Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21]CC1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21]
Reactant: c1ccc(COc2ccccc2CCCCc2ccc3ccccc3c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1CCCCc1ccc2ccccc2c1
Yield: 78 %

Procedure:
The whole of this 4-(2-naphthyl)-1-(2-benzyloxyphenyl)butane was dissolved in 20 ml of methylene chloride, and 9.5 ml of a 1M solution of boron tribromide in methylene chloride were added, whilst ice-cooling and stirring, to the solution. The resulting mixture was then stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was diluted with methylene chloride, washed with water, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.56 g (yield 78%) of the title compound as colorless solid.
Reaction SMILES: Cl.[NH2:2][C@@:3]([C:15]1([C:18](O)=[O:19])[CH2:17][CH2:16]1)([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[F:14])[CH3:4]>C1COCC1>[NH2:2][C@@:3]([C:15]1([CH2:18][OH:19])[CH2:16][CH2:17]1)([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[F:14])[CH3:4]
Reactant: C[C@@](N)(c1cc([N+](=O)[O-])ccc1F)C1(C(=O)O)CC1
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@](N)(c1cc([N+](=O)[O-])ccc1F)C1(CO)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Procedure for intermediate Da3 (R1,2=cyclopropyl, R3=Me): A solution of the hydrochloride of 1-[(S)-1-amino-1-(2-fluoro-5-nitro-phenyl)-ethyl]-cyclopropanecarboxylic acid (1.8 g) in THF (10 ml) was cooled to 0° C. and treated with a solution of BH3-THF complex in THF (1M, 22.7 ml) and stirring was continued at 0° C. for 3 h. The reaction mixture was pored into crashed ice/saturated aqueous NaHCO3 (1/1, 200 ml), extracted with ethyl acetate, the organic layer was dried and evaporated to give crude {1-[(S)-1-amino-1-(2-fluoro-5-nitro-phenyl)-ethyl]-cyclopropyl}-methanol as a pale yellow solid. MS (ESI): m/z=255.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C=Nc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccnc1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 3-isocyanatopyridine as the starting materials in 20% yield. LCMS for C30H32ClN8O2 (M+H)+: m/z=571.0.
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]1([CH:16]2[CH2:21][C:20](O)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:10]1([CH:16]2[CH2:21][C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][CH2:18][N:17]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2)CC1C1CCCCC1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CC=C(c2ccccc2)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of BF3.OEt2 (4.93 ml, 38.9 mmol) in CH2Cl2 (30 ml) was added to a stirred solution of benzyl 2-cyclohexyl-4-hydroxy-4-phenylpiperidine-1-carboxylate (5 g, 12.71 mmol) in CH2Cl2 (244 ml) at 0° C. The mixture was stirred at room temperature for 15 minutes. Saturated sodium bicarbonate (100 ml) was added after 15 minutes. Extracted twice with CH2Cl2 and the combined organics were dried and concentrated. The crude product was not purified.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][CH2:16][C:17]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][CH2:24][N:25](C(=O)C(F)(F)F)[CH2:26]4)=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][CH2:16][C:17]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][CH2:24][NH:25][CH2:26]4)=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CCC(=O)N1CCC(c2ccc(Cl)cc2)CC1)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(CCC(=O)N1CCC(c2ccc(Cl)cc2)CC1)c1ccc2c(c1)CNCC2
Yield: 90.8 %

Procedure:
A solution of 4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxo-1-[2-(trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinyl]-1-butanone (1.1 g, 2.17 mmol) and potassium carbonate (900 mg, 6.5 mmol) in a mixed solvent of water (10 ml) and methanol (40 ml) was stirred at room temperature for 2 hours and then extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, whereby 810 mg of the title compound was obtained as colorless powder.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=[O:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[CH3:22][N:8]1[C:3]([C:2]([F:1])([F:20])[F:21])=[CH:4][C:5](=[O:19])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:7]1=[O:9]
Reactant: COc1ccc(Cn2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Cn2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
A solution of 3.0 grams (0.01 mole) of 6-trifluoromethyl-3-(4-methoxy-phenylmethyl)-2,4(1H,3H)-pyrimidinedione in 25 mL of N,N-dimethylform-amide was stirred and 1.4 grams (excess) of potassium carbonate was added. To this was then added 0.7 mL (0.01 mole) of methyl iodide. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 18 hours, then poured into a mixture of 100 mL of ice and 100 mL of aqueous 10% hydrochloric acid. The resultant solid was collected by filtration and washed with water. The solid was then dissolved in 200 mL of ethyl acetate and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure, yielding 2.1 grams (66.9% yield) of 1-methyl-6-trifluoromethyl-3-(4-methoxyphenylmethyl)-2,4(1H,3H)-pyrimidinedione, mp 79°-80° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[NH2:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:32]3[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:26]([NH2:25])=[O:27])=[CH:5][C:4]=2[N:3]=1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(C(N)=O)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 14.7 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), (3-aminocarbonylphenyl)boronic acid (0.603 g, 3.65 mmol), potassium carbonate (1.4 g, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.021 g, 0.030 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel. The vessel was then sealed and heated at 110° C. for 64 hours and allowed to cool to room temperature. A precipitate formed and was isolated by filtration, washed with water and DME, and recrystallized from methanol (100 mL/900 mg). The crystals were isolated by filtration, washed with methanol, and dried in a vacuum oven at 65° C. to provide 191 mg of 3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-7-yl]benzamide as an off-white solid, mp >250° C.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)CC(C)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:23][CH2:22]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Solvent: CC(C)CCO
Product: O=c1[nH]c(N2CCN(c3ccccc3Cl)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-(2-chlorophenyl)piperazine (84.9 μl; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 and worked up; yield: 65 mg (37%), crystals;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:43]=[CH:42][C:34]3[N:35]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[S:37][C:33]=3[CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd]>[CH3:22][N:8]([C:4]1[CH:3]=[C:2]([C:31]2[CH:43]=[CH:42][C:34]3[N:35]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[S:37][C:33]=3[CH:32]=2)[CH:7]=[N:6][CH:5]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CN(c1cncc(Br)c1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cncc(N(C)S(=O)(=O)c4ccc(C(F)(F)F)cc4)c3)cc2s1
Reaction time: 0.25 h

Procedure:
To a microwave vial equipped with a stir bar was charged with N-(5-bromopyridin-3-yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.250 g, 0.6 mmol) in 1,4-dioxane (3 ml), was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.300 g, 0.9 mmol), Pd FibreCat® (0.024 g, 20%) and 2M sodium carbonate (0.8 ml, 2 mmol). The vial was capped and then placed into a CEM Microwave for 15 minutes at 100° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired product, N-deacylated material and boronic ester in the mixture. The reaction was stopped at this point, to prevent further de-acylation of product. The mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was collected by extracting with DCM (3×20 ml). Combined organic extracts, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was diluted with ethyl acetate and stirred 10 minutes. The precipitate was collected by filtration and washed with 1:1 ethyl acetate/hexanes. This gave N-(6-(5-(N-methyl-4-(trifluoromethyl)phenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.160 g, 50% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 507 (MH+). Calc'd exact mass for C22H17F3N4O3S2: 506. 1H NMR (400 MHz, DMSO-d6): 2.23 (s, 3H), 3.31 (s, 3H), 7.71 (d, J=7.53 Hz, 1H), 7.81 (d, J=7.03 Hz, 3H), 7.87 (s, 1H), 8.02 (d, J=6.53 Hz, 2H), 8.26 (s, 1H), 8.42 (s, 1H), 8.91 (s, 1H), 12.44 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13]>Cl>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([SH:1])=[CH:7][CH:6]=1)[CH3:13]
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc(S)cc1

Procedure:
70 g G 4-mercapto-phenyl-acetic acid are heated at reflux for 30 minutes in 500 cc of 4 N hydrochloric acid in ethanol. The reaction mixture is then completely concentrated at reduced pressure. The oily residue is divided between ether and water, the ether phase is subsequently washed with a 10% sodium bicarbonate solution and water, is dried over sodium sulphate, and the solvent is removed by distillation. The crude 4-mercapto-phenyl-acetic acid ethyl ester, obtained as oily residue, may be purified by distillation; B.P. 103° at 0.4 mm of Hg.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](S(C3C=CC=CC=3)(=O)=O)[N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][O:26][Na]>C1COCC1>[CH3:25][O:26][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[N:11]=1
Reactant: CO[Na]
Reactant: O=S(=O)(c1ccccc1)c1cccc(S(=O)(=O)c2ccccc2)n1
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a N2 purged reactor is charged 5.0 g (13.9 mmol) of 4d and 50 mL of anhydrous THF. The resulting slurry is treated drop-wise with MeONa (25 wt % in MeOH) (1.1 equiv). The resulting slurry is stirred for 1 h at room temperature, and a complete conversion is observed by LC-MS. The slurry is filtered, washed with IPA; and dried in oven overnight at 50° C. to give 1.94 g 3d as a white solid. The mother liquor is concentrated, 15 mL of IPA is added, and the mixture warmed until complete dissolution. The mixture is cooled down to 10° C. and held for 1 h. A second crop of solid is collected by filtration, and dried to yield another 1.17 g of white solid 3d, total 90% yield; mp 74.6-75.8° C. 1H NMR (400 MHz, CDCl3) δ 8.12-8.09 (m, 2H), 7.78-7.73 (m, 2H), 7.64 (tt, J=7.4, 1.3 Hz, 1H), 7.58-7.53 (m, 2H), 6.88 (dd, J=7.7, 1.4 Hz, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.0, 155.7, 139.7, 138.9, 133.6, 129.1, 128.9, 115.5, 114.9, 54.0; HRMS (ESI) m/z 250.0528 (M+H+), calc. for C12H12NO3S 250.0532.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([NH:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=O)=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:10](=[O:11])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: COCCNC(=O)NNC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COCCn1c(-c2ccc(Cl)cc2)n[nH]c1=O

Procedure:
1.28 g (4.71 mmol) of 2-(4-chlorobenzoyl)-N-(2-methoxyethyl)-hydrazinecarboxamide from Example 13A are heated under reflux overnight in 10 ml 3 N aqueous sodium hydroxide. After cooling, it is acidified to about pH 2.5 with 1 N hydrochloric acid with ice-cooling and the resulting precipitate filtered off and dried in vacuo. 1.09 g (92% of theory) of the target compound, which is reacted without further purification, are thus obtained.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:13])[CH2:5][CH:6]([C:8]1([CH3:12])[CH2:11][CH2:10][CH2:9]1)[NH3+:7].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([F:22])=[CH:17][N:16]=1.C(N(CC)CC)C.O>C1COCC1.CCO.ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:7][CH:6]([C:8]2([CH3:12])[CH2:11][CH2:10][CH2:9]2)[CH2:5][C:4]([O:3][CH3:2])=[O:13])[C:18]([F:22])=[CH:17][N:16]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)CC([NH3+])C1(C)CCC1
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CC(Nc1nc(Cl)ncc1F)C1(C)CCC1
Temperature: 55 °C
Reaction time: 17 h

Procedure:
Racemic 3-methoxy-1-(1-methylcyclobutyl)-3-oxopropan-1-aminium chloride, 117a, (3.3 g, 15.9 mmol) was dissolved in a mixture of 59 mL THF and 6.6 mL EtOH and the solution was cooled in an ice bath. 2,4-Dichloro-5-fluoro-pyrimidine (2.9 g, 18.0 mmol) was added followed by dropwise addition of triethylamine (5.1 g, 51.0 mmol). The reaction mixture was stirred at 55° C. for 17 hours. The reaction mixture was cooled to room temperature after which water and dichloromethane were added. The phases were separated and the aqueous layer was washed with dichloromethane. The organic layers were combined and washed with brine. The solvents were removed and the residue was purified via silica gel chromatography (EtOAc/Hexanes) to afford the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.23 minutes (M+H) 302.35.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:3]=1.[CH3:20][O:21][C:22]([C@H:24]1[CH2:28][C@H:27]([NH2:29])[CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23].C(N(CC)CC)C>O1CCOCC1.ClCCl>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[N:3]=[C:2]([NH:29][C@@H:27]2[CH2:26][N:25]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C@@H:24]([C:22]([O:21][CH3:20])=[O:23])[CH2:28]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1ccccc1-c1nc(Cl)c2ccccc2n1
Reactant: COC(=O)[C@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](Nc2nc(-c3ccccc3OC)nc3ccccc23)CN1C(=O)OC(C)(C)C
Yield: 51.7 %

Procedure:
4-Chloro-2-(2-methoxyphenyl)quinazoline (0.463 g, 1.709 mmol), (2R,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.480 g, 1.709 mmol) and triethylamine (0.715 mL, 5.127 mmol) in dioxane (9 mL) were heated at reflux for 3 days. The mixture was cooled, diluted with dichloromethane (50 mL), and washed with water (50 mL). The organic extracts were dried (MgSO4) and concentrated. Purification by silica gel chromatography (10% methanol in dichloromethane) gave the title compound as a solid (0.423 g, 52%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC(O)CC2)c(F)c1
Yield: 43.8 %

Procedure:
3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (173 mg, 0.46 mmol) was dissolved in ethanol (5 ml), treated with sodium borohydride (18 mg, 0.48 mmol) and refluxed 1 hour. Solvent was evaporated, the residue treated with water (5 ml), neutralised with 1 N hydrochloric acid, extracted with dichloromethane (3×10 ml), and dried (magnesium sulfate). Evaporation gave the desired product (76 mg). MS (ESP): 378 (MH+) for C18H20FN3O5.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH3:7][S:8](Cl)(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.OS([O-])(=O)=O.[K+]>C(Cl)Cl.O>[CH2:1]([O:6][S:8]([CH3:7])(=[O:10])=[O:9])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCCCO
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C#CCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 ml (43.2 mmol) 4-pentyn-1-ol in 140 ml CH2Cl2 were treated with 3.7 ml (47.6 mmol) methanesulfonyl chloride and 11.1 ml (64.84 mmol) N,N-diisopropylethylamine at 0° C. for 10 min. The solution was stirred at RT for 1 h and was diluted with CH2Cl2. Water was added, the mixture was stirred for 10 min and was added to a 10% aqueous KHSO4 solution. The phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic ones were washed with a saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4 and evaporated to give crude Methanesulfonic acid pent-4-ynyl ester as yellow oil, MS: 156 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].Cl[C:34]1[C:39]([F:40])=[CH:38][CH:37]=[C:36]([CH2:41][O:42][CH3:43])[N:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[C:36]([CH2:41][O:42][CH3:43])[N:35]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)OC1(C)C
Reactant: COCc1ccc(F)c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCc1ccc(F)c(-c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)n1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a degassed solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Preparation 7, 325 mg, 0.72 mmol), 2-chloro-3-fluoro-6-(methoxymethyl)pyridine (Preparation 52, 191 mg, 1.09 mmol) and potassium carbonate (200 mg, 1.45 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added Pd(PPh3)4 (83 mg, 0.072 mmol) and the reaction was heated to 80° C. for 18 hours. The reaction was cooled and concentrated in vacuo. The resulting residue was partitioned between EtOAc (15 mL) and water (15 mL). The aqueous layer was extracted with EtOAc (2×15 mL) and the organic extracts were combined, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 1:1 EtOAc in heptanes to afford the title compound (250 mg, 75%).
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Cl.[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:25]=4[O:24][CH3:23])[CH2:30]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: COc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc(-c2nc(C(=O)N3CCc4c(ccc(OC)c4OC)C3)c3ccccc3n2)cc1
Yield: 13 %

Procedure:
Reaction of 2-(4-methoxylphenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 24 (13% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.72 and 2.98 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.69-3.87 (5s, 9H), 4.41 and 4.93 (2s, 2H), 6.63 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.11-7.14 (m, 2H), 7.71-7.74 (m, 1H), 7.83-7.95 (2d, 1H), 8.03-8.10 (m, 2H), 8.45-8.51 (m, 2H); MS (ESI) m/z 456 ([M+H]+).