Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([O:24][CH2:25]Cl)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[C:17]([O:24][CH2:25][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(=O)OCCl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(=O)OCn1cc(F)c(=O)[nH]c1=O
Yield: 40.5 %

Procedure:
Using a reactor similar to that used in Example 1, 3.90 g (0.03 mol) of 5-fluorouracil was dissolved in 50 ml of dimethylformamide. Then, 3.0 g of triethylamine was added to this solution. To the mixture was added dropwise 4.73 g (0.0287 mol) of caproyloxymethyl chloride. The mixture was reacted for 3 hours at 50° C. After completion of the reaction, the reaction liquid was filtered to remove the precipitated triethylamine hydrochloride and then the dimethylformamide was removed by distillation from the filtrate. Next, 50 ml of chloroform was added to the residue and the mixture was stirred and filtered to remove insoluble unreacted 5-fluorouracil. The chloroform phase was washed with water and then dried. By removing the chloroform by distillation, 3.0 g of 1-caproyloxymethyl-5-fluorouracil was obtained as white crystals having a melting point of 95°~96° C. in a yield of 38.7%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)[N:10]=2)[CH:7]=1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)cn3nc(N)nc23)cc1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cc(F)cn4n3)cc2)CC1

Procedure:
[6-Fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 6-fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(4-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as an orange solid (23% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.45 (s, 1H), 8.26 (d, J=8.0 Hz, 2H), 8.11 (d, J=7.7 Hz, 2H), 7.58 (d, J=9.0 Hz, 1H), 7.48 (dd, J=11.5 Hz, 7.8 Hz, 2H), 6.98 (d, J=7.9 Hz, 2H), 6.76 (s, 1H), 3.27 (bm, 4H), 3.12 (s, 3H), 2.62 (bm, 4H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4OC(C=O)=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[C:33]([F:36])([F:35])[F:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([CH2:41][CH2:42][NH2:43])(=[O:40])=[O:39].[C:44]([OH:47])(=O)[CH3:45].C([BH3-])#N.[Na+]>ClCCl.C(OCC)(=O)C>[F:36][C:33]([F:34])([F:35])[C:10]1[CH:11]=[C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[CH:27]=[CH:28][O:47][C:44]=4[CH2:45][NH:43][CH2:42][CH2:41][S:38]([CH3:37])(=[O:40])=[O:39])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: CC(=O)O
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)c(C(F)(F)F)c4)c3c2)o1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)CCNCc1occc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)c(C(F)(F)F)c3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
The mixture of 5-(4-(4-benzyloxy-3-trifluoromethylphenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde (211 mg, 0.40 mmol), 2-methanesulphonyl-ethylamine (99 mg, 2.0 mmol), acetic acid (0.5 ml) in dichloromethane (15 ml) was stirred at room temperature for 1.5 hours then was heated to reflux for 1 hour. The mixture was cooled to 0° C. with ice bath. Sodium cyanoborohydride (50 mg, 0.8 mmol) was added at 0° C. The reaction mixture then was stirred at room temperature for 1 hour. Diluted with ethyl acetate (50 ml), then quenched with saturated sodium bicarbonate solution slowly. Extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the resulting residue was accomplished using flash chromatography on silica gel with 2% methanol in ethyl acetate which afforded a yellow solid (0.10 g, 43% yield). H1 NMR (400 MHz, DMSO). δ10.0 (s, 1H), 8.7 (s, 1H), 8.5 (s, 1H), 8.1 (d, 1H), 8.1 (s, 2H), 7.8 (d, 1H), 7.4 (m, 5H), 7.3 (m, 1H), 7.0 (d, 1H), 6.5 (d, 1H), 5.3 (s, 2H), 3.8 (s, 2H), 3.2 (m, 2H), 3.0 (s, 3H), 2.9 (m, 2H). ESI-MS m/z 597 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[CH3:28][CH:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[CH3:30].[OH-].[Na+]>O>[ClH:1].[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:42][C:39]4[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][CH2:33][CH2:32][NH:31][CH:29]([CH3:28])[CH3:30])=[CH:37][CH:38]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CC(C)NCCCCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)NCCCCc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Product: Cl
Yield: 127.4 %

Procedure:
A solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (10 g) and 4-[4-(1-methylethyl)aminobutyl]phenol (4.9 g) was stirred at 55° under nitrogen and a solution of sodium hydroxide (0.94 g) in water (7 ml) was added. The reaction was stirred and heated at 55°-65° for 5 hours. The usual work-up yielded the crude trihydrochloride salt. Crystallization of the product from methanol-ethanol yielded 5.3 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2-[4-[4-(1-methylethyl)aminobutyl]phenoxy]ethyl]piperazine trihydrochloride, mp 245°-248°.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12].[CH3:23][C:24]1[C:25]([CH2:31][N:32]([CH2:39][C:40]2[C:45]([CH:46]([CH3:48])[CH3:47])=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:11]([N:36]1[CH2:37][CH2:38][CH:33]([N:32]([CH2:31][C:25]2[C:24]([CH3:23])=[CH:29][C:28]([CH3:30])=[CH:27][N:26]=2)[CH2:39][C:40]2[C:45]([CH:46]([CH3:48])[CH3:47])=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:34][CH2:35]1)=[O:12]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C(=O)Nc3nc4ccccc4[nH]3)CC2)c(C)c1

Procedure:
To a suspension of 2-aminobenzimidazole (81 mg, 0.61 mmol) in CH2Cl2 (5 mL) and DMF (0.5 mL) was added 1,1′-carbonyldiimidazole (99 mg, 0.61 mmol) and the reaction stirred at reflux for 30 min. then at room temperature for 2 h after which a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidine-4-yl-amine (109 mg, 0.31 mmol) in DMF (1 mL) was added and the reaction stirred at 65° C. overnight. The solution was cooled, treated with saturated aqueous NaHCO3 (25 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were washed with brine (1×30 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:1:1 then 50:1:1 then 25:1:1) provided
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:29])[CH:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:16][OH:17])=[CH:9][CH:8]=1)=[O:5])[CH3:2].[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:29])[CH:15]([NH:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH2:16][O:17][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(F)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-hydroxypropanamide (1.88 g) was reacted with mesyl chloride to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (1.70 g).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=O)[CH2:2]2.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([C:19]2([NH2:22])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([CH2:9][C:10]([NH:22][C:19]1([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)[CH2:20][CH2:21]1)=[O:12])[CH2:2]2
Reactant: O=C(O)CC1CN2CCC1CC2
Reactant: Cc1ccc(C2(N)CC2)cc1
Product: Cc1ccc(C2(NC(=O)CC3CN4CCC3CC4)CC2)cc1
Yield: 20.1 %

Procedure:
Using general procedure I, 2-(quinuclidin-3-yl)acetic acid (169 mg, 1.00 mmol) and 1-p-tolylcyclopropanamine (149 mg, 1.10 mmol) gave the title compound as a white solid (60 mg, 18%). 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 6.96-7.07 (m, 4H), 3.22-3.37 (m, 2H), 2.85-3.05 (m, 4H), 2.39-2.45 (m, 2H), 2.21 (s, 3H), 1.45-1.92 (m, 5H), 1.07-1.23 (m, 5H) ppm. 13C NMR (400 MHz, CDCl3) δ 171.6, 139.8, 136.1, 129.2, 125.6, 52.1, 50.9, 46.5, 46.0, 39.2, 34.9, 30.8, 24.5, 21.1, 18.7, 17.6 ppm. Purity: 96.2% HPLCMS (210 nm); retention time 1.21 min; (M+1) 299.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.ClCCl>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][S:12]([C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:2]([F:1])=[CH:3][CH:4]=2)(=[O:14])=[O:13])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=S(=O)(Cl)c1ccc(F)c2c1CCCC2
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3c2CCCC3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Fluoro-5,6,7,8-tetrahydro-naphthalene-1-sulfonyl chloride (860 mg, 3.46 mmol) was dissolved in THF (10 mL). Triethylamine (350 mg, 0.49 mg, 3.46 mmol) was added, followed by 4-amino-piperidine-1-carboxylic acid tert-butyl ester (694 mg, 3.46 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was diluted with dichloromethane (50 mL) and charged to a separatory funnel. The organic layer was washed with water and brine, then dried over MgSO4. Filtration and concentration in vacuo afforded a yellow foam. Wt.: 1.35 g (95%). 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, 1H), 6.95 (t, 1H), 4.47 (d, 1H), 3.93 (m, 2H), 3.27 (m, 1H), 3.11 (m, 2H), 2.76 (m, 4H), 1.81 (m, 6H), 1.44 (s, 9H), 1.32 (m, 2H); LC/MS m/z 411 (M−H)−.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9](N2C=C(C)C(=O)NC2=O)[CH2:8][C@@H:7]1[F:20])(=O)C.[F:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24]([NH2:31])[N:23]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(#N)C>[F:20][C@@H:7]1[C@@H:6]([CH2:5][OH:4])[O:10][C@@H:9]([N:28]2[CH:27]=[N:26][C:25]3[C:29]2=[N:30][C:22]([F:21])=[N:23][C:24]=3[NH2:31])[CH2:8]1
Reactant: Nc1nc(F)nc2nc[nH]c12
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1F
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC#N
Product: Nc1nc(F)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1

Procedure:
A mixture of 2.88 g (10 mMoles) 1-(5-O-acetyl-2,3-dideoxy-3-fluoro-β-D-ribofuranosyl) thymine, 4.6 g (30 mMoles) 2-fluoroadenine, 7.4 ml bistrimethylsilyl acetamide, and 250 ml acetonitrile was heated on reflux for 25 minutes. Subsequently, 6.5 ml (33 mMoles) trifluoromethanesulfonic acid trimethyl ester was added and the reaction mixture heated on reflux for further 8 hours. After removal of the solvent under vacuum the residue was suspended in 100 ml chloroform and neutralized with NaHCO3 solution. The organic phase was dried over sodium sulfate filtered and the chloroform removed under vacuum. The residue was separated by column chromatography on silica gel, eluting with chloroform (1 l of 5% n-hexane; 15 l of 2.5% n-hexane; 1 l of 1% n-hexane). The obtained mixture was deacetylated in a conventional manner by means of ammonia/methanol and was subjected to column chromatographic separation. Chloroform (1% methanol) was used as eluent. 0.51 g was isolated of the β anomer, the title compound. Further compound remained in the mixture with the α anomer.
Reaction SMILES: CC1C=CN=CC=1C1C=CC=C2C=1C=NN2.I[C:18]1[C:19]([O:24][CH3:25])=[N:20][CH:21]=[N:22][CH:23]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1.CC1(C)C(C)(C)OB(C2C=CC([N+]([O-])=O)=CC=2C)O1>CN(C=O)C>[CH3:25][O:24][C:19]1[C:18]([C:29]2[CH:30]=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:28]=2[O:27][CH3:26])=[CH:23][N:22]=[CH:21][N:20]=1
Reactant: COc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ncncc1I
Agent: Cc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccncc1-c1cccc2[nH]ncc12
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1-c1cncnc1OC
Yield: 25 %

Procedure:
Intermediate 30B was prepared by the procedure described for the preparation of Intermediate 1C using Intermediate 30A and 2-(2-methoxy-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared by the procedure described for the preparation of Intermediate 26A), and was obtained as a gummy yellow solid. The solid was dissolved in DMF and purified by reverse phase preparative HPLC (PHENOMENEX® Luna 30×100 mm column with a linear gradient of Solvent A (10% methanol/90% water with 0.1% TFA) and Solvent B (90% methanol/10% water with 0.1% TFA) over 12 min; monitored at 254 nM). The collected fractions were then applied to a 1 g Waters OASIS® MCX cation exchange cartridge, which was washed with methanol, and the product was then eluted off with 15 mL of 2 M ammonia in methanol. Evaporation of the collected eluent provided Intermediate 30B (46 mg, 25% yield) as a solid. HPLC Ret timed: 1.34 min. MS: m/z=262 [M+H]+; 1H NMR (500 MHz, CD3OD) δ ppm 8.48 (s, 1 H), 8.05 (s, 1 H), 7.94-7.90 (m, 2 H), 7.57 (d, 1 H), 3.93 (s, 3 H), 3.61 (s, 3 H).
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([O:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Oc1ccccc1)N1CCNCC1
Reaction time: 12 h

Procedure:
Crude piperazine-1,4-dicarboxylic acid tert-butyl ester phenyl ester was dissolved in 10 ml dichloromethane and treated with 4 ml TFA. After stirring for 12 h the solution was concentrated and the residue codistilled twice with toluene. Yield: 3.0 g.
Reaction SMILES: C[C:2](C(C)CC1C=CC=CC=1)([C@H:6]1[CH2:11][C@@H:10]([CH2:12]S(C2N(C3C=CC=CC=3)N=NN=2)(=O)=O)[O:9][C:8]([CH3:28])([CH3:27])[O:7]1)[C:3]([O-:5])=[O:4].[F:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:50]([CH:51]=O)=[C:49]([CH:53]([CH3:55])[CH3:54])[N:48]=[C:47]([N:56]([CH3:61])[S:57]([CH3:60])(=[O:59])=[O:58])N=2)=[CH:41][CH:40]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+:73]>O1CCCC1.C(OCC)(=O)C>[F:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[C:50](/[CH:51]=[CH:12]/[C@H:10]3[O:9][C:8]([CH3:27])([CH3:28])[O:7][C@@H:6]([CH2:2][C:3]([O:5][C:50]([CH3:51])([CH3:49])[CH2:45][C:42]4[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=4)=[O:4])[CH2:11]3)=[C:49]([CH:53]([CH3:54])[CH3:55])[N:48]=[C:47]([N:56]([CH3:61])[S:57]([CH3:60])(=[O:58])=[O:59])[N:73]=2)=[CH:43][CH:44]=1
Reactant: CC(Cc1ccccc1)C(C)(C(=O)[O-])[C@H]1C[C@@H](CS(=O)(=O)c2nnnn2-c2ccccc2)OC(C)(C)O1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C=O
Reactant: [NH4+]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@H](CC(=O)OC(C)(C)Cc2ccccc2)OC(C)(C)O1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
2-methyl-1-phenylpropan-2-yl-2-((4R,6S)-2,2-dimethyl-6-((1-phenyl-1H-tetrazol-5-ylsulfonyl)methyl)-1,3-dioxan-4-yl)acetate (25.75 g) prepared in Example 15 and N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (15.55 g) were dissolved in tetrahydrofuran (60 ml), followed by cooling to −78° C. under an argon atmosphere, and lithium bis(trimethylsilyl)amide (120 ml of a 0.5M solution in tetrahydrofuran) was added thereto over 10 minutes, followed by stirring at the same temperature for 2 hours. Then, the mixture was stirred for 4 hours while warming to 0° C. A saturated ammonium chloride aqueous solution (250 ml) was added to the reaction liquid, followed by stirring for 10 minutes, and ethyl acetate (500 ml) was added thereto. The organic layer was separated and washed successively with purified water (250 ml), a saturated sodium bicarbonate aqueous solution (250 ml,) and a saturated sodium chloride aqueous solution (250 ml), dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting solid was stirred with isopropyl ether, filtered and collected. This solid was dried in a vacuum oven overnight (50° C., 200 mbar) to give the title compound (26.06 g, 90%).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[NH2:33].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:21]=[CH:20][C:19]=1[NH2:33]
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Reactant: Ic1cnc2cc(-c3ccncc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1Cl
Yield: 46 %

Procedure:
Combine 3-iodo-7-pyridin-4-yl-imidazo[1,2-a]pyridine (2.18 g, 6.8 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (crude material from previous step, excess), potassium carbonate (2.8 g, 3 equiv.), dioxane (30 mL), and water (15 mL). De-gas thoroughly with nitrogen then add dichloro-bis(triphenylphosphine) palladium (II) (0.143 g, 3 mol %). Heat reaction at 80° C. overnight. Concentrate to dryness then slurry in DCM and filter via Celite®, washing with DCM. Concentrate filtrate then purify by silica plug (Hexanes→1:1 Hexanes:Ethyl Acetate→2.5% Methanol:DCM→5% Methanol:DCM) to give an orange-yellow solid (1.42 g, 46%). MS (ES), m/z 321.1 (M+1).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]2[O:38][C:39]([CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:40][CH:41]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)=[CH:40][CH:41]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:21])([CH3:23])[CH3:22]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)o2)c2ccccc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(-c3ccc(CN4CCOCC4)o3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-[5-(morpholin-4-ylmethyl)fur-2-yl]naphthalene (26 mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:14]C(=O)CC)(=[O:13])[CH2:11][CH3:12].C([O-])(=O)CC.[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([CH3:12])[C:10]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCC(=O)OC(=O)CC
Agent: CCC(=O)[O-]
Agent: [Na+]
Product: CC(=Cc1ccc(F)cc1)C(=O)O
Temperature: 140 °C
Reaction time: 20 h

Procedure:
p-Fluorobenzaldehyde (200 g, 1.61 mol), propionic anhydride (3.5 g, 2.42 mol) and sodium propionate (155 g, 1.61 mol) are mixed in a one liter three-necked flask which had been flushed with nitrogen. The flask is heated gradually in an oil-bath to 140° C. After 20 hours, the flask is cooled to 100° C. and poured into 8 l of water. The precipitate is dissolved by adding potassium hydroxide (302 g) in 2 l of water. The aqueous solution is extracted with ether, and the ether extracts are washed with potassium hydroxide solution. The combined aqueous layers are filtered, are acidified with concentrated HCl, and are filtered. The collected solid, p-fluoro-α-methylcinnamic acid, is washed with water, and is dried and used as obtained.
Reaction SMILES: [C:1]([C:9]1[CH:15]=[C:14]2[O:16][CH2:17][O:18][C:13]2=[CH:12][C:10]=1[NH2:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[O:20]([C:22]#[N:23])[Na]>CC(O)=O>[CH2:17]1[O:18][C:13]2[CH:12]=[C:10]3[C:9]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:23][C:22](=[O:20])[NH:11]3)=[CH:15][C:14]=2[O:16]1
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1)OCO2
Reactant: N#CO[Na]
Solvent: CC(=O)O
Solvent: O
Product: O=c1nc(-c2ccccc2)c2cc3c(cc2[nH]1)OCO3
Temperature: 10 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of 2-benzoyl-4,5-(methylenedioxy)aniline (200 mg) in AcOH (10 mL) was added water (1 mL) and NaOCN (64 mg) at 10° C. The mixture was stirred at 10° C. for 1 h, then at rt for 2 h. Water (70 mL) was added to the mixture. The resulting yellow solid was collected by filtration, washed with water and 3:2 hexane/EtOAc, recrystallized from DMSO/water to yield the title compound as a yellow solid (104 mg, 47%), mp: 351-354° C. 1H NMR (DMSO-d6): 11.86 (s, 1H), 7.63-7.58 (m, 5H), 6.94 (s, 1H), 6.85 (s, 1H), 6.16 (s, 2H). Anal. calcd. for C15H10N2O3: C, 67.67; H, 3.79; N, 10.52. Found: C, 67.53; H, 3.76; N, 10.29.