Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=1.C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cc2cc(C3CCCCC3)ccc2o1
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1F
Yield: 65.9 %

Procedure:
A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.30 mmol), 4-bromo-2-fluorobenzaldehyde (48 mg, 0.24 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II)chloride (12 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (the aqueous work-up is optional). Purification by silica gel chromatography on ISCO system gave the title compound (51 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.00-7.97 (m, 2H), 7.46 (s, 1H), 7.43 (d, 2H), 7.32 (s, 1H), 7.25 (d, 1H), 2.62 (m, 1H), 1.95-1.77(m, 4H), 1.58-1.56 (m, 4H), 1.46-1.44 (m, 2H). MS (ESI) m/z: Calculated: 322.27; Observed: 323.2 (M++1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:3]1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.ClCCl>[O:24]1[C:2]2([CH2:7][CH2:6][O:5][CH:4]([CH2:8][O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH2:3]2)[O:1][CH2:22][CH2:23]1
Reactant: OCCO
Reactant: O=C1CCOC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CC3(CCO2)OCCO3)cc1
Yield: 101.9 %

Procedure:
4-Nitro-benzenesulfonic acid 4-oxo-tetrahydro-pyran-2-ylmethyl ester (0.5 g, 1.59 mmol), ethylene glycol (986 mg, 15.9 mmol) and p-toluene sulfonic acid (61 mg, 0.32 mmol) were refluxed in benzene (20 ml) for 20 hours. The solvent was removed in vacuo to afford a solid. The solid was dissolved in dichloromethane (30 ml) and successively washed with a saturated aqueous solution of sodium bicarbonate (2×5 ml) and water (2×5 ml). The organic phase was dried (Na2SO4), filtered and the solvent removal in vacuo afforded 582 mg (100%) of 4-nitro-benzenesulfonic acid 1,4,8-trioxa-spiro[4.5]dec-7-ylmethyl ester as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+].O>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH:8]=[C:7]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:6]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(F)ccc1S2
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)C=C(N1CCN(C)CC1)c1cc(F)ccc1S2

Procedure:
18 g of 8-fluoro-2-methyl-dibenzo[b,f]thiepin-10(11H)-one in 140 ml of absolute benzene are together with 33.2 ml of N methylpiperazine within 1/2 hour at 20°-25° treated with a solution of 5.8 ml of titanium tetrachloride in 40 ml of absolute benzene. The reaction mixture is subsequently heated for 20 hours under reflux conditions. The reaction mixture is poured, with vigorous stirring, into a mixture of 40 ml of saturated aqueous sodium bicarbonate solution and 120 ml of water, subsequently filtered and extracted with chloroform. The organic phase is dried and evaporated. One obtains 1-(8-fluoro-2-methyl-dibenzo[b,f]thiepin-10-yl)-4-methyl-piperazine, which is converted into the corresponding maleate by treatment with maleic acid. The maleate melts at 244° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.Cl.C[O:46][C:47](=[O:65])[C@@H:48]([NH2:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][N:59]=[C:58]([CH2:62][F:63])[CH:57]=2)=[CH:52][CH:51]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:64][C@@H:48]([CH2:49][C:50]5[CH:55]=[CH:54][C:53]([C:56]6[CH:61]=[CH:60][N:59]=[C:58]([CH2:62][F:63])[CH:57]=6)=[CH:52][CH:51]=5)[C:47]([OH:46])=[O:65])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(CF)c2)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(CF)c2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid and (S)-2-amino-3-[4-(2-fluoromethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedures L and B. LCMS (m/z): 861.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]/[O:12]C)/[CH2:6][CH2:5]2.CC(=CCC)C.Cl([O-])=[O:21].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([OH:12])=[O:21])[CH2:6][CH2:5]2
Reactant: CO/C=C1\CCc2cc(Br)ccc21
Reactant: [O-][Cl+][O-]
Agent: CCC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a solution of the product from Example 70, Part B (300 mg, 1.3 mmol) and 2-methyl-2-pentene (8 ml) in tert-butanol (32 ml) was added a solution of sodium chlorite (1.36 g, 0.12 mmol) in H2O (12 ml) containing sodium dihydrogen phosphate (1.07 g, 8.9 mmol) and the mixture was stirred vigorously for 20 min at room temperature. Solvents were concentrated in vacuo and the residue was diluted with H2O, extracted with EtOAc (3×), extracts combined, dried (Na2SO4), and concentrated in vacuo to give the title compound (180 mg, 56%).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:16]=[C:15]([CH2:17][N:18](C(OC(C)(C)C)=O)[C:19]2[CH:20]=[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][CH3:34])=[CH:28][C:27]=3[CH3:36])[C:22]([CH3:25])=[CH:23][CH:24]=2)[CH:14]=[CH:13][C:12]=1[CH2:44][O:45][C:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([O:9][CH2:10][C:11]1[CH:16]=[C:15]([CH2:17][NH:18][C:19]2[CH:20]=[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][CH3:34])=[CH:28][C:27]=3[CH3:36])[C:22]([CH3:25])=[CH:23][CH:24]=2)[CH:14]=[CH:13][C:12]=1[CH2:44][O:45][C:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(-c2cc(N(Cc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)C(=O)OC(C)(C)C)ccc2C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)c1ccc(-c2cc(NCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1 g (1.4 mmol) of 2-benzoyloxymethyl-5-{[tert-butoxycarbonyl(6,2′-dimethyl-4′-propionyl-biphenyl-3-yl)amino]methyl}benzyl benzoate are dissolved in 50 ml of dichloromethane. 1,1 ml (14 mmol) of trifluoroacetic acid are added and the medium is stirred at room temperature for 6 hours. After extraction with water/dichloromethane, the desired product is obtained in the form of a yellowish oil (m=820 mg, Y=95%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1cc(-c2cncc(C)c2)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cncc(C)c2)cnc1-c1ccccc1F
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-chloro-5′-methyl-3,3′-bipyridine-5-carboxylate (3-2, 4.25 g, 16.16 mmol) in degassed dimethylformamide (81 mL) at 25° C. was added 2-fluorophenylboronic acid (2.94 g, 21.01 mmol), PdCl2dppf (1.18 g, 1.62 mmol) and 4M aqueous cesium carbonate (10.1 mL, 40.4 mmol). The reaction flask was purged with nitrogen, sealed and stirred for 4 hours at 40° C. The crude reaction mixture was partitioned between water and EtOAc, separating layers and washing the organic layer with saturated sodium bicarbonate solution and brine. The solvent was removed by rotary evaporation and the crude product was taken up in DCM (40 mL). Quadrapure TU (6 g) was added and the mixture was stirred overnight at room temperature. Filtration and concentration afforded the title compound (3-3) as a solid. ESI+MS [M+H]+ C19H15FN2O2=323.1.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].[CH:14]([CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]>O1CCCC1>[OH:15][CH:14]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1
Reactant: Brc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(O)c2ccsc2)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 112.9 %

Procedure:
Under a nitrogen atmosphere, 5.0 g (30.67 mmol) of 3-bromothiophene in 5 ml of tetrahydrofuran were slowly added dropwise to 24.77 ml (32.2 mmol) of isopropylmagnesium chloride/lithium chloride complex (1.3 M in tetrahydrofuran) at 5° C. After the mixture had been stirred at 5° C. for 0.5 h, 6.54 g (30.67 mmol) of tert-butyl 3-formylpiperidine-1-carboxylate were slowly added dropwise. After removal of the cold bath, the reaction mixture was stirred for a further 1 h. Conventional work-up gave 10.3 g of tert-butyl 3-(hydroxythiophen-3-ylmethyl)piperidine-1-carboxylate; HPLC/MS (M+H-tBuO)+=244 as oil (diastereomers).
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[CH2:17]([NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)[CH3:18].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH2:17]([NH:19][C:20](=[O:33])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:28][CH2:29][N:30]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:31][CH2:32]2)=[CH:25][CH:26]=1)[CH3:18]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (50.00 mg, 0.232 mmol), N-ethyl-4-(piperazin-1-yl)benzamide (67.8 mg, 0.290 mmol) and (cyanomethyl)trimethylphosphonium iodide (90 mg, 0.372 mmol) in propiononitrile (Volume: 1.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.202 mL, 1.162 mmol) at 23° C. The reaction was stirred at 95° C. for 3 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×2 mL) and dried in vacuo to provide N-ethyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0595 g, 0.138 mmol, 59.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3 H) 2.51-2.60 (m, 4 H) 3.18-3.31 (m, 6 H) 3.62 (s, 2 H) 6.71-6.77 (m, 1 H) 6.94 (m, J=9.09 Hz, 2 H) 7.08 (dd, J=3.54, 1.52 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.68 (dd, J=3.03, 1.52 Hz, 1 H) 7.71 (m, J=8.84 Hz, 2 H) 8.17 (t, J=5.56 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.62 (br. s., 1 H). ESI-MS: m/z 431.4 (M+H)+. mp=251.7-259.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:19]([N:22]=[C:23](SC)[O:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH3:21]>C(O)CC>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:23]([O:24][CH2:25][CH2:26][CH3:27])[N:22]([CH2:19][CH2:20][CH3:21])[C:4]2=[O:6]
Reactant: CCCN=C(OCCC)SC
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CCCO
Product: CCCOc1nc2ccc(I)cc2c(=O)n1CCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
To a solution of 0.38 g (1.44 mmoles) of 2-amino-5-iodobenzoic acid and 0.14 g (1.38 mmol) of triethylamine in 7.15 mL of n-propanol was added 0.25 g (1.143 mmol) of S-methyl O-propyl propylcarbonimidothioate. The reaction mixture was stirred at room temperature for 18 h, heated to 60° C. for 24 h, and then heated to reflux for 6 h. The reaction was then concentrated under reduced pressure to give about 0.6 g of crude material, which was purified by flash chromatography on silica (93:7 hexanes:ethyl acetate) to give 0.21 g of the title compound, 1H NMR (400 MHz, CDCl3): δ0.96 (t,3H); 1.06 (t,3H); 1.64-1.79 (m,2H); 1.81-1.92 (m,2H); 4.05 (t,2H); 4.43 (t,2H), 7.19 (d,1H); 7.85 (dd,1H); 8.49 (d,1H). In addition, 0.11 g of propyl-5-iodoanthranilate was obtained from the flash chromatography, 1H NMR (400 MHz, CDCl3): δ1.02 (t,3H); 1.76-1.86 (m,2H); 4.23 (t,2H); 5.8 (br s,2H); 6.45 (d,1H); 7.45 (dd, 1H); 8.13 (d,1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1.CO[CH:14]=[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([I:25])[CH:23]=2)[C:18](=[O:26])[NH:17][C:16]1=[O:27]>CN(C)C=O>[I:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:26])[NH:17][C:16](=[O:27])[C:15]2=[CH:14][NH:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1
Reactant: COc1cnc(CN)cc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: COc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-methoxy-pyridin-4-ol (116 mg, 0.75 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (247 mg, 0.75 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness and treated with acetonitrile, the solid filtered and dried to give a pink solid, 293 mg, (87%); MS (ES+): m/z 451.9 (M+H).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.Br[C:17]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O>>[N+:25]([C:24]1[CH:23]=[CH:22][CH:21]=[C:18]2[C:17]=1[C:12]1[CH:11]=[CH:10][CH:9]=[C:4]3[C:5](=[O:7])[O:14][C:1](=[O:13])[C:2](=[CH:19]2)[C:3]=13)([O-:27])=[O:26]
Reactant: O=Cc1cccc([N+](=O)[O-])c1Br
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Product: O=C1OC(=O)c2cc3cccc([N+](=O)[O-])c3c3cccc1c23

Procedure:
As described in example 50, the following compounds were prepared from dimethyl homophthalate and 2-bromo-3-nitrobenzaldehyde (Rahman, L. K. A.; Scrowston, R. M. J. Chem. Soc. Perkin Trans. 1 1984, 385):
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([N:14]([CH3:23])[C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH:9]=[C:10]([C:11](O)=[O:12])[C:5]2=[N:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:30].C1COCC1>C1COCC1>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([N:14]([CH3:23])[C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH:9]=[C:10]([C:11]([NH2:30])=[O:12])[C:5]2=[N:4][N:3]=1
Reactant: N
Reactant: Cc1nnc2c(C(=O)O)cc(N(C)[C@@H](C)c3ccccc3)nn12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1nnc2c(C(N)=O)cc(N(C)[C@@H](C)c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of compound (S)-3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylic acid (200 mg, 0.64 mmol) in anhydrous THF (10 mL) was added oxalyl chloride (0.3 mL) dropwise. The reaction mixture was stirred at room temperature for 2 hrs, then 2N NH3/THF (1 mL) solution was added, and stirred for another 2 hrs. The mixture was concentrated in vacuum and the residue was purified by flash column chromatography (silica-gel, DCM: MeOH=20:1) to give product (S)-3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxamide (Compound 7) as a yellow solid (180 mg, 90%). 1H NMR (300 MHz, DMSO) δ 8.66 (s, 1H), 8.40 (s, 1H), 7.66 (s, 1H), 7.26˜7.36 (m, 5H), 5.71˜5.74 (q, 1H), 2.90 (s, 3H), 2.59 (s, 3H), 1.61 (d, J=6.9 Hz, 3H). LRMS (M+H+) calcd. 310; found 310.
Reaction SMILES: CO.C(O[C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])C.[CH2:26]([NH2:28])[CH3:27]>O>[CH2:26]([NH:28][C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])[CH3:27]
Reactant: CCN
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Solvent: O
Solvent: CO
Product: CCNC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Yield: 80 %

Procedure:
To the solution of methanol (20 ml) was added 4-(1H-5-indazolylamino)-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester (1 g) prepared from preparation example 1, added70% aq. ethylamine (25ml) at room temperatute, and reacted at 30-35° C. for 3 hr. The reaction mixture was cooled and slowly added H2O (30 ml) and stirred for 0.5 hr. The reaction mixture was filtered, washed with 30% aqueous methanol solution (10 ml) obtained the desired compound (0.8 g, 80%)
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][CH3:14].C1(C2C=CC=CC=2)C=CC=CC=1CN.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:7]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=1
Reactant: CCc1cccn1Cc1ccccc1-c1ccccc1
Agent: NCc1ccccc1-c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCc1cccn1Cc1ccccc1
Reaction time: 18 h

Procedure:
1-(biphenyl-2-ylmethyl)-2-ethyl-1H-pyrrole, 13: To the crude 12 (14 g, 83 mmol) in dry benzene (200 mL) at room temperature is added biphenyl-2-ylmethanamine solution (100 mmol) and triethylamine (110 mmol). The solution is heated to reach 65° C. and stirred for 18 h. The resulted reaction mixture is filtered and concentrated. The crude product was purified by silica gel chromatography to afford 13
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][N:55]([CH2:62][CH2:63]O)[C:56]1[CH:61]=[CH:60][N:59]=[N:58][CH:57]=1.Cl>C(Cl)Cl.C(Cl)Cl.CO>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:63][CH2:62][N:55]([CH3:54])[C:56]4[CH:61]=[CH:60][N:59]=[N:58][CH:57]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CN(CCO)c1ccnnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)c1ccnnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (314 mg, 1.2 mmol) and 2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (80 mg, 0.52 mmol) in methylene chloride (5 ml) and the mixture stirred for 2 hours at ambient temperature. The solvent was removed by evaporation, the residue was triturated with ether and the resulting solid was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol (9/1 followed by 8/2) to give a white solid. This solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (0.5 ml of a 4M solution) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(pyridazin-4-yl)amino)ethoxy)quinazoline hydrochloride (110 mg, 60%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44](O)=O.C=O>ClC(Cl)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:44])[C:9]1([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: CC(C)(C)CCC1(NCc2ccccc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: C=O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 50 °C
Yield: 58.9 %

Procedure:
To a solution of the product of Example 74G (10 mg, 0.016 mmol) in dichloroethane (0.1 mL) was added formic acid (1.2 μL, 0.032 mmol) followed by addition of aqueous 37% formaldehyde solution (1.3 μL, 0.018 mmol). The mixture was heated at 50° C. for 2 h. After cooling to room temperature, the solution was diluted with ethyl acetate (1 mL), washed with water (0.5 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (2% methanol/dichloromethane) afforded a greenish brown solid (6 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.31-0.50 (m, 1H), 0.73 (s, 9H), 0.90-1.07 (m, 1H), 2.11-2.30 (m, 1H), 2.35-2.48 (m, 1H), 2.71 (s, 3H), 3.00-3.10 (m, 3H), 3.45-3.62 (m, 1H), 4.07 (d, J=12.87 Hz, 1H), 7.26-7.40 (m, 5H), 7.42-7.60 (m, 3H), 7.64 (t, J=7.54 Hz, 1H), 7.71-7.80 (m, 1H), 7.93 (d, J=8.09 Hz, 1H), 8.22 (d, J=6.62 Hz, 1H), 10.06 (s, 1H), 13.53 (s, 1H); MS m/z 637.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][CH2:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][C@H:14]([CH2:13][OH:12])[CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: OC[C@H]1CCNC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Solvent: CC(=O)N(C)C
Product: OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1
Yield: 100.2 %

Procedure:
A solution of Intermediate 24b (485 mg, 2.83 mmol) and (S)-3-(hydroxymethyl)pyrrolidine (1.00 g, 9.90 mmol) in DMA (10 mL) was heated in the microwave at 175° C. for 2.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM, to give the title compound as a brown gum (670 mg, quant.). LCMS (Method 3): Rt 0.44 min, m/z 237 [MH+].