Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.CS(O)(=O)=O.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:23]3[CH:24]=[CH:25][C:20]([OH:26])=[CH:21][CH:22]=3)([C:23]3[CH:24]=[CH:25][C:20]([OH:26])=[CH:21][CH:22]=3)[C:4]=2[CH:3]=1
Reactant: Oc1ccccc1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Agent: CS(=O)(=O)O
Solvent: O
Product: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccc(Br)cc32)cc1
Temperature: 150 °C
Reaction time: 24 h
Yield: 68.5 %

Procedure:
10 g of 2-bromofluorene, 2 equivalents of methane sulfonic acid and 100 g of phenol were placed into a 500 ml round-bottom flask, followed by stirring at 150° C. for 24 hours. The reaction solution was cooled and then mixed with water to filter solids. The solids were then recrystallized in toluene, to yield 12 g of (2-bromo-9,9-di(4-hydroxyphenyl)fluorene) (5).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13](C4C=CC(C=O)=CC=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(Cl)Cl.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH:35]1[CH3:40])[CH3:33].[BH4-].[Na+]>CC(O)=O>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:10]2[C:11]3[C:2](=[O:1])[NH:3][N:4]=[C:5]4[CH:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:13][NH:12][C:7]([C:6]=34)=[CH:8][CH:9]=2)[CH2:36][CH:35]1[CH3:40])[CH3:33]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CCN1CCNCC1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN1CCN(Cc2ccccc2-c2ccc3c4c(n[nH]c(=O)c24)C(c2ccccc2)CN3)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 163.2 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (86 mg, 0.23 mmol) in dryness DCM (15 mL) was added HOAc followed by 1-ethyl-2-methylpiperazine (90 mg, 0.7 mmol), after the addition the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. Sodium borohydride (85 mg, 1.4 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound as white solid (90 mg, yield 71%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 (t, 3H), 1.42 (m, 3H), 3.23 (s, 1H), 3.47-3.56 (m, 6H), 3.80 (t, 2H), 4.46 (m, 3H) 4.91 (m, 10H), 7.20-7.29 (m, 3H), 7.30-7.32 (m, 3H), 7.46-7.48 (m, 3H), 7.59 (m, 1H), 7.69 (t, 1H). LC-MS (ESI) 552 (M+1)+.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]2([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:4]=1)=[O:2].CC(=CC)C.P([O-])(O)(O)=[O:33].[Na+].Cl([O-])=O.[Na+]>CC(O)(C)C.O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]([C:5]2[CH:4]=[C:3]([C:1]([OH:33])=[O:2])[C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)([OH:26])[CH2:14][CH2:15]1)=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C=O)c3ccccc3c2)CC1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(=O)O)c3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5 g (4.2 mmol) of tert-butyl 4-(4-formyl-2-naphthyl)-4-hydroxypiperidine-1-carboxylate in 25 mL of 2-methyl-2-propanol was added 2.3 mL (21 mmol) of 2-methyl-2-butene followed by dropwise addition of a solution of 1.00 g (8.45 mmol) of sodium dihydrogen phosphate and 877 mg (59.7 mmol) of sodium chlorite in 15 mL of water. The resulting mixture was stirred at ambient temperature for 2 h then evaporated in vacuo to remove all volatiles. The residue was diluted with water (5 mL) and an aqueous 2 N HCl solution was then added dropwise to the stirred mixture until a pH of 4 was achieved. The aqueous phase was then extracted with ethyl acetate (3×5 mL) and the combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the crude title compound as a colorless oil. LC/MS 394.2 (M+23).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C@H:14]2[N:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1.O.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25](B2OC(C)(C)C(C)(C)O2)[C:24]([CH3:37])=[N:23]1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][N:17]([CH3:19])[C@H:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:25]3[C:24]([CH3:37])=[N:23][N:22]([CH3:21])[C:26]=3[CH3:27])[CH:16]=2)[CH2:12][CH2:13]1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)[C@@H]1CCc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)[C@H](N(C)C)CC2
Temperature: 85 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
(Method 1): To a solution of K2CO3 (1.9 mmol) and (R)-(6-bromo-indan-1-yl)-dimethyl-amine (1 mmol) in 1,2-dimethoxyethane (8.8 mL)/water (1.2 mL) was added Pd(PPh3)4 (0.1 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (1.2 mmol). The reaction mixture was degassed and stirred at 85° C. for 6 h. The solvent was evaporated, crude was redissolved in dichloromethane and filtered through a pad of Celite. The filtrate was extracted with 6M HCl (3×0.16 mL). The aqueous layer was basified with 6M NaOH to pH 13 and extracted with dichloromethane. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crude was purified by flash chromatography (CH2Cl2-MeOH-NEt3 as eluents) to yield (1R)-dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine as an oil (52% yield). Product was obtained with a final ee of 99.6% (determined by chiral HPLC).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CSC>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(Br)ccc1I
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1I
Temperature: 65 °C
Yield: 96.1 %

Procedure:
To a stirred mixture of acid 2-iodo-5-bromobenzoic acid (15.0 g, 45.9 mmol) in dry THF (100 mL) under argon was added neat BH3.DMS (16.0 mL, 169 mmol) dropwise over 20 minutes. The resulting mixture was heated at 65° C. for 8 hours, cooled to room temperature and quenched by the dropwise addition of water (40 mL). The reaction mixture was concentrated in vacuo. The crude alcohol was diluted with of EtOAc (300 mL), washed with 1N NaOH (2×30 mL), 1N HCl (1×30 mL), saturated aqueous NaHCO3 solution (1×30 mL) and brine (1×30 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo to give 2-iodo-5-bromobenzyl alcohol (13.8 g, 96%). 1H NMR (CDCl3): δ 7.56 (d, 1H, J=8.25 Hz), 7.54 (s, 1H), 7.04 (d, 1H, J=8.25 Hz), 4.47 (s, 2H). HPLC: Rt=3.12 min. m/z=312 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CN(C=O)C>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:6][C:5]3[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=3)[C:1]#[N:2])=[N:19]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Yield: 82.9 %

Procedure:
Under the protection by nitrogen, meta-cyanobenzaldehyde (137.6 g, 1.05 mol), 7-chloroquinaldine (177 g, 1.0 mol) and sodium acetate (82 g) are added into 200 ml of acetic anhydride and 800 ml of dimethyl fomamide (DMF), and the resulted mixture solution is stirred and heated to reflux for 24 hours. After distilling the most solvent, 300 ml of water is added into the residue, and then extracted by ethyl acetate (500 ml×3), washed with saturated saline water, dried with anhydrous sodium sulfate and condensed in the vacuum. The resulted residue is then purified through Flash Column Chromatography to obtain 241 g of the title compound, with a yield of 83%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1.O[C:28]1[CH:29]=[CH:30][C:31]2[CH2:37][CH2:36][CH2:35][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:33][C:32]=2[CH:42]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:20]1[CH2:25][CH2:24][CH:23]([O:26][C:28]2[CH:29]=[CH:30][C:31]3[CH2:37][CH2:36][CH2:35][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:33][C:32]=3[CH:42]=2)[CH2:22][CH2:21]1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(OC3CCOCC3)ccc2CCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94 %

Procedure:
To triphenylphosphine (1.18 g, 4.50 mmol), tetrahydropyran-4-ol (0.429 g, 4.50 mmol) and methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in THF (10 ml) was added at 0° C. a solution of diisopropyl azodicarboxylate (0.886 ml, 4.50 mmol) in THF (2 ml), and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography (silica gel: 45 g, ethyl acetate/hexane=1/25). The objective fractions were concentrated under reduced pressure to obtain methyl 2-[(tetrahydropyran-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (427 mg, 1.41 mmol, 94%).
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1>[Pd].COCCOCCOC>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1cc(C)c2c(c1)-c1c(nc(N)[nH]c1=O)CC2
Agent: [Pd]
Solvent: COCCOCCOC
Product: Cc1cc(C)c2ccc3nc(N)[nH]c(=O)c3c2c1

Procedure:
A mixture of 3-amino-5,6-dihydro-7,9-dimethylbenzo[f]quinazolin-1(2H)one (0.25 g, 1.04 mmole) and 10% palladium on carbon (0.5 g) in diglyme (25 ml) was vigorously stirred and refluxed under a nitrogen atmosphere for 2.5 hours, and then filtered while still hot through a bed of celite. Diglyme was removed from the filtrate under reduced pressure, and the residue was triturated with hot methanol, filtered, washed with methanol and ether, and dried to give 3-amino-7,9-dimethylbenzo[f]quinazolin-1(2H)-one as an off-white solid. (0.14 g, 55%) 1H NMR(DMSO-d6, 200 MHz) δ: 2.43(s, 3H, CH3); 2.60(s, 3H, CH3); 6.48(s, 2H, NH2); 7.14(s, 1H, Ar); 7.25(d, J=9.2 Hz, 1H, Ar); 8.11(d, J=9.1 Hz, 1H, Ar); 9.38(s, 1H, Ar); 11.07(s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(Cc2ccc(Cl)nc2)CC1
Yield: 74 %

Procedure:
To a suspension of 2-chloro-5-(chloromethyl)pyridine (971 mg, 5.99 mmol) in acetonitrile (50 mL) was added a solution of N-methylpiperazine (1.20 g, 12.0 mmol) in acetonitrile (3 mL) followed by potassium carbonate (0.83 g, 5.99 mmol). The obtained yellow solution was heated at reflux for 40 min. The mixture was allowed to cool for 10 min and the solvent was removed in vacuo. The residue was partitioned between water, NaCl (s), and ethyl acetate. The aqueous layer was extracted with another portion of ethyl acetate. The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo affording 1.0 g (74% yield) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.31 (d, J=2 Hz, 1 H), 7.65 (dd, J=8, 2 Hz, 1 H), 7.29 (d, J=8 Hz, 1 H), 3.49 (s, 2 H), 2.46 (br s, 8 H), 2.28 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 150.2, 150.1, 139.5, 132.8, 124.0, 59.2, 55.0, 53.0,46.0; MS (ESP) m/z 226 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([CH2:11][C:12]#[N:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1>C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:11]=[C:12]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:13]=[C:7]2[OH:9])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cc(CC#N)c(C(=O)O)cc1Br
Solvent: CC(=O)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1Br

Procedure:
Similar procedure as described in example 9B was used, starting from 5-Bromo-2-cyanomethyl-4-methoxy-benzoic acid, 3-amino-5-methylpyrazol and acetic acid to give 7-Bromo-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol. LC-MS: m/e 349 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([N:12]([CH3:51])[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C@H:22]1[CH2:29][N:28]2[C:30]3[CH:31]=[C:32]([C:43]([O:45]C)=[O:44])[CH:33]=[CH:34][C:35]=3[C:36]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:27]2[C:26]2[CH:47]=[CH:48][CH:49]=[CH:50][C:25]=2[O:24][CH2:23]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][S:9]([N:12]([CH3:51])[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C@H:22]1[CH2:29][N:28]2[C:30]3[CH:31]=[C:32]([C:43]([OH:45])=[O:44])[CH:33]=[CH:34][C:35]=3[C:36]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:27]2[C:26]2[CH:47]=[CH:48][CH:49]=[CH:50][C:25]=2[O:24][CH2:23]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1CCN(C)S(=O)(=O)NC(=O)OC(C)(C)C)COc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCN1CCCC1CO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of methyl (7S)-7-[(1-{2-[{[(tert-butoxycarbonyl)amino]sulfonyl}(methyl)amino]ethyl}pyrrolidin-2-yl)methoxy]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (7 mM) in MeOH was treated with 2 N NaOH (10 eq). The mixture was stirred at 60° C. for 3 h. MeOH was eliminated in vacuo, the residue was dissolved in EtOAc and neutralized by adding 6 N HCl. The aqueous was extracted with EtOAc and the organics combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product. The material was taken on without further purification. (ES+) m/z 711 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:21][CH2:22][CH2:23][OH:24])[CH2:19][OH:20]>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:8][N:21]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:19][OH:20])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Reactant: OCCNCCO
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(CN(CCO)CCO)cc(C(C)(C)C)c1O
Temperature: 77.5 °C
Reaction time: 6 h

Procedure:
In a round bottom flask taken 2.24 gm of 3,5-ditertbutyl-4-hydroxy benzyl bromide and 0.6 ml of N, N-diethanol amine and dissolved in 100 mL of benzene. The reaction mixture was refluxed with constant stirring at 75-80° C. for 6 hrs. The product was crystallized out in the form of colorless needles. The solvent was decanted, crystals were filtered off and washed with pure benzene. The yield of the product is 1.43 gm (64%). Product was identified by 1H-NMR and FT-IR spectroscopic techniques.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH:15]2C2C=CC=CC=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1(C2C3C(=CC=CC=3)C(=O)C2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:1]([N:8]1[C:12]([CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:15]2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=C1c2ccccc2CC1c1ccccc1)c1cncn1Cc1ccccc1
Reactant: O=C1CC(C2CCCCC2)c2ccccc21
Product: C(=C1CC(C2CCCCC2)c2ccccc21)c1cncn1Cc1ccccc1

Procedure:
1-Benzyl-5-(3-cyclohexylindan-1-ylidenemethyl)-1H-imidazole was prepared as 1-benzyl-5-(2-phenylindan-1-ylidenemethyl)-1H-imidazole above except that 3-cyclo-hexylindan-1-one was used as a starting material. The crude product as its hydro-chloride salt was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: Nc1ccc2c(c1)CCN(C[C@@H](O)C(F)(F)F)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCN(C[C@@H](O)C(F)(F)F)CC3)ncc1Cl

Procedure:
(R)-3-{7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-1,1,1-trifluoro-propan-2-ol was prepared from (R)-3-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 328. Product isolated as a white solid (85 mg, 52%). m.p.=174-175° C.; LCMS (m/e) 593 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.24 (d, 1H, J=8.7 Hz), 8.03 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.32-7.26 (m, 1H), 7.04 (d, 1H, J=8.1 Hz), 6.87 (s, 1H), 6.57 (s, 1H), 6.51 (d, 1H, J=8.7 Hz), 4.50-4.32 (m, 1H), 4.10-4.00 (m, 1H), 3.94 (s, 3H), 3.93-3.89 (m, 4H), 3.21-3.15 (m, 4H), 2.97-2.79 (m, 7H), 2.77-2.67 (m, 3H).
Reaction SMILES: C([O:8][N:9]1[CH:12]([CH2:13][O:14]CC2C=CC=CC=2)[CH:11]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]1=[O:40])C1C=CC=CC=1.[H][H]>CO.[Ni]>[OH:8][N:9]1[CH:12]([CH2:13][OH:14])[CH:11]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]1=[O:40]
Reactant: [H][H]
Reactant: O=C(Nc1ncnc2c1ncn2C1C(=O)N(OCc2ccccc2)C1COCc1ccccc1)c1ccccc1
Agent: [Ni]
Solvent: CO
Product: O=C(Nc1ncnc2c1ncn2C1C(=O)N(O)C1CO)c1ccccc1

Procedure:
1-N-Benzyloxy-3-(N-benzoyladenin-9-yl)-4-benzyloxymethyl-2-azetidinone (10 mmole) is taken up in methanol (50 ml) and hydrogenated using Raney nickel (5 g) and hydrogen at a pressure of 40 psi for 6 hours. The reaction mixture is filtered, the catalyst washed with methanol (20 ml) and the combined methanol fractions are concentrated to give the title compound as a solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Na+].[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12]>CN(C)C=O>[N+:11]([CH:14]([CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:1]([O:8][CH3:9])=[O:7])[CH3:15])([O-:13])=[O:12]
Reactant: CC[N+](=O)[O-]
Reactant: COC(=O)/C=C\C(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)O)C(C)[N+](=O)[O-]
Temperature: 60 °C

Procedure:
Into a 100 ml, one neck flask is placed 10 grams of sodium methyl maleate, 60 mls N,N-dimethyl formamide (DMF) and 40 grams nitroethane. The solution is heated at 60° C. for two hours and then partially distilled in vacuo to remove the DMF and nitroethane. The residue, by NMR analysis (D2O), has the following structure: ##STR39## CH2 (b) multiplet, 2.5-2.72δ
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])=[CH:4][C:3]=2[O:2]1.C(OCC)(=O)[CH2:17][C:18](OCC)=[O:19]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:11]3[CH2:17][C:18](=[O:19])[CH:14]=[C:13]([OH:15])[CH2:12]3)=[CH:4][C:3]=2[O:2]1
Reactant: CC(=O)C=Cc1ccc2c(c1)OCCO2
Reactant: CCOC(=O)CC(=O)OCC
Product: O=C1C=C(O)CC(c2ccc3c(c2)OCCO3)C1

Procedure:
5-(3,4-Ethylenedioxyphenyl)-3-hydroxycyclohex-2-en-1-one was prepared from 1-(3,4-ethylenedioxyphenyl)but-1-en-3-one and diethyl malonate following essentially the same procedure as that described in Example 1 part (ii). The product was obtained as a crystalline solid, mp 188° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:33])=[O:32]>C(#N)C.C(N(CC)C(C)C)(C)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:30][CH:28]([C:25]4[CH:26]=[CH:27][C:22]([CH3:21])=[C:23]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=4)[CH3:29])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(C(C)N)cc1S(C)(=O)=O
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc(C)c(S(C)(=O)=O)c4)c3C2)c(C#N)c1
Yield: 49.9 %

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (360 mg, 1.26 mmol) and 1-(4-methyl-3-(methylsulfonyl)phenyl)ethanamine (400 mg, 1.88 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (1 mL) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid (290 mg).
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:29])([F:28])[F:27])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16]C(=O)C3C=CC(Cl)=CN=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1.Cl[C:31]1[N:32]=[CH:33][C:34]([F:43])=[C:35]2[C:40]=1[N:39]=[CH:38][C:37]([C:41]#[N:42])=[CH:36]2.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:27])([F:29])[F:28])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:31]3[N:32]=[CH:33][C:34]([F:43])=[C:35]4[C:40]=3[N:39]=[CH:38][C:37]([C:41]#[N:42])=[CH:36]4)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1
Reactant: N#Cc1cnc2c(Cl)ncc(F)c2c1
Reactant: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: C[C@@]1(c2cc(Nc3ncc(F)c4cc(C#N)cnc34)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 100 °C
Yield: 45 %

Procedure:
To a solution of (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (6a, 0.076 g, 0.260 mmol) and 8-chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile (intermediate 17, 0.065 g, 0.312 mmol) in 2-propanol (2.6 ml) was added 4-methylbenzene sulfonic acid (monohydrate, Fluka, 0.099 g, 0.520 mmol). The reaction mixture was heated to 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between DCM and aqueous saturated sodium bicarbonate. The aqueous layer was backextracted with DCM. The combined organic extracts were washed with brine and dried over sodium sulfate. The filtrate was concentrated and the residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min. The product containing fractions were combined and neutralized with aqueous sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (0.054 g, 0.117 mmol, 44.8% yield) as yellow solid. MS m/z=464.0 [M+H]+. Calculated for C20H14F5N7O: 463.4