Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1.C(O)(=O)C.C(O)(=O)C.C(N)CN.S([O-])(O)=O.[Na+]>CO>[O:1]=[C:2]1[C:6](=[CH:31][C:29]2[O:30][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:33])([F:18])[F:34])[CH:21]=3)=[CH:27][CH:28]=2)[S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1
Reactant: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: NCCN
Product: O=C(O)c1ccccc1NN1C(=O)C(=Cc2ccc(-c3cccc(C(F)(F)F)c3)o2)SC1=S
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
A mixture of 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (0.090 g, 0.34 mmol), 5-(3-trifluoromethyl-phenyl)-furan-2-carbaldehyde (0.086 g, 0.36 mmol) (purchased from Aldrich Chemical Company) and ethylenediamine diacetate (0.065 g, 0.036 mmol) in methanol (8 mL) was stirred at room temperature for 17 h. The reaction mixture was poured into stirred 0.6 N aq sodium hydrogensulfite (50 mL). The mixture was vigorously stirred for 15 mm. The solid product was filtered off and washed on funnel successively with 0.6 N aq sodium hydrogensulfite (2 mL), water (2×2 mL), ether (2 mL) and hexanes (2 mL). The material was dried in a vacuum oven at 65° C. for 19 h to afford 2-{4-Oxo-2-thioxo-5-[1-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-methylidene]-thiazolidin-3-ylamino}-benzoic acid (130 mg, 79%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 6.53 (1H, m), 6.86 (1H, m), 7.29 (1H, m), 7.43 (1H, d, J=3.6 Hz), 7.59 (1H, d, J=3.6 Hz), 7.78 (1H, s), 7.82 (2H, m), 7.92 (1H, m), 8.16 (1H, m), 8.21 (1H, m). LC/MS: APCI 489.3, HPLC 97.1%
Reaction SMILES: [OH-].[K+].[I:3]I.[N+:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)([O-:7])=[O:6].C(=O)([O-])O.[Na+]>CN(C=O)C>[I:3][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)[NH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: II
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Potassium hydroxide (6.45 g) and iodine (15.6 g) were added to a DMF (60 ml) solution containing 5-nitroindazole (5.0 g), followed by stirring at 65° C. for 1 hour. The reaction solution was adjusted to room temperature and poured into a saturated aqueous sodium hydrogen carbonate solution, a solid precipitate was collected by filtration, and a yellow solid of 3-iodo-5-nitro-1H-indazole (6.83 g) was thus obtained.
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:8]=3[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([CH2:21]P(=O)(OCC)OCC)#[N:20]>>[Br:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:8]=3[CH:7]([CH2:21][C:19]#[N:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1ccc2c(=O)c3cccc(Br)c3ccc2c1
Product: Cc1ccc2c(c1)C=Cc1c(Br)cccc1C2CC#N
Yield: 69 %

Procedure:
The same procedure as in Step A of Example 2 was repeated using 0.86 g of 1-bromo-8-methyl-5-oxo-5H-dibenzo[a,d]cycloheptene and 1.4 ml of diethyl (cyanomethyl)phosphonate to give 0.64 g (69%) of the product as an oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[NH2:14][CH2:15][C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[OH:17].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:24][C:20]1[CH:19]=[C:18]([C@@H:16]([OH:17])[CH2:15][NH:14][C:10](=[O:12])[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(O)cc1)NC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
To a mixture of 3-(4-hydroxyphenyl)propanoic acid (15.0 g), (1R)-2-amino-1-(3-chlorophenyl)ethanol hydrochloride (18.8 g), and 1-hydroxybenzotriazole (14.6 g) in N,N-dimethylformamide (100 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.0 g), and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed successively with sodium bicarbonate solution and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-3-(4-hydroxyphenyl)propanamide (11.61 g) as a white amorphous powder.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[S:16])[NH2:15])=[CH:4]1)[CH3:2].CO[CH:19](OC)[CH2:20]Br>C(COC)OC>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[S:16][CH:19]=[CH:20][N:15]=2)=[CH:4]1)[CH3:2]
Reactant: COC(CBr)OC
Reactant: CCn1cc(C(N)=S)c2ccc(OC)cc21
Solvent: COCCOC
Product: CCn1cc(-c2nccs2)c2ccc(OC)cc21
Temperature: 80 °C
Yield: 47.3 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-thiocarboxamide (83 mg, 0.36 mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 μL, 1.86 mmol) were heated at 80° C. for 16 h. More bromoacetaldehyde dimethyl acetal (250 μL was added. This was heated at 80° C. for 2 h. Addition of 250 μL more bromoacetaldehyde dimethyl acetal was followed by heating for another 2 hours. The reaction mixture was cooled to room temperature, absorbed onto silica and purified by silica gel chromatography (hexanes/EtOAc, 7/3) to afford 1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole as a brown oil (44 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15]([O:17]CC)=O)=[C:12]([CH3:14])[N:13]=1.O.[NH2:21][NH2:22]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15]([NH:21][NH2:22])=[O:17])=[C:12]([CH3:14])[N:13]=1
Reactant: NN
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2Cl)nc1C
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccc(Cl)cc2Cl)sc1C(=O)NN
Yield: 88.3 %

Procedure:
Ethyl 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate (250 mg) prepared in the Step 23-1-1 was dissolved in ethanol (10 ml), and hydrazine monohydrate (794 mg) was added thereto. The mixture was heated under reflux for 23 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration, washed with water, and dried to give 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylic acid hydrazide (211 mg, 88%).
Reaction SMILES: C(OC(N[C@H](C(O)=O)C(C)C)=O)(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.C(N)C1C=CC=CC=1.C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:73][C:74]([C:76]1([NH:81][C:82]([CH:84]2[CH2:88][CH:87]([O:89][C:90]3[C:99]4[C:94](=[CH:95][C:96]([O:100][CH3:101])=[CH:97][CH:98]=4)[N:93]=[C:92]([C:102]4[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=4)[CH:91]=3)[CH2:86][N:85]2[C:108](=[O:128])[NH:109][CH:110]([C:115](=[O:127])[NH:116][CH:117]2[C:125]3[C:120](=[CH:121][CH:122]=[CH:123][CH:124]=3)CC2O)[C:111](C)([CH3:113])[CH3:112])=[O:83])[CH2:78][CH:77]1[CH:79]=[CH2:80])=[O:75])C>>[CH2:117]([NH:116][C:115]([C@@H:110]([NH:109][C:108]([N:85]1[CH2:86][C@H:87]([O:89][C:90]2[C:99]3[C:94](=[CH:95][C:96]([O:100][CH3:101])=[CH:97][CH:98]=3)[N:93]=[C:92]([C:102]3[CH:103]=[CH:104][CH:105]=[CH:106][CH:107]=3)[CH:91]=2)[CH2:88][C@H:84]1[C:82]([NH:81][C@:76]1([C:74]([OH:75])=[O:73])[CH2:78][C@H:77]1[CH:79]=[CH2:80])=[O:83])=[O:128])[CH:111]([CH3:113])[CH3:112])=[O:127])[C:125]1[CH:120]=[CH:121][CH:122]=[CH:123][CH:124]=1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: NCc1ccccc1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)NCc1ccccc1)C(C)C)C(=O)O

Procedure:
N-(tert-butoxycarbonyl)-L-valine was attached to the resin as described for the preparation of compound 16 followed by reaction with benzylamine as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC>95%. M+H+706.2.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C@H:18]4[O:23][CH2:22][CH2:21][N:20]([C:24]5[N:29]=[CH:28][C:27]([C:30]6[CH:31]=[N:32][N:33]([CH:35]7[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]7)[CH:34]=6)=[CH:26][N:25]=5)[CH2:19]4)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1.Br[CH2:42][CH2:43][OH:44].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C@@H:18]4[CH2:19][N:20]([C:24]5[N:29]=[CH:28][C:27]([C:30]6[CH:31]=[N:32][N:33]([CH:35]7[CH2:40][CH2:39][N:38]([CH2:42][CH2:43][OH:44])[CH2:37][CH2:36]7)[CH:34]=6)=[CH:26][N:25]=5)[CH2:21][CH2:22][O:23]4)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(C7CCNCC7)c6)cn5)CCO4)c3n2)cn1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(C7CCN(CCO)CC7)c6)cn5)CCO4)c3n2)cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 144.3 %

Procedure:
(S)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)morpholine HCl salt 20 mg (0.04 mmol) was dissolved in dimethylformamide 1 ml, and 2-bromoethanol 6.6 mg (0.05 mmol) and K2CO3 15 mg (0.11 mmol) were added and then charged with nitrogen, followed by stirring at 60° C. for 4 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to remove dimethylformamide, followed by extraction with EA and brine, and the organic layer was dried over MgSO4. Separation by column chromatography (methylene chloride:methanol=10:1) gave a product 33 mg (65%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[N:35]([CH3:43])[CH:34]=2)[CH2:29]1>>[F:42][C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:43])[CH:34]=[C:33]2[CH2:32][CH:30]1[CH2:31][N:28]([CH2:16][CH:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:29]1
Reactant: Cn1cc(CC2CNC2)c2cc(F)ccc21
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cc2cn(C)c4ccc(F)cc24)C1)O3

Procedure:
This compound was prepared as described for Example 2, using (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.24 g, 0.53 mmol), 3-azetidin-3-ylmethyl-5-fluoro-1-methyl-1H-indole (0.12 g, 0.53 mmol), to afford 0.65 g of the (S)-enantiomer of the title compound as a light brown oil. The oxalate was prepared in methanol and collected as 0.047 g of a yellow solid, m.p. 193-195° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11](O)=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([O:31][CH2:32][CH2:33][NH2:34])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:29]([O:31][CH2:32][CH2:33][NH:34][C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=1)=[O:12])[CH3:30]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Reactant: CCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 59.1 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-ethoxy-ethyl)-amide (52 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (75 mg), 2-ethoxyethylamine (18 mg), HBTU (83 mg), and DIEA (48 uL). LC/MS: m/z 480.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.41 (bs, 1H), 8.47 (t, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.76 (d, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 3.66 (s, 3H), 3.56-3.39 (m, 6H), 1.13 (t, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][Br:7].[P:8](OCC)([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9]>>[Br:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][P:8](=[O:9])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: BrCCOCCBr
Reactant: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(CCOCCBr)OCC
Temperature: 160 °C

Procedure:
1-bromo-2-(2-bromoethoxy)ethane (1.0 eq) was mixed with triethyl phosphate (1 eq) then heated to 160° C. for 20 minutes by microwave. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 70-100% EtOAc/Hex to give the product as a colorless oil.
Reaction SMILES: ClC1C(=O)C(=O)C(Cl)=C(Cl)C=1Cl.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[CH2:20][CH:19]=[CH:18]2>C(OCC)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([CH3:25])=[CH:20][CH:19]=[CH:18]2
Reactant: COc1ccc2c(c1)C=CCC2C
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: CCOCC
Product: COc1ccc2c(C)cccc2c1
Yield: 52.8 %

Procedure:
Tetrachloro-1,2-benzoquinone (3.6 g, 14.5 mmol) was added in one portion to a stirred solution of 6-methoxy-1-methyl-1,2-dihydronaphthalene (2.3 g, 13.2 mmol) in diethyl ether (20 ml). The reaction was concetrated down after 24h and purified by column chromatography using petroleum ether as eluent to gave the title compound as a white solid (1.2 g, 53%). 1H-NMR (250 MHz, CDCl3) 2.5 (s, 3H), 3.8 (s, 3H), 7.0-7.8 (m, 6H), 13C-NMR (250 MHz, CDCl3) 19.3, 55.2, 106.5, 118.1, 124.4, 125.2, 125.7, 126.2, 128.0, 134.2. 134.7, 157.3; Mass Spectrum (M+1) m/e=173.
Reaction SMILES: S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].Cl.Cl.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([NH2:20])[C:14]=1[NH2:21].Cl.[CH3:23][C:24]1[C:29]([CH:30]=O)=[CH:28][N:27]=[C:26]([NH:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:12][C:13]1[C:14]2[N:21]=[C:30]([C:29]3[C:24]([CH3:23])=[N:25][C:26]([NH:32][CH2:33][CH2:34][CH2:35][CH:36]4[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]4)=[N:27][CH:28]=3)[NH:20][C:15]=2[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Reactant: Cc1cc(C)c(N)c(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Product: Cc1cc(C)c2nc(-c3cnc(NCCCC4CCN(C)CC4)nc3C)[nH]c2c1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
In a 100 L glass-lined reactor, sodium metabisulfite (Na2S2O5) (1.96 kg, 9.79 mol) was dissolved in purified water (54.63 kg), followed by the addition of 3,5-dimethyl-1,2-benzenediamine-2HCl (2.07 kg, 9.86 mol) and the resultant mixture stirred at about 20-25° C. to effect solution. Next, concentrated hydrochloric acid (1.65 kg, 16.79 mol) was added, followed by addition of 4-methyl-2-((3-(1-methylpiperidin-4-yl)propyl)amino)pyrimidine-5-carbaldehyde, prepared as in STEP B above (2.74 kg, 9.79 mol) and the resultant mixture stirred at about 23-27° C. to effect solution. The resultant mixture was heated to about 57-62° C. and monitored for completion by HPLC. The reaction mixture was cooled to about 20-25° C. and then half of the volume (˜30 L) was then added, via a metering pump, to a stirring 50 L glass reactor system containing a solution of potassium carbonate (3.9 kg, 28.2 mol) dissolved in purified water (15 kg), resulting in the formation of a precipitate. The precipitated product was stirred for ˜1 h and then allowed to settle. The clear supernatant (˜20 L) was removed from the top of the 50 L reactor system and purified water (˜20 kg) was added. The resultant mixture was stirred for 10 min, filtered, washed with water (13 kg) and dried at 35-40° C. under vacuum to yield solid [5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine, compound 2. MS: [M+H]2=393, 1H NMR (600 MHz, Methanol-d6) δ, 1.38-1.43 (m, 2H), 1.43-1.52 (m, 2H), 1.53-1.61 (br m, 1H), 1.64-1.71 (m, 2H), 1.90-1.96 (br m, 2H), 2.42 (s, 3H), 2.53 (s, 3H), 2.54 (s, 3H), 2.74 (s, 3H), 2.78-2.86 (br m, 2H), 3.15-3.36 (m, 2H), 3.36-3.47 (m, 2H) 4.35 (s, 1H), 6.90 (s, 1H), 7.20 (s, 1H), 8.44 (br s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([OH:12])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>CN(C)C=O>[C:3]1([CH:9]([O:12][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#CC(O)c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(OCC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a stirred suspension of NaH (60%, 76 mg, 1.89 mmol) in 5 mL of anhydrous N,N-dimethylformamide was added 1-phenylprop-2-yn-1-ol (250 mg, 1.89 mmol). After 15 min at room temperature, methyl bromoacetate (179 μL, 1.89 mmol) was added. The resulting mixture was stirred at room temperature for 90 min before it was quenched with saturated ammonium chloride and extracted with ethyl acetate (2×15 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuuo. The residue was purified by flash chromatography oh silica gel, eluting with ethyl acetate:hexane (1:9), to provide the title compound as a colorless oil (160 mg, 41% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@@H:7]2[C@@H:11]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:10]3[C:9](=[O:17])[O:8]2)[CH2:4][O:3]1.[Si]([C:23]([F:26])([F:25])[F:24])(C)(C)C.[F-].C([N+](CC)(CC)CC)C>C1COCC1.O>[CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@@H:7]2[C@@H:11]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:10]3[C:9]([C:23]([F:26])([F:25])[F:24])([OH:17])[O:8]2)[CH2:4][O:3]1
Reactant: CC1(C)O[C@H]2[C@@H]([C@H]3COC(C)(C)O3)OC(=O)[C@H]2O1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC[C@H]([C@H]2OC(O)(C(F)(F)F)[C@H]3OC(C)(C)O[C@@H]23)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 1000 mL three neck round bottom flask, a solution of (3aS,6R,6aS)-6-((R)-2, 2-dimethyl-1, 3-dioxolan-4-yl)-2, 2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (30 g, 116.2 mmol, 1eq) in THF (600 mL) was treated with TMSCF3 (2M in THF, 122 mL, 244 mmol, commercially available from Sigma Aldrich, India) and tetraethylammonium fluoride (TEAF, 2.48 g, 23.24 mmol, Apollo scientific, UK) at rt under a nitrogen atmosphere. The reaction mixture was stirred at rt for 30 minutes and additional TEAF (24.8 g, 232.4 mmol, Apollo scientific, UK) was added to the reaction mixture. The resulting reaction mixture was stirred at rt for 12 h under a nitrogen atmosphere. Upon completion of the reaction (TLC, 30% EtOAc-hexanes, Rf 0.6), the reaction mixture was diluted with water (1000 mL), and it was then extracted with EtOAc (500 mL×2). The combined organic extracts were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure. The residue obtained was purified by silica gel (60-120 mesh) column chromatography (gradient elution, 5-10% EtOAc-hexanes) to give (3aS,6R,6aS)-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-4-(trifluoromethyl)tetrahydrofuro[3,4-d][1,3]-dioxol-4-ol, as a yellow semi solid mixture of two isomers (27.3 g, 71.8%): 1H NMR (400 MHz, CDCl3) δ 4.95 (m, 2H), 4.78 (d, J=8 Hz, 1H), 4.61-4.32 (m, 2H), 4.23 (dd, J=8, 4 Hz, 1H), 4.18-4.10 (m, 3H), 4.06 (dd, J=8.0, 4.0 Hz, 2H), 3.98 (m, 1H), 1.52 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H); 19F NMR (376.17 MHz, CDCl3) δ −78.24 & −82.32 ppm.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)=[CH:11][C:10]=1[CH2:28][CH2:29][CH3:30])([O:5]C)=[O:4]>CO.C(Cl)Cl>[C:3]([CH:7]([C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)=[CH:11][C:10]=1[CH2:28][CH2:29][CH3:30])([OH:5])=[O:4]
Reactant: CCCc1cc(Cn2cnc3ccncc32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(Cn2cnc3ccncc32)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 75.6 %

Procedure:
A 5N sodium hydroxide solution (0.1 mL) was added to a stirred mixture of the product of Step A (19 mg, 0.038 mmol) in methanol (1 mL). A few drops of methylene chloride were added to allow stirring then the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo then 5% citric acid solution added. The mixture was extracted with ethyl acetate (3×30 mL), washed water, brine, dried (magnesium sulfate), and the solvent was removed in vacuo to give the titled compound (14 mg).
Reaction SMILES: ClC(OC(Cl)=O)C.C([N:15]([CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:16][CH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=2)=[CH:20][CH:19]=1)C1C=CC=CC=1.ClCCCl.N>CO>[C:37]1([CH2:36][CH2:35][CH2:34][NH:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)=[CH:32][CH:33]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCN(CCCc3ccccc3)Cc3ccccc3)cc2)nc1
Agent: CC(Cl)OC(=O)Cl
Agent: N
Solvent: ClCCCl
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CCNCCCc3ccccc3)cc2)nc1
Yield: 66.9 %

Procedure:
Add 1-chloroethylchloroformate (0.056 mL, 0.52 mmol) to a stirred solution of 6-(4-{2-[benzyl-(3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide (0.1211 g, 0.2603 mmol) (Example 3) and 1,2-dichloroethane (5 mL). Heat the reaction to reflux under nitrogen for 1.5 h. Add methanol (7 mL) and heat at reflux under nitrogen for 1 h. Cool the reaction to room temperature and add 2 M ammonia in methanol (5 mL). Concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 1% concentrated ammonium hydroxide/10% ethanol/chloroform to yield 0.0654 g (67%) of 6-{4-[2-(3-phenyl-propylamino)-ethyl]-phenoxy}-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 7.48 minutes, Purity: 99.2%; mass spectrum (ion spray): m/z=376.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)C>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)O)c(O)c1
Yield: 74088.5 %

Procedure:
To a stirred, refluxing suspension of 4-aminosalicylic acid (76.57 g, 0.5 mmol) in 250 mL absolute ethanol was added dropwise, over a 30 minute period, acetic anhydride (83.2 g, 0.815 mmol). After the addition was complete, the mixture was refluxed for another 15 minutes and then cooled. The product collected by filtration, washed with small amount of ethanol and dried on air to give 72.3 g (74.15%) of the title compound as a grey solid mp 242°14 4° C. Previously reported mp: 234°-5° C. (P. Barraclough et al. Eur. J. Chem. 25, p 467, 1990).