Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:34][C:35]([O:38][C:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[C:43]([N+:50]([O-:52])=[O:51])[CH:42]=1)=[O:40])([CH3:37])[CH3:36]>CN(C)C=O>[NH2:4][C:45]([C:44]1[CH:48]=[CH:49][C:41]([C:39]([O:38][C:35]([CH3:37])([CH3:36])[CH3:34])=[O:40])=[CH:42][C:43]=1[N+:50]([O-:52])=[O:51])=[O:46]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
N,N-Diisopropylethylamine (0.41 mL, 2.30 mmol) was added to a mixture of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (321 mg, 0.84 mmol) and 4-{[(1,1-dimethylethyl)oxy]carbonyl}-2-nitrobenzoic acid (prepared according to Gao, Y. et. al WO2001070737) (205 mg, 0.77 mmol) in N,N-dimethylformamide (2 mL), and the reaction mixture was stirred at room temperature for 30 minutes. Ammonia was bubbled into the reaction mixture and stirring was continued for 45 minutes. The reaction mixture was quenched with 0.5M aqueous hydrochloric acid solution (20 mL) and extracted with ethyl acetate (3×20 mL), and the combined extract was washed with water (20 mL), then brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography (25 to 75% ethyl acetate in hexanes) to give the 1,1-dimethylethyl 4-(aminocarbonyl)-3-nitrobenzoate (160 mg, 78% yield). 1H NMR (400 MHz, CDCl3): 8.55 (s, 1H), 8.25 (d, 1H), 7.64 (d, 1H), 6.51 (br, 1H), 6.26 (br, 1H), 1.61 (s 9H); MS (EI) for C12H14N2O5: 267 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][N:28]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NC(C)C)(C)C>O1CCOCC1.[Cu]I>[N:28]1[CH:27]=[C:32]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:31]=[N:30][CH:29]=1
Reactant: Brc1ccncn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cncnc4)c3n2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a flask was added 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (159 mg, 0.45 mmol), 4-Bromopyrimidine (87 mg, 0.55 mmol, commercially available [CAS 4595-59-9]), PdCl2(NCPh)2 (13 mg, 7 mol %), and CuI (10 mg, 12 mol %). The flask was charged with Ar, then 3 mL of dioxane (degassed with Ar), tri-(tert-butyl)phosphine (0.12 mL of a 0.25M soln in dioxane, 33 mol %), and diisopropylamine (0.15 mL) were added. The r×n mixture was stirred at 23° C. under Ar overnight, then filtered through a pad of Si-gel, concentrated, purified by Si-gel chromatography (EtOAc/heptane 5-40:95-60) to give an orange solid. Recrystallization from EtOAc/heptane (1:2) yielded the product as an orange solid (131 mg, 68%). MS (ISP) 434.1 [(M+H)+]; mp 175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:28][CH2:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, azetidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.25 minutes; C19H16Cl2N4O3 (403.27); mass spectrum: (M+H)+=403.1.
Reaction SMILES: OS(O)(=O)=O.[O:6]=[C:7]1[N:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23](OC)[C:24](=C=O)[C:25]3[CH:30]=[C:29]([Br:31])[C:28]([O:32]COCC[Si](C)(C)C)=[C:27]([Br:41])[CH:26]=3)=[O:21])[CH2:16][CH2:15]2)[CH2:12][CH2:11][C:10]2[CH:46]=[CH:47][CH:48]=[CH:49][C:9]=2[NH:8]1>C1COCC1.CO>[O:6]=[C:7]1[N:13]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C@@H:23]([C:20]([O:22][CH3:23])=[O:21])[CH2:24][C:25]3[CH:26]=[C:27]([Br:41])[C:28]([OH:32])=[C:29]([Br:31])[CH:30]=3)=[O:21])[CH2:18][CH2:19]2)[CH2:12][CH2:11][C:10]2[CH:46]=[CH:47][CH:48]=[CH:49][C:9]=2[NH:8]1
Reactant: CO[C@H](OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)C(=C=O)c1cc(Br)c(OCOCC[Si](C)(C)C)c(Br)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere 5.46 mL methanolic H2SO4 (0.5 M) were added to a solution of 4.30 g (5.69 mmol) of (R)-2-[3,5-dibromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-methoxy-carbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 40 mL THF and 40 mL MeOH and the reaction solution was stirred for 6 h at RT. The reaction mixture was evaporated down i.vac and the residue was reacted further without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])[C:3]([OH:5])=O.CCN=C=NCCCN(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34].CCOC(C)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH3:34][O:33][N:32]([CH3:31])[C:3](=[O:5])[C:2]([CH3:1])([CH3:18])[CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)[Si](OCC(C)(C)C(=O)O)(C(C)C)C(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(C)(C)CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 2,2-dimethyl-3-triisopropylsilanyloxy-propionic acid in anhydrous dichloromethane (13 ml) was slowly treated with EDCI (1.03 g, 5.38 mmol) followed by N,O -dimethylhydroxylamine hydrochloride (525 mg, 5.4 mmol), DMAP (55 mg, 0.045 mmol), and TEA (0.75 ml, 5.38 mmol). After stirring overnight at room temperature the reaction mixture was partitioned between DCM/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a greenish oil. Silica gel chromatography using 10-60% EtOAc in hexanes as eluant provided 1.13 mg (79%) of N-methoxy-2,2,N-trimethyl-3-triisopropylsilanyloxy-propionamide as a colorless oil. M+H=318.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[C:8]2[N:13]([C:14](=[O:18])[C:15]=1[O:16][CH3:17])[CH2:12][CH2:11][O:10][C:9]2([CH3:20])[CH3:19])=[O:5].[CH3:22][Mg+].[Br-]>C1COCC1.CCOCC>[C:4]([C:6]1[N:7]=[C:8]2[N:13]([C:14](=[O:18])[C:15]=1[O:16][CH3:17])[CH2:12][CH2:11][O:10][C:9]2([CH3:19])[CH3:20])(=[O:5])[CH3:22]
Reactant: C[Mg+]
Reactant: COc1c(C(=O)N(C)OC)nc2n(c1=O)CCOC2(C)C
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(C(C)=O)nc2n(c1=O)CCOC2(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a solution of N,3-dimethoxy-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.40 g, 1.35 mmol, 1.0 equiv) in THF (13 mL) at 0° C. (ice/water bath) under a nitrogen atmosphere, was added CH3MgBr (0.63 mL of a 3 M solution in ether, 1.88 mmol, 1.4 equiv). After stirring 3 h, the reaction was cautiously quenched by addition of 1N HCl (10 mL). After stirring 1 h, the reaction was poured into water and extracted with CH2Cl2 (×5). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by silica gel chromatography (20-100% ethyl acetate/hexane) to provide the title compound (0.054 g, 16% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.98 (s, 3H), 3.96-4.05 (m, 4H), 2.52 (s, 3H), 1.61 (s, 6H); LCMS (ES+, (M+H)+) m/z 253.23.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:26])=[C:4]([C:9]2[C:10]([OH:25])=[N:11][C:12]3[C:17]([C:18]=2[O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=[CH:14][N:13]=3)[C:5]([F:8])=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[F:36][CH:37]([F:47])[CH2:38]OS(C(F)(F)F)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([Cl:26])=[C:4]([C:9]2[C:10](=[O:25])[N:11]([CH2:38][CH:37]([F:47])[F:36])[C:12]3[C:17]([C:18]=2[O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=[CH:14][N:13]=3)[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CC(C)C(=O)Oc1c(-c2c(F)ccc(Br)c2Cl)c(O)nc2ncccc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Oc1c(-c2c(F)ccc(Br)c2Cl)c(=O)n(CC(F)F)c2ncccc12
Reaction time: 8 h

Procedure:
To a solution of Isobutyric acid 3-(3-bromo-2-chloro-6-fluoro-phenyl)-2-hydroxy-[1,8]naphthyridin-4-yl ester (1.749 g) in acetonitrile (17 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.83 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before drop wise addition of a solution of 2,2-difluoroethyltrifluoromethanesulfonate (1.022 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 7 hours when further 2,2-difluoroethyltrifluoromethanesulfonate (0.5 g) and the reaction was stirred overnight. A further portion of 2,2-difluoroethyltrifluoromethanesulfonate (0.5 g) and N,N-diisopropylethylamine (“Hunig's base”) (0.83 ml) was added and the reaction was stirred for 5 hours then left to stand overnight. The reaction was concentrated and partitioned between ethyl acetate and 2M hydrochloric acid. The organic layer was dried and concentrated and the oily residue was purified by column chromatography on silica (eluent: 4:1 hexane:ethyl acetate) to give Compound No. D23 of Table D as a light yellow solid (1.56 g).
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:32])[C:29]([CH3:31])=[CH2:30]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([NH:22][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH:23]=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 56 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methacrylamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and methacrylic acid using Method E (56% yield). HPLC: 98%, RT=4.345 min. MS: m/z=423 [M+H]+, RT=4.33 min. 1H-NMR (DMSO-d6), 1H), 8.51 (s, 1H), 8.42 (d, 1H), 7.96 (s, 1H), 7.73 (d, 1H), 7.42-7.33 (m, 4H), 7.19 (d, 2H), 7.13 (t, 1H), 7.09 (d, 2H), 7.02 (d, 2H), 6.79 (d, 1H), 5.80 (s, 1H), 5.51 (s, 1H), 1.94 (s, 3H).
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].Br[CH:28]1[O:33][C:31](=[O:32])[CH2:30][CH2:29]1>>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])([O:4][CH:28]1[O:33][C:31](=[O:32])[CH2:30][CH2:29]1)=[O:5])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(Br)O1
Product: CCP(=O)(OC1CCC(=O)O1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 1, P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid is reacted with 4-bromo-γ-butyrolactone to give 4-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxy]-γ-butyrolactone. ##STR7##
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:63]=[O:64]>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:63][OH:64])[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To a solution of (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 1h (0.82 g, 1.16 mmol, obtained from the synthetic method described in step 7 of example 1) in N,N-dimethylformamide (20 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.02 mL, 0.12 mmol) and formaldehyde (1.7 mL, 23.2 mmol, 37% in water) in turn. The mixture was stirred at room temperature for 5 hours and quenched with 10 mL of saturated aqueous sodium bicarbonate. The resulting mixture was filtered. The filtrate was extracted with ethyl acetate (20 mL×1 and 10 mL×3). The combined organic layers were washed with water (10 mL×3) and then saturated aqueous sodium chloride (10 mL×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=5/1 to give the title compound 8a as yellow oil (0.56 g, 65.1%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.99 (s, 1H), 7.55-7.49 (m, 2H), 7.43 (d, 1H), 7.34-7.24 (m, 13H), 7.07 (dd, 2H), 6.95 (d, 2H), 6.72 (d, 2H), 5.38 (dd, 1H), 4.84 (m, 3H), 4.72 (d, 1H), 4.56-4.43 (m, 2H), 4.16 (d, 1H), 4.01 (d, 1H), 3.92 (q, 2H), 3.81 (m, 3H), 3.57 (dd, 1H), 3.25 (d, 1H), 2.70 (s, 3H), 1.27 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[CH3:34][O:35][C:36]1[N:37]=[CH:38][C:39]([C:42](O)=[O:43])=[N:40][CH:41]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:42]([C:39]3[CH:38]=[N:37][C:36]([O:35][CH3:34])=[CH:41][N:40]=3)=[O:43])[CH:3]=[CH:4][C:5]=2[F:33])[N:9]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)c([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Reactant: COc1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
N-[(4aR,7aS)-7a-(5-Amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.361 g, 0.77 mmol, isomer 1) is dissolved in a mixture of dichloromethane (4 mL) and DMF (0.5 mL). 5-Methoxypyrazine-2-carboxylic acid (240 mg, 1.55 mmol), 1-hydroxybenzotriazole (210 mg, 1.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (300 mg, 1.55 mmol) are added to the mixture and the mixture is stirred overnight at room temperature. The reaction solution is added directly onto a 12 g silica gel loading column and purified using a 40 g silica gel column and eluting with a 0-100% ethyl acetate/hexanes gradient. The product is dissolved in ethyl acetate (200 mL), washed with 1 N NaOH (2×50 mL), and with brine (1×50 mL). The silica gel purification is repeated as described above to give the title compound (350 mg, 74%). ES/MS (m/e): 603 (M+H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.O.[Cu]I>[N:12]1[N:13]([C:2]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Temperature: 120 °C

Procedure:
A solution of 2-iodo-5-methylbenzoic acid (1-13, 4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120° C. for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in water with 0.1% AcOH) to give the faster eluting 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid 1-5, followed by the undesired regioisomer isomer, 1-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid (1-14). Data for 1-5: 1HNMR (500 MHz, DMSO-d6) δ 12.98 (br s, 1H), 8.04 (s, 2H), 7.72-7.45 (m, 3H), 2.41 (s, 3H) ppm.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:23])=[C:19]([CH2:21][OH:22])[CH:20]=1>CN(C=O)C.C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:23])=[C:19]([CH:20]=1)[CH2:21][O:22][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)ccc1Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Imidazole (5.22 g) and tert-butyldimethylsilyl chloride (8.64 g) were added to a solution of (5-bromo-2-chlorophenyl)methanol (8.47 g) in DMF (80 ml). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed twice with water. The aqueous layer was again extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (12.6 g).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH2:18][CH3:19])=[O:9])=[O:2]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C=O)ccc1O

Procedure:
5-Formylsalicylic acid (3.0 g, 17 mmol), conc. sulfuric acid (1 mL) and absolute ethanol (100 mL) were heated at reflux for 3.5 days with stirring under N2. The reaction was cooled, then carefully quenched by adding saturated sodium bicarbonate (40 mL). Solvent was removed in vacuo, and the resulting mixture was acidified with 1M HCl (50 mL), then extracted with EtOAc. The organic phase was extracted with water, then brine, and dried (MgSO4). Removal of solvent and chromatography on silica gel, eluting with 0% to 25% EtOAc in hexanes gave a colorless crystalline solid (2.3 g), mp 67°-69° C. after solvent removal. 1 H-NMR(300 MHz, CDCl3): 11.49 (s, 1H), 9.90 (s, 1H), 8.40 (d, 1H, J=2 Hz), 8.00 (dd, 1H, J=8,2 Hz), 7.11 (d, 1H, J=8 Hz), 4.48 (q, 2H, J=7 Hz), 1.46 (t, 3H, J=7 Hz). IR(KBr): cm-1 3186, 1684.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)[CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(C=O)c3)ccc2-n2c(C)nnc21
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(CN4CCN(C)CC4)c3)ccc2-n2c(C)nnc21
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(3-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 5) (75 mg) was dissolved in DCM (5 ml). 1-methylpiperazine (25 μl) and acetic acid (8.62 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (160 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, overnight. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. over the weekend to give (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (49.2 mg) as a white solid. LCMS (formate): MH+ 582/584, RT 0.77 min
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:13][CH:14]=3)[C:9]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)C(C)(C)Cc1c(C(=O)c2ccccc2)c2cc(OC(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy indol-2-yl]-2,2-dimethylpropanoate (609 mg) from Example 8 (Step A) was dissolved in 10 mL of 1,2-dichloroethane and the solution charged with 0.5 mL of benzoyl chloride and 680 mg of AlCl3. The reaction was heated to 80° C. under argon for 1.5 h, then quenched with 20 mL of 0.5N Na, K tartrate solution, extracted with 3×20 mL of ether, washed with 10 mL of H2O and dried (MgSO4). Removal of solvent provided an oily residue which was chromatographed on silica gel to give the title compound.