Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([OH:36])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH3:50]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH3:50])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCOc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)quinolin-6-ol (0.054 g, 0.11 mmol) and potassium carbonate (0.059 g, 0.43 mmol) in DMF was added 1-bromo-2-(2-methoxyethoxy)ethane (0.057 ml, 0.43 mmol), the resulting mixture was stirred at 80° C. for 1 h. The crude product was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-60% (EtOAc-DCM) to afford 4-(4-chlorophenyl)-N-(4-(6-(2-(2-methoxyethoxy)ethoxy)quinolin-4-ylthio)phenyl)phthalazin-1-amine as a light yellow solid. MS: m/z [M+H]+. 610.0 Calc'd for C34H29ClN4O3S: 609.1.
Reaction SMILES: [CH3:1][C@H:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[NH:3]1.C([Li])CCC.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>O1CCCC1>[O:18]=[C:15]([N:3]1[C@@H:2]([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5][C:4]1=[O:9])[CH2:16][CH3:17]
Reactant: C[C@@H]1NC(=O)OC1(C)C
Reactant: CCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC(C)(C)[C@@H]1C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Reaction of the auxiliary (5) (0.577 g, 4.47 mmol) in solution in tetrahydrofuran (20 ml) at -78° C. with butyllithium (1.6M, 2.82 ml, 4.52 mmol) and propionyl chloride (0.427 ml, 4.92 mmol) for 30 minutes and then at room temperature for 1 hour, with work-up and recrystallisation from 40-60 petroleum ether furnished the title compound (17) as a solid (0.780 g, 94%); mp 86° C.; v. (CHCl3) 1703 and 1781 cm-1 ; [α]D 25 (c 0.9 in CHCl3)=+58.1; (Found: C, 58.08; H, 7.85; N, 7.53. C9H15NO3 requires C, 58.36; H, 8.16; N, 7.56%); δH (CDCl3 ; 300 MHz) 1.05 (3H, t, J=7.4, CH3CH2), 1.18 (3H, d, J=6.5, CHCH3), 1.31 (3H, s, C(CH3)2), 1.34 (3H, s, C(CH3)2), 2.82 (2H, q, J=7.3, CH2CH3), 4.09 (1H, q, J=6.5, CHCH3); δC (125 MHz; CDCl3) 8.08 (CH3), 14.41 (CH3), 21.30 (CH3), 27.58 (CH3), 29.09 (CH2), 58.72 (CH), 81.36 (C), 152.91 (CO), 174.49 (CO) ; m/z (CI+, NH3) 186 (M+ +1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]1.[F:29][C:30]([F:59])([F:58])[C:31]1[C:35](B(O)O)=[CH:34][N:33]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:32]=1>>[CH3:28][S:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:35]4[C:31]([C:30]([F:58])([F:59])[F:29])=[N:32][N:33]([C:39]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[CH:34]=4)[CH:3]=3)[N:8]=[CH:7][CH:6]=2)[CH2:13][CH2:14]1)(=[O:27])=[O:26]
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Reactant: CS(=O)(=O)c1ccccc1OC1CCN(c2ccnc3ccc(Br)cc23)CC1
Product: CS(=O)(=O)c1ccccc1OC1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1
Yield: 94.2 %

Procedure:
80 mg 6-bromo-4-[4-(2-methylsulfonylphenoxy)-piperidin-1-yl] quinoline (compound in Production Example 222) and 95 mg 3-trifluoromethyl-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 31) were reacted in the same manner as in Example 9, to give 124 mg 4-[4-(2-methylsulfonylphenoxy)piperidin-1-yl]-6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl) quinoline. This product was reacted in the same manner as in Example 67, to give 70 mg of the title compound as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([CH:8]1[CH:12]=[CH:11]OC1=O)=[O:7])([O-:3])=[O:2].[ClH:18]>>[Cl:18][CH2:11][CH2:12][CH2:8][C:6]([C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=1[N+:1]([O-:3])=[O:2])=[O:7]
Reactant: Cl
Reactant: O=C1OC=CC1C(=O)c1ccccc1[N+](=O)[O-]
Product: O=C(CCCCl)c1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 95 %

Procedure:
A mixture of dihydro-3-(o-nitrobenzoyl-2(3H)-furanone (2.0 g, 8.5 mmole) in 10 g of 37% HCl solution is stirred at 70° C. until reaction is complete by TLC, cooled to room temperature and extracted with toluene. The organic extracts are combined and concentrated in vacuo to give the title product as a golden oil, 1.84 g (95% yield), 99% pure by HPLC analysis, identified by 1HNMR.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH2:16][C:17]#[N:18])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>[Ni].C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH2:16][CH2:17][NH2:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2CC#N
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2CCN

Procedure:
The compound prepared in (2) above (650 mg) was dissolved into a mixed solvent of 10 ml of acetic acid and 30 ml of acetic anhydride. The mixture was catalytically hydrogenated with the addition of 2 ml of Raney nickel. After removing the catalyst by filtration, the reaction mixture was concentrated and chloroform was added to the residue, which was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was recrystallized from chloroform and ether to obtain 510 mg of the title compound.
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)COCC[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH3:18])[CH2:12][CH2:11]1.[F:34][C:35]([F:63])([F:62])[C:36]1[CH:37]=[C:38]([CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=1)[CH2:39][O:40][CH2:41]C1(C2C=CC=CC=2)CCCNCC1>>[F:34][C:35]([F:62])([F:63])[C:36]1[CH:37]=[C:38]([CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=1)[CH2:39][O:40][CH2:41][C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH3:18])[CH2:12][CH2:11]1
Reactant: CCN1CCCC(CCOCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Product: CCN1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Yield: 62 %

Procedure:
Isomer B of 4-((3,5-bis(trifluoromethyl)benzyloxy)ethyl)-1-ethyl-4-phenylazepane was made from Isomer B of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepane in the same manner as described above to give the product as a clear sticky oil (2 mg, 62% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Cl-].[CH3:34][Zn+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3[CH3:34])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: C[Zn+]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C)c1
Reaction time: 2 h
Yield: 76.3 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 30 mg, 0.058 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-t-butylphosphine)palladium (0) (3.0 mg, 0.0058 mmol) and methylzinc chloride (0.087 ml, 0.17 mmol). After stirring for 2 hours, the reaction was loaded directly onto a silica gel column, eluting with hexanes:ethyl acetate (3:1) to yield ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-methylphenyl)acetate (20 mg, 76% yield) as a clear oil.
Reaction SMILES: [CH:1]1([CH:4]([N:11]([CH2:15][CH2:16][CH3:17])[C:12]([NH2:14])=[S:13])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH:26]([CH3:37])[C:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[Cl:36])=O>C(O)C>[Cl:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=1[C:27]1[N:14]=[C:12]([N:11]([CH:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH3:17])[S:13][C:26]=1[CH3:37]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCCN(C(N)=S)C(c1ccccc1)C1CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccccc1)C1CC1
Temperature: 75 °C
Yield: 79 %

Procedure:
To 1.35 g of N-(α-cyclopropylbenzyl)-N-propylthiourea (Compound 75) in 35 ml of ethanol, add 546 mg of triethylamine, then slowly 1.52 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone (Compound 15). After 3 hours of heating at 75° C., remove the precipitate formed by filtration. The ethanolic solution is evaporated to dryness. Take up the residue in ethyl ether and wash with water until bromide ions have disappeared. Dry the organic phase over anhydrous sodium sulphate and then evaporate to dryness. Purify the residue on a silica column, using a mixture of cyclohexane and ethyl acetate (10:1 V/V) as eluent, to obtain the expected product. Recrystallise in acetonitrile (white crystals).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:16]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[NH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:38][CH2:39][CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[C:16]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: NCC1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NCC3CCOCC3)c2C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (350 mg, 0.65 mmol, example 1b) was dissolved in DMF (2 mL). 4-Aminomethyltetrahydropyran (74.4 mg, 0.65 mmol) was added and the reaction mixture was stirred at 80° C. for 6 h. The solvent was evaporated under reduced pressure and the crude was used in the next step as such. MS (ES+) m/z 507.3 (M+H)+
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[F:10][C:11]1[C:16]([F:17])=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:14]=[CH:13][C:12]=1[C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1>C(NC(C)C)(C)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.[Cu]I>[F:10][C:11]1[C:16]([F:17])=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:14]=[CH:13][C:12]=1[C:27]1[N:32]=[CH:31][C:30]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:29][N:28]=1
Reactant: C#CCCCCCCC
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCCCCCCC#Cc1cnc(-c2ccc(OCCCCCCCC)c(F)c2F)nc1
Yield: 91.7 %

Procedure:
--Non-1-yne (1.0 ml, 6.4 mmol) was added via syringe to degassed mixture of 2-(2',3'-difluoro-4'-octyloxyphenyl)-5-bromopyrimidine 4 (1.27 g, 3.18 mmol), tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) and copper(I) iodide (29 mg, 0.15 mmol) in diisopropylamine (60 ml) under nitrogen. The mixture was heated under gentle reflux for 4 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (5% ethyl acetate-light petroleum, the sample was preloaded onto silica in dichoromethane) to give the nonynylpyrimidine 38 (1.29 g, 92%) (from MeOH), transitions/° C. K 64.4 (N 63.3) I; νmax /cm-1 (KBr) 2920, 2850, 2220, 1615, 1520, 1470, 1430s, 1295, 1205 and 1090s, δ 0.90 (6H, m), 1.20-1.55 (18H, m), 1.64 (2H, quint, J7, CH2CH2C≡C), 1.85 (2H, quint, J7, OCH2CH2), 2.46 (2H, t, J7, CH2C≡C), 4.10(2H, t, J7, OCH2), 6.83 (1H, ddd, J8, 7 and 2, 5'-H), 7.85 (1H, ddd, J8, 7 and 2, 6'-H) and 8.79 (2H, s, 4-and 6-H); m/z 442 (M+), 330, 288, 287, 274, 273, 247 and 220.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.[BH4-].[Na+]>FC(F)(F)C(O)=O>[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]3)[CH2:16][CH2:20][CH2:19][CH2:18]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc2c(c1)CC(=O)NC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(N3CCCC3)ccc2C(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
To a solution of 6-Amino-4H-isoquinoline-1,3-dione (17.6 mg, 0.1 mmol) in trifluoroacetic acid (250 μL) is added 2,5-dimethoxytetrahydrofuran (15 μL, 0.11 mmol). The reaction mixture is shaken for 5 minutes at ambient temperature, followed by addition of sodium borohydride (9 mg, 0.22 mmol). After shaking at ambient temperature for 15 minutes, gas evolution had ceased and the reaction mixture is quenched with saturated bicarbonate solution. Upon quenching, a precipitate formed. The precipitate is filtered off, rinsed with water, and dried to yield 19.5 mg of 6-Pyrrolidin-1-yl-4H-isoquinoline-1,3-dione.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH2:18]([NH2:21])[CH:19]=[CH2:20]>C(O)C>[CH2:18]([NH:21][C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[N:3][C:1]#[N:2])[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Solvent: CCO
Product: C=CCNC(=NC#N)NC1CCCc2ccccc21

Procedure:
A solution of 24.5 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 38 ml of allylamine in 400 ml of ethanol was heated at reflux for 87 hours. The solvent was removed from the reaction mixture by evaporation in vacuo, leaving a pale yellow semisolid which was crystallized from isopropyl acetate to give 11 g of N-allyl-N"-cyano-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 130°-132° C.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(#N)C>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: CC#N
Product: CCCCCCCC/C=C/CCCCCCCC(=O)O

Procedure:
Oleic acid (5 g, 17.7 mmol) were dissolved in 20 ml dry acetonitrile and the mixture was refluxed for 24 hours. The solvent was removed under reduced pressure.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:22]([OH:24])=O)=[CH:20][CH:21]=1)=[O:16].[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:22](=[O:24])[NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:39])=[CH:20][CH:21]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: COC(=O)c1ccc(C(=O)O)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
Under an argon atmosphere 21.0 g (129 mmol) carbonyldiimidazol was added to a solution of 24.1 g (129 mmol) thiophene-2,5-dicarboxylic acid monomethyl ester in 600 ml THF. After 2 h at rt 26.9 g (129 mmol) (2-amino-phenyl)-carbamic acid tert-butyl ester were added and the reaction mixture was stirred for further 4 h at rt. The solvent was evaporated and the residue dissolved in 500 ml ethyl acetate. The organic phase was washed three times with 100 ml saturated aqueous NaHCO3 solution, twice with 80 ml water and was dried over sodium sulfate. The solvent was removed down to 80 ml when crystallization started. After 12 h the crystalls were filtered off and washed with little ice-cold t-butyl methyl ether and cold heptane. Drying under high vacuum yielded 38.9 g (103.4 mmol) 5-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-thiophene-2-carbox-ylic acid methyl ester, 1H-NMR (D6-DMSO) δ=1.45 (s, 9H), 3.87 (s, 3H), 7.14 (m, 1H), 7.22 (m, 1H), 7.46 (m,1H), 7.59 (m, 1H), 7.89 (m, 1H), 7.96 (m, 1H), 8.73 (br, 1H), 10.02 (s, 1H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([CH2:45][C:46](Cl)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:46](=[O:47])[CH2:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)Cc1ccccc1)CC2(C)C
Temperature: 25 °C
Yield: 11.3 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (9.2 mg, 0.021 mmol) in CH2Cl2 (5 mL) was added Et3N (8.98 μl, 0.064 mmol) followed by 2-phenylacetyl chloride (4.26 μl, 0.032 mmol) and the mixture stirred at room temperature. (Mixture became a clear, colorless solution within 30 min.) After 3 h, the solvent was removed and the residue was taken up in MeOH/DMF and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm). The product was dissolved in MeOH and repurified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm) to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2-phenylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (1.3 mg, 10% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 7.38-7.60 (1H, m), 7.00-7.40 (7H, m), 6.97 (1H, d, J=7.02 Hz), 4.75-4.85 (1H, m), 4.35-4.47 (0.5H, m), 4.17-4.34 (1H, m), 3.98 (0.5H, d, J=16.48 Hz), 3.77-3.93 (1.5H, m), 3.57-3.77 (3H, m), 3.53 (0.5H, d, J=13.12 Hz), 1.22-1.42 (9H, m), 1.11-1.22 (3H, m), 0.87-1.04 (9H, m). LCMS (M+H) calcd for C33H40FN2O4: 547.29. found: 547.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]3[CH2:18][CH2:17][CH2:16][C:11]3=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[O:24]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:20]=[CH:19][C:9]3[N:10]4[CH2:18][CH2:17][CH2:16][C:11]4=[N:12][S:13](=[O:15])(=[O:14])[C:8]=3[CH:7]=2)=[CH:25]1
Reactant: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(Br)c3)cc21
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(-c4ccoc4)c3)cc21
Temperature: 80 °C

Procedure:
A suspension of the product obtained in Step A of Example 16 (300 mg, 0.76 mmol), 111 mg (0.99 mmol) of 3-furanboronic acid, 137 mg (0.99 mmol) of K2CO3 and 45 mg (0.038 mmol) of tetrakistriphenylphosphine in a mixture of 6 ml of ethanol and 1.8 ml of water is heated at 80° C. for 3 hours under N2. The ethanol is evaporated off in vacuo and the residue is taken up in water and 1N HCl. The precipitate is filtered off to yield the title product.
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH3:12])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16]>C(#N)C>[CH2:19]([O:18][C:14](=[O:17])[NH:15][NH:16][C:2]1[C:3](=[O:13])[N:4]([CH3:12])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:20]
Reactant: CCOC(=O)NN
Reactant: Cn1c(=O)c(Cl)nc2ccccc21
Solvent: CC#N
Product: CCOC(=O)NNc1nc2ccccc2n(C)c1=O
Temperature: 9 °C

Procedure:
A solution of 152 g. (0.78 m.) of 3-chloro-1-methyl-1H-quinoxalin-2-one, 116 g. (1.1 m.) of ethyl carbazate and 1 l. of acetonitrile is refluxed for 16 hours. The mixture is cooled to 9° C. and the product collected by filtration and used directly for cyclization.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8](Br)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:20]=[O:21])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)c2[nH]ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(F)c2cc[nH]c12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-fluoro-7-bromoindole (1.0 g, 4.7 mmol) in THF (5 mL) at −78° C. was added n-BuLi (5.6 mL, 2.5M in hexanes) dropwise. The mixture was stirred for 15 min at −78° C., was allowed to warm to 5° C. for 30 min and was then re-cooled to −78° C. DMF (1.8 mL) was then added and the mixture was allowed to warm to room temperature slowly. The reaction was quenched with water and was extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated to afford 4-fluoroindole-7-carboxaldehyde.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH2:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])(OCC)=O>O.C(#N)C>[C:31]1(=[O:40])[N:17]([CH:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][C:6]([O:5][CH2:2][CH2:3][CH3:4])=[O:18])[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]12
Reactant: CCCOC(=O)CC(N)c1ccc(OC)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCOC(=O)CC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acid propyl ester hydrochloride (1.50 g, 5.52 mmol) and sodium carbonate (0.59g, 5.52 mmol) in 50 mL of water was added N-carboethoxy-phthalimide (1.21 g, 5.52 mmol) in 12 mL of acetonitrile. The reaction was complete in one hour. The acetonitrile was removed in vacuo and 5 mL of ether was added to the mixture, which was stirred overnight at room temperature. The resulting slurry was filtered and the solid was washed with 60 mL of water. The solid was dried in vacuo (24° C., <1 mm) to afford 1.69 g (83.2%) of propyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a white powder: mp 51.2°-52.8° C.; 1H NMR (DMSO-d6 250 MHz) δ7.86 (m, 4H), 6.92-7.33 (m, 4H), 5.66 (dd, 1H, J1=7.5, 2.5 Hz), 3.90 (t, 2H, J=5 Hz), 3.72 (S, 3H), 3.3-3.63 (m, 2H), 1.42 (hex, 2H, J=7.5 Hz), 0.75 (t, 3H, J=7.5 Hz); 13C (DMSO-d6 ) δ 170.2, 167.5, 158.7, 134.7, 131.0, 130.5, 128.3, 123.2, 113.9, 65.6; 55.0, 49.5, 21.3, 9.98. Anal. Calcd for C19H17NO5 :=C, 68.65; H, 5.76; N, 3.81; Found=C, 68.42; H, 5.49; N, 3.76.