Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][N:18]=2)[C:13]([CH2:20][C:21](O)=[O:22])=[CH:12][CH2:11][C@H:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:47])[CH2:34][CH2:33]1.Cl.CCN(C(C)C)C(C)C.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[C@@H:10]1[CH2:11][CH:12]=[C:13]([CH2:20][C:21](=[O:22])[N:32]2[CH2:33][CH2:34][CH:35]([N:38]3[C:46]4[C:41](=[N:42][CH:43]=[CH:44][CH:45]=4)[NH:40][C:39]3=[O:47])[CH2:36][CH2:37]2)[C:14]2=[N:15][CH:16]=[CH:17][N:18]=[C:19]2[C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2C(CC(=O)O)=CC[C@H]1c1cccc(F)c1F
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2C(CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)=CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
In a 100 mL round-bottomed flask was dissolved 2-((5S,6S)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7-dihydro-5H-cyclohepta[b]pyrazin-9-yl)acetic acid (63.4 mg, 0.147 mmol) (crude 10, azeotroped twice with dry benzene and further dried under high vacuum) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (96 mg, 0.441 mmol) (bis-HCl salt) in methylene chloride (2 mL) to give a colorless suspension. Hunig's base (0.128 mL, 0.735 mmol) and 3-(diethoxyphosphoryloxy)-1,2,3-benzo-triazin-4(3H)-one (88 mg, 0.29 mmol) were added. The reaction mixture was diluted with dimethylformamide (0.5 mL) The mixture was stirred at rt overnight. LCMS indicated complete conversion. It was diluted with ethyl acetate and washed with water and 0.5N sodium hydroxide. The organic layer was washed with brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by flash column chromatography CISCO) up to 10% methanol in methylene chloride afforded the desired product (59.6 mg, 64%) as a greenish solid: 1H NMR (400 MHz, CDCl3) 11.29 (s, 1H), 8.53 (s, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.08 (d, J=5.2 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.28-7.17 (m, 1H), 7.15-6.94 (m, 3H), 6.61 (dd, J=15.2, 9.3 Hz, 1H), 6.55-6.40 (m, 1H), 5.51 (q, J=8.6 Hz, 1H), 4.85 (d, J=12.2 Hz, 1H), 4.59 (s, 1H), 4.22 (s, 1H), 4.07-3.85 (m, 2H), 3.76 (d, J=16.2 Hz, 1H), 3.28 (t, J=12.0 Hz, 1H), 2.71 (t, J=12.3 Hz, 1H), 2.50-2.08 (m, 4H), 2.02-1.83 (m, 2H), 1.27 (s, J=2.3 Hz, 9H).
Reaction SMILES: [O:1]1[C:5]2([CH2:21][CH2:20][CH2:19][C:7]3([CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH2:8]3)[CH2:6]2)OCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:17][C:15]([CH3:18])([CH3:16])[CH2:14][CH2:13][CH2:12][CH:9]1[CH2:10][CH2:11][C:7]2([CH2:19][CH2:20][CH2:21][C:5](=[O:1])[CH2:6]2)[CH2:8]1
Reactant: CC(C)(O)CCCC1CCC2(CCCC3(C2)OCCO3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(O)CCCC1CCC2(CCCC(=O)C2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1,4-dioxa-dispiro[4.1.4.3]tetradec-9-yl)-2-methyl-pentan-2-ol (28′) (290 mg, 0.97 mmol) in acetone (6 mL) was added H2O (catalytic amount) and p-toluenesulfonic acid (catalytic amount). The reaction mixture is stirred at room temperature overnight and then dried over anhydrous MgSO4. The solution is filtered through silica and the filtrate concentrated under reduced pressure. The resulting residue is purified over silica (isooctane/EtOAc, 7:3) to afford the desired product as a colorless oil which was characterized as follows:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].O.NN>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:27][CH:28]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Compound (f) of Example 6 (3.85 g, 0.01 mole) is dissolved in 100 mL of absolute ethanol with warming. Hydrazine hydrate (7.5 mL) is added at once. The solution is heated to reflux for 10 minutes and the reaction mixture sets up. The mixture is cooled to room temperature and filtered. The precipitate is washed with excess hot ethanol. The ethanol fraction is rotovapped to a pale yellow oil. Chromatography on silica gel using methylene chloride/25% methanol as the mobile phase yields 1.6 g (66%) of a pale yellow oil. 1H NMR (CDCl3) 7.83 (1H, d, J=7 Hz); 7.6-7.2 (7H, m); 3.92 (2H, s); 3.66 (3H, s); 2.16 (2H, bs). Mass Spec. (DCl) m/z 242 (M+H). Analysis--calc'd for C15H15NO2.H2O: C, 71.97; H, 6.44; N, 5.60; found: C, 71.60; H, 6.27; N, 5.70.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH:5]2[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:3]1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[C:25]1([C:4]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:5]3[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][N:6]3[C:2](=[O:1])[O:3]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCCN12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
1,1-Dimethylethyl tetrahydro-3-oxo-1,1-diphenyl-1H-[1,3]oxazolo[3,4-a][1,4]diazepine-8(5H)-carboxylate (0.30 g, 0.73 mmol) was dissolved in ethyl acetate (5 mL). A 4 M hydrogen chloride/ethyl acetate solution (4 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and then ethyl acetate was added to the residue. The resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (0.16 g, yield 70%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7](C(=O)CCCCCCCC)[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2].[CH3:22][CH:23]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][C:25](Cl)=[O:26]>>[C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:25](=[O:26])[CH2:24][CH:23]([CH3:22])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Reactant: CCCCCCCCC(=O)N1CC(=O)N(C(C)=O)CC1=O
Product: CC(=O)N1CC(=O)N(C(=O)CC(C)CC(C)(C)C)CC1=O

Procedure:
##STR26## Synthesized as for 1-Acetyl-4-nonanoyl-2,5-piperazinedione in EXAMPLE I using 3,5,5-trimethylhexanoyl chloride in place of nonanoyl chloride.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:19]=2)=[O:15])=[CH:9][C:8]=1[CH3:32])(=O)=O.C(N(CC)CC)C.[C]=O.[C:44]([O:47]CC)(=[O:46])C>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][C:12]1[CH:11]=[C:10]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si:25]([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:26])[CH3:27])[CH:19]=2)=[O:15])[CH:9]=[C:8]([CH3:32])[C:7]=1[C:44]([OH:47])=[O:46]
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(C)c1C(=O)O
Temperature: 80 °C
Yield: 71 %

Procedure:
To a solution of trifluoromethanesulfonic acid, 2,6-dimethyl-4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]phenyl ester (Example 105, 562 mg, 1.09 mmol) in acetonitrile (7 mL) and water (1 mL) at 25° C. was added palladium (II) acetate (24 mg, 0.109 mmol), 1,3-bis(diphenylphosphino)propane (45 mg, 0.109 mmol), followed by triethylamine (2.18 mmol, 0.303 mL). The reaction was then pressurized to 40 psi with carbon monoxide and heated to 80° C. for 4 h. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) containing 1 mL of triethylamine. The separated aqueous layer was re-extracted with ethyl acetate (2×50 mL) and the combined organic layers were discarded. The aqueous phase was adjusted with 1N hydrochloric acid solution to pH 2 and extracted with ethyl acetate (100 mL). The organic extract was washed with water (25 mL) and brine (25 mL), dried (MgSO4), filtered and evaporated under reduced pressure to yield 2,6-dimethyl-4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]benzoic acid (1.7 g, 71% yield) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[N:24]1[CH2:23][CH2:22][N:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=2)[CH2:26][CH2:25]1
Reactant: Clc1ncnc2ccc(Br)cc12
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(N2CCN(c3ncnc4ccc(Br)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
A mixture of 300 mg 6-bromo-4-chloroquinazoline, 350 mg 1-[3-(trifluoromethyl)phenyl]piperazine, 0.18 mL triethylamine and 5 mL N,N-dimethylformamide was stirred at room temperature for 4 hours. After the solvent was evaporated, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give a yellow oil. This product was crystallized from diethyl ether to give 360 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19]([NH:21][CH2:22][C:23](=O)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=O)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1>C(O)(=O)C.C1(C)C(C)=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19]2[N:2]([CH3:1])[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][N:21]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: CN
Reactant: COc1cc(/C=C/C(=O)NCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2ncc(-c3ccccc3)n2C)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A solution of methylamine (2 M solution in methanol, 2.7 mL) in acetic acid (5 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-oxo-2-phenylethyl)acrylic acid amide (100 mg) in xylene (10 mL), and the reaction solution was heated under reflux for 3.5 hours while evaporating methanol. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl acetate:methanol=5:1) to obtain 11 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:22][N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31]C(=O)C)[CH2:25][CH2:24]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.C1COCC1.CO.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:22][N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:4][CH:3]=1
Reactant: CC(=O)OCCN1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NN1CCN(CCO)CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Acetic acid 2-(4-{[5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-amino}-piperazin-1-yl)-ethyl ester (100 mg, 200 μmol) was combined with THF (2 mL), methanol (1 mL) and water (1 mL) to give a light yellow solution. Lithium hydroxide (14.3 mg, 599 μmol) was added and the mixture was stirred for 1 h at room temperature. Subsequently the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 12 g, 0% to 100% ethyl acetate in n-heptane) to give the title compound (32 mg, 35%) as light yellow solid; MS (EI) 459.2 (M+H)+.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].I[C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>[Pd](Cl)Cl.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1COCC1>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:9]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: COC(=O)c1ccccc1I
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To 500 mL of THF was added water (18.4 mL, 1.02 mol), potassium carbonate (70.5 g, 0.510 mol), methyl 2-iodobenzoate (53.5 g, 0.204 mol), 4-cyano-phenylboronic acid (30.0 g, 0.204 mol) and bis-(tri-o-tolylphosphine) palladium (II) chloride (1.65 g, 2.04 mmol). This mixture was heated to reflux for 3.5 hours and then cooled to ambient temperature for continued stirring overnight. The solvent was then removed under reduced pressure prior to dilution with EtOAc/water. The organic layer was extracted with additional EtOAc. The combined organics were washed with water, then brine. The organics were then dried over sodium sulfate, filtered, and then concentrated to obtain the crude product. This crude product was passed through a silica pad, eluting with 8:1 heptane:EtOAc to get 41.6 grams of methyl 4′-cyano-1,1′-biphenyl-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:12][Mg]Br.O>O1CCCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:5]([OH:6])[CH3:12])[C:7]([F:10])=[CH:8][CH:9]=1
Reactant: O=Cc1c(F)ccc(Br)c1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1c(F)ccc(Br)c1F
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-2,6-difluorobenzaldehyde (5 g) in tetrahydrofuran (50 ml) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 24.9 ml) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.91 g).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[NH:15][C:16](=[O:19])[CH2:17][Br:18].C(Cl)Cl>C(N(CC)CC)C>[C:1]1([S:7]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[NH:15][C:16](=[O:19])[CH2:17][Br:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(CBr)Nc1cccc(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1cccc(OS(=O)(=O)c2ccccc2)c1

Procedure:
To a mixture of 4.4 g. of benzene sulfonyl chloride and 5.7 g. of 3'-hydroxy bromoacetanilide in 100 ml. of methylene chloride is added dropwise 2.6 g. of triethylamine. The product is recovered by washing with cold water, drying and removal of the solvent. There is obtained 9.0 g. of the title compound, nD30 = 1.5830.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[N:4]([NH2:15])[CH:3]=1.[CH3:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=2)[N:4]([NH:15][C:23]([C:22]2[C:17]([CH3:16])=[N:18][C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:20][CH:21]=2)=[O:24])[CH:3]=1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(C(F)(F)F)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2cc(C(F)(F)F)ccc21
Yield: 28.5 %

Procedure:
A mixture of 3-methyl-5-trifluoromethyl-indol-1-ylamine (223 mg, 1.04 mmol), 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (224 g, 1.04 mmol), HATU (475 mg, 1.25 mmol), DIPEA (404 mg 3.13 mmol) is stirred in DMF at 150° C. for 1 h. The reaction is quenched with water, extracted with extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 10% MeOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-methyl-5-trifluoromethyl-indol-1-yl)-amide (122 mg, 28%). MS: 412 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.22 (s, 1H), 8.79 (d, 1H), 8.66 (d, 1H), 8.06 (t, 1H), 7.91 (s, 1H), 7.60 (dd, 1H), 7.51 (s, 2H), 7.29 (s, 3H), 2.88 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19]4[CH2:25][CH2:26][NH:27][CH2:28][C:18]=4[C:17]=3[CH:16]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:34](C)=O.[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19]4[CH2:25][CH2:26][N:27]([CH3:34])[CH2:28][C:18]=4[C:17]=3[CH:16]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc31)CNCC2
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCc2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc3n2C)C1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in CH3OH (3 mL) was added formaldehyde (30 L, 0.29 mmol) and NaBH(OAc)3 (110 mg, 0.52 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. Then the mixture was concentrated and the residue was dissolved in CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-one (102 mg, 98%) as a yellow solid. The free base was converted to the HCl salt to give the title compound (100 mg, 90%) as a yellow solid: mp 264-268° C. (decompose); 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.56-7.36 (m, 8H), 7.10 (dd, J=8.5, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 3.0 Hz, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.58 (m, 1H), 4.27 (m, 1H), 3.78 (m, 1H), 3.72 (s, 3H), 3.50 (m, 1H), 3.18 (m, 2H), 2.97 (s, 3H); ESI MS m/z 400 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.9 min.
Reaction SMILES: [N:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]([C:24]1[C:25](=[O:44])[C:26]2[CH:31]=[N:30][C:29](S(C)(=O)=O)=[N:28][C:27]=2[N:36]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:37]=1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[C:25](=[O:44])[C:26]2[CH:31]=[N:30][C:29]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][S:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)(=[O:9])=[O:8])=[CH:13][CH:14]=3)=[N:28][C:27]=2[N:36]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:37]=1)=[O:23])[CH3:20]
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(Nc3ccc(CCS(=O)(=O)N4CCOCC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 (g) the title compound was prepared from 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (from Example 35(A), 75 mg, 0.28 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a yellow solid (57 mg, 38%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.26 (s, 1H), 8.46 (s, 1H), 7.65 (br, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 5.04 (m, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.68 (m, 4H), 3.22 (m, 4H), 3.10 (m, 4H), 2.00 (m, 4H), 1.80 (m, 1H), 1.62 (m, 2H), 1.48 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.31(m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][CH2:11][C:12](=[O:36])[NH:13][C:14]1[C:18]([C:19]2[N:23](COCC[Si](C)(C)C)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)=[N:17][O:16][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9](=[O:37])[NH:10][CH2:11][C:12](=[O:36])[NH:13][C:14]1[C:18]([C:19]2[NH:23][C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)=[N:17][O:16][N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2nonc2NC(=O)CNC(=O)OCc2ccccc2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)OCc1ccccc1)Nc1nonc1-c1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
0.55 g of ({4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-furazan-3-ylcarbamoyl}-methyl)-carbamic acid benzyl ester (1.00 mmol; 1 eq.) are added portionwise to 2.75 mL of trifluoroacetic acid (35.3 mmol; 35 eq.) at room temperature. The solution is stirred for 1 h and then concentrated to dryness under reduced pressure. The residue is dissolved in 3 mL of THF. Then, 2 mL of an aqueous solution of 8% sodium hydrogen carbonate are added. The resulting biphasic mixture is heated to 50° C. and vigorously stirred for 1.5 h. Then, the mixture is diluted with 10 mL of ethyl acetate and 5 mL of water and the organic layer is separated, washed with brine (5 mL), dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure to give 0.4 g of the desired product as a white solid.