Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.NC1N=CN=C2N([CH:21]([C:23]3[O:24][C:25](=[O:45])[C:26]4[C:31]([C:32]=3[C:33]3[S:34][C:35]([CH2:38][N:39]5[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]5)=[CH:36][CH:37]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:22])N=C(C3C=C(O)C=C(F)C=3)C=12.[CH3:46]N(C)CC=CC1C=C(C2C3C(=CC=CC=3)C(=O)OC=2C(O)C)C=CC=1.[CH2:72]([O:79][C:80]1[CH:81]=[C:82]([C:87]2[C:95]3[C:90](=[N:91][CH:92]=[N:93][C:94]=3[NH2:96])[NH:89][N:88]=2)[CH:83]=[C:84]([F:86])[CH:85]=1)C1C=CC=CC=1>>[NH2:96][C:94]1[N:93]=[CH:92][N:91]=[C:90]2[N:89]([CH:21]([C:23]3[O:24][C:25](=[O:45])[C:26]4[C:31]([C:32]=3[C:33]3[S:34][C:35]([CH2:38][N:39]5[CH2:40][CH2:41][N:42]([CH3:46])[CH2:43][CH2:44]5)=[CH:36][CH:37]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:22])[N:88]=[C:87]([C:82]3[CH:81]=[C:80]([O:79][CH3:72])[CH:85]=[C:84]([F:86])[CH:83]=3)[C:95]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCNCC2)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(C=CCN(C)C)c1
Reactant: Nc1ncnc2[nH]nc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Agent: Cl
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCN(C)CC4)s3)c3ncnc(N)c23)c1
Yield: 43 %

Procedure:
The title compound was made in a similar way as that of the compound of example 134, step a, from 4-(3-(3-(dimethylamino)prop-1-en-1-yl)phenyl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate B42, 280 mg, 0.801 mmol), and 3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G-18, 0.417 mmol, 140 mg) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(5-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)-1H-isochromen-1-one (120 mg, 0.18 mmol, 43% yield) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])([O-])=O>C1COCC1.CO.O>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(c1ccccc1)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccccc1C(=O)c1ccccc1
Temperature: 70 °C

Procedure:
A mixture of nitrobenzophenone resin, 3-Scheme 6, (950 mg), NaSH (1.0 g) in THF (10 mL), MeOH (5 mL), water (5 mL) was heated in an oil bath at 70° C. for 16 h. The mixture was cooled, filtered and washed with methanol, water, methylene chloride and finally with methanol. Drying at 60° (in vacuo gave a slight yellow resin. Recovered (900 mg). IR 1640 (broad).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.02 g, 3 mmol) in DCM (30 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (541 mg, 3 mmol), EDC (633 mg, 3.3 mmol), and TEA (1.05 mL, 7.5 mmol). This mixture was stirred at room temperature for 18 h. The reaction mixture was washed with H2O (20 mL), dried over Na2SO4, filtered, concentrated and purified with CombiFlash to afford 0.7052 g (50%) of the title compound. LC-MS m/z 466 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.[Si](OCC)(OCC)(OCC)OCC.[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:28]=1[NH2:29])([CH3:26])[CH3:25].OS(O)(=O)=O>>[Br:10][C:6]1[CH:5]=[C:4]([C:2](=[N:29][C:28]2[C:30]([CH:34]([CH3:35])[CH3:36])=[CH:31][CH:32]=[CH:33][C:27]=2[CH:24]([CH3:26])[CH3:25])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Product: CC(=Nc1c(C(C)C)cccc1C(C)C)c1cccc(Br)c1
Temperature: 170 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
In 25 mL Claisens flask in an argon atmosphere, a mixture of 3.98 g (20.0 mmol) of 3-bromoacetophenone, 5.00 g (24.0 mmol) of Si(OEt)4, and 3.90 g (22.0 mmol) of 2,6-diisopropylaniline was heated to 170° C., and then 0.20 mL of 96% H2SO4 was added. This mixture was stirred at this temperature for 1 hr, and the formed ethanol was slowly distilled off. Later, 300 mL of cold water was added, and the product was extracted with 2×70 mL of diethyl ether. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether, 50:1, vol.). This procedure gave 6.30 g (88%) of 13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:42])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[C:34]([F:41])[CH:33]=1)([CH3:27])([CH3:26])[CH3:25].CCN(CC)CC>ClCCCl>[C:24]([O:28][C:29](=[O:42])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:40])=[C:34]([F:41])[CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(N=C=O)c(F)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with 3-(3-fluoro-4-isocyanato-phenyl)-propionic acid tert-butyl ester in 1,2-dichloroethane in the presence of Et3N for 3 days under reflux conditions to give the title compound as brown oil. MS: m/e=591.3 [M+H+].
Reaction SMILES: [CH:1](Br)=[CH2:2].[Mg].CN(C)[CH:7]=[CH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O1CCCC1.CCOCC>[CH2:1]=[CH:2][CH:7]=[CH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(=O)C=CN(C)C
Reactant: C=CBr
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC=CC(=O)CCCCC
Temperature: 25 °C

Procedure:
To a solution of Grignard reagent prepared from vinyl bromide (10.7 g), and magnesium (2.43 g) in dry tetrahydrofuran (40 ml) is added gradually a solution of 1-(dimethylamino)-1-octen-3-one (16.9 g), described in Example 37, in dry tetrahydrofuran (20 ml). The mixture is stirred and heated to reflux for 1 hr. The reaction mixture is cooled to room temperature, diluted with ether, washed with hydrochloric acid (10 ml), followed by saturated ammonium chloride solution. The ether extract is dried, and the solvent is removed. The residue is chromatographed to yield the title compound, λmaxEtOH 260nm (ε = 17,050), γmaxfilm 1686, 1668 cm-1.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([OH:18])=O.[CH:19]([NH:22][CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.C(#N)C>[Cl:3][C:13]1[CH:14]=[CH:15][N:10]=[C:11]([C:16]([N:22]([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20])=[O:18])[CH:12]=1
Reactant: CC(C)NC(C)C
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccn1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)c1cc(Cl)ccn1)C(C)C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
Thionyl chloride (60 ml, 823 mmol) was diluted with toluene (100 ml) and heated to 45° C. To the mixture, N,N-dimethylformamide (16 ml, 207 mmol) was added and the resultant mixture was stirred in the same conditions for one hour. To the mixture, picolinic acid (25 g, 203 mmol) was added and the resultant mixture was stirred at 80° C. for one hour and 20 minutes. After the reaction mixture was concentrated and diisopropylamine (185 ml, 807 mmol) and acetonitrile (500 ml) were added to the residue, the mixture was stirred at room temperature for 21 hours and 30 minutes. After the reaction mixture was concentrated, the residue was separated with ethyl acetate and water. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, filtrated and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (31.1 g, yield: 63.6%) as a pale brown solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[CH3:19])(C(C)(C)C)(C)C.Cl.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:37][C@H:36]3[N:32]([CH2:33][CH2:34][CH2:35]3)[C:31]([CH3:39])([CH3:38])[CH2:30]2)[C:25]([F:40])=[CH:24][N:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[CH3:38][C:31]1([CH3:39])[CH2:30][C@H:29]([NH:28][C:26]2[C:25]([F:40])=[CH:24][N:23]=[C:22]([NH:16][C:15]3[CH:17]=[CH:18][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([CH3:19])[CH:14]=3)[N:27]=2)[CH2:37][C@H:36]2[N:32]1[CH2:33][CH2:34][CH2:35]2
Reactant: Cc1cc(N)ccc1OCCO[Si](C)(C)C(C)(C)C
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Nc2ncc(F)c(N[C@@H]3C[C@@H]4CCCN4C(C)(C)C3)n2)ccc1OCCO
Yield: 59.9 %

Procedure:
The general displacement procedure described herein was used with 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-methylaniline (563 mg, 2.0 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (478 mg, 1.4 mmol) and pTsOH.H2O (544 mg, 2.9 mmol) in IPA (10 mL) at reflux to give the product (360 mg, 59% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 9:1) as eluent.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:39][CH2:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc2ccoc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(CBr)c2occc2c1
Temperature: 80 °C
Reaction time: 0.05 h

Procedure:
7-Methyl-5-nitro-1-benzofuran (2.1 g, 12 mmol; Intermediate 63) was dissolved in CCl4 and heated to 80° C. Benzoyl peroxide (0.43 g, 1.6 mmol) was added followed by NBS (2.1 g, 12 mmol) that was added in small portions. The reaction mixture was heated at reflux overnight with stirring. Additional benzoyl peroxide (0.08 mmol) and NBS (0.2 mmol) were added and the reaction mixture was stirred for one additional night. After this time, the mixture was filtered and concentrated. The crude was redissolved in DCM and washed with water. The organic solvent was dried (MgSO4) and evaporated. The residue was purified using preparative HPLC with a gradient of 45-70% MeCN. This afforded 0.7 g (22%) of 7-(bromomethyl)-5-nitro-benzofuran as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.78 (s, 2H) 6.96 (d, J=2.3 Hz, 1H) 7.84 (d, J=2.3 Hz, 1H) 8.28 (d, J=2.3 Hz, 1H) 8.49 (d, J=2.3 Hz, 1H). HPLC Rt=1.9 min (System A; 30-80% MeCN over 3 min ACE column).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=O.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH2:30]([O:37][CH2:38][C:39](Cl)=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl.C1(C)C=CC=CC=1>[CH2:30]([O:37][C@@H:38]1[C:39](=[O:40])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C@@H:11]1[C:10]([O:14][CH2:15][CH3:16])=[O:13])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)C=O
Reactant: O=C(Cl)COCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1[C@H](OCc2ccccc2)C(=O)N1c1ccc(OC)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of p-anisidine (107, 5.4 mmol) in 10 ml anhydrous dichloromethane and 2 ml toluene were added ethyl glyoxylate (8.0 mmol, 50% solution in toluene) and anhydrous magnesium sulfate (3.0 g). The reaction mixture was heated at 70° C. for 3 h. Afterwards, the mixture was filtered and cooled to 0° C. with an ice/water bath. Triethylamine (10.8 mmol) and benzyloxyacetyl chloride (8.1 mmol) were added dropwise and the reaction mixture was stirred at room temperature for 18 h. Afterwards, it was concentrated in vacuo and triturated with ethyl ether and hexane to give compound 108 as a tan solid (69% yield). LS/MS M+H 356.2, calc. 356.12.
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].C[O:16][CH2:17][CH2:18]OC.C(N(CC)CC)C.[CH2:28]([N:46]=[C:47]=[O:48])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CCCCCCC>[CH2:28]([NH:46][C:47]([O:13][CH2:12][CH3:11])=[O:48])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].[CH2:28]([NH:46][C:47]([O:16][CH2:17][CH3:18])=[O:48])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].[CH2:12]([OH:13])[CH2:11][CH2:10][CH2:9][C:8]#[C:7][C:6]#[C:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:14]
Reactant: COCCOC
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Agent: OCCCCC#CC#CCCCCO
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC
Reaction time: 0.83 h
Yield: 99 %

Procedure:
A mixture of 40 parts 5,7-dodecadiyne-1,12-diol, 215 parts 1,2-dimethoxyethane, 1 part dibutyltin-di-2-ethylhexanoate and 15 parts triethylamine was prepared and the resulting mixture was stirred vigorously. A solution of 133 parts n-octadecylisocyanate in 44 parts of 1,2-dimethoxyethane was added dropwise over a period of 60 min. The reaction temperature rose to 42° C. from 18° C. within 50 min. and then subsided. After the addition, 80 parts of 1,2-dimethoxyethane was then added to the reaction mixture and the mixture was stirred for an additional 2 hrs. To this mixture was added 1390 parts of heptane. The precipitate was collected by filtration, washed with petroleum ether (bp 30°-60° C.) and dried, giving 154.6 parts (99% yield) of desired product, mp 118°-119° C. Anal: calculated C50H92N2O4, C, 76.47%; H, 11.81%; N, 3.57%; found: C, 75.57%; H, 11.65%; N, 3.43%. IR (KBr pellet): 3330 cm-1 (N--H stretching), 2920+2850 cm-1 (C--H stretching), 1680 cm-1 (C=O), 1530 cm-1 (N--H bending), 1470 cm-1 (C--H), 1260 cm-1 (C--O--C stretching). Upon exposure to light, the crystals changed to blue, indicating the compound was solid state polymerizable.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>>[N+:18]([CH:21]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)([O-:20])=[O:19]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of methyl 4-formylbenzoate (34 g, 207 mmol) in nitromethane (500 mL) was added ammonium acetate (24 g, 311 mmol) and then the mixture was stirred at 120° C. for 1 h. Evaporated the solvent and diluted with ethyl acetate, the mixture was hydrolyzed and extracted. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain methyl 4-(2-nitrovinyl)benzoate as a yellow solid (26.6 g, yield 62%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.87 (s, 3H), 7.09-8.04 (m, 4H), 8.17-8.21 (d, J=14 Hz, 1H), 8.30-8.34 (d, J=14 Hz, 1H). LC-MS (ESI) m/z: 208 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:10]([Cl:17])[N:9]=[C:8]2[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:10]([Cl:17])[N:9]=[C:8]2[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:22][CH:23]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCc1nc(Cl)c(CC(=O)OC)n1Cc1ccc(N)cc1
Reactant: O=Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CC(=O)OC)n1Cc1ccc(NCc2ccccc2)cc1
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A mixture of methyl 1-(4-aminobenzyl)-2-butyl-4-chloroimidazole-5-acetate (1.00 g, 3.0 mmol, 1 eq), benzaldehyde (0.30 mL, 3.0 mmol, 1 eq), 4 Å powdered molecular sieves (enough to make a slurry) and 40 mL THF was stirred overnight. The next day, more benzaldehyde (0.2 mL) and acidic Al2O3 (activity 1, 1 g) were added and the slurry stirred another 24 hours. The solids were filtered and the solvent from the filtrate removed in vacuo. The residue was dissolved in methanol (10 mL) and sodium cyanoborohydride was added (0.19 g, 3.0 mmol, 1 eq). The mixture was stirred for 24 hours, after which the solvent was removed in vacuo to yield a green oil which was flash chromatographed over silica gel in 70:30 hexane/ethyl acetate to give 740 mg of product as an oil. NMR (200 MHz, CDCl3) δ7.42-7.24 (m, 5H); 6.74 (d, 2H, J=7 Hz); 6.56 (d, 2H, J=7 Hz); 4.98 (s, 2H); 4.31 (s, 2H); 3.61 (s, 3H); 3.48 (s, 2H); 2.60 (t, 2H, J=7 Hz); 1.67 (t of t, 2H, J=7,7 Hz); 1.35 (t of q, 2H, J=7,7 Hz); 0.89 (t, 3H, J=7 Hz). Mass Calcd. for C24H28ClN3O2 : 425.1868. Found: 425.1853.
Reaction SMILES: C([O:8][C:9](=[O:33])[C@@H:10]([O:25][C@H:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[Cl:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([O:25][C@H:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])[C:9]([OH:33])=[O:8])=[CH:17][CH:16]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)[C@H](C)O[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)O[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O

Procedure:
A mixture of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethoxy)-propionic acid benzyl ester and 10% Pd/C wet in EtOAc was hydrogenated under H2 balloon for 30 mins. The reaction was filtered off the catalyst and concentrated. The residue was purified by HPLC (15 to 70% ACN-H2O (0.1% TFA)) to give oil: 128 mg. HPLC retention time=1.07 minutes (condition C); MS (m−1)=375.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[CH2:24]([O:23][C:21](=[O:22])[NH:1][C@@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@H](N)Cn1ncc2ccc(O)cc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Yield: 78 %

Procedure:
1-((S)-2-Aminopropyl)-1H-indazol-6-ol [prepared in accordance with commonly owned WO 02/098862A1, the contents of which are by this reference incorporated herein] (2.00 g, 10.5 mmol) was suspended in THF (20 mL) and saturated aqueous sodium bicarbonate (10 mL) and benzyl chloroformate (1.50 mL, 15 mol) were added. The mixture was stirred at room temperature until the starting amine dissolved. Saturated aqueous sodium bicarbonate (150 mL) was added and the reaction mixture extracted with ethyl acetate (3×150 mL). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated to give a tan foam (2.65 g, 78%) which was pure by LC/MS (+APCI) m/z 326 (M+H+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[C:49]3[C:44](=[CH:45][C:46]([CH3:50])=[CH:47][CH:48]=3)[N:43]=[C:42]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[OH:57])[N:41]=2)[CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C=O)C>[OH:57][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[C:42]1[N:41]=[C:40]([N:37]2[CH2:36][CH2:35][CH:34]([NH:33][C:6]([C@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:39][CH2:38]2)[C:49]2[C:44](=[CH:45][C:46]([CH3:50])=[CH:47][CH:48]=2)[N:43]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: Cc1ccc2c(N3CCC(N)CC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC(NC(=O)[C@H]4CCCO4)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
(R)-Tetrahydrofuran-2-carboxylic acid (193 mg, 1.66 mmol) was dissolved in DMF (6 mL), followed by the addition of HATU (696 mg, 1.83 mmol). The mixture was then stirred for 15 min at room temperature under an N2 atmosphere. The 2-[4-(4-Amino-piperidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol (556 mg, 1.66 mmol) was dissolved in DMF (8 mL) and added to the mixture, followed by triethylamine (336 mg, 0.463 mL, 3.32 mmol). After 30 min, theDMF was removed in vacuo and the crude product partitioned between water and ethyl acetate. The aqueous layer was separated, washed with ethyl acetate, and the combined organic layers dried over MgSO4, filtered, and concentrated to give crude product as an orange oil. Purification via silica gel chromatography (20% ethyl acetate/80% 1:1 CH2Cl2:hexane) gave pure (R)-Tetrahydro-furan-2-carboxylic acid {1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-amide (303 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J=8.2, 1.5 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.67 (s, 1H), 7.40-7.36 (m, 2H), 6.97-6.93 (m, 2H), 4.48-4.45 (m, 2H), 4.20 (dd, J=8.2, 5.3 Hz, 1H), 4.06-3.96 (m, 1H), 3.88 (dd, J=14.3, 6.6 Hz, 1H), 3.74 (dd, J=14.5, 6.7 Hz, 1H), 3.43-3.32 (m, 2H), 2.51 (s, 3H), 2.16-2.07 (m, 1H),
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:11])=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH:2]=C.C[N+]1([O-])CC[O:16]CC1.CCCCCC>O1CCOCC1.[Os](=O)(=O)(=O)=O>[Cl:11][C:5]1[C:4]([CH2:1][CH:2]=[O:16])=[C:9]([Cl:10])[N:8]=[CH:7][N:6]=1
Reactant: C=CCc1c(Cl)ncnc1Cl
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=CCc1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a stirred solution of 5-allyl-4,6-dichloropyrimidine (2.5 g) in dry dioxane (25 mL), N-methyl morpholine N-oxide (2.3 g) and osmium tetroxide (0.85 mL, 25% solution in water) were added. The reaction mixture was stirred at room temperature for 2 hours before being quenched by solid sodium bisulphate. The reaction mixture was filtered through celite bed. The celite bed was washed with dioxane (10 mL). The combined filtrate was taken into a 100 mL three necked round bottom flask and sodium metaperiodate (6 g, in 5 mL water) was added. The reaction mixture was stirred at room temperature for about 3 hours, then diluted with water (30 mL). Aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure gave crude product, which was treated with hexane to offer a solid. The solid obtained was filtered, washed with cold hexane (50 mL) and dried under vacuum to get 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.7 g) as white solid. 1H NMR (DMSO-d6): δ 4.21 (s, 2H), 8.86 (s, 1H), 9.7 (s, 1H).