Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=2[CH:28]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[N:24]1[CH2:23][C:22]2[CH:28]=[C:18]([Br:17])[CH:19]=[CH:20][C:21]=2[O:27][CH2:26][CH2:25]1
Reactant: Brc1ccc2c(c1)CNCCO2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(N3CCOc4ccc(Br)cc4C3)c2cc1OC
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A mixture of commercially available 4-chloro-6,7-dimethoxyquinoline (120 mg, 0.53 mmol), 7-bromo-2,3-dihydro-1,4-benzoxazepine hydrochloride (example 2, step 1) (200 mg, 0.53 mmol), diisopropylethylamine (0.14 g, 1.1 mmol), in NMP (2 mL) was stirred in a microwave reactor at 120° C. for 45 min. After cooling to room temperature, the reaction mixture was purified directly by silica gel flash chromatography (0-10% methanol-dichloromethane gradient) to give 4-[6,7-bis(methyloxy)quinolin-4-yl]-7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine (155 mg, 70% yield), MS (EI) for C20H19N2O3: 415 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[C:16]([F:25])([F:24])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].O>CC(N(C)C)=O.C1(C)C=CC=CC=1>[F:24][C:16]([F:25])([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: Oc1cccc(F)c1
Reactant: O=C(N1CCCC1)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(N1CCCC1)C(F)(F)Oc1cccc(F)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-fluoro-phenol (4.5 g, 40.0 mmol), and K2CO3 (6.1 g, 44.0 mmol) in 40 g of DMAC at 100° C. was added 2-bromo-2,2-difluoro-1-pyrrolidine-1-yl-ethanone (9.1 g, 40.0 mmol). The mixture was kept at that temperature for 1 h and then heated to 120° C. for 2 h. The reaction mixture was then cooled to room temperature and poured on 120 mL of H2O and 30 mL of toluene. The aqueous phase was extracted with 25 g of toluene. The combined organic layers were extracted with 10% NaOH (10 g) and H2O (2×15 g) and dried over Na2SO4. The product (8.3 g, >90% purity by NMR) was obtained after removal of all volatiles under reduced pressure as a slightly yellow liquid. The material could be used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
2-Chloro-9-methyl-6-morpholino-9H-purine-8-carbaldehyde was treated with 1.1 eq 1-(methylsulfonyl)piperazine, 7 eq trimethylorthoformate, 1 eq of acetic acid in 2 mL of dichloroethane for 6 hours upon which 1.1 eq of sodium triacetoxyborohydride was added to the reaction mixture. The reaction mixture was extracted with dichloromethane and water to give crude intermediate 4-(2-chloro-9-methyl-8-((4(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine which was then reacted with 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via General Procedure A and purified via reverse phase HPLC to give 41.8 mg 138 as a white solid. MS (Q1) 512.2 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: COCC(=O)Nc1cc2c(cc1F)/C(=C/c1[nH]c3c(c1C)C(=O)N(CCN1CCCC1)CCC3)C(=O)N2
Yield: 63.7 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a obtained from step 1 of Example 7 as starting materials to obtain (Z)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 52 (45 mg, yield 63.7%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([OH:27])=O)[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:10]=1.[CH3:36][NH:37][CH3:38].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([N:37]([CH3:38])[CH3:36])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)O)c3)cc12
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of {3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (100 mg, 0.19 mmol), dimethylamine (2 N solution in THF, 0.19 mL, 0.38 mmol), diisopropylethylamine (49 mg, 0.38 mmol) in THF was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluromiumhexafluorophosphate (110 mg, 0.29 mmol). The resulting suspension was heated to 60° C. with stirring till the 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluromiumhexafluorophosphate completely dissolved. The THF was evaporated and the residue was used in the next step reaction without further purification. MS: m/z 517 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]OS(C)(=O)=O)[CH:5]=[N:6][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.O>[N:14]([CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1cncc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cncc(Br)c1
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of crude methanesulfonic acid 5-bromo-pyridin-3-ylmethyl ester (4.20 g) in DMF (60 mL) was added NaN3 (10.0 g, 153.8 mmol). The mixture was stirred under N2 overnight then diluted with water. The mixture was extracted with EtOAc (2×300 mL) and the combined organic layers washed with water before drying over Na2SO4. The solution was concentrated in vacuo to afford crude 3-azidomethyl-5-bromo-pyridine (2.04 g) as a dark brown oil. This crude material was used directly in the next step.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([CH2:28][O:29][CH3:30])=[N:8][N:9]3[C:14]([C:15]4[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][O:24][CH3:25])=[CH:17][C:16]=4[O:26][CH3:27])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:31]1[CH2:36][CH2:35][CH:34]([CH:37]=O)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([CH2:28][O:29][CH3:30])=[N:8][N:9]3[C:14]([C:15]4[C:16]([O:26][CH3:27])=[CH:17][C:18]([CH2:23][O:24][CH3:25])=[CH:19][C:20]=4[O:21][CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:37][CH:34]2[CH2:35][CH2:36][O:31][CH2:32][CH2:33]2)[CH2:3][CH2:2]1
Reactant: O=CC1CCOCC1
Reactant: COCc1cc(OC)c(-c2cccc3c(NCC4CC4)c(COC)nn23)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc(OC)c(-c2cccc3c(N(CC4CCOCC4)CC4CC4)c(COC)nn23)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a solution of N-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]amine (80 mg) dissolved in tetrahydrofuran (2 mL) was added tetrahydropyran-4-carbaldehyde (44 mg) and sodium triacetoxyborohydride (82 mg), and the reaction mixture was stirred for 30 minutes at room temperature. Water and saturated aqueous sodium bicarbonate were added to the reaction mixture, extraction was performed with ethyl acetate and the organic extract was washed with brine. The organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (63 mg) was obtained as a yellow oil from the n-hexane:ethyl acetate (1:2) fraction.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:18](/B(O)O)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH3:23].[ClH:27]>CCOCC>[ClH:27].[CH:18](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCC/C=C/B(O)O
Reactant: CN(C)CCCNc1ccc2ncc(Br)n2n1
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCN(C)C)nn12
Yield: 40 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (31 mg, 40%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.63 (d, J=9.7 Hz, 1H), 7.55 (s, 1H), 6.74 (d, J=9.7 Hz, 1H), 6.69-6.66 (m, 2H), 3.52 (t, J=6.5 Hz, 2H), 3.29-3.26 (m, 2H), 2.90 (s, 6H), 2.32-2.38 (m, 2H), 2.18-2.16 (m, 2H), 1.54-1.48 (m, 2H), 1.46-1.39 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 155.6, 137.0, 134.2, 129.1, 126.8, 125.0, 116.3, 114.7, 57.3, 43.6, 38.5, 34.4, 23.8, 25.1, 23.1, 14.3; HPLC tR=9.2 min (Luna), 97.9%; ES-MS: (M+H)=302 m/z.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][C:11]#[N:12])[C:3]=1[N+:13]([O-])=O.O.C(O)(=O)C>C(O)C.[Zn]>[NH2:13][C:3]1[C:4]([NH:8][CH2:9][CH2:10][C:11]#[N:12])=[N:5][CH:6]=[N:7][C:2]=1[Cl:1]
Reactant: N#CCCNc1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: N#CCCNc1ncnc(Cl)c1N
Reaction time: 0.5 h

Procedure:
2-[(6-Chloro-5-nitro-4-pyrimidinyl)amino]ethyl cyanide (18.7 g, 82.2 mmol) was dissolved in 180 ml ethanol, 180 ml water and 18 ml acetic acid, and zinc powder was added slowly thereto at 0° C. The reaction solution was returned to room temperature and stirred for 30 minutes. Then, the insoluble matters were filtered off, and the filtrate was evaporated. The residue was diluted with ethyl acetate and washed with water and brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was suspended in diethyl ether, and the precipitated solid was collected by filtration to give the title compound which was then washed with diethyl ether to give the title compound (44.6 g, 51%).
Reaction SMILES: [C:1]([N:8]([CH3:29])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH2:24][CH3:25])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[C:34]#[N:35]>>[C:34]([C:33]1[CH:32]=[C:31]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH3:25])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:29])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)[CH:38]=[CH:37][CH:36]=1)#[N:35]
Reactant: CCOc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1cccc(Br)c1
Product: CCOc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 11 (374 mg, 0.92 mmol) is coupled to 3-bromobenzonitrile (200 mg, 1.10 mmol) using Method B to give the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:19]=3[N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:32][CH:31]=3)[C:17](=[O:43])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]([N:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)=[O:27])=[CH:25][C:19]=3[N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:32][CH:31]=3)[C:17](=[O:43])[CH2:16]2)=[O:14])=[CH:44][CH:45]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2c(c1)N(Cc1ccc(OC3CCNCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc2c(c1)N(Cc1ccc(OC3CCNCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2)N1CCCC1
Reaction time: 8 h

Procedure:
5 mg (0.008 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(4-piperidyloxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic acid trifluoroacetate was dissolved in 5 ml of dichloromethane. 1 mg (0.018 mmol) of pyrrolidine, 3 mg (0.018 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.005 ml (0.036 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[NH2:26][C:27]1[S:28][CH2:29][CH2:30][N:31]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:26][C:27]3[S:28][CH2:29][CH2:30][N:31]=3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1=NCCS1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1=NCCS1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 9.3 %

Procedure:
A suspension of 2-(4-chlorophenyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3.5 hours with a stream of nitrogen bubbling through it. Solid 2-amino-2-thiazoline (2.67 g, 0.0261 mole) was added to the reaction mixture. The resulting suspension was allowed to stir at room temperature overnight. The solvent was evaporated under reduced pressure to give a white solid. The solid was triturated in water (200 ml), filtered, and the filter cake was rinsed twice more with water. The resulting solid was heated in boiling isopropyl alcohol to dissolve most of it, filtered while hot, and cooled to room temperature. A white precipitate formed. Water was added, and the white solid was filtered and rinsed once with isopropyl alcohol and twice with isopropyl ether. A 1.0-g sample of the resulting 3.3 g of white solid was dried at high vacuum to give 0.6 g (29%) of title compound, mp. 227°-229° C.
Reaction SMILES: [C:1](O[CH:5]([CH3:9])[C:6]([OH:8])=[O:7])(=[O:3])C.C(N(CC)CC)C.ClC(OCC(C)C)=O.N[C:26]1[CH:31]=[CH:30]C(C2C(C)CC(=O)NN=2)=[CH:28][CH:27]=1>ClCCl.CN(C)C=O>[C:9]1([CH2:5][C:6]([OH:8])=[O:7])[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1.[CH3:1][OH:3]
Reactant: CC(=O)OC(C)C(=O)O
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CO
Product: O=C(O)Cc1ccccc1
Temperature: -20 °C

Procedure:
In 45 ml of dichloromethane was dissolved 2.0 g of α-acetoxypropionic acid. To this solution was added 2.1 ml of triethylamine and the mixture was cooled at -20° C. To this mixture was added dropwise 1.95 ml of isobutyl chloroformate and the mixture was reacted for 30 minutes at a temperature from -10° C. to -20° C. To the mixture was then added a solution of 3.0 g of 6-(p-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone in 20 ml of dimethylformamide, and the mixture was reacted for 90 minutes at room temperature. After the solvent was distilled off under reduced pressure, water was added to the residue and the whole was extracted with dichloromethane. The solvent was distilled off and the residue was purified by column chromatography on silica gel (solvent: benzene-acetic acid-methanol in a ratio of 10:3:0.6) whereby 2.7 g of the end product was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][NH:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:27]=1>>[N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:36]4[CH2:35][CH2:34][NH:33][CH:32]([C:29]5[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=5)[CH2:37]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: Fc1ccc(C2CNCCN2)cc1
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccc(F)cc5)C4)c(F)cc3cc2c1=O
Product: c1cnc2ncccc2c1
Yield: 142.2 %

Procedure:
(RS)-3-Ethoxycarbonyl-7,9-difluoro-8-[3-(4-fluorophenyl)-1-piperazinyl]-1-methyl-4-oxo -1,4-dihydrobenzo[9 [1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2 g) and (RS)-2-(4-fluorophenyl)piperazine (4 g). After 1 recrystallization in a mixture of dimethylformamide (3.5 cc) and ethanol (31.5 cc), (RS)-3-ethoxycarbonyl-7,9-difluoro-8-[3-(4-fluorophenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.1 g) is obtained in the form of a beige solid, m.p. 242° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CO>[NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([F:23])[CH:25]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: COC(=O)c1ccc(-c2nc(Br)cc(C(=O)OC)c2N)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC)c(F)c3)cc(C(=O)OC)c2N)cc1
Temperature: 125 °C
Yield: 80 %

Procedure:
A mixture of methyl 3-amino-6-bromo-2-(4-(methoxycarbonyl)phenyl)-isonicotinate (2.00 g, 5.48 mmol), 3-fluoro-4-methoxyphenylboronic acid (0.931 g, 5.48 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.316 g, 0.274 mmol) in a flask was flushed with nitrogen. Toluene (25 mL), MeOH (5 mL) and a 2 N aqueous solution of sodium carbonate (6.2 mL, 12.4 mmol) was added and the reaction was heated in a 125° C. oil bath for 2 hr. The reaction was partitioned between EtOAc and a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine. It was dried with sodium sulfate and the solvents removed. Flash silica gel chromatography (elution with hexane containing 10% EtOAc) afforded methyl 3-amino-6-(3-fluoro-4-methoxyphenyl)-2-(4-(methoxycarbonyl)phenyl)isonicotinate (1.8 g). MS (ESI) m/z 411.2 (M+H). 1H NMR (CDCl3) δ ppm 8.18 (2H, d, J=8.24 Hz), 8.06 (1H, s), 7.81 (2H, d, J=8.24 Hz), 7.74 (1H, dd, J=12.97, 1.98 Hz), 7.68 (1H, d, J=8.85 Hz), 6.99 (1H, t, J=8.70 Hz), 5.98 (2H, br. s.), 3.97 (3H, s), 3.96 (3H, s), 3.92 (3H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[C:11]([C:23]([C:25]2C=CC=CN=2)=S)[CH:10]=1.C[Mg+].[Br-].C1C[O:37]CC1>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[C:11]([C:23]([CH3:25])=[O:37])[CH:10]=1
Reactant: C1CCOC1
Reactant: O=C1c2ccccc2-c2cc(C(=S)c3ccccn3)cc(COC3CCCCO3)c21
Agent: C[Mg+]
Agent: [Br-]
Product: CC(=O)c1cc(COC2CCCCO2)c2c(c1)-c1ccccc1C2=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
1-(2-Tetrahydropyranyl)oxymethyl-3-(2-pyridyl)thiocarbonyl-9-fluorenone (470 mg) was dissolved in THF (10 ml) and cooled to -15° under N2. A solution of MeMgBr in THF (1.2 eq) was added dropwise over 5 min and the reaction allowed to stir at -10° C. for 0.5 hr. The reaction was quenched with saturated ammonium chloride solution, diluted with EtOAc, and washed with water, sat'd NaCl sol'n then dried and evaporated which gave a residue which was chromatographed on silica gel to give the product (233 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1COCC1.C([Li])CCC.[Cl-:20].[Cl-].[CH3:22][Zr:23]([CH3:45])(=[SiH2:44])([CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[CH3:43])[CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:33]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O-:9].[Cl-:20].[CH3:45][Zr:23]([CH3:22])(=[SiH2:44])([CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[CH3:43])[CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:33]
Reactant: Cc1ccc(O)c(C)c1
Agent: CC1=Cc2ccccc2C1[Zr](C)(C)(=[SiH2])C1C(C)=Cc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc([O-])c(C)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.0 g (8.2 mmol) of 2,4-dimethylphenol in 20 ml of toluene/2 ml of THF were admixed at room temperature with 3.0 ml (8.2 mmol) of a 20% strength solution of butyllithium in toluene. The mixture was stirred for another 1 hour at 60° C. At room temperature, 1.9 g (4.0 mmol) of dimethylsilanediylbis(2-methylindenyl)zirconium dichloride were added as a solid. The suspension was stirred at 60° C. for 8 hours and subsequently filtered hot through Celite. After evaporation of the solvent to about 7 ml, the yellow solid which had precipitated at −30° C. was filtered off and dried under reduced pressure. This gave 0.65 g (29%) of dimethylsilanediylbis(2-methylindenyl)zirconium monochloride mono(2,4-dimethylphenoxide) (5).