Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:6]=2[C:5]1=[O:23])[CH:2]=[CH2:3].C12BC(CCC1)CCC2.C1C[O:36]CC1>>[OH:36][CH2:3][CH2:2][CH2:1][N:4]1[CH2:10][CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:6]=2[C:5]1=[O:23]
Reactant: C1CCOC1
Reactant: C=CCN1CC(Cc2ccccc2)Oc2ccc(I)cc2C1=O
Agent: B1C2CCCC1CCC2
Product: O=C1c2cc(I)ccc2OC(Cc2ccccc2)CN1CCCO
Reaction time: 1 h
Yield: 77 %

Procedure:
To a magnetically stirred solution of 2-allyl-4benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one (0.9234 grams, 2.2 mmol) in 4 mL THF at room temperature under an atmosphere of nitrogen was added 6.0 mL of a 0.5M solution of 9-borabicylo[3.3.1]nonane in THF (3 mmol) and the mixture stirred for 1 hour. The reaction was quenched with 6 mL, of a solution of 2 grams of sodium hydroxide and 22 mL of a 1:1 mixture of ethanol and water. To the resulting solution was added 7 mL of a 30% solution hydrogen peroxide in water. After 30 minutes the mixture was partitioned between diethyl ether and water. The organic layer was washed with 10% citric acid and brine, dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (SiO2, using 1:5 ethyl acetate/methylene chloride as the eluting solvent, Rf (product)=0.22) to yield 0.74 grams (77%) of 2-(3-hydroxypropyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one. 1H NMR (CDCl3, dTMS) 8.08 (1H, d, 4JHH =2 Hz, C9-H), 7.71 (1H, dd, 4JHH =2 Hz, 3JHH =8 Hz, C7-H), 7.4-7.2 (5H, m, C6H5), 6.78 (1H, d, 3JHH =8 Hz, C6-H), 4.64 (1H, m, ArOCH), 3.70 (2H, m, CH2OH), 3.58 (2H, bt, 3JHH =5 Hz, NCH2CH2), 3.39 (1H, dd, 2JHH =15 Hz, 3JHH =8 Hz, C3-H), 3.24 (1H, dd, 2JHH =15 Hz, 3JHH =3 Hz, C3-H), 3.1 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, CHHPh), 2.76 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, CHHPh), 1.68 (2H, m, CH2CH2OH). 13C NMR (CDCl3) 168.3, 152.6, 141.6, 139.4, 136.2, 132.1, 131.9, 129.2, 129.0, 128.8, 128.4, 127.0, 124.7, 86.8, 85.7, 58.0, 49.9, 44.5, 38.8, 30.3, IR (NaCl, cm-1) 3422 (b), 1636, 1463, 1436, 1217, 1064.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)[C:7]([F:19])=[C:6]([I:20])[C:3]=1[C:4]#[N:5].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO.O>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:8]3[C:7]([F:19])=[C:6]([I:20])[C:3]([C:4]#[N:5])=[C:2]([NH:30][C@H:28]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)[CH3:29])[N:9]=3)[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: N#Cc1c(Cl)nc(Nc2cc(C3CC3)[nH]n2)c(F)c1I
Solvent: O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)c(I)c1C#N)c1ccc(F)cc1
Yield: 20 %

Procedure:
A solution of 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-4-iodonicotinonitrile (Method 39, 0.28 g, 0.69 mmol), (S)-1-(4-fluorophenyl)ethanamine (0.19 g, 1.3 mmol), and DIEA (0.11 g, 0.90 mmol) in n-BuOH (1 ml) was heated to 140° C. for 18 hours. The reaction was diluted with water (10 ml), extracted with DCM (2×20 ml) and the combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.07 g, 20%). MS: Calcd.: 506. Found: [M+H]+ 507.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]([CH3:37])[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CN(C=O)C>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([N:34]4[CH2:35][CH2:36][CH:31]([N:30]([CH3:37])[CH3:29])[CH2:32][CH2:33]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: CN(C)C1CCNCC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (50.0 mg, 0.102 mmol, prepared in Example 7, step B), N,N-dimethylpiperidin-4-amine (39.2 mg, 0.306 mmol), copper(I)iodide (3.88 mg, 0.0204 mmol), (S)-pyrrolidine-2-carboxylic acid (4.70 mg, 0.0408 mmol), K2CO3 (70.5 mg, 0.510 mmol) and DMF (10 mL). The reaction mixture was stirred at 100° C. overnight. Then the reaction was cooled to room temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (35.8 mg, 71.6%). LRMS (APCI pos): >98% purity, 254 nm, m/e 491 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[NH:32]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:33]([C:49](ON1C(=O)CCC1=O)=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C(#N)C.O>[NH:32]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:33]([C:49]([NH:1][C@H:2]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
H-Glu(OBzl)OBzl (2.0 g) was dissolved in a mixture of acetonitrile (50 ml) and water (10 ml). The solution was cooled to 0° C. and triethylamine (400 mg) and Boc-Lys(Z)OSu (1.91 g) were added. The mixture was stirred at 0°-5° C. for 2 hours and at room temperature for 3 hours. The solvent was distilled off and the residue was poured into a mixture of ethyl acetate (100 ml) and 2.5% hydrochloric acid. The organic layer was washed with water (50 ml×2), 2.5% sodium hydrogen carbonate (50 ml) and water (50 ml×3) in that order and dried over magnesium sulfate. The solvent was then distilled off to give Boc-Lys(Z)-Glu(OBzl)OBzl (2.70 g).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:37])[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][N+:16]([CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:8][C:9]=2[O:30][CH3:31])[O:4]1.[BH4-].[Na+]>C(O)C.O.C(OCC)C>[CH3:2][C:3]1([CH3:37])[CH2:12][CH:11]([C:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[CH2:15][CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:8][C:9]=2[O:30][CH3:31])[O:4]1
Reactant: CCCCCc1cc(OC)c2c(c1)OC(C)(C)CC2c1cc[n+](Cc2ccc3ccccc3c2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCCCCc1cc(OC)c2c(c1)OC(C)(C)CC2C1=CCN(Cc2ccc3ccccc3c2)CC1
Reaction time: 0.5 h

Procedure:
This pyridinium bromide (5.86g.) was dissolved in a mixture of ethanol (70 ml.) and water (23 ml.) and sodium borohydride (0.74g.) was added portionwise to the stirred solution at ambient temperature. At the end of the addition, the solution was stirred for a further 0.5 hours and was then diluted with diethyl ether (300 ml.) and water (300 ml.). The organic layer was separated, dried over anhydrous potassium carbonate and evaporated under reduced pressure. The residual amber gum (4.96g.) was purified via column chromatography on silica gel using 60°-80° petroleum ether/ethyl acetate mixtures as eluent to give 2,2-Dimethyl-5-methoxy-4-[1-(2-naphthylmethyl)-1,2,5,6-tetrahydropyrid-4-yl]-7-n-pentylchroman as an orange oil (2.70g.).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)[C:3]([O:5][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)Cc1ccc(C(O)C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C(O)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 2-hydroxy-2-(4-isobutylphenyl)acetic acid (3.8 g) in N,N-dimethylformamide (30 ml) was added potassium carbonate (7.6 g) and benzylbromide (2.2 ml). The mixture was stirred at room temperature for 4.5 hours and poured into ice water and 7% hydrochloric acid. The organic layer was extracted with ethyl acetate, washed with aqueous sodium bircarbonate solution and water, dried over magnesium sulfate and evaporated. The residual white powder was collected with n-hexane by filtration to give benzyl 2-hydroxy-2-(4-isobutylphenyl)acetate as a white powder (4.42 g).
Reaction SMILES: [CH3:1][C:2]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])([CH2:6][CH2:7][O:8][CH3:9])[CH2:3][C:4]#[CH:5].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:27]([SnH:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>>[CH2:36]([Sn:31]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])/[CH:5]=[CH:4]/[CH2:3][C:2]([CH3:1])([O:10][Si:11]([CH3:14])([CH3:12])[CH3:13])[CH2:6][CH2:7][O:8][CH3:9])[CH2:37][CH2:38][CH3:39]
Reactant: C#CCC(C)(CCOC)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/CC(C)(CCOC)O[Si](C)(C)C)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 15 g. (0.069 moles) of 4-methyl-4-trimethylsilyloxy-7-oxa-1-octyne and 75 mg. of azobisisobutyronitrile is added dropwise, under nitrogen atmosphere, 21.1 g. (0.073 moles) of tri-n-butyltin hydride. The solution is stirred at 130°-135° C. for 11/2 hours, then cooled to ambient temperature. Distillation provides 29 g. (86%) of product as a colorless oil; b.p. 165°-167° C. (0.25 mm.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([F:27])([F:26])C(C1C=CC=CC=1)=O>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:17]([F:27])[F:26])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1cc(OC(F)F)ccc1Br
Temperature: 80 °C
Yield: 78.3 %

Procedure:
To a solution of 4-bromo-3-fluoro-phenol (962 mg, 5.037 mmol) in acetonitrile (25 mL) was added a solution of potassium carbonate (28.3 g, 181 mmol) dissolved in water (25 mL) all under nitrogen. To the reaction mixture was added 2-chloro-2,2-difluoroacetophenone (5 g, 25 mmol) and the reaction was heated to 80° C. for 4 hours. The reaction was cooled to room temperature and extracted with ethyl acetate (3×50 mL). The organic layer was dried with sodium sulfate, filtered and concentrated onto silica gel. Silica gel chromotography (5% ethyl acetate 95% heptane to 100% ethyl acetate over 55 minutes) furnished a clear oil (950 mg, 78%). LCMS m/z 531.7 (M−1)1H NMR (400 MHz, METHANOL-d4) δ ppm 6.85 (s, 1H) 6.92 (dd, J=8.88, 2.63 Hz, 1H) 7.05 (t, 1H) 7.38 (t, 1H)
Reaction SMILES: C([O:5][C:6](=[O:27])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(C)(C)C.C(OC(=O)N[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=CC(O)=CC=2)[CH:36]1[CH2:46]C1C=CC(Cl)=C(Cl)C=1)(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)OCC1C=CC=CC=1>CN(C)C=O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=3)[CH2:16][CH2:17][CH:8]2[NH:7][C:6](=[O:27])[O:5][CH2:46][C:36]2[CH:37]=[CH:42][CH:43]=[CH:44][CH:35]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)cc1
Agent: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)cc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
tert-Butyl[1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (2 g, 6.95 mmol, prepared analogously to tert-butyl[1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate, cf. example 34.2 were suspended in dimethylformamide (40 mL). Triethylamine (0.969 mL, 6.95 mmol) and benzyl carbonochloridate (1.186 g, 6.95 mmol) were added. The reaction mixture was stirred at room temperature over night. The solvent was evaporated in vacuo. To the crude product ethyl acetate and water were added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 393 mg (0.931 mmol, 13.4%, colorless foam).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[N:7][CH:8]=3)[N:3]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc2cnccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc2cnccc2n1)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 19.1 %

Procedure:
2-Amino-1,6-naphthyridine (200 mg, Production Example 25b) was dissolved in dichloromethane (6.0 ml), to which were then added triethylamine (0.20 ml) and 4-chlorobenzenesulfonyl chloride (0.31 g), followed by stirring at 40° C. for 1.5 hours. An aqueous saturated sodium bicarbonate was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column, to give the title compound (84 mg, 21.44%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([Br:25])=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([Br:25])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 72.2 %

Procedure:
A flask was charged with 2,4-bis-benzyloxy-5-bromobenzyl alcohol (10.5 g; 26 mmol), manganese dioxide (45 g; 0.520 mol), and dichloromethane (250 mL). The reaction was stirred at reflux for three days. The slurry was then filtered through celite, and evaporated to give 2,4-bis-benzyloxy-5-bromobenzaldehyde (7.46 g; 18.77 mmol).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:10]=2)[C:5]1=[O:20]>C(O)(=O)C>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:10]=2)[C:5](=[O:20])[N:4]([CH3:3])[CH:13]=1
Reactant: Cn1ccc2cc(-c3ccccn3)ccc2c1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1cc(Br)c2cc(-c3ccccn3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
At 0° C., bromine (78 mg, 0.49 mmol) in acetic acid (0.3 mL) was added dropwise to 2-methyl-6-pyridin-2-ylisoquinolin-1-one (115 mg, 0.49 mmol) in acetic acid (20 mL). The mixture was stirred at room temperature for 20 min. Extractive work up with CH2Cl2 and purification by silica gel chromatography (PE:EA=5:1˜1:1) gave the title compound (73.0 mg, 47.7%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.79 (d, J=4.4 Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.44 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.85 (t, J=7.2 Hz, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 1H), 3.64 (s, 3H). LCMS: 314.9 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCc1ccccn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccn1
Yield: 35.5 %

Procedure:
Using an analogous procedure to that described in Example 38, 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1 mmol), (prepared as described for the starting material in Example 24), was reacted with 2-(chloromethyl)pyridine hydrochloride (310 mg, 1.9 mmol) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-pyridyl)methoxy)quinazoline (146 mg, 33%).
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH2:6][CH2:5][N:4]1[CH3:18]>[Pd].CO>[F:1][CH2:2][CH:3]1[N:4]([CH3:18])[CH2:5][CH2:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][CH:10]=2)[CH2:8]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1CF
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(N)nc2)CC1CF
Reaction time: 15 h

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 111e (2.6 g, 10.2 mmol) and MeOH (50 mL), and the resulting mixture was added Pd/C (10%) (260 mg). The reaction mixture was stirred under H2 for 15 h. After the reaction was finished, it was filtered and concentrated to afford 111f, which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClC(Cl)C.ClCCl>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:15]=[CH:16][C:17]([CH2:20][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]3[CH2:10][C@H:9]3[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A suspension of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.28 g, 1.58 mmol) and 4-biphenylcarbaldehyde (0.32 g, 1.74 mmol) in dichloroethane (20 mL) were heated to reflux until a clear solution formed. The solution was cooled to RT then NaB(OAc)3H (0.50 g, 2.37 mmol) was added and stirred for 2 h. Water (50 mL) and dichloromethane (50 mL) were added and the organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material was purified on silica gel eluting with an increasing gradient from hexanes to 40% ethyl acetate/hexanes to give the title compound as a white solid (0.33 g, 61%). 1H NMR (400 MHz, DMSO) δ 12.15 (s, 1H), 7.65-7.59 (m, 4H), 7.46-7.41 (m, 4H), 7.34 (t, J=7.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.51 (d, J=8.4 Hz, 2H), 6.22 (s, 1H), 4.29 (s, 2H), 2.23-2.18 (m, 1H), 1.62-1.57 (m, 1H), 1.32-1.28 (m, 1H), 1.21-1.16 (m, 1H). ES-MS m/z 344.2 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH:9]=O)[CH2:3][CH2:2]1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1.[Ni]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:3][CH2:2]1
Reactant: O=CCCN1CCOCC1
Reactant: C1CCNC1
Agent: [Ni]
Solvent: C1COCCO1
Product: C1CCN(CCCN2CCOCC2)C1

Procedure:
143 g (1 mol) of 3-morpholinopropionaldehyde in 143 g of dioxane are pumped into 71 g (1 mol) of pyrrolidine and 40 g of Raney nickel at 120° C. and hydrogenated at 160 bar. The reaction mixture is suction filtered, concentrated by evaporation and distilled. B.p. 0.1 : 82° C., purity according to gas chromatogram: 94.5%. Yield: 51 g; molar mass found: 196 v. the molecular weight calculated for C11H22N2O: 198.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[OH:10].I[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[O:10][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: COc1cccc(F)c1O
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(F)c1Oc1cccc([N+](=O)[O-])c1
Temperature: 98 °C
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
To a 250 mL pressure resistant vial which contained a mixture of 2-fluoro-6-methoxy-phenol (1000 mg, 7 mmole), 1-iodo-3-nitro-benzene (2500 mg, 10 mmole), Cs2CO3 (1200 mg, 7 mmole) and N,N-dimethylglycine.HCl (200 mg, 1.5 mmole) in dioxane (40 mL) was added CuI (140 mg, 0.7 mmole) at rt. The reaction mixture was bumbled with Ar for 5 min at rt and then the vial was sealed. The reaction mixture was stirred and heated to 98° C. for 5 d. After cooling to rt, the reaction mixture was poured into 250 mL ice-water which was extracted with ethyl acetate (3×50 mL), washed with water (2×50 mL), brine (50 mL) and dried over Na2SO4. After removal of solvent, the residue was purified by silica gel column chromatography with ethyl acetate/hexane as eluent to give 1450 mg (75% yield) of product (10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](SC)=[N:7][C:6]=2[CH:17]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[N:7][C:6]=2[CH:17]=1
Reactant: CN1CCNCC1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2cscc21
Solvent: CC(=O)O
Product: CN1CCN(C2=Nc3cc(Cl)ccc3Nc3cscc32)CC1

Procedure:
A solution of 0.9 g. of 7-chloro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in 4.5 ml. of N-methylpiperazine is treated with 2-3 drops of glacial acetic acid and heated under reflux for 4 days. The solution is concentrated to dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled and made alkaline with concentrated ammonium hydroxide. The sticky precipitate is collected and dissolved in chloroform. The dried chloroform solution is concentrated under reduced pressure to give 7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine as an oil. An ethanolic solution of the oil is treated with 70% perchloric acid and diluted with water. The precipitate is recrystallized from methanol to give yellow crystals, m.p. 268°-270° C. (dec.).