Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].C(Cl)Cl.[C:22]([NH:41][C:42]1[S:43][CH:44]=[C:45]([C:47](=[N:51][O:52][CH2:53][CH2:54][N:55]=[N+:56]=[N-:57])[C:48](O)=[O:49])[N:46]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ON1C2C=CC=CC=2N=N1.Cl>O.C(N(CC)CC)C>[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH:10]([NH:13][C:48](=[O:49])[C:47]([C:45]3[N:46]=[C:42]([NH:41][C:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:43][CH:44]=3)=[N:51][O:52][CH2:53][CH2:54][N:55]=[N+:56]=[N-:57])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:1].[CH2:7]([NH:8][CH2:9][CH3:10])[CH3:6]
Reactant: [N-]=[N+]=NCCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Product: CCNCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.54 g of 7-amino-cephalosporanic acid, 25 ml of anhydrous methylene chloride and 2.6 ml of triethylamine was stirred at room temperature for 15 minutes and then 6.02 g of 1-hydroxy-1H-benzotriazole 2-(2-tritylamino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetate were added thereto. The mixture was stirred at room temperature for 45 hours and 25 ml of water and 5 ml of N hydrochloric acid were added thereto. The decanted organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was taken up in 30 ml of ethyl acetate and 2.4 ml of diethylamino were added to the solution. The mixture was cooled at 0° C. and was vacuum filtered to obtain 5.9 g of the syn isomer of diethylamine 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH:6]=1.C(O)(=O)C.[C-:14]#[N:15].[K+]>CO>[CH3:7][C:4]1([CH3:8])[CH2:5][C:6]([C:14]#[N:15])=[CH:2][C:3]1=[O:9]
Reactant: CC1(C)CC=C(Br)C1=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CC(C#N)=CC1=O
Temperature: 27.5 °C
Reaction time: 4.5 h

Procedure:
To a stirred solution of 2-bromo-5,5-dimethylcyclopent-2-enone (prepared according to procedure reported in Organic Letters 2002, 4, 71-74, 17 g, 90 mmol) in methanol (200 ml) was added acetic acid, (5.15 ml, 90 mmol) at 25-30° C. Solid potassium cyanide (11.71 g, 180 mmol) was added and continued stirring the reaction mass for 4-5 h at 25-30° C. The progress of reaction was monitored by TLC. After completion of reaction, filtered the reaction mass through cotton filter and then filtrate was concentrated under reduced pressure. A crude oily compound was dissolved in Ethyl acetate (500 ml) and washed with water (100 ml) to remove the unreacted potassium cyanide. Organic layer was dried over sodium sulphate and concentrated under reduced pressure till dryness. Crude compound was purified over silica gel (100-200 mesh) by using 10% ethylacetated in hexane as eluent to obtain title produced (7.1 g)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH:17]([CH2:23][NH2:24])[CH2:18]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:25](Br)[CH:26]=[CH2:27].C(N(CC)CC)C>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH:17]([CH2:23][NH:24][CH2:27][CH:26]=[CH2:25])[CH2:18]3)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2cccc3c2CC(CN)C3)cc1
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCNCC1Cc2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.3 %

Procedure:
4-Isopropyl-N-(2-aminomethyl-indan-4-yl)-benzenesulfonamide (80 mg, 0.23 mmol), allyl bromide (30 mg, 0.23 mmol) and triethylamine (20 mg, 0.23 mmol) were dissolved in 2 mL of DMF and stirred at room temperature for 18 h. The solution was concentrated, water added and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and the filtrate was evaporated in vacuo to give a residue which was purified by column chromatography using (dichloromethane-MeOH, 0-5%) to give a yellow oil (10 mg, 6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=O)[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[N:14]=[N:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=1.BrC(Cl)(Cl)C(Br)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]2[N:15]([C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:20][N:19]=2)[N:14]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: NNc1ccc(Cl)nn1
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(Nc2nnc3ccc(Cl)nn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-methoxyphenyl isocyanate and 3-chloro-6-hydrazinopyridazine in acetonitrile was stirred at room temperature for 30 minutes, and 1,2-dibromo-1,1,2,2-tetrachloroethane was added and the mixture was stirred at room temperature for further 2 hours. This reaction solution was combined with triethylamine and triphenylphosphine with cooling in ice, and stirred at room temperature for 3 days. Then, the reaction solution was concentrated under reduced pressure, purified by a standard method to obtain 6-chloro-N-(3-methoxyphenyl)-1,2,4-triazolo[4,3-b]pyridazin-3-amine. Dat (F:276).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>CN(C)C=O>[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[N:9]=[CH:10][N:11]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=34)[N:4]=2)[CH2:26]1
Reactant: CC1(C)CCCNC1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCC(C)(C)C4)n3)ncn2-c2ccccc2C1=O
Yield: 92.8 %

Procedure:
1.15 g (3.5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 1 hour with 1 g (8.8 mmol) of 3,3-dimethylpiperidine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/ethanol 9/1 there were obtained 1.32 g (92%) of 3-[5-(3,3-dimethylpiperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 167°-168°, which was converted into the hydrochloride.
Reaction SMILES: C(=O)[CH2:2][CH2:3][CH:4]=[O:5].N1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10].C1COCC1>CC1OCCC1>[OH:10][CH:9]1[O:11][C@H:13]2[CH2:14][C:3]([CH:4]=[O:5])=[CH:2][C@H:12]2[CH2:8]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=CCCC=O
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The solution of succinaldehyde 8 from the first step (109.5 g, 1.272 mol) in 2-MeTHF was stirred at r.t. (S)-Proline (2.93 g, 25.4 mmol, 0.02 eq.) was added as a solid and the reaction stirred at r.t. for 20 h. THF (650 ml) was added, followed by [Bn2NH2][OCOCF3] (8.43 g, 25.4 mmol, 0.02 eq.). The reaction was stirred for a further 14 h. Celite (60 g) was added to the reaction and the volume of the reaction mixture was reduced by ¾ under reduced pressure. tert-Butyl methyl ether (TBME) (an equal volume to the volume of THF/2-MeTHF removed) was added slowly (over ˜15 mins) and with vigorous stirring of the mixture. The mixture was stirred for 20 min before filtration of the resulting solids (through a sinter funnel). The solids were washed with TBME (3×150 ml) and the filtrate was concentrated under reduced pressure. The material was purified by column chromatography (˜600 g silica), eluting with petrol/EtOAc (6:4 to 5:5), to give the lactol 7 (as an approximately 2:1 mixture of diastereoisomers), as a brown oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][N:36]3[CH2:37][CH2:38][N:33]([C:30](=[O:32])[CH3:31])[CH2:34][CH2:35]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(CCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 65.2 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(2-bromo-ethyl)-pyrrolo[2,1-f][1,2,4]-triazin-4-ylamine (70 mg, 0.156 mmol), 1-acetyl-piperazine (40.1 mg, 0.313 mmol, 2.0 eq), triethylamine (20.6 mg, 0.20 mmol, 1.3 eq), and sodium iodide (2.3 mg, 0.016 mmol, 0.1 eq) in anhydrous DMF (1.6 mL) was stirred at 50° C. for 15 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with 50% aqueous brine (3×), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then elided with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-hexane to provide the title compound (50.3 mg, 65%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.89 (s, 1H), 7.80 (dd, 1H), 7.57 (s, 1H), 7.36 to 7.30 (m, 5H), 7.13 (dd, 1H), 6.65 (s, 1H), 5.65 (s, 2H), 3.40 (q, 4H), 3.07 (t, 2H), 2.68 (t, 2H), 2.45 (t, 2H), 2.38 (t, 2H), 1.97 (s, 3H); ES-MS m/z 495.3 [M+H]+, RT (min) 2.02.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[O:19])[CH:5]=[C:6]2[C:14]=1[C:13](=[CH2:15])[C:12]1([OH:17])[O:16][N:7]2[CH2:8][CH:9]2[CH:11]1[NH:10]2.[H-].[Na+].[CH3:22]I>CN(C)C=O>[OH:17][C:12]12[O:16][N:7]([CH2:8][CH:9]3[CH:11]1[NH:10]3)[C:6]1[C:14](=[C:2]([O:1][CH3:22])[CH:3]=[C:4]([CH:18]=[O:19])[CH:5]=1)[C:13]2=[CH2:15]
Reactant: C=C1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C1c2c(OC)cc(C=O)cc2N2CC3NC3C1(O)O2
Reaction time: 1 h

Procedure:
To a solution of 6,9-dihydroxy-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (30 mg) in dimethylformamide (1.0 ml) was added a suspension of sodium hydride (60% in oil, 4.6 mg) in dimethylformamide (0.5 ml) in an ice-water bath. To this mixture was added a solution of methyl iodide (7.2 μl) in dimethylformamide (0.1 ml) in an ice-water bath. After stirring for 1 hour in an ice-water bath, the reaction mixture was evaporated to dryness in vacuo, and the residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (8:1, v/v) to afford 9-hydroxy-6-methoxy-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (19 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18]Br)[CH2:14][CH2:13]1)[CH3:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([CH2:10][CH3:11])[CH2:13][CH2:14]1
Reactant: Oc1cccc(F)c1F
Reactant: CC[C@H]1CC[C@H](CBr)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
30 g of 2,3-difluorophenol was dissolved in 300 ml of DMF, and 56.8 g of (trans-4-ethylcyclohexyl)methyl bromide and 73.4 g of tripotassium phosphate were added thereto, and then stirred for 1 hours at 100 to 110° C. Water and toluene were added thereto, and the organic layer was fractioned while the aqueous layer was extracted with toluene. The organic layers were combined, washed with saturated saline, and then subjected to column chromatography. Then, the solvent was evaporated under reduced pressure. The residue was purified by recrystallization, to thereby obtain 37 g of 2,3-difluoro-1-(trans-4-ethylcyclohexyl)methoxybenzene.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCI
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Br)c(C=O)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of 2-bromo-5-hydroxybenzaldehyde (5 g, 24.87 mmol) in DMF (20 mL) was added iodoethane (5.82 g, 37.3 mmol) and K2CO3 (6.88 g, 49.7 mmol) portion wise. The resulting reaction mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with EtOAc/hexanes (1:1) and water. Layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title intermediate (4.6 g) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[N:23](C3CCCCO3)[N:22]=2)=[N:4][C:5]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([CH3:19])[CH:10]=2)=[N:6][CH:7]=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.[CH3:66][N:67]([CH3:71])[CH2:68][CH2:69][NH2:70].Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:4][C:5]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:12]([C:13]([NH:70][CH2:69][CH2:68][N:67]([CH3:71])[CH3:66])=[O:15])=[C:11]([CH3:19])[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)c(C)cc1Nc1ncc(Cl)c(Nc2cc(C)n(C3CCCCO3)n2)n1
Reactant: CN(C)CCN
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: Cc1cc(Nc2nc(Nc3cc(C)c(C(=O)NCCN(C)C)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-chloro-4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylbenzoic acid (35.0 mg, 0.077 mmol) in DMF (0.5 mL) was added HATU (29.1 mg, 0.077 mmol), DIEA (26.7 μL, 0.153 mmol) and N1,N1-dimethylethane-1,2-diamine (25.2 μL, 0.230 mmol). The reaction mixture was stirred at room temperature overnight. 1N HCl aqueous solution (0.5 mL) was then added and the reaction mixture was heated at 100° C. for 1.5 hours to remove the tetrahydro-2H-pyran-2-yl protecting group. The mixture was purified by preparative RP-HPLC to provide 4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-N-(2-(dimethylamino)ethyl)-2,5-dimethylbenzamide; ESMS m/z 443.2 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[C:12]([NH2:13])=[CH:11][C:10]([CH2:14][S:15](/[CH:18]=[CH:19]/[C:20]2[C:25]([O:26][CH3:27])=[CH:24][C:23]([O:28][CH3:29])=[CH:22][C:21]=2[O:30][CH3:31])(=[O:17])=[O:16])=[CH:9][N:8]=1>N1C=CC=CC=1>[CH3:5][O:6][C:7]1[C:12]([NH:13][C:1](=[O:3])[CH3:2])=[CH:11][C:10]([CH2:14][S:15](/[CH:18]=[CH:19]/[C:20]2[C:25]([O:26][CH3:27])=[CH:24][C:23]([O:28][CH3:29])=[CH:22][C:21]=2[O:30][CH3:31])(=[O:17])=[O:16])=[CH:9][N:8]=1
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(N)c2)c(OC)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(NC(C)=O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Acetyl chloride (0.054 mL, 0.76 mmol) was added dropwise into the solution of (E)-2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-amine (80 mg, 0.21 mmol) in dry pyridine (5 mL) on an ice bath. The mixture was warmed to room temperature and stirred overnight. After evaporated to dryness, the residue was purified by silica gel chromatography, eluting with PE/EtOAc (1:3 v/v) to afford pure product as a white solid (38 mg, 44%). 1H-NMR (CDCl3-d6): δ 2.21 (s, 3H, CH3), 3.86 (s, 6H, 2×OCH3), 3.87 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 4.21 (s, 2H, CH2), 6.11 (s, 2H, Ph-H), 7.13 (d, 1H, J=15.6 Hz, CH), 7.61 (s, 1H, NH), 7.88 (d, 1H, J=15.6 Hz, CH), 7.89 (d, 1H, J=2.0 Hz, Py-H), 8.65 (d, 1H, J=2.0 Hz, Py-H); HR-MS (ESI+) m/z 437.1460 [M+H]+ C20H24N2O7S requires 436.1304,
Reaction SMILES: [CH:1]1C(C(C2C=CC(F)=CC=2)=O)=CC=C(F)[CH:2]=1.[C:17]([O-:23])(=[O:22])[CH2:18][C:19]([O-:21])=[O:20].N1C=CC=[CH:26][CH:25]=1>ClCCl.C1COCC1.Cl[Ti](Cl)(Cl)Cl>[C:17]([O:23][CH2:25][CH3:26])(=[O:22])[CH2:18][C:19]([O:21][CH2:1][CH3:2])=[O:20]
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: c1ccncc1
Reactant: O=C([O-])CC(=O)[O-]
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To THF (80 ml) were added sequentially, a 1.0 M solution of TiCl4 in dichloromethane (80 ml), p,p′-difluorobenzophenone (8.73 g) and diethtyl malonate (6.4 g) in THF 20 ml. After stirring at 0° C. for 40 min, a solution of pyridine (12.8 ml) in THF (28 ml) was added dropwise. The ensuing mixture was stirred for 4 days. The reaction was quenched with water and diethyl ether. The aqueous phase was separated and extracted twice more with diethyl ether. The combined organic phases were washed with brine, sat. sodium bicarbonate solution and again with brine. Drying of the organic phase (MgSO4), filtration and concentration afforded a residue from which residual diethyl malonate was removed by Kugelrohr destillation. The residue was flash chromatographed to provide 1,1-di-p-fluorophenyl-2,2-di-ethoxycarbonylethylene (25%, m.p.=117-119° C.). To this product (5.9 g) were added ammonium chloride (1.31 g), KCN (2.18 g), DMF (175 ml) and water (22 ml) and the mixture was heated to 100° C. for 8 hrs. The cooled reaction mixture was poured into water and extracted (3×) with ethyl ether. The combined organic phases were washed with water, aq. 2N HCl, aq. 5% NaHCO3 and brine. Drying (Na2SO4), filtration and evaporation of volatiles gave a residue which was recrystallised from ether-hexane to afford the title compound (56%; M.p. 90-91° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12]Br)=[O:5])[CH3:2].[CH2:14]([O:16][C:17](=[O:31])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
2-Bromo-4-bromomethyl-thiazole-5-carboxylic acid ethyl ester (22.1 g, 67.3 mmol) was dissolved in 169 mL of dry N,N-dimethylformamide. N-(2,4-dimethoxy-benzyl)glycine ethyl ester (17.1 g, 67.3 mmol) and potassium carbonate (10.2 g, 74.0 mmol) were added and the reaction was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-70% ethyl acetate in hexanes to produce 19.5 g of a light yellow solid. MS: (+) m/z 501.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)#[N:18]>>[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([OH:12])=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:7]=2)=[O:24])=[CH:21][CH:20]=1)#[N:18]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: CC(C)(C)c1cc(NC(=O)c2ccc(C#N)cc2)cc(C(C)(C)C)c1O
Yield: 50.2 %

Procedure:
Using the method of Example 12, 3.4 g of 4-amino-2,6-di-t-butylphenol was reacted with 2.3 g of 4-cyanobenzoic acid to provide 2.7 g of 4-cyano-N-(3',5'-di-t-butyl-4'-hydroxyphenyl)benzamide.
Reaction SMILES: FC(F)(F)C(O[Si](C)(C)C)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([F:43])([F:42])[C:20]([N:22]2[CH2:31][CH2:30][N:29]3[C@H:24]([CH2:25][O:26][C@@H:27]([C:32]4[C:33]([CH3:41])=[C:34]([C:37]([F:40])=[CH:38][CH:39]=4)[C:35]#[N:36])[CH2:28]3)[CH2:23]2)=[O:21])=[CH:15][N:14]=1.[CH:44](OCC)(OCC)OCC.[N:54]([Si](C)(C)C)=[N+:55]=[N-:56]>C(OCC)(=O)C.CO>[N:12]1([C:13]2[N:14]=[CH:15][C:16]([C:19]([F:43])([F:42])[C:20]([N:22]3[CH2:31][CH2:30][N:29]4[C@H:24]([CH2:25][O:26][C@@H:27]([C:32]5[C:33]([CH3:41])=[C:34]([C:37]([F:40])=[CH:38][CH:39]=5)[C:35]#[N:36])[CH2:28]4)[CH2:23]3)=[O:21])=[CH:17][N:18]=2)[CH:44]=[N:54][N:55]=[N:56]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1c([C@H]2CN3CCN(C(=O)C(F)(F)c4cnc(N)nc4)C[C@H]3CO2)ccc(F)c1C#N
Reactant: CCOC(OCC)OCC
Agent: C[Si](C)(C)OC(=O)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c([C@H]2CN3CCN(C(=O)C(F)(F)c4cnc(-n5cnnn5)nc4)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Trimethylsilyl trifluoroacetate (23.8 μL, 0.137 mmol) was added to a suspension of 3-((3S,9aS)-8-(2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile (36.1 mg, 0.081 mmol) in ethyl acetate (735 μL). The mixture was stirred for 5 min at room temperature and triethyl orthoformate (23.67 μL, 0.142 mmol) was added. After stirring for 5 more min at room temperature, azidotrimethylsilane (16.91 μL, 0.129 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with methanol and purified on mass-directed preparative HPLC. Appropriate fractions were collected and solvent was removed under reduced pressure. The residue was converted to hydrochloric acid salt. LC/MS: [(M+1)]+=500.0; 1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.35 (s, 2H), 7.85-7.94 (m, 1H), 7.43-7.54 (m, 1H), 5.14-5.27 (m, 1H), 4.01-4.60 (m, 5H), 3.13-3.95 (m, 6H), 2.53 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19]([O:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:4]=1>O1CCOCC1.CO>[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:4]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(C(=O)OC(C)(C)C)CC3)CC4)nc(N)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 mL of 4 N HCl in 1,4-dioxane was added to a solution of 1-(tert-butoxycarbonyl)piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.10 g, 0.18 mmol) in methanol (1.0 mL). The reaction mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford the product as an HCl salt. Analytic LCMS (M+H)+: m/z=452.2.