Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:2]([C:10]([O:12]N1C(=O)CCC1=O)=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[NH2:30][C@H:31]([C:38]([O:40][CH3:41])=[O:39])[CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35].Cl.C(OCC)(=O)C>C(N(CC)CC)C>[NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@H:2]([C:10]([NH:30][C@H:31]([C:38]([O:40][CH3:41])=[O:39])[CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:12])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Temperature: 20 °C
Reaction time: 15 h

Procedure:
16.25 g of Z-Thr(But)-OSu and 8.47 g of H-Ser(But)-OMe. HCl are added to 200 ml of ethyl acetate, 5.6 ml of triethylamine are added at 0°C and the solution is stirred for 15 hours at 20°C and washed with 1 N citric acid, 1 N sodium bicarbonate and water. After drying over sodium sulphate, the solution is evaporated, whereupon the product, which is pure according to thin layer chromatography, is obtained as an oil.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](F)=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].CCN(C(C)C)C(C)C>C(#N)C>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:13][N:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([CH2:27][N:28]5[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]5)=[CH:39][CH:40]=4)[N:20]=3)[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
To a mixture of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (100 mg, 0.386 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 118 mg, 0.386 mmol) in acetonitrile (2 mL) at room temperature was added Hunig's Base (0.081 mL, 0.463 mmol). The reaction mixture was stirred at room temperature for 3 days. The volatiles were removed under reduced pressure, and the residue was partitioned between dichloromethane (30 mL) and a saturated aqueous solution of sodium bicarbonate (30 mL). The aqueous layer was extracted with dichloromethane (2×20 mL), and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford a light yellow oil. The compound was purified by flash silica gel chromatography using a mixture of ethyl acetate/hexane (0-70%) to give tert-butyl 1-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (175 mg, 0.332 mmol, 86% yield) as a white, crystalline solid. The compound had an HPLC retention time=3.34 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=527.13. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9H), 3.26-3.33 (m, 3H), 3.54-3.59 (m, 2H), 3.70 (s, 2H), 7.46 (d, J=8.28 Hz, 2H), 7.56-7.62 (m, 2H), 7.63-7.68 (m, 1H), 7.78 (d, J=7.28 Hz, 2H), and 8.16 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:26]([N:25]([CH3:29])[CH3:24])=[O:27])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1N
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1NC(=O)N(C)C
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-1-(3-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g) in pyridine (5 ml) is added N,N-dimethylcarbamic chloride (0.42 ml), and the mixture is stirred at 60-70° C. for two hours. The mixture is made acidic with hydrochloric acid, and then extracted with ethyl acetate. The mixture is washed with a saturated aqueous sodium hydrogen carbonate solution, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:10→1:1→3:1), and recrystallized from ethanol/diethyl ether to give 7-chloro-1-(3-methoxy-4-dimethylaminocarbonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.33 g) as white plates.
Reaction SMILES: ClS(O)(=O)=O.[NH2:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1.[C:12]([CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]#[N:18])(=O)[CH2:13][CH3:14]>O.CC1C=CC=CC=1C>[CH2:13]([C:12]1[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:17]([NH2:18])[N:8]2[N:9]=[CH:10][N:11]=[C:7]2[N:6]=1)[CH3:14]
Reactant: CCCCCCCCC(C#N)C(=O)CC
Reactant: Nc1nc[nH]n1
Agent: O=S(=O)(O)Cl
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCc1c(CC)nc2ncnn2c1N
Temperature: 140 °C
Yield: 83 %

Procedure:
In a 2.5 l jacketed vessel fitted with condenser and water separator, 737 g of o-xylene was initially charged, and 39.5 g of chlorosulfonic acid was added. 191.2 g of 3-amino-1,2,4-triazole and 1254 g of a solution of 2-propionyldecanonitrile (37.7% by weight in o-xylene) were added, and the mixture was heated to reflux. The mixture was stirred under reflux for 12 hours, and the water of reaction formed was removed via a phase separator. Once no more water was separated off, the mixture was cooled to 140° C. and 59.4 g of triethylamine were added. On further cooling, the product precipitated in the form of colorless crystals. At a temperature 105° C., 152.8 g of methanol were added. The mixture was cooled further to 20° C., and the solid formed was separated off. The filtercake was washed with a mixture of 850 g of methanol and 119 g of water and then dried under reduced pressure. This gave 525.5 g of colorless crystals having a content of 98.3% a/a (HPLC). The title compound was obtained as a mixture of two modifications having melting points of 199° C. and 201° C., respectively. Yield: 83.0%.
Reaction SMILES: [CH3:1][C:2]1([C:7]2([C:10]3[CH:15]=[CH:14][C:13]([C@@:16]4([CH2:22][OH:23])[O:20][C:19](=[O:21])[NH:18][CH2:17]4)=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH3:1][C:2]1([C:7]2([C:10]3[CH:11]=[CH:12][C:13]([C@@:16]4([CH2:22][O:23][S:37]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)(=[O:39])=[O:38])[O:20][C:19](=[O:21])[NH:18][CH2:17]4)=[CH:14][CH:15]=3)[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(C2(c3ccc([C@]4(CO)CNC(=O)O4)cc3)CC2)OCCO1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C2(c3ccc([C@]4(COS(=O)(=O)c5ccccc5)CNC(=O)O4)cc3)CC2)OCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5(R)-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]-5-hydroxymethyloxazolidin-2-one (2.55 g) and triethylamine (1.7 mL) in tetrahydrofuran (20 mL) was added benzenesulfonyl chloride (1.2 mL) at 0° C., the mixture was stirred at room temperature overnight, and heated at 40° C. for 10 hours. After dilution with water, the mixture was extracted with tetrahydrofuran. The organic extracts were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=1:1) of the residue gave 5(R)-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]-5-phenylsulfonyloxymethyloxazolidin-2-one (3.05 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2c(Br)cncc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.75 h
Yield: 39.1 %

Procedure:
A 50 mL round-bottomed flask, under nitrogen fitted with a thermometer probe, and a condenser/inert gas bubbler (via a Claisen head), was charged with a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-c]pyridine (0.96 g, 2.84 mmol) in anhydrous THF (10 mL). To the resultant solution, at −35° C., was added dropwise a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 2.84 mL, 5.68 mmol) and the mixture then stirred at −35° C. for 45 min. Methyl iodide (1.06 mL, 17.04 mmol) was added to the reaction mixture dropwise. The resulting solution was allowed to reach room temperature and was stirred for 3 h. The reaction was quenched by addition of a solution of 1N HCl (5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2×75 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, 0-100% DCM:cyclohexane). The residue was triturated with EtOAc (2 mL) and the precipitate was collected by filtration to give the title compound as a white solid (0.39 g, 39%). LCMS (Method A): RT=4.47 min, [M+H]+ 351 (79Br), 353 (81Br)
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:6][CH3:7])=[O:5].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[C:15]([C:14]1[C:13]([N+:10]([O-:12])=[O:11])=[CH:20][CH:19]=[CH:18][C:17]=1[O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:6][CH3:7])=[O:5])#[N:16]
Reactant: CNC(=O)C(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CNC(=O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 77 %

Procedure:
Prepared as in Example 215c from 3-hydroxy-N,2,2-trimethylpropanamide (Example 221d) and 2,6-dinitrobenzonitrile in 77% yield as a pale yellow solid. MS 378 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>O1CCCC1.C(OCC)(=O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:19])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(Br)cc1)c1cccnc1
Reaction time: 0.42 h
Yield: 39.5 %

Procedure:
3-Bromopyridine (0.4 ml, 4.0 mmol) was dissolved in 15 ml of tetrahydrofuran in an argon atmosphere. n-Butyllithium (1.58 M n-hexane solution, 2.4 ml, 3.8 mmol) was added to the solution at −78° C., and the mixture was stirred for 25 min. Subsequently, a solution of 502 mg (2.7 mmol) of 4-bromobenzaldehyde in tetrahydrofuran (2 ml) was added dropwise thereto at −78° C., and the mixture was stirred at −78° C. for one hr, was stirred under ice cooling for one hr, and was then stirred at room temperature for one hr. The reaction solution was diluted with 30 ml of ethyl acetate, and the diluted solution was washed with a saturated aqueous ammonium chloride solution. The aqueous layer was extracted twice with 5 ml of ethyl acetate. The organic layers were combined and were washed with 25% brine. The organic layer was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give 282 mg (yield 40%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][S:21]([CH3:20])(=[O:23])=[O:22])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1-c1ccc2cc(NS(C)(=O)=O)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (137 mg, 1.20 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. A small amount of water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic phase was pooled and concentrated. It was purified by prep-HPLC to give the desired product (80.5 mg, 41.0%). LCMS (ESI): RT (min)=1.181, M+H+=330.9, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.17 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 7.38-7.34 (m, 1H), 7.15 (d, J=9.2 Hz, 2H), 3.30 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: C(Cl)(=O)C.[N:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:8]1[CH2:9][CH2:10][N:5]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:6][CH2:7]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(4-(piperazin-1-yl)phenyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.14 (s, 1H), 7.38-7.50 (m, 7H), 7.28-7.38 (m, 4H), 6.87-6.91 (m, 2H), 4.74 (s, 4H), 3.39-3.90 (m, 4H), 3.01-3.17 (m, 4H); MS (ESI(+)) m/e 427 (M+H)+.
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH:51]([N:58]([CH3:60])[CH3:59])[C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[CH3:59][N:58]([CH3:60])[CH:51]([C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)[CH2:50][NH:49][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)C(CN)c1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCC(c3cccnc3)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and (2-Amino-1-(3-pyridyl)ethyl)dimethylamine (0.055 g, 0.334 mmol). The mixture was stirred at rt for 2 h then sodium triacetoxyborohydride (0.177 g, 0.835 mmol) was added and it was stirred at rt for three days. The mixture was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was used in the next step with no additional purification. LCMS: m/e 748.3 (M+H)+, 3.47 min (method 6).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2-c1cccc(OCCCn2ccnc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ncnc2c1c(-c1cccc(O)c1)cn2-c1cccc(OCCCn2ccnc2)c1

Procedure:
1.35 g of 5-(3-benzyloxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 16 h in 30 ml of methanol in the presence of 0.3 g of 5% palladium/carbon. After filtration through Celite, the solvent is stripped off and the residue is slurried in ether, filtered, slurried again in EA, filtered and dried. 5-(3-Hydroxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 120°-122° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][C:12]([CH3:16])([CH2:14]O)[CH3:13]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:10][CH2:11][C:12]([CH3:16])([CH3:14])[CH2:13][O:7]2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)COC(c2ccc(Br)cc2)OC1
Yield: 92.9 %

Procedure:
A mixture of 4-bromobenzaldehyde (100 g, 0.54 mole), neopentyl glycol (15 g, 1.10 mole), and p-toluenesulfonic acid (800 mg, 4 mmole) in benzene (800 mL) was heated to reflux using a Dean Stark apparatus for 16 h. The reaction mixture was cooled to room temperature and most of the benzene was removed. The residue was partitioned between ethyl acetate (500 mL) and cold water (150 mL). The organic phase was washed with water (2×150 mL) and brine (1×150 mL), then dried (Na2SO4) and concentrated to give the desired product (136 g, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.3 %

Procedure:
A mixture of 4-(4-hydroxy-phenyl)-piperazin-1-carboxylic acid tert-butyl ester (278 mg, 1 mmol), bromomethyl-benzene (171 mg, 1 mmol) and K2CO3 (138 mg, 1 mmol) in DMF (3 mL) was stirred at rt for 24 h and then at 50° C. for 6 h, followed by addition of water (150 mL). The resulting solid was collected by filtration and washed with water to yield the desired compound (340 mg, 92%) as a white solid: MS (ESI) m/z 369 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 3.01 (t, J=4.8 Hz, 4H), 3.57 (t, J=4.8 Hz, 4H), 5.02 (s, 2H), 6.87-6.93 (m, 4H), 7.33-7.44 (m, 5H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].C[C:11]1[C:16]([C:17]([O-:19])=O)=[C:15](C)[C:14]([C:21]([O-:23])=O)=[C:13](C)[C:12]=1[C:25]([O-:27])=O.Cl>CC(C)=O.O1CCCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:25]([C:12]1[CH:11]=[C:16]([C:17](=[O:19])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:15]=[C:14]([C:21](=[O:23])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:13]=1)=[O:27]
Reactant: Cc1c(C(=O)[O-])c(C)c(C(=O)[O-])c(C)c1C(=O)[O-]
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)CC(=O)c1cc(C(=O)CC(=O)C(C)(C)C)cc(C(=O)CC(=O)C(C)(C)C)c1
Reaction time: 7 h
Yield: 52.7 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 2.29 gm (57 mmol) of 60% sodium hydride, 5.24 gm (52 mmol) of pinacolone, 4.0 gm (15.8 mmol) of trimethyl-1,3,5-benzenetricarboxylate, and 40 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and the refluxing under heat was continued for 7 hours. After cooling the reaction mixture, 30 ml of 2N aqueous hydrochloric acid was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Acetone was added to the crude product, and recrystallization afforded 3.8 gm of the target compound as yellow crystals (yield: 52%).
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][N:7](C(ON1C(=O)CCC1=O)=[N+](C)C)[CH3:8].[Br:21][C:22]1[CH:23]=[C:24]([C:39]([OH:41])=O)[CH:25]=[C:26]2[C:31]=1[O:30][C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:28][C:27]2=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:24]([C:39]([N:7]([CH3:8])[CH3:6])=[O:41])[CH:25]=[C:26]2[C:31]=1[O:30][C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:28][C:27]2=[O:38]
Reactant: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.2 %

Procedure:
TSTU (6.55 g, 21.74 mmol) was added to a stirred solution of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (7 g, 19.77 mmol) and DIPEA (3.79 mL, 21.74 mmol) dissolved in DCM (100 mL) under nitrogen. The resulting suspension was stirred at room temperature for 4 h. More TSTU (6.55 g, 21.74 mmol) and DIPEA (3.79 mL, 21.74 mmol) were added and stirring was pursued for a further 16 h. The reaction mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate and extracted with DCM and a little MeOH. The combined organic phases were dried over MgSO4, concentrated and purified by flash chromatography on silica gel eluting with 3 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford 8-bromo-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (7.70 g, 102%) as a beige solid. Mass Spectrum: m/z [M+H]+=381.
Reaction SMILES: [C:1]([CH2:3][C:4]([CH3:9])(O)[CH2:5][C:6]#[N:7])#[N:2].[BrH:10]>C(O)(=O)C>[NH2:2][C:1]1[N:7]=[C:6]([Br:10])[CH:5]=[C:4]([CH3:9])[CH:3]=1
Reactant: CC(O)(CC#N)CC#N
Reactant: Br
Solvent: CC(=O)O
Product: Cc1cc(N)nc(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
56.4 g of 1,3-dicyano-2-methyl-2-hydroxypropane was added carefully to a 33% solution of hydrogen bromide in glacial acetic acid at ice-bath temperature. The reaction mixture was then stirred for 3 days at ambient temperature. The solvent was removed in vacuo and the residual oil was brought to pH 12 with a 10 molar aqueous solution of sodium hydroxide. This alkaline solution was extracted three times each with 100 ml ethyl acetate. The combined organic layers were dried with magnesium sulphate and the solvent removed in vacuo. 56 g (66%) of 6-amino-2-bromo-4-methylpyridine was obtained as a colourless solid of melting point 99° C.