Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:48]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:47])[CH2:39][CH2:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.[CH3:49][C:50]1[O:54][N:53]=[C:52]([C:55](Cl)=[O:56])[CH:51]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:48]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:47])[CH2:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([C:55]([C:52]2[CH:51]=[C:50]([CH3:49])[O:54][N:53]=2)=[O:56])[CH2:45][CH2:46]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: O=C(CCC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(CCC(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 54 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3piperidin-4-ylpropanamide bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 54% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.34 (m, 2H), 8.12 (s, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 6.40 (s, 1H), 4.42 (m, 2H), 3.88 (m, 2H), 3.03 (m, 2H), 2.83 (m, 4H), 2.45 (s, 3H), 2.27 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H), 1.10 (m, 1H). LCMS for C31H33ClN7O3 (M+H)+: m/z=586.2.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:15]O>>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
To a suspension of 2-chloronicotinic acid 3 (15.8 g, 0.1 mol) in 100 ml of dry MeOH at 0° C. was added thionyl chloride (17.8 g, 0.15 mol) dropwise. The reaction was then slowly warmed to room temperature and stirred for 2 days. The solvent was then removed via vacuum and the residue was dissolved in sat. NaHCO3. The resulted basic solution was then extracted with EtOAc (3×100 ml). The combined organic phases were washed with brine, dried with NaSO4, concentrated via vacuum to give 2-chloronicotinic methyl ester 4(15.3 g, 89%) as an oil: 1H NMR (CDCl3, 300 MHZ) δ 8.52 (dd, J=1.8, 4.5 Hz, 1H), δ 8.19 (dd, J=2.1, 7.8 Hz, 1H), δ 7.38 (dd, J=4.8, 7.8 Hz, 1H), δ 3.97 (s, 3H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[N:3]=1.[CH3:22][C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14])[N:3]=[C:2]2[NH:28][C:25]1[CH:24]=[C:23]([CH3:22])[NH:27][N:26]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2cccc(F)c2n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3c(F)cccc23)n[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (4-chloro-8-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone (0.4 g, 1.32 mmol), 5-methyl-1H-pyrazol-3-amine (0.15 g, 1.58 mmol), DIEA (0.69 mL, 4.0 mmol), and KI (0.24 g, 1.45 mmol) in DMF (8 mL) was stirred at rt for 20 h. The mixture was diluted with H2O (35 mL), and the precipitated solid was collected by filtration, washed with H2O, and triturated with MeOH at 0° C. A portion of the resulting solid was purified by preparative reverse phase HPLC to afford (8-fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone. 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.52 (s, 1H), 7.41 (t, 2H), 7.64-7.80 (m, 2H), 8.11 (t, 2H), 8.57 (d, 1H), 10.84 (s, 1H), 12.27 (br s, 1H); LC-MS (ESI) m/z 366 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:3]=1.[NH2:24][CH3:25]>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:4]1[N:3]=[C:2]([NH:24][CH3:25])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CN
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Product: CNc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product of Step C (300 mg) was added H2NCH3 (3.34 mL, 2 M solution in THF). The reaction stirred at room temperature overnight before concentrating. The product was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel with a gradient elution of 0% to 20% EtOAc in hexane affording the title compound. HPLC/MS: 353.9 (M+1), 355.9 (M+3); Rt=4.21 min.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1.ClC1C=C(Cl)C=CC=1C(O)=O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Agent: O=C(O)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 72.05 %

Procedure:
Into a 300 ml glass reactor equipped with a reflux condenser and a stirrer, and 50 g (0.207 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7- hexafluoro-1-[3H]-isobenzofuranone, 59.3 g (0.31 mol) of 2,4-dichlorobenzoic acid and 100 ml of xylene were charged, and the mixture was reacted at 150° C. for 12 hours with vigorous stirring. Then, the reaction mixture was separated by distillation to obtain 32.8 g of tetrafluorophthalic anhydride. The yield was 72.05%.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(Cl)cc2)=NN1
Yield: 81.5 %

Procedure:
To a solution of 3-(4-chlorobenzoyl)propionic acid (20 g) in absolute ethanol (200 ml) was added 5 g of hydrazine monohydrate. A thick solid was formed which dissolved after heating. The resulting solution was refluxed for 3 h, cooled and the solid formed filtered and dried to yield 16 g (80%) of 6-(4-chlorophenyl)-4,5-dihydropyridazinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([OH:25])=O)[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26].FC1C=CC=C(F)C=1NC(=O)NC1C=CC(C2C=C(C([NH:52][CH:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])=O)ON=2)=CC=1C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:52][CH:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])=[O:25])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26]
Reactant: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1ccc(F)cc1F
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1)C(C)C
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)c(C)c2)no1)C(C)C

Procedure:
The title compound was prepared from 3-(4-(3-(2,4-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylic acid using the same procedure as described for preparation of the compound of step 8 of Example 98. The title compound was obtained in crude form.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:48][C@@H:49]2[O:51][CH2:50]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1>CN(C=O)C>[CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:48][C@H:49]3[CH2:50][O:51]3)=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(O)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol (0.42 g, 1.0 mmol, 1.0 eq.) and Cs2CO3 (1.0 g, 3.0 mmol, 3.0 eq.) in DMF (3 mL) was stirred and preheated to 80° C. The reaction mixture was then treated with a solution of (2R)-(−)-glycidyl tosylate (0.27 g, 1.2 mmol, 1.2 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C. for ˜30-60 min following completion of the addition. Analysis of the reaction by TLC and LC/MS showed that the starting phenol had been consumed and the desired alkylated-phenol was the major product. The reaction was then cooled and diluted with EtOAc and washed with brine. The organic phase was dried with Na2SO4 and evaporated in vacuo. The crude alkylated-phenol was then purified by flash column chromatography over silica gel (EtOAc/hexanes ˜1:3).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:12][C:10](=O)[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.IC.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:10][NH:9][C:7](=[O:8])[C:5]1[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=1)[OH:12]
Reactant: O=c1[nH]c(=O)c2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1ccccc1O
Temperature: 80 °C
Yield: 77.4 %

Procedure:
Carsalam (30.00 g, 0.1840 mol), iodomethane (10.23 ml, 0.1643 mol), sodium carbonate (19.51 g, 0.1840 mol) and dimethylformamide (150 ml) were placed in a 500 ml round bottom flask. The reaction mixture was heated overnight at 80° C. After cooling to room temperature, the reaction mixture was filtered and a white solid collected. This was washed with water and the remaining solid placed into a 250 ml round bottom flask. Water was added to the filtrate from the initial filtration and more, white solid precipitated. This material was combined with the solid already in the 250 ml flask and 2N aqueous sodium hydroxide (150 ml) was added. The mixture was heated for one hour before heating was discontinued and the reaction mixture was allowed to cool overnight. Overnight, a white solid precipitated and was isolated by filtration and allowed to dry in vacuo. 21.52 g of N-methylsalicylamide was isolated.
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]([CH3:21])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)[C:10]=1[CH3:11])=O)C.[OH-].[K+].Cl.C(=O)=O>C(OCC)(=O)C.CCCCCC.C(O)(=O)C.O.C(O)CO>[CH3:21][C:8]1[NH:7][CH:6]=[C:10]([CH3:11])[C:9]=1[C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1[nH]c(C)c(-c2cccc(C(=O)O)c2)c1C
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: OCCO
Solvent: CC(=O)O
Product: Cc1c[nH]c(C)c1-c1cccc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
4-(3-Carboxy-phenyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (15.0 g), 15 mL of ethylene glycol, 45 mL of water and 17.4 mL of 9 N potassium hydroxide were refluxed at 105° C. for 30 minutes. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed conversion of all starting material at Rf 0.5 to a new product at Rf 0.3. The mixture was cooled 100° C. and 21 mL of 10 N hydrochloric acid were added to a pH of 2.5 accompanied by rapid release of carbon dioxide gas. The mixture was cooled to ambient temperature and vigorously stirred for 30 minutes. The solids were collected by vacuum filtration and washed three times with 20 mL of water each time to give 10.9 g (97% yield) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-benzoic acid as a light purple solid. 1H-NMR (dimethylsulfoxide-d6) δ 2.08, 2.16 (2×s, 2×3H, 2×CH3), 6.45 (s, 1H, pyrrole CH), 7.46, 7.75 (multiplets, 4H, aromatic), 10.42 (br s, 1H, NH), 12.81 (br s, 1H, COOH). MS m/z 216 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19](I)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:29]([Sn:33](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH2:30][CH2:31][CH3:32])[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(Cl)c3)n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a stirred solution of 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (Example E.75) (0.43 g, 1.0 mmol) in THF (7 mL) was added at 0° C. iso-propylmagnesium chloride lithium chloride (1M in THF, 1.22 mL, 1.22 mmol). The reaction mixture was allowed to stir for 15 min at 0° C., tributyltin chloride (0.43 g, 1.33 mmol) was added, the reaction mixture was stirred at room temperature for 5 h, poured into saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (ethylacetate/heptane) to yield the title compound (0.55 g, 92%) as a light yellow oil. MS (ISP) 593.2 [(M+H)+].
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[N:6]([CH3:8])[CH3:7].[C:15](OCC)(=[O:17])C>[Pd]>[CH3:15][O:17][C:4]1[CH:3]=[C:11]([NH2:12])[CH:10]=[CH:9][C:5]=1[N:6]([CH3:7])[CH3:8]
Reactant: COc1cc(N(C)C)ccc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [Pd]
Product: COc1cc(N)ccc1N(C)C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A suspension of 3-methoxy-N,N-dimethyl-4-nitroaniline (Bionet) (0.5 g, 2.6 mmol) and Pd/C (Aldrich, 10%, 0.1 g) in ethyl acetate (10 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-methoxy-N,N-dimethyl-benzene-1,4-diamine as a dark brown oil (0.4 g, 94%).
Reaction SMILES: NC1N=C(N)C2C(CN(C3C=CC=CC=3)C3C=CC=CC=3)=CSC=2N=1.[NH2:26][C:27]1[N:28]=[C:29]([NH2:37])[C:30]2[C:35]([CH3:36])=[CH:34][S:33][C:31]=2[N:32]=1.[CH:38]1[C:48]2[C:42](=[N:43][C:44]3[CH:52]=[CH:51][CH2:50][CH2:49][C:45]=3[CH2:46][CH:47]=2)[CH:41]=[CH:40][CH:39]=1>>[NH2:26][C:27]1[N:28]=[C:29]([NH2:37])[C:30]2[C:35]([CH2:36][CH:49]3[C:45]4[CH2:46][CH:47]=[C:48]5[CH:38]=[CH:39][CH:40]=[CH:41][C:42]5=[N:43][C:44]=4[CH:52]=[CH:51][CH2:50]3)=[CH:34][S:33][C:31]=2[N:32]=1
Reactant: C1=CC2=C(CC=c3ccccc3=N2)CC1
Reactant: Cc1csc2nc(N)nc(N)c12
Agent: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)csc2n1
Product: Nc1nc(N)c2c(CC3CC=CC4=C3CC=c3ccccc3=N4)csc2n1

Procedure:
9-[(2,4-Diaminothieno[2,3-d]pyrimidin-5-yl)methyl]-9,10-dihydrodibenz-[b,f]azepine (Formula I: Ar=2,4-diaminohieno[2,3-d]pyrimidi-5-yl; W=CH2; X=N; Z=CH2CH2; m=n=0) is prepared similarly to N-[(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed in Example 11 above, by using 2,4-diamino-5-methylthieno[2,3-d]pyrimidine (1.3 g, 7.4 mmol) in Step 1 and 9,10-dihydrodibenz[b,f]azepine (158 mg, 0.8 mmol) in Step 3. The final product and its intermediates chromatography.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([N:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:15][CH:16]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:46]1[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=1)=[O:35]
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCO)cc1OC
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCOc2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
5-[4-(9H-9-Carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]-1-pentanol (0.12 g, 0.22 mmol) prepared in Example 135 was mixed with 4-fluorophenol (50 mg, 0.44 mmol), tetrahydrofuran (4 ml), diethyl azodicarboxylate (69 μl, 0.44 mmol) and triphenylphosphine (0.11 g, 0.44 mmol), followed by stirring overnight at room temperature. After distilling off the solvent, the residue was partitioned between ethyl acetate and water, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and then evaporated to remove the solvent. The residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/10) to give the titled compound (0.13 g, yield: 93%) as a white crystal (cis:trans=4:1).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[H][H].CCCCCCC>C(O)(=O)C.[Ni]>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[CH:23]1[CH:14]([CH2:15][C:16]2[C:21]([NH:22]1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CC2Cc3ccccc3NC12
Temperature: 110 °C
Yield: 95.7 %

Procedure:
In a 350 mL high pressure autoclave, 6 g (17.2 mmol) of camptothecin was suspended in 60 mL of acetic acid, and into which 2.4 g of stabilized nickel catalyst (N113) was added. After substituting the atmosphere in the autoclave with hydrogen, the suspension was heated at 110° C. under 2.0 MPa for 3 hours with stirring, whereat the starting material disappeared. The reaction liquid was cooled off to room temperature, filtered on 3 g of Celite and washed with 30 mL of acetic acid. The filtrate was washed with heptane (once with 80 mL and twice with 60 mL each), extracted with 60 mL of chloroform, and the organic layer was washed successively with 30 mL of water and 30 mL of saturated saline. The organic layer was dried over 2 g of magnesium sulfate, filtered and concentrated. To the resulting orange colored oil, 10 mL of chloroform was added and heated at 35° C. to form a homogeneous solution. Upon adding thereto 10 mL of heptane, a precipitate was formed. Distilling the solvent off under reduced pressure and drying the residue, 5.8 g of 1,2,6,7-tetrahydrocamptothecin was obtained as an orange colored powder (yield: 96.8%, in which the diastereoisomeric ratio* was 21:76).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:18][N:19]1[CH:23]=[C:22]([NH:24][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH:13]4[O:14][CH2:15][CH:16]([OH:17])[CH:12]4[O:11][CH2:10]3)[CH:5]=[CH:4][N:3]=2)[CH:21]=[N:20]1
Reactant: Cn1cc(N)cn1
Reactant: OC1COC2C(Nc3ccnc(Cl)n3)COC12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2nccc(NC3COC4C(O)COC34)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a suspension of 6-((2-chloropyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-ol (354 mg, 1.37 mmol) in n-BuOH (3 mL) were added 1-methyl-1H-pyrazol-4-amine (220 mg, 1.65 mmol) and DIPEA (531 mg, 4.11 mmol). Then the mixture was stirred under nitrogen atmosphere at 150° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a yellow solid (120 mg, 22%).
Reaction SMILES: [I:1]Cl.[C:3]1([S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Ca+2]>CO>[I:1][C:14]1[CH:13]=[C:12]([S:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)(=[O:10])=[O:11])[CH:17]=[CH:16][C:15]=1[NH2:18]
Reactant: ClI
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)c2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
Iodine chloride (1.94 g, 12 mmol) in methanol (30 mL) was added to a mixture of [4-(phenylsulfonyl)phenyl]amine (Step 1, 2.33 g, 10 mmol) and calcium carbonate (2.0 g, 20 mmol) in methanol (20 mL). The reaction was stirred at room temperature for 72 hours. The reaction mixture was filtered and the filtrate evaporated. The residue was taken up in ethyl acetate and washed with sodium sulfite solution and brine, then evaporated. The residue was triturated with diethyl ether to give [2-iodo-4-(phenylsulfonyl)phenyl]amine (2.3 g). 1H NMR (400 MHz, d6-DMSO) δ 7.99 (1H, d, J=2.1 Hz), 7.87-7.85 (2H, m), 7.64-7.54 (4H, m), 6.77 (1H, d, J=8.6 Hz), 6.24 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=3)[S:10][C:3]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: COc1ccc(I)nc1
Product: COc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Yield: 33.9 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.214 g, 0.64 mmole) with 2-iodo-5-methoxypyridine (0.152 g, 0.64 mmole) using tereakis(triphenylphosphine)palladium(0) (30 mg) as catalyst in a manner as previously described for example 39b to give a yellow solid (0.060 g, 34%). 1H NMR (300 MHz, CDCl3) δ 8.55 (1H, d, J=5.1 Hz), 8.43 (1H, s), 8.28 (1H, dd, J=1.3, 4.6 Hz), 7.34 (1H, m), 7.28 (1H, m), 7.24 (1H, d, J=5.8 Hz), 4.04 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:13]1[CH2:14][CH:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[CH2:10][C:11](=[O:16])[CH:12]=1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2c(Cl)cccc2Cl)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2c(Cl)cccc2Cl)C1
Yield: 79.7 %

Procedure:
A mixture of 5-(2,6-dichlorophenyl)cyclohexane-1,3-dione (1.8 g) and ammonium acetate (1.7 g) in ethanol (20 ml) was refluxed for 60 hours, and the reaction solution was concentrated under reduced pressure. To the residue were added ethyl acetate (80 ml) and water (20 ml), and the mixture was shaken and separated. The ethyl acetate layer was washed with water (10 ml, thrice) and concentrated under reduced pressure. To the residue was added ethyl acetate (8 ml) to precipitate crystals, which were filtered and dried to give 1-amino-5-(2,6-dichlorophenyl)cyclohexen-3-one (1.43 g) as pale yellow crystals.