Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]3[N:10]=[C:11]([C:15]4[S:16][C:17](Br)=[CH:18][C:19]=4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:12][C:13]=3[N:14]=2)=[C:4]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:3]=1.C([Li])CCC.[CH3:54][Sn:55](Cl)([CH3:57])[CH3:56]>C(OCC)C>[CH3:54][Sn:55]([CH3:57])([CH3:56])[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]3[N:10]=[C:11]([C:15]4[S:16][C:17]([Sn:55]([CH3:57])([CH3:56])[CH3:54])=[CH:18][C:19]=4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:12][C:13]=3[N:14]=2)=[C:4]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCCCCCc1cc(Br)sc1-c1nc2sc(-c3sc(Br)cc3CCCCCCCCCCCCCC)nc2s1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1cc([Sn](C)(C)C)sc1-c1nc2sc(-c3sc([Sn](C)(C)C)cc3CCCCCCCCCCCCCC)nc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 100 mL Schlenk flask was placed 250 mg (0.29 mmol) of 2,5-bis(5-bromo-3-tetradecyl-2-thienyl)-thiazolo[5,4-d]thiazole. The flask was evacuated and refilled with Ar three times. 35 mL of dry THF was added to the flask. The flask was subsequently cooled to −78° C. n-Butyl lithium (0.64 mmol) was then added dropwise to the above solution. After the solution was stirred at −78° C. for 1 hour, 0.7 mL of 1.0 M solution of trimethyl tin chloride was syringed into the reaction mixture. After the solution was allowed to warm up to room temperature, 100 mL of diethyl ether was added to the solution. The solution was washed three times with 100 mL of water and then the organic layer was dried over anhydrous MgSO4. After the solvent was removed in vacuum, 2,5-bis(5-trimethylstannyl-3-tetradecyl-2-thienyl)-thiazolo[5,4-d]thiazole was isolated in quantitative yield.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:44])[C@@H:18]([NH:28][C:29]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[C:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:32]=2)=[O:30])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:12]1)=[O:10])[CH3:7]>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:44])[C@@H:18]([NH:28][C:29]([C:31]2[CH:36]=[C:35]([CH:1]([CH3:3])[CH3:2])[N:34]=[C:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:32]=2)=[O:30])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: CC(C)[Mg]Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(C)C)nc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Isopropylmagnesium bromide (29.5 mg) was added to an orange solution of 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (56 mg) and iron(III) acetylacetonate (1.8 mg) in anhydrous THF (1 ml) under argon. After stirring at RT for 30 min, it was quenched with a 1M HCl solution and extracted with EA. The org. phases were dried (Na2SO4) and evaporated off to give 50 mg of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9]S(O)(=O)=O.[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>CCOCC>[Cl:16][CH2:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: O=S(=O)(O)CSc1ccccc1Br
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: CCOCC
Product: ClCSc1ccccc1Br
Temperature: 0 °C
Yield: 86.2 %

Procedure:
A mixture of 60.4 g of [(o-bromophenyl)thio]methanesulfonic acid, sodium salt and 98.0 g of phosphorus pentachloride is blended until liquified, diluted with 600 ml of ether, and then poured on 1.2 kg of crushed ice. The ether layer is separated, washed, dried, and concentrated to give about 43.7 g of the named compound, bp about 86° (0.6 mm), mp about 28°-30°.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:15]23[CH2:29][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=42)[C:21]2[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1)C1C=CC=CC=1.[C:30](=[O:36])([O-])[O:31][CH2:32][CH2:33]Cl>C1(C)C=CC=CC=1>[CH2:32]([O:31][C:30]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:15]23[CH2:29][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=42)[C:21]2[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1)=[O:36])[CH3:33]
Reactant: O=C([O-])OCCCl
Reactant: c1ccc(CN2CCOC(CC34CC(c5ccccc53)c3ccccc34)C2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCOC(CC23CC(c4ccccc42)c2ccccc23)C1

Procedure:
A solution of 9-(4-benzyl-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (590 mg) and chloroethyl carbonate (671 mg) in dry toluene was refluxed for 3 hours. The reaction solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(4-ethoxycarbonyl-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 143° - 144.5° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:35])([CH3:34])[C@@H:14]([O:26]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].C(O)(=O)C>[Pd].CO>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:34])([CH3:35])[C@@H:14]([OH:26])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CCOC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)OCCOC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Following the general procedure of hydrogenolysis of benzyl ethers of Description 18, a mixture of (ethoxycarbonyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (32c) (5.2 g, 10 mmol), 1.3 g of 10 wt.-% of palladium on activated carbon in 20 mL of methanol (MeOH), and 1.0 mL (1.05 g, 17.5 mmol) of glacial acetic acid was stirred overnight under a hydrogen atmosphere. Upon the completion of reaction and following aqueous work-up, 3.6 g (84% yield) of the title compound (32) was obtained as a colorless, viscous oil. RT=21.95 min and 30.99 min (by LC/UV). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=0.99-1.01 (2s, 3H), 1.13-1.15 (2s, 3H), 1.32-1.37 (m, 3H), 1.59-1.62 (m, 3H), 2.00-2.01 (2s, 3H), 2.04-2.12 (m, 2H), 3.12-3.26 (m, 3H), 3.33-3.47 (m, 2H), 3.94-3.98 (m, 1H), 4.06-4.08 (2d, J=6.8, 6.0 Hz, 1H), 4.14-4.19 (2d, J=8.8, 8.8 Hz, 1H), 4.23-4.28 (m, 2H), 5.85-5.88 (br. m, 1H), 6.85 (m, 1H) ppm. MS (ESI) m/z: 428.14 (M+H)+, 450.14 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: COC[O:4][C:5]1[C:13]([CH:14](OC)[O:15]C)=[CH:12][C:11]([I:19])=[C:10]2[C:6]=1[CH:7]([OH:30])[N:8]([C:21]([CH3:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:9]2=[O:20].Cl.[CH3:32]O>CO>[OH:4][C:5]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]([I:19])=[C:10]2[C:6]=1[CH:7]([O:30][CH3:32])[N:8]([C:21]([CH3:22])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:29])[C:9]2=[O:20]
Reactant: COCOc1c(C(OC)OC)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Reactant: CO
Agent: Cl
Product: COC1c2c(O)c(C=O)cc(I)c2C(=O)N1C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
4-Methoxymethoxy-5-dimethoxymethyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (490 mg, 0.929 mmol) was dissolved in methanol (10 mL), and the solution was treated with 10% hydrogen chloride-methanol solution (5 mL), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in acetonitrile (5 mL). The solution was added with 1 mol/L hydrochloric acid (5 mL) and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-hydroxy-5-formyl-3-methoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (329 mg, yield 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:14])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[N:7]2.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C.C(#N)C>C(O)CCC>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:14][CH:12]([C:10]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[C:8]3[C:3]([CH:4]=[CH:5][N:6]=[N:7]3)=[C:2]([Cl:1])[CH:11]=2)[CH3:13])[N:26]=[CH:25][N:24]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Solvent: CC#N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Yield: 45.8 %

Procedure:
A solution of the single enantiomer of 1-[5-chloro-8-(3-fluorophenyl)cinnolin-7-yl]ethanamine (400 mg, 1.3 mmol) from step O, 4-amino-6-chloropyrimidine-5-carbonitrile (250 mg, 1.6 mmol), and N,N-diisopropylethylamine (0.69 mL, 4 mmol) in 1-butanol (13 mL) was heated at 120° C. for 3 hours. The reaction mixture was concentrated and the residue was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min). The pure fractions were concentrated to remove all of the acetonitrile and the remaining aqueous solution was saturated with sodium bicarbonate. The aqueous solution was extracted with ethyl acetate (300 mL). The organic layer was separated, washed with brine, dried with sodium sulfate, filtered, and concentrated to give a solid. This solid was treated with acetonitrile and concentrated (2×) to give the desired product (0.25 g, 44%). LCMS for C21H16ClFN7 (M+H)+: m/z=420.1; Found: 420.1. 1H NMR (300 MHz, DMSO-d6): δ 9.48 (d, J=6.0 Hz, 1 H), 8.44 (d, J=7.8 Hz, 1 H), 8.28 (d, J=6.0 Hz, 1 H), 7.87 - 7.81 (m, 2 H), 7.61 - 7.44 (m, 2 H), 7.34 - 7.17 (m, 4 H), 5.24-5.11 (m, 1 H), 1.43 (d, J=7.0 Hz, 3 H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:8]1[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:10][CH:9]=1)([O:5]CC)=[O:4]>C(O)C>[C:3]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:27][CH:28]=1)([OH:5])=[O:4]
Reactant: CCOC(=O)c1ccc(OCCCCCCP(=O)(OCC)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CCCCCCOc1ccc(C(=O)O)cc1)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.9 %

Procedure:
A solution (21 ml) of 1N sodium hydroxide in ethanol was added to a solution of 8.3 g of diethyl [6-(4-carbethoxyphenoxy)hexyl]phosphonate (Example 8) in 20 ml of ethanol. The reaction mixture was stirred at room temperature for two days. The solid fraction was collected, digested with 100 ml of ether, filtered and dried to give 7.0 g of diethyl [6-(4-carboxyphenoxy)hexyl]phosphonate in the form of its sodium salt, m.p. 215°-216° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=2[CH:22]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]([F:30])([F:31])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=2[CH:22]=1
Reactant: COC(=O)C1=Cc2cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2CCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To methyl 2-[3,5-bis(trifluoromethyl)benzyloxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (494 mg, 1.15 mmol) dissolved in a mixed solvent of methanol (7 ml) and THF (7 ml) was added a 1N aqueous solution of sodium hydroxide (3.5 ml), and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was mixed with 1 N hydrochloric acid (3.5 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-[3,5-bis(trifluoromethyl)benzyloxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (475 mg, 1.10 mmol, 96%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=2[O:16][CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1>C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=2[O:16][CH3:17])[NH2:13])=[C:5]([CH3:18])[O:4][N:3]=1.[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=2[O:16][CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(C)noc1C
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1-c1c(C)noc1C
Reaction time: 24 h

Procedure:
3,5-Dimethyl-4-[2-(methyloxy)-5-nitrophenyl]isoxazole (for a preparation see Intermediate 61, 68 g, 274 mmol) was dissolved in ethyl acetate (1 l) and the solution washed with sodium sulphite solution (5%, 500 ml). The organic layer was dried (sodium sulphate) and filtered through a 3 cm pad of silica gel. The filtrate was diluted with ethanol (1 l) and added to Pd/C (E101 type NO/W, 10 g) in a 5 l nitrogen/vacuum purged hydrogenation flask under vacuum, The mixture was stirred for 24 h. The mixture was purged with vacuum/nitrogen cycles (×3), filtered through Celite under nitrogen and the filtrate evaporated in vacuo to give [3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amine 3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)aniline (62.3 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH:19]4[CH2:25][CH2:24][C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:20]4=[O:35])[CH:18]=3)=[CH:10][C:9]=2[O:36][CH3:37])[CH:5]=[CH:4][N:3]=1.[CH2:38]([Mg]Br)[CH3:39]>C1COCC1.CN1C(=O)CCC1>[CH2:38]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH:19]4[CH2:25][CH2:24][C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:20]4=[O:35])[CH:18]=3)=[CH:10][C:9]=2[O:36][CH3:37])[CH:5]=[CH:4][N:3]=1)[CH3:39]
Reactant: CC[Mg]Br
Reactant: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1-c1ccnc(Cl)c1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCc1cc(-c2ccc(-c3cn(C4CCc5ccccc5N(CC(F)(F)F)C4=O)nn3)cc2OC)ccn1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 3-{4-[4-(2-chloropyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (50 mg, 0.095 mmol), previously prepared, and ferric acetylacetonate (3.34 mg, 9.47 μmol) in THF (852 μl) and NMP (95 μl) at 0° C. was added ethyl magnesium bromide (1M in THF, 189 μl, 0.189 mmol). The reaction was held at 0° C. and stirred for 15 minutes. The reaction was quenched at 0° C. with a small addition of 1 mL of a saturated NH4Cl aq. solution. The reaction was diluted with 50 mL of H2O and was extracted with 3×50 mL portions of DCM. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo Analytically pure material was obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% Formic Acid. Lyophilisation afforded 3-{4-[4-(2-ethylpyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1 benzazepin-2-one.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:17]>>[Cl:17][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: Cl
Reactant: COc1ccc(CO)cc1OC1CCCC1
Product: COc1ccc(CCl)cc1OC1CCCC1
Temperature: 23 °C
Reaction time: 0.67 h

Procedure:
The toluene solution from Example 2 was cooled to 20° C. and concentrated hydrochloric acid (37.5%; 9.80 g) was added keeping the temperature between 20 and 22.7° C. A sample was taken 40 minutes after the addition was complete and analysed (GC) and the reaction was deemed to be complete. The phases were allowed to separate and the lower, aqueous phase discarded. Sodium bicarbonate (1.20 g) was charged to the reactor to neutralize the remaining hydrochloric acid. After stirring for 15 minutes the mixture was cooled to 23° C. and filtered to remove the solid (sodium bicarbonate, sodium chloride). A part of the toluene (17.07 g) was removed by distillation in vacuo (end of distillation: 28° C., 7 mbar).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH3:30][C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[CH3:23][C:19]([N:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:3]=[C:2]([N:32]2[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=[C:31]2[CH3:30])[N:10]=3)[CH2:18][CH2:17]1)([CH3:22])[CH2:20][OH:21]
Reactant: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropan-1-ol and 2-methyl-1H-benzo[d]imidazole were reacted to give 264. LCMS m/z: 520.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[N:3]=1.[C:27]([O:31][C:32]([NH:34][CH:35]([CH3:39])[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:36](=[O:37])[C@@H:35]([NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH3:39])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[N:3]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(CO)cc2)nc(N)n1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc2)nc(N)n1

Procedure:
(S)-2-tert-Butoxycarbonylamino-propionic acid 4-[2-amino-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzyl ester was prepared according to the method described for Example 64 by using the title compound of Example 44 and 2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: C(OC(=O)C)(=O)C.[F:8][C:9]1[CH:10]=[C:11]([CH:16](O)[CH2:17][N+:18]([O-:20])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1.C(O)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][N+:18]([O-:20])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: O=[N+]([O-])CC(O)c1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1cc(F)cc(F)c1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Add acetic anhydride (160 mL) to a solution of 1-(3,5-difluorophenyl)-2-nitroethanol (330 g) and 4-dimethylaminopyridine (18 g) in dichloromethane (1000 mL), at room temperature using a water bath to keep the temperature below 35° C. Add acetic acid over 30 min and stir the reaction mixture overnight. Dilute with dichloromethane (660 mL) and wash with 2% aqueous HCl, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, dry (magnesium sulfate) and concentrate. Wash the crude with hexanes to give the title compound (220 g).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[C:20]([NH2:25])[N:19]=[CH:18]4)=[C:13]([CH3:26])[CH:12]=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:25][C:20]1[N:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([C:14]3[C:9](=[O:8])[NH:10][CH:11]=[CH:12][C:13]=3[CH3:26])[CH:16]=2)[N:21]=1
Reactant: COc1ccc(COc2nccc(C)c2-c2ccc3nc(N)ncc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc[nH]c(=O)c1-c1ccc2nc(N)ncc2c1

Procedure:
To a solution of 6-(2-(4-methoxybenzyloxy)-4-methylpyridin-3-yl)quinazolin-2-amine (0.650 g, 1.75 mmol) in CH2Cl2 (1 mL) at RT was added TFA (1.00 ml, 13.0 mmol). After 10 min the solvent and excess acid was removed in vacuo. The residue was taken up in EtOAc and saturated NaHCO3 was added. The resulting white precipitate was removed by filtration. The solid material, 3-(2-aminoquinazolin-6-yl)-4-methylpyridin-2(1H)-one, was dried in vacuo and used without further purification. M+H+=253.1.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:12]1[CH:17]=[C:16]([C:18]([CH3:26])([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]=1[OH:27])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N+:38]#[N:39])([O-:31])=[O:30].Cl>CO.C(O)(=O)C.O>[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[N:39][C:14]1[CH:15]=[C:16]([C:18]([CH3:26])([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[C:12]([C:4]([CH3:3])([CH3:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:13]=1[OH:27])([O-:31])=[O:30]
Reactant: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Reactant: N#[N+]c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(c1ccccc1)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Temperature: -4 °C

Procedure:
To a 500-ml 3-necked flask fitted with a stirrer, thermometer, pressure equalized addition funnel and nitrogen inlets and outlets were charged 13.5 grams (0.21 mole) of potassium hydroxide pellets and 10 ml of water. The resulting hot solution was diluted with 80 ml of methanol. After flushing with nitrogen, 16.5 grams (0.05 mole) of 2,4-di-(α,α-dimethylbenzyl)phenol and 85 ml of methanol were added to give a clear solution which was then cooled to -4° C. A cold solution of o-nitrobenzenediazonium chloride in concentrated hydrochloric acid solution (42.9 grams=0.06 mole of diazonium solution) was added over a period of 15 minutes with rapid stirring while keeping the temperature between -2° and 0° C. The deep purple color of the azodye-phenoxide developed instantaneously as the diazonium solution was added. The resulting mixture was stirred for another 10 minutes at -1° to 1° C. The suspension was then acidified with 20 ml of glacial acetic acid over a 2-minute period at 1° to 3° C. The resulting brick red suspension was stirred for 15 minutes as the temperature was allowed to rise to ambient temperature and then filtered. The filter cake was washed with a cold solution of 40 grams ice in 160 ml of methanol and then with 1800 ml of water.
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Br:49])[CH:44]=2)[C:37]1=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.B>>[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Br:49])[CH:44]=2)[CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1C(Cc2cccc(Br)c2)OCCN1Cc1ccccc1
Agent: B
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Product: Brc1cccc(CC2CN(Cc3ccccc3)CCO2)c1

Procedure:
N-Benzyl-2-(3-bromobenzyl)-morpholine was prepared as described for example 71, intermediate (a), but using N-benzyl-2-(3-bromobenzyl)-morpholin-3-one and borane and was isolated as a pale yellow oil.