Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2(N)[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]3[C:6]2=[N:7][CH:8]=[N:9]3)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(N(CC)CC)C.C(#N)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[N:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: NC1(NC2CC2)N=C(C(F)(F)F)N=C2N=CN=C21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-n2cnc3c(NC4CC4)nc(C(F)(F)F)nc32)cc1OC
Temperature: 52.5 °C
Reaction time: 18 h
Yield: 10.4 %

Procedure:
A mixture of 6-cyclopropylamino-2-trifluoromethyladenine (46 mg, 0.2 mmol), 3,4-dimethoxyphenyl boronic acid (44 mg, 0.24 mmol), copper(II) acetate (36 mg, 0.2 mmol), triethylamine (1.0 mmol, 101 mg), anhydrous acetonitrile (4 ml) and molecular seives (˜10 pellets) was stirred at 50-55° C. for 18 hours. Ethyl acetate (20 ml) was added and the solid was removed by filtration. The filtrate was washed with 20 ml of 5% sodium bicarbonate aqueous solution. Evaporation and chromatography over SiO2 using hexane/ethylacetate/methanol (50:50:1) as elunt gave 7.9 mg of the title compound (yield 10%). 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.39 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 6.35(b, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.18 (b, 1H), 0.91 (m, 2H), 0.69 (m, 2H)
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH:9]1[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH:11]12[CH:10]=[CH:9][CH:15]([CH2:14][CH2:13][CH2:12]1)[CH:5]1[CH:6]2[C:1](=[O:8])[CH:2]=[CH:3][C:4]1=[O:7]
Reactant: C1=CCCCC=C1
Reactant: O=C1C=CC(=O)C=C1
Solvent: ClCCl
Product: O=C1C=CC(=O)C2C3C=CC(CCC3)C12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17.2 g of 1,4-benzoquinone in 240 mL DCM were added 7.6 mL of BF3-diethyletherate followed by 17.2 mL of 1,3-cycloheptadiene at −20° C. The cooling bath was removed after 20 min and the mixture furthermore stirred for 30 min at rt. The reaction mixture was then poured into ice cold KOH (30% aq.) solution and it was vigorously stirred for 10 min. After filtration over celite the organic phase was dried over K2CO3 and concentrated in vacuo to obtain 21.7 g of the desired compound as mixture of stereoisomers as brown solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[N+:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][NH:19][NH2:20])([O-:14])=[O:13]>>[NH2:10][C:6]1[NH:20][N:19]([CH2:18][C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cccc([N+](=O)[O-])c1
Product: Nc1cc(=O)n(Cc2cccc([N+](=O)[O-])c2)[nH]1

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 16.7 g of 3-nitrobenzylhydrazine, analogously to the procedure described in Example 1 yield 12.3 g of the compound identified above as yellow crystals of melting point 163°, corresponding to 52% of theory.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:26][CH:25]([CH2:27][OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:26][CH:25]([CH2:27][OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: OCC1CNC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 128.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and azetidin-3-yl-methanol. HPLC (Condition 4) tR=5.33 min, UPLC-MS (Condition 3) tR=1.06 min, m/z=446.2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].I([O-])(=O)(=O)=[O:22].[Na+].CCCCCC.C(OCC)(=O)C>CO.O>[CH3:20][O:19][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][CH2:6][CH2:7][S:8]([CH2:9][CH2:10][CH2:11][C:12]([F:17])([F:18])[C:13]([F:16])([F:14])[F:15])=[O:22]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(CCCCSCCCC(F)(F)C(F)(F)F)OC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: O
Product: COC(CCCCS(=O)CCCC(F)(F)C(F)(F)F)OC
Yield: 76.6 %

Procedure:
To a solution of 5,5-dimethoxy-1-(4,4,5,5,5-pentafluoropentylthio)pentane (460 mg, 1.4 mmol) in methanol (10 mg) were added sodium periodate (420 mg, 2.0 mmol) dissolved in water (8 ml) and methanol (5 ml), and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give 5,5-dimethoxy-1-(4,4,5,5,5-pentafluoropentylsulfinyl)pentane (365 mg, yield 76%).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[Li+].[OH-]>>[F:16][C:15]([F:17])([F:18])[O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]#[C:6][CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:13][CH:12]=1
Reactant: COC(=O)CCC#Cc1ccc(OC(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CCC#Cc1ccc(OC(F)(F)F)cc1

Procedure:
In analogy to the procedure described for example 1 e], 5-(4-trifluoromethoxy-phenyl)-pent-4-ynoic acid methyl ester was treated with LiOH to obtain the title compound as brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[C:7]2[C:12]=1[N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1)[C:10](=[O:24])[CH2:9][CH2:8]2>[C].[Pd].CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[C:7]2[C:12]=1[N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1)[C:10](=[O:24])[CH2:9][CH2:8]2
Reactant: COC(=O)c1ccc(CN2C(=O)CCc3c(C=C4SC(=O)NC4=O)ccc(OC)c32)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(=O)CCc3c(CC4SC(=O)NC4=O)ccc(OC)c32)cc1
Reaction time: 5 h
Yield: 74.4 %

Procedure:
7.0 g of 10% palladium carbon was added to a DMF solution (70 ml) of 7.0 g of 5-[8-methoxy-1-(4-methoxycarbonyl benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethylidene]thiazolidine-2,4-dione, and a catalytic reduction was carried out at 40° C. for 5 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was recrystallized from an ethyl acetate-diethyl ether mixed solvent, giving 5.23 g (74% yield) of 5-[8-methoxy-1-(4-methoxycarbonylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione as a white powder.
Reaction SMILES: N[S:2]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[CH3:19])[C:6]=1[C:7]([N:9](CC)CC)=[O:8])(=[O:4])=[O:3]>C(O)(=O)C>[CH3:21][Si:20]([CH3:23])([CH3:22])[CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:5]2[C:6]=1[C:7](=[O:8])[NH:9][S:2]2(=[O:4])=[O:3])[CH3:19]
Reactant: CCN(CC)C(=O)c1c(C(C)[Si](C)(C)C)cccc1S(N)(=O)=O
Solvent: CC(=O)O
Product: CC(c1cccc2c1C(=O)NS2(=O)=O)[Si](C)(C)C
Yield: 0.1 %

Procedure:
To a solution of sec-BuLi (0.97M, 5.10 mL, 4.96 mmol) and TMEDA (0.75 mL, 4.96 mmol) in THF at -78° C. was added the amide (1.25 g, 4.50 mmol) in THF. Excess SO2 in THF was added quickly at -78° C. then warmed to room temperature. The THF was removed in vacuo and the residue treated at 0° C. with two equivalents of a 1:1 solution of sodium hydroxide (0.36 g, 9.0 mmol) and hydroxylamine-O-sulfonic acid (1.0 g, 9.0 mmol) in H2O. The reaction was stirred at room temperature for 4 hrs, extracted with EtOAc, dried over MgSO4, concentrated and flash chromatographed on silica gel with 20% ethyl acetate/hexane to give 0.62 g (41%) of 2-aminosulfonyl-N,N-diethyl-6-[1-(trimethylsilyl)-ethyl]benzamide. The benzamide (0.95 g, 2.66 mol) was refluxed in glacial acetic acid (20 mL) for 18 hr, stripped to dryness, triturated with hot cyclohexane (30 mL) and a trace of EtOAc (3 mL), cooled with scratching and filtered. There was obtained 0.81 g (85%) of 4-[1-(trimethylsilyl)ethyl]saccharin, mp 123°-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH:6]=1.[C:15]([O:18][CH2:19][CH2:20]Br)(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:15]([O:18][CH2:19][CH2:20][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:5]2[CH:6]=[C:2]([Br:1])[CH:3]=[N:4]2)[CH:9]=1)(=[O:17])[CH3:16]
Reactant: Oc1cccc(Cn2cc(Br)cn2)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cccc(Cn2cc(Br)cn2)c1
Temperature: 200 °C
Yield: 33.6 %

Procedure:
A mixture of 3-((4-bromo-1H-pyrazol-1-yl)methyl)phenol (0.6 g, 2.37 mmol), 2-bromoethyl acetate (0.792 g, 4.74 mmol) and potassium carbonate (0.655 g, 4.74 mmol) in DMF (5 mL) was heated at 200° C. in a microwave reactor for 1 h. After this time, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (0.27 g, 34% yield) as a colorless oil. LCMS, [M+H]+=339.0. 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.34 (s, 1H), 7.24 (dd, J=8.3, 7.6 Hz, 2H), 6.83 (dd, J=8.3, 2.4 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 5.20 (s, 2H), 4.41-4.32 (m, 2H), 4.14-4.08 (m, 2H), 2.06 (s, 3H).
Reaction SMILES: CO.[NH2:3][C:4]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:5]=1[CH:6]([OH:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH3:28][C:29]([CH3:33])([CH3:32])[CH:30]=O.C([BH3-])#N.[Na+]>C(OC(=O)C)C.C(O)(=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:4]([NH:3][CH2:28][C:29]([CH3:33])([CH3:32])[CH3:30])=[C:5]([CH:23]=1)[CH:6]([OH:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1C(O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1ccccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
To a methanol (5 ml) solution of 2-amino-5-chloro-α-(2-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.5 g) were added trimethyl acetaldehyde (132 mg) and acetic acid (92 mg). The mixture was stirred for 10 minutes at room temperature, to which was added sodium cyano borohydride (97 mg), followed by stirring for one hour at room temperature. To the reaction mixture was added acetic acid ethyl ester (50 ml). The mixture was washed with water and dried over anhydrous Na2SO4. The solvent was then distilled off. The residue was purified by means of a silica gel column chromatography to give the object 5-chloro-α-(2-tert-butoxycarbonylaminomethylphenyl)-2-neopentylaminobenzyl alcohol (0.61 g) as a colorless oily product.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Br[C:19]1[C:20]([C:33]#[N:34])=[N:21][C:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.CO.ClCCl.O>[Si:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]2[C:20](=[C:33]([NH2:34])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=2)[N:21]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(C#N)n1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(n1)c(N)nc1ccccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-bromo-6-(tert-butyldimethylsilyloxy)picolinonitrile (from step 3) (1.0 eq.) in toluene/ethanol (10:1, 0.2 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give a solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22](O)=[O:23])[CH2:16][CH2:15]1)(OC(C)(C)C)=O.O.[OH-].[Na+]>C1COCC1>[CH3:7][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(CCCO)CC1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
To a refluxing solution of 1 M LiAlH4 (40 mmol) in THF (30 mL) was added dropwise a solution of N—BOC-4-piperidinepropionic acid (3.0 g, 11.6 mmol). The reaction mixture was heated for 3 h then cooled to rt. Upon further cooling to 0° C., water (1.5 mL) was added slowly, and the reaction mixture was allowed to warm to rt over 15 min. The mixture was again cooled to 0° C., and 10% aq. NaOH (1.5 mL) was added slowly. Upon warming to rt over 15 min, the mixture was cooled to 0° C. and more water (4.5 mL) was added. The resultant mixture was allowed to warm to rt over 18 h, and was then filtered through a pad of diatomaceous earth. The filtrate was concentrated, and the residue was purified by Method 1 to afford 1.9 g (100%) of 3-(1-methyl-piperidin-4-yl)-propan-1-ol as a yellow oil. MS (ESI): mass calcd for C9H19NO, 157.15; m/z found 158.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 3.45-3.41 (m, 2H), 2.77-2.74 (m, 2H), 1.89-1.85 (m, 2H), 1.64-1.61 (m, 2H), 1.47-1.43 (m, 2H), 1.21-1.12 (m, 5H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]12[O:23][CH:15]1[CH2:16][C:17]1[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[OH:23][C@@H:15]1[CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:14]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: c1ccc2c(c1)CC1OC21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN([C@@H]2c3ccccc3C[C@H]2O)CC1
Temperature: 60 °C

Procedure:
11.6 g of tert-butyl piperazine-1-carboxylate (62 mmol) and 8.2 g of indene oxide (62 mmol) are dissolved in 30 ml of acetonitrile. The reaction mixture is then heated at 60° C. overnight and evaporated to dryness. The residue obtained is purified by flash chromatography on 1 kg of silica (eluant: dichloromethane/ethanol 95/5) to yield tert-butyl trans-4-(2-hydroxy-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate in the form of a white meringue.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24]O>C1C=CC=CC=1>[Cl:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24][Cl:3]
Reactant: OCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
17.6 g of thionyl chloride are added to a suspension of 45 g of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole in 45 ml of benzene, there being a considerable evolution of gas and solution occurs. Following this heating is carried out for 30 minutes at boiling point for completion of the reaction. The solvent is distilled off in vacuo and this operation is carried out with the addition of benzene. The residue is caused to crystallise with the help of petroleum ether. 5-Chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole is obtained with a 98.5% yield; F 96.5°-97°.
Reaction SMILES: [CH3:1]C(C)([O-])C.[Na+].IC.[O:9]=[C:10]1[NH:15][C:14]2[CH:16]=[C:17]([C:19]3[C:20](=[O:29])[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:18][C:13]=2[CH:12]=[CH:11]1.O>C1COCC1>[CH3:1][N:15]1[C:10](=[O:9])[CH:11]=[CH:12][C:13]2[NH:18][C:17]([C:19]3[C:20](=[O:29])[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:14]1=2
Reactant: CC(C)(C)[O-]
Reactant: O=c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2[nH]1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cn1c(=O)ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc21
Reaction time: 20 h

Procedure:
Sodium tert-butoxide (10 mg, 0.11 mmol, 1.0 equiv) and iodomethane (13 μL, 0.22 mmol, 2.0 equiv) were added sequentially to a suspension of the product from Example 3 (30 mg, 0.11 mmol, 1 equiv) in THF (10 mL) at 23° C. The reaction mixture was stirred for 20 hours. Additional sodium tert-butoxide (20 mg, 0.22 mmol, 2.0 equiv) and iodomethane (26 μL, 0.44 mmol, 4.0 equiv) were added in 2 equal portions over 1 hour, and then the reaction mixture was allowed to stir an additional 1 hour. Water (5 mL) was added, and the resulting mixture was concentrated to a volume of 2 mL. The mixture was purified by reverse phase HPLC to afford the titled compound as a yellow solid.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12](O)=[O:13])[N:9]=[CH:8]2)[CH:2]=1.C(Cl)(=O)C([Cl:24])=O>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]([Cl:24])=[O:13])[N:9]=[CH:8]2)[CH:2]=1
Reactant: O=C(O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
A solution of 10a (2.0 g, 7.6 mmol) in oxalyl chloride (30 ml) was stirred at 60° C. overnight. Excess oxalyl chloride was removed under reduced pressure to leave 11a.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([OH:22])=O)=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[F:49][C@H:50]([CH3:53])[CH2:51][NH2:52]>ClCCl>[F:49][C@@H:50]([CH3:53])[CH2:51][NH:52][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:22]
Reactant: C[C@@H](F)CN
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(C(=O)NC[C@H](C)F)c3ncc(C)cc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
See FIG. 19(d). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.32 mmol) was taken in dichloromethane (10 mL) to get a suspension. Added triethyl amine (0.133 mL, 0.96 mmol) followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.381 mL, 0.64 mmol). The reaction mass was stirred at RT for 5 minutes. (R)-2-fluoropropan-1-amine (49.4 mg, 0.64 mmol) was added and stirred at RT for overnight. After the completion of the reaction, diluted the reaction mass with DCM, washed ith water, and brine solution. The organic layer was dried over sodium sulphate, evaporated and the crude compound was purified by silica gel chromatography. Yield-75%. ES+MS m/z: 373.2 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25-1.42 (m, 4 H ) 2.24 (s, 3H) 2.40 (s, 3 H ) 3.42-3.81 (m, 2 H ) 3.94 (s, 3 H ) 4.65-4.85 (m, 1 H ) 4.93 (td, J=6.50, 3.39 Hz, 1 H ) 5.64 (s, 2 H ) 7.76 (s, 1 H ) 8.16 (s, 1 H ) 8.29-8.47 (m, 2 H ) 8.91 (t, J=6.03 Hz, 1 H ).
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4](Br)[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]=12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[C:3]([S:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)=[C:4]([S:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)[C:5]([Br:13])=[C:6]3[C:11]([NH:10][C:8](=[O:9])[C:7]=23)=[O:12])=[CH:19][CH:18]=1
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2c(Sc3ccc(Cl)cc3)c(Sc3ccc(Cl)cc3)c(Sc3ccc(Cl)cc3)c(Br)c21
Yield: 25.1 %

Procedure:
2 g (4.46 millimols) of tetrabromophthalimide, 1.61 g (11.15 millimols) of p-chlorothiophenol, 2.31 g (16.73 millimols) of potassium carbonate and 20 ml of tetrahydrofuran are stirred at 25° C. for 14 hours. After acidification with dilute HCl solution, the mixture is extracted with tetrahydrofuran/toluene and the extracts are dried and evaporated. After recrystallisation from toluene/cyclohexane, 0.61 g (25% of theory) of 3,4,5-tris-(p-chlorophenylthio)-6-bromophthalimide is obtained; melting point 164°-9° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:29]1[CH2:30][CH2:31][C@@H:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:28]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([O:16]C)=[N:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.Cl.[CH2:19]([O:21][C:22](=[O:25])[CH2:23][NH2:24])[CH3:20].C(N(CC)CC)C.Cl>CN(C=O)C.C(O)C(F)(F)F.O1CCOCC1>[CH2:19]([O:21][C:22](=[O:25])[CH2:23][NH:24][C:2]1[C:3]2[N:4]([C:13](=[O:16])[NH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2)[CH3:20]
Reactant: COc1nnc2c(Cl)nc3ccc(F)cc3n12
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc2ccc(F)cc2n2c(=O)[nH]nc12

Procedure:
A solution of 152 mg of 4-chloro-8-fluoro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 127 mg of glycine ethyl ester hydrochloride, and 602 mg of triethylamine in DMF (4.0 mL) was stirred at room temperature for 41 hrs. The reaction mixture was concentrated, dissolved in 25% IPA/methylene chloride and washed with 50% saturated sodium bicarbonate, and then water. The organic emulsion was collected and concentrated to provide a yellow solid. A solution of this solid in trifluoroethanol (10 mL) was treated with 5 equiv. of 4.0 N HCl in dioxane for 15 min., and the mixture was concentrated. The residue was dissolved in 20% IPA/methylene chloride, and washed with 50% saturated sodium bicarbonate, and then water. The organic emulsion was collected and concentrated to provide a yellow solid which was triturated. The resulting off-white solid was collected, dried, washed with ether and dried to provide the title compound. MS (M+H)+=306.0.