Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[S:25][CH:26]=[C:27]([Cl:29])[N:28]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:29][C:27]1[N:28]=[C:24]([N:21]2[CH2:20][CH2:19][O:18][CH2:23][CH2:22]2)[S:25][C:26]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[CH3:16]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Clc1csc(N2CCOCC2)n1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nc12
Temperature: 120 °C
Reaction time: 16 h
Yield: 106.5 %

Procedure:
A 20 L reactor flask under nitrogen is charged with 2900 ml of dry and degassed DMF then with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (287 g, 0.836 mol), 2-morpholino-4-chlorothiazole (205.4 g, 1.01 mol, 1.2 equv.), Pd(OAc)2 (3.74 g, 7.91 mmol, 0.01 equiv.), triphenylphosphine (8.77 g, 33.1 mmol, 0.04 equiv.), Copper iodide (8 g, 41.59 mmol, 0.05 equiv.) and cesium carbonate (544.9 g, 1.65 mol). The reaction mixture is heated at 120° C. After 16 h at 120° C., 1.87 g of Pd(OAc)2 and 4.38 g of triphenylphosphine more is added. After 1 h, the mixture is cooled, quenched with NH4Cl solution (4300 mL) and extracted with MTBE (2900 mL), the aqueous phase is extracted twice more with 2000 ml of MTBE. The organic phases are washed with sat NaCl aq (2000 mL), then treated with charcoal 72 g in flask bottle and filtered on Celite®. The filtrate is concentrated under vacuum to afford 373.8 g (79.3%) of the title compound which is 81.4%-area HPLC analysis the rest being solvent and with no detectable Example 200 by-product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:16])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:26](Cl)[C:27]([OH:29])=[O:28]>CC(O)C>[CH3:1][C:2]1[C:3]2[O:16][CH:26]([C:27]([OH:29])=[O:28])[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: Cc1cccc(Cc2ccccc2O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cccc2c1OC(C(=O)O)Oc1ccccc1C2
Reaction time: 30 h

Procedure:
(3-Methyl-2-hydroxyphenyl)(2-hydroxyphenyl)-methane (3.4 g, 16 mmol), potassium carbonate (8.84 g, 64 mmol), potassium iodide (0.53 g, 3.2 mmol), dichloroacetic acid (2.06 g, 16 mmol), and 65 ml of 2-propanol were heated at reflux with stirring under nitrogen for 30 hours. Another 2.05 g (16 mmol) of dichloroacetic acid was added and heating at reflux continued for 60 hours. The 2-propanol was then removed by evaporation under reduced pressure and the residue was diluted with distilled water and acidified with 2N hydrochloric acid. This mixture was extracted with ether and the ether extract was dried over magnesium sulfate and evaporated under reduced pressure to obtain 1.8 g (42 percent of theory) of the title compound as a solid residue. A purified sample melting at 171° C. was obtained by recrystallization from a mixture of methylcyclohexane and acetone. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][N:12]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])[N:10]=2)[CH:6]=[CH:7][CH:8]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][N:12]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc(OCCCCl)ns2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(-c2nc(OCCCCl)ns2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
2 g of 3-[5-(3-methoxyphenyl)-1,2,4-thiadiazole-3-oxy]-propyl chloride [for preparation, see Example 65 E)] were dissolved in 100 ml dichloromethane. A solution of 20 ml borotribromide in dichloromethane was added to the solution and the reaction mixture was stirred for 8 hours at room temperature under a nitrogen atmosphere. Then the reaction mixture was poured into water for workup and made alkaline by adding sodium carbonate. Then extraction was performed with dichloromethane and the organic phase was dried and concentrated. 1.9 g of crude 3-[5-(3-hydroxyphenyl)-1,2,4-thiadiazole-3-yloxy]-propyl chloride was obtained as a yellow oil.
Reaction SMILES: [N:1]([CH:4]([C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)[CH2:5][CH:6]=[O:7])=[N+:2]=[N-:3].[BH4-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[N:1]([CH:4]([C:8]1[CH:9]=[N:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=1)[CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(CC=O)c1ccc(C(F)(F)F)nc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=NC(CCO)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of the crude 3-azido-3-(6-(trifluoromethyl)pyridin-3-yl)propanal (5.0 g, 20.5 mmol) in tetrahydrofuran (100 mL) at 0° C. was added sodium tetrahydroborate (1.52 g, 40.1 mmol). The mixture was stirred at room temperature for 10 minutes. After completion of the reaction, brine was added and the mixture was extracted with ether. The organic layer was dried and concentrated to afford a crude oil which was purified by silica gel chromatography to afford a light yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1)=[C:20]=[S:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:19][C:20]([NH:14][C:13]2[C:8]([O:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9][CH:10]=[CH:11][CH:12]=2)=[S:21])=[CH:23][CH:24]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Reactant: CC(=O)c1ccc(N=C=S)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=S)Nc2cccnc2Oc2ccccc2C(C)(C)C)cc1
Yield: 19.7 %

Procedure:
127.15 mg (0.525 mmol) of 1b were mixed with 92.16 mg (0.525 mmol) of 1-(4-isothiocyanatophenyl)ethanone, 5 mL of CH2Cl2 and 6.61 mg (0.052 mmol) of DMAP and refluxed under Argon for 72 h. 225a was filtered and purified by crystallization in MeOH to yield 43.3 mg of an off-white solid used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>C(O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[O:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[N:1]=2)=[CH:16][CH:15]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
2-Amino-4-(trifluoromethyl)phenol (250 mg, 1.41 mmol) and 1-bromo-4-isothiocyanatobenzene (302 mg, 1.41 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight. The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 85:15 hexanes/ethyl acetate to provide the title compound (315 mg, 62%). LC-MS m/z 357.1 (MH+), retention time 4.20 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([SH:26])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:27][C:28]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:27][C:28]1[CH:37]=[CH:36][C:35]([CH2:38][S:26][C:15]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:12]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)([CH3:11])[CH3:10])=[CH:13][N:14]=2)=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)c1cc(CBr)ccc1Br
Reactant: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2S)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A mixture of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazole-2-thiol (700 mg, 1.7 mmol, 1.0 eq), methyl 2-bromo-5-(bromomethyl)benzoate (630 mg, 2.0 mmol, 1.2 eq) and potassium carbonate (350 mg, 2.6 mmol, 1.5 eq) in acetone (9 mL) was stirred at room temperature 1 h. The solids were filtered and the organics were concentrated and purified (silica, 0 to 60% EtOAc/Hex) to afford the title compound (900 mg, 83%). MS (EI) m/z 638.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.P(Cl)(Cl)Cl.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([Cl:20])=[CH:22][CH:23]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(Cl)c2cccnc2c1O
Reactant: Nc1ccc(Cl)cc1
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)c2cccnc2c1O
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
A suspension of 5-chloro-8-hydroxyquinoline-7-carboxylic acid (0.224 g) of Preparation 3 in 50 mL xylene is heated to reflux. To this is added dropwise PCl3 (0.069 g). After 15 min, 4-chloroaniline (0.128 g) is added. Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The solid is then partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with water, dried and condensed. The crude product is recrystallized from EtOAc to yield 0.073 g of the title product as an orange solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:31]=[CH:30][CH:29]=[CH:28][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CS(C)=O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][O:13][C:12]1[CH:11]=[C:10]([CH:27]=[CH:26][CH:25]=1)[O:9][CH2:8][C:7]1[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=1[CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: ClCc1ccccc1COc1cccc(OCc2ccc3ccccc3n2)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccccc1COc1cccc(OCc2ccc3ccccc3n2)c1
Reaction time: 5 h

Procedure:
Sodium cyanide (14 mg, 0.28 mmol) is added to a solution of 2-[3-(2-chloromethyl-benzyloxy)-phenoxymethyl]-quinoline (110 mg, 0.28 mmol, example 37) in DMSO (5 mL) and the reaction is stirred 5 h. The reaction is partitioned between water and ethyl acetate, the organic phase is washed with water, dried and concentrated to provide the title compound which is used without further purification. MS (ESI) 381 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:2]1.[CH3:12]C(C)([O-])C.[K+].IC>C1COCC1.CCOCC.C1OCCOCCOCCOCCOCCOC1>[CH3:12][N:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:2]1
Reactant: COC(=O)C(=O)c1cc[nH]c1
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOCC
Product: COC(=O)C(=O)c1ccn(C)c1
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A solution of methyl pyrrol-3-yloxoacetate (3.3 g, 22 mol) in THF (70 ml) was added at room temperature to a stirred suspension of potassium tert-butoxide (2.7 g, 24 mmol) and 18-crown-6 (0.1 g, 0.39 mmol) in ether (250 ml). The reaction mixture was stirred for 30 minutes then iodomethane (1.6 ml, 26 mmol) in ether (50 ml) was added dropwise. The reaction mixture was stirred for 16 hours then filtered through hyflo supercell and washed with brine, dried and concentrated to give methyl N-methyl-pyrrol-3-yloxoacetate (2.84 g, 79% yield) as a clear oil, IR (thin film) 1725, 1645 cm-1, 1H nmr: delta 3.64 (3H, s), 3.85 (3H, s), 6.5 (1H, m) 6.7 (1H, m), 7.6 (1H, m) ppm.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([CH2:11][OH:12])([F:10])[CH:5]([F:13])[C:4]=1[F:14].[BrH:15]>>[OH:12][CH2:11][C:6]1([F:10])[C:7]([F:9])=[CH:8][C:3]([CH2:2][Br:15])=[C:4]([F:14])[CH:5]1[F:13]
Reactant: Br
Reactant: OCC1=C(F)C(F)C(F)(CO)C(F)=C1
Product: OCC1(F)C(F)=CC(CBr)=C(F)C1F
Yield: 90 %

Procedure:
A 90% yield of 4-hydroxymethyl-2,3,4,5-tetrafluorobenzyl bromide obtained from 1,4-bis(hydroxymethyl)-2,3,4,5-tetrafluorobenzene by treatment with 48% hydrobromic acid was reported by Costello and Milner in Synthetic Communications, 17, 219-221 (1987). However, it has since been shown that treatment of benzenedimethanols lacking nuclear halogen substituents shows no particular selectivity, and accordingly, the unusually high yield in this isolated example is believed to be an anomaly due to insolubility of the monohalogenated product in the reaction media.
Reaction SMILES: [C:1]([C:5]1[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15]Br>C(Cl)Cl>[Br:15][C:13]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=2[S:11][C:12]=1[CH3:14]
Reactant: BrBr
Reactant: Cc1cc2cccc(C(C)(C)C)c2s1
Solvent: ClCCl
Product: Cc1sc2c(C(C)(C)C)cccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A solution of 7-tert-butyl-2-methyl-benzo[b]thiophene 94.69 g, 23.0 mmol) in CH2Cl2 (100 mL) is cooled to 0° C. It is treated with Br2 (1.18 mL, 23.0 mmol). The resulting reaction mixture is stirred at rt overnight. It is washed with 10% Na2SO3 (2×50 mL); brine (50 mL); dried with Na2SO4, filtered and concentrated gives the title compound (4.99 g, 17.57 mmol, 76%). 1H NMR (CDCl3): δ 1.53 (s, 9H), 2.56 (s, 3H), 7.32 (dd, J=7.5, 1.3 Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 7.63 (dd, J=7.5 Hz, 1.3 Hz, 1H) ppm. ES-MS (m/z): calcd for C13H15BrS (M+1)+: 284.2. found: 284.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.Cl[C:23]1[N:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][C:29]([O:33][CH3:34])=[CH:28]2>>[F:20][C:5]1[C:4]([F:21])=[CH:3][C:2]([NH:1][C:23]2[N:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[CH:30][C:29]([O:33][CH3:34])=[CH:28]3)=[CH:7][C:6]=1[C:8]1([CH3:19])[CH2:13][CH:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]1
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: COc1cnc2c(Cl)nccc2c1
Product: COc1cnc2c(Nc3cc(F)c(F)c(C4(C)CC(C(F)(F)F)OC(N)=N4)c3)nccc2c1

Procedure:
The titled compound was synthesized by procedure and steps analogous to those described in Method B, Example 8 above, but using (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (17i, example 163, Method Y, step 9) and 8-chloro-3-methoxy-1,7-naphthyridine (intermediate 31) in step 2. MS m/z=468.2 [M+H]+. Calculated for C21H18F5N5O2: 467.4
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2[F:36])[CH2:2]1.C(Cl)Cl.CO.[C:43]1(=O)[CH2:47][CH2:46][CH2:45][CH2:44]1>CC(O)=O>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[C:11]([O:13][CH3:14])=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:2][N:1]([CH:43]6[CH2:47][CH2:46][CH2:45][CH2:44]6)[CH2:4]5)=[O:37])=[C:8]([F:36])[CH:9]=4)=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C1CCCC1
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CN(C3CCCC3)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 3 h
Yield: 4.5 %

Procedure:
To a solution of N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide (100 mg, 0.19 mmol) in AcOH:DCM:MeOH (2.5 mL, 1:2:2) was added cyclopentanone (100 μL, 1.09 mmol), borane-pyridine complex (100 μL, 0.8 mmol), and left to stir for 3 h. The solvent was then removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (5.0 mg, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.35 (m, 2H) 1.38-1.78 (m, 11H) 1.96 (br. s., 2H) 2.67 (br. s., 1H) 2.87 (t, J=7.33 Hz, 2H) 3.49 (t, J=7.33 Hz, 2H) 3.91 (s, 3H) 4.08 (t, J=13.77 Hz, 2H) 4.33-4.44 (m, 1H) 4.78-4.88 (m, 1H) 7.19 (d, J=6.57 Hz, 1H) 8.05 (s, 1H) 8.25 (d, J=13.39 Hz, 1H) 8.30 (s, 1H) 8.41 (dd, J=6.82, 3.03 Hz, 1H). [M+H] calc'd for C29H36F3N7O3, 588. found 588.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH2:18][OH:19])[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH2:34]>C(Cl)(Cl)(Cl)Cl.CC#N>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([OH:34])=[O:19])[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: O=C(c1cccc2ccccc12)N1CC(CO)C(CN2CCC(c3ccc(F)cc3)CC2)C1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A mixture of 0.126 g (0.28 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethyl pyrrolidine, 0.18 g (0.85 mmol) of NaIO4, and 0.0029 g (0.014 mmol) of RuCl3.3 H2O in 2 mL of CCl4, 3 mL of H2O and 2 mL of CH3CN was stirred at rt for 1 h. The reaction mixture was partitioned between CH2Cl2 and H2O. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give the title compound. 1H NMR (key peaks) (CDCl3) δ7.81-7.88 (m, 3H), 7.43-7.74 (m, 4H), 7.11-7.14 tm, 2H), 6.97 (t, 2H, J=8.0 Hz), Mass Spectrum (ESI) m/e=461 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=1.[Cl:33][C:34]1[N:35]=[N:36][C:37](Cl)=[CH:38][CH:39]=1>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]([C:37]1[N:36]=[N:35][C:34]([Cl:33])=[CH:39][CH:38]=1)[CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: Clc1ccc(Cl)nn1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(Cl)nn2)cc1)C(=O)O

Procedure:
Similarly prepared from methyl 2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3,6-dichloropyridazine.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[CH:7][N:8]=1)([O-])=O>[Pd].CO>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[NH2:1]
Reactant: C[Si](C)(C)CCOCn1ccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccnc1N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96 %

Procedure:
A suspension of 2-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (Step 14.3) (1.84 g, 7.57 mmol) and palladium on carbon (200 mg) in MeOH (30 mL) was stirred for 40 min at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and concentrated to afford 1.55 g of the title compound: ESI-MS: 214.1 [M+H]+; tR=3.26 min (System 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2cnc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cnc(N3CCNCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A mixture of 189e (1.0 g, 2.2 mmol) and 4.0 M HCl/dioxane (60 mL) was stirred at room temperature for 5 h. It was then concentrated under reduced pressure to afford crude 189f as a yellow solid (760 mg, 98%), which was used in the next step without further purification. MS: [M+H]+ 395.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH:22]=[CH:23][C:24]4[S:25][C:26]([Cl:29])=[CH:27][CH:28]=4)(=[O:21])=[O:20])[CH2:15][C:14]3=[O:30])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.C1(O)C=CC=CC=1.C([O-])(=O)C.[NH4+:42]>C(OCC)(=O)C>[NH2:42][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH:22]=[CH:23][C:24]4[S:25][C:26]([Cl:29])=[CH:27][CH:28]=4)(=[O:20])=[O:21])[CH2:15][C:14]3=[O:30])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)CCN1Cc1ccc2c(Cl)cnnc2c1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: Nc1cnnc2cc(CN3CCN(S(=O)(=O)C=Cc4ccc(Cl)s4)CC3=O)ccc12
Temperature: 120 °C
Yield: 35.8 %

Procedure:
1-(4-Chlorocinnolin-7-ylmethyl)-4-[2-(5-chlorothiophen-2-yl)-ethenesulfonyl]-piperazin-2-one (0.06 g, 0.12 mmol) is treated with phenol (0.20 g) and ammonium acetate (0.2 g, 2.6 mmol) and heated to 120° C. for 45 minutes. The reaction mixture is cooled, diluted with ethyl acetate and washed with 1 N NaOH (3×100 mL) and water. The organic layer is concentrated and the residue is purified by reverse phase HPLC (20% aqueous TFA (0.1%)/acetonitrile to 100% acetonitrile). Fractions containing the desired product are lyophilized to obtain the title compound (0.02 g, 0.043 mmol). MS m/z: [M+H]+=464; 1H NMR (CD3OD, 300 MHz) δ8.6 (s, 1H), 8.4 (d, 1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.35 (d, 1H), 7.1 (d, 1H), 6.8 (d, 1H), 4.9 (s, 2H), 4.05 (s, 2H), 3.6 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:4]1>CO.[Pd]>[NH2:18][C:9]1[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][CH:3]([N:2]([CH3:21])[CH3:1])[CH2:4]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CN(C)C1CCN(c2ccc(C(F)(F)F)cc2N)C1
Temperature: 25 °C

Procedure:
To a solution of (R)-N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)pyrrolidin-3-amine (1.75 g, 5.77 mmol) in MeOH (60 mL) was added 10% Pd/C (0.30 g, 0.29 mmol). H2 gas was bubbled through the solution for 5 minutes, and the reaction was stirred at RT under an atmosphere of H2 gas. The reaction was monitored by LCMS for disappearance of starting material and formation of product. The mixture was filtered through celite with MeOH, and concentrated to afford the product as an orange/red oil.