F)(F)Oc1ccc(Nc2ncc(CCl)cn2)cc1
Reactant: Oc1ccc2c(c1)c(C(F)(F)F)nn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(Nc2ncc(COc3ccc4c(c3)c(C(F)(F)F)nn4C3CCCCO3)cn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
To a solution of 5-(chloromethyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (0.04 g, 0.132 mmol) in DMF (2 mL), 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-ol (0.045 g, 0.158 mmol) and Cs2CO3 (0.086 g, 0.263 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, then diluted in EtOAc and washed sequentially with 10% NaOH and brine. The organic layer was dried over Na2SO4 and concentrated to afford 5-(((1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (38 mg, 52%). LCMS: RT 2.33 min; 554.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:15]=3[C:25]([F:28])([F:27])[F:26])[O:11][N:10]=2)=[CH:5][CH:4]=1.[NH:29]1[CH2:32][CH:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1.C(O)(=O)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[C:15]([C:25]([F:27])([F:26])[F:28])=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:29]4[CH2:30][CH:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32]4)=[CH:8][CH:7]=3)[N:13]=2)[O:18][N:17]=1
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: FC(F)(F)c1c(-c2ccccn2)noc1-c1nc(-c2ccc(CBr)cc2)no1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 3-(4-(bromomethyl)phenyl)-5-(3-(pyridin-2-yl)-4-(trifluoromethyl)-isoxazol-5-yl)-1,2,4-oxadiazole (2.52 g, 5.59 mmol) and tert-butyl azetidine-3-carboxylate, acetic acid (1.82 g, 8.39 mmol) in N,N-dimethylformamide (40 mL) cooled with an ice-water bath was added triethylamine (2.34 mL, 16.8 mmol) drop-wise. The reaction mixture was stirred for 30 minutes, diluted with ethyl acetate (350 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), washed with water (100 mL), washed with brine (100 mL), and dried over anhydrous sodium sulfate. Concentration gave a crude product which was triturated with methanol. The resulting solid was collected by vacuum filtration. The filtrate was concentration and purified by silica gel chromatography (eluting with Hexanes/ethyl acetate-4/1) to yield additional product. The material was combined to give tert-butyl 1-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (2.46 g, 83% yield).
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])C(C#N)=[N:18]2)=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4])#[N:2].Cl.[C:28]([OH:31])(=[O:30])[CH3:29]>>[C:1]([C:3]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[C:29]([C:28]([OH:31])=[O:30])=[N:18]2)=[CH:13][CH:12]=1)([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:4])#[N:2]
Reactant: CC(C#N)(c1ccccc1)c1ccc(-n2nc(C#N)c(=O)[nH]c2=O)cc1
Reactant: CC(=O)O
Agent: Cl
Product: CC(C#N)(c1ccccc1)c1ccc(-n2nc(C(=O)O)c(=O)[nH]c2=O)cc1

Procedure:
A mixture of 6.86 parts of 2-[4-(1-cyano-1-phenylethyl)phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile, 30 parts of concentrate hydrochloric acid and 150 parts of acetic acid was stirred and refluxed for 24 hours. The reaction mixture was evaporated and the residue was dissolved in trichloromethane. The latter was dried, filtered and evaporated, yielding 7.2 parts of 2-[4-(1-cyano-1-phenylethyl)phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid (intermediate 86).
Reaction SMILES: COC1C=C(C=CC=1OC)C[O:7][CH2:8][C@@H:9]([O:14][CH2:15]/[CH:16]=[C:17](/[CH3:39])\[CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]([CH3:38])([CH3:37])[CH2:23][CH2:24][C:25](=[CH2:36])[CH2:26]/[CH:27]=[C:28](\[CH3:35])/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[C:10]([O:12][CH3:13])=[O:11].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C([O-])(O)=O.[Na+]>ClCCl.P([O-])([O-])([O-])=O>[OH:7][CH2:8][C@@H:9]([O:14][CH2:15]/[CH:16]=[C:17](/[CH3:39])\[CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]([CH3:38])([CH3:37])[CH2:23][CH2:24][C:25](=[CH2:36])[CH2:26]/[CH:27]=[C:28](\[CH3:35])/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:33])[CH3:34])[C:10]([O:12][CH3:13])=[O:11]
Reactant: C=C(C/C=C(\C)CCC=C(C)C)CCC(C)(C)/C=C/CC/C(C)=C\CO[C@H](COCc1ccc(OC)c(OC)c1)C(=O)OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: C=C(C/C=C(\C)CCC=C(C)C)CCC(C)(C)/C=C/CC/C(C)=C\CO[C@H](CO)C(=O)OC
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of methyl (R)-3-(3,4-dimethoxybenzyloxy)-2-[(2Z,6E,13E)-3,8,8,14,18-pentamethyl-11-methylene-nonadeca-2,6,13,17-tetraen-1-yloxy]-propanoate (10) (9.00 mg, 14.7 μmol, 1.00 eq.) in dichloromethane (2.00 mL) and phosphate buffer (0.20 mL, pH=7) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.00 mg, 22.1 μmol, 1.50 eq.) at 5° C. After being stirred at the same temperature for 1 h, the reaction mixture was diluted with dichloromethane and treated with saturated aq. NaHCO3 at 0° C. The reaction mixture was extracted with two portions of dichloromethane. The combined extract was washed with saturated aq. NaHCO3, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane:diethyl ether=89:11) to give methyl (R)-3-hydroxy-2-[(2Z,6E,13E)-3,8,8,14,18-pentamethyl-11-methylene-nonadeca-2,6,13,17-tetraen-1-yloxy]-propanoate (11) (4.10 mg, 8.89 μmol, 61%) as a colorless oil and recover (10) (3.10 mg, 5.12 μmol, 34%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH:17]3[CH2:18][CH2:19][CH:13]2[CH2:14][O:15][CH2:16]3)[N:3]=1.CN(CCN(C)C)C.[Li]CCCC.CN([CH:36]=[O:37])C.Cl>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:36]=[O:37])[N:8]2[CH3:11])=[C:4]([N:12]2[CH:17]3[CH2:18][CH2:19][CH:13]2[CH2:14][O:15][CH2:16]3)[N:3]=1
Reactant: Cn1cnc2c(N3C4CCC3COC4)nc(Cl)nc21
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C=O)nc2c(N3C4CCC3COC4)nc(Cl)nc21
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a solution of 2-chloro-9-methyl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine (620 mg, 2.22 mmol) and TMEDA (498 μL, 3.33 mmol) in THF (11 mL) at −78° C. was added n-BuLi (1.3 mL, 3.33 mmol, 2.5M solution in hexanes). The resulting mixture was warmed to −40° C. and allowed to stir for 30 min before cooling back to −78° C. DMF (517 μL, 6.65 mmol) was added and the resulting mixture was stirred at −78° C. for 30 min then poured onto 1M HCl. The aqueous layer was extracted with EtOAc and the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as a pale yellow solid (500 mg, 73%). 1H NMR (CDCl3, 400 MHz): δ 9.88 (1 H, s), 5.79 (1 H, d, J=6.14 Hz), 5.05 (1 H, d, J=6.84 Hz), 4.05 (3 H, s), 3.80-3.78 (4 H, m), 2.29-2.01 (4 H, m)
Reaction SMILES: [C:1]([OH:4])(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([NH2:22])[CH:9]=[CH:10][C:11]=1[S:12][CH:13]1[CH2:19][CH:18]2[N:20]([CH3:21])[CH:15]([CH2:16][CH2:17]2)[CH2:14]1>C(O)=O>[Cl:5][C:6]1[CH:7]=[C:8]([NH:22][CH:1]=[O:4])[CH:9]=[CH:10][C:11]=1[S:12][CH:13]1[CH2:14][CH:15]2[N:20]([CH3:21])[CH:18]([CH2:17][CH2:16]2)[CH2:19]1
Reactant: CN1C2CCC1CC(Sc1ccc(N)cc1Cl)C2
Reactant: CC(=O)O
Solvent: O=CO
Product: CN1C2CCC1CC(Sc1ccc(NC=O)cc1Cl)C2
Reaction time: 1.5 h
Yield: 13.7 %

Procedure:
A mixture of acetic acid (0.96 g) and formic acid (0.53 g) was heated under reflux for 2 hours. To this was added 3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylamine (265 mg) and heating continued for 1.5 hours. The crude mixture was placed on an SCX cartridge and eluted with methanol followed by 2M ammonia in methanol. The impure product was then subjected to flash chroamtography on silica gel (gradient elution with increasing percentage of methanol in chloroform) to yield material of 93% purity. Final clean up by preparative LC-MS gave 3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylformamide (40 mg)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])([O-])=O.CO>O=[Pt]=O.C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]1[C:16](=[O:25])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]1=[O:24]
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
Combine a mixture of 2-(2-(5-nitro-1H-indol-3-yl)ethyl)isoindole-1,3-dione (1.8 g, 5.4 mmol), PtO2 (500 mg), 100 mL MeOH and 100 mL THF and hydrogenate at atmospheric pressure overnight. Filter the reaction through a pad of celite and concentrate to dryness. Redissolve the residue in 50/50 chloroform/dichloromethane and refilter through a pad of celite. Concentration under vacuum give the title compound as a dark solid: ISMS 306 (M+1); Analysis for C18H13N3O4 0.1C7H8 0.2 dichloromethane: calcd: C, 68.70; H, 4.89; N, 12.58; found: C, 69.08; H, 4.75; N, 12.69; 1H NMR (CDCl3) 7.9–7.8 (m, 3H), 7.75–7.65 (m, 2H), 7.2–7.1 (m, 1H), 7.05–7.0 (m, 2H), 6.7–6.6 (m, 1H), 4.0–3.9 (m, 2H), 3.4 (bs, 2H), 3.1–3.0 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:20])[CH:17]([CH3:19])[CH3:18])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:20])[CH:17]([CH3:19])[CH3:18])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC(C)C(C)Oc1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OC(C)C(C)C)ncn1
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
In 3.5 ml of tetrahydrofuran was suspended 0.09 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.13 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing 0.35 g of 4-chloro-6-(1,2-dimethylpropyloxy)pyrimidine in tetrahydrofuran at 0° C., followed by stirring at the same temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.41 g of 4-(2-butynyloxy)-6-(1,2-dimethylpropyloxy)pyrimidine (the present compound (12)).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[O:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:16]1[O:17][C:13]2[CH:12]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:23])[CH:9]=3)[CH:22]=[CH:21][C:14]=2[N:15]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)oc3c2)ccn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)picolinamide (25 mg, 0.075 mmol, 1.0 eq) in 1 mL of NMP was added (1R,2R)-2-aminocyclohexanol hydrochloride (17 mg, 0.112 mmol, 1.5 eq) and DIPEA (404, 0.225 mmol, 3.0 eq) and reaction mixture stirred at room temperature for 48 hours. Thereafter, the product was purified via reverse phase HPLC. LC/MS (m/z) [383.1] (MH+)