Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:29]([N:31]([CH2:46][CH3:47])[C:32]([CH:34](OS(C)(=O)=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33])[CH3:30]>CN(C=O)C>[NH3:8].[CH2:46]([N:31]([CH2:29][CH3:30])[C:32]([CH:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:14][C:15](=[O:28])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:33])[CH3:47]
Reactant: CCN(CC)C(=O)C(OS(C)(=O)=O)c1ccccc1
Reactant: O=C(Nc1ccc(N2CCNCC2)c(F)c1)c1ccccc1-c1cccnc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3cccnc3)cc2F)CC1
Product: N
Reaction time: 5 h

Procedure:
A solution of N-(3-fluoro-4-piperazin-1-yl-phenyl)-2-pyridin-3-yl-benzamide (0.16 g, 0.4 mmol) and methanesulfonic acid diethylcarbamoyl-phenyl-methyl ester (0.06 g, 0.2 mmol) in DMF (1 mL) was heated at 50° C. After five hours, the reaction mixture was quenched with H2O (5 mL) and extracted with EtOAc (4×10 mL). The organic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure. Chromatography of the residue (SiO2: NH3 (MeOH):CH2Cl2) yielded the title compound.
Reaction SMILES: CC1C=C(C)NN=1.[CH3:8][C@@H:9]1[C@H:18]2[C:12](=[C:13]([CH3:22])[CH2:14][CH2:15][C@@H:16]([C:19]([CH3:21])=[CH2:20])[CH2:17]2)[CH2:11][CH2:10]1.[OH-:23].[Na+]>ClCCl>[CH3:8][C@@H:9]1[C@H:18]2[C:12](=[C:13]([CH3:22])[CH2:14][CH2:15][C@@H:16]([C:19]([CH3:21])=[CH2:20])[CH2:17]2)[C:11](=[O:23])[CH2:10]1
Reactant: C=C(C)[C@@H]1CCC(C)=C2CC[C@H](C)[C@@H]2C1
Reactant: [OH-]
Agent: Cc1cc(C)[nH]n1
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C)[C@@H]1CCC(C)=C2C(=O)C[C@H](C)[C@@H]2C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
At −30° C., a solution of 3,5-dimethyl-1H-pyrazole (7.2 g, 74.9 mmol) in dichloromethane (40 ml) was treated with CrO3 (7.5 g, 74.9 mmol, added in two portions) while the reaction temperature rose to −20° C. The resulting mixture was stirred at −20° C. for 0.5 h and treated within 20 min. with a solution of α-bulnesene (3.0 g, 14.7 mmol) in dichloromethane (20 ml) while the reaction temperature rose to −10° C. The resulting mixture was stirred between −20° C. and −10° C. for 4 h before allowing the reaction temperature to slowly reach 20° C. (overnight), treated with 8M aqueous NaOH (70 ml), stirred at 20° C. for 20 h, and extracted with MTBE (400 ml). The aqueous phase was extracted with MTBE (150 ml) and the joined organic phases were washed twice with 2 M aq. HCl (100 ml), once with H2O (100 ml), once with aqueous saturated NaCl solution (100 ml), dried with MgSO4, filtered, and the solvent evaporated. FC (200 g 0.015-0.040 mm-SiO2, flow: 60 ml/min., hexane/methyl t-butyl ether 100:0 to 85:15 in 30 min.) of the crude product (2.4 g) gave (3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-3,3a,4,5,6,7-hexahydroazulen-1(2H)-one (130 mg, 4%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]([CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][N:15]=[C:16]2[NH2:19])=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6].Cl.Cl.[CH3:22]OC(=O)C(N)CC1C=C2C(=CC=1)C(N)=NC=C2>>[ClH:1].[ClH:1].[CH3:22][O:6][C:5](=[O:7])[CH:4]([NH2:3])[CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][N:15]=[C:16]2[NH2:19])=[CH:11][CH:10]=1
Reactant: COC(=O)C(N)Cc1ccc2c(N)nccc2c1
Reactant: Nc1nccc2ccc(CC(N)C(=O)O)cc12
Agent: Cl
Product: COC(=O)C(N)Cc1ccc2ccnc(N)c2c1

Procedure:
Compound 37i was prepared from 37h using the procedure described for 1j. 1H-NMR 200 MHz (CD3OD) δ: 3.38-3.60 (2H, m), 3.80 (3H, s), 4.52 (1H, t, J=7 Hz), 7.25 (1H, dd, J=7 Hz and J=1 Hz), 7.59 (1H, d, J=7 Hz), 7.87-7.99 (2H, m), 8.48 (1H, br.s).
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C([N:43]1[CH2:48][CH2:47][CH2:46][CH:45]([CH:49]=O)[CH2:44]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:53])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:53])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:49][CH:45]2[CH2:46][CH2:47][CH2:48][NH:43][CH2:44]2)[CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@]1(C(=O)O)CN(CC2CCCNC2)C[C@@H]1CCCB(O)O
Reaction time: 2 h
Yield: 39.6 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and N-boc-piperidine-3-carboxaldehyde (149 mg, 0.7 mmol), stirred for 2 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 16 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(piperidin-3-ylmethyl)pyrrolidine-3-carboxylic acid (62 mg, 29%) as a granular pale amber solid. NMR (D2O) δ 3.70-4.00 (m, 2 H), 3.20-3.45 (m, 5 H), 2.65-2.90 (m, 2 H), 2.50-2.65 (m, 2 H), 2.15-2.30 (m, 1 H), 1.75-2.00 (m, 2 H), 1.50-1.75 (m, 2 H), 1.10-1.40 (m, 4 H), 0.65-0.75 (m, 2 H). MS (m−H2O+1): 296.3; MS (m−2H2O+1): 278.1.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]#[C:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)=O)[CH3:2].[CH3:21][NH:22][NH2:23].C(O)C.[H][H]>[Pd].C1COCC1>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]1[N:22]([CH3:21])[N:23]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(C#CC(=O)c1ccc([N+](=O)[O-])cc1)OCC
Reactant: CNN
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(OCC)c1cc(-c2ccc(N)cc2)nn1C
Temperature: 70 °C
Yield: 89.8 %

Procedure:
4,4-Diethoxy-1-(4-nitrophenyl)but-2-yn-1-one (Intermediate 9, 5.77 g, 22.4 mmol), methylhydrazine (1.2 ml, 22.4 mmol), and ethanol (100 ml) were combined and warmed at 70° C. for 45 min. THF (50 ml) and palladium on carbon (10%, 100 mg) were added. The suspension was stirred under 1 atmosphere of hydrogen gas for 16 hrs. The mixture was filtered and evaporated to give the title compound as a light yellow solid (5.54 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[CH3:49][C:50]1[CH:55]=[CH:54][C:53]([S:56][CH2:57][CH2:58]CO)=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][CH2:58][CH2:57][S:56][C:53]2[CH:54]=[CH:55][C:50]([CH3:49])=[CH:51][CH:52]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(SCCCO)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCSc4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 60.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[(4-methylphenyl)sulfanyl]-1-propanol (74 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (82 mg, yield 56%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[O:75]1[CH2:80][CH2:79][CH:78]([NH2:81])[CH2:77][CH2:76]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:81][CH:78]4[CH2:79][CH2:80][O:75][CH2:76][CH2:77]4)=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: NC1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)NC1CCOCC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added tetrahydro-2H-pyran-4-amine hydrochloride (13 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of tetrahydro-2H-pyran-4-amine hydrochloride were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(tetrahydro-2H-pyran-4-yl)acetamide. (32 mg, 0.065 mmol, 46%)
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)(=[O:3])[CH3:2].S(Cl)([Cl:29])(=O)=O>C(Cl)(Cl)Cl.Cl.C(OCC)(=O)C.CCOCC>[Cl:29][CH2:2][C:1]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)=[O:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)CCl)c3c2)c1=O
Temperature: 25 °C

Procedure:
To a solution of 3-(3-acetyl-1,2-benzisothiazol-5-yl)-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.570 g, 0.00154 mol) in chloroform is added sulfuryl chloride (0.350 ml, 0.00433 mol). The resultant mixture is stirred one hour at reflux. Concentrated hydrochloric acid (one drop) is added followed by sulfuryl chloride (1.05 ml, 0.0130 mol) and the resultant mixture is stirred three days at reflux. The mixture is cooled to room temperature, diluted with ethyl acetate and ether, washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to a solid. The resultant solid is chromatographed on silica gel with hexanes:ethyl acetate to afford a white solid. The solid is chromatographed on silica gel with chloroform to afford a white solid, which is recrystallized from ethyl acetate and hexanes to give the title compound as a white crystalline solid (mp 215-215° C.) which is identified by NMR spectral analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[C:29]([N:48]1[CH:52]=[C:51](B(O)O)[CH:50]=[N:49]1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:51]5[CH:50]=[N:49][N:48]([C:29]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)[CH:52]=5)[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[CH2:13][CH2:14]2)=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: OB(O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CS(=O)(=O)c1ccc(OC2CCN(c3ccnc4ccc(Br)cc34)CC2)cc1
Product: CS(=O)(=O)c1ccc(OC2CCN(c3ccnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)cc1
Yield: 85.1 %

Procedure:
80 mg 6-bromo-4-{4-[4-(methylsulfonyl)phenoxy]piperidino}quinoline (compound in Production Example 89) and 80 mg 1-trityl-1H-4-pyrazolylboronic acid were reacted in the same manner as in Example 9, to give 102 mg 4-[4-(4-methylsulfonylphenoxy)piperidin-1-yl]-6-(1-trityl-1H-pyrazol-4-yl) quinoline. This product was reacted in the same manner as in Example 67, to give 52 mg of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)/[C:7](=[O:19])[N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si](C)(C)C)=[CH:4][CH:3]=1.[C:28]([CH:31]=[N:32][C:33]([O:35][Si:36]([CH3:39])([CH3:38])[CH3:37])=[CH2:34])([CH3:30])=[CH2:29]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:19])[C:6]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:34][C:33](=[O:35])[NH:32][CH:31]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[CH3:11][O:12][CH:13]([Si:36]([CH3:37])([CH3:38])[CH3:39])[CH3:14]
Reactant: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(C)C=NC(=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: COC(C)[Si](C)(C)C
Yield: 32.8 %

Procedure:
In a manner similar to the method described in example 55b, E/Z-6-chloro-3-(3-chlorobenzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (8 g, 20 mmol) prepared in example 55a was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (21 g, 99 mmol) prepared in example 87a in toluene (200 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white gum (3.5 g, 33%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:51][C:52]1[CH:60]=[C:59]2[C:55]([C:56]([C:61](O)=[O:62])=[N:57][NH:58]2)=[CH:54][CH:53]=1>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:61]([C:56]3[C:55]4[C:59](=[CH:60][C:52]([F:51])=[CH:53][CH:54]=4)[NH:58][N:57]=3)=[O:62])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1n[nH]c2cc(F)ccc12
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)c(F)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(NC(=O)c3n[nH]c4cc(F)ccc34)c(F)c2)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
To a stirred suspension of (+)-(R)-2-(4-amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (40 mg) in THF (6 ml) and DMF (2 ml) were added sequentially N-methylmorpholine (0.12 ml), TBTU (128 mg) and 6-fluoro-1H-indazole-3-carboxylic acid (47 mg, CAS 129295-30-3) and the mixture was heated at 50° C. for 24 h and then at 60° C. for 18 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (R)-2-{3-fluoro-4-[(6-fluoro-1H-indazole-3-carbonyl)-amino]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (15 mg, 24%) as a white solid. MS (ISP): 476.1 ([M+NH4]+), 459.1 ([M+H]+), 403.1 ([M+H—C4H8]+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)(=[O:29])=[O:28]
Reactant: COC(=O)c1ccccc1-c1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccccc1-c1ccc(COS(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate and 8.4 g (83.0 mmol) of triethylamine were dissolved in methylene chloride (150 ml). Under cooling with ice, a solution of 5.7 g (50 mmol) of methanesulfonyl chloride in methylene chloride (25 ml ) was dropwise added thereto, followed by further stirring for one hour. The reaction liquid was poured into water, followed by the extraction with methylene chloride. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. 13.1 g of the title compound was obtained as a wax (yield 100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=O)[CH2:20]Br.C(=O)(O)[O-].[Na+].O>C(O)C>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:1]=[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]2[CH:20]=1
Reactant: Nc1nccc2ccccc12
Reactant: Cc1ccccc1C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1cn2ccc3ccccc3c2n1
Yield: 81.9 %

Procedure:
A mixture of 3.0 g of 1-aminoisoquinoline, 6.7 g of 2'-methyl-2-bromoacetophenone and 17.5 g of sodium bicarbonate in 50 ml of ethanol was refluxed for 2 hours. After being cooled, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel and recrystallized from dichloromethane/petroleum ether to give 4.4 g of the title compound as pale brown prisms.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([C:16]#[N:17])([CH3:15])[CH3:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:18][C:19]1[N:20]=[CH:21][N:22](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=1>C(#N)C>[C:16]([C:13]([C:11]1[CH:12]=[C:3]([CH2:2][N:20]2[C:19]([CH3:18])=[CH:23][N:22]=[CH:21]2)[CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])([CH3:15])[CH3:14])#[N:17]
Reactant: COC(=O)c1cc(CBr)cc(C(C)(C)C#N)c1
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Product: COC(=O)c1cc(Cn2cncc2C)cc(C(C)(C)C#N)c1

Procedure:
A mixture of methyl 3-bromomethyl-5-(1-cyano-1-methylethyl)benzoate (0.7 g), 4-methyl-1-tritylimidazole (0.8 g) and acetonitrile (2 ml) was heated under reflux for 48 h, then evaporated to dryness. The residue of 3-[3-(1-cyano-1-methylethyl)-5-methoxycarbonylbenzyl]-4-methyl-1-tritylimi dazolium bromide was washed with diethyl ether (2×10 ml), and the residue was treated with glacial acetic acid (4 ml) and water (1 ml) and heated at 90° for 15 minutes. The mixture was diluted with water (20 ml), and washed with diethyl ether, and the aqueous phase was basified with 10N aqueous sodium hdroxide and extracted three times with ethyl acetate. The extracts were combined and evaporated to dryness, and the residue was purified by flash column chromatography, eluting with methanol:chloroform (1:49 by volume), to give methyl 5-(1-cyano-1-methylethyl)-3-(5-methylimidazol-1-ylmethyl)benzoate, mp 101°-104°.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[CH:34][CH:35]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:36][C:33]4[N:32]=[CH:31][C:30]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:35][CH:34]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCCCC2)cn1
Reactant: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Product: CCOCc1cc2cnc(Nc3ccc(N4CCCCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 15.2 %

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.60 g, 1.79 mmol) and 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine (0.438 g, 2.47 mmol) were heated to reflux in toluene (6 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was filtered off and washed with toluene (2×4 mL) to give 8-cyclopentyl-6-ethoxymethyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.122 g, 15.2%). MS (APCI) Calc'd for M+1: 449.3. Found: 449.3. Anal. Calc'd for C25H32N6O2: C, 66.94; H, 7.19; N, 18.74. Found: C, 66.72; H, 7.13; N, 18.57.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6](O)=O)[CH2:4][SH:5].Br[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14].[OH2:16]>>[NH:12]([CH2:11][CH2:10][CH2:6][C@@H:3]([C:4]([OH:16])=[S:5])[NH2:2])[C:13]([NH2:15])=[O:14]
Reactant: O
Reactant: N[C@@H](CS)C(=O)O
Reactant: NC(=O)NCCBr
Agent: Cl
Product: NC(=O)NCCC[C@H](N)C(O)=S
Temperature: 50 °C

Procedure:
26.25 g of cysteine hydrochloride and 27.83 g of β-bromoethylurea are dissolved in 150 cc of water under nitrogen. A solution of 13.35 g of soda in 30 cc of water is added during a 40 minute period and the mixture is heated for 3 hours at 50° C. After cooling, there is added to the solution, four times its volume of water and the resulting mixture is passed over a cation exchange resin. After washing with water, the product fixed on the resin is eluted with an ammoniacal solution. The eluate is evaporated to dryness and the residue is crystallized in an aqueous methanol solution. There are obtained 19.5 grams of the white product melting at 220° C. with decomposition.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.ON1C2C=CC=CC=2N=N1.[NH2:38][C@H:39]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:40][N:41]1[CH2:45][CH2:44][C@H:43](O)[CH2:42]1.C(Cl)[Cl:54]>>[ClH:54].[C:1]1([C:7]2([C:10]([NH:38][C@@H:39]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:40][N:41]3[CH2:42][CH2:43][CH2:44][CH2:45]3)=[O:12])[CH2:8][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[C@@H](CN1CC[C@H](O)C1)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: ClCCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: Cl
Product: O=C(N[C@H](CN1CCCC1)c1ccccc1)C1(c2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-phenylcyclopropanecarboxylic acid (1 eq.), were added at about 20-35° C., DCC (1 eq) in DCM and 1-Hydroxybenzotriazole (1 eq.). The mixture was stirred for 10 min and to this mixture was added (S)-1-((R)-2-amino-2-phenylethyl)pyrrolidin-3-ol (1 eq) and the contents were allowed to stir at about 20-35° C. for 12 h. The reaction mixture was filtered, the filtrate was diluted with DCM and the organic layer was washed with sat.NaHCO3 solution, brine and dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude was purified by flash chromatography using silica gel (230-400 mesh) to give the desired product as a pale yellow gum. The resultant product is treated with hydrochloric acid to form the corresponding hydrochloric acid salt by following standard salt forming procedures known in the art.