Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][C:10]1[CH:40]=[C:39]([F:41])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:24][CH:23]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:12]([F:42])[CH:11]=1.O=C1CCC(=O)N1[O:50][C:51](=O)[CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][NH:66][C:67](=[O:77])[CH2:68][CH2:69][N:70]1[C:74](=[O:75])[CH:73]=[CH:72][C:71]1=[O:76].CCN(C(C)C)C(C)C>>[O:76]=[C:71]1[CH:72]=[CH:73][C:74](=[O:75])[N:70]1[CH2:69][CH2:68][C:67]([NH:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][C:51]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([F:42])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:26][CH:27]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:39]([F:41])[CH:40]=1)=[O:50])=[O:77]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CN)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CNC(=O)CCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid TFA salt (120 mg, 0.2 mmol), 3-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (103 mg, 0.2 mmol), and DIPEA (129 mg, 174 uL, 1.0 mmol), and after HPLC purification, resulted in a white solid (75 mg, 43%). ES(+)-HRMS m/e calcd. for C42H50F2N6O13 (M+Na)+ 907.3296, obsd. 907.3296.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:7][N:6]1[C:2]([C:17]2[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=2)=[CH:3][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5]1
Reactant: COC(=O)c1cc(Br)n(C)c1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
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: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)n(C)c1
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A solution of methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (950 mg, 4.36 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1088 mg, 5.23 mmol)[prepared according to Preparation 3], potassium carbonate (3011 mg, 21.78 mmol) and bis(tri-t-butylphosphine)palladium(0) (111 mg, 0.218 mmol) in 1,4-Dioxane (18.200 ml) and Water (3.64 ml) was stirred at 80° C. in a sealed tube for 1 h. Additional 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1088 mg, 5.23 mmol) and bis(tri-t-butylphosphine)palladium(0) (111 mg, 0.218 mmol) were added and the solution stirred for 1 h. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylate (300 mg, 1.341 mmol, 30.8% yield) as a clear oil: LCMS m/e ES 220 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11]([C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:29])OC2C=CC=CC=2)[CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12].[NH2:30][C:31]1[CH:54]=[CH:53][C:34]([O:35][C:36]2[C:45]3[C:40](=[CH:41][C:42]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[C:43]([C:46]#[N:47])[CH:44]=3)[N:39]=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>>[C:46]([C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][C:42]=1[O:48][CH2:49][CH2:50][O:51][CH3:52])[N:39]=[CH:38][CH:37]=[C:36]2[O:35][C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:21]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([S:11]([CH3:10])(=[O:12])=[O:13])[CH:15]=2)=[O:29])=[CH:54][CH:53]=1)#[N:47]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(S(C)(=O)=O)c4)cc3)c2cc1C#N
Yield: 75.5 %

Procedure:
Diisopropylethylamine (0.057 ml, 0.328 mmol) and phenyl N-[3-(methylsulfonyl)phenyl]carbamate (96 mg, 0.328 mmol) were reacted with 4-(4-aminophenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline (100 mg, 0.298 mmol), and the title compound (120 mg, 0.225 mmol, 75.6%) was obtained as white crystals by the same procedure as in Example 34.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][NH:14]3)=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[N:3]=1.Br[CH2:25][CH2:26][O:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH2:25][CH2:26][O:27][CH3:28])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[N:3]=1
Reactant: COCCBr
Reactant: Cc1cc(C)n(-c2nc(Nc3ccccc3)c3nc[nH]c3n2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCn1cnc2c(Nc3ccccc3)nc(-n3nc(C)cc3C)nc21
Temperature: 120 °C
Yield: 8.4 %

Procedure:
[2-(3,5-Dimethyl-pyrazol-1-yl)-9H-purin-6-yl]-phenyl-amine (300 mg, 0.88 mmol), 2-bromoethylmethylether (0.12 mL, 1.32 mmol), potassium carbonate (121 mg, 0.88 mmol) and acetonitrile were mixed and heated in a microwave oven at 120° C. for 40 min. Water was added resulting in a white precipitate. The crude product was purified by preparative LCMS to give [2-(3,5-dimethyl-pyrazol-1-yl)-9-(2-methoxy-ethyl)-9H-purin-6-yl]-phenyl-amine (27 mg, 9%) as a white crystalline compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1ncc(Br)cc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-bromo-2-methoxypyridin-3-amine (1.231 mmol) was dissolved in pyridine (3 ml) at 0° C. Benzene sulfonyl chloride (1.847 mmol) was added drop wise and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate (100 mL). The ethyl acetate layer was washed with water, separated and dried over sodium sulfate. The organic layer was evaporated to dryness. The crude material obtained was purified by (silica column, EtOAc/Hexane as eluent) to obtain the title compound. 1HNMR (300 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.77 (m, 2H), 7.68 (d, J=2.4 Hz, 1H), 7.64 (m, 1H), 7.55 (m, 1H), 3.61 (s, 3H); MS (m/z): 343 (M)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:14][CH2:15][CH2:16][O:17][CH3:18]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Nc1cccc(CO)c1
Reactant: COCCCCl
Product: COCCCN(C(C)=O)c1cccc(CO)c1

Procedure:
Analogously to Example 8c, 0.40 g of N-(3-hydroxymethylphenyl)acetamide and 0.978 ml of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a beige oil. Rf=0.17 (6:1 EtOAc-heptane); Rt=2.55.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>>[C:14]([OH:16])(=[O:15])/[CH:13]=[CH:2]/[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)O
Product: COc1cc(/C=C/C(=O)O)ccc1O

Procedure:
Ferulic acid is a compound contained, as an ester thereof, in natural substances, particularly plants such as rice and adlay and may be obtained as a purified product from such a plant or a synthesized product industrially obtained. A ferulic ester is obtained in a hydrous ethanol fraction after rice bran oil obtained from rice bran is partitioned with hydrous ethanol and hexane at room temperature under weakly alkaline conditions. Ferulic acid can be obtained by hydrolyzing the ferulic ester obtained by the above-described process with sulfuric acid with heating under pressure and purifying the resultant hydrolyzate or by culturing Pseudomonas in a medium containing clove oil from buds and leaves of Syzygium aromaticum MERRILL et PERRY, Myrtaceae by steam distillation, or eugenol obtained by purifying the clove oil and subjecting the medium to isolation and purification. When ferulic acid is prepared by chemical synthesis, it may be prepared by, for example, a condensation reaction of vanillin and malonic acid (Journal of American Chemical Society, 74, 5346, 1952).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[O:6][CH:7]([C:10]([O:12]CC)=[O:11])[CH2:8][O:9][C:4]=2[CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[O:6][CH:7]([C:10]([OH:12])=[O:11])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1COc2cc(Cl)c(Cl)cc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1COc2cc(Cl)c(Cl)cc2O1
Yield: 75.7 %

Procedure:
Hydrolysis of ethyl 6,7-dichloro-1,4-benzodioxan-2-carboxylate (5.0 g.) with sodium hydroxide (10%, 10.9 ml.) in ethanol (50 ml.) gave 6,7-dichloro-1,4-benzodioxan-2-carboxylic acid (3.4 g.) m.p. 155°-158° C. with a consistent NMR spectrum and identical Rf (TLC) with an authentic sample.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][C:26]1[S:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=1>>[C:31]([C:29]1[N:30]=[C:26]([CH2:25][NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[S:27][CH:28]=1)#[N:32]
Reactant: N#Cc1csc(CN)n1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCc2nc(C#N)cs2)cn1
Yield: 68 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using 2-aminomethyl-thiazole-4-carbonitrile instead of aminomethyl-isoxazolidin-3-one to the title compound (SiO2, heptane:ethyl acetate=90:10 to 40:60, 188 mg, 68%) which was obtained as a white solid. MS: m/e=432.3 [M-FH]+.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)C(=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[I:32]C1C=CN=CC=1N>>[I:32][C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[NH:2][CH3:1]
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1cnccc1I
Product: CNc1cnccc1I

Procedure:
The title compound was prepared in analogy to example 25, intermediate b, from 4-iodo-pyridin-3-ylamine. Brown oil (22%) which was pure enough to be used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([S:24][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(SCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a solution of 25 g of 3,4-difluorobenzonitrile in 100 ml of N,N-dimethylformamide is added 25 g of potassium carbonate and 22.3 g of benzylmercaptan. The mixture is stirred for 3 hours at room temperature and water is added. The crystals are filtered off, washed with water and pentane and dried to give 41 g of 4-benzylthio-3-fluorobenzonitrile in the form of crystals melting at 87° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[C:4]([CH3:12])[CH:3]=1.Cl.[N:14](OCCC(C)C)=[O:15]>C(OCC)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:14][OH:15])[C:8]2=[O:11])=[C:4]([CH3:12])[CH:3]=1
Reactant: CC(C)CCON=O
Reactant: Cc1cc(F)cc2c1CCC2=O
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(F)cc2c1CC(=NO)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a stirred solution of 6-fluoro-4-methyl-2,3-dihydro-1H-inden-1-one (1 g, 6.09 mmol) in a mixture of diethyl ether (10 mL) and concentrated HCl (10 mL) was added isopentyl nitrite (0.73 mL, 5.47 mmol) and stirred at RT for 3 h. The precipitated solid was collected by filtration and washed with MeOH to obtain 6-fluoro-2-(hydroxyimino)-4-methyl-2,3-dihydro-1H-inden-1-one as a brown solid (800 mg, 68%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[CH3:25][N:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2
Reactant: O=C(N1Cc2ccccc2Nc2ccccc21)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2ccccc2CN(C(=O)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(10,11-Dihydro-5H-dibenzo[b,e][1,4]diazepin-10-yl)-2,2,2-trifluoroethanone of Step A (3.12 g) was added to dry N,N-dimethylformamide (50 mL) containing sodium hydride (60% dispersion in oil, 0.60 g, washed with hexane). After a short while iodomethane was added (2.0 g) and the mixture stirred overnight at room temperature, quenched with ice and diluted with brine. The precipitate was collected and redissolved in dichloromethane. The solution was dried over anhydrous sodium sulfate and filtered through a short column of Magnesol® which was eluted with several additional volumes of dichloromethane. The total effluent was evaporated to dryness and the residue crystallized from hexane to provide the title compound as colorless crystals (1.23 g), m.p. 104–106° C.
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C([O:26][C:27](=O)[C:28]#[C:29][CH:30]1[CH2:32][CH2:31]1)C>C(O)C>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:27](=[O:26])[CH:28]=[C:29]([CH:30]6[CH2:32][CH2:31]6)[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Reactant: CCOC(=O)C#CC1CC1
Solvent: CCO
Product: O=c1cc(C2CC2)n2c(n1)O[C@H](COc1ccc(C3C4CCCC3CCC4)cc1)C2
Temperature: 82 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.7 g, 2.23 mmol) (Example 20) in ethanol (40 mL) was added 0.462 g (3.35 mmol) of cyclopropyl-propynoic acid ethyl ester (Example 99). The reaction mixture was stirred at 82° C. for 30 minutes. The reaction mixture was concentrated and purified by chromatography on silica gel, eluting with MeOH/CH2Cl2 to afford 0.145 g of the title compound. [α]D25 −10.51 (c 0.5, CHCl3).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH:31]=[O:32])[CH2:27][CH2:26]2)[CH:14]=1)=O)C1C=CC=CC=1>[C].[Pd].C(O)C>[CH:31]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH2:22][O:21][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:12][NH2:11])[CH2:30][CH2:29]1)=[O:32]
Reactant: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCCCN1CCN(C=O)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CN)cc1OCCCN1CCN(C=O)CC1
Temperature: 60 °C
Reaction time: 9 h
Yield: 85 %

Procedure:
A mixture comprising 30.4 g of N-benzyloxycarbonyl-3-[3-(4-formylpiperazin-1-yl)-propoxy]-4-methoxybenzylamine, 3.1 g of 5% palladium carbon and 300 ml of ethanol, was stirred at 60° C. for 9 hours under a hydrogen atmosphere. Palladium carbon was filtered off, and then the filtrate was distilled off under reduced pressure to obtain 17.99 g of the above-identified compound as slightly brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([C:22]([F:23])([F:25])[F:24])[CH:11]=2)=[CH:14][CH:15]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanol (2.72 g) and triethylamine (1.55 ml) in dichloromethane (30 ml) was added dropwise methanesulfonyl chloride (0.86 ml) under ice-cooling. The reaction mixture was allowed to warm to room temperature and stirred for 1 hr.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH3:24])[CH2:9][CH2:8][CH2:7][N:6]([CH2:10][C@@H:11]([C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[C:14]=2[CH3:23])[OH:12])[CH2:5]1.[CH3:25][C:26]1[C:34]2[CH2:33][O:32][C:31](=[O:35])[C:30]=2[CH:29]=[CH:28][C:27]=1[C@@H:36]1[CH2:38][O:37]1>>[OH:12][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:10][N:6]1[CH2:7][CH2:8][CH2:9][C:4]([CH2:3][NH:2][CH2:38][C@H:36]([OH:37])[C:27]2[CH:28]=[CH:29][C:30]3[C:31](=[O:35])[O:32][CH2:33][C:34]=3[C:26]=2[CH3:25])([CH3:24])[CH2:5]1
Reactant: Cc1c([C@@H](O)CN2CCCC(C)(CN)C2)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CNCC2(C)CCCN(C[C@H](O)c3ccc4c(c3C)COC4=O)C2)ccc2c1COC2=O

Procedure:
5-{(1R)-1-Hydroxy-2-[3-({[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)-3-methylpiperidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(R)-2-[3-(aminomethyl)-3-methylpiperidin-1-yl]-1-hydroxyethyl]-4-methyl-2-benzofuran1(3H)-one hydrochloride [INTERMEDIATE 8] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one [INTERMEDIATE 2B].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C1N=C[N:16](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[NH4+].[NH4+].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)c1ccc(Br)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(Br)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a solution of give 2-bromo-5-(dimethylamino)benzoic acid (7.89 g, 32.3 mmol) in DMF (25 mL) was added N,N-carbonyldiimidazole (13.1 g, 80.8 mmol). The reaction mixture was allowed to stir at rt for 30 min and then ammonium carbonate (14.0 g, 145 mmol) was added. The reaction mixture was allowed to stir at rt overnight and then poured into water. The mixture was extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered and concentrated to give 2-bromo-5-(dimethylamino)benzamide (2.14 g, 27%). The product could be further purified by recrystallization from MeOH.
Reaction SMILES: [CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)[CH:9]=1.C1C(=O)N([Br:57])C(=O)C1>CC#N>[CH3:47][Si:44]([CH3:46])([CH3:45])[CH2:43][CH2:42][O:41][CH2:40][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:48])[CH3:49])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)[C:9]=1[Br:57]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (350 mg, 0.50 mmol) in CH3CN (5.0 mL) was added NBS (90 mg, 0.50 mmol). The mixture was stirred at it for 3 h and concentrated in vacuo. The residue was purified by Biotage (CH2Cl2/EtOAc, 100:1 to 10:1) to give the title compound as light yellow solid. LC/MS RT=2.49 min. Mass calculated for, M+H 768.29, observed 389.17.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][C:11]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([N:27]2[CH2:41][C:30]3=[C:31]4[N:36]([N:37]=[C:29]3[CH2:28]2)[C:35]([CH3:38])=[C:34]([Cl:39])[C:33]([CH3:40])=[N:32]4)=[O:26])([C:14]([F:17])([F:16])[F:15])[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[Cl:39][C:34]1[C:33]([CH3:40])=[N:32][C:31]2[N:36]([N:37]=[C:29]3[CH2:28][N:27]([C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:11]4([C:14]([F:16])([F:15])[F:17])[CH2:12][CH2:13][NH:9][CH2:10]4)=[O:26])[CH2:41][C:30]3=2)[C:35]=1[CH3:38]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1(C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1(C(F)(F)F)CCNC1)C3
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.4 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (1.06 mL; 4.22 mmol; 25 eq.) was added to a solution of 3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-3-trifluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (98 mg; 0.17 mmol; 1 eq.) in 1,4-dioxane (10 mL) and the resulting mixture was stirred at room temperature for 20 hours then concentrated in vacuo. The residue was partitioned between DCM and sat. aq. NaHCO3 and the aqueous layer was extracted with DCM. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (15 mg, 25%) as a white solid. HPLC (max plot) 95.9%, Rt 3.23 min. UPLC/MS: (MS+) 480.3 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:13])[C:9]=1[CH:10]=[N:11]O)[C:5]#[N:6].N>C(O)(=O)C.[Zn]>[NH2:11][CH2:10][C:9]1[C:8]([F:13])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: N#Cc1cc(F)c(C=NO)c(F)c1
Agent: N
Agent: [Zn]
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(CN)c(F)c1
Temperature: 60 °C
Yield: 85.7 %

Procedure:
An excess of zinc powder was added to a stirred mixture of 3,5-difluoro-4-((hydroxyimino)methyl)benzonitrile (130 mg, 0.7 mmol) in acetic acid (10 mL) then heated to 60° C. for 2 h. The mixture was made basic by addition of aqueous ammonia and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 4-(aminomethyl)-3,5-difluorobenzonitrile (100 mg, 0.6 mmol) as a colourless oil.