Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:2]1[C:39]2[C:38](=[CH:37][CH:36]=[C:35]([NH:34][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:40]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1ccccc1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and aniline by a procedure similar to Example 27, Step D. 1H NMR (400 MHz, DMSO-d6) δ 6.50 (d, 1H, J=5.2 Hz), 6.76 (d, 1H, J=7.3 Hz), 7.00-7.08 (m, 4H), 7.13-7.31 (m, 5H), 7.40-7.63 (m, 6H), 7.88 (d, 1H, J=8.2 Hz), 7.98 (s, 1H), 8.02 (s, 1H), 8.25 (d, 1H, J=5.2 Hz), 8.52 (d, 1H, J=8.3 Hz), 8.87 (d, 1H, J=6.9 Hz), 9.41 (s, 1H), 10.97 (s, 1H); ESIMS (M+H)+=610.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH3:23][O:24][C:25]1[C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=[C:27]([CH:35]=O)[CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:35][C:27]3[CH:26]=[C:25]([O:24][CH3:23])[C:30]4[O:31][CH2:32][CH2:33][O:34][C:29]=4[CH:28]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: COc1cc(C=O)cc2c1OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc(OC)c5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To 10 mL of a chloroform solution containing 598 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 384 mg of 8-methoxy-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde, 113 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 639 mg of sodium triacetoxyborohydride was added, and stirred for 2 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=5:1] to give 492 mg of 7-methoxy-1-(2-(4-((8-methoxy-2,3-dihydro-1,4-benzodioxin-6-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.[NH2:22][C:23]1[N:24]=[C:25]([NH2:35])[C:26]2[CH:32]=[C:31]([CH2:33]O)[CH:30]=[N:29][C:27]=2[N:28]=1.[NH2:36][C:37]1[CH:58]=[CH:57][C:40]([C:41]([NH:43][C@H:44]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[O:42])=[CH:39][CH:38]=1>CC(N(C)C)=O>[NH2:22][C:23]1[N:24]=[C:25]([NH2:35])[C:26]2[CH:32]=[C:31]([CH2:33][NH:36][C:37]3[CH:38]=[CH:39][C:40]([C:41]([NH:43][C@H:44]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[O:42])=[CH:57][CH:58]=3)[CH:30]=[N:29][C:27]=2[N:28]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Reactant: Nc1nc(N)c2cc(CO)cnc2n1
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of triphenylphosphine (430 mg, 1.64 mmol) in anhydrous DMAC (4 ml) at 0° C. was treated dropwise under N2 with bromine (84 μL, 1.64 mmol). The solution was stirred at 0° C. for 15 minutes, treated with the compound obtained in Example 2 (100 mg, 0.76 mmol), and stirred at 25° C. for 1.7 hours to give the compound of Formula IIIA. This solution was treated with diethyl p-aminobenzoyl-L-glutamate (194 mg, 0.603 mmol), stirred at 25° C. for 17 hours and poured into ice water (40 ml). The resulting solution (pH 2) was filtered to remove triphenylphosphine oxide, adjusted to pH 6.8 with 50% NaOH, and cooled in an ice bath. The precipitate of crude product (VII; R=H, R1 =C2H5) was collected by centrifugation, washed with H2O and dried in vacuo (P2O5); yield 136 mg (73%). The retention time (HPLC) and rf value (TLC) of this product were identical to those obtained from the analytical sample obtained in Part A of this example. Mass spectrum: m/e 496 (M+1)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([Br:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[Br-:21].[CH2:14]([N+:11]1[CH:12]=[CH:13][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(Cc2ccncc2)cc1
Solvent: CC(C)=O
Product: [Br-]
Product: c1ccc(Cc2cc[n+](Cc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
A solution of 4-benzylpyridine (5.0 g, 29.5 mmol) in anhydrous acetone (25 ml) was treated with benzyl bromide (3.6 ml, 30 mmol) and stirred at room temperature for 18 hours. The precipitate was collected, washed with diethyl ether then dried to give the quaternary salt as a colourless solid (9.52 g, 95%). mp 214°-216° C. δ (360 MHz, D2O) 4.29 (2H, s, CH2), 5.74 (2H, s, CH2), 7.30-7.52 (10H, m, Ar-H), 7.84 (2H, d, J=7Hz, Py-H), 8.68 (2H, d, Py-H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C@@H:28](O)[CH3:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:19])([F:20])[CH2:15]2)[C:8]2[C:9](=[N:11][N:12]([C@@H:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])[CH3:29])[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: C[C@H](O)c1ccccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1Cl)n1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
To a solution of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (41.3 μmol), (S)-1-(2-chlorophenyl)ethanol (12.9 mg, 82.6 μmol) and PPh3 (21.7 mg, 82.6 μmol) in THF (250 μL) was added DEAD (13.1 μL, 82.6 μmol) at 0° C. After being stirred at the room temperature for 2 h, the reaction mixture was directly purified by preparative HPLC (column: Gemini 5 um C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as white solid (3.5 mg, 20%). MS (m/e): 421.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[CH:20]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][CH:29]=1)([CH3:22])[CH3:21]>>[CH:30]([OH:32])=[O:31].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH:20]([CH3:21])[CH3:22])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reactant: CC(C)Oc1ccc(C(=O)O)nc1
Product: CC(C)Oc1ccc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)COCC3(F)F)c2)nc1
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) and 5-isopropoxy-pyridine-2-carboxylic acid (prepared according to Nagase, T. et al., Patent Application Publ. No. US20100249147) yielded the title compound as an off-white solid. MS (ISP): m/z=437.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[Na].[CH3:23]Br>CN(C)C=O>[CH3:23][N:10]([C:2]([CH3:1])([CH3:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: CC(C)(NS(=O)(=O)c1ccccc1)c1ccccc1
Reactant: CBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CN(C(C)(C)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
27.5 g (0.1 mole) of N-(α,α-dimethylbenzyl) benzenesulfonamide was added to 5.8 g (0.12 mole) of 50% sodium hydride in 200 ml of dry N,N-dimethyl formamide. The mixture was stirred at room temperature for 30 minutes to react them. To the resulting sodium salt of N-(α,α-dimethylbenzyl)benzenesulfonamide was added 16.1 g (0.17 mole) of methyl bromide. The mixture was heated to 60° C. and stirred for 1 hour. The N,N-dimethyl formamide was distilled off under reduced pressure, and cold water was added. The resulting white solid was recrystallized from methanol to afford N-methyl-N-(α,α-dimethylbenzyl)benzenesulfonamide in a yield of 87%. This compound is designated as compound No. 64 in Table 2 below, and its melting point and elemental analysis values are shown in Table 2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.C1C=C2C=NNC(=O)C2=CC=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C(O)CCC>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1nncc2ccccc12
Agent: O=c1[nH]ncc2ccccc12
Solvent: CCCCO
Product: Clc1ccc(Nc2nncc3ccccc23)cc1

Procedure:
30 g (149 mmol) 1-chlorophthalazine (prepared from phthalazone in the manner described under Example 67A.1) and 20 g (157 mmol) 4-chloroaniline are heated in 630 ml n-butanol for 30 min to 65° C. The crude product is filtered off, washed with ether, taken up in 2 l di-chloromethane/methanol 9:1, and washed with sat. NaHCO3 solution and brine. The aqueous phases are extracted three times with dichloromethane/methanol 9:1, the organic phases dried (Na2SO4), and evaporated to a residual volume of ≈50 ml, leading to crystallization of the title compound: m.p.: 211° C.; Anal. calc.(C14H10N3Cl) C, 65.76%; H, 3.94%; N, 16.43%, Cl, 13.86%. found C, 66.02%; H, 3.92%; N, 16.53%, Cl, 13.51%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1>>[Br-:1].[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)=[CH:8][CH:9]=1
Reactant: Cc1cccnc1
Reactant: BrCCCCCc1ccc(-c2ccccc2)cc1
Product: Cc1ccc[n+](CCCCCc2ccc(-c3ccccc3)cc2)c1
Product: [Br-]
Temperature: 65 °C
Yield: 90 %

Procedure:
A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (358 mg, 1.18 mmol) and 3-picoline (1 mL) was heated at 60-70° C. for 12 hrs. The resulted mixture was washed with diethyl ether and then dissolved in water (15 mL). The aqueous solution was extracted with diethyl ether (30 mL×3). Water was removed by lyophilization to afford 421 mg of the title compound. Yield: 90%. 1H NMR (300 MHz, CDCl3) δ 1.45 (m, 2H), 1.70 (m, 2H), 2.08 (m, 2H), 2.59 (s, 3H), 2.63 (t, J=7.5 Hz, 2H), 4.92 (t, J=7.5 Hz, 2H), 7.18-7.58 (m, 9H), 7.94 (t, J=7.2 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 9.26 (d, J=6.3 Hz, 1H), 9.46 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 18.8, 25.7, 30.7, 31.9, 35.2, 61.5, 126.8, 126.9, 127.0, 127.7, 128.3, 128.7, 128.8, 138.5, 139.5, 140.7, 141.1, 142.1, 144.5, 145.5 ppm.
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[O:11][CH:10]2[C:7]([C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)=[O:4].O>C(O)(=O)C.[Zn]>[C:3]([CH:5]1[O:11][CH:10]2[C:7]([C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)(=[O:4])[CH3:2]
Reactant: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)CCl)OC12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 1.59 g of diphenylmethyl α-(3ξ-chloroacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 16 ml of acetic acid is added 1.5 g of zinc powder, and the mixture stirred at room temperature for 1 hour, then poured into water and extracted with methylene chloride. The extract is washed with water, dried on magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on 30 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 1.21 g of diphenylmethyl α-(3ξ-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 81% yield.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:17])([CH3:16])[SiH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O)([O-:20])=[O:19].[NH3:29]>C(O)C>[CH3:16][C:8]([O:7][C:1]([C:2]1[CH:24]([C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[C:2]([C:1]([O:7][C:8]([CH3:17])([CH3:16])[SiH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:6])=[C:3]([CH3:5])[NH:29][C:3]=1[CH3:5])=[O:6])([CH3:17])[SiH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: N
Reactant: CC(=O)CC(=O)OC(C)(C)[SiH2]c1ccccc1
Solvent: CCO
Product: CC1=C(C(=O)OC(C)(C)[SiH2]c2ccccc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)(C)[SiH2]c2ccccc2)=C(C)N1

Procedure:
10.0 g of dimethylphenylsilylmethyl acetoacetate, 3.0 g of 3-nitrobenzaldehyde and 2.2 ml of concentrated ammonia in 15 ml of 96 percent strength ethanol are heated under reflux for 20 hours. After cooling and filtering, 11.0 g of yellow crystals of melting point 125° C. (ethanol) are obtained.
Reaction SMILES: O.O.O.O.O.O.O.O.O=[C:10]1[C:15](=O)[C:14](=O)[C:13](=O)[C:12](=O)[C:11]1=O.[NH2:21][C:22]1[C:23]2[C:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=3[C:35]=1[NH2:36])=[CH:27][CH:26]=[CH:25][CH:24]=2>C(O)(=O)C.C(O)C>[CH:10]1[C:15]2[C:25]3[C:24](=[N:21][C:22]4[C:23]5[C:28]([C:29]6[C:34]([C:35]=4[N:36]=3)=[CH:33][CH:32]=[CH:31][CH:30]=6)=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:23]3[C:22](=[CH:35][CH:34]=[CH:29][CH:28]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1c(N)c2ccccc2c2ccccc12
Reactant: O=C1C(=O)C(=O)C(=O)C(=O)C1=O
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: c1ccc2c(c1)c1ccccc1c1nc3c4ccccc4c4ccccc4c3nc21

Procedure:
In the course of the synthesis of hexaazatristriphenylene HATT (also referred to as “Mickey-Mouse” HATNA), BK3—31, a different product was observed, Scheme 2. The three-fold condensation of hexaketocyclohexane octahydrate SM4 with 9,10-diaminophenanthrene SM7 in acetic acid/ethanol under air resulted in an orange solid phenanthrazine BK2—97E, which was sublimed under high vacuum. Phenanthrazine was confirmed by 1H NMR and E1 mass analysis. In this regard, 9,10-diaminophenanthrene SM7 may have been partially oxidized to phenanthrene-9,10-dione SM34 under air. The double bond (9=10) in 9,10-diaminophenanthrene SM7 behaves more like a single double bond rather than one in an aromatic system, i.e. it can be oxidized more easily. Condensation of SM7 and SM34 led to BK2—97E. To give evidence for the proposed mechanism, two control experiments were performed. 9,10-diaminophenanthrene SM7 was refluxed in acetic acid/ethanol for 24 hours. E1 mass analysis showed the presence of phenanthrazine, BK3—29. Hexaazatristriphenylene HATT, BK3—31 was obtained when the condensation was performed in acetic acid under nitrogen (MALDI TOF measurement confirmed the presence of HATT).
Reaction SMILES: [CH:1]1([CH:4]=[C:5]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=3)[O:7][CH2:6]2)[CH2:3][CH2:2]1.Cl.[Cl:21][C:22]1[CH:29]=[C:28]([NH:30][NH2:31])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>>[Cl:21][C:22]1[CH:29]=[C:28]([N:30]2[CH:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]3[CH2:6][O:7][C:8]4[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[CH:11]=[CH:12][C:13]=4[C:14]3=[N:31]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1CC1)C2=O
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CC2)cc1Cl

Procedure:
The title compound was prepared from methyl 3-(cyclopropylmethylene)-4-oxochroman-7-carboxylate; Preparation 33 and 2-chloro-4-hydrazinylbenzonitrile hydrochloride; Preparation 1 according to Method B and Method C. The crude product was purified by reverse-phase HPLC (65 to 85% acetonitrile/water/0.05% trifluoroacetic acid) to give 2-(3-chloro-4-cyanophenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid (yellow solid, 14 mg). The title compound was largely present as (±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br. s., 1H), 7.97 (d, J=8.2 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.59 (dd, J=8.2, 1.6 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.6, 1.6 Hz, 1H), 4.84 (dd, J=10.5, 5.9 Hz, 1H), 4.46 (dd, J=12.9, 10.5 Hz, 1H), 4.39 (t, J=10.0 Hz, 1H), 3.93 (ddd, J=13.1, 10.2, 5.7 Hz, 1H), 0.74-0.85 (m, 1H), 0.63-0.71 (m, 1H), 0.52-0.61 (m, 1H), 0.37-0.45 (m, 1H), 0.18-0.26 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:23]([CH3:24])=[CH:22][S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:23]([CH3:24])=[CH:22][S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Reactant: NCc1ccccc1
Product: Cc1csc2nc(-c3ccno3)nc(NCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[CH3:8][C:9]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=1[C:11](Cl)=[O:12]>>[CH3:8][C:9]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=1[C:11]([P:1](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:12]
Reactant: COP(OC)OC
Reactant: Cc1ccc(C)c(C(=O)Cl)c1
Product: COP(=O)(OC)C(=O)c1cc(C)ccc1C
Yield: 80 %

Procedure:
Dimethyl 2,5-dimethylbenzoylphosphonate was prepared in 80% yield by adding an equimolar amount of trimethyl phosphite to 2,5-dimethylbenzoyl chloride.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][O:40][C:41](=[O:58])[C:42]1[CH:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][C:43]=1[F:57].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][O:40][C:41](=[O:58])[C:42]1[CH:47]=[CH:46][C:45]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:44][C:43]=1[F:57]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 74.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 122, 0.57 g, 1 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (prepared as in Example 95, 1.2 g, 4.2 mmol) and dichlorobis(triphenylphosphine)palladium (II) (70 mg, 0.1 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.25 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl]-2-fluoro-benzoic acid methyl ester (400 mg, 72%) as a white solid: LC/MS m/e calcd for C28H24F2N2O5S [M+H]+ 539.57, observed 539.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[O:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:27][CH2:28][N:29]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:31]3)[S:23][N:22]=2)=[CH:17]1
Reactant: c1cc(-c2nsc(N3CCNCC3)n2)co1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccoc3)ns2)CC1
Yield: 28.5 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (311 mg, 1.15 mmol), 1-[3-(3-furyl)-1,2,4-thiadiazol-5-yl]piperazine (300 mg, 1.27 mmol) and diisopropylethylamine (0.221 ml, 1.27 mmol) in dimethyl sulfoxide (3.8 ml) was stirred at 80° C. for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 117 mg (28.3%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: ClCc1ccncc1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccncc2)C1

Procedure:
The title compound is synthesized by coupling of (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloromethyl-pyridine HCl salt analogously to the preparation of Intermediate 193.2 as a white solid; ES-MS: M+=279.2: AtRet=2.84.