Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: Brc1ccc(N2CCOCC2)cc1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 4-(4-bromo-phenyl)-morpholine (101.0 mg, 0.4172 mmol) in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.018 g, 12%). MP=247-249° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.28-8.24 (m, 2H), 8.15-8.11 (m, 2H), 7.55-7.51 (m, 2H), 7.49-7.44 (m, 2H), 7.04-7.01 (m, 1H), 6.96-6.91 (m, 2H), 6.68 (s, 1H), 3.90-3.85 (m, 4H), 3.15 (s, 3H), 3.14-3.10 (m, 4H). MS=450 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>CO.C1COCC1.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CNc2nc(-c3cncnc3)nc3cccc(-c4ccccc4)c23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CNc2nc(-c3cncnc3)nc3cccc(-c4ccccc4)c23)cc1
Temperature: 45 °C
Reaction time: 12 h
Yield: 64.8 %

Procedure:
To a solution of methyl 4-((5-phenyl-2-(pyrimidin-5-yl)quinazolin-4-ylamino)methyl)benzoate (400 mg, 0.89 mmol) in MeOH-THF—H2O (6 mL-6 mL-0.5 mL) was added LiOH (112 mg, 2.67 mmol). Upon completion of addition, the reaction mixture was heated to 45° C. where it stirred for 12 h. After this time, the reaction mixture was concentrated under reduced pressure to remove the MeOH and THF and then carefully acidified with 1.5N HCl. The resulting precipitate was collected by filtration to afford 4-((5-phenyl-2-(pyrimidin-5-yl)quinazolin-4-ylamino)methyl)benzoic acid (250 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.87 (bs, 1H), 9.68 (s, 2H), 9.39 (s, 1H), 8.09 (m, 1H), 7.98 (t, J=8.0 Hz, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.53-7.48 (m, 6H), 7.26 (d, J=8.0 Hz, 2H), 6.65 (bs, 1H), 4.78 (d, J=5.2 Hz, 2H). LCMS Method O: retention time 1.73 min, [M+1]=434.2. HPLC Method B: purity 98.1%, retention time 8.24 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.C([Li])CCC.CCCCCC.Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([C:31]([O:33][CH3:34])=[O:32])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: COC(=O)Cl
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN(CCC)C1CCc2cccc(C(=O)OC)c2C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
Alternatively, to a solution of 8-bromo-2-dipropylamino-1,2,3,4-tetrahydronaphthalene (220 mg, 0.71 mMol) in tetrahydrofuran (5 mL) at -78° C. was added a solution of n-butyl lithium in hexane (1.6 M, 1 mL, 1.6 mMol), and the solution was stirred for two hours at -78° C. The solution was then cannulated into a solution of methyl chloroformate (0.5 mL, 6.5 mMol) in tetrahydrofuran (10 mL) at -78° C., and the reaction mixture was allowed to warm gradually to room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and was then extracted with diethyl ether. The combined extracts were dried over sodium sulfate and evaporated in vacuo to give a greenish-yellow oil. Purification by flash chromatography (3:1 hexane:tetrahydrofuran+tr. NH4OH) gave the title compound as a colorless glass (130 mg, 63%). The hydrochloride salt was formed and recrystallized (acetone/diethyl ether) to give colorless crystals (m.p.=132° C.).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([OH:12])[CH2:7][NH:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].O.CCOCC>CN(C=O)C>[C:9]([NH:8][CH2:7][CH:6]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])[CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)NCC(O)CNC(C)=O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCC(CNC(C)=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of N-(3-acetylamino-2-hydroxypropyl)acetamide (synthesized as described in J. Org. Chem., 2000, 65(4), 1200, which is incorporated herein by reference in its entirety) (741 mg, 4.25 mmol) and 1H-imidazole (579 mg, 8.51 mmol) in dry DMF (17 mL), a solution of tert-butylchlorodimethylsilane (962 mg, 6.38 mmol) in dry DMF (8 mL) was added dropwise, and the reaction was stirred at r.t. overnight. The reaction was portioned between H2O/Et2O, the phases were separated and the aqueous layer was washed twice with Et2O and three times with EtOAc. All the organics were combined, dried over Na2SO4, filtered and concentrated, affording N-[3-acetylamino-2-(tert-butyldimethylsilanyloxy) propyl]acetamide (1140 mg, 3.95 mmol, 93% yield) as off-white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.CCCCCC.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1.O>CS(C)=O.O1CCCC1>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: BrCCCCCCOC1CCCCO1
Reactant: c1cc[nH]c1
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: O
Solvent: CCCCCC
Product: c1ccn(CCCCCCOC2CCCCO2)c1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
First, 38.0 g (0.567 mol) of pyrrole and 200 mL of dehydrated tetrahydrofuran (THF) were fed into a 2 liter reactor vessel under a stream of argon gas and cooled to 5° C. or less. Then, 354 mL (0.567 mol) of 1.6M n-butyl lithium hexane solution were dripped into this mixture at 10° C. or less. After stirring for one hour at the same temperature, 600 ml of dimethylsulfoxide were further added, and THF was removed by distillation by heating for solvent substitution. Then, 165.2 g (0.623 mol) of 6-bromo-1-(tetrahydropyranyloxy)hexane were further dripped at room temperature. After dripping, the mixture was stirred for 2 hours at the same temperature. Then, 600 mol of water were added to the resultant reaction mixture to extract hexane and the organic layer was washed with water. Furthermore, after drying with anhydrous magnesium sulfate, the solvent was removed by distillation. The resultant residues were purified by silica gel column with hexane/ethyl acetate=4/1, and thus 107.0 g of N-[6-(tetrahydropyranyloxy)hexyl]pyrrole were obtained. The yield was 75.2%. Formula (27) below shows the reaction formula of the step 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22][NH2:23])[CH:18]=[CH:17][CH:16]=[N:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([N:14]4[CH:18]=[CH:17][CH:16]=[N:15]4)[CH:20]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1cccc(-n2cccn2)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(-n4cccn4)c3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 3-pyrazol-1-yl-benzylamine (111 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-pyrazol-1-yl-benzylamino)-2H-phthalazin-1-one: 60 mg (30.4%): m/z (M+H)=352. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 8.46 (d, 1H), 7.93 (m, 2H), 7.72 (m, 3H), 7.45 (m, 1H), 7.32 (d, 1H), 7.19 (dd, 1H) 6.86 (s, 1H), 6.52 (t, 1H), 4.50 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:30])=[CH:5][C:6]=1[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:10]2[CH:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:22](=[O:24])[CH:23]=[C:9]2[N:8]=1.C=O.[C:33](O)(=O)[CH3:34]>>[CH3:1][C:2]1[O:3][C:4]([CH3:30])=[CH:5][C:6]=1[CH:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:10]2[CH:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:22](=[O:24])[CH:23]=[C:9]2[N:8]1[CH2:11][N:10]([CH3:21])[CH2:9][CH2:23][C:33]1[CH:34]=[CH:2][CH:6]=[CH:7][N:8]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)C1C(=O)C=C2N=C(c3cc(C)oc3C)C=C(Cc3ccccc3F)N21
Agent: C=O
Product: CCOC(=O)C1C(=O)C=C2N(CN(C)CCc3ccccn3)C(c3cc(C)oc3C)C=C(Cc3ccccc3F)N21
Temperature: 25 °C

Procedure:
2-(2,5-Dimethyl-3-furyl)-6-ethoxycarbonyl-4-(2-fluorophenylmethyl)-pyrrolo[1,2-a]pyrimid-7-one (50 mg, 122 umol) was added into a solution of formaldehyde (5 μL, 184 μmol) and a secondary amine (184 μmol) in acetic acid (2 mL). The resulting solution was stirred at room temperature for ten minutes, and then 50° C. for another ten minutes. HOAc was evaporated and the residue was diluted with DCM and purified by prep-TLC (MeOH/DCM−1:9) to yield the desired product, which was characterized by proton NMR and mass spectra.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[OH:26][C@H:25]([CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: C1COCCN1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN1CCOCC1
Yield: 90.4 %

Procedure:
Using an analogous procedure to that described in Example 292, (2R)4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), (prepared as described for the starting material in Example 292), was reacted with morpholine (211 mg, 2.49 mmol) to give (2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (338 mg, 85%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>CC1C=CC=CC=1C.CC(=O)OCC.CCCCCCC>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:19]2[N:20]=[CH:21][C:16]([Br:15])=[CH:17][N:18]=2)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ncc(Br)cn2)C1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
To a solution of (+/−)-3-amino-1-N-Boc-piperidine (1 g) in dry o-xylene (20 mL) were added successively 5-bromo-2-chloropyrimidine (965 mg), anhydrous K2CO3 (1.38 g), DIEA (3.42 mL). The reaction mixture was stirred at reflux for 3 d under nitrogen. After cooling to RT, the brown suspension was filtered and the filtrate was concentrated to yield a crude brown-orange oil. FC (EA/n-heptane: 3/7) gave 850 mg (46%) of the title compound as a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)n1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(COc2cccc(N3CCCC3)n2)cc1
Yield: 92.4 %

Procedure:
In a dried microwave reactor into which an argon gas was introduced, 526 mg (2.0 mmol) of 2-(benzyloxy)-6-bromopyridine, 200 μl (2.4 mmol) of pyrrolidine, 283 mg (2.8 mmol) of sodium t-butoxide, 9 mg (0.005 mmol) of tris(dibenzylideneacetone)dipalladium(0) (0.5 mol % of Pd), 19 mg (0.015 mmol, 1.5 mol %) of (±)-BINAP and 3 ml of toluene were placed, followed by stirring and reacting the mixture using microwave at 120° C. for 10 min. The reaction mixture was diluted with 20 ml of ethyl acetate, filtered through Cellite, and kept under a reduced pressure to remove the solvent. The residue was subjected to column chromatography using 10% ethyl acetate/hexane as an eluent to obtain 470 mg (yield 92%) of 2-(benzyloxy)-6-(pyrrolidin-1-yl)pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].[H][H]>[C].[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: [H][H]
Reactant: Cc1cc(C(=O)CCC(=O)O)ccc1F
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CCCC(=O)O)ccc1F
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 87.8 %

Procedure:
In a 50-ml autoclave, 1.0 g of 4-(4-fluoro-3 -methylphenyl)-4-oxobutanoic acid and 2.5 ml of methanol were charged, followed by the addition of 0.1 g of 10% palladium-carbon. After hydrogen pressure was increased to 30 kg/cm2 at room temperature, the resulting mixture was stirred at 50° C. for 3.5 hours. After the completion of the reaction, the reaction mixture was filtered, followed by washing with methanol. The filtrate was thereafter concentrated under reduced pressure. Water was added to the residue so obtained. The crystals so precipitated were filtered, washed with water and dried under reduced pressure, whereby 0.82 g of the title compound was obtained.
Reaction SMILES: CC(=O)C.C(=O)=O.N.[Na].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][O:18]2)=[CH:13][CH:12]=1.Br[CH2:27][CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.[Cl-].[NH4+]>[Fe](Cl)(Cl)Cl.O.O(CC)CC>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:27][CH2:28][CH2:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][O:18]2)=[CH:13][CH:12]=1
Reactant: BrCCCOC1CCCCO1
Reactant: Fc1ccc(C2OCc3ccccc32)cc1
Agent: Cl[Fe](Cl)Cl
Agent: N
Agent: O=C=O
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: Fc1ccc(C2(CCCOC3CCCCO3)OCc3ccccc32)cc1
Reaction time: 8 h

Procedure:
To a stirred and cooled (2-propanone/CO2 -bath) amount of 1080 parts of ammonia was added 1 part of iron (III) chloride, followed by the portionwise addition of 7.7 parts of sodium under nitrogen atmosphere. After stirring for 20 minutes, there was added dropwise a solution of 64.5 parts of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran in 105 parts of 1,1'-oxybisethane while still cooling. Then there was added dropwise a solution of 75 parts of 2-(3-bromopropoxy)tetrahydro-2H-pyran in 37 parts of 1,1'-oxybisethane. Upon completion, stirring was continued for 2 hours under nitrogen atmosphere in a 2-propanone/CO2 -bath. Without cooling and without nitrogen, there were added dropwise slowly 490 parts of 1,1'-oxybisethane and stirring was continued overnight at room temperature. 225 Parts of a saturate ammonium chloride solution were added dropwise followed by the addition of 200 parts of water. The layers were separated and the aqueous phase was extracted twice with 1,1'-oxybisethane. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (99.5:0.5 by volume) as eluent. The second fraction was collected and the eluent was evaporated, yielding 39.6 parts of 1-(4-fluorophenyl)-1,3-dihydro-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]isobenzofuran as a residue (intermediate 93).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:28]([C@:30]1(C)[S:36][C@H:35]2[N:32]([C:33](=[O:37])[CH2:34]2)[C@H:31]1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=O.C(Cl)Cl>C(OCC)C>[CH3:28][C@@:30]1(/[CH:8]=[CH:7]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[S:36][C@H:35]2[N:32]([C:33](=[O:37])[CH2:34]2)[C@H:31]1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39]
Reactant: C(Cc1ccccn1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@]1(/C=C/c2ccccn2)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 353 mg (1.0 mmol) of (2-picolyl)methylene-triphenylphosphorane and 381 mg (1.00 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo-[3.2.0]heptane-2-carboxylate in 10 ml of diethyl ether was stirred at room temperature under argon for 2 hours. The mixture was treated with 10 ml of methylene chloride, insoluble material was removed by suction filtration and the filtrate was concentrated. The residue remaining behind was chromatographed over silica gel (particle size 0.040-0.063 mm) with methylene chloride:ethyl acetate (95:5) as the eluent. Yield: 128 mg (28%) of a colorless foam MS: (M·) 456 IR (KBr): 1779, 1747, 1634, 1291, 988 cm-1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.CCN(CC)CC>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:19][C:18]3[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Brc1ccc(-c2nnn[nH]2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nnnc2-c2ccc(Br)cc2)cc1

Procedure:
At room temperature, to a stirred mixture of 5-(4-bromophenyl)-1H-tetrazole (2.15 g, 9.55 mmol) in CH3CN, add 4-methoxybenzyl chloride (1.42 mL, 10.50 mmol) followed by Et3N (1.46 mL, 10.50 mmol) and stir over night. Concentrate the mixture to half the volume and add water (100 mL). Filter the white precipitate and wash with water (100 mL). Dry the material to give 5-(4-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole as white flocculent crystals (1.37 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2C1CCNCC1.N1C=CC(CCCCl)=N1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Agent: ClCCCc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Temperature: 100 °C

Procedure:
A mixture of 3.26 gm (14 mMol) 5-chloro-3-(4-piperidinyl)-1H-indole, 2.03 gm (14 mMol) 3-(1H-pyrazol-3-yl)-1-chloropropane and 3.71 gm (35 mMol) sodium carbonate in 76 mL dimethylformamide was heated at 100° C. for 18 hours. The reaction mixture was cooled to ambient and the solvent removed under reduced pressure. The residue was partitioned between water and dichloromethane, then the phases were separated. The organic phase was washed with water followed by saturated aqueous sodium chloride and the remaining organics were dried over sodium sulfate. The dichloromethane was removed under reduced pressure and the residual yellow oil subjected to flash silica gel chromatography, eluting with a gradient system of dichloromethane containing 0-10% methanol. Fractions shown to contain product were concentrated under reduced pressure to give 1.72 gm (35.9%) 5-chloro-3-<1-<3-<1H-pyrazol-4-yl>propyl>-4-piperidinyl>-1H-indole as a colorless foam. The oxalate salt was formed to give the title compound as a light yellow foam. m.p.=110° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:47][CH3:48])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:39][CH:38]2[N:23]([C:24](=[O:46])[C:25]([CH3:45])([CH3:44])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]3[C:35]([C:41]([OH:43])=O)([NH:36][C:37]2=[O:40])[CH2:34]3)[CH2:22]1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:90][S:91]([CH:94]6[CH2:96][CH2:95]6)(=[O:93])=[O:92])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:1][C:2]1[C:3]([O:47][CH3:48])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:39][CH:38]2[N:23]([C:24](=[O:46])[C:25]([CH3:45])([CH3:44])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]3[C:35]([C:41]([NH:90][S:91]([CH:94]4[CH2:96][CH2:95]4)(=[O:93])=[O:92])=[O:43])([NH:36][C:37]2=[O:40])[CH2:34]3)[CH2:22]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(C)(C)C(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(C)(C)C(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title compound was prepared from 18-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-14,14-dimethyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (54) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=798 (M+H)+. 1H NMR (CDCl3): 0.96 (m, 1H), 1.05-1.15 (m, 2H), 1.17 (s, 3H), 1.32 (s, 3H), 1.23-1.36 (m, 7H), 1.38 (d, J=6.8 Hz, 6H), 1.43-1.53 (m, 2H), 1.75-1.94 (m, 3H), 2.39 (m, 1H), 2.56 (m, 3H), 2.85-2.95 (m, 1H), 3.20 (m, 1H), 4.02 (s, 3H), 4.15 (dd, J=3.7 Hz, J=11.6 Hz, 1H), 4.23 (d, J=11.6 Hz, 1H), 4.73 (t, J=7.5 Hz, 1H), 4.99 (t, J=9.4 Hz, 1H), 5.52 (m, 1H), 5.80 (q, J=8.8 Hz, 1H), 7.08 (s, 1H), 7.17 (m, 2H), 7.54 (s, 1H), 7.84 (d, J=9.2 Hz, 1H), 10.3 (s, 1H).