Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=374.1 [M+H]+.
Reaction SMILES: [CH:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[C:25]([C:32](=[O:34])[CH3:33])=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH:1]([CH:4]1[N:9]([C:22]2[N:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[C:25]([C:32](=[O:34])[CH3:33])=[CH:24][N:23]=2)[CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: CC(C)C1NCCn2c1nc1ccc(S(C)(=O)=O)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1cnc(N2CCn3c(nc4ccc(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a solution of 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (7.50 mg, 0.03 mmol) in DMSO (1 mL) were added 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (11.5 mg, 0.05 mmol) and DIEA (9.90 mg, 0.08 mmol) under N2. The mixture was stirred at 100° C. for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and then purified by preparative HPLC to afford a racemic mixture of 1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (2.40 mg, 20% yield) as a white solid. LC-MS m/z 482.1 [M+H]+. 1H NMR (CD3OD 400 MHz): δ 8.76 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.84-7.83 (m, 1H), 6.15 (d, J=8.0 Hz, 1H), 5.45 (d, J=13.6 Hz, 1H), 4.42-4.36 (m, 1H), 4.20 (brs, 1H), 3.91-3.80 (m, 1H), 3.09 (s, 3H), 2.60-2.46 (m, 4H), 1.34 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(C=O)c1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
10 g of 5-bromo-2-hydroxy-3-methoxybenzaldehyde, 23.9 g of potassium carbonate and 12.2 g of (2-chloromethoxyethyl)trimethylsilane is suspended in 500 ml of DMF and stirred at room temperature for 48 hours. The DMF is distilled off in vacuo, the residue is dissolved in ethyl acetate, and the resulting solution is extracted with water. It is then dried over magnesium sulphate and filtered, and the solvent is distilled off. The crude product is purified by silica gel chromatography (heptane/ethyl acetate).
Reaction SMILES: [CH2:1]1[CH2:27][O:26][C:3]2([CH2:8][CH2:7][N:6]([C:9]3[N:14]=[C:13]([N:15]4[CH2:20][CH2:19][C:18]5([O:24][CH2:23][CH2:22][O:21]5)[CH2:17][CH2:16]4)[CH:12]=[C:11](Cl)[N:10]=3)[CH2:5][CH2:4]2)[O:2]1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]1[CH2:27][O:26][C:3]2([CH2:8][CH2:7][N:6]([C:9]3[N:14]=[C:13]([N:15]4[CH2:20][CH2:19][C:18]5([O:24][CH2:23][CH2:22][O:21]5)[CH2:17][CH2:16]4)[CH:12]=[C:11]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:10]=3)[CH2:5][CH2:4]2)[O:2]1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)nc(N2CCC3(CC2)OCCO3)n1
Reactant: C1CNCCN1
Product: c1c(N2CCNCC2)nc(N2CCC3(CC2)OCCO3)nc1N1CCC2(CC1)OCCO2
Yield: 55.7 %

Procedure:
The reaction of 2,4-bis(4,4-ethylenedioxy-1-piperidinyl)-6-chloropyrimidine with piperazine as described in Example 4 gives the title compound in a yield of 55.7%, m.p.: 130°-140° C.
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:21]2[N:22]=[C:23]([NH2:26])[NH:24][CH:25]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1COCC1>[NH2:26][C:23]1[NH:24][C:25]([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[OH:34])=[C:21]([C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:1][CH3:2])=[CH:4][CH:5]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[N:22]=1
Reactant: COc1ccc([C@H](Cc2ccc(C(F)(F)F)cc2)c2c[nH]c(N)n2)cc1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([C@H](Cc2ccc(C(F)(F)F)cc2)c2nc(N)[nH]c2C(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.3 %

Procedure:
To a solution of 4-{(1S)-1-(4-methoxylphenyl)-2-[4-(trifluoromethyl)phenyl]ethyl}-1H-imidazole-2-amine (0.05 g, 0.14 mmol) in H2O (1 mL) and THF (0.5 mL) was added benzaldehyde (0.018 g, 0.17 mmol) and sodium carbonate (0.01 g, 0.08 mmol). The reaction was stirred at room temperature for 12 h. The reaction was concentrated and purified by RP HPLC to provide (2-amino-4-{(1S)-1-(4-methoxyphenyl)-2-[4-(trifluoromethyl)phenyl]ethyl}-1H-imidazole-5-yl) (phenyl)methanol (0.01 g, 14%).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:35])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:34])[CH:17]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[N:23][O:24][C:25]=3[CH3:26])=[O:20])[C@H:5]2[S:4]1.[CH3:36][N:37]1[C:41]([SH:42])=[N:40][N:39]=[N:38]1>P([O-])([O-])([O-])=O.CC(C)=O>[CH3:36][N:37]1[C:41]([S:42][CH2:2][C:3]2([CH3:35])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]3[C:16](=[O:34])[CH:17]([NH:18][C:19]([C:21]4[C:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[Cl:33])=[N:23][O:24][C:25]=4[CH3:26])=[O:20])[C@H:5]3[S:4]2)=[N:40][N:39]=[N:38]1
Reactant: Cn1nnnc1S
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CBr)S[C@H]12
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CSc3nnnn3C)S[C@H]12

Procedure:
By treating in the similar manner as described in Example 11 using 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate and 1-methyl-IH-tetrazole-5-thiol in a mixture of pH 6.85 phosphate buffer and acetone, there was obtained amorphous 2,2,2-trichloroethyl 2-(1-methyl-IH-tetrazol-5-yl)thiomethyl-2methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate.
Reaction SMILES: [CH2:1]([SH:6])[CH2:2][CH2:3][CH2:4][SH:5].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].N([C:32]([CH3:36])([CH3:35])C#N)=NC(C)(C)C#N>>[CH2:7]([S:5][CH2:4][CH2:3][CH2:2][CH2:1][S:6][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:36][CH2:32][CH3:35])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: SCCCCS
Reactant: C=CCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCCSCCCCSCCCCCCCCCCCCCCCCCC

Procedure:
The procedure used was essentially the same as described in Example 1. A stirred mixture of 12.22 g. (0.1 moles) of 1,4-butane dithiol and 50.5 g. (0.2 moles) of 1-octadecene were reacted at 80° C. in the presence of 0.5 g. of 2,2'-azobis(isobutyronitrile). The reaction mixture was recrystallized twice from hexanes (2×300 g.) collected by filtration, washed with 100 g. of cold hexanes, and air dried to yield 45.5 g. of pure product. Anal. Calcd. for C40H82S2 : C, 76.6; H, 13.2; S, 10.2 Found: C, 76.2; H, 12.9: S, 10.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[N:6]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH:22]=[CH:21]2>>[ClH:17].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:34]3[CH2:33][CH2:32][N:31]([S:28]([C:23]4[CH:22]=[CH:21][C:20]5[C:25](=[CH:26][CH:27]=[C:18]([Cl:17])[CH:19]=5)[CH:24]=4)(=[O:30])=[O:29])[CH2:36][CH2:35]3)=[O:13])=[CH:14][CH:15]=2)[N:6]=1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Agent: Cl
Product: Nc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)cs1

Procedure:
In a similar manner to Example 4 except for the use of 4-(2-aminothiazol-4-yl)benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[CH3:18][NH2:19]>CN(C=O)C>[F:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([NH:19][CH3:18])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (15 g, 130 mmol) was added slowly to a solution of acid 2-fluoro-4-nitro-benzoic acid (20 g, 110 mmol) in DMF (20 mL) at −5° C. The mixture was stirred for an additional 1 h at −5° C. At 0° C., a methylamine solution (2M, 400 mL, 800 mmol) in tetrahydrafuran was added drop-wise to the solution. The reaction mixture was slowly warmed to 25° C. and then poured into ice-water (125 mL). The suspension was extracted with ethyl acetate (2×200 mL). Combined organic phase was washed with brine (1×200 mL), dried (MgSO4) and concentrated to dryness in vacuo. The title compound 21 was obtained as a yellow solid (20 g, 90% yield). MS: 163 (M+H)+. 1H NMR (acetone-d6, 500 MHz): δ 7.66 (1H, dd, J=8.5, 8.5 Hz), 6.41 (1H, dd, J=8.6, 2.1 Hz), 6.32 (1H, dd, J=13.6, 2.0 Hz), 3.05 (3H, d, J=4.4 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>ClCCl>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH:23][C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[CH:20]=[CH:19][N:18]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cn1ccnc1C(=NOCc1nccc(N)n1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ccnc1C(=NOCc1nccc(NC(=O)C2CC2)n1)c1ccccc1
Yield: 7 %

Procedure:
A solution of 2-[({[(1-methyl-1H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-amine (200 mg, 0.64 mmol), triethylamine (0.18 mL, 1.29 mmol), cyclopropanecarboxylic acid chloride (136 mg, 1.29 mmol) in dichloromethane (10 mL) was stirred 6 h30 at room temperature. After dilution with water (50 mL), the layers were separated and the aqueous layer further extracted with dichloromethane (30 mL). The combined organic layers were dried over MgSO4 and the solvents removed in vacuo. Purification on silica gel afforded N-{2-[({[(1-methyl-1 H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-yl}cyclopropanecarboxamide as an oil [19 mg, yield 7%; HPLC/MS: m/z=377 (M+H); log P(HCOOH)=1.50].
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:22][CH2:23][CH2:24][Cl:25].C1(C)C=CC=CC=1>CCOCC.CCCCCC>[Cl:25][CH2:24][CH2:23][CH2:22][N:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Reactant: ClCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: ClCCCN1c2ccccc2CCc2ccccc21
Reaction time: 12 h

Procedure:
A solution of 10,11-dihydro-5H-dibenz[b,f]azepine (19.5 gms.; 0.10 moles) in dry ether was added to a solution of 7.7 gms. (0.12 mole) of butyl lithium in hexane. The stirred solution was warmed for approximately one hour and then 31.0 gms. (0.20 mole) of bromopropylchloride in ether was added and the resulting mixture heated at reflux for 16 hours. Aliquot analysis showed no reaction had taken place. Approximately one liter of toluene was added to the reaction mixture, lower boiling solvents were removed by distillation and the reaction mixture heated at reflux with stirring for 12 hours. On working up the reaction mixture, there was obtained 7.0 gms. of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine which distilled at 150°-153°C. (0.03 mm.). An additional 6.0 gms. of impure material which contained approximately 15% of unreacted 10,11-dihydro-5H-dibenz[b,f]azepine was obtained which distilled at 140°-150°C. (0.03 mm.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Si:34]([O:41][CH2:42][CH2:43][CH2:44]O)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][S:54]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=2)(=[O:56])=[O:55])=[C:49]([CH2:67][C:68]2[C:73]([F:74])=[CH:72][CH:71]=[CH:70][C:69]=2[F:75])[CH:48]=1>O1CCCC1>[C:37]([Si:34]([CH3:35])([CH3:36])[O:41][CH2:42][CH2:43][CH2:44][N:53]([C:50]1[CH:51]=[CH:52][C:47]([Cl:46])=[CH:48][C:49]=1[CH2:67][C:68]1[C:73]([F:74])=[CH:72][CH:71]=[CH:70][C:69]=1[F:75])[S:54]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=1)(=[O:56])=[O:55])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCCO[Si](C)(C)C(C)(C)C)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 0.5 h

Procedure:
To 4.3 g of triphenylphosphine in 20 ml of tetrahydrofuran are added, at room temperature, 3.25 ml of diisopropyl azodicarboxylate. After 30 minutes, 3.5 ml of 3-[tert-butyl(dimethyl)silyloxy]propanol dissolved in 30 ml of tetrahydrofuran are introduced. The mixture is left at room temperature for 30 minutes, and 5 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide are then introduced. After 48 hours at room temperature, the reaction medium is concentrated and then chromatographed on a column of silica gel to give 8.09 g of the expected product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=O)[S:15][CH:16]=1>N1CCCCC1.C(O)C>[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[S:15][CH:16]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1csc(C=O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1csc(C=C2C(=O)Nc3ccccc32)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
A reaction mixture of 133.0 mg of oxindole, 151.2 mg of the 4-methylthiophene-2-carboxaldehyde, and 3 drops of piperidine in 3 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 147.3 mg (61%) of the title compound as a yellow solid.
Reaction SMILES: COC1C=C(OC)C=CC=1[CH2:5][NH:6][CH:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH2:8]1.Cl[CH2:53][CH2:54][N:55]=C=O.[OH-:58].[Na+]>ClCCl>[NH2:17][C:12]1[C:11]2[C:10]3[C:9](=[N:34][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:32]=2)[CH2:8][CH:7]([N:6]2[CH2:53][CH2:54][NH:55][C:5]2=[O:58])[C:16]=3[CH2:15][S:14][N:13]=1
Reactant: COc1ccc(CNC2CC3=NN(Cc4ncc(C)c(OC)c4C)N=C4C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC2=C34)c(OC)c1
Reactant: O=C=NCCCl
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)cnc(CN2N=C3CC(N4CCNC4=O)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
A mixture composed of di-tert-butyl {8-[(2,4-dimethoxybenzyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 42 (47 mg), dichloromethane (1 ml) and 2-chloroethyl isocyanate (8 μl) was stirred at room temperature for 12 hours. A 0.1 N sodium hydroxide solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dehydrated dichloromethane (1.5 ml). 1,3-Dimethoxybenzene (16 μl) and trifluoroacetic acid (1.5 ml) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and a 0.1 N sodium hydroxide solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Dimethylformamide (1 ml) and potassium tert-butoxide (15 mg) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was separated with water and chloroform. Then, the organic layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (9 mg, 31%) as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.O>[Si:20]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNc1ccc(CO)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CNc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of [4-(methylamino)phenyl]methanol (500 mg, 3.7 mmol) and imidazole (248 mg, 3.7 mmol) in DCM (20 mL) was added TBSCl (548 mg, 3.7 mmol) at r.t., and the reaction was stirred for 2 h. The reaction was diluted with water (50 mL) and extracted with DCM (50 mL×3). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=40:1) to give 600 mg (66%) of the title compound as a yellow oil. [M+H] Calc'd for C14H15NOSi, 252. Found 252.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].CS(C)=O.[CH3:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([C:30](=[O:32])[CH3:31])[C:27]([OH:29])=[CH:28][C:21]=2[O:20]1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([C:30](=[O:32])[CH3:31])[C:27]([O:29][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:28][C:21]=2[O:20]1)=[O:18]
Reactant: COC(=O)C1CCc2cc(C(C)=O)c(O)cc2O1
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1CCc2cc(C(C)=O)c(OCCCCCOC(C)=O)cc2O1
Temperature: 25 °C
Reaction time: 19 h
Yield: 105.1 %

Procedure:
A 12-L three-neck, round-bottom flask equipped with a mechanical stirrer and a nitrogen bubbler, was charged with 375.0 g (1.79 moles) of 5-bromo-1-pentanyl acetate, 3.5 L of dimethyl sulfoxide, 407.0 g (1.63 moles) of rac-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid methyl ester and 510.0 g of anhydrous granular potassium carbonate in finely powdered form. The mixture was stirred at room temperature under nitrogen for 19 hours, poured into an extractor containing 10 L of deionized water, and extracted with 2×4 L and 1×2 L=10 L of ethyl acetate. The organic layer was washed with 2×4 L=8 L of 1:1 deionized water-saturated brine, followed by 2 L of saturated brine, dried (anhydrous sodium sulfate), and filtered. The solvent was removed at 45°/70 mm and then under high vacuum to give 648.3 g of crude rac-6-acetyl-3,4-dihydro-7-[(5-acetoxypentyl)oxy]-2 H-1-benzopyran-2-carboxylic acid methyl ester. The crude product was dissolved in 2 L of anhydrous ether and the solution was poured into a 12 L three-neck flask equipped with a mechanical stirrer. The stirred solution was cooled in an ice-bath and 2 L of petroleum ether (35°-60°) was slowly added, which resulted in the formation of a precipitate heavy enough to stop the stirrer. The solid was broken with a spatula and stirring was continued in the ice-bath for 1 hour. The product was collected by filtration, washed with cold (3°) 1:1 ether-petroleum ether, and dried at room temperature under high vacuum to give 601.5 g (97.7% yield) of rac-6-acetyl-3,4-dihydro-7-[(5-acetoxypentyl)oxy]-2H-1-benzopyran-2-carboxylic acid methyl ester as a white powder, mp 37°-49° C. UV (EtOH): λ max, 312 (ε=7,200), 268 (ε=11,200), 230 (ε=16,900), and 216 (ε=19,000) nm; MS: m/z 378 (M+, 40).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:9][C:10]=2[O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[NH2:26][C:27]1[C:35]2[O:34][CH:33]=[C:32]([Cl:36])[C:31]=2[CH:30]=[CH:29][CH:28]=1>>[ClH:1].[ClH:36].[Cl:36][C:32]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:26][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:9][C:10]=4[O:12][CH:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[N:5]=[CH:4][N:3]=3)[C:35]=2[O:34][CH:33]=1
Reactant: Clc1ncnc2cc(OCCN3CCCC3)cc(OC3CCCC3)c12
Reactant: Nc1cccc2c(Cl)coc12
Product: Cl
Product: Clc1coc2c(Nc3ncnc4cc(OCCN5CCCC5)cc(OC5CCCC5)c34)cccc12

Procedure:
Using an analogous procedure to that described in Example 47, 4-chloro-5-cyclopentyloxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.1 g) was reacted with 7-amino-3-chlorobenzofuran (0.051 g) to give the title compound, as a dihydrochloride salt (0.074 g), a portion of which was converted into the free base using an analogous procedure to that described in Example 3. The free base gave the following characterising data: NMR Spectrum: (CDCl3) 1.7–1.8 (m, 2H), 1.8–2.0 (m, 6H), 2.1–2.3 (m, 4H), 2.7 (br s, 4H), 3.02 (m, 2H), 4.3 (t, 2H), 5.08 (m, 1H), 6.61 (d, 1H), 6.84 (d, 1H), 7.3–7.45 (m, 2H), 7.65 (s, 1H), 8.64 (s, 1H), 8.76 (d, 1H), 10.3 (s, 1H); Mass Spectrum: M+H+ 493 and 495.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(CCCCN=[N+]=[N-])(CCCc1cccnc1)C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCN)(CCCc1cccnc1)C(=O)OCC
Reaction time: 48 h

Procedure:
To a solution of 42.59 g (0.11 mole) of diethyl [4-azidobutyl][3-(3-pyridyl)-propyl]-malonate in 270 mL THF and 3.1 mL water is added 29 g (0.11 mole) of triphenyl phosphine and the solution is stirred well for 48 hours. Solvent is evaporated and the residue subjected to flash chromatography to give diethyl [4-aminobutyl][3-(3-pyridyl)- propyl]malonate as an oil.