Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[CH:3]=1.C(OC([N:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=2)[CH2:29]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[C:32]([C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[C:4]([O:12][C@@H:13]([C@H:15]4[CH2:19][NH:18][C:17](=[O:20])[CH2:16]4)[CH3:14])[CH:3]=3)[CH:31]=2)[CH2:36][CH2:37][NH:28]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: C[C@@H](Oc1cc(Br)cc2ncccc12)[C@H]1CNC(=O)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1cc(-c2ccc3c(c2)CNCC3)cc2ncccc12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
150 mg Example 27, 241 mg 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 15 mg bis(triphenylphosphine)palladium(II) chloride, 671 μL 2N aqueous sodium carbonate and 2 mL DMF were heated for 2 hours at 90° C. The mixture was partitioned between DCM and NaHCO3 (sat aq) and the organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in 10 ml 25% TFA in DCM and stirred at 25° C. overnight then concentrated in vacuo. Purification by flash chromatography using 0-25% MeOH/DCM gave 75 mg (43%) of Example 101 (R)-4-{(R)-1-[7-(1,2,3,4-Tetrahydroisoquinolin-7-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:21]#[N:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][C:7]=1Br.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]3[C:40](=[O:41])[NH:39][CH2:38][CH2:37][NH:36][C:35]=3[CH:42]=2)O1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:21]#[N:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][C:7]=1[C:31]1[CH:32]=[CH:33][C:34]2[C:40](=[O:41])[NH:39][CH2:38][CH2:37][NH:36][C:35]=2[CH:42]=1
Reactant: N#CC1(c2ccc(-c3cnc(N)c(Br)n3)cc2)CCOCC1
Reactant: CC1(C)OB(c2ccc3c(c2)NCCNC3=O)OC1(C)C
Product: N#CC1(c2ccc(-c3cnc(N)c(-c4ccc5c(c4)NCCNC5=O)n3)cc2)CCOCC1
Yield: 32.9 %

Procedure:
General method C was applied to 4-(4-(5-amino-6-bromopyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carbonitrile (215 mg, 0.6 mmol) and 8-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one (173 mg, 0.6 mmol) to provide 4-(4-(5-amino-6-(5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl)pyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carbonitrile as a yellow solid (87 mg, 33% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.47 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.01 (d, J=8.3 Hz, 2 H), 7.58 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 1H), 7.04 (s, 1H), 6.40 (br. s., 1H), 4.93 (br. s., 2H), 4.57 (br. s., 1H), 4.12 (d, J=8.8 Hz, 2H), 3.94 (t, J=11.7 Hz, 2H), 3.50-3.73 (m, 4 H), 2.02-2.26 (m, 4H); MS (EI) m/z=441.5 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[ClH:5].[C:6]([NH:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=1)=[O:13])([CH3:9])([CH3:8])[CH3:7]>C(#N)C>[ClH:5].[C:6]([NH:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:4]=[CH:8][C:6]([CH3:9])=[CH:7][CH:1]=2)=[C:16]([O:21][C:17]2[CH:18]=[CH:19][C:14]([CH3:12])=[CH:15][CH:16]=2)[CH:15]=1)=[O:13])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: CC(C)=O
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2Oc2ccc(C)cc2)cc1
Yield: 64 %

Procedure:
The process of Example 1 was repeated substituting acetone for the acetonitrile as solvent. Starting with 26 g of 3,4-dihydroxyphenyl N-(tert-butyl)aminomethyl ketone hydrochloride there was obtained 33 g of 3,4-bis-(p-toluyloxy)phenyl N-(tert-butyl)aminomethyl ketone hydrochloride (64% yield) containing only a trace of tributylamine hydrochloride.
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[CH:5][CH2:4][CH2:3][OH:2])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCC=Cc1ccc(OCc2ccccc2)cc1
Yield: 69.3 %

Procedure:
In an argon atmosphere, 3-hydroxypropyltriphenylphosphonium bromide (4.02 g) was suspended in dehydrated THF (30 ml); 60% oily sodium hydride (0.4 g) was added, followed by refluxing for 3 hours. To the reaction mixture, a solution of 4-benzyloxybenzaldehyde (2.12 g) in dehydrated THF (7 ml) was added drop by drop, followed by refluxing for 67 hours. After cooling, the insoluble matter was filtered off; the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to yield the titled compound (1.76 g) as colorless crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1.[Br:37]N1C(=O)CCC1=O>ClCCl.CCOCC>[Br:37][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(CCBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
8.68 g (33.08 mmol) of triphenylphosphine are added, under an argon atmosphere, to a solution of 7.85 g (33.08 mmol) of tert-butyl [4-(2-hydroxyethyl)phenyl]carbamate in 85 mL of dichloromethane. The mixture is cooled to 0° C. and 5.95 g (33.08 mmol) of N-bromosuccinimide are added portionwise over 25 minutes. Stirring is continued for 3 hours at 0° C. The solvent is then evaporated off, the oil obtained is taken up in ether and the precipitate formed is filtered off and discarded. The filtrate is evaporated and the residue is purified by chromatography on silica gel (eluent: 10/90 EtOAc/heptane) to give 6.90 g of tert-butyl [4-(2-bromoethyl)phenyl]carbamate, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.O.ClCCl.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][NH:20][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)CN
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: O
Solvent: ClCCl
Product: CC(C)CNc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyrimidine (548 mg, 3 mmol) in isobutylamine (1.5 mL) was stirred at room temperature for 17 hours. To the mixture was added water (5 mL) and dichloromethane (5 mL). The organic layer was separated and purified by flash silica (Si) chromatography (0-100% dichloromethane-cyclohexane gradient) to give the title compound (455 mg) as a colourless oil. LCMS (2 min, formic) Rt 1.20 min, m/z (ES+) 220 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9](OC)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.[NH3:17]>>[NH2:17][C:9]1[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:11](=[O:12])[CH:10]=1
Reactant: N
Reactant: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Product: Nc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: -78 °C

Procedure:
8-Chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.4 g) was treated with 80 mL of liquid anhydrous ammonia chilled to -78° C. The mixture was sealed in a pressure vessel and warmed to 26° C. for 22.5 hours. The excess ammonia was evaporated to give a solid. The solid was recrystallized from 5 mL hot dimethylformamide and water; crystallization was initiated by cooling the solution in an ice bath. The solid was filtered, washed (water) and vacuum dried (100° C., 15 Pa) to give the title compound (0.274 g); mp 344.5°-346.4° C. (dec); NMR: 11.47 (s,1), 8.10 (d,1, J=8.7), 7.53 (d,1, J=2.0), 7.27 (dd,1, J=8.7, 2.0), 7.1 (broad s,2, NH2), 6.23 (s,1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Br:11])[C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Br:11])[C:3]=1[CH2:12][Br:13]
Reactant: Cc1c(Br)cc([N+](=O)[O-])cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(Br)c(CBr)c(Br)c1
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
To a mixture of 2,6-dibromo-4-nitrotoluene (5.00 g, 16.95 mmol) in CCl4 (131 mL) was added N-bromosuccinimide (4.22 g, 23.73 mmol) and dibenzoyl peroxide (411 mg, 1.70 mmol). The mixture was evacuated and flushed with argon three times, then heated using an oil bath. At reflux azo-bis-isobutyronitrile (278 mg, 1.695 mmol) was added. The reaction was stopped after 3.75 h, cooled to rt and filtered washing with CCl4. The filtrate was concentrated under reduced pressure to give a yellow solid, which was purified using flash chromatography on Biotage 40M column, eluting with 90:10 hexanes-CH2Cl2 to yield 1,3-dibromo-2-(bromomethyl)-5-nitrobenzene. 1H NMR (500 MHz, CDCl3): δ 4.8 (s, 2H), 8.4 (s, 2H).
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6].[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[C:8]1([S:14]/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Sc1ccccc1
Reactant: CO/C=C/C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)/C=C/Sc1ccccc1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-4-methoxy-3-buten-2-one (purity 90%, 5.66 ml, 49.9 mmol) and thiophenol (5.13 ml, 49.9 mmol) in benzene (60 ml) was added p-toluene 25 sulfonic acid-monohydrate (30 mg, 0.16 mmol), followed by heating while stirring on an oil bath at 55° C. for 30 minutes. After ice cooling, an aqueous saturated sodium hydrogen carbonate solution was added thereto, followed by extracting with cyclohexane 3 times. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution twice and with saturated brine, followed by drying with anhydrous magnesium sulfate. After concentrating under a reduced pressure, the residue was treated with the column chromatography (190 g, n-hexane:ethyl acetate=10:1). After evaporated under a reduced pressure, the titled compound was recrystallized from n-hexane-n-nonane to obtain as a colorless crystalline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH:17]1[C:22]([NH:23][NH2:24])=[CH:21][CH:20]=[C:19]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:18]=1.Cl>CO>[NH2:28][S:25]([C:19]1[CH:18]=[CH:17][C:22]([N:23]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:24]2)=[CH:21][CH:20]=1)(=[O:27])=[O:26]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: COC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A 100 mL round-bottomed flask equipped with magnetic stirrer and nitrogen inlet was charged with methyl 4-[4-(chloro)phenyl]-2,4-dioxobutanoate from Step 1 (5.0 g, 20.78 mmol), 4-sulfonamidophenylhydrazine hydrochloride (5.11 g, 22.86 mmol) and methanol (50 mL). The reaction vessel was heated to reflux and held for 16 hours. A precipitate formed overnight. The suspension was cooled to 0° C., held for 0.5 hour, filtered and washed with cold water to provide, after air-drying, 7.91 g (91%) of crude product. Recrystallized 3.50 g from boiling ethanol to yield 3.14 g (97% of pure methyl (1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate: mp 227° C.; 1H NMR (CDCl3/300 MHz); 7.91 (d, J=8.86 Hz, 2H), 7.44 (d, J=8.86 Hz, 2H), 7.33 (d, J=8.66 Hz, 2H), 7.14 (d, J=8.66 Hz, 2H), 7.03 (s, 1H), 3.96 (s, 3H). Mass Spectrum, MH+=392. Anal. Calc'd for C17H14N3O4ClS: C, 52.11; H, 3.60; N, 10.72; Cl, 9.05; S, 5.18. Found: C, 52.07; H, 3.57; N, 10.70; Cl, 9.11; S, 8.27.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH3:28][NH:29][CH2:30][CH3:31].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH2:30]([N:29]([CH3:28])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26])[CH3:31]
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Reactant: CCNC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Yield: 89.4 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), N-methylethanamine (174 ul, 2.02 mmole), N-ethyldiisopropylamine (564 ul, 3.23 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (7 ml) is stirred for at 70° C. The solvent is removed under reduced pressure and the residue is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording N4-ethyl-N4,1-dimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (149 mg, 89.4%) as a white solid. Mp.: 201-3° C. MS: m/z=413.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]=[N:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C@H:36]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[F:59])=[CH:48][CH:47]=1)[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:58][C:56]1[CH:55]=[CH:54][C:53]([F:59])=[C:52]([C:49]2[CH:48]=[CH:47][C:46]([CH2:45][C@@H:36]([NH:35][C:8]([C:6]3[N:5]=[N:4][N:3]([O:2][CH3:1])[CH:7]=3)=[O:10])[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40])=[CH:51][CH:50]=2)[CH:57]=1
Reactant: COn1cc(C(=O)O)nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COn1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.3 %

Procedure:
1-Methoxy-1H-[1,2,3]triazole-4-carboxylic acid (4.3 mg, 30 μmol) and HATU (11.4 mg, 30 μmol) were combined in DMF (1 mL) and stirred at room temperature for 15 minutes. (2S,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (10 mg, 27 μmol) and DIPEA (14 μL, 82 μmol) were added, and the resulting mixture was stirred for 15 minutes at room temperature. The solvent was removed in vacuo and the residue was purified by preparative HPLC to yield the title compound (1.1 mg). MS m/z [M+H]+ calc'd for C23H24ClFN4O5, 491.14. found 491.2.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:33][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:33][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH2:27][C:28]([N:30]([CH3:31])[CH3:32])=[O:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)COc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
A mixture of 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-N,N-dimethyl-acetamide (276 mg, 0.59 mmol) and 10% palladium on activated carbon (50.0 mg) in methanol (200 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb pressure for 6 h. The mixture was then cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-N,N-dimethyl-acetamide (140 mg, 50.7%) as a white solid: LC/MS m/e calcd for C25H31N3O4S [M+H]+ 470.61, observed 470.2. solid 1H NMR (400 MHz, CD3OD) δ ppm 7.86-7.93 (m, 4H), 7.59 (d, J=8.1 Hz, 3H), 7.52 (s, 1H), 6.32 (s, 1H), 4.84 (s, 2H), 4.28 (t, J=7.8 Hz, 1H), 3.08 (s, 3H), 3.10 (s, 3H), 2.98 (s, 3H), 2.22-2.30 (m, 1H), 2.03-2.13 (m, 2H), 1.61-1.79 (m, 4H), 1.48 (br. s., 1H), 1.21-1.23 (m, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:26][C:27]1[S:31][CH:30]=[N:29][CH:28]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:30]3[S:31][C:27]([CH3:26])=[CH:28][N:29]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1cncs1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ncc(C)s3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 5-methylthiazole
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:16])[C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=2[N:6]=1.[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[C:20](Cl)[N:19]=1>CN(C=O)C>[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[C:20]([N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=3[N:6]=[C:5]2[CH:4]([F:3])[F:16])[N:19]=1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.6 %

Procedure:
NaH (148 mg, 6.17 mmol) was added to a solution of 2-difluoromethyl-4-methoxy-1H-benzimidazole (Example 2) (638 mg, 3.22 mmol) in DMF (10 mL) at 0° C., and the mixture was warmed to room temperature and stirred for 45 min. 2,6-Dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine (800 mg, 2.93 mmol) was then added and the resulting mixture was stirred at room temperature for 5 days, quenched with H2O, and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (3×), dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica, eluting with hexanes/EtOAc (100:0 to 60:40), gave 2-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-tetrahydro-2H-pyran-2-yl-9H-purine (645 mg, 51%): 1H NMR (CDCl3) δ 8.38 (s, 1H), 7.52 (t, JHF=54.2 Hz, 1H), 7.37-7.31 (m, 2H), 6.84 (m, 1H), 5.86 (dd, J=10.7, 2.5 Hz, 1H), 4.23 (ddd, J=10.0, 3.8, 1.8 Hz, 1H), 4.07 (s, 3H), 3.83 (dt, J=11.7, 2.8 Hz, 1H), 2.26 (m, 1H), 2.14 (m, 1H), 2.03 (m, 1H), 1.91-1.69 (m, 3H).
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)[C:4](=[O:17])[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[F:25][C:26]([F:36])([F:35])C1C=CC=C(NN)C=1>C(N(CC)CC)C>[F:25][C:26]([F:36])([F:35])[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:3]2[C:4](=[O:17])[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)=[CH:6][NH:2]2)[CH:19]=1
Reactant: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1ccccc1
Reactant: NNc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1cccc(C(F)(F)F)c1

Procedure:
A 3.5 gram portion of the atropic ester of Example 1 was reacted with 2.7 grams α,α,α-trifluoro-3-tolylhydrazine hydrochloride in the presence of triethylamine to produce 2.4 grams 1,4-bis-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 207°-208° C. A 1.8 gram portion of the above pyrazolinone was alkylated with 2 grams methyl iodide to produce 1.25 grams of the desired product, m.p. 110°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13]>N1CCCCC1.C(O)C>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:30]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c1C
Temperature: 90 °C
Yield: 68.1 %

Procedure:
A mixture of 5-Chloro-1,3-dihydro-indol-2-one (335 mg, 2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90° C. for 2 hours. The reaction was cooled to room temperature; the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 565 mg (68%) of the title compound as an orange solid.
Reaction SMILES: [OH:1][CH:2]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][NH:4][S:5]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].Cl.CC(O)CC.Cl[C:29]1[N:34]=[C:33]([NH:35][CH2:36][CH3:37])[C:32]([C:38]#[N:39])=[CH:31][N:30]=1>CO>[C:38]([C:32]1[C:33]([NH:35][CH2:36][CH3:37])=[N:34][C:29]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([S:5](=[O:6])(=[O:7])[NH:4][CH2:3][CH:2]([OH:1])[CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:14][CH:13]=2)=[N:30][CH:31]=1)#[N:39]
Reactant: CCNc1nc(Cl)ncc1C#N
Reactant: Nc1ccc(S(=O)(=O)NCC(O)CN2CCCCC2)cc1
Agent: Cl
Solvent: CO
Solvent: CCC(C)O
Product: CCNc1nc(Nc2ccc(S(=O)(=O)NCC(O)CN3CCCCC3)cc2)ncc1C#N
Temperature: 50 °C
Yield: 10.2 %

Procedure:
4-[N-(2-Hydroxy-3-piperidinopropyl)sulphamoyl]aniline (Method 118; 200 mg, 0.64 mmol) was dissolved in methanol (4 ml). 1M Ethereal hydrogen chloride (1.28 ml, 1.28 mmol) was added and the mixture gently warmed to give a solution. The volatiles were partially evaporated to give a volume of approx. 1.5 ml. 2-Butanol (5 ml) was added and the cloudy solution warmed to 50° C. 2-Chloro-5-cyano-4-ethylaminopyrimidine (Method 56; 233 mg, 1.28 mmol) was added in portions and the reaction was then heated at 95° C. for 20 hours. The hot supernatant was decanted from the solid residue and the solution allowed to cool. The resulting precipitate was collected by filtration, washed with diethyl ether and suspended in water (approx. 35 ml). The suspension was adjusted to pH>10 with 2M aqueous sodium hydroxide solution and extracted with ethyl acetate (3×15 ml). The extracts were dried, the volatiles evaporated and the residue purified by chromatography on silica eluting with DCM/methanolic ammonia (100:0) increasing in polarity to (85:15). The product was triturated with diethyl ether and collected by filtration to give the title compound (30 mg, 10%). NMR: 1.15 (t, 3H), 1.35 (m, 2H), 1.43 (m, 4H), 2.10-2.35 (m, 6H), 2.68 (m, 1H), 2.83 (m, 1H), 3.48 (quin, 2H), 3.56 (m, 1H), 4.59 (s, 1H) 7.36 (brt, 1H), 7.70 (d, 2H), 7.88 (t, 1H), 7.95 (d, 2H), 8.40 (s, 1H) 10.16 (s, 1H); m/z: 460.