Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([F:33])[CH:35]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: Fc1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 5.0 g (16.37 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 21 D) 1)b)] dissolved in 75 ml of THF are deprotonated at -75° C. with 32.7 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated starting at -75° C. with 3.4 g (18.0 mmol) of 3-fluorobenzyl bromide (Fluka; Buchs/Switzerland) (warming up during 60 min up to max. -50° C.). Column chromatography (SiO2, hexane/ethyl acetate 3:1) yields the title compound: TLC Rf (D)=0.6; tRet (I)=17.2 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:22]([C:24]1[C:29](Br)=[N:28][CH:27]=[CH:26][N:25]=1)=O.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>C1COCC1>[CH3:22][C:24]1[C:29]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[N:28][CH:27]=[CH:26][N:25]=1
Reactant: COC(=O)c1nccnc1Br
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nccnc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
EXAMPLE 97 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 3-bromo-pyrazine-2-carboxylic acid methyl ester followed by reduction with lithium tri-sec-butylborohydride at 0° C. in THF: MS (m+1)=375.5.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([CH:10]=[O:11])[C:4]=1[OH:12])=[O:2].[CH:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:3]1[CH:8]=[C:7]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=[C:5]([CH:10]=[O:11])[C:4]=1[OH:12])=[O:2]
Reactant: O=Cc1cc(Br)cc(C=O)c1O
Reactant: C#CCCCCCCCCCC
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCCCCCCCCC#Cc1cc(C=O)c(O)c(C=O)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
2,6-Diformyl-4-bromophenol (2.50 g, 10.9 mmol), 1-dodecyne (2.00 g, 12.0 mmol), CuI (65 mg, 0.33 mmol), and bis(triphenylphosphine)palladium)II) dichloride were suspended in degassed acetonitrile (MeCN) (5 mL) and degassed benzene (1 mL). The yellow suspension was sparged with argon for 30 min and degassed Et3N (1 mL) was added. The resulting brown suspension was sealed in a pressure vial, warmed to 80° C. and held there for 12 h. The mixture was then partitioned between EtOAc and KHSO4 solution. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated under reduced pressure. The dark yellow oil was purified by column chromatography on silica gel (25% Et2O in hexanes) to give 1.56 g (46%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.ClC(N(C)C)=C(C)C.[NH2:26][CH2:27][C:28]([CH:31]1[CH2:33][CH2:32]1)([OH:30])[CH3:29].C(N(C(C)C)C(C)C)C>ClCCl>[CH:31]1([C:28]([OH:30])([CH3:29])[CH2:27][NH:26][C:15]([C:5]2[CH:4]=[N:3][C:2]([Br:1])=[C:7]([C:8]3[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=3)[N:6]=2)=[O:17])[CH2:33][CH2:32]1
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: CC(O)(CN)C1CC1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 0.700 g (0.00223 mol) 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid in 7.0 ml dichloromethane was added a solution of 0.35 g (0.00262 mol) (1-chloro-2-methyl-propenyl)-dimethyl-amine and the mixture was stirred at room temperature for 45 min. To the resulting yellow solution was added dropwise during 15 minutes a solution of 0.296 g (0.00257 mol) 1-amino-2-cyclopropyl-propan-2-ol and 0.433 g ethyldiisopropylamine in 4.0 ml dichloromethane and the mixture was stirred at room temperature for 1 h. The resulting mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with heptane to ethyl acetate=7:3 to yield 0.748 g (81% Th) of the title compound as slightly yellow foam. MS (ISP) (M+H+)=410.1 and 412.0.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CCNCC1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCCC1)CC2

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), piperidine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 309 (M+, 1), 131 (4), 99 (7), 98 (bp), 77 (3), 55 (5).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)N[C@@H]1CCCc2c(Br)cncc21
Product: CC(=O)N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 87 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (+)-(R)—N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide (intermediate A-12) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as white solid in 87% yield. MS: 335.1 (M+H+).
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:12](OCC)(OCC)(OCC)[CH3:13].[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]12([NH:11][C:12](=[N:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH3:13])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NC1CCCCC1
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(C)(OCC)OCC
Product: CC(=NC1CCCCC1)NC12CC3CC(CC(C3)C1)C2
Reaction time: 0.08 h
Yield: 2.8 %

Procedure:
Adamantyl amine (1.87 g, 10 mmol), triethyl orthoacetate (1.62 g, 10 mmol) and cyclohexyl amine (0.99 g, 10 mmol) were mixed together then placed in preheated oil bath (140° C.) under nitrogen. After 5 min the reaction became exothermic and the reaction mixture became a slurry and upon continuation for 20 min it became a clear colorless solution. Now the reflux condenser was then replaced by distillation condenser and the low volatiles were distilled off at 75°-77° C. (head temperature) and later the undistilled residue was dried on manifold to give a light-yellow solid. The crude product was flash chromatographed on silica gel using chloroform as eluent to afford the title compound (0.076 g, 2.78%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[Br:5][C:6]1[C:11]([CH2:12][CH3:13])=[C:10]([Cl:14])[N:9]=[N:8][C:7]=1[NH2:15].CCOC1C=CC(N)=CC=1>CCO>[Br:5][C:6]1[C:7]2[N:8]([CH:2]=[CH:3][N:15]=2)[N:9]=[C:10]([Cl:14])[C:11]=1[CH2:12][CH3:13].[ClH:1]
Reactant: O=CCCl
Reactant: CCc1c(Cl)nnc(N)c1Br
Agent: CCOc1ccc(N)cc1
Solvent: CCO
Product: CCc1c(Cl)nn2ccnc2c1Br
Product: Cl
Temperature: 50 °C
Yield: 376.5 %

Procedure:
Chloroacetaldehyde (17.26 ml, 0.111 mol, 50% in H2O) was added to a solution of crude 4-bromo-6-chloro-5-ethylpyridazin-3-amine (5.23 g, 0.022 mol) from 1c in EtOH (30 mL). The mixture was heated in a sealed vial at 50° C. for 24 h. Solvent was removed in vacuo and the solid was resuspended in acetone/Et2O (1/1, 5 mL), filtered, and then washed with Et2O to give 8-bromo-6-chloro-7-ethylimidazo[1,2-b]pyridazine as an HCl salt (3.02 g, >80% pure). LC/MS, m/e 260 (M+1). HPLC Rt, 2.68 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:32]([CH3:34])[CH3:33])[CH:26]=4)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH2:40][C:41](Cl)=[O:42]>C1COCC1.CCOC(C)=O>[CH3:33][N:32]([CH2:31][C:27]1[CH:26]=[C:25]([NH:24][C:20]2[N:19]=[C:18]([C:17]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:36]5[S:35][CH:39]=[CH:38][CH:37]=5)[CH:3]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:23]=[CH:22][N:21]=2)[CH:30]=[CH:29][CH:28]=1)[CH3:34]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4ccc(F)c(N)c4)nn4ccccc34)n2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4ccc(F)c(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Reaction time: 20 h
Yield: 77.2 %

Procedure:
To a stirred solution of 4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine (58 mg, 0.13 mmol) in THF (3 mL) was added TEA (27 μL, 0.19 mmol) and 2-thiopheneacetyl chloride (17 μL, 0.13 mmol). After 20 h, the reaction mixture was diluted with EtOAc (20 mL), adsorbed onto silica gel, and purified by column chromatography to give the title compound (58 mg, 77% yield). 1H NMR (400 MHz, d6-DMSO) 610.15 (s, 1H), 9.54 (s, 1H), 8.83 (d, J=7.0 Hz, 1H), 8.48 (d, J=8.8 Hz, 1H), 8.26-8.29 (m, 2H), 7.69 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.36-7.39 (m, 2H), 7.18 (t, J=7.8 Hz, 1H), 7.13 (t, J=6.9 Hz), 6.96-6.98 (m, 2H), 6.87 (d, J=7.1 Hz, 1H), 6.52 (d, J=5.3 Hz, 1H), 3.99 (s, 2H), 3.32 (s, 2H), 2.15 (s, 6H). ES-LC/MS m/z=578 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]([NH:5][C:6]1[C:14]([C:15](=[O:17])[NH2:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=O.Cl.[CH3:27]COCC>CO>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[NH:16][C:15](=[O:17])[C:14]2[C:6](=[C:7]([C:8]([O:10][CH3:27])=[O:9])[CH:11]=[CH:12][CH:13]=2)[N:5]=1
Reactant: NC(=O)c1cccc(C(=O)O)c1NC(=O)C(F)(F)c1ccc(F)cn1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc12
Yield: 62 %

Procedure:
2-(2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamido)-3-carbamoylbenzoic acid (28.5 g, 81 mmol) in MeOH (1000 mL) was treated with 2M HCl/ether (4 mL) and then heated at reflux overnight. The mixture was concentrated to 10% of the original volume and the resulting precipitate was collected by filtration and washed with a small amount of MeOH to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (17.5 g, 62%). Separately, 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-hydroxyquinazoline-8-carboxylic acid (10.5 g, 31 mmol) in MeOH (200 mL) was treated with 2M HCl/ether (1 mL) and was heated at reflux overnight. The mixture was concentrated to 10% of the original volume and the resulting precipitate was collected by filtration and washed with a small amount of MeOH to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (5.5 g, 51%). The filtrates from the two procedures above were concentrated at 65° C. and allowed to cool. The solid was collected by filtration to afford additional methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (3 g). Purification of the filtrate by silica gel chromatography eluting with EtOAc/hexanes afforded additional methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (4 g). The isolated solids were combined to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate as a solid (30 g). LC-MS (ESI) m/z 350 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH2:15]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:10](=[O:15])[CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:3]=1
Reactant: c1ccncc1
Reactant: Nc1cc(Br)ccn1
Reactant: O
Solvent: ClCCl
Product: O=C(CC1CC1)Nc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of 2-cyclopropylacetic acid (250 mmol) in DCM was added 1 mL of DMF. Oxalyl chloride (312 mmol) was added dropwise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to afford 30.3 g of the crude acid chloride that was added dropwise to a solution of 4-bromo-2-aminopyridine (202 mmol) and pyridine (506 mol) in 500 mL dichloromethane. The reaction mixture was stirred at room temperature for 4 h. Water was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by chromatography on silica gel to afford 26.0 g of N-(4-bromopyridin-2-yl)-2-cyclopropylacetamide (50% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])=[CH:6][C:5]=1[CH3:20].C=O.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[CH3:24])=[CH:6][C:5]=1[CH3:20]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)c1ccc(CNc2ccc(O)cc2F)cc1C
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN(C)c2ccc(O)cc2F)cc1C
Reaction time: 0.67 h
Yield: 50.5 %

Procedure:
A mixture of 4-[(2-fluoro-4-hydroxy-phenylamino)-methyl]-2-methyl-benzoic acid methyl ester (1.89 g, 6.53 mmol) and 2.0 mL of 37% formaldehyde in 20 mL of acetic acid is stirred for 40 minutes. Sodium triacetoxyborohydride (2.80 g, 13.2 mmol) is added. Upon completion, the mixture is concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer is extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4) and concentrated. The residue is purified on 120 g silica with ethyl acetate in heptane gradient (10% to 60%) to provide 1.0 g (51%) of the titled compound as a white solid. LC-ES/MS m/e 304.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:14](=O)[CH3:15])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[CH3:2].C[NH:19][C:20](=[NH:22])[SH:21].S([O-])([O-])(=O)=O.[CH2:28](N(CC)CC)C>C(O)CCC>[CH2:1]([O:3][C:4]([C:5]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:22]=[C:20]([S:21][CH3:28])[NH:19][C:14]=1[CH3:15])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=Cc1cccc(Cl)c1)C(C)=O
Reactant: CNC(=N)S
Reactant: CCN(CC)CC
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCO
Product: CCOC(=O)C1=C(C)NC(SC)=NC1c1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
3.33 g (13.2 mmol) of 2-acetyl-3-(3-chlorophenyl) acrylic acid ethylester was dissolved in 30 ml of n-butanol. 2.93 g (10.5 mmol) of methylisothiourea-sulfate and 2.00 g (19.8 mmol) of triethylamine were added at room temperature and stirred at 100° C. for one day. After n-butanol was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: C([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=[O:10])=[C:7](Br)[C:6]=1[O:16][CH3:17])(=O)C.[CH2:18]([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[C:24]([C:7]2[C:8]([CH:9]=[O:10])=[CH:11][C:12]([O:13][CH3:14])=[C:5]([OH:4])[C:6]=2[O:16][CH3:17])=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1ccccc1B(O)O
Reactant: COc1cc(C=O)c(Br)c(OC)c1OC(C)=O
Product: CCOC(=O)c1ccccc1-c1c(C=O)cc(OC)c(O)c1OC

Procedure:
6′-Formyl-3′-hydroxy-2′,4′-dimethoxy-biphenyl-2-carboxylic acid ethyl ester was prepared from 4-acetoxy-2-bromo-3,5-dimethoxybenzaldehyde (Example 162, step a) and 2-ethoxycarbonylphenyl boronic acid using the protocol described in Example 147, step a. Mass Spectrum: 331 (M+1).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH:12]([OH:46])[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:19]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:43])([F:42])[F:41])[CH:34]=3)=[N:18][C:17]=2[N:16]([CH3:44])[C:15]1=[O:45])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].I[CH3:48]>C1COCC1>[Si:3]([O:10][CH2:11][CH:12]([O:46][CH3:48])[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[C:19]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:41])([F:43])[F:42])[CH:34]=3)=[N:18][C:17]=2[N:16]([CH3:44])[C:15]1=[O:45])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: Cn1c(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CO[Si](C)(C)C(C)(C)C)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 118 %

Procedure:
To a slurry of sodium hydride (240 mg, 9.6 mmol) in anhydrous THF (10 ml) was added dropwise a solution of 1-(3-(tert-butyldimethylsilyloxy)-2-hydroxypropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (124 mg, 0.19 mmol) in THF (3 mL) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 10 minutes. Then iodomethane (1.2 ml, 19.4 mmol) was added dropwise and the resulting mixture was allowed to warm from 0° C. to room temperature over 2 h. The mixture was quenched with ice-water (5 mL). The mixture was concentrated, diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was dried over sodium sulfate, filtered and concentrated to give crude product (150 mg, 100% yield) as yellow oil. LCMS MH+ 669.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[Cl:22][C:23]1[CH:29]=[C:28]([P:30]([CH3:33])([CH3:32])=[O:31])[CH:27]=[CH:26][C:24]=1[NH2:25].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([P:30]([CH3:32])([CH3:33])=[O:31])=[CH:29][C:23]=2[Cl:22])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CP(C)(=O)c1ccc(N)c(Cl)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2Cl)nnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 2-Chloro-4-(dimethylphosphoryl)aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].C1COCC1.C(O)C.[BH4-].[Na+]>O>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1cccnc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a mixture of methyl 2-chloronicotinate (5 g), dehydrated THF (30 ml) and ethanol (30 mL) was added sodium borohydride (4.41 g) at 0° C. The reaction mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.22 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[N:32][C:31]([CH3:34])=[N:30]1)[NH2:25].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CN1CCCC1=O.O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[C:6]3[N:7]=[C:2]([NH:25][C:24]4[CH:26]=[CH:27][C:28]([N:29]5[CH:33]=[N:32][C:31]([CH3:34])=[N:30]5)=[C:22]([O:21][CH3:20])[CH:23]=4)[N:3]=[C:4]([NH:18][CH3:19])[C:5]=3[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)n1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CNc1nc(Nc2ccc(-n3cnc(C)n3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hh) (141.2 mg, 0.508 mmol) and 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation D) (208 mg, 1.017 mmol) in N-Methyl-2-pyrrolidinone (4067 μL) was added H2SO4 (43.4 μL, 0.813 mmol). The solution was heated to 100° C. When the reaction was complete, water and NaHCO3 were added. After extraction into CH2Cl2, the organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Applied the residue to SG and eluted with a EtOAc/Hex gradient, which yielded 7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (Example 44).