Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([P:8]([CH2:17][S:18](OC1C=CC=CC=1)(=[O:20])=[O:19])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH2:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[O:10]([P:8]([CH2:17][S:18]([NH:42][CH2:41][CH:38]1[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]1)(=[O:20])=[O:19])([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=P(CS(=O)(=O)Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)CP(=O)(Oc2ccccc2)Oc2ccccc2)CC1

Procedure:
A solution of 2.405 g (5.947 mM) of phenyl di-phenoxyphosphorylmethanesulfonate and 1.66 g (7.73 mM) of 1-(tert-butoxycarbonyl)piperidine-4-ylmethylamine in 50 ml of toluene was refluxed overnight. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate:2/1 to 1/1) to provide the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:17]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25](=[O:26])[NH:27][CH2:28][C:29](=[O:30])[NH:14][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)OCc1ccccc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and benzyloxycarbonylamino-acetic acid (CA [1138-80-3]).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][N:6]=[CH:5]2.Cl[C:13]1[N:18]=[N:17][C:16]([N:19]([CH3:30])[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[CH:15][CH:14]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:30][N:19]([CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]1)[C:16]1[N:17]=[N:18][C:13]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][N:6]=[CH:5]3)=[CH:14][CH:15]=1
Reactant: Brc1ccc2cnncc2c1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CN(c1ccc(-c2ccc3cnncc3c2)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 6-bromophthalazine (0.11 g, 0.50 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (0.16 g, 0.58 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.14 g, 0.55 mmol), potassium acetate (0.15 g, 1.5 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.04 g, 0.05 mmol) in dioxane (3 mL) was heated at 80° C. for 3 h. Potassium carbonate (0.20 g, 1.5 mmol) and water (0.4 mL) were added and the mixture was stirred for 48 h at 90° C. After cooling, the reaction was purified by solid phase extraction (SiliaBond Carbonate®, MeOH as eluent). After evaporation of the solvent under reduced pressure, the material afforded was purified via reverse phase preparative HPLC using 5 to 95% acetonitrile in water modified with 3% n-PrOH. LCMS: Rt=0.43 min [M+H] (LCMS method Q); 377.245; 1H NMR (400 MHz, DMSO-d6) δ 9.74-9.62 (m, 2H), 8.75 (s, 1H), 8.74 (dd, J=8.5, 2.0 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.12 (d, J=9.5 Hz, 1H), 7.19 (d, J=9.5 Hz, 1H), 5.19 (tt, J=12.0, 3.5 Hz, 1H), 2.98 (s, 3H), 1.56 (dd, J=12.0, 3.5 Hz, 2H), 1.45 (t, J=12.0 Hz, 2H), 1.27 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:27][CH2:26][CH2:25][CH2:24][CH:16]2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[CH:11][CH:10]=1)C1C=CC=CC=1.FC1C=CC=CC=1C1(C2C=CC(O)=CC=2)CCCCCC1=O>>[CH:20]1[C:19]2[C:15]3([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[CH2:27][CH2:26][CH2:25][CH2:24][CH:16]3[O:17][C:18]=2[CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(COc2ccc(C34CCCCC3Oc3ccccc34)cc2)cc1
Agent: O=C1CCCCCC1(c1ccc(O)cc1)c1ccccc1F
Product: Oc1ccc(C23CCCCC2Oc2ccccc23)cc1

Procedure:
The title compound 961 was synthesized from compound 34 (10 mg) using the procedure described for the synthesis of compound 20. Purity LC MS/UV: m/z=265 (M−1) was confirmed. Yield: 7 mg (93%). 1H-NMR (400 MHz, CDCl3): δ ppm 7.26-7.20 (m, 2H), 7.17-7.11 (m, 1H), 6.87-6.84 (m, 3H), 6.80-6.77 (m, 2H), 4.83 (t, J=4.29, 4.29 Hz, 1H), 4.67 (s, 1H), 2.35-2.22 (m, 1H), 2.05-1.96 (m, 1H), 1.86-1.50 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[OH:29][C@@H:26]1[CH2:27][CH2:28][N:24]([C:3]2[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:23][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([S:16]([C:19]([F:21])([F:20])[F:22])(=[O:18])=[O:17])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:25]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1
Product: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)sulfonyl)phenyl)nicotinamide (Stage 214.1) and pyrimidin-5-ylboronic acid to afford a solid. UPLC-MS (Condition 3), tR=0.92 min, m/z=−492.3; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.74 (br. s, 1H) 1.85 (br. s, 1H) 2.91 (d, J=10.95 Hz, 1H) 3.18-3.26 (m, 2H) 3.32-3.45 (m, 1H) 4.22 (br. s, 1H) 4.90 (d, J=3.52 Hz, 1H) 8.05-8.16 (m, 3H) 8.16-8.25 (m, 2H) 8.81-8.86 (m, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.65 (s, 1H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([F:12])[C:9]([CH3:11])=[N:10][C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][C:15]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:6]3[CH:7]=[C:8]([F:12])[C:9]([CH3:11])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:16][C:15]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Cc1nc2ncc(Br)n2cc1F
Product: Cc1nc2ncc(-c3ccc(F)c(-c4ccccc4C#N)c3)n2cc1F
Yield: 58 %

Procedure:
3-Bromo-6-fluoro-7-methylimidazo[1,2-α]pyrimidine (24 mg, 0.50 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(6-fluoro-7-methylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (21 mg, 58%) as a white powder: δH (400 MHz, CDCl3) 2.67 (3H, d, J 3), 7.39-7.43 (1H, m), 7.53-7.62 (4H, m), 7.69-7.74 (1H, m), 7.84 (1H, d, J 1), 7.86 (1H, s), 8.67 (1H, d, J 5); m/z (ES+) 347 (M++H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:22][CH:21]=[N:20][C:19]=2[CH2:23][CH3:24])=[N:16][CH:17]=1.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:22][C:21]([Cl:25])=[N:20][C:19]=2[CH2:23][CH3:24])=[N:16][CH:17]=1
Reactant: CCc1ncoc1-c1ccc(Br)cn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(Cl)oc1-c1ccc(Br)cn1
Temperature: 25 °C
Yield: 89 %

Procedure:
LiHMDS (1.0 M in THF, 8.5 mL, 8.5 mmol) was added dropwise to a solution of Example 44A (1.97 g, 7.78 mmol) in THF (26 mL) at −78° C. After 30 min solid hexachloroethane (1.84 g, 7.78 mmol) was added in one portion and the reaction mixture was stirred while warming to ambient temperature overnight. The reaction was diluted with water and extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (Analogix® Intelliflash 280™; SF25-120 g column; 100% hexane 0-5 min, then 0% to 25% EtOAc/hexanes eluant, 5-40 min) afforded 1.99 g (89%) of the title compound as a yellow oil that solidified on standing. 1H NMR (300 MHz, CDCl3) δ 8.67 (dd, J=2.4, 0.6, 1H), 7.86 (dd, J=8.5, 2.4, 1H), 7.47 (dd, J=8.5, 0.6, 1H), 3.02 (q, J=7.5, 2H), 1.27 (t, J=7.5, 3H). MS (DCI+) m/z 287/289 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1COS(C)(=O)=O
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN1CCCC1
Temperature: 25 °C

Procedure:
17.3 To a stirred solution of 200 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester at r.t. in 5 ml THF under an argon atmosphere were added 0.38 ml pyrrolidine. The mixture was heated to reflux for 6 h, then cooled to r.t. and concentrated. The crude product was purified by column chromatography (silica gel, gradient CH2Cl2->CH2Cl2/MeOH 9:1) to give 138 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as off-white amorphous solid. MS 414.4 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[CH3:20][O:21][CH2:22][CH2:23]Br>>[CH3:20][O:21][CH2:22][CH2:23][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1
Reactant: COCCBr
Reactant: Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Product: COCCNc1ccc2ncnc(Nc3cccc(C)c3)c2c1
Yield: 20 %

Procedure:
Using an analogous procedure to that described in Example 16, 6-amino-4-(3'-methylanilino)quinazoline was reacted with 2-bromoethyl methyl ether to give 6-(2-methoxyethylamino)-4-(3'-methylanilino)quinazoline in 20% yield, m.p. 163°-167° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12].[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>CN(C)C=O>[O:12]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][N:6]1[CH2:5][C:4]1[CH:3]=[C:2]([CH:15]=[CH:14][CH:13]=1)[O:1][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C1CCCCN1Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCCN1Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
In an argon stream with ice cooling, a solution of 2.3 g of the 1-(3-hydroxybenzyl)-2-piperidone obtained in Reference Example 2 in 10 ml of N,N-dimethylformamide was added dropwise to a soltuion of 0.44 g of 60% sodium hydride in 5 ml of N,N-dimethylformamide. Subsequently, a solution of 2.8 g of N-(3-bromopropyl)phthalimide in 10 ml of N,N-dimethylformamide was added dropwise to the mixture at room temperature, followed by stirring at 65° C. for 8 hours. The resulting mixture was cooled, ice-cold water was thereafter added thereto, the mixture was subjected to extraction with diethyl ether, 6N hydrochloric acid was then added to the organic layer for extraction into the aqueous layer, and the aqueous layer was made alkaline with sodium hydroxide, followed by extraction with diethyl ether again. The organic layer was dried over magnesium sulfate and thereafter distilled to remove the solvent, giving N-[3-[3-(2-oxopiperidinomethyl)-phenoxy]propyl]phthalimide. This compound was hydrolyzed with hydrazine in the same manner as in Example 1, (ii) to afford 1.4 g of 3-[3-(2-oxopiperidinomethyl)phenoxy]propylamine (yield 51% ).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2Cl.Cl.Cl.[CH3:17][N:18]([CH3:26])[C@H:19]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([N:18]([CH3:26])[CH3:17])[CH2:20][CH2:21]1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Reactant: N#Cc1cnc2ccc(Br)cc2c1Cl
Agent: Cl
Product: CN(C)[C@H]1CC[C@H](Nc2c(C#N)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure C, 6-bromo-4-chloroquinoline-3-carbonitrile (262 mg, 0.98 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine dihydrochloride (422 mg, 1.96 mmol) to afford the desired product (56 mg, 15%) as a yellow solid. ESI MS m/z 373 [C18H21BrN4+H]+
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[OH:11][C:12]1[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([OH:18])[CH:17]=1>O>[OH:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[C:13]=1[CH:3]=[O:4]
Reactant: Oc1cc(O)cc(F)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c(O)cc(O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
Dimethylformamide (DMF) (12.7 g) is added to vigorously stirred phosphorous oxychloride (14.4 g) at 0° C. The reaction mixture is stirred at this temperature for 30 minutes, then 3,5-dihydroxyfluorobenzene (6 g) is added. The sticky red syrup is allowed to warm to room temperature and stirred for 2 hours, then left to stand for 14 hours. Water (100 mL) is added and the mixture extracted three times with ethyl acetate (100 mL). The combined organic phases are washed with brine (100 mL), dried over magnesium sulphate and evaporated. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give an orange solid which is triturated with ethyl acetate to give 2,4-dihydroxy-6-fluorobenzaldehyde (2 g) as a yellow solid.
Reaction SMILES: C(OC([CH:8]1[NH:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[N:16]1[C:10]2[CH2:9][CH2:8][NH:13][CH2:12][C:11]=2[S:14][C:15]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cc1nc2c(s1)CNC(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of methylene chloride was dissolved 4.10 g (12.6 mmol) of ethyl 6-t-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-acetate, and under ice-cooling, 10 ml of CF3CO2H was added to the residue and the mixture was stirred at room temperature for 2 hours.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14][N:5]1[CH2:4][C@@H:3]([OH:15])[CH2:2][NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccccc1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1ccccc1
Yield: 18.3 %

Procedure:
A solution of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 0.97 mmol), benzoic acid (122.5 mg, 1.07 mmol), HATU (387.6 mg, 1.02 mmol) and TEA (196.1 mg, 1.94 mmol) in DCM (20 mL) was stirred at room temperature for 2 h until completion of the reaction. The reaction mixture was then diluted with water and extracted with DCM (20 ml×2). The combined organic layers were dried and concentrated with the residue purified by pre-HPLC and SFC separation to give the desired compound (55 mg, Yield 18%). 1H NMR (400 MHz, MeOD): 7.66 (d, J=8.0 Hz, 2H), 7.36-7.34 (m, 1H), 7.26 (d, J=7.6 Hz, 2H), 6.99-6.89 (m, 4H), 4.01-3.96 (m, 1H), 3.61 (s, 2H), 3.43-3.37 (m, 2H), 2.77-2.72 (m, 4H), 2.56-2.53 (m, 2H). LCMS (m/z): 311.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(Cl)cc(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cc(Cl)cc(Cl)c2)CCNC1
Reaction time: 1 h

Procedure:
Preparation according to Preparation 2: tert-butyl 3-(3,5-dichlorophenyl)-3-hydroxypyrrolidin-1-carboxylate (1.3 g, 3.9 mmol), dichloromethane (10 mL) and trifluoroacetic acid (3 mL). Stirred for 1 h. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 40:60). Yield: 0.57 g. MS m/z (rel. intensity, 70 eV) 233 (M+, 64), 231 (M+, bp), 145 (56), 111 (55), 75 (72).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:19]=[C:18]([CH3:20])[C:12]3[N:13]([CH3:17])[C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([C:9]2[CH:19]=[C:18]([CH3:20])[C:12]3[N:13]([CH3:17])[C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[C:21](=[O:23])[CH3:22])[CH:3]=1
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N(c1cc(C)c2c(c1)oc(=O)n2C)c1cc(Cl)ncn1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
100 mg (0.300 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-3,4-dimethyl-3H-benzoxazol-2-one were placed together with 1.00 ml (10.6 mmol) acetic anhydride in a microwave container and stirred for 20 min at 150° C. The reaction mixture was diluted with water and extracted with DCM. The organic phase was separated off, dried and evaporated down. The residue was purified by preparative HPLC. The product-containing fractions were combined and evaporated down.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][CH2:34][O:35][CH3:36])[CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][O:35][CH3:36])[CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COCCn1cc(C(=O)Oc2ccccc2)cn1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COCCn1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1-(2-methoxy-ethyl)-1H-pyrazole-4-carboxylic acid phenyl ester, the title compound was obtained as light yellow crystals 43% yield). MS: m/e=418(M+H+), mp 191-193° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Cl>CN(C)C(=O)C>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21][N:7]1[CH:6]=[N:5][C:4]2[C:8]1=[N:9][CH:10]=[N:11][C:3]=2[NH:2][CH3:1]
Reactant: CNc1ncnc2nc[nH]c12
Reactant: Fc1cccc(Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNc1ncnc2c1ncn2Cc1c(F)cccc1Cl
Yield: 54.8 %

Procedure:
To a mixture of 6-methylaminopurine (298 mg, 2 mmols), potassium carbonate (276 mg, 2 mmols) and N,N-dimethylacetamide (10 ml) was added 2-chloro-6-fluorobenzyl chloride (718 mg, 4 mmols), and the resultant mixture was allowed to react at 110° C. for 8 hours with stirring. The reaction product was then treated in the same manner as Example 12 to give 9-(2-chloro-6-fluorobenzyl)-6-methylaminopurine as needles (320 mg, yield 55%), m.p. 188°-190° C.
Reaction SMILES: C([Mg]Br)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH:14]([F:16])[F:15].CN(C)[CH:19]=[O:20].O>C1COCC1>[F:15][CH:14]([F:16])[C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)c(C(F)F)c1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(F)cc1C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
Isopropyl magnesium bromide (30 mL, 1M in THF, 30 mmol) was added dropwise to an ice-cooled solution of 1-bromo-2-(difluoromethyl)-4-fluorobenzene (44; 6 g, 26.7 mmol) in THF (100 mL). The reaction mixture was then allowed to warm to room temperature and stirred for 3 hr. Dimethylformamide (3.5 ml, 45.2 mmol) was added and the reaction stirred for 3 hr. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 2-(difluoromethyl)-4-fluorobenzaldehyde 45 (3.2 g, 68.5%)
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[S-:12][C:13]#[N:14].[NH4+]>CC(C)=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:14]=[C:13]=[S:12])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: N#Cc1ccc(C(=O)N=C=S)cc1
Yield: 98.5 %

Procedure:
4-Cyanobenzoyl chloride (10 g) was added in portions to a solution of ammonium thiocyanate (4.6 g) in acetone (100 ml) at room temperature, followed by heating under reflux for 10 minutes. The reaction mixture was ice-cooled, and after removal of the insoluble substance by filtration, the filtrate was evaporated under reduced pressure to give 4-cyanobenzoyl isothiocyanate (11.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([C:21]([F:23])([F:24])[F:22])[CH:19]=[CH:20][C:14]=1[O:13][CH3:12])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COc1ccc(C(F)(F)F)cc1N
Product: COc1ccc(C(F)(F)F)cc1NC(=O)c1cc(Br)ccc1O
Yield: 71.3 %

Procedure:
Using 5-bromosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[C:7]2C(O[C:11](=O)[NH:12][C:6]2=[CH:5][CH:4]=1)=O.Cl[C:18]1[CH:29]=[C:22]2[C:23]([O:25][C:26](=O)[NH:27][C:21]2=[CH:20][CH:19]=1)=[O:24].N1C2C(=CC=CC=2)C(=O)C1=O.FC1C=C2C(=CC=1)NC(=O)C2=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:14]=1[O:15][CH3:16])[N:12]=[C:11]1[C:23](=[O:24])[C:22]3[C:21]([N:27]1[C:26]2=[O:25])=[CH:20][CH:19]=[CH:18][CH:29]=3
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1OC
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Agent: O=C1Nc2ccccc2C1=O
Solvent: CN(C)C=O
Product: COc1cc2nc3n(c(=O)c2cc1OC)-c1ccccc1C3=O
Yield: 16 %

Procedure:
Using the procedure in Example 12, and substituting N-methylpyrrolidone (NMP) for N,N-dimethylformamide (DMF), 5,6-dimethoxyisatoic anhydride for 5-chloroisatoic anhydride and isatin for 5-fluoroisatin gave 367 mg (16%) of the title compound: mp 350° C. (dec); 1H NMR(CDCl3)δ 4.02-4.08 (d, 6H), 7.40-7.45 (m, 2H), 7.74-7.80 (m, 2H), 7.88-7.92 (m, 1H), 8.60-8.65 (d, 1H); MS (M+H)+ 308.