Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH:23](N)[CH3:24].C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([OH:9])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:21]3[CH2:22][C@@H:23]([CH3:24])[N:20]=[C:18]23)=[CH:6][CH:7]=1
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Reactant: CC(N)CN
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CN2C(=O)c3ccccc3[C@@](O)(c3ccc(F)cc3)C2=N1
Yield: 30.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (12.5 g) (Step 1 of Example 2), 1,2-diaminopropane (13.5 g), and toluene (150 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was evaporated to dryness. The residue was treated with hot ethanol (200 mL). The insoluble material was collected by filtration and dried to give the title compound (4.3 g) as a white solid m.p. 229-232° C. Mass spectrum (EI, M+) m/z 310. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, 1H), 7.62 (t, 1H), 7.51 (t, 1H), 7.33 (m, 3H), 7.10 (t, 2H), 7.04 (s, 1H), 4.13 (m, 1H), 4.02 (dd, 1H), 3.52 (dd, 1H), and 1.20 ppm (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[Br:11]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:6]([Br:11])=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1
Reactant: CC(C)(C)c1cc(N)no1
Reactant: O=C1CCC(=O)N1Br
Product: CC(C)(C)c1onc(N)c1Br
Yield: 91 %

Procedure:
This compound was prepared from 3-amino-5-tert-butylisoxazole and N-bromosuccinimide as described in Example 25a in 91% yield, Rf 0.27 (3:1 hexanes/ethyl acetate).
Reaction SMILES: [CH3:1][C@:2]1([NH:36]C(=O)OC(C)(C)C)[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.C(Cl)[Cl:45].[ClH:47]>O1CCOCC1>[ClH:45].[ClH:47].[CH3:1][C@:2]1([NH2:36])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:10])([F:11])[F:9])[CH2:3]1
Reactant: ClCCl
Reactant: COCCOc1ccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COCCOc1ccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(N)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (72 mg, 0.12 mmol), DCM (1 mL) and 4N HCl in dioxane (0.3 mL) was stirred at ambient temperature overnight. Removal of the solvents under reduced pressure gave (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine dihydrochloride (65 mg, 95%) as a yellow solid. LCMS APCI (+) m/z 501 (M+H). Specific rotation: [α]25D=−0.89° (c=0.97, MeOH).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].[CH:22]([CH:24]=[CH2:25])=[O:23].OS(O)(=O)=O>CCCCCC.C1COCC1>[Br:13][C:14]1[C:15]([F:21])=[C:16]([CH:22]([CH:24]=[CH2:25])[OH:23])[C:17]([F:20])=[CH:18][CH:19]=1
Reactant: C=CC=O
Reactant: Fc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: C=CC(O)c1c(F)ccc(Br)c1F
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
121.1 ml (0.194 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise to a solution, cooled to -10° C., of 21.5 g (0.212 mol) of diisopropylamine in 194 ml of anhydrous THF. The mixture is stirred for 10 min at -10° C. under a nitrogen atmosphere, is then cooled to -76° C. and a solution of 37.4 g (0.194 mol) of 1-bromo-2,4-difluorobenzene in 270 ml of anhydrous THF is added dropwise over 30 minutes, at a temperature below -70° C. The mixture is stirred for 2 minutes at -70° C. and then a solution of 14.7 g (0.212 mol) of acrolein in 30 ml of anhydrous THF is added dropwise over 10 minutes at a temperature below -60° C. The mixture is then stirred for 30 minutes at -70° C., and the temperature is then allowed to return to 0° C. The mixture is poured onto a mixture of 350 g of ice and 35 ml of concentrated H2SO4. Extraction with ether, washing with water, drying over Na2SO4, filtration, evaporation under vacuum and distillation are carried out. Weight obtained: 29 g (Yd.=60%) B.p.0.5 =86°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:24])[S:12][C:13]=2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:24][C:11]2[S:12][C:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[O:32])=[CH:29][CH:28]=1)#[N:26]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(C#N)cc3)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 26.8 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 6 and p-cyanobenzoyl chloride prepared in the step 1 of Example 13 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1-10:1) to obtain a product as a yellow solid in a yield of 26.8%, mp: 190-192└. 1H-NMR (CDCl3, 400 MHz) δ: 3.80 (3H, s, OCH3), 4.32 (2H, s, CH2), 6.75 (2H, d, J=8.72 Hz, ArH), 7.25 (2H, d, J=8.68 Hz, ArH), 7.37 (2H, d, J=8.68 Hz, ArH), 7.59 (2H, d, J=8.40 Hz, ArH), 7.82 (2H, d, J=8.40 Hz, ArH), 8.19 (2H, d, J=8.72 Hz, ArH); EI-MS m/e (%): 470.1 (M+, 100), 130.0 (76); HREI-MS Calcd. for C25H18N4O4S: 470.1049. found: 470.1050. Anal. Calcd. for C25H18N4O4S: C, 63.82; H, 3.86; N, 11.91. found: C, 64.16; H, 3.68; N, 12.19.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:22])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:25](CC)CC)C>CN(C=O)C>[NH2:25][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]#[N:22])=[O:15])[CH2:10]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCC[C@H]1C#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)N1CCC[C@H]1C#N

Procedure:
(S)-1-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine (title compound of Reference Example 2, 60.7 g) and triethylamine (30.1 mL) were dissolved in DMF (300 mL). Methanesulfonyl chloride (16 mL) was added thereto under ice-cooling. After stirring at room temperature for 3 hr, the reaction mixture was washed with water and dried. The solvent was evaporated under reduced pressure. Ethanol was added to the residue to give (S)-1-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine (64.1 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](COCC(OCC)=O)[CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[C:24](=[O:30])[NH:25][C:26](=[S:29])[NH:27][CH:28]=2)[CH:16]=1.Cl[C:32]1[C:33]([CH2:38][S:39][CH2:40][CH2:41][NH:42][C:43]2NC(=S)[C:46](CC3C=NC=CC=3)=[CH:45][N:44]=2)=[N:34]C=CC=1>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:32][C:23]2[C:24](=[O:30])[NH:25][C:26](=[S:29])[NH:27][CH:28]=2)=[CH:5][CH:6]=1.[CH3:46][C:45]1[NH:44][CH:43]=[N:42][C:41]=1[CH2:40][S:39][CH2:38][CH2:33][NH:34][C:26]1[NH:25][C:24](=[O:30])[C:23]([O:22][CH2:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:28][N:27]=1
Reactant: O=c1[nH]c(=S)[nH]cc1OCc1cccnc1
Reactant: CCOC(=O)COCc1cccnc1
Reactant: S=c1[nH]c(NCCSCc2ncccc2Cl)ncc1Cc1cccnc1
Product: Cc1[nH]cnc1CSCCNc1ncc(OCc2cccnc2)c(=O)[nH]1
Product: O=c1[nH]c(=S)[nH]cc1Cc1ccncc1

Procedure:
Ethyl 3-pyridylmethoxyacetate is converted into 5-(3-pyridylmethoxy)-2-thiouracil by the general procedure of Example 1 (i). Substitution of 5-(3-pyridylmethoxy)-2-thiouracil for 5-(4-pyridylmethyl)-2-thiouracil in the general procedure of Example 1 gives 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethoxy)-4-pyrimidone.
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10](=[O:12])[O-:11])([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])O.[N:13]([C:16]1[CH:17]=[C:18]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)[CH:19]=[CH:20][CH:21]=1)=[C:14]=[O:15]>>[N:22]1([C:18]2[CH:17]=[C:16]([NH:13][C:14](=[O:15])[NH:1][C@@H:2]([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])[CH2:9][C:10]([O-:11])=[O:12])[CH:21]=[CH:20][CH:19]=2)[CH:23]=[CH:24][CH:25]=[CH:26]1
Reactant: O=C=Nc1cccc(-n2cccc2)c1
Reactant: C[N+](C)(C)CC(N)(O)CC(=O)[O-]
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1cccc(-n2cccc2)c1
Yield: 63.7 %

Procedure:
According to the method described in example S11, aminocarnitine (1.28 HBr salt, 68 mg, 0.31 mmol) was reacted with 1-(3-isocyanatophenyl)-1H-pyrrole (116 mg, 0.63 mmol) to yield the title compound as a white solid (68 mg, 62%). 1H NMR (400 MHz, CD3OD) δ ppm=7.69 (t, J=1.89 Hz, 1 H), 7.29 (t, J=7.96 Hz, 1 H), 7.11-7.18 (m, 3 H), 6.25 (t, J=2.15 Hz, 1 H), 4.62 (br. s, 1 H), 3.76 (dd, J=13.64, 9.09 Hz, 1 H), 3.51-3.58 (m, 1 H), 3.23 (s, 9 H), 2.46-2.61 (m, 2 H). MS ESI [M+H]+, calcd for [C18H23N4O3+H]+: 344.41 found m/z 344.7 (100).
Reaction SMILES: Cl(O)(=O)(=O)=O.[OH2:6].[OH2:7].O.[N+]([O-])([O-])=O.[Tl+].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=O)[CH3:30])=[CH:25][CH:24]=2)[CH:17]=1.[CH3:34]O>>[F:14][C:15]([F:33])([F:32])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:7][CH3:34])=[O:6])=[CH:25][CH:24]=2)[CH:17]=1
Reactant: O
Reactant: CC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CO
Agent: O=[N+]([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [Tl+]
Product: COC(=O)Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 73.5 ml of 70% perchloric acid in 370 ml of methanol is cooled to 0° C and 73.76 g of thallium nitrate trihydrate followed by 42.25 g of 4'-(α,α,α-trifluoro-m-tolyloxy)acetophenone are added. The mixture is allowed to stir overnight while warming to room temperature. A white solid is rmoved by filtration and the filtrate is diluted with one liter of water. The resulting mixture is extracted with three 200 ml portions of chloroform. The combined organic extracts are washed with two 200 ml portions of water, 200 ml of saturated NaHCO3, saturated NaCl and dried over MgSO4. Evaporation of the solvent affords a yellow oil, which is filtered through aluminum oxide (benzene) and distilled at 0.07 mm to give the product as a yellow oil, bp 120°-148° C.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:11]2[C:12]3[C:13]([C:32]4[CH:31]=[CH:30][C:29]([Cl:28])=[C:34]([Cl:35])[CH:33]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:26][CH:25]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3ccc(Cl)c(Cl)c3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 3,4-dichlorophenylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: [Br:1][C:2]1C2C(=CC=CC=2)[C:5]([C:12]2(C=COC)[CH:17]=[CH:16][CH:15]=[CH:14][CH2:13]2)=[CH:4][CH:3]=1.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][C:2]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:5]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:5]=[CH:4][C:4]=2[CH:3]=1
Reactant: COC=CC1(c2ccc(Br)c3ccccc23)C=CC=CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1cc2ccc3ccccc3c2c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
180 g of the 1-bromo-4-[1-(2-methoxyvinyl) phenyl]naphthalene obtained and 1.0 L of dichloromethane were placed in a flask. During stirring at room temperature, 25 mL of methanesulfonic acid were added to the flask. Stirring was conducted at room temperature for 8 hours. After the completion of the reaction, 1 L of a 10% aqueous solution of potassium carbonate was added. An aqueous phase was removed and an organic phase which had been separated was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by means of silica gel column chromatography, whereby 24.4 g (yield: 15%) of 5-bromobenzo[c]phenanthrene was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC(N(C2C=CC([N+]([O-])=O)=CC=2)C2SC=CN=2)=CC=1)([O-])=O>C(O)(=O)C.[Zn]>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[NH:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Nc2nccs2)cc1
Agent: O=[N+]([O-])c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2nccs2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(Nc2nccs2)cc1
Temperature: 67.5 °C
Yield: 21.7 %

Procedure:
Zinc powder (1.2 g, 18.46 mmol) was added to a solution of 400 mg of a mixture of (4-nitro-phenyl)-thiazol-2-yl-amine and bis-(4-nitrophenyl)-thiazol-2-yl amine in acetic acid (8 ml) and then heated at 65-70° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with dilute sodium hydroxide solution, then water, brine and dried. Evaporation yielded a crude mixture which was chromatographed over silica gel using 1% methanol in chloroform to give N-thiazol-2-yl-benzene-1,4-diamine (75 mg, 21.7%), as a solid.
Reaction SMILES: O.[OH-].[Li+].C([O:6][P:7]([CH2:16][CH2:17][CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH3:20])([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:8])C>O.C(O)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:19]([CH2:18][CH2:17][CH2:16][P:7]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=[O:6])[OH:8])[CH3:20])=[CH:27][CH:26]=1
Reactant: CCOC(OCC)P(=O)(CCCN(C)Cc1ccc(Cl)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(OCC)P(=O)(O)CCCN(C)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
0.43 g of lithium hydroxide monohydrate in 6 ml of water is added to a solution of 2.0 g of 3-[N-(p-chlorobenzyl)-N-methylamino]propyl(diethoxymethyl)phosphinic acid ethyl ester in 5.5 ml of ethanol, and the mixture is heated at 60° for 25 hours. The reaction mixture is cooled to room temperature, the solvent is removed under reduced pressure, and the evaporation residue is taken up in water and neutralised with phosphoric acid. The suspension formed is concentrated to dryness by evaporation, and the residue is taken up in hot methanol, filtered and concentrated by evaporation again. Crystallisation of the residue from propanol yields 3-[N-(p-chlorobenzyl)-N-methylamino]propyl(diethoxymethyl)phosphinic acid having a melting point of 170°-171.5°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.Br[C:13]1[C:18]([CH2:19][O:20][CH3:21])=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:21][O:20][CH2:19][C:18]1[C:13]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:3]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COCc1cccnc1Br
Reactant: CCOC(=O)c1c[nH]nc1C
Product: CCOC(=O)c1cn(-c2ncccc2COC)nc1C
Yield: 83 %

Procedure:
This compound is prepared essentially as described in Preparation 12 by using ethyl 3-methyl-1H-pyrazole-4-carboxylate and 2-bromo-3-(methoxymethyl)pyridine in a 83% yield. MS (m/z): 276 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([OH:7])=O.C(OC(=O)[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:5]([C:4]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[O:7])[CH2:22]1
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N1CCC[C@@H](N)C1
Temperature: 25 °C
Yield: 11.1 %

Procedure:
A mixture of 0.143 g (0.786 mmol) 2,6-dimethoxybenzoic acid (commercially available), 0.15 g (0.749 mmol) (R)-piperidin-3-yl-carbamic acid tert-butyl ester (commercially available), 0.264 g (0.824 mmol) TBTU and 0.145 g (1.123 mmol) DIPEA in 9.2 mL DMF was stirred at room temperature over night. DMF was evaporated and the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated and the residue was treated with 4N HCl in dioxane and stirred at 50° C. over night. The mixture was evaporated to dryness and treated with NaHCO3 aq. and DCM. The organic layer was separated, dried with MgSO4 and evaporated to yield 22 mg (11%) of the title compound as colourless oil. (MH+) 265.1.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[OH:15][C:16]1[CH:17]=[C:18]2[C:22](=[N:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[NH:21]1[C:22]2[C:18](=[CH:17][C:16]([O:15][C:2]3[C:11]4[C:6](=[CH:7][C:8]5[O:14][CH2:13][O:12][C:9]=5[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:24][N:23]=2)[CH:19]=[CH:20]1
Reactant: Clc1ncnc2cc3c(cc12)OCO3
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1nc(Oc2cnc3[nH]ccc3c2)c2cc3c(cc2n1)OCO3
Temperature: 85 °C
Yield: 62.6 %

Procedure:
8-Chloro[1,3]dioxolo[4,5-g]quinazoline (100 mg, 0.48 mmol), (WO 9749688), was dissolved in dimethylacetamide (2.5 ml). 5-Hydroxy-7-azaindole (71 mg, 0.53 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (73 mg, 0.53 mmol) were added and the mixture heated to 85° C. for 3 hours. The reaction mixture was cooled, filtered and concentrated. The resulting residue was purified by column chromatography eluting with methylene chloride/methanol (91/9) to yield 4-(7-azaindol-5-yloxy)-6,7-methylenedioxyquinazoline (92 mg, 63%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]3[CH2:32][CH2:31][N:30](C(OCC4C=CC=CC=4)=O)[CH2:29][CH2:28]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]4[O:20][C:21]([CH3:24])=[CH:22][CH:23]=4)=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:26][O:25][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:9]=2)[CH:16]=[CH:15][C:14]=1[NH:17][CH2:18][C:19]1[O:20][C:21]([CH3:24])=[CH:22][CH:23]=1
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.5 %

Procedure:
A mixture of benzyl 4-[4-amino-3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (0.18 g, 0.000317 mol) and 20% palladium hydroxide on carbon (0.02 g) in ethyl acetate (10 mL) was stirred under atmosphere of hydrogen at room temperature for 18 hours. The mixture was filtered and solvents were removed. The residue was purified by flash column chromatography on silica using 5%-10% methanol/dichloromethane (2% NH4OH) to give 3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.02 g, 0.000046 mol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH2:18][N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][C:12]=3[C:11]3=[N:25][CH:26]=[N:27][N:10]3[C:9]2=[O:28])=[CH:5][CH:4]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH2:18][N:19]4[CH2:24][CH2:23][N:22]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:21][CH2:20]4)=[CH:17][C:12]=3[C:11]3=[N:25][CH:26]=[N:27][N:10]3[C:9]2=[O:28])=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CCNCC4)cnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc32)cc1
Reaction time: 4 h
Yield: 39.1 %

Procedure:
6-(4-Methoxybenzyl)-9-(piperazin-1-ylmethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 65, 34 mg, 0.09 mmol), ACN (1 mL), TEA (75 μl, 0.53 mmol), and methane sulfonyl chloride (50 mg, 0.44 mmol) were combined and the mixture was stirred for 4 h. The reaction was filtered through a plug of C18. Purification (HPLC, 10-70% ACN in water) afforded the title compound (17 mg, 33%) as a white solid. 1H NMR (400 MHz, CDCl3 and DMSO-d6) δ 2.48 (d, J=1.63 Hz, 2H), 2.76 (d, J=2.26 Hz, 3H), 3.09 (br s, 4H), 3.54 (br s, 4H), 3.65 (d, J=2.51 Hz, 3H), 4.21 (br s, 2H), 5.63 (d, J=1.76 Hz, 2H), 6.72 (dd, J=8.78, 2.26 Hz, 2H), 7.47 (dd, J=8.66, 2.38 Hz, 2H), 8.26 (d, J=2.38 Hz, 1H), 8.85 (br s, 1H), 9.00 (br s, 1H). [M+H]=484.2.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][N:5]2[N:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:4]2[CH2:3]1.[H][H]>C(O)C.[Pd]>[NH2:12][C:10]1[CH:11]=[C:4]2[CH2:3][N:2]([CH3:1])[C:7](=[O:8])[CH2:6][N:5]2[N:9]=1
Reactant: CN1Cc2cc([N+](=O)[O-])nn2CC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1Cc2cc(N)nn2CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 146c (450 mg, 2.3 mmol) in ethanol (30 mL) was added Pd/C (10%, 400 mg). The reaction was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE® and the filtrate was concentrated under reduced pressure to afford 146d as a yellow solid (320 mg, 84%), which was used without further purification in the next step. MS-ESI: [M+H]+ 167.1
Reaction SMILES: COC(C1N(C)C2C(C=1)=CC(N)=CC=2)=O.C(OC(C1N(C)C2C(C=1)=CC(N)=CC=2)=O)C.C(OC([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([NH2:46])=[CH:41][CH:40]=2)=O)C.[CH3:47][N:48](C)[C:49](C1NC2C(C=1)=CC(N)=CC=2)=[O:50].COC(C1N(C)C2C(C=1)=CC=C(N)C=2)=O>>[CH3:47][NH:48][C:49]([N:38]1[C:39]2[C:44](=[CH:43][C:42]([NH2:46])=[CH:41][CH:40]=2)[CH2:45][CH2:37]1)=[O:50]
Reactant: CN(C)C(=O)c1cc2cc(N)ccc2[nH]1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Agent: CCOC(=O)c1cc2cc(N)ccc2n1C
Agent: COC(=O)c1cc2cc(N)ccc2n1C
Agent: COC(=O)c1cc2ccc(N)cc2n1C
Product: CNC(=O)N1CCc2cc(N)ccc21

Procedure:
5-Amino-1-methyl-1H-indole-2-carboxylic acid methyl ester/5-Amino-1-methyl-1H-indole-2-carboxylic acid ethyl ester (5.25) for Example 32, 47: Pharmagene Laboratories Limited Patent: WO2005/80367 A1; 2005/Boehringer Ingelheim (Canada) Ltd. Patent: US2003/236251 A1; 2003) 5-Amino-1H-indole-2-carboxylic acid ethyl ester (5.26) for Examples 6, 8, 10-12, 16, 26, 28, 30, 31, 33-44, 49, 50, 53, 58-61, 63, 65, 67-193, 197-214, 253-258, 260-262, 273-277, 283: Bayer Healthcare AG; WO2008/56768; A2; 2004) 5-Amino-1H-indole-2-carboxylic acid dimethylamide (5.27) for Example 219, 222, 232: Vertex Pharmaceuticals Incorporated Patent: WO2006/10008; A1; 2006) 6-Amino-1-methyl-1H-indole-2-carboxylic acid methyl ester (5.28) for Examples 66, 265, 266-270: Banyu Pharmaceutical Co. Patent: WO2007/29847 A1; 2007