Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[CH3:14][C:15]([NH2:19])([CH3:18])[CH2:16][NH2:17]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][CH2:16][C:15]([CH3:18])([NH2:19])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: CC(C)(N)CN
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(Cl)nc(NCC(C)(C)N)c2c1
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.35 mmol) and 2-methylpropane-1,2-diamine (365 μL, 3.52 mmol) in methanol (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL) and stirred for 30 minutes. The formed solid was collected by filtration and dried in vacuo to afford 500 mg of the desired product as a white solid (yield was 80.6%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30](O)=[O:31])[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:68][C:67]([C:69]#[N:70])=[CH:66][CH:65]=1>>[C:69]([C:67]1[S:68][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:70]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)s1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)s2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Yield: 26.6 %

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.46 g, 0.79 mmol), was reacted with diisopropylethylamine (0.51 g, 4 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with 5-amino-thiophene-2-carbonitrile prepared in Example 186 (0.15 g, 1.2 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-thiophen-2-yl)-amide as a yellow solid (Yield 0.12 g, 26%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][OH:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25])([CH3:18])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[OH:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:16]([CH3:18])[CH3:17])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)=[O:11]
Reactant: CC(C)c1ccccc1S
Reactant: O=C(CO)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1Sc1ccc(C(=O)CO)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
Then 2-hydroxy-1-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-ethanone 28 was prepared as follows. To a solution of compound 27 (0.4 g, 1.8 mmole) and o-isopropylthiophenol (0.31 ml, 1.8 mmole) in DMF (10 ml) was added Cs2CO3 (0.59 g, 1.8 mmole). The mixture was stirred for 10 minutes and EtOAc (30 ml) was added. The mixture was filtered, concentrated and chromatographed on a silica gel column eluting with 30% EtOAc in hexane. The desired product 28 was obtained as an oil, 0.22 g, 34.8%. 1H-NMR (CDCl3, 300 MHz) δ1.17 (d, J=7.0 Hz, 6H), 3.40–3.46 (m, 2H), 4.80 (s, 2H), 6.82 (d, J=8.4 Hz, 1H), 7.27–7.31 (m, 1H), 7.51–7.55 (m, 3H), 7.72 (d, J=8.4 Hz, 1H), 8.17 (s, 1H); MS (DCI/NH3) m/z 355 (M+H)+, 372 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:14])[C:3]=1[CH3:15].[F:16][C:17]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:18]=1[NH2:19].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:16][C:17]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:14])[C:3]=1[CH3:15]
Reactant: Cc1c(Cl)c(C(=O)O)c2n(c1=O)CCC2
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)c2n(c1=O)CCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.1 %

Procedure:
Compound 8d (183 mg, 1.04 mmol) and 2-fluoro-4-iodoaniline (384 mg, 1.62 mmol) stirred in dry THF (8 ml) at 0° C. under nitrogen. LiHMDS (1M in THF, 2.4 mL, 2.4 mmol) was added dropwise, and the reaction stirred 4 h while warming to RT. The solution was quenched with 1N HCl and extracted with 10% MeOH/CH2Cl2 (3×). Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (10% to 20% MeOH/CH2Cl2) gave 76 mg (22%) of compound 8e as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ7.57 (d, 1H, J=9.1 Hz), 7.37 (d, 1H, J=8.3 Hz), 6.38 (t, 1H, J=9.0 Hz), 4.00 (t, 2H, J=7.6 Hz), 3.41 (t, 2H, J=8.1 Hz), 2.06-2.09 (m, 2H), 1.61 (s, 3H). MS (ES) [m+H] calc'd for C16H14FIN2O3, 429. found 429.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl[CH:16](Cl)[O:17]C.Cl>ClCCl.O>[CH:16]([C:9]1[S:5][C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)=[O:17]
Reactant: COC(Cl)Cl
Reactant: COC(=O)Cc1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccc(C=O)s1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a suspension of aluminium trichloride (853 mg, 6.4 mmol) in dichloromethane (4 mL) at −10° C. was added a solution of methyl 2-(2-thienyl)acetate (500 mg, 3.2 mmol) in dichloromethane (3 mL). The resulting solution was stirred at −10° C. for 10 minutes. A solution of dichloro(methoxy)methane (434 μL, 4.8 mmol) in dichloromethane (3 mL) was then added dropwise over 30 minutes. The reaction mixture was stirred at −10° C. for 1 h. The resulting solution was poured into a flask containing water (20 mL), crushed ice and concentrated HCl (1 mL) and stirred vigorously for 30 minutes. The solution was washed with dichloromethane (3×20 mL) and the combined organic phases washed with aqueous saturated sodium bicarbonate (30 mL) followed by brine (30 mL). The phases were separated over a hydrophobic frit and concentrated in vacuo to give the title compound as a red oil (533 mg, 91%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:4][N:3]=1.CS(O[CH2:17][CH:18]1[CH2:20][CH2:19]1)(=O)=O.C(N(CCCC)CCCC)CCC>C(OCC)C>[CH:18]1([CH2:17][N:4]2[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:6][C:2]([CH3:1])=[N:3]2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: CS(=O)(=O)OCC1CC1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOCC
Product: CCOC(=O)c1cc(C)nn1CC1CC1
Yield: 47.7 %

Procedure:
A mixture comprising 3.8 g of ethyl 3-methyl-1H-pyrazole-5-carboxylate, 3.8 g of cyclopropylmethyl methanesulfonate and 4.6 g of tri-n-butylamine was allowed to react at 110 ° C. for three hours without using any solvent. Then the reaction mixture was allowed to cool and diethyl ether was added thereto. The obtained mixture was successively washed with 1 N hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography (eluent: hexane:ethyl acetate=14 : 1). Thus 0.62 g of the aimed ethyl 1-cyclobutyl-3-methyl-1H-pyrazole-5-carboxylate (compound No. 1001) (yield: 12.1 %) and 2.45 g of ethyl 1-cyclopropylmethyl-3-methyl-1H-pyrazole-5-carboxylate (yield: 54.3 %) were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25](=O)[C:26]#[CH:27])[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.Cl.[OH:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[NH:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][N:36]=[C:34]([C:33]([OH:32])([CH3:38])[CH3:37])[N:35]=3)[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(OC)c3)c(Cl)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)c1
Temperature: 85 °C
Yield: 35.5 %

Procedure:
To a solution of 5-chloro-6-(3-methoxy-benzyloxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl) -3H-pyrimidin-4-one from Example 6, Step E (32.5 mg, 0.08 mmol) in acetonitrile (1 mL) was added 2-hydroxy-2-methylpropionamidine HCl (16 mg, 0.12 mmol) and potassium carbonate (32 mg, 0.23 mmol) and the slurry was heated at 85° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (14.4 mg, 37% yield). MS (M+H): 507; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.17 (s, 3H), 2.21 (s, 3H), 3.85 (s, 3H), 5.49-5.58 (m, 2H), 6.90 (d, J=7.43, 1H), 7.07 (s, 1H), 7.09 (s, 1H), 7.31-7.35 (m, 1H), 7.54-7.58 (m, 2H), 7.93 (s, 1H), 8.13 (d, J=6.65 Hz, 1H), 8.77 (d, J=5.09, 1H).
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[O:12]=[C:13]([CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].IC>CC(C)=O>[O:12]=[C:13]([CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:2])=[O:19]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)CCCCC(=O)O
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CCCCC(C)=O
Reaction time: 1 h
Yield: 97.8 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (3.4 mL, 22.86 mmol) was added to a solution of 6-oxoheptanoic acid 23 (1.1 g, 7.63 mmol) in acetone (15 mL) at 23° C. After stirring for 15 min iodomethane (2.4 mL, 38.3 mmol) was added. The reaction was stirred for 1 h and then the solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 7:3 hex/EtOAc) to provide 1.18 g (95%) of the methyl ester 24 (see scheme 4).
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:37]=[CH:36][C:27]([C:28]([NH:30][N:31]2[NH:35][CH:34]=[CH:33][S:32]2)=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[CH3:20][S:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([C:25]2[CH:26]=[C:27]([C:28](=[O:29])[NH:30][N:31]3[NH:35][CH:34]=[CH:33][S:32]3)[CH:36]=[CH:37][C:24]=2[CH3:23])=[N:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.80 min, MH+ 523. NMR: δH [2H6]-DMSO 9.35,(1H, t), 9.17,(2H, m), 8.38,(1H, d), 8.26,(1H, s), 8.09,(1H, d), 7.83,(1H, d), 7.52,(1H, d), 7.31,(1H, t), 7.22,(1H, s), 7.11,(2H, m), 4.52,(2H, d), 2.99,(3H, s), 2.46,(3H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.CCO>[Pd].CCN(CC)CC>[CH3:21][C:15]1[C:14]([CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)=[CH:2]3)[OH:13])=[CH:19][CH:18]=[C:17]([CH3:20])[N:16]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2cc1Cc1ccc(C(F)(F)F)cc1
Reaction time: 18 h

Procedure:
A 250 mL Parr flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol (155 mg, 0.32 mmol, Example 14a) was added EtOH (25 mL) and Et3N (1 mL) followed by 5% palladium on carbon (75 mg). The flask was pressurized to 50 psi with H2 gas and shaken for 18 hours. HPLC analysis indicated the conversion was approximately 40%. The reaction mixture was filtered through Celite® and concentrated. The residue was dissolved in MeOH and run in the H-cube hydrogenation apparatus using a 10% Pd/C cartridge at 50° C., 70 psi H2 and 1.2 ml/minute (all with closed loop recycling). After the cycling was complete, the solution was concentrated to dryness and the residue was chromatographed on silica gel (10% EtOAc-DCM increasing to 5% MeOH-DCM) to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.76 (d, J=8.5 Hz, 1H), 7.58-7.47 (m, 3H), 7.40-7.31 (m, 3H), 7.30-7.20 (m, 2H), 6.94 (d, J=7.7 Hz, 1H), 4.05 (overlapping s, 6H), 2.51 (s, 3H), 2.45 (s, 3H). MS (ESI): mass calcd. for C26H23F3N2O2, 452.2, m/z found 453.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([N:17]2[CH:21]=[C:20]([C:22](O)=[O:23])[C:19]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:18]2)([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:33][N:34](C(C)C)C(C)C.CN.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:15]([CH2:14][C:11]1([N:17]2[CH:21]=[C:20]([C:22](=[O:23])[NH:34][CH3:33])[C:19]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:18]2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(=O)O)c(Nc3ccccc3)n2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1cn(C2(CC#N)CCN(C(=O)OC(C)(C)C)CC2)nc1Nc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxylic acid (25 mg, 0.059 mmol) in DCM (0.6 mL) was added DIPEA (0.030 mL, 0.18 mmol), methylamine (0.040 mL, 0.082 mmol, 2.0 M in THF), HOBT (13 mg, 0.082 mmol), and EDC (16 mg, 0.082 mmol). The resulting mixture was maintained at ambient temperature for 18 hours, then purified directly by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound.
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH2:14][CH:15]=[C:16]([O:21][CH3:22])[CH2:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])[CH2:2][CH3:3].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH2:14][CH:15]=[C:16]([O:21][CH3:22])[CH2:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23])[CH2:2][CH3:3]
Reactant: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Yield: 67.1 %

Procedure:
Reflux 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol (3.0 g.) with aluminium isopropoxide in toluene and cyclohexanone according to the conditions of Oppenauer oxidation. Isolate and recrystallize the product from methanol to give 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17-one (2.0 g.), m.p. 128°- 31° C. with softening at 125°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25]CC)=O)=[C:11]([CH:21]=O)[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:29][NH2:30]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]2[C:23](=[O:25])[NH:30][N:29]=[CH:21][C:11]=2[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C=O)C(C)CN(C)C2=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CC1CN(C)C(=O)c2c(OCc3ccccc3)c3c(=O)[nH]ncc3n21

Procedure:
A solution of ethyl 8-(benzyloxy)-2,4-dimethyl-1-oxo-6-formyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (0.29 g, 0.79 mmol), and hydrazine monohydrate (0.20 mL, 3.96 mmol) in glacial acetic acid (2 mL) was heated in a microwave oven at 100° C. for 5 minutes. The reaction mixture was concentrated under vacuum and the residue partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was dried over MgSO4, filtered, and concentrated to provide the titled dione.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].Cl.[CH2:24](O)[CH3:25]>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([O:8][CH2:24][CH3:25])=[O:7])[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1OCC
Yield: 45.5 %

Procedure:
To a suspension of 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)benzoic acid (16.4 g, 0.05 mol, see EP 812 845) in ethanol (160 mL) was added concentrated hydrochloric acid (12.5 mL, 0.15 mol), which gave a solution on stirring. The solution was heated to reflux for 25 hours and then allowed to cool. It was concentrated under vacuum to give an orange oil which gave crystals on cooling. These were collected by filtration to give 13.7 g of crude product, which was purified by recrystallisation in acetonitrile to give 8.1 g of product as fine white crystals (45.5%).
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)O)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]1([CH2:4][C:6]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=S(=O)(c1ccccc1)n1cc(C(O)C2CC2)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1cc(CC2CC2)c2cccnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
Cyclopropyl(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanol (0.285 g, 0.87 mmol) was dissolved in dry dichloromethane (9 mL) and chilled to 0° C. Triethylsilane (1.11 mL, 6.94 mmol, 8 eq.) and TFA (0.201 mL, 2.60 mmol, 3 eq.) were then added. The reaction mixture was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature. After about 1.5 hours, the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The extracts were dried over sodium sulfate and concentrated. Flash 40 Biotage (40M cartridge, DCM to 5% EtOAc/DCM) afforded 3-(cyclopropylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (159 mg, 59%). m/z (APCI-pos) M+1=313.1.
Reaction SMILES: FC(F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:16][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[CH:3][N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)ccc1F
Yield: 64.9 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (277 mg, 1.45 mmol, from Example 1, Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 416 mg, 1.32 mmol), DIPEA (226 mg, 1.58 mol), HOBT (216 mg, 1.98 mol) and HATU (753 mg, 1.98 mol) in DMF (6 mL), using a procedure analogous to that described in Example 1 Step C, except for the purification method. The compound was purified by preparative TLC (silica gel, 20% hexane in ethyl acetate, then 10% methanol in dichloromethane) to give 360 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 2.62 (m, 2H), 2.88 (m, 2H) 3.88-4.16 (m, 5H), 4.73 (s, 1H), 4.85 (m, 1H) 5.26-5.39 (m, 1H) 6.90 (bs, 1H), 7.06(m, 2H), 7.24(m, 1H). ESI-MS 489 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38]Br.N1CCOCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:22]=[N:21][N:20]([CH2:38][C:37]4[C:40]([F:44])=[CH:41][CH:42]=[CH:43][C:36]=4[Cl:35])[CH:19]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1
Reactant: Fc1cccc(Cl)c1CBr
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1cn[nH]c1)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCc2cnn(Cc3c(F)cccc3Cl)c2)c(=O)c2[nH]c(Cl)nc21
Temperature: 45 °C
Yield: 74.9 %

Procedure:
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) in dry DMF (2 ml) was stirred with sodium carbonate (64 mg, 0.6 mmol) and 2-chloro-6-fluorobenzyl bromide (134 mg, 0.6 mmol) and heated at 45° C. for 18 h under nitrogen. After cooling to rt the mixture was degassed by evacuating and readmitting nitrogen, and stirred with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.303 mmol) and morpholine (0.13 ml) for 5.5 h. The mixture was partitioned between EtOAc and 2M HCl, the organic phase separated and evaporated and the residue purified by aminopropyl SPE (5 g, washing with THF-MeOH (1:1) then neat MeOH and finally eluting with DCM-MeOH (1:1) containing 5% AcOH) to give the title compound (57 mg) as a solid.