Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14].C(N(CC)CC)C>ClCCl>[CH3:15][C:13](=[CH2:14])[C:12]([O:8][C@@H:6]1[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[CH:9]([CH3:11])[CH3:10])=[O:16]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
In a 100 ml flask, equipped with a magnetic stirrer, 5.0 g of L-(−)-menthol and 3.51 g of methacryloyl chloride were added to a solution of 6.67 ml of triethylamine in 30 ml of dichloromethane at room temperature. The clear solution turned turbid after a few minutes (exothermic reaction). After 4 hours, the suspension was extracted with 25 ml of 0.5 N HCl, 25 ml of water, 25 ml of saturated aqueous NaHCO3 and 25 ml of brine to give a clear orange solution (after drying over Na2SO4). Concentrating at reduced pressure gave a light brown/orange oil, which was stored overnight at 4° C. Purification by column chromatography (eluens: ethyl acetate/heptane=1/4) gave 5.30 g (73.8%) of a colourless oil. 1H-NMR confirmed the expected structure.
Reaction SMILES: [C:1]([C:4]([CH2:21][C:22]#[C:23][C:24]1([O:30]C(=O)C)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)(=[O:3])[CH3:2].C(C(CC#CC(OC(=O)C)CCCCC)(CCCCCCC(OCC)=O)C(OCC)=O)(=O)C>>[C:1]([CH:4]([CH2:21][C:22]#[C:23][C:24]1([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CC#CC1(OC(C)=O)CCCCC1)(C(C)=O)C(=O)OCC
Agent: CCCCCC(C#CCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OCC)OC(C)=O
Product: CC(=O)C(CC#CC1(O)CCCCC1)CCCCCCC(=O)O

Procedure:
This compound is prepared by the same procedure described in Example 35, Step B, except that diethyl 2-acetyl-2-[3-(1-acetoxycyclohexyl)-2-propyn-1-yl]azelate is substituted for diethyl 2-acetyl-2-(4-acetoxy-2-nonyn-1-yl)azelate. The chromatographically purified product is a yellowish viscous oil; pmr (CDCl3)δ 2.14 (3H,s CH3C0), 6.50 (2H,s OH and COOH).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C@H:9]1[CH2:29][C@@:28]2([CH3:30])[C@@H:20]([CH2:21][C@H:22]([CH3:37])[C@:23]2([O:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C:24](=[O:27])[CH2:25][OH:26])[C@H:19]2[C@H:10]1[C@:11]1([CH3:39])[C:16]([CH2:17][CH2:18]2)=[CH:15][C:14](=[O:38])[CH:13]=[CH:12]1.O.Cl>N1C=CC=CC=1>[C:1]([O:26][CH2:25][C:24](=[O:27])[C@:23]1([O:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C@:28]2([CH3:30])[C@H:20]([C@H:19]3[C@H:10]([C@@H:9]([Cl:8])[CH2:29]2)[C@:11]2([CH3:39])[C:16](=[CH:15][C:14](=[O:38])[CH:13]=[CH:12]2)[CH2:17][CH2:18]3)[CH2:21][C@@H:22]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC(=O)[C@@]1(OC(=O)C(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reaction time: 3.5 h

Procedure:
Acetic anhydride (0.22 ml.) was added to a solution of 11β-chloro-21-hydroxy-17-isobutyryloxy-16β-methylpregna-1,4-diene-3,20 dione (71 mg.) in pyridine (1 ml.) at room temperature. After 3.5 hours, a little water was added and the solution was poured into dilute hydrochloric acid. Filtration of the precipitated solid and crystallization from methanol afforded the title compound, m.p. 204°-205° (K), [α]D + 95.2 (c 0.6 chloroform) λmax 240 nm (ε 15,450) (Found: C, 67.05; H, 7.4; Cl, 7.05, C28H37Cl O6 requires C, 66.6; H, 7.4; Cl, 7.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](S(C)(=O)=O)=[N:9][C:8]=2[C:7]([C:20]#[N:21])=[C:6]1[N:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1.[OH-:40].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([OH:40])=[N:9][C:8]=2[C:7]([C:20]#[N:21])=[C:6]1[N:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1
Reactant: [OH-]
Reactant: Cn1c(S(C)(=O)=O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3ccccc3Cl)c2c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3ccccc3Cl)c2c1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (100 mg) in ethanol (1 ml) was added 1N sodium hydroxide (1 ml), and the resulting mixture was stirred at 80° C. for 5 hours. After the reaction solution was allowed to cool, a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (81 mg) as a white solid.
Reaction SMILES: O=[O+][O-].[O:4]=O.[C:6]([O:10][C:11](=[O:26])[N:12]([CH2:16][C:17]1[CH:22]=[C:21]([CH:23]=C)[CH:20]=[CH:19][C:18]=1[Cl:25])[CH:13]1[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl.CO>[C:6]([O:10][C:11](=[O:26])[N:12]([CH2:16][C:17]1[CH:22]=[C:21]([CH:23]=[O:4])[CH:20]=[CH:19][C:18]=1[Cl:25])[CH:13]1[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=O
Reactant: C=Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1cc(C=O)ccc1Cl)C1CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A O3/O2-mixture (generated by a Fischer ozonolyser) was gently bubbled through a sol. of (2-chloro-5-vinyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (10.0 g, 32.5 mmol) in CH2Cl2 (356 mL) and MeOH (44 mL) at −78° C. for 60 min. The mixture turned light blue, and pure O2 was bubbled through the mixture until it became colourless. The mixture was purged with a stream of nitrogen for 60 min, and Me2S (44.0 mL) was added. The mixture was stirred at −78° C. for 2 h. The solvents were removed under reduced pressure, and the residue was dried under high vacuum overnight to yield to crude title compound (11.7 g, quantitative yield) that was used further without purification. LC-MS: tR=1.04 min; ES+: 295.34.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19](OCC3C=CC=CC=3)=O)[CH2:16][C:14]2([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[Si](C)(C)C.C(N(C(C)C)CC)(C)C.[F:50][C:51]1[CH:52]=[N:53]C(Cl)=[N:55][CH:56]=1>C(#N)C>[Br:35][C:31]1[CH:30]=[C:29]([C:14]23[CH2:16][N:17]([C:19]4[N:53]=[CH:52][C:51]([F:50])=[CH:56][N:55]=4)[CH2:18][CH:13]2[CH2:12][S:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:15]3)[CH:34]=[CH:33][CH:32]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: O=C(NC1=NC2(c3cccc(Br)c3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1=NC2(c3cccc(Br)c3)CN(c3ncc(F)cn3)CC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74 %

Procedure:
To a solution of racemic benzyl 2-benzamido-7a-(3-bromophenyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.6 g, 2.9 mmol) in acetonitrile (60 mL) is added iodotrimethylsilane (1.3 mL, 9.1 mmol). The resultant solution is stirred at ambient temperature for 3 hours and concentrated to dryness. The residue is purified by ion exchange chromatography (first elute with MeOH/CH2Cl2 (¼, 50 mL), followed by 7 N NH3 in MeOH/CH2Cl2 (¼, 50 mL)) to give after evaporation of the solvent 1.7 g of intermediate, N-[7a-(3-bromophenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide. This is then dissolved in 1,4-dioxane (30 mL) and diisopropylethylamine (2.0 mL, 11 mmol) and 5-fluoro-2-chloropyrimidine (850 μL, 8.90 mmol) are added sequentially. The resulting solution is heated at 110° C. for 1 hour before additional diisopropylethylamine (1.0 mL, 5.7 mmol) is added and heating is continued for another 17 hours before it is cooled to room temperature and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with gradient of ethyl acetate/dichloromethane (0% to 30%) to give the title compound (1.1 g, 73%). ES/MS (m/z): (79Br/81Br) 512/514 (M+H).
Reaction SMILES: [ClH:1].[CH:2]1([CH2:6][N:7]2[CH2:25][CH2:24][C@@:14]34[C:15]5[CH:16]=[C:17]([O:22]C)[CH:18]=[CH:19][C:20]=5[CH2:21][C@@H:8]2[C@@H:9]3[C@@H:10]([CH3:27])[CH2:11][C:12](=[O:26])[CH2:13]4)[CH2:5][CH2:4][CH2:3]1.Br.[NH4+].[OH-]>O>[ClH:1].[CH:2]1([CH2:6][N:7]2[CH2:25][CH2:24][C@@:14]34[C:15]5[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=5[CH2:21][C@@H:8]2[C@@H:9]3[C@@H:10]([CH3:27])[CH2:11][C:12](=[O:26])[CH2:13]4)[CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc2c(c1)[C@]13CCN(CC4CCC4)[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Agent: Br
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: C[C@H]1CC(=O)C[C@]23CCN(CC4CCC4)[C@H](Cc4ccc(O)cc42)[C@H]13
Yield: 84 %

Procedure:
A sample of 17-cyclobutylmethyl-3-methoxy-8β-methylmorphinan-6-one (prepared in Example 2) and 48% aqueous HBr (1.0 g/5 ml, respectively) was refluxed for 20 minutes in a pre-heated oil bath at 140° C. The mixture was cooled in ice and diluted with 30 ml of water. The aqueous solution was adjusted to about pH 11 by addition of concentrated NH4OH. The basic mixture was extracted with three portions of chloroform, and the organic extract was treated as in Example 1D. The residue was chromatographed over Silica Gel G as in Example 1D and the product was isolated as in the HCl salt, yield 84%, mp 150° C. dec, with foaming. The tartaric acid salt of 17-cyclobutylmethyl-3-hydroxy-8β-methylmorphinan-6-one can be prepared by procedures apparent to those skilled in the art.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]([OH:23])[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=1)[N:6]=[C:5]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31].[F:32][C:33]([F:38])([F:37])[CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]([O:23][CH2:35][CH2:34][C:33]([F:38])([F:37])[F:32])[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=1)[N:6]=[C:5]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]
Reactant: CC1(C)C(=O)Nc2nc(-n3nc(Cc4ccccc4F)c4cc(F)ccc43)nc(O)c21
Reactant: OCCC(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)C(=O)Nc2nc(-n3nc(Cc4ccccc4F)c4cc(F)ccc43)nc(OCCC(F)(F)F)c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under argon, 80 mg (0.19 mmol) of the compound from example 31 was largely dissolved in 2 ml THF, 32.5 mg (0.29 mmol) of 3,3,3-trifluoropropan-1-ol, 75 mg (0.29 mmol) of triphenyl phosphine and 56 μl (0.29 mmol) of diisopropyl azodicarboxylate were added and it was stirred for 3 d at RT. A further 11 mg (0.01 mmol) of 3,3,3-trifluoropropan-1-ol, 25 mg (0.01 mmol) of triphenyl phosphine and 19 μl (0.01 mmol) of diisopropyl azodicarboxylate were added and it was stirred for 1 d at RT. The reaction mixture was concentrated by evaporation and the residue was purified by preparative HPLC (Reprosil C18, gradient of acetonitrile/0.01% aq. formic acid). Yield: 48 mg (49% of theor.)
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[O:18][N:17]=[C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:15]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.NC1ON=C(C2CCN(C(OC)=O)CC2)C=1C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])[O-].[K+].[K+].ClC(OCC)=O>C(Cl)Cl.N1C=CC=CC=1>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([C:16]2[C:15]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=4[C:2](=[O:4])[NH:13][C:14]=3[O:18][N:17]=2)[CH2:20][CH2:21]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)N1CCC(c2noc(N)c2-c2ccccc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CCOC(=O)Cl
Agent: COC(=O)N1CCC(c2noc(N)c2-c2ccccc2)CC1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC(c2noc3[nH]c(=O)c4ccccc4c23)CC1
Temperature: 0 °C
Reaction time: 6.5 h
Yield: 130.2 %

Procedure:
Triphosgene (1.83 g) was dissolved in methylene chloride (20 mL), a solution (30 mL) of a mixture (1:1, 5.57 g) of 5-amino-3-(1-ethoxycarbonylpiperidin-4-yl)-4-phenylisoxazole and 5-amino-3-(1-methoxycarbonylpiperidin-4-yl)-4-phenylisoxazole, and pyridine (3.50 g) in methylene chloride was added dropwise under ice-cooling. After the completion of the dropwise addition, the mixture was stirred under ice-cooling for 20 min, and then at room temperature for 6.5 hrs. The reaction mixture was ice-cooled, aluminum chloride (16.7 g) was added, and the mixture was stirred overnight at room temperature. After the completion of the reaction, the reaction mixture was poured into ice-water, and potassium carbonate was added to alkalify the reaction mixture. An excess amount of ethyl chloroformate was added to the reaction mixture, and the mixture was stirred at room temperature. The insoluble material was filtered off through celite, and the aqueous layer was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration with diethyl ether and a small amount of methanol to give a mixture (1:1, 2.74 g) of 1-(1-ethoxycarbonylpiperidin-4-yl)-isoxazolo[5,4-c]isoquinolin-5(4H)-one and 1-(1-methoxycarbonylpiperidin-4-yl)-isoxazolo[5,4-c]isoquinolin-5(4H)-one as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([CH:12]1[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13]1)=[O:11])[CH3:8].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C.O>[CH2:7]([O:9][C:10]([C:12]1([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Yield: 61.5 %

Procedure:
6.7 g potassium carbonate was added to 7 g 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 50 mL DMF and stirred at RT. After 30 min 6.1 g ethyl bromoacetate was added and the reaction was stirred at RT over night. The reaction was diluted with water and extracted with ethyl acetate/hexane (1/1). The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel (15% ethyl acetate in hexane) to give 5.6 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([CH2:17][OH:18])=[CH:11]3)[CH:5]=[CH:6][CH:7]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([O:18][CH2:17][C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[CH:16][CH:15]=2)(=[O:21])[CH3:20]
Reactant: Cc1cccc(-c2ccc3[nH]c(CO)cc3c2)c1
Reactant: CC(=O)Cl
Product: CC(=O)OCc1cc2cc(-c3cccc(C)c3)ccc2[nH]1

Procedure:
A mixture of (5-bromo-1H-indol-2-yl)methanol (9 g, 39.8 mmol), 3-methylbenzeneboronic acid (6.14 g, 43.78 mmol), potassium carbonate (13.75 g, 99.5 mmol), palladium(II) acetate (0.045 g) and tetrabutylammonium bromide (12.84 g, 39.8 mmol) in 10% dioxane in water (degassed, 0.38 L) was stirred at 70° C. The reaction was monitored by TLC. Additional 3-methylbenzeneboronic acid (5.6 g, 39.8 mmol) was added. After no 5-bromo-1-(4-tert-butylbenzyl)-1H-indole was detected by TLC, the reaction was cooled to room temperature and the solvent was decanted. The residual thick oil was stirred with hexane. The hexane was decanted and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water filtered and concentrated. The residue was purified by flash column chromatography using hexane/ethyl acetate (55:45) as an eluant to give [5-(3-Methylphenyl)-1H-indol-2-yl]methanol as a brown solid (6.0 g). Reaction of [5-(3-Methylphenyl)-1H-indol-2-yl]methanol with acetyl chloride according to the procedure described in step 4 of Example 1 afforded the title compound as an oil (3.94 g); Mass spectrum (ESI, [M−H]−) m/z 278. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.46 (s, 1H), 7.42–7.36 (m, 3H), 7.30 (s, 1H), 7.10 (d, 1H, J=7.48 Hz), 6.50 (s, 1H), 2.37 (s, 3H), and 2.07 ppm (s, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.Cl.[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][CH2:41][NH2:42])[CH2:35][CH2:34]1.C(N(CC)CC)C>C(O)C>[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:34][CH2:35][N:36]([CH2:39][CH2:40][CH2:41][NH:42][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]3[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:37][CH2:38]1
Reactant: Cc1cccc(N2CCN(CCCN)CC2)c1C
Reactant: Clc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc(N2CCN(CCCNc3ncnc4c3nc(-c3ccccc3)n4-c3ccccc3)CC2)c1C
Temperature: 80 °C
Reaction time: 15 h
Yield: 46.1 %

Procedure:
To a mixture of 6-chloro-8,9-diphenyl-9H-purine (150 mg, 0.49 mmol) and 3-(4-(2,3-dimethylphenyl)piperazin-1-yl)propan-1-amine dihydrochloride (313 mg, 0.98 mmol) in ethanol (4.9 mL) was added triethyl amine (0.27 mL, 1.96 mmol) and stirred at 80° C. for 15 hrs. The resulting reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer thus separated was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was purified by preparative HPLC (purification system, Gilson) to provide the title compound (117 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]([CH3:20])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([C:21]#[N:22])[CH:3]=1.Cl[C:24]1[N:29]=[C:28]([N:30]([CH:40]2[CH2:42][CH2:41]2)[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:27]2=[N:43][CH:44]=[C:45]([C:46]#[N:47])[N:26]2[N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:8][C:7]1[C:2]([NH:1][C:24]2[N:29]=[C:28]([N:30]([CH:40]3[CH2:42][CH2:41]3)[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:27]3=[N:43][CH:44]=[C:45]([C:46]#[N:47])[N:26]3[N:25]=2)=[CH:3][C:4]([C:21]#[N:22])=[C:5]([N:9]([CH3:20])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])[CH:6]=1
Reactant: CN(CCNC(=O)OC(C)(C)C)c1cc(Cl)c(N)cc1C#N
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(N(C)CCNC(=O)OC(C)(C)C)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 69.1 %

Procedure:
A mixture of tert-butyl (2-((4-amino-5-chloro-2-cyanophenyl)(methyl)amino)ethyl)carbamate (207 mg, 0.637 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (226 mg, 0.637 mmol), Cs2CO3 (415 mg, 1.28 mmol), dppf (35.3 mg, 0.064 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (36.9 mg, 0.064 mmol), and Pd(OAc)2 (42.9 mg, 0.191 mmol) in a microwave vial was flushed with nitrogen. Dioxane (9 mL) was added and the vial was sealed and heated at 100° C. for 4 hr. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed and radial silica gel chromatography with hexane containing 5 to 40% EtOAc afforded tert-butyl (2-((5-chloro-2-cyano-4-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)(methyl)amino)ethyl)carbamate (283 mg) as an oil.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[C:1]([C:4]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)C1CCc2ccccc2C1=O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)C1(Cc2ccccc2)CCc2ccccc2C1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2-Acetyl-1-tetralone (5.0 g) was added into a mixture of potassium carbonate (3.8 g) and acetonitrile (60 ml). The mixture was stirred at 60° C. for 30 minutes and benzyl chloride was added and the stirring was continued at 60° C. for 5 hours. The mixture was filtered and evaporated. The yield was 7.2 g and was used for further reactions without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)=[O:4].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][N:2]([CH3:19])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:4]
Reactant: CN(C)C(=O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN(C)C(=O)[C@@H]1CCCN1c1ccc(N)cc1
Yield: 89 %

Procedure:
(R)-1-(4-Nitro-phenyl)-pyrrolidine-2-carboxylic acid dimethylamide (Method 52; 0.85 g) was dissolved in MeOH (50 ml), to this was added ammonium formate (1.0 g, 16 mmol) and palladium (0.1 g). The reaction was heated at reflux for 60 minutes (reaction decolourised). MeOH was removed in vacuo and saturated ammonium chloride (50 ml) was added. The system was extracted with DCM (2×100 ml), dried and solvent was removed in vacuo to yield the title compound as a brown gum (0.67 g, 87%). The product rapidly turned black on exposure to air. The product was used immediately without any purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:12]([NH:19][CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH2:12]([N:19]([CH2:20][CH2:21][OH:22])[C:9](=[O:11])[CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1cccnc1Cl
Reactant: OCCNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1cccnc1Cl)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 102.7 %

Procedure:
To a solution of the compound (3.40 g) obtained in step 4, N-benzylethanolamine (4.53 g) and HOBt.H2O (4.60 g) in DMF (50 mL) was added WSC.HCl (5.80 g), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 80% ethyl acetate/hexane→2% methanol/ethyl acetate) to give N-benzyl-2-(2-chloropyridin-3-yl)-N-(2-hydroxyethyl)acetamide (6.20 g, 100%) as a pale-yellow oil.