Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([NH:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[NH2:22][CH2:21][CH2:20][NH:19][C:17]([C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:6][CH2:5][C:4]1[CH:30]=[CH:31][CH:32]=[C:2]([Cl:1])[CH:3]=1)[CH:16]=2)=[O:18].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 1 h

Procedure:
To a cooled solution, 0° C., of tert-Butyl (2-(7-((3-chlorobenzyl)oxy)quinoline-3-carboxamido)ethyl)carbamate in DCM (1 mL) was added TFA (1 mL). The reaction was stirred for 1 hour, and concentrated under reduced pressure. The reaction mixture was taken up in MeOH and concentrated under reduced pressure to afford the title compound as a white solid, TFA salt (57 mg, 100%) 1H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J=2.0 Hz, 1H), 8.88 (t, J=5.5 Hz, 1H), 8.76 (s, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.51-7.39 (m, 4H), 5.34 (s, 2H), 3.55 (q, J=6.3 Hz, 2H), 3.10-2.95 (m, 2H). [M+H]=356.3
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].CN1CCCN(C)C1=O>C1COCC1>[CH2:16]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2cc(O)cnc2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1cc2cc(OCc3ccccc3)cnc2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-hydroxy-6,7-dimethoxyquinoline (150 mg; 0.73 mmol) in 3 mL THF is added benzyl bromide (0.13 mL;188 mg; 1.10 mmol) and NaH (59 mg; 1.46 mmol). This is stirred at room temperature for 1 hour and 25 mg of NaH added followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU)(255 mg; 2.07 mmol) and stirred at room temperature for 31/2 hours. The reaction mixture is partitioned between EtOAc and distilled H2O and extracted 2× with EtOAc. The latter is washed with brine, dried (MgSO4), filtered, evaporated to dryness and chromatographed with 1% MeOH/CHCl3 to obtain 3-benzyloxy-6,7-dimethoxyquinoline m.p. 146.5-148.5° C.).
Reaction SMILES: O[CH:2]1[CH2:9][CH2:8][CH:7]([OH:10])[CH:6]2[N:11]([CH3:12])[CH:3]1[CH2:4][CH2:5]2.[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][C:29]([OH:31])=[O:30])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])([CH3:15])[CH3:14].[OH2:32]>C1(C)C(C)=CC=CC=1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][C:29]([O:31][CH:3]2[CH2:4][CH2:5][CH:6]3[N:11]([CH3:12])[CH:2]2[CH2:9][CH2:8][CH:7]3[O:10][C:29](=[O:30])[CH2:28][C:19]2[CH:20]=[C:21]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:22]([OH:32])=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:18]=2)=[O:30])[CH:20]=[C:21]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:22]=1[OH:23])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(CC(=O)O)cc(C(C)(C)C)c1O
Reactant: CN1C2CCC1C(O)CCC2O
Reactant: O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1C
Product: CN1C2CCC(OC(=O)Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C1CCC2OC(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 28 %

Procedure:
Under nitrogen a stirred solution of the diol mixture 2,6-dihydroxy-9-methyl-9-azabicyclo [3.3.1]nonane and 2,5-dihydroxy-9-methyl-9-azabicyclo[4.2.1]nonane (4.28 g, 0.025 mole), 3,5-di-tert-butyl-4-hydroxyphenylacetic acid (14.55 g, 0.055 mole) and titanium tetraisopropylate (0.7 ml) in 100 ml of xylene was heated under reflux for 18 hours water being removed with a Dean-Stark trap. The xylene was evaporated under reduced pressure and the residue was dissolved in ether. The ether solution was washed with water then 10% aqueous sodium hydroxide and again with water. The dried (Na2SO4) solution was crystallized from petroleum ether and then from hexane to give 4.6 g (28%) of the desired ester, m.p. 98°-100° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18].C([O-])([O-])=O.[K+].[K+].C1([CH:31]([B-](F)(F)F)[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)C=CC=CC=1.[K+]>O1CCOCC1.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([CH2:31][N:32]4[CH2:33][CH2:34][CH:35]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:36][CH2:37]4)=[C:3]([C:17]#[N:18])[C:4]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1c(Cl)ccn2c(-c3ccccc3)cnc12
Reactant: F[B-](F)(F)C(c1ccccc1)N1CCCCC1
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: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1c(CN2CCC(c3ccccc3)CC2)ccn2c(-c3ccccc3)cnc12
Temperature: 150 °C
Yield: 61.9 %

Procedure:
To a mixture of compound D6 (0.15 g, 0.593 mmol) and K2CO3 (0.35 g, 2.55 mmol) in 1,4-dioxane (4 ml) and DMF (1.5 ml) was added compound D7 (0.237 g, 0.85 mmol). The resulting mixture was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.098 g, 0.085 mmol). The reaction mixture was then subjected to microwave heating in a sealed tube at 150° C. for 10 min. The reaction mixture was cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The residue thus obtained was purified by preparative reverse phase HPLC to yield compound E1 (0.072 g, 31%).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[S:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C=O.[C:51](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[F:42][C:36]1[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:35]=1[C:23]1[S:22][C:21]([CH2:20][CH2:19][OH:18])([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][N:30]([CH3:51])[CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2)(c1ccccc1)c1ccccc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO)c3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Preparation of 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-[2,5-c]pyridine: To a solution of 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.157 g, 0.225 mmol) in 5 mL DCE was added formaldehyde (0.067 mL, 37 wt % in water, 0.901 mmol) followed by sodium triacetoxyborohydride (0.052 g, 0.248 mmol). The resulting suspension was stirred vigorously at room temperature overnight, then treated with saturated Na2CO3 solution (30 mL) and stirred for 10 minutes. The mixture was extracted with EtOAc (3×30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-1% MeOH/DCM) to afford the desired product as a bright yellow foam, 0.119 g, 74%.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>>[O:26]1[CH2:27][CH2:28][N:1]([C:2]2[CH:15]=[CH:14][C:13]3[S:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5](=[O:16])[C:4]=3[CH:3]=2)[CH2:24][CH2:25]1
Reactant: Nc1ccc2sc3ccccc3c(=O)c2c1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1c2ccccc2sc2ccc(N3CCOCC3)cc12
Temperature: 180 °C

Procedure:
2-Aminothioxanthone (4.9 g.), anhydrous potassium carbonate (4.5 g.) and di(ethylene-glycol) diethyl ether (150 ml) were heated to reflux (180° C.) and 5.2 g. of 2-bromoethyl ether was added. The reaction was held at reflux for 24 hours, filtered hot and the solvent removed under vacuum. The residue was recrystallized from acetone to give 2-morpholinothioxanthone, mp 166-167° C. Structure was confirmed by IR, NMR, C-13 NMR and MS.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.[CH:39]([N:42]([CH:45]([CH3:47])[CH3:46])[CH2:43]C)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1C=C(N)C=[CH:67][C:66]=1[N:72](C)C>>[CH3:39][N:42]([CH3:43])[C:45]1[CH:47]=[CH:67][C:66]([NH:72][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:65]([O:64][CH3:63])[CH:46]=1
Reactant: COc1cc(N)ccc1N(C)C
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN(C(C)C)C(C)C
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N(C)C)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 55.9 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.35 mmol), was reacted with diisopropylethylamine (0.22 g, 1.7 mmol), diphenylphosphinic chloride (0.16 g, 0.7 mmol), then reacted with 2-methoxy-N,N-dimethyl-benzene-1,4-diamine prepared in Example 163 (0.07 g, 0.45 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-dimethylamino-2-methoxy-phenyl)-amide as a light yellow solid (Yield 0.12 g, 57%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[CH:6][CH:5]=1)#[N:3].[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:23]=[CH:22]2.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:17][CH:16]=3)[C:10](=[O:15])[CH2:11]1)(=[O:31])=[O:30])[CH:23]=[CH:22]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: N#Cc1ccc(CN2CCNCC2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A mixture of 1-(4-cyanobenzyl)-2-piperazinone hydrochloride (201 mg), 6-chloronaphthalene-2-sulfonyl chloride (205 mg), sodium carbonate (254 mg), ethyl acetate (10 ml) and water (5 ml) was stirred at room temperature for 2 hours. The organic layer was separated, washed with saturated brine, dried (MgSO4) and concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give pale pink crystals of the title compound (239 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C4CCCCO4)=[CH:19][CH:18]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)[CH2:31][CH3:32]>>[C:34]1([C:30]([CH2:31][CH3:32])=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[C:12]2[CH:13]=[N:14][C:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCC(=O)c1ccccc1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(CCCN2CCCC2)nc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(CCCN2CCCC2)nc1)c1ccccc1
Yield: 18 %

Procedure:
Following the general procedure of McMurry reaction as described in example 1, step B, (6-(3-(pyrrolidin-1-yl)propyl)pyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yl-oxy)phenyl)methanone (1.0 g, 2.5 mmol) was reacted with propiophenone (1.0 g, 7.6 mmol) to give 186 mg desired product (17.8% yield, Z/E=3/1). m/z=413[M+1]+.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].CN(C(ON1N=[N:40][C:35]2C=[CH:37][CH:38]=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCCC1>CN(C=O)C>[N:40]1([C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:24])=[CH:12][CH:11]=3)=[CH:23][CH:22]=2)=[O:21])[CH2:37][CH2:38][CH2:39][CH2:34][CH2:35]1
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(C(=O)N3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 30 mg (0.10 mmol) 4-((4-(2-acetamidopropyl)phenyl)ethynyl)benzoic acid (I72.2) in 1 mL DMF are added 20.0 μl (0.10 mmol) TEA and 50 mg (0.15 mmol) TBTU. The mixture is stirred at r.t. for 5 min before it is added to 10 mg (0.12 mmol) piperidine in 500 μl DMF. After stirring at r.t. for 72 h the mixture is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [C:1]([C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:2][C:1]1([C:4]2[C:14]3[CH2:13][CH2:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[C:9](=[O:19])[C:8]=3[CH:7]=[CH:6][CH:5]=2)[O:22][CH2:21][CH2:20][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cccc2c1CCc1ccccc1C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2cccc3c2CCc2ccccc2C3=O)OCCO1

Procedure:
7.4 g. of 1-acetyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, 9.5 g. of ethylene glycol, 30 ml. of toluene and 60 mg. of p-toluenesulfonic acid are heated in a water separator at reflux for 8 hours. Thereafter, the mixture is concentrated under reduced pressure, taken up in ethyl acetate, washed with sodium carbonate solution and water, dried and evaporated, whereby 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is obtained as yellow crystals having a melting point of 144°-145° C. (from ethyl acetate/petroleum ether).
Reaction SMILES: O=[C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH:5]([CH2:10][CH2:11]O)[C:4]([CH3:13])=[CH:3]1.CC12[O:23][CH2:22][CH2:21]C1C(C)(C)CC=C2.CC12OCCC1C(C)(C)CC(=O)C2>>[CH3:13][C:4]1[CH:5](/[CH:10]=[CH:11]/[C:22]([CH3:21])=[O:23])[C:6]([CH3:9])([CH3:8])[CH2:7][CH2:2][CH:3]=1
Reactant: CC1(C)CC=CC2(C)OCCC12
Reactant: CC1=CC(=O)CC(C)(C)C1CCO
Agent: CC1(C)CC(=O)CC2(C)OCCC12
Product: CC(=O)/C=C/C1C(C)=CCCC1(C)C

Procedure:
Identification has been carried out by mass spectrum as stated above. The composition can be characterized by the presence of compounds 1 [2-(4-hydroxy-2,6,6-trimethylcyclohex-2-en-1-yl)ethanol] and 2 [2-(4-keto-2,6,6-trimethylcyclohex-2-en-1-yl)ethanol] and especially 3 [1,5,5-trimethyl-9-oxa-bicyclo-[4.3.0]non-2-ene] and 4 [1,5,5-trimethyl-9-oxa-bicyclo[4.3.0]nonan-3-one]. (See Table A).
Reaction SMILES: C([NH:7][C:8]1[N:13]=[N:12][C:11]([CH2:14][C:15]([O-:17])=[O:16])=[CH:10][CH:9]=1)(=O)C(C)(C)C.[CH3:18][Si](C=[N+]=[N-])(C)C.C(OCC)C>Cl.O>[NH2:7][C:8]1[N:13]=[N:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)C(=O)Nc1ccc(CC(=O)[O-])nn1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COC(=O)Cc1ccc(N)nn1
Reaction time: 1 h

Procedure:
A solution of 2-(6-pivalamidopyridazin-3-yl)acetate (740 mg, 2.52 mmol) in 6 N hydrochloric acid (24 mL) was heated to 105° C. for 12 h, then cooled and concentrated in vacuo. The resulting crude residue was redissolved in methanol (10 mL) and treated dropwise with a 2 N solution of trimethylsilyldiazomethane in diethylether (2.52 mL, 5.04 mmol). After 1 h, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (sodium sulfate), filtered and concentrated to provide title compound. LC-MS (IE, m/z): 168 [M+1]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:13](Cl)(Cl)=[O:14].Cl.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[C:29]([C:31]3[CH:40]=[C:39]4[C:34]([CH2:35][CH2:36][NH:37][CH2:38]4)=[CH:33][CH:32]=3)[N:28]=[C:27]([NH2:41])[N:26]=2)[CH2:21][CH2:20]1>>[NH2:41][C:27]1[N:28]=[C:29]([C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][N:37]([C:13]([NH:1][CH:2]4[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]4)=[O:14])[CH2:38]3)=[CH:33][CH:32]=2)[CH:30]=[C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[N:26]=1
Reactant: O=C(Cl)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from ethyl 4-aminopiperidine-1-carboxylate (Aldrich, Cat. #198064), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=523.3.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][C:3]=1[O:10][CH3:11].[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH3:18][O:17][CH:12]([O:15][CH3:16])[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([O:10][CH3:11])[CH:4]=1
Reactant: COC(OC)OC
Reactant: COc1cc(C=O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(OC)OC)ccc1Cl
Yield: 86 %

Procedure:
A heterogenous mixture of methanol (2 ml), CH2Cl2 (3 ml), 4-chloro-3-methoxybenzaldehyde (2 g, 11.7 mmol; prepared essentially as described by R. M. Riggs et al., J. Med. Chem., 30 1887, 1987.), trimethyl orthoformate (1.7 ml, 15.5 mmol) and a large crystal of p-toluenesulfonic acid was stirred at room temperature for one hour. Additional MeOH (1 ml) and a crystal of p-toluenesulfonic acid were added and the solution was warmed until homogenous. Upon completion of the reaction, the solution was stirred 5 min with excess solid NaHCO3 and rotory evaporated to remove solvents. The paste was dissolved in 40 ml EtOAC, partitioned against dilute NaHCO3 solution, and evaporated to yield a light brown oil. The reaction was repeated with another 2 g of 4-chloro-3-methoxybenzaldehyde and both product oils were combined to give 4.37 g (86%) of dimethyl acetal 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](O)=[O:16])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][CH3:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH2:35][CH:36]([NH:39][CH2:40][C:15](=[O:16])[C@@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Product: CC(C)(C)OC(=O)N1CCC(NCC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1

Procedure:
The title compound was prepared according to EXAMPLE 229 from 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)-propionic acid (EXAMPLE 228) and 4-methylaminopiperidine-1-carboxylic acid tert-butyl ester (Preparation 86). Purification by chromatography using dichloromethane/methanol (95:5) as the eluent gave the title compound as a pale yellow powder. m/z (ES+)=558.48 [M+H]+; RT=3.82 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].Cl.[NH2:13][OH:14].C(OCC)(=O)C.O>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[N:13][OH:14])[CH3:10]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=NO)c1cc(O)ccc1O
Yield: 91 %

Procedure:
To a solution of 1-(2,5-dihydroxyphenyl)ethanone (10.0 g, 65.73 mmol) in ethanol (200 mL) was added hydroxylamine hydrochloride (13.7 g, 197.2 mmol). After heating to reflux for 16 hours, the solvent was reduced under reduced pressure. Ethyl acetate (200 mL) and water were added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried and concentrated to provide the product (10 g, 91%) as yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36]Br)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16].[F-].[K+].[Cl:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:43]=1[C:44]([OH:46])=[O:45].CCCCCC.CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36][O:46][C:44](=[O:45])[C:43]1[C:42]([Cl:41])=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:51])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)n(C)c2ccccc12
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c2c(Cl)cccc2Cl)n(C)c2ccccc12
Yield: 100.7 %

Procedure:
The titled product (63 mg, 100%, white solid) was prepared as described in Example 82 using N-[(1-methyl-3-isobutyl-indole-2-cabonyl)leucinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (52.9 mg, 0.089 mmol), potassium fluoride (13.0 mg, 0.22 mmol), and 2,6-dichlorobenzoic acid (17.1 mg, 0.089 mmol) in DMF (2.0 ml). TLC (hexane/EtOAc, 50/50): Rf=0.39.