Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:27]([O:30][CH2:31]Br)(=[O:29])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:31][O:30][C:27](=[O:29])[CH3:28])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(=O)OCBr
Agent: [Na+]
Product: CC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
In the same manner as in Example 81, 146 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 41 and 0.047 ml of bromomethyl acetate. NMR (CDCl3) δ: 1.21 (3H, d, J=7.3 Hz), 1.35 (3H, d, J=6.3 Hz), 1.83 (1H, d, J=4.8 Hz), 2.14 (3H, s), 2.50 (1H, t, J=5.9 Hz), 3.29 (1H, dd, J1=6.8 Hz, J2=2.8 Hz), 3.51-3.61 (1H, m), 4.22-4.31 (2H, m), 4.86 (2H, d, J=5.9 Hz), 5.89 (1H, d, J=5.6 Hz), 5.97 (1H, d, J=5.6 Hz), 6.52 (1H, d, J=10.5 Hz), 7.13 (1H, d, J=10.5 Hz), 8.79 (1H, s)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1.[C@@H:15]12[CH2:21][C@@H:18]([NH:19][CH2:20]1)[CH2:17][N:16]2C(OC(C)(C)C)=O>>[C@@H:15]12[CH2:21][C@@H:18]([NH:19][CH2:20]1)[CH2:17][N:16]2[CH2:14][C@@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[OH:13]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Product: Cc1c([C@@H](O)CN2C[C@H]3C[C@@H]2CN3)ccc2c1COC2=O

Procedure:
5-{(1R)-2-[(1R,4R)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1 (3H)-one was prepared in an analogous fashion as described for the synthesis of INTERMEDIATE 3 starting from 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one (INTERMEDIATE 2) and commercially available tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[C:10]([C:9]1[N:24]=[C:23]([C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[F:20])[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[N:8]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reactant: N#Cc1ccccc1F
Agent: [Li]CCCC
Product: CC(C)(C)c1nc(-c2ccccc2F)c2cc(Cl)ccc2n1
Yield: 57 %

Procedure:
The preparation of 4-phenylquinazolines from amidobenzenes or benzonitriles, as shown in the reaction when p-chloropivalamidobenzene was dilithiated with n-BuLi followed by the addition of o-fluorobenzonitrile to give 57% of 2-t-butyl-6-chloro-4-o-fluorophenylquinazoline [26], and the treatment of o-aminobenzonitrile with phenylmagnesium halide from which the resulting intermediate 2-H2NC6H4C(Ph)=N− then cyclized with carbonyl compounds (e.g., acid chlorides, anhydrides, formates) to give 4-phenyl-quinazolines [27]. Alternatively, the reaction between benzanilides and benzonitriles in the presence of PCl5 and AlCl3 in PhNO2 at 120-150° C. also afforded 2,4-diphenylquinazoline [28];
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1.[SH:18][CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[OH:21][CH2:20][CH2:19][S:18][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1C
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)c2ccc(SCCO)cc2)cc1C
Reaction time: 6 h

Procedure:
12.2 g (0.05 mol) of 4'-chloro-3,4-dimethylbenzophenone and 4.3 g (0.055 mol) of 2-mercaptoethanol in 50 ml of dimethylacetamide are heated to 95° under nitrogen. 13.8 g (0.1 mol) of calcined K2CO3 are then added. The suspension is kept at 90°-100° C. for 6 hours. 100 ml of water are poured over the resulting reaction mixture and the mixture is extracted with ether. The ether layer is washed with water, dried over Na2SO4 and concentrated. The crystals obtained are recrystallised from methanol and dried in vacuo at 60° C. Yield: 10.1 g (71%). Melting point 92°-93° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=[CH:17][CH:16]=2.C(C1C(C2[NH:35][C:36]3[C:41]([C:42]=2[CH2:43][CH2:44]C(Cl)=O)=CC=CC=3)=C(C)ON=1)C.CNC.N1CCCC1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24]([N:35]1[CH2:36][CH2:41][CH2:42][CH2:43][CH2:44]1)=[O:25])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1CCC(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCC(=O)Cl
Agent: CNC
Solvent: C1CCNC1
Product: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCC(=O)N1CCCCC1

Procedure:
Also, following the above procedure and using in place of 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-indole propionyl chloride an equivalent amount of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole propionyl chloride and using in place of dimethylamine an equivalent amount of pyrrolidine there is obtained
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[N:24]#[C:25]Br.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl.O.[Cl-].[Na+].O>[NH2:24][C:25]1[O:20][C:19]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[CH3:23])=[C:17]([F:18])[C:13]3[N:14]=[CH:15][NH:16][C:12]=3[CH:11]=2)=[N:21][N:22]=1
Reactant: N#CBr
Reactant: Cc1cc(Br)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(Br)ccc1Nc1c(-c2nnc(N)o2)cc2[nH]cnc2c1F
Reaction time: 16 h
Yield: 55 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20a (0.041 g, 0.109 mmol) is suspended in 1,4-dioxane (1.5 mL) and 36 μL of a 3 M solution of cyanogen bromide in methylene chloride is added. NaHCO3 (9 mg, 0.109 mmol) in water (1.5 mL) is then added. After 16 hours, the reaction mixture is diluted with water and brine and extracted with THF. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. Purification by FCC eluted with 98:2 ethyl acetate:MeOH provides 24 mg (55%) of pure desired product as a yellow solid: LC/MS ESI (+) m/z 403, 405 (M+ Br pattern) detected;
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)C.O>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:21][CH:22]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(OC2CCN(c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
4-[4-(Trifluoromethoxy)phenoxy]piperidine (26.1 g), benzyl 4-bromophenyl ether (26.3 g), palladium (II) acetate (22.4 mg), Tri-tert-butyl phosphonium tetraphenyl borate (52.3 mg), sodium tert-butoxide (10.6 g) and toluene (130 mL) were placed in a vessel and heated to reflux for 4 hr under Ar. The reaction mixture was then cooled to room temperature and water (260 mL) and ethyl acetate (260 mL) were added. The organic material was taken up in ethyl acetate. The organic layer was washed two times with water (260 mL×2). The organic layer was filtered to remove a harz and then the organic layer was condensed under reduced pressure to give 43.34 g (97.82% crude yield, 97.34% HPLC purity) of the pale yellow product. The crude product (43.3 g) and ethanol (433 mL) were placed in a vessel and heated until to dissolve and then the mixture was allowed to cool to 0° C. for 1 hr. The mixture was then filtered and the crystalline powder washed with cooled ethanol (43 mL) and then dried at 40° C. for 15 hr to afford 39.7 g (91.7% yield) of a pale yellow crystal target compound.
Reaction SMILES: B.C1(C)C=CC=CC=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1)=[O:14]>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([C@H:13]([OH:14])[C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16]2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(Cl)c2)C1
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cc(F)cc(Cl)c2)C1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A mixture of 10 M H3B.S2Me in THF (47.7 mL, 0.477 mol) and 1 M R-CBS-oxazaborolidine in toluene (72 mL, 0.072 mol) were dissolved in 100 mL anhydrous THF and cooled to −15° C. (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate in 400 mL anhydrous THF was added dropwise to the above solution and stirred at −15° C. for 2 hr. The reaction was quenched with methanol (500 mL). The solvent was removed under reduced pressure and the residue was purified by column chromatography. The product was re-crystallized three times with EtOAc/Hexanes to give (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (55 g, 0.156 mol). 1H NMR (CDCl3, 400 MHz) δ7.10 (s, 1H), 7.04-6.90 (dd, 2H), 4.46-4.30 (d, 1H), 4.05-2.40 (m, 5H), 1.74 (s, 1H), 1.60 (s, 1H), 1.53-1.31 (m, 11H), 1.30-1.14 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([Cl:10])[C:6]=2[CH:11]=1.CN(C)[C:14]1[O:15][C:16](=[O:24])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=1>C(O)(=O)C>[Cl:10][C:7]1[C:6]2[CH:11]=[C:2]([N:1]3[C:16](=[O:24])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[NH:19][C:14]3=[O:15])[CH:3]=[CH:4][C:5]=2[S:9][N:8]=1
Reactant: Nc1ccc2snc(Cl)c2c1
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: CC(=O)O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc2snc(Cl)c2c1
Temperature: 97.5 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
A mixture of 5-amino-3-chloro-1,2-benzisothiazole (1.10 g) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (1.38 g) in acetic acid (15.1 mL) is stirred at 90-105° C. for two hours, cooled to room temperature, and filtered to obtain 0.500 g of the title product as a solid. The resultant filtrate is diluted with water and filtered to obtain an additional 1.11 g of the title product.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH:38]1(N2C3C(O[C@@H]([C@H]4CNC(=O)C4)C)=NC(C4C=CC(N5CCNCC5)=CC=4)=CC=3N=C2)C[CH2:39]1.C1(S(Cl)(=O)=O)CC1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH:28]6[CH2:39][CH2:38]6)(=[O:26])=[O:27])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=S(=O)(Cl)C1CC1
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(=O)(=O)C4CC4)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1

Procedure:
Following the procedure described for intermediate 3.45, starting from (R)-4-((R)-1-((3-cyclopropyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (180 mg, 0.4 mmol) and cyclopropanesulfonyl chloride (0.05 ml, 0.44 mmol), to provide 25.3 mg of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(4-(cyclopropylsulfonyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH2:14][OH:15])[C:7]2=[O:12].[OH-].[K+].I[CH3:19].O>CS(C)=O.C(OCC)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH2:14][O:15][CH3:19])[C:7]2=[O:12]
Reactant: O=C1c2cccc(Br)c2CCN1CCO
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: COCCN1CCc2c(Br)cccc2C1=O
Reaction time: 0.5 h

Procedure:
0.39 g of 5-bromo-2-(2-hydroxyethyl)-3,4-dihydroisoquinolin-1(2H)-one is dissolved under an inert atmosphere in 3 cm3 of dimethylsulfoxide at a temperature close to 20° C. 105 mg of finely ground potassium hydroxide are added. The reaction mixture is stirred for 30 min at a temperature close to 20° C., then 0.108 cm3 of iodomethane is introduced. The stirring is continued for 20 h at a temperature close to 20° C. 30 cm3 of water and 30 cm3 of ethyl ether are added. After decanting, the organic phase is washed with 30 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator under reduced pressure (5 kPa). 170 mg of 5-bromo-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one are obtained in the form of a yellow oil.
Reaction SMILES: Cl.[Si]([O:19][CH2:20][CH2:21][O:22][CH2:23][C@H:24]([O:35][C:36]1[C:37]2[N:44]=[N:43][N:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])[C:38]=2[N:39]=[CH:40][N:41]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=1)=[O:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO>[Cl:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[N:42]1[C:38]2[N:39]=[CH:40][N:41]=[C:36]([O:35][C@@H:24]([CH2:23][O:22][CH2:21][CH2:20][OH:19])[C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=3)=[O:26])[C:37]=2[N:44]=[N:43]1
Reactant: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2nnn3-c2ccccc2Cl)nc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(NC(=O)[C@H](COCCO)Oc2ncnc3c2nnn3-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.3 %

Procedure:
Hydrochloric acid (10%, 2 mL) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate AP3) (335 mg, 0.47 mmol) in methanol (30.0 mL) at 0° C. The resulting solution was stirred at 0° C. for 10 minutes and allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated NH4Cl (25 mL) and most of the MeOH was removed by evaporation. The aqueous residue was extracted with EtOAc (3×25 mL), the organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (67.0 mg, 30.1%). 1H NMR (400 MHz, CDCl3) δ2.31 (s, 3H), 3.73-3.85 (m, 4H), 4.20-4.35 (m, 2H), 6.06 (t, 1H), 7.49-7.63 (m, 4H), 7.68 (d, 1H), 8.05 (s, 1H), 8.09-8.22 (m, 2H), 8.68 (s, 1H), OH not observed; m/z (ESI+) (M+H)+=470.41; HPLC tR=1.80 min
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:26])([F:25])[F:16])=[CH:23][N:22]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: FC(F)(F)c1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)nc1

Procedure:
6-Bromo-N-[5-(trifluoromethyl)pyridin-2-yl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (75 mg, 0.28 mmol) and 5-(trifluoromethyl)-2-bromopyridine (192 mg, 0.85 mmol) in a similar manner as described in Example 22 to give 6.5 mg (6%) of a off-white solid. 1H-NMR (DMSO-d6): δ 10.95 (s, 1H), 8.36 (s, 1H), 7.79 (d, 1H), 7.64 (dd, 1H), 7.57 (s, 1H), 7.23 (d, 1H), 7.13 (dd, 1H), 6.62 (d, 1H), 5.40-5.36 (m, 1H), 2.70-2.55 (m, 2H), 2.06-1.78 (m, 4H); MS m/z (M−1) 408, 410.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[P:6]([O:13]CC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].BrCC>>[Br:1][CH2:2][CH2:3][CH2:4][P:6]([O:10][CH2:11][CH3:12])(=[O:13])[O:7][CH2:8][CH3:9]
Reactant: BrCCCBr
Reactant: CCOP(OCC)OCC
Solvent: CCBr
Product: CCOP(=O)(CCCBr)OCC
Temperature: 130 °C

Procedure:
A mixture of 605 g (3.0 mol) of 1,3-dibromopropane and 250 g (1.5 mol) of triethyl phosphite was heated at an oil bath temperature of 130° C., while stirring and passing in nitrogen, for approximately 5 hours until approximately 154 g (1.5 mol) of bromoethane distilled over into a strongly ice-cooled receiver. The reaction mixture was distilled first in a bulb tube and then fractionally.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=4)=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([N:34](CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.Cl.CN>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:34][CH3:32])=[O:29])=[CH:25][CH:24]=4)=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(CC)CC
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(F)(F)C(=O)N3C)cc1
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A mixture of 0.10 g (0.22 mmole) of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-256), 0.089 g (0.88 mmole) of triethylamine, 0.125 g (0.33 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes, then 0.022 g (0.33 mmole) of methylamine hydrochloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.089 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-methyl-benzamide (I-258)
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[C:18]([O:25][C:26](=[O:32])[C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29])[CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+].Cl>CO>[CH3:30][C:27]([CH3:31])([CH2:28][CH3:29])[C:26](=[O:32])[O:25][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[C:15]([O:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:33])[C:3]([OH:34])=[O:2])=[CH:10][CH:9]=1)[CH:24]=[CH:23]2
Reactant: CCC(C)(C)C(=O)Oc1cccc2ccc(OCCOc3ccc(C(=O)C(=O)OC)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)(C)C(=O)Oc1cccc2ccc(OCCOc3ccc(C(=O)C(=O)O)cc3)cc12
Reaction time: 0.25 h

Procedure:
To a solution of 4-[[2-[8-(2,2-dimethyl-1 -oxobutoxy)-2-naphthalenyloxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.3 g) in methanol (7 mL) was added aqueous 1N sodium hydroxide (1.35 mL). After 15 minutes, the reaction was acidified with 1N hydrochloric acid (2 mL) and extracted with dichloromethane. The organic layer was washed with brine and evaporated to provide 4-[[2-[8-(2,2-dimethyl-1-oxobutoxy)-2naphthalenyloxy]ethyl]oxy]-alpha-oxobenzeneacetic acid as a white solid, mp 167°-168° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[CH3:20])=[O:11])[CH2:3]1.[C:21]([C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([S:29]([N:7]2[C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[CH3:20])=[O:11])[CH2:5][C@H:6]2[CH3:8])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:22]
Reactant: Cc1c(F)cccc1NC(=O)CN1C[C@@H](C)N[C@@H](C)C1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Product: Cc1c(F)cccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(C#N)c2)[C@@H](C)C1

Procedure:
The title compound was prepared from the product of step (i) (0.503 mmol) and 3-cyanobenzenesulphonyl chloride (0.503 mmol) by the method of Example 58 step (ii) as a white solid. Yield: 44 mg
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:11])([F:12])[F:13])=[C:2]([Cl:1])[CH:3]=2)=[CH:37][CH:36]=1)=[O:34]
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 70 °C
Reaction time: 19 h
Yield: 64 %

Procedure:
Trifluoromethanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 26, Step 1, 92 mg, 0.2 mmol), (4-methoxycarbonylphenyl)boronic acid (42 mg, 0.3 mmol) and 1,1,bis(diphenylphosphino)-ferrocenpalladium(II)dichloromethane (8 mg, 0.01 mmol) in dioxane (0.6 ml) was treated with water (0.44 ml) and 2N—Na2CO3 (0.3 ml, 0.6 mmol) and stirred at 70° C. under argon for 19 h. The reaction mixture was cooled down to r.t., diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (10 g silica gel, heptane/AcOEt 4:1) to give the title compound as a white solid (62 mg). MS (m/e)=484.1 [M+H+].