Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([Cl:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[C:13]1([CH:19]([OH:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:22][N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[Cl:11][C:10]1[C:5]2[C:4]([O:21][CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:20])=[N:3][C:2]([NH:28][C:26]3[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=3)=[N:7][C:6]=2[NH:8][CH:9]=1
Reactant: CC(O)c1ccccc1
Reactant: Cn1cc(N)cn1
Reactant: Clc1nc(Cl)c2c(Cl)c[nH]c2n1
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Product: CC(Oc1nc(Nc2cnn(C)c2)nc2[nH]cc(Cl)c12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 13.4 mmol) in 1,4-dioxane (45 mL) was added potassium t-pentoxide (31.2 mL, 1.7 M in toluene) followed by 1-phenylethanol (1.62 mL, 13.4 mmol). The reaction solution was stirred at ambient temperature for 0.5 hr. To the same reaction vessel, 1-methyl-1H-pyrazol-4-amine (1.96 g, 20.2 mmol) and BrettPhos Palladacycle (214 mg, 0.020 mmol) were added and nitrogen gas was bubbled through the reaction mixture for 5 min. The reaction mixture was then sealed and heated to 80° C. for 2 hrs. A black precipitate was filtered off and washed with EtOAc. The combined filtrates were combined and diluted with water (75 mL), extracted EtOAc (2×75 mL), washed with brine, dried over sodium sulfate, filtered and concentrated under in vacuo. The crude residue was purified by flash chromatography (eluting with a gradient of 30%-100% EtOAc in heptanes) to give the title compound (1.76 g, 34%) as a green foam. m/z (APCI+) for C18H17ClN6O 369.1/370.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.Br[CH2:40][C:41]1[S:42][CH:43]=[C:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:45]=1>ClCCCl.C(#N)C>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:40][C:41]4[S:42][CH:43]=[C:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:45]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCCl
Solvent: CC#N
Product: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Temperature: 25 °C

Procedure:
To a slurry of the product of step (iii) (1.1 g) in dry 1,2-dichloroethane (20 ml) was added bis(trimethylsilyl)trifluoroacetamide (1.9 ml) under nitrogen. The mixture was heated under reflux for 1 hour until the mixture became a homogeneous solution. The solution was allowed to cool to room temperature and a solution of the product of step (ii) (0.83 g) in dry acetonitrile (10 ml) was added. The solution was then heated at reflux for 7 hours. The reaction mixture was allowed to cool and evaporated under reduced pressure. Purification was by chromatography eluting with 30% ethyl acetate in toluene. The resulting oil was triturated with diethyl ether/isohexane to give the product as a cream solid. Yield 1.52 g.
Reaction SMILES: Cl.[C:2]1([C@:8]23[CH2:16][NH:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[N:32]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[C:30]([F:37])=[CH:29][N:28]=1.[CH:38](N(C(C)C)CC)(C)C.[OH-].[Li+]>O1CCOCC1>[ClH:26].[F:37][C:30]1[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])=[N:32][C:27]([N:15]2[CH2:14][C@@H:13]3[C@@:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([N:9]=[C:10]([NH:17][C:18](=[O:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:11][CH2:12]3)[CH2:16]2)=[N:28][C:29]=1[CH3:38]
Reactant: CC(C)(O)c1nc(Cl)ncc1F
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CNC[C@H]2CS1)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccccc3)C2)nc(C(C)(C)O)c1F
Temperature: 100 °C

Procedure:
To a solution of N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide hydrochloride (95 mg, 0.25 mmol) and 2-(2-chloro-5-fluoro-pyrimidin-4-yl)propan-2-ol (195 mg, 0.57 mmol) in 1,4-dioxane (5.0 mL) is added diisopropylethylamine (150 μL, 0.86 mmol). The resulting solution is heated at 100° C. for 23 hours, cooled to room temperature, and concentrated. The residue is dissolved in methanol (5.0 mL), followed by the addition of lithium hydroxide (100 mg, 4.11 mmol). The resulting solution is heated at 55° C. for 16 hrs and then cooled to room temperature and concentrated. The residue is purified with a 5 g SCX column, eluting first with MeOH/DCM (¼, 50 mL), followed by elution with ammonia in MeOH (7.0 N)/DCM (¼, 50 mL). The basic filtrate is concentrated, and further purified by silica gel flash chromatography, eluting with a gradient of ammonia in MeOH (2.0 M) in dichloromethane (0% to 10%) to give the free base form of the title compound as a colorless oil. EI/MS (m/e): 402.00 (M+H). 19F-NMR (CDCl3): δ (ppm)-154.62. 1H-NMR (CDCl3): δ (ppm) 7.38 (m, 5H), 4.11 (d, 1H), 4.01 (d, 1H), 3.83 (m, 2H), 3.05 (dd, 1H), 2.92 (dd, 1H), 2.81 (m, 1H), 2.37 (s, 3H), 1.53 (s, 6H). The purified material is dissolved in dichloromethane (2 mL), followed by the addition of HCl (1.0 M in diethyl ether, 60 μL, 0.06 mmol) and then concentrated to give the title compound as a white solid (22 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[OH:28]O>>[Cl:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:28])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(SCCCCOc2cc3c(cc2Cl)NC(=O)OC3(C)C)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cc3c(cc2Cl)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 7-chloro-6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[O:22][N:21]=[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[N:19]=3)[C:6](=[O:31])[N:5]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:4]=2[N:3]=1.N1CCOCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[O:22][N:21]=[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[N:19]=3)[C:6](=[O:31])[N:5]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1nc(Cc3ccc(Cl)cc3)no1)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccc(Cl)cc3)no2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 72 h

Procedure:
A solution of 8-chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.18 g, 0.34 mmol) in DMF (5 ml) was degassed by sequential evacuation of the flask and admission of nitrogen (×3) and morpholine (0.5 ml, 5.8 mmol), and Pd(PPh3)4 (80 mg, 0.068 mmol) added. The solution was stirred for 72 h then concentrated and the residues loaded onto an aminopropyl SPE (10 g) with MeOH. Elution with MeOH followed by 5% AcOH/MeOH provided the title compound as a pale yellow solid, which was washed with ether to yield a white solid (0.053 g, 32%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[CH:3]=[C:4]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])=[CH:23][CH:22]=1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Reactant: NCc1ccc(Br)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(Br)cc3)c2)nc1
Temperature: 80 °C
Reaction time: 14.5 h
Yield: 70.7 %

Procedure:
To a round-bottomed flask containing 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine (68.0 g, 259 mmol) and 4-bromobenzylamine (58 g, 259 mmol) in acetonitrile (680 mL) was added DIPEA (113 mL, 648 mmol). The stirred mixture was then heated to 80° Celsius. After 14.5 h, the mixture was cooled to RT and was concentrated to 261 g. The resulting residue was added to i-PrOH (900 mL) and heated to 70° Celsius until homogeneous. The solution was cooled to RT and the crystalline solids were isolated through filtration. The filter cake was washed with cold i-PrOH (200 mL), the solids were collected and dried in a vacuum oven at 40° Celsius for 3 days to give the title compound (78.4 g, 71%). MS (ESI): mass calcd. for C20H18BrN3O3, 427.1; m/z found, 428.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.66 (t, J=5.9, 1H), 8.36 (d, J=2.1, 1H), 8.16 (d, J=9.5, 1H), 7.57-7.37 (m, 3H), 7.27-7.23 (d incident with solvent signal, 1H), 7.22-7.13 (m, 2H), 6.34 (dd, J=9.5, 2.6, 1H), 6.18 (d, J=2.6, 1H), 5.12 (s, 2H), 4.44 (d, J=5.8, 2H), 2.35 (s, 3H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH3:17][C:16]([CH3:18])=[CH:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: CC(C)=CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCN1C(=O)c2ccccc2C1=O

Procedure:
Phthalimide, potassium salt (20.5 g, 0.11 mol) was suspended in dry DMF (100 mL). To the suspension was added 1-bromo-3-methyl-2-butene (14.8 g, 0.1 mol) with stirring. The reaction mixture was stirred under N2 at 45° C. for 24 h. TLC (silica gel, 30% ethyl acetate-hexane) showed one major UV-visible spot with Rf =0.65. DMF was removed under vacuum and the residue was taken up with water (200 mL) and extracted with ethyl acetate (3×150 mL). The extracts were combined and dried over Na2SO4. Evaporation of solvent gave the title product as a white solid. Yield: 21.0 g (98%). mp: 95°-97° C. MS: 233 (M+NH4)+, 216 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:16])[CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([NH2:33])[CH3:32])=[CH:27][C:26]=2[C:34]([F:37])([F:36])[F:35])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[CH2:12][C:13]([NH:33][CH:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=2)[CH3:32])=[O:15])=[CH:8][CH:9]=1)(=[NH:3])[NH2:2]
Reactant: CC(N)c1ccc(OCc2ccncc2)c(C(F)(F)F)c1
Reactant: N=C(N)c1ccc(NC(=O)CC(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)CC(=O)Nc1ccc(C(=N)N)cc1)c1ccc(OCc2ccncc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
134.1 mg (0.4 mmol) of N-(4-carbamimidoyl-phenyl)-malonamic acid*trifluoro-acetic acid salt (intermediate 4) was dissolved in absolute DMF and to this solution 118.5 mg (0.4 mmol) of the amine from step 2, 509 mg (0.8 mmol) 1-propane-phoshonic-acid-anhydride and 51.7 mg (0.4 mmol) N,N-diisopropy-ethyl-amine were added. After stirring for 24 h at ambient temperature the reaction mixture was filtered, evaporated to dryness and purified by preparative HPLC. Yield 45 mg (18%), colourless crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[ClH:16]>CCOC(C)=O.CCCCCC>[Cl:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: CN(C)S(=O)(=O)Oc1ccc(CO)cc1
Reactant: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)Oc1ccc(CCl)cc1

Procedure:
To a solution of JRL01115 (725 mg, 3.135 mmol) in dichloromethane (10 mL) at ice/water temperature was added thionyl chloride (0.35 mL, 4.703 mmol). After stirring at room temperature for 1 h, the volatiles were removed from the reaction mixture and the oil resulted co-evaporated 3 times with chloroform (3×30 mL) to give to LWO02144 as a yellow oil (767 mg, 98%); Rf 0.52 (EtOAc/hexane, 1:1), c.f. 0.19 (JRL01115); 1H (400 MHz, CDCl3) 2.99 (6H, s, NMe2), 4.58 (2H, s), 7.28 (2H AA′BB′) and 7.42 (2H, AA′BB′); LRMS (FAB+) 403.0 [18, (M+H+NBA)+], 391.2 (21), 249.9 [100, (M+H)+], 214.0 [45, (M+H—Cl)+], 113.0 (17); HRMS (FAB+) 249.02239, C9H12ClNO3S requires 249.02264. LWO02144 was very pure and hence was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:33])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][C:29](O)=[O:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:34]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:33])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][C:29]([N:54]4[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]4)=[O:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:34]=1
Reactant: O=C(O)COc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Reactant: CN1CCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)COc2ccccc2C(=O)Nc2ccc(C(=O)N3CCCCc4cc(Cl)ccc43)cn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-chloro-1-[6-(2-carboxymethoxybenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in dichloromethane (10 ml) is added with stirring N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.25 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. Subsequently, to the reaction mixture is added N-methylpiperazine (0.11 ml), and thereto is added triethylamine (0.23 ml). The mixture is stirred at room temperature overnight, and thereto is added water. The mixture is extracted with dichloromethane, and the extract is washed successively with diluted aqueous sodium hydroxide solution and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-1-{6-[2-(4-methyl-1-piperazinyl)carbonylmethoxybenzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (390 mg) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](C(O)=O)[CH:7]=[CH:6]2.[N-:16]=[N+]=[N-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([NH2:16])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(=O)O)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(N)ccc2c1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a 50 ml two-necked flask, 1.0 g (3.5 mmol) of 6-methoxynaphthalene-2-carboxylic acid (Compound 1), 2.28 g (35.0 mmol) of sodium azide and 15.0 g of polyphosphoric acid (PPA) were added, and the mixture was stirred at 40° C. for 12 hours. To the resulting mixture, 100 g of ethyl acetate was added and the obtained mixture was washed with saturated aqueous sodium hydrogen carbonate, followed by drying the product over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[O:37]1[CH2:42][CH2:41][N:40]([CH2:43]CO)[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][CH2:43][N:40]2[CH2:41][CH2:42][O:37][CH2:38][CH2:39]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OCCN1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCN4CCOCC4)c(C)c3C)c2cc1OC
Yield: 99.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-morpholino-1-ethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (74 mg, yield 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8]([CH3:17])([C:9]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=O)[CH:7]([CH3:18])[C:6]2=[CH:19][CH:20]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:17][C:8]1([CH2:9][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=[C:6]2[CH:7]1[CH3:18]
Reactant: COc1ccc2c(c1)C(C)(C(=O)N1CCCCC1)C2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(CN1CCCCC1)C2C

Procedure:
A solution of the 1,2 -dimethyl compound obtained in Step 1. above (43.8 g) in anhydrous THF (640 ml) is added dropwise to a suspension of LAH (7.6 g) in anhydrous THF (200 ml). The reaction mixture is heated to reflux for 45 minutes, cooled and quenched with water, aqueous NaOH (15%), and water. The reaction mixture is filtered, evaporated in vacuo and chromatographed (silica gel: ethyl acetate/hexane) and the major fractions combined, and evaporated yielding the desired product as an oil which is identified by NMR. The oil is dissolved in methanolic hydrochloric acid, the methanolic solution evaporated and the residue recrystallized (acetonitrile/ether), M.P.=179°-181° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:13])=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]#[N:7].C[N:15](C)C=O.Cl.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33](=N)OCC)[CH2:29][CH2:28]1)=[O:26].[H-].[Na+]>O>[CH3:12][O:11][C:10]1[C:3]([O:2][CH3:1])=[C:4]2[C:5]([C:6]([NH2:15])=[N:7][C:33]([N:30]3[CH2:31][CH2:32][N:27]([C:25]([C:21]4[O:20][CH:24]=[CH:23][CH:22]=4)=[O:26])[CH2:28][CH2:29]3)=[N:13]2)=[CH:8][CH:9]=1
Reactant: CCOC(=N)N1CCN(C(=O)c2ccco2)CC1
Reactant: COc1ccc(C#N)c(N)c1OC
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(N)nc(N3CCN(C(=O)c4ccco4)CC3)nc2c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.78 g. (0.01 mole) 3,4-dimethoxy-2-aminobenzonitrile in 30 ml. of N,N-dimethylformamide is added 2.88 g. (0.01 mole) ethyl 4-(2-furoyl)piperazin-1-ylformimidate hydrochloride followed by 855 mg. (0.02 mole) of a 56.1% dispersion of sodium hydride in mineral oil. The reaction mixture is stirred at ambient temperature for 30 minutes, and then it is heated to ca. 100° C. and maintained at that temperature for 12 hours. The reaction mixture is cooled to ambient temperature, diluted with an excess of water, and then extracted with chloroform. The chloroform extract is washed several times with water, dried using anhydrous magnesium sulfate, and then evaporated to dryness in vacuo. This affords crude 7,8-dimethoxy-4-amino-2-[4-(2-furoyl)piperazin-1-yl]quinazoline, which is purified further by recrystallization from aqueous ethanol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CCNCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3 (4.4 g, 13 mmol) in 90 ml of methylene chloride was added 45 ml of TFA. After stirring at room temperature for 24 hours, the solvents were removed in vacuo and the residue partitioned between chloroform and 10% Na2CO3. The organics were dried over MgSO4, filtered, and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:38])[CH:20]([CH:21]=[C:22]([Cl:34])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH:19]1[C:35](Cl)=[O:36].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[F:16][C:15]1[CH:14]=[CH:13][C:10]([CH2:11][O:12][C:35]([CH:19]2[CH:20]([CH:21]=[C:22]([Cl:34])[C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:25][CH:24]=3)[C:18]2([CH3:38])[CH3:17])=[O:36])=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)Cl
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)OCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
4.4 g (0.02 mol) of 3-phenoxy-4-fluoro-benzyl alcohol and 7.1 g (0.02 mol) of 2,2-dimethyl-3-(2-chloro-2-(4-trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.5 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20°-25° C., while stirring. Stirring was then continued at 25°-35° C. for 3 hours. The reaction mixture was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a water-pump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.7 g (81.4% of theory) of 2,2-dimethyl-3-(2-chloro-2-(4 -trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid 4-fluoro-3-phenoxy-benzyl ester were obtained as a yellow oil with the refractive index nD23 : 1.5443.