Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[CH2:21]([N:23]([CH2:39][CH3:40])[C:24](=[O:38])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][N:32]1[C:36]([I:37])=[CH:35][N:34]=[CH:33]1)[CH3:22].[C:41]1(=[O:45])[CH2:44][CH2:43][CH2:42]1>C1COCC1.O.C(O)(=O)C>[CH2:39]([N:23]([CH2:21][CH3:22])[C:24](=[O:38])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([C:41]1([OH:45])[CH2:44][CH2:43][CH2:42]1)[N:32]1[C:36]([I:37])=[CH:35][N:34]=[CH:33]1)[CH3:40]
Reactant: CCN(CC)C(=O)c1ccccc1Cn1cncc1I
Reactant: O=C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccccc1C(n1cncc1I)C1(O)CCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (0.38 g, 3.76 mmol) in THF (25 mL) at −78° C. under nitrogen is added n-BuLi (2.5M in hexanes, 1.50 mL, 3.75 mmol) and the mixture is warmed to 0° C. After 15 min, the LDA solution is cooled to −78° C. and a solution of N,N-diethyl-2-(5-iodo-imidazol-1-ylmethyl)-benzamide (1.00 g, 2.51 mmol) in THF (5 mL) is added over 10 min. Fifteen min after the end of addition, cyclobutanone (0.90 g, 12.53 mmol) in THF (2 mL) is added to the brown solution. After 1.5 h, 10% acetic acid in water is added. The organic phase is washed with saturated aqueous sodium bicarbonate and the combined organic phase is dried over MgSO4, filtered through a cotton plug and concentrated in vacuo. The residue is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 49:1 to 97:3) to N,N-diethyl-2-[(1-hydroxy-cyclobutyl)-(5-iodo-imidazol-1-yl)-methyl]-benzamide; MS (ESI) m/z 454.2 (M+H).
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH2:16][S:17]C(=O)C)[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=[O:3])[NH2:2]>O.N>[C:1]([CH2:4][CH:5]([CH2:16][SH:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=[O:3])[NH2:2]
Reactant: CC(=O)SCC(CC(N)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Solvent: O
Product: NC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.25 h

Procedure:
1-[2-Carbamoylmethyl-3-acetylthiopropanoyl]-L-proline (1.2 g.) is dissolved in a mixture of water (20 ml.) and concentrated ammonia (20 ml.). After 15 minutes the reaction mixture is processed as described in "A" above to obtain 1-[2-carbamoylmethyl-3-mercaptopropanoyl]-L-proline.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])=[N:5][N:6]=1.[C:12]([C:14]([C:29]#[N:30])=[C:15](SC)[NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])#[N:13]>>[C:12]([C:14]([C:29]#[N:30])=[C:15]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][N:5]=1)[NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])#[N:13]
Reactant: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C#N
Reactant: NCCSCc1nnc(N)s1
Product: Cc1nc[nH]c1CSCCNC(NCCSCc1nnc(N)s1)=C(C#N)C#N

Procedure:
By the procedure of Example 24(iii) reacting 2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole with 1,1-dicyano-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene, gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][CH2:8][C:7](=O)[CH2:6]2.[CH2:14]([NH:17][CH2:18][CH2:19][C:20](OC)=[O:21])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[S:9][CH2:8][C:7]3[N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][C:20](=[O:21])[C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CS2
Reactant: CCCNCCC(=O)OC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCN1CCC(=O)C2=C1CSc1ccc(OC)cc12

Procedure:
A mixture of 7.5 g 6-methoxythiochroman-3-one [J. Org. Chem. 34, 1566 (1969)], 5.8 g of methyl 3-(propylamino)-propionate and 0.8 ml of trifluoroacetic acid in 80 ml of toluene is heated under reflux for 22 hours in a Dean Stark apparatus. Additional 0.8 ml portions of trifluoroacetic acid are added after 2, 5, and 16 hours. The solvent is removed, the residue is taken up in ether and the product is extracted with 3N hydrochloric acid. After neutralization the aqueous layers are extracted with ethyl acetate, the organic layer is dried and the solvent is removed. The product crystallized from a small volume of methanol to afford 9-methoxy-4-propyl-1,2,3,5-tetrahydro-4H-[1]-benzothiopyrano[3,4-b]pyridine-1-one, melting point 108°-110°.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+:15]>>[CH2:1]([O:13][Na:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCO
Reactant: [Na+]
Agent: [H-]
Product: CCCCCCCCCCCCO[Na]
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
A 500 ml round bottom flask equipped with a condenser, thermometer (with controller) and overhead stirrer was charged with 93 g (0.5 moles) of C12H25OH and (0.25 moles) of NaH. The mixture exothermed to 70° C. After the exotherm began to subside, the mixture was heated to 100° C. with stirring. After about two hours, a light grey paste was formed. This paste was subjected to a Kugelrohr distillation at 180° C. The non-volatile residue was 54.6% of the charge (theory for C12H24ONa=53.0%). The hard, dry, white powder residue was recovered. Analysis by titration showed the yield was 96.5% of theory for the named compound.
Reaction SMILES: [NH:1]([CH3:52])[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:26]([NH:28][C@H:29]([C:41]([NH:43][C@H:44]([C:49]([OH:51])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:30][C:31](=[O:40])[O:32]CC1C=CC=CC=1)=[O:27])[CH2:18][C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1>[Pd].CN(C=O)C.CCO>[NH:1]([CH3:52])[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:26]([NH:28][C@H:29]([C:41]([NH:43][C@H:44]([C:49]([OH:51])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:30][C:31](=[O:32])[OH:40])=[O:27])[CH2:18][C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC)C(C)C)C(=O)N[C@@H](CC(=O)N(CC)CC)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: [Pd]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC)C(C)C)C(=O)N[C@@H](CC(=O)N(CC)CC)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)O

Procedure:
More specifically exemplified, the protected peptide, DAT-N-Me-Val-Ile-Asp(NEt2)-Asp(OBzl)-Leu-OH was assembled by the preceding procedure on a BHA photoresin using BOP/HOBt as the coupling agent, followed by cleavage of the resulting protected peptide resin by photolysis under argon at -5° for 6 h. DMF:EtOH (4:1) was used as the photolysis medium. Deprotection of the cleavage product was effected by hydrogenolysis using 5% Pd/C as catalyst. Purification of the product was done by HPLC, the product being dissolved in 0.1N aqueous NH4OH solution and the solution adjusted to pH6 with 0.1N aqueous AcOH. Whatman Partisil® 100DS-3 C-18 column (2.2×50 cm2), 10 micron particle size, was used. Elution was done with a gradient of acetonitrile and 0.06% aqueous TFA. Pure fractions (determined by analytical HPLC) were pooled and lyophilized to give DAT-N-Me-Val-Ile-Asp(NEt2)-Asp-Leu-OH. MS: 791 (M+H)+.
Reaction SMILES: [CH3:1][C:2]12[O:13][C:8]([CH3:14])([CH2:9][C:10](=[O:12])[CH2:11]1)[CH:7]1[CH:3]2[O:4][C:5]([CH3:16])([CH3:15])[O:6]1.C([N-]C(C)C)(C)C.[Li+].[F:25][C:26]([F:41])([C:37]([F:40])([F:39])[F:38])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[S:29](F)(=[O:31])=[O:30]>C1COCC1.O>[CH3:14][C:8]12[O:13][C:2]([CH3:1])([CH:11]=[C:10]([O:12][S:29]([C:28]([F:33])([F:34])[C:27]([F:35])([F:36])[C:26]([F:25])([F:41])[C:37]([F:40])([F:39])[F:38])(=[O:31])=[O:30])[CH2:9]1)[CH:3]1[CH:7]2[O:6][C:5]([CH3:16])([CH3:15])[O:4]1
Reactant: CC1(C)OC2C(O1)C1(C)CC(=O)CC2(C)O1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC2C(O1)C1(C)CC(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=CC2(C)O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of 1,4,4,7-tetramethyl-3,5,11-trioxa-tricyclo[5.3.1.02,6]undecan-9-one (Bulletin of the Chemical Society of Japan (1983), 56(9), 2680-99, 386 mg, 1.71 mmol) in THF (10 mL) was cooled to −78° C. under Ar and treated with lithium diisopropylamide (LDA) (1.00 mL of 2M in heptane/THF/ethylbenzene, 2 mmol). The resulting mixture was stirred at −78° C. for 2 h and treated dropwise with nonafluoro-1-butanesulfonylfluoride (0.60 mL, 3.4 mmol). The reaction mixture was allowed to warm to RT and stirred overnight and diluted with water (10 mL). The product was extracted with ether (4×10 mL). The organic layers were combined, dried (Na2SO4) and the product was purified on silica gel (0-2% EtOAc/hexane) to give the title compound (546 mg, 63%). 1H-NMR (CDCl3; 400 MHz): δ 5.78 (br s, 1H), 4.37 (d, 1H, J=5.5 Hz), 4.28 (d, 1H, J=5.5 Hz), 2.52 (dd, 1H, J=17.6, 2.0 Hz), 2.04 (d, 1H, J=17.6, 1.4 Hz), 1.43 (s, 3H), 1.38 (s, 3H), 1.32 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:33]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[O:41][CH3:42])[CH3:32])=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: CNCc1ccccc1OC
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: COc1ccccc1CN(C)C(=O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with N-methyl-2-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=580.98 (M+H+); retention time=0.96 minutes.
Reaction SMILES: C[O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[O:4]1.[H][H]>[Co].CO>[C:3]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:5][O:4]1)=[O:2]
Reactant: COC1OC(=O)c2ccccc21
Reactant: [H][H]
Agent: [Co]
Solvent: CO
Product: O=C1OCc2ccccc21
Temperature: 120 °C
Yield: 99 %

Procedure:
The autoclave described in Example 1 is filled with 106.6 g of 3-methoxyphthalide, 400 ml of methanol and 15 g of RCH 45/20 cobalt catalyst (commercial product of Hoechst AG). After the addition of hydrogen to a pressure 100 bars, the autoclave is heated at 120° C., the pressure increasing to about 113 bars. After a temperature of 120° C. is reached, the pressure drops to 100 bars and is brought back up to 120 bars by another injection of hydrogen. After 2 hours of reaction at 120° C., the pressure has dropped again to 100 bars; the mixture is cooled, relieved of pressure, and filtered of catalyst. After withdrawal of the solvent, 86.2 g of phthalide (99% of the theory) is obtained having a melting point of 72°-73° C. (GC analysis 99.2% phthalide).
Reaction SMILES: C[C@H]1[C@@]2(O)O[C@H](C[C@H](OC)C(C)=CC=CC=C[C@@H](C)C[C@@H](C)C([C@H](OC)[C@H](O)C(C)=C[C@@H](C)C(C[C@@H]([C@@H](C[C@H]3C[C@@H](OC)[C@H](O)CC3)C)OC([C@H]3N(C(C2=O)=O)CCCC3)=O)=O)=O)CC1.[CH:66]1[CH:71]=[C:70]2[C:72]([O:74][C:75]3([C:85]4[CH:86]=[CH:87][C:88]([OH:90])=[CH:89][C:84]=4[O:83][C:77]4[CH:78]=[C:79]([OH:82])[CH:80]=[CH:81][C:76]3=4)[C:69]2=[CH:68][CH:67]=1)=[O:73]>>[CH:67]1[CH:66]=[CH:71][C:70]([C:72]([OH:74])=[O:73])=[C:69]([C:75]2[C:76]3[CH:81]=[CH:80][C:79]([OH:82])=[CH:78][C:77]=3[O:83][C:84]3[C:85]=2[CH:86]=[CH:87][C:88]([CH:89]=3)=[O:90])[CH:68]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccccc21
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
FA was performed on the 14th day after intravitreal injection of Rapamycin. Briefly, a 25-gauge butterfly catheter was placed in the tail vein on an anesthetized animal and a Heparin-Lock solution (0.50 mL of 10,000 IU/mL Heparin Sodium with 0.95 mL 0.9% Saline) was used to fill the catheter line to maintain intravenous access. A dose of 10 mg/kg of Diofluor 10% (Fluorescein Sodium 10%) was delivered through the tail vein, followed by a flush of sterile saline to ensure full delivery of Diofluor 10%. An infusion pump (Becton-Dickinson) connected to a 60 cc syringe was used to infuse the Diofluor 10% at a constant rate of 6 mL/min (8.4-13.2 pounds per square inches) to allow for consistency in the synchronization of the fluorescein bolus injection and the angiogram acquisition. Photographs were taken with a fluorescence fundus camera at 1-10, 30, 60, 90, 180, and 300 sec after Diofluor 10% administration. The leakiness of CNV was assessed by two independent readers masked to the treatment.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>>[CH3:9][Si:10]([C:13]#[C:14][C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=1)([CH3:12])[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(I)cn1
Product: C[Si](C)(C)C#Cc1cnc(N)nc1
Yield: 72.6 %

Procedure:
Prepared from commercially available 2-amino-5-iodopyrimidine (60 g, 271 mmol) and trimethylsilylacetylene (49 mL, 354 mmol) as described in example D.1 method 1 step 1. Obtained the title compound as a light brown solid (37.66 g, 73%). MS (ISP) 192 [(M+H)+].
Reaction SMILES: COC(SC)=C(C#N)C#N.N#CN.[C:14]([C:16](=[C:19]([NH:22][C:23]#[N:24])[S:20][CH3:21])[C:17]#[N:18])#[N:15].[ClH:25]>>[NH2:15][C:14]1[C:16]([C:17]#[N:18])=[C:19]([S:20][CH3:21])[N:22]=[C:23]([Cl:25])[N:24]=1
Reactant: Cl
Reactant: CSC(NC#N)=C(C#N)C#N
Agent: COC(SC)=C(C#N)C#N
Agent: N#CN
Product: CSc1nc(Cl)nc(N)c1C#N

Procedure:
Process for the production of 4-amino-2-chloro-5-cyano-6-(methylthio)pyrimidine of the formula: ##STR9## comprising reacting malononitrile with carbon disulfide in the presence of a strong base to obtain a dianion of dicyanodithioacetic acid of the formula: ##STR10## and then is methylating the dianion of dicyanodithioacetic acid of formula II with a methylating agent to obtain a dicyanoketene dimethyl thioacetal of the formula: ##STR11## condensing the dicyanoketene dimethyl thioacetal of formula III with cyanamide in the presence of a base to obtain an anion of 2-cyano-3-cyanamino-3-methylthio-acrylonitirile of the formula: ##STR12## and then the anion of 2-cyano-3-cyanoamino-3-methylthio-acrylonitrile of formula IV is cyclized in the presence of hydrochloric acid to obtain the 4-amino-2-chloro-5-cyano-6-(methylthio)pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:15]=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)C=O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(O)Cc1cccnc1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccnc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 100%), 2-(pyridin-3-yl)acetic acid hydrochloride (4.5 g, 25.92 mmol), HATU (10 g, 26.30 mmol 100%) and DIEA (8.5 g, 65.77 mmol, 100%) in N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 20° C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2-1:1) to provide the title compound as a yellow solid.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([CH:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:28])=[C:12]2[N:11]=[C:10]([N:29]2[CH2:34][CH2:33][S:32][CH2:31][CH2:30]2)[C:9]=1[C:35]#[N:36].Cl>CCO>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([CH:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:28])=[C:12]2[N:11]=[C:10]([N:29]2[CH2:30][CH2:31][S:32][CH2:33][CH2:34]2)[C:9]=1[C:35]#[N:36]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(C#N)c(N2CCSCC2)nc2c(C3C(=O)Nc4ccccc4C3=O)cnn12
Agent: Cl
Solvent: CCO
Product: N#Cc1c(N2CCSCC2)nc2c(C3C(=O)Nc4ccccc4C3=O)cnn2c1N
Temperature: 60 °C

Procedure:
A mixture of 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-5-thiomorpholinodioxo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (5 mg), EtOH (1 mL) and 3N HCl (1 mL) was heated at 60° C. until LCMS indicated complete reaction. The mixture was cooled to room temperature and the solvent was evaporated. Purification by prep-LC afforded 7-amino-5-thiomorpholinodioxo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile. LCMS tR=3.12 Min (10 min run, UV254nm). Mass calculated for, M+ 418.12, observed LC/MS m/z 419.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:32][C:12]3=[CH:13][C:14]4[C:15]([CH3:31])([CH3:30])[C:16](=[O:29])[N:17]([CH2:20][C:21](=[O:28])[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[CH:19]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>>[OH:28][CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][N:17]1[C:18]2[CH:19]=[C:11]3[N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:32][C:12]3=[CH:13][C:14]=2[C:15]([CH3:31])([CH3:30])[C:16]1=[O:29]
Reactant: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4CC(=O)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4CC(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
To a mixture of 2-(4-methoxy-phenyl)-7,7-dimethyl-5-(2-oxo-2-phenyl-ethyl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (33 mg) and trifluoroacetic acid (77 μl) is added drop-wise SiEt3 (30 μl) at RT for 48 h. The mixture is concentrated in vacuo and the residue is taken-up in MeOH (5 ml), CH2Cl2 (5 ml) and saturated NaHCO3 solution. The resulting solution is stirred at RT for 30 min, neutralized with hydrochloric acid (1 N) and extracted with CH2Cl2. The organic layer is washed with water, dried over MgSO4 and evaporated. The desired compound (15 mg) is obtained by preparative RP-HPLC, eluted with a water/MeCN gradient.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH3:19])[CH3:2].CN(C)CCCN=C=NCC.[CH3:32][C:33]1[N:34]=[C:35]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[S:36][C:37]=1[C:38](O)=[O:39]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:38]([C:37]3[S:36][C:35]([C:41]4[CH:42]=[CH:43][C:44]([C:47]([F:50])([F:48])[F:49])=[CH:45][CH:46]=4)=[N:34][C:33]=3[CH3:32])=[O:39])[CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH3:19])[CH3:2]
Reactant: CCOC(=O)CNc1cc(C2CCCNC2)ccc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)CNc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.1 %

Procedure:
(2-Methyl-5-piperidin-3-yl-phenylamino)-acetic acid ethyl ester (Example 13-1; 63 mg, 0.23 mmol) was dissolved in 2 mL CH2Cl2 and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (87 mg, 0.46 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (65 mg, 0.23 mmol) were added. The reaction was stirred at ambient temperature under nitrogen for 24 h. The reaction was flash chromatographed with 30% ethyl acetate/hexanes to yield 19 mg (15%) of the desired (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenylamino)-acetic acid ethyl ester as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]C1C=C2C(C=CN2)=CC=1)([CH3:4])([CH3:3])[CH3:2].C(O[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]([NH2:33])=[O:32])[CH:26]=[C:25]2[N:34]=[C:35]=[O:36])C=C>>[C:1]([O:5][C:6](=[O:17])[CH2:7][C:30]1[CH:29]=[C:28]2[C:24]([C:25]([N:34]=[C:35]=[O:36])=[CH:26][N:27]2[C:31](=[O:32])[NH2:33])=[CH:23][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: CC(C)(C)OC(=O)Cc1ccc2cc[nH]c2c1
Product: CC(C)(C)OC(=O)Cc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from (1H-indol-6-yl)-acetic acid tert-butyl ester using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S-:4].[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]>CN(C)C=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S:4][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Fc1ccc([S-])c(F)c1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Sc2ccc(F)cc2F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A solution of potassium 2,4-difluorothiophenoxide (5.5 g) in N,N-dimethylformamide (9 ml) was added dropwise to a solution of 4'-chloro-3'-nitroacetophenone (5 g) in toluene (50 ml). The mixture was stirred at room temperature for 2 hours, washed with water, dried and evaporated to dryness. The residue was washed with a mixture of hexane and ethanol to give crystals of 4'-(2,4-difluorophenylthio)-3'-nitroacetophenone (7.4 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[C:5]([CH3:18])([CH3:17])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21]>CCO.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[C:5]([CH3:18])([CH3:17])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21]
Reactant: COC/C=C/c1ccc2c(c1)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Agent: [Pd]
Solvent: CCO
Product: COCCCc1ccc2c(c1)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Reaction time: 1.5 h
Yield: 115.3 %

Procedure:
To a mixture of 1,1-dimethylethyl N-((4-hydroxy-1,1-dimethyl-7-((1E)-3-(methyloxy)-1-propen-1-yl)-2-oxo-naphthalen-3-yl)carbonyl)glycinate (245 mg, 590 μmol, Example 98A) in EtOH (5897 μL), was added palladium (10 wt. % on activated carbon (62.8 mg, 590 μmol)) at ambient temperature. The mixture was placed under hydrogen gas using a balloon, and the reaction mixture was stirred for 1.5 hours before it was filtered through a pad of Celite, washed with DCM, and concentrated to give the title compound (284 mg) as a light yellow oil. MS m/e=440 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(Cl)c(Cl)c1

Procedure:
prepared by reaction of 3-Chloro-3-(3,4-dichloro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.99 min; [M+H]+=302.2.