Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[F:33])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:7])=[O:6].N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C1COCC1>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[CH2:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[N:4]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:6])=[O:7])[CH2:3][CH2:2][NH:1][C:40](=[O:42])[CH3:41]
Reactant: COc1ccc(S(=O)(=O)N(CCN)c2ccc(C)cc2Cc2c(F)cccc2F)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCNC(C)=O)c2ccc(C)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 48 h
Yield: 46.4 %

Procedure:
To 1 g of N-(2-aminoethyl)N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxybenzenesulfonamide (compound 215) dissolved in 25 ml of THF are added 0.167 ml of pyridine and 0.22 g of acetic anhydride. After 48 hours at room temperature, the reaction medium is concentrated. The residue is chromatographed on a column of silica gel, eluting with a 99/1 (v/v) dichloromethane/methanol mixture to give 0.505 g of the expected product.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11]C(=O)C)=[CH:6][C:5]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)C.[OH-].[Na+]>O>[NH2:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[C:5]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=1
Reactant: CCCCCCOc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCOc1cc(N)c(Cl)cc1C(=O)O

Procedure:
A mixture of 4-acetylamino-5-chloro-2-hexyloxybenzoic acid methyl ester (2.1 g), ethanol (10 ml), and water (30 ml) containing sodium hydroxide (2.6 g) is heated under reflux for 4 hours. The ethanol is distilled off under reduced pressure, and the resulting solution is acidified with dilute hydrochloric acid and extracted with chloroform. The organic layer is treated in the same manner as in part (2) of this Reference Example to give the title compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:8]#[N:9])([O-])=O.[OH-].[Na+]>>[NH2:2][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([NH2:13])[CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(N)cc(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 210 grams of stannous chloride dihydrate in 590 ml. of concentrated hydrochloric acid is added portionwise 25 grams of 3,5-dinitrobenzonitrile. The mixture is stirred for three hours at room temperature, then cooled to 0° in an ice-salt bath and a cold 50% sodium hydroxide solution added to the mixture until the mixture is strongly basic. During the addition the temperature is kept below 5°.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH2:20][CH:21]=[CH2:22]>CCOCC>[CH2:1]([O:8][C@H:9]([C@@H:10]([OH:11])[CH2:22][CH2:21][CH:20]=[CH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC[Mg]Br
Reactant: O=C[C@H](Cc1ccccc1)OCc1ccccc1
Solvent: CCOCC
Product: C=CCC[C@H](O)[C@H](Cc1ccccc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
The latter aldehyde was dissolved in Et2O (20 mL). Under anhydrous conditions, the solution of the aldehyde was added dropwise over 15 min to a stirred solution of 3-butenyl magnesium bromide at -78°. The latter solution had been prepared by diluting 71 mL of a 0.64M solution of the Grignard reagent in Et2O with 155 mL of Et2O. After 1 h, the reaction mixture was diluted with Et2O (100 mL). The resulting mixture was washed with a saturated aqueous solution of NH4Cl and then with brine. The organic phase was dried (MgSO4) and evaporated to dryness. The residue was purified by chromatography (SiO2, eluent: hexane-EtOAc, 9:1) to give (2S,3S)-2-benzyloxy-1-phenyl-6-hepten-3-ol (4.82 g), 1H NMR (CDCl3) δ 7.25 (m, 10H), 5.75 (m,1H), 4.95 (m,2H), 4.40 (dd,2H), 3.50 (m, 2H), 2.90 (m,2H), 2.10 (m,3H), 1.60 (m,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)[CH2:6][CH2:5]2.Cl>C(O)C.CCOCC>[ClH:1].[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1N1CCc2cc(Cl)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Nc1ccccc1N1CCc2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
A mixture of 13.7 g of 5-chloro-1-(2-nitrophenyl)indoline and 0.25 g of 1% Pt on C in 250 ml absolute ethanol is shaken at 50 psi of H2 until the theoretical amount of H2 is taken up. The mixture is filtered and the solvent removed at 50° C. to leave the product base as an oil. This is dissolved in 200 ml of ether, cooled to 0° C., and treated with gaseous HCl to precipitate 1-(2-aminophenyl)-5-chloroindoline hydrochloride, m.p. 235°-238° C. dec.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH3:23])[CH:12]=O.C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:16]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])=[CH:10][C:9]=1[O:8][CH3:7])[CH2:19][C:20]#[C:21][CH2:22][CH3:23]
Reactant: CCC#CCCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCC#CCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 63.5 %

Procedure:
Piperidine (0.17 mL, 1.7 mmol) was added to a suspension of 3-methoxy-4-(hex-3-ynyloxy)benzaldehyde (0.40 g, 1.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.35 g, 1.6 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH providing (E)-2-[[3-(4-(hex-3-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.40 g, 65%) as a colourless crystalline solid; mp 165-166° C.; δH (400 MHz, DMSO-d6) 1.04 (t, J=7.6 Hz, 3H, CH3), 2.14 (q, J=7.6 Hz, 2H, CH3CH2), 2.61 (t, J=7.6 Hz, 1H, OCH2CH2C), 3.83 (s, 3H, OCH3), 4.05 (t, J=7.6 Hz, 2H, OCH2), 6.79 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.99 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.7, 14.0, 19.2, 55.7, 66.9, 76.1, 83.0, 110.9, 113.0, 116.6, 120.1, 120.3, 122.5, 122.6, 127.6, 131.1, 134.0, 141.0, 141.5, 149.1, 149.5, 164.1, 169.4; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1647; vmax 755, 1235, 1510, 1601, 1669, 3234, 3563 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][S:59](=[O:63])(=[O:62])[CH2:58][CH2:57]1>CN(C=O)C>[O:62]=[S:59]1(=[O:63])[CH2:60][CH2:61][N:56]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:23][CH:22]=2)=[O:21])[CH2:57][CH2:58]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol (69 mg, 0.2 mmol)) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and thiomorpholine-S,S-dioxide (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (73 mg, 55%) as a white solid. MS: m/e=446.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[C:7](Cl)([Cl:9])=[O:8].C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:9][C:7]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O=C(Cl)Cl
Reactant: O[C@H]1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)O[C@H]1CCOC1
Temperature: 25 °C
Yield: 85 %

Procedure:
A stirred solution of (S)-tetrahydrofuran-3-ol (7.9 g, 90 mmol) in anhydrous CH2Cl2 (50 mL) under an N2 atmosphere was cooled in an ice bath, and a 20% solution of phosgene in toluene (134 mL, 270 mmol) was slowly added. The reaction was allowed to warm to room temperature overnight, and the solvent was removed under vacuum to afford (S)-tetrahydrofuran-3-yl chloroformate (12.1 g, 85%) as a clear liquid. 1H NMR (400 MHz, CDCl3) δ 5.42-5.39 (m, 1H), 4.01-3.84 (m, 4H), 2.31-2.13 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][C@@H:12]([O:15][CH3:16])[CH2:11]2)=[O:9])[N:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:36][C:27]1[CH:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:10]3[CH2:14][CH2:13][C@@H:12]([O:15][CH3:16])[CH2:11]3)=[O:9])[N:3]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: CO[C@@H]1CCN(C(=O)c2cccc(Br)n2)C1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CO[C@@H]1CCN(C(=O)c2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)C1

Procedure:
The title compound was prepared as described Example 1 using 2-bromo-6-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}pyridine (53 mg, 0.19 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (55 mg, 0.19 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[C:9]1=[O:13]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2cc(C(F)(F)F)ccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2cc(C(F)(F)F)ccc2C1=O
Yield: 9.4 %

Procedure:
Using analogous reaction conditions as described in Example 1, 6-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-17c: 150 mg, 0.698 mmol) was reacted with 3-iodo-4-methyl-pyridine (152.8 mg, 0.698 mmol), 1,4-dioxane (10 mL), copper iodide (13.3 mg, 0.0698 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (29.73 mg, 0.209 mmol) and potassium phosphate (369.94 mg, 1.745 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 20 mg of the product (9.38% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([Cl:19])([Cl:18])[Cl:17])[CH:8]=2)[N:3]=1.[Na].[CH3:21][C:22]1[N:26]=[CH:25][NH:24][N:23]=1.CN(C)C=O>O>[CH3:21][C:22]1[N:26]=[CH:25][N:24]([C:2]2[CH:11]=[C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:16]([Cl:19])([Cl:18])[Cl:17])[CH:8]=3)[N:3]=2)[N:23]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)c2cc(C(Cl)(Cl)Cl)ccc2n1
Reactant: Cc1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncn(-c2cc(C(Cl)(Cl)Cl)c3cc(C(Cl)(Cl)Cl)ccc3n2)n1
Temperature: 100 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
A mixture of 3.99 g of 2-chloro-4,6-bis-trichloromethyl-quinoline, 1.26 g of the sodium salt of 3-methyl-1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 20 hours. The reaction mixture is poured into 100 ml of water, the precipitated product is filtered and recrystallized from 10 ml of ethanol. Thus 2.76 g of the desired compound are obtained, yield 62%. M.p.: 169°-170° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[N:9]1(C(OC(C)(C)C)=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[Br:8][C:14]1[CH:13]=[C:12]2[C:17](=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=1)[NH:9][CH2:10][CH2:11]2
Reactant: CCOC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(Br)cc2c1NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.8 %

Procedure:
NBS (51.3 g, 0.29 mol) was added in several portions to a solution of 1-(1,1-dimethylethyl) 7-ethyl 2,3-dihydro-1H-indole-1,7-dicarboxylate (140.3 g, 0.48 mol) in CH2Cl2 (1200 mL) and the reaction mixture was stirred at room temperature overnight. The reaction solution was washed with 2 M NaOH (500 mL) and water (500 mL), and was then dried (Na2SO4). The solution was concentrated in vacuo to 500 mL and TFA (130 mL, 1.69 mol) was added. The mixture was stirred at room temperature overnight. A solution of 2 M NaOH was added to bring the reaction mixture to pH>8. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×300 mL). The combined organic layers were dried (Na2SO4) and the solvent was evaporated, giving 129.1 g (99%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:41])([F:40])[O:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:22])[F:21])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Br[CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][CH2:53][CH3:54]>>[CH2:51]([O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:40])([F:41])[O:26][C:27]([F:38])([F:39])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:22])[F:21])=[CH:12][CH:13]=2)=[N:4][CH:3]=1)[CH2:52][CH2:53][CH3:54]
Reactant: Oc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Reactant: CCCCOCCOCCBr
Product: CCCCOCCOCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-hydroxy-2-[4-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propoxy)phenyl]pyrimidine (1.22 g, 1.85 mmol, Example 10) and 1-bromo-2-(2-butoxyethoxy) ethane (0.81 g, 3.62 mmol). The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with 30 volume percent ethyl acetate/hexane, to yield 1.13 g of purified product.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[Cl:22]Cl.O>C(O)(=O)C>[Cl:22][C:11]1[CH:12]=[CH:13][C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:2]=2[Cl:1])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 5 h

Procedure:
A solution of 3(2-chloro-4-trifluoromethylphenoxy)-benzoic acid (5 g) in glacial acetic acid (30 ml) was heated under reflux while chlorine was passed through the solution for 5 hours. The solution was left to stand for two days at room temperature and then poured into cold water (500 ml). An off-white gummy solid separated. This was extracted with ethyl acetate and the extract dried and evaporated. The brown oil remaining was dissolved in sodium bicarbonate solution and the solution extracted with ethyl acetate. The aqueous chloride was acidified with hydrochloric acid. The solution was decanted from the precipitated gum, and the gum taken up in boiling hexane. The hexane solution was filtered and allowed to cool. The required 2-chloro-5(2-chloro-4-trifluoromethylphenoxy)benzoic acid was obtained (1.0 g) as crystals of melting point 103°-104°. This acid was used as starting material for compounds 7 and 8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:23][C:11]=2[N:12](CC2C=CC(OC)=CC=2)[N:13]=1>ClCCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:23][C:11]=2[NH:12][N:13]=1
Reactant: CCOC(=O)c1cc2c(-c3ccc(F)cc3F)nn(Cc3ccc(OC)cc3)c2s1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(-c3ccc(F)cc3F)n[nH]c2s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Ethyl 3-(2,4-difluorophenyl)-1-(4-methoxybenzyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate (1.0103 g, 2.358 mmol) was dissolved in a mixture of 1,2-dichloroethane (11.79 ml) and trifluoroacetic acid (11.79 ml) at 25° C. in a sealed heavy-walled reaction vessel. The reaction mixture was heated to 100° C. and allowed to stir for 2 h. The reaction was stopped, cooled to room temperature, and concentrated under reduced pressure. The residue was taken up in ethyl acetate (20 mL), washed with saturated aqueous sodium bicarbonate (1×15 mL) and saturated aqueous sodium chloride (1×15 mL), dried (sodium sulfate), and concentrated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 120 g column) on a CombiFlash purification system eluting with ethyl acetate-hexanes (0-60%). The title compound (719.0 mg, 2.332 mmol, 99% yield) was recovered as a white solid. LC-MS [M+1]=309.3.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29].C(N(C(C)C)C(C)C)C.[O:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:46][CH:43]4[CH2:44][CH2:45][O:40][CH2:41][CH2:42]4)=[O:22])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a mixture of 0.08 g (0.19 mmole) of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292), 0.13 mL (0.76 mmole) of ethyldiisopropyl amine and 0.021 g (0.21 mmole) of tetrahydro-pyran-4-ylamine in 2.0 mL of dimethylformamide was added 0.082 g (0.21 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.086 g of give 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-297) as a white solid.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C1(C)C=CC=CC=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][OH:10]
Reactant: OCc1ccccc1CO
Reactant: C1=COCCC1
Solvent: Cc1ccccc1
Product: OCc1ccccc1COC1CCCCO1
Temperature: 30 °C
Reaction time: 5 h

Procedure:
To a suspension of 1,2-benzenedimethanol (5 g, 36.19 mmol) in toluene/2,3-dihydropyran (206 ml/11 ml) at 30° C. was added 3.62 g Dowex (50WX2-100). The reaction stirred at 30° C. for 5 hours. The mixture was filtered to remove Dowex, then concentrated in vacuo and put on vacuum pump overnight w/stirring to remove 2,3-dihydropyran. The crude reaction product was purified by normal phase chromatography (20% EtOAc/hexanes—25% -30%) to give a clear liquid (5.72 g).
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1)C.[C:23](#[N:25])[CH3:24].C([Li])CCC>C1COCC1.C1CCCCC1>[N:16]1([CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:22])[CH2:24][C:23]#[N:25])=[CH:11][CH:10]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)Cc1ccc(OCCCN2CCOCC2)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: N#CCC(=O)Cc1ccc(OCCCN2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
The [4-(3-morpholin-4-yl-propoxy)-phenyl]-acetic acid ethyl ester is then condensed with the lithium anion of acetonitrile by the following method: A solution of dry acetonitrile (0.254 mL) in 5 mL of THF, that had been cooled in a dry ice-acetone bath for 2 h under Ar(g), is treated dropwise with 2.43 mL of a 2M solution of n-butyl lithium in cyclohexane. This mixture is allowed to stir at −78° C. for an additional 1.5 h, and is subsequently treated with 1.15 gms. of [4-(3-morpholin-4-yl-propoxy)-phenyl]-acetic acid ethyl ester in dropwise fashion. The resulting solution is allowed to stir at −78° C. for an additional 30 minutes, and is then allowed to warm to room temperature overnight. The reaction mixture, subsequently, is vacuum filtered affording the desired nitrile, 4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-oxo-butyronitrile, as a white solid (11% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[N:17]=[C:16](S(C)(=O)=O)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:34]([OH:37])([CH3:36])[CH3:35].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[N:17]=[C:16]([O:37][CH:34]([CH3:36])[CH3:35])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)O
Reactant: COc1ccc(CCNc2cc(-c3ccc(OC)c(OC)c3)nc(S(C)(=O)=O)n2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCNc2cc(-c3ccc(OC)c(OC)c3)nc(OC(C)C)n2)cc1OC
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of [2-(3,4-dimethoxy-phenyl)-ethyl]-[6-(3,4-dimethoxy-phenyl)-2-methanesulfonyl-pyrimidin-4-yl]-amine [200 mg, 0.42 mmol, Intermediate (33)], and isopropyl alcohol (1 mL) in N,N′-dimethylformamide (2 mL) at 0° C. is treated with sodium hydride (60%, 102 mg, 12.7 mmol). After 1 hour at 20° C., the mixture is concentrated, and extracted twice with EtOAc (50 mL). The combined extracts are washed twice with water, dried over magnesium sulfate, filtered, and concentrated. The residue is subjected to chromatography on silica gel eluting with 60% EtOAc in heptane to afford [2-(3,4-dimethoxy-phenyl)-ethyl]-[6-(3,4-dimethoxy-phenyl)-2-isopropoxy-pyrimidin-4-yl]-amine [0.15 g, 79%, Example 17(a)] LCMS: RT=2.57 minutes, MS: 454 (M+H). 1H NMR (300 MHz, CDCl3), □7.64 (1H, d, J=2.1 Hz), 7.55 (1H, dd, J=8.4, 2.4 Hz), 6.91 (1H, d, J=8.4 Hz), 6.86-6.76 (3H, m), 6.3 (1H, s), 5.43-5.34 (1H, m), 4.83 (1H, brs), 3.99 (3H, s), 3.95 (3H, s), 3.89 (3H, s), 3.75-3.65 (2H, m), 2.91 (2H, t, J=6.9 Hz) 1.45 (6H, d, J=6 Hz). IC50=6728 nM