Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]=[C:27]=[O:28])=[CH:20][CH:19]=1>>[CH2:25]([NH:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:28])[CH2:24][C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: O=C=NCCc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)NCCc4ccccc4)cc23)CC1
Yield: 64.1 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 12.51 mg (0.0852 mMol) 2-phenethyl isocyanate, 15.8 mg (65%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]([CH2:14][CH3:15])[CH2:12][OH:13])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.[C:23](Cl)(=[O:27])[C:24](C)=[CH2:25]>ClCCl>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH:11]([CH2:14][CH3:15])[CH2:12][O:13][C:23](=[O:27])[CH:24]=[CH2:25])[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(CC(CC)CO)CC1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCC(CC)CC1CCC(CCC)CC1
Reaction time: 8 h

Procedure:
2-(4-propyl-cyclohexylmethyl)-butan-1-ol (13 g, 61.2 mmol) is dissolved in dichloromethane (50 ml) and triethylamine (3.5 ml) and a solution of methacryloyl chloride (2.2 ml, 21.8 mmol) in dichloromethane (30 ml) is added dropwise at 0° C. The reaction is stirred overnight, evaporated, filtered through silica with heptane/ethyl acetate (19:1) and the crude product is crystallised from ethanol to give acrylic acid 2-(4-propyl-cyclohexylmethyl)-butyl ester as a colourless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([O:24][C:25](=[O:32])[C@@:26]([F:31])([CH3:30])[C:27](O)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:32])[C@@:26]([F:31])([CH3:30])[C:27]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:28])[CH3:23]
Reactant: CCOC(=O)[C@](C)(F)C(=O)O
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CCOC(=O)[C@](C)(F)C(=O)N[C@@H]1C(=O)N(CCOC)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (R)-2-fluoro-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (59%). MS: m/e=429(M+H+).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][C:13]1([CH:17]=[O:18])[CH2:16][O:15][CH2:14]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1[O:8][C:9]([CH:17]([C:13]2([CH3:12])[CH2:16][O:15][CH2:14]2)[OH:18])=[CH:10][CH:11]=1
Reactant: Cc1ccco1
Reactant: CC1(C=O)COC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(O)C2(C)COC2)o1
Temperature: -70 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
12.0 ml (30 mmol, 1.7 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 2.46 g (30 mmol, 1.7 eq) of 2-methylfuran in 50 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 3 hours. The reaction medium was cooled to −70° C. and then 2.17 g (18 mmol, 1 eq) of 3-methyloxetane-3-carbaldehyde at 83% were added. The reaction medium was stirred at ambient temperature for 3 hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution and evaporated. 3.02 g of (5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methanol were obtained in the form of an orange oil. Yield=92%.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:37]([NH:39][CH3:40])[CH3:38]>C1COCC1>[CH2:37]([N:39]([CH3:40])[CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:12])=[O:13])[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: CCNC
Solvent: C1CCOC1
Product: CCN(C)CCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 80 °C

Procedure:
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (1.18 g, 2.26 mmol) and ethylmethylamine (2.0 mL, 23 mmol) in THF (20 mL) was stirred for 16 hours at 70° C. in a sealed tube. More ethylmethylamine (2.0 mL, 23 mmol) was added, and the reaction mixture was heated to 80° C. for 20 hours in a sealed tube. After cooling to ambient temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.75% ammonium hydroxide/7.5% methanol in chloroform. Drying in vacuo at 69° C. for 20 minutes yielded ethyl-methyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine as a buff foam (0.409 g, 44.2%). Methanol, chloroform and ethereal hydrochloride were added. The resulting solution was concentrated and dried for 16 hours at 84° C. in vacuo. The hydrochloride was obtained as a buff semi-solid (0.424 g). Mass Spectrum (+EI, [M+H]+) m/z 410. 1HNMR (500 MHz, DMSO-d6): δ14.21 (s, 1H), 10.00-10.01 (s, 1H), 8.74-8.77 (m, 1H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.73 (dd, 1H, J=8.06 Hz and 7.57 Hz), 7.56-7.65 (m, 3H), 7.37 (d, 1H, J=2.20 Hz), 7.15-7.18 (m, 1H), 4.40 (t, 2H, J=5.00 Hz), 3.53-3.59 (m, 1H), 3.39-3.49 (m, 1H), 3.21-3.25 (m, 1H), 3.10-3.20 (m, 1H), 2.81 (d, 3H, J=4.88 Hz), 1.21-1.25 ppm (m, 3H). Elemental Analysis for C22H23N3O3S.1.00 mol HCl.0.30 mol H2O:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[Cl:13])=[CH:10][C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=2)#[N:2].[CH2:17](Br)[C:18]#[CH:19].[O-]CCCC.[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(N(C)C)=O>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[Cl:13])=[CH:10][C:9]([O:14][CH2:19][C:18]#[CH:17])=[C:8]([O:15][CH3:16])[CH:7]=2)#[N:2]
Reactant: C#CCBr
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCC[O-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: C#CCOc1cc2c(Cl)c(C#N)cnc2cc1OC
Yield: 62.8 %

Procedure:
The product from step 1 (1 g) was reacted with propargyl bromide (0.95 g) in the presence of potassium butoxide (0.53 g), tetrabutylammonium iodide (0.16 g) and 18C-6 crown ether (0.05 g), in solution in DMA (100 ml, 10° C. to ambient temperature). 3-cyano-4-chloro-6-propargyloxy-7-methoxyquinoline (0.73 g) was obtained.
Reaction SMILES: CC1(C)COC([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:40]3[CH:45]=[CH:44]C=[CH:42][CH:41]=3)([O:30][CH2:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][O:23]C4CCCCO4)[CH:15]=3)=[CH:9][CH:8]=2)=N1.[OH-].[Na+].CCO.[C:52]([OH:55])(=[O:54])[CH3:53]>>[OH:23][CH2:22][CH2:21][O:20][C:16]1[CH:15]=[C:14]([C:13]([C:10]2[CH:9]=[CH:8][CH:7]=[CH:12][CH:11]=2)([O:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:41]=[CH:42][C:53]([C:52]([OH:55])=[O:54])=[CH:44][CH:45]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)COC(c2ccc(C(OCCCc3ccccc3)(c3ccccc3)c3cccc(OCCOC4CCCCO4)c3)cc2)=N1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1

Procedure:
A solution of 7 (550 mg) in 3 mL of 80% aqueous acetic acid was heated at 75° C. for overnight. Then the solution was evaporated and the residue obtained was refluxed with 20% NaOH/EtOH (1:1, v/v, 3 mL) for 2 h. The solvent was removed, 10 mL of ice cooled water was added to the residue and the aqueous solution acidified with 1N HCl, extracted with CH2Cl2 (60 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent gave yellow solid Yield: 485 mg (quantitative).
Reaction SMILES: CO[C:3]1[C:4](=[O:16])[C:5]2[C:10]([C:11](=[O:15])[C:12]=1[O:13][CH3:14])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>[Cl-].[Cl-].[Zn+2]>[CH3:14][O:13][C:12]1[C:11](=[O:15])[C:10]2[C:5]([C:4](=[O:16])[C:3]=1[CH2:19][CH2:18][CH2:17][CH2:21][CH2:5][CH2:4][CH2:3][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COC1=C(OC)C(=O)c2ccccc2C1=O
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCCCCCCCCCCC1=C(OC)C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 13.4 %

Procedure:
To 0.64 g (4.71 mmoles) of ZnCl2 in 50 mL of THF was added 7.0 g (0.697 mmoles/g in THF, 4.88 mmoles) of dodecyl MgBr. This mixture was added dropwise to 1.00 g (4.67 mmoles) of 2,3-dimethoxy-1,4-naphthoquinone in 50 mL of THF. The mixture was stirred overnight and worked up as in Example 30. Thus, 0.223 g (0.626 mmoles, 13.4%) of 2-methoxy-3-dodecyl-1,4-naphthoquinone was obtained, mp: 61° to 63° C. 1H NMR (δ, CDCl3): 8.05 (m,2H), 7.65 (m,2H), 4.10 (s,3H), 2.55 (m,2H), 1.30 (br s,20H), 0.85 (m,3H). IR (cm-1, KBr): 2950w, 2918s, 2842m, 1666s, 1642m, 1608m, 1589m, 1571w, 1462m, 1338m, 1329m, 1261m, 1255w, 1209m.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7]
Reactant: COC(=S)c1cc(Br)c(C)s1
Reactant: COc1ccccc1N
Product: COC(=S)c1cc(Nc2ccccc2OC)c(C)s1
Yield: 68.9 %

Procedure:
A stirred suspension of 103 mg (0.386 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate and 57 mg (0.46 mmol, 1.2 eq) of 2-methoxyaniline (Aldrich, Milwaukee, Wis.) was treated in a manner similar to Example 241, step (b) to give 78 mg the title compound (65%) as a yellow oil. 1H-NMR (CDCl3, 400 MHz) δ7.82 (s, 1H), 7.12-6.52 (m, 4H), 6.52 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.40 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C14H15NO3S2, 310.1 (M+H), found 310.2.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:21])[CH:3]=1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:39]>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:20]([I:39])=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:21])[CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1Oc1ccc(N)cc1Cl
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(F)cc1Oc1cc(I)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 242A (8.15 g) in dichloromethane (60 mL) was added bis(pyridine)iodonium tetrafluoroborate (9.79 g). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous Na2S2O3, water, brine and dried over Na2SO4. The mixture was filtered, and the solvent was evaporated and the residue was loaded on a column and eluted with 10% ethyl acetate in hexane to give the pure product.
Reaction SMILES: [CH3:1][C:2]1([C:7]2(/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.[H][H]>C1COCC1.[Pt](=O)=O>[CH3:1][C:2]1([C:7]2([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: [H][H]
Reactant: CC(=O)/C=C/C1(C2(C)OCCO2)CC1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CC(=O)CCC1(C2(C)OCCO2)CC1

Procedure:
1.23 g of 153 is dissolved in THF, and 200 mg of platinum(IV) oxide is added in an argon stream. Using a hydrogenating apparatus, it is hydrogenated until no more hydrogen is consumed, flushed with nitrogen, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.19 g of title compound 154 accumulates as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])=O.[C:14]([NH2:17])(=[O:16])[CH3:15]>>[CH3:15][C:14]1[O:16][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])[N:17]=1
Reactant: CC(N)=O
Reactant: O=C(O)c1cccc(C(=O)CBr)c1
Product: Cc1nc(-c2cccc(C(=O)O)c2)co1
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 74.3 %

Procedure:
A mixture of 3-(2-bromo-acetyl)-benzoic acid (2.43 g) and acetamide (1.77 g) was heated with stirring to 130° C. for 40 min. The mixture was cooled and diluted with H2(30 mL) and the precipitate formed was collected by filtration to give 3-(2-methyl-oxazol-4-yl)-benzoic acid (1.51 g) as brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][N:7]3[CH:14]=[CH:13][CH:12]=[C:8]3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[Cl-:17].[Cl-].[Cl-].[Al+3].[OH-].[NH4+]>C(Cl)Cl>[Cl:17][C:13]1[CH:12]=[C:8]2[N:7]([CH:14]=1)[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=1[NH:10][C:9]2=[O:11]
Reactant: [Cl-]
Reactant: O=C1Nc2cc(Cl)ccc2Cn2cccc21
Agent: [Al+3]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1Nc2cc(Cl)ccc2Cn2cc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.33 g of 8-chloro-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one in 50 mL of methylene chloride is added 5.33 g of aluminum trichloride. The reaction is stirred for 1 hour at room temperature and 0.77 mL (1.2 g) of methanesulfonyl chgloride is added. Stirring is then continued at room temperature overnight. The reaction mixture is basified with 10% ammonium hydroxide and the resulting solid collected by filtration. The solid is dissolved in methylene chloride, the solution is washed with water, dried over magnesium sulfate and evaporated to dryness to yield 2,8-dichloro-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-11-one, which is used without further purification.
Reaction SMILES: [Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24]1[N:25]=[CH:26][C:27]2[CH2:33][N:32]([C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]#[CH:41])=[O:35])[CH2:31][CH2:30][C:28]=2[N:29]=1.[N:42]([Si](C)(C)C)=[N+:43]=[N-:44]>CN(C)C=O.O.C(OCC)(=O)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24]1[N:25]=[CH:26][C:27]2[CH2:33][N:32]([C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]3[N:42]=[N:43][NH:44][CH:41]=3)=[O:35])[CH2:31][CH2:30][C:28]=2[N:29]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CCCCOC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCCCc1c[nH]nn1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Yield: 34.4 %

Procedure:
Add copper(II)sulfate pentahydrate (0.090 g; 0.2 equiv; 0.36 mmoles) and L-ascorbic acid sodium salt (0.714 g; 2.0 equiv; 3.61 mmoles) to a deoxygenated solution of pent-4-yn-1-yl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.754 g; 1.0 equiv; 1.80 mmoles) in dimethylformamide (15 mL) and water (15 mL). Add azidotrimethylsilane (1.92 mL; 8 equiv; 14.42 mmoles) and heat the reaction to 90° C. for 3 hours. Dilute the reaction mixture with water (250 mL) and ethyl acetate. Extract the mixture with ethyl acetate (3×50 mL). Wash the combined organic extracts with water (3×) and brine, dry over sodium sulfate, filter, and concentrate to a tan/orange oil. Purify the crude product by column chromatography (0 to 5% methanol in dichloromethane) to afford 3-(1H-1,2,3-triazol-4-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.26 g; 35%): MS (m/z): 420(M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:24]#[N:25])[C:7]=1[C:8]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=[CH:10][C:9]=1[F:23].Br[C:27]1[N:31]2[N:32]=[CH:33][C:34]([C:36]([OH:39])([CH3:38])[CH3:37])=[N:35][C:30]2=[N:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:24]#[N:25])[C:7]=1[C:8]1[CH:13]=[C:12]([C:27]2[N:31]3[N:32]=[CH:33][C:34]([C:36]([OH:39])([CH3:37])[CH3:38])=[N:35][C:30]3=[N:29][CH:28]=2)[CH:11]=[CH:10][C:9]=1[F:23]
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3c(F)cccc3C#N)c2)OC1(C)C
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4c(F)cccc4C#N)c3)cnc2n1

Procedure:
6,2′-Difluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 32% yield using a similar procedure to that described in Example C, step f, to give a yellow solid: mp 206° C.; 1H NMR (360 MHz, CDCl3) δ1.71 (6H, s), 3.28 (1H, br s), 7.37-7.66 (4H, m), 8.15 (2H, m), 8.26 (1H, s), 8.78 (1H, s); MS (ES+) mn/z 392 [M+H]+. Anal. Found: C, 64.66; H, 3.93, N, 17.71%. Required for C21H15F2N5O: C, 64.45; H, 3.86; N, 17.89%.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[O:6]=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:11]([O:12][CH3:13])[C:9]=1[OH:10].O>C1(C)C=CC=CC=1>[Cl:4][C:15]1[CH:14]=[C:11]([O:12][CH3:13])[C:9]([OH:10])=[C:8]([CH:16]=1)[CH:7]=[O:6]
Reactant: COc1cccc(C=O)c1O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)cc(C=O)c1O
Reaction time: 16 h

Procedure:
A solution of sulfuryl chloride (15 mL, 190 mmol) in toluene (20 mL) is added dropwise over 1.5 h to a solution of o-vanillin (25.0 g, 164 mmol) in toluene (90 mL) and the reaction is then stirred 16 h. Water (30 mL) is added over 10 minutes with ice-bath cooling. The solid is filtered, washed with water and dried to provide the title compound. MS (EI) 186 (M)+.
Reaction SMILES: CC[O-].[Na+].[CH2:5]([O:7][C:8](=[O:25])[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20](=O)N(C)C)=[CH:15][CH:14]=1)([CH3:11])[CH3:10])[CH3:6].[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:29][C:28]=1[CH2:38]COS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:5]([O:7][C:8](=[O:25])[C:9]([CH3:10])([O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19][CH2:20][CH2:38][C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:31][C:27]=2[CH3:26])=[CH:17][CH:18]=1)[CH3:11])[CH3:6]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(=O)N(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc(SCCc2nc(-c3ccccc3)oc2C)cc1
Yield: 17.1 %

Procedure:
Freshly prepared NaOEt (from 50 mg (2.2 mmol) Na) was charged with 2-(4-dimethylcarbamoylsulfanyl-phenoxy)-2-methyl-propionic acid ethyl ester (420 mg, 1.35 mmol) and refluxed for 3 h. Toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)-ethyl ester (572 mg, 2.2 mmol) was added and the mixture was refluxed for another 3 h. The reaction was cooled and concentrated. The residue was shaken with EtOAc/water. After a second water wash, the organic layer was dried (MgSO4) and concentrated to give 500 mg crude product. Purification by flash chromatography (15% EtOAc/hexane) provided the product (98 mg, 17%): Rf=0.32 in 15% EtOAc/hexane; MS m/e 426 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([O:28][CH3:29])=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:22])=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([CH2:43]O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([O:28][CH3:29])=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:43][CH:40]3[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:36])[CH2:38][CH2:39]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc(Nc2ncnc3cc(O)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Product: COc1cc(Nc2ncnc3cc(OCC4CCN(C(=O)OC(C)(C)C)CC4)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Yield: 69.5 %

Procedure:
Using an analogous procedure to that described in Example 12, 4-(2,4-dichloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.109 g) was reacted with 1-tert-butoxycarbonylpiperidin-4-ylmethanol (0.065 g) to give 4-(2,4-dichloro-5-methoxyanilino)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-5-tetrahydropyran-4-yloxyquinazoline (0.11 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:13]([O-])=O)=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2>[Pd].CO>[NH2:13][C:3]1[C:2]([OH:1])=[C:10]2[C:6]([CH2:7][N:8]([CH3:12])[C:9]2=[O:11])=[CH:5][CH:4]=1
Reactant: CN1Cc2ccc([N+](=O)[O-])c(O)c2C1=O
Agent: [Pd]
Solvent: CO
Product: CN1Cc2ccc(N)c(O)c2C1=O
Reaction time: 18 h
Yield: 63.5 %

Procedure:
38 mg of palladium on carbon at 10% were added to a solution of 0.35 g (1.68 mmol) of 7-hydroxy-2-methyl-6-nitro-2,3-dihydroisoindol-1-one in 20 ml of methanol under nitrogen. The reaction medium was stirred under a hydrogen atmosphere for 18 hours. The reaction medium was filtered and concentrated. The residue was chromatographed on a prepacked C18 column (12 g column, 30 ml/min, 95/5 water/acetonitrile). 0.19 g of product was obtained in the form of a brown oil. Yield=64%.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[C:6]([OH:9])(=[O:8])[CH3:7]>C([O-])(=O)C.[Na+]>[C:6]([O:9][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])(=[O:8])[CH3:7]
Reactant: ClCC1CO1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)OCC(O)CCl
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Epichlorohydrin (187 g, 2.0 mol) was added dropwise over a 75 minute period to a mechanically stirred suspension of 10.0 g (0.062 mol) of anhydrous ferric chloride in 138 mL (2.4 mol) of glacial acetic acid at 0°-10° C. After the addition was completed, the reaction mixture was stirred one hour and was allowed to stand at room temperature for two days. Anhydrous sodium acetate (5.1 g, 0.062 mol) was added and excess acetic acid was then removed in vacuo. The mixture was diluted with 200 mL of methylene chloride and filtered through Celite™ (i.e. diatomaceous earth). The solution was washed with 10% potassium carbonate and dried over potassium carbonate and sodium sulfate. Removal of the methylene chloride in vacuo gave 275 g of crude 3-chloro-2-hydroxy-1-propyl acetate, and an additional 9 g was recovered by extracting the potassium carbonate solution with methylene chloride (93% crude yield). This material was used without purification in the subsequent step. 1H NMR (CDCl3) δ2.10 (s, 3H, --COCH3); 3.80 (m, 6H, --CH2CH(OH)CH2 --); IR (film) 3500 (--OH); 1735 cm-1 (--COCH3).
Reaction SMILES: [C:1]([N:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])N=CC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]1[CH:31]([C:32]([OH:34])=[O:33])[CH2:30][CH2:29][C:27](=O)[CH2:26]1.C(O)(=O)C.Cl>O>[C:1]([N:9]1[C:27]2[CH2:26][CH2:25][CH:31]([C:32]([OH:34])=[O:33])[CH2:30][C:29]=2[C:23]2[C:18]1=[C:19]([F:24])[CH:20]=[CH:21][CH:22]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: O=C(c1ccccc1)N(N=Cc1ccccc1)c1ccccc1F
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CCc2c(c3cccc(F)c3n2C(=O)c2ccccc2)C1
Reaction time: 2 h

Procedure:
A solution of 6.4 g. benzaldehyde 1-benzoyl-1-(2-fluorophenyl)hydrazone and 5.35 g. of cyclohexanone-4-carboxylic acid in 50 ml. glacial acetic acid and 10 ml. of glacial acetic acid saturated with hydrogen chloride was heated under reflux for two hours. An additional 10 ml. glacial acetic acid saturated with hydrogen chloride was then added and heating under reflux was continued two additional hours. A further 5 ml. glacial acetic acid saturated with hydrogen chloride was added and heating under reflux was continued another two hours. The mixture was cooled, 25 ml. water was added portion-wise, and the resulting solid was collected by filtration and washed with water to yield 3.54 g. of the title compound; m.p. 250°-251°C. (acetic acid-water).