Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:10](O)=[O:11].O>C1(C)C=CC=CC=1>[N:1]1([CH:10]=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=CN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of indoline (47.4 g, 398 mmol) and formic acid (30 g, 652 mmol, 1.64 eq.) in toluene (175 mL) was heated at reflux with azeotropic removal of water. After 3 h, the reaction mixture was cooled to RT. The solution was washed with water and brine, dried over Na2SO4 and concentrated. The residue was triturated with TBME and heptanes. The precipitate was filtered off, washed with heptanes and pentane and dried in vacuo at 45° C. for 4 h. Yield: 50.46 g, (86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15]C.Cl[C:33]1C=C(Cl)C=CC=1C1N=C(C)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C.IC(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:30])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH:28]([CH3:29])[CH3:33])=[N:13][C:14]=1[CH3:15]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CC(C)I
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and 2-iodopropane, and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.50–7.46, 7.34–7.26, 5.76, 5.43, 4.47, 3.72, 3.14–3.11, 2.41, 2.26, 1.20, 1.12; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1441. Anal. Calcd for C24H25Cl2N3O: C, 65.16; H, 5.70; N, 9.50. Found: C, 65.33; H, 5.83; N, 9.34.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.Cl>[OH-].[Na+]>[CH2:19]([O:26][C:27]([NH:2][C@@H:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)O)OCc1ccccc1

Procedure:
(2S)-2-Amino-3-[4-(trifluoromethoxy)phenyl]propanoic acid hydrochloride (3 mg) prepared in Reference Example 3 (3b) was dissolved in 0.5 N sodium hydroxide (100 μL), and then (benzyloxy)carbonyl chloride (ZCl, 5 μL) was added thereto. The resulting mixture was stirred, and then water (100 μL) was added thereto. The resulting mixture was changed to acidic with 1 N hydrochloric acid (50 μL) and extracted with ethyl acetate (300 μL) to obtain the corresponding (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid. The optical purity was determined by HPLC under the following conditions.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([NH:39][NH2:40])=O)[N:32]=1>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:33]3[N:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: NNC(=O)c1cccnn1
Reactant: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Cl)c1Cl)N1CCn2c(nnc2-c2cccnn2)C1
Temperature: 120 °C
Reaction time: 0.67 h

Procedure:
4-[(2,3-Dichloro-4-fluorophenyl)carbonyl]-2-piperazinone (I34) (0.23 g, 0.790 mmol) was dissolved in Dichloromethane (DCM) (1.975 ml) and triethyloxonium tetrafluoroborate (0.180 g, 0.948 mmol) was added. The solution was left to stir under an argon atmosphere for 40 minutes. A clear solution was formed. 3-pyridazinecarbohydrazide (I23) (0.131 g, 0.948 mmol) was added and the solution was stirred under an argon atmosphere for a further 40 minutes. The solvent was removed under reduced pressure and then 1-butanol (1.975 ml) was added and the solution was left to reflux under an argon atmosphere at 120° C. for 3 hours. The reaction was followed by LCMS. The solvent was removed under reduced pressure. The crude material was purified by flash chromatography (Biotage SP4, 50 g cartridge) with a gradient of MeOH 0-10% in DCM. The solvent was removed under reduced pressure and the isolated material was purified further using MDAP. The columns were combined and the solvent removed under reduced pressure. The material was triturated with ether to afford the desired material in 27 mg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:9](=[O:21])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:8]2[C:6]3=[N:7][C:2]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:3][CH:4]=[C:5]3[CH:11]([CH3:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:9]2=[O:21])=[CH:23][CH:24]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(N2C(=O)N(c3ccc(OC)cc3)C(C)c3cnc(Cl)nc32)cc1
Product: COc1ccc(N2C(=O)N(c3ccc(OC)cc3)C(C)c3cnc(Nc4ccccc4)nc32)cc1
Temperature: 100 °C

Procedure:
The mixture of (±)-7-chloro-1,3-bis-(4-methoxy-phenyl)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.30 g; 0.72 mmol) (from Example 4a supra) and aniline (0.20 mL; 2.16 mmol) (Aldrich) was heated at 100° C. for 40 minutes. The mixture was then cooled to room temperature and triturated with hexanes. The resulting solid was dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage, 12S, dichloromethane followed by 30:70 to 50:50 ethyl acetate-hexanes gradient) to give (±)-1,3-bis-(4-methoxy-phenyl)-4-methyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.303 g; 90.1%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:1][C:2]2[C:3]([C:8]([O:10][CH2:18][C:17]3[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=3)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ncccc1O
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: O=C(OCc1ccc(Cl)cc1)c1ncccc1OCc1ccc(Cl)cc1

Procedure:
8.4 g (60 mmol) of 3-hydroxypyridine-2-carboxylic acid were alkylated (3 h, 110° C.) with 5.2 g (approximately 130 mmol, 60%) of sodium hydride and 19.3 g (120 mmol) of 4-chlorobenzyl chloride in N,N-dlmethylacetamide in analogy with Example 30a). After concentration in vacuo and extraction with Na bicarbonate solution, the residue was purified on silica gel using heptane/ethyl acetate (1:1), and 14.8 g of the product were crystallized from appropriate fractions using diisopropyl ether, m.p. 92°-94° C.
Reaction SMILES: O1[C:5]2([CH2:10]CC(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)C[CH2:6]2)OCC1.[C:28]12([CH2:38][O:39][C:40]3[C:52](Cl)=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42]([F:54])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.C1(B(O)O)CC1.C(/B1OC(C)(C)C(C)(C)O1)=C\C>>[C:28]12([CH2:38][O:39][C:40]3[C:52](/[CH:6]=[CH:5]/[CH3:10])=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42]([F:54])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3(CC2)OCCO3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: C/C=C/B1OC(C)(C)C(C)(C)O1
Agent: OB(O)C1CC1
Product: C/C=C/c1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2

Procedure:
Following the procedure as described in Example 305/306 Step 2 and making variations as required to replace tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate and to replace cyclopropylboronic acid with trans-propenylboronic acid pinacol ester, tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate was obtained as a yellowish oil (1.20 g, quant.). To a mixture of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate (0.30 g, 0.75 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. Concentration in vacuo gave the title compound as a yellowish residue (0.260 g, quant.) which was used without further purification: MS (ES+) m/z 345.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:12][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Brc1cnc(NC2CC2)nc1
Yield: 95.1 %

Procedure:
A solution of 5-bromo-2-chloropyrimidine (3.87 g, 20 mmol) and cyclopropylamine (5.7 g, 0.1 mol) in 20 mL THF was heated at 65° C. for 5 hrs in a sealed tube. The mixture was evaporated in vacuo, to the residue ethanol was added, after filtration, the cake was washed with ethanol to give 4.07 g product as a colorless solid (95.5%). 1H NMR (300 MHz, CDCl3) δ: 8.32 (2H, s), 5.58 (1H, brs), 2.72 (1H, brs), 0.82-0.84 (2H, m), 0.54 (2H, brs). LCMS: m/z [M+H]+ 214.0011.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[I:13]Cl.Cl>CO>[I:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: ClI
Agent: Cl
Solvent: CO
Product: COc1cc(OC)c(C=O)cc1I

Procedure:
Ex-35B: To a solution of 2.4-dimethoxybenzaldehye (20.0 g, 120.4 mmol) in methanol (550 mL) was added iodine monochloride (23.5 g in 60 mL methanol) dropwise over 20 min at ambient temperature. The solution was allowed to stir at this temperature. HPLC showed about 94% conversion after 3 hours. The reaction mixture was then poured into a solution of HCl (0.5M, 600 mL). The precipitate was collected by filtration, washed with water, dried in vacuo (40° C.) to give crude product of 33.02 g. The crude product was further purified by recrystallization from THF/heptane (1:1) to give 5-iodo-2,4-dimethoxybenzaldehyde as an off-white solid (27.5 g, m.p 170–172° C.). The mother liquid was concentrated to dryness. The residual material was dissolved in EtOH (100 mL) and acetone (20 mL) followed by addition of water (20 mL) to give additional product (3.12 g, m.p. 169–171° C.). Overall isolated yield of this reaction was 87.5%. 1H NMR (CDCl3) δ 10.20 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H). HRMS Calcd. for C9H9IO3: 291.9596 (M+); Found: 291.9602. Anal. Calcd. for C8H9NO3S: C, 37.01; H, 3.11; 1, 43.33; Found: C, 37.12; H, 3.15; I, 43.33.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:19][CH2:18][C:17]2[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=2[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](OC1CC=C2C(CCC(=O)N2)C1)(=O)[C:22]1C=CC=C[CH:23]=1.C(I)CC.[H-].[Na+]>>[CH2:21]([N:16]1[C:17]2[CH2:18][CH2:19][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][C:12]=2[CH2:13][CH2:14][C:15]1=[O:20])[CH2:22][CH3:23]
Reactant: O=C1CCC2CC(OC(=O)c3ccccc3)CC=C2N1
Reactant: O=C1CCC2=C(CCC(OC(=O)c3ccccc3)C2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCCI
Product: CCCN1C(=O)CCC2=C1CCC(OC(=O)c1ccccc1)C2

Procedure:
Following the above procedure, 59 g. of a mixture of 6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and 6-benzoyloxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone were reacted with n-propyl iodide in the presence of sodium hydride to yield 1-n-propyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2-(1H)-quinolinone and the corresponding 3,4,4a,5,6,7-hexahydro isomer. The compounds were purified by chromatography over florisil using an ether-chloroform solvent mixture as the eluant. Also following the above procedure, a mixture of the 1-benzyl-6-benzoyloxyhexahydro-2(1H)-quinolinones was prepared by substituting benzyl bromide for methyl iodide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1F.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[Cl:17]
Reactant: Nc1ccccc1Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1Cl
Temperature: 140 °C
Reaction time: 144 h
Yield: 12 %

Procedure:
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (2.00 g, 8.62 mmol) is suspended in xylenes (15 mL) and 2-chloro aniline (9.06 mL, 86.15 mmol) is added. The reaction mixture is heated to 140° C. under a nitrogen atmosphere. After 6 days, the reaction mixture is cooled to room temperature, and diluted with ethyl acetate. The reaction mixture is washed with water, 10% HCl solution and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure. The crude product is triturated with diethyl ether, twice, to give 0.35 g (12%) pure desired product as a brownish solid.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH:17]=[CH2:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](Cl)=[O:14])=O.C(N(CC)CC)C.[C:28]([CH:33]([CH:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[OH:36])[OH:34])([O:30][CH2:31][CH3:32])=[O:29]>CCOCC>[CH2:16]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:36][CH:35]([CH:33]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[OH:34])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:14])[CH:17]=[CH2:18]
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: C=CCN(C(=O)C(F)(F)F)c1ccccc1CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCNc1ccccc1CC(=O)OC(C(=O)OCC)C(O)C(=O)OCC

Procedure:
A mixture of 2-[N-trifluoroacetyl-(allylamino)]phenylacetyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields diethyl O-[2-(allylamino)phenylacetyl]tartrate as a white, crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[N:43]=[C:42]2[O:44][C:45]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:46](I)[C:47](=[O:48])[C:41]2=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:46]3[C:47](=[O:48])[C:41]4[C:42]([O:44][C:45]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:43][C:38]([Cl:37])=[CH:39][CH:40]=4)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2nc(Cl)ccc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4nc(Cl)ccc4c3=O)cc2)CCC1
Yield: 64 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-chloro-3-iodo-2-phenyl-pyrano[2,3-b]pyridin-4-one was reacted to give the title compound (8.4 mg, 64%) as a colourless gum. LCMS (Method B): RT=4.42 min, [M+Na]+=525/527.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.7 g), 1-(bromomethyl)-4-fluorobenzene (0.27 mL), potassium carbonate (0.51 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.56 g, 62%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([OH:22])[CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][C:44]([O:47][CH2:48][C@H:49](O)[CH3:50])([CH3:46])[CH3:45].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:23][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:49]([CH3:50])[CH2:48][O:47][C:44]([CH3:46])([CH3:45])[CH3:43])[CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)=[O:4]
Reactant: C[C@@H](O)COC(C)(C)C
Reactant: COC(=O)c1cc(O)cc(Oc2cnc(C(=O)N(C)C)cn2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(C)(C)C)c1
Temperature: 0 °C

Procedure:
To methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-hydroxy-benzoate (10 g, 32 mmol) was added triphenylphosphine (10.3 g, 39.4 mmol), THF (100 mL) and (2R)-1-[(2-methylpropan-2-yl)oxy]propan-2-ol (CAS no. 136656-73-0) (5.21 g, 39.4 mmol). The resulting slurry was cooled to 0° C. and diethylazodicarboxylate (50% w/v in toluene, 13.7 mL, 39.4 mmol) was charged dropwise keeping the temperature below 10° C. After 2 hours the solvent was evaporated under reduced pressure and taken up with ethyl acetate (23 mL). A solid crashed out which was filtered and the mother liquors were evaporated under reduced pressure, taken up into ethyl acetate (23 mL) and isohexane (53 mL) and the resulting solid filtered, the mother liquors were evaporated under reduced pressure and the resulting residue was purified by flash chromatography eluting with 80% ethyl acetate/20% isohexane to afford the product (13.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:15][CH2:16][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:18])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].ClC1C=CC=C[N+]=1C.[CH3:38][O:39][CH:40]([O:45][CH3:46])[CH2:41][C:42](O)=[O:43].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([N:15]([CH2:16][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:18])[C:42](=[O:43])[CH2:41][CH:40]([O:45][CH3:46])[O:39][CH3:38])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(CC(=O)O)OC
Reactant: COC(=O)[C@H](CCOCc1ccccc1)NCC(C)Nc1ccc(Cl)c(Cl)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: COC(=O)[C@H](CCOCc1ccccc1)N(CC(C)Nc1ccc(Cl)c(Cl)c1)C(=O)CC(OC)OC
Yield: 95.5 %

Procedure:
A solution of 1.26 g (2.96 mmol) of (S)-4-benzyloxy-2-[2-(3,4-dichloro-phenylamino)-propylamino]-butyric acid methyl ester in 30 ml CH2Cl2 was treated with a solution of 0.91 g (3.55 mmol) of 2-chloro-1-methylpyridinium iodide and 0.48 g (3.55 mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl 3,3-dimethoxy-propionate by hydrolysis with LiOH) in 20 ml of CH2Cl2. The suspension was cooled and treated at 0° C. with 1.77 ml (7.41 mmol) of tributylamine. The cooling bath was removed after 10 min and stirring was continued over night. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over Na2SO4 to yield 1.53 g (96%) of the title compound as a 71:29 mixture of the (R) and (S) diastereomers. Yellow oil, MS: 541.2 (MH+, 2Cl).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[N:30]=[C:18]2[N:19]=[C:20]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:22]([NH2:23])[N:17]2[N:16]=1.CCN(CC)CC>CC#N>[CH3:9][C:4]1[C:3]([CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:20]3[N:21]=[C:22]([NH2:23])[N:17]4[N:16]=[C:15]([C:11]5[O:10][CH:14]=[CH:13][CH:12]=5)[N:30]=[C:18]4[N:19]=3)[CH2:29][CH2:28]2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Reactant: Cc1noc(C)c1CCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1noc(C)c1CN1CCN(c2nc(N)n3nc(-c4ccco4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Chloromethyl-3,5-dimethyl-isoxazole (1.5 eq.) was directly added to a solution of 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see Example 1(a) above) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has-been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1 H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 6H). MS: m/z 3.96 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13]>>[CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH:5]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)(CCC=O)[N+](=O)[O-]
Product: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]

Procedure:
Then, 4-methyl-4-nitropentanal and hydantoin are reacted to give 5-(4-methyl-4-nitropentylidene)hydantoin (see JP-A-11-140076).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([NH2:9])=[S:8])([CH3:5])[CH3:4].Br[CH:11]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:13]=2[C:12]1=O>C(O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:13]2[C:12]3[N:9]=[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[CH2:2][OH:1])[S:8][C:11]=3[CH2:17][CH2:16][O:15][C:14]=2[CH:18]=1
Reactant: O=C1c2ccc(Br)cc2OCCC1Br
Reactant: CC(C)(CO)NC(N)=S
Solvent: CCO
Product: CC(C)(CO)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
A mixture of 0.67 g (5.0 mmol) of 1-(1-hydroxy-2-methylpropan-2-yl)thiourea and 1.60 g (5.00 mmol) of 4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in 30 ml of ethanol was heated under reflux for 3 hours. The mixture was concentrated, the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane. Yield 1.38 g (75%). MS(ESI+): 369.3