Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(C)(=O)=O)c1

Procedure:
A mixture of 7.7 g (0.023 mol) of 4-benzyloxy-3-(N-methylsulphonylamino)phenyl acetate, 4.75 g (0.035 mol) of crushed potassium carbonate and 3.3 ml (0.0276 mol) of benzyl bromide in 150 ml of anhydrous acetone is stirred at reflux temperature for 4 hours. After filtration and evaporation, the compound of the title is obtained, which is recrystallized in ethyl acetate.
Reaction SMILES: C(NP(CC1C=C2C(=CC=1)NN=C2C1NC2C(C=1)=CC=CC=2)(C1C=CC=CC=1)=O)C.[N+](C1C=CC([O:40][P:41]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)(=[O:61])[O:42][C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[NH:48][N:47]=[C:46]3[C:52]2[NH:53][C:54]3[C:59]([CH:60]=2)=[CH:58][CH:57]=[CH:56][CH:55]=3)=CC=1)([O-])=O.C(NCC)C.N12CCCN=C1CCCCC2>ClCCl>[NH:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:60]=[C:52]1[C:46]1[C:45]2[C:49](=[CH:50][CH:51]=[C:43]([O:42][P:41]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)(=[O:40])[OH:61])[CH:44]=2)[NH:48][N:47]=1
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Oc2ccc3[nH]nc(-c4cc5ccccc5[nH]4)c3c2)c2ccccc2)cc1
Agent: CCNP(=O)(Cc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Solvent: CCNCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=P(O)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
For the purpose of preparing the compound [3-(1H-indol-2-yl)-1H-indazol-5-ylmethyl]phenylphosphinic acid N-ethylamide, a solution of 150 mg of phenyl-phosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester 4-nitrophenyl ester (prepared according to procedure E) and 1.5 ml of diethylamine (2M solution in tetrahydrofuran) in dichloromethane (stabilized with amylene) is stirred at ambient temperature. 44 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added and the medium is stirred overnight at ambient temperature. The solvent is evaporated off in a rotary evaporator and the reaction crude is purified by preparative LC/MS so as to isolate a compound of mass [M+H]+=390, which does not correspond to the expected product. A second fraction of 23 mg of a gray solid identified as phenylphosphonic acid mono-[3-(1H-indol-2-yl)-1H-indazol-5-yl]ester are collected.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=2[NH:3]1.[Br:17]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:17][C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH:12]=1
Reactant: N#Cc1ccc2c(c1)[nH]c(=O)c1ccsc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carbonitrile (1.0 eq, 350 mg, 1.55 mmol) was mixed with N-bromosuccinimide (1.1 eq, 303 mg, 1.70 mmol) in acetic acid (4 ml). The mixture was stirred at 100° C. for 4 hours. The mixture was cooled down to 80° C., more NBS (303 mg) was added and the mixture stirred overnight. Water was added and the material filtered and dried. Trituration in methanol and filtration afforded 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carbonitrile as a grey solid (396 mg, 84% yield). LCMS (ES)>80% pure, m/z 305 [M]+, 307 [M+2]+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:3].C([N-]C(C)C)(C)C.[Li+].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:33])[CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1.CCOCC>O1CCCC1>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([OH:33])([C:2]([CH3:3])([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:1])[CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)c1ccncn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(c1ccncn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 2.7 %

Procedure:
Treatment of the product of part (i) (2.46 g) with lithium diisopropylamide (0.02 mole) in dry tetrahydrofuran followed by 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (4.49 g) according to the method of Example 3 gave the title compound, (0.185 g), m.p. 126°-127° (from ether).
Reaction SMILES: C([Li])(C)(C)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1.Cl.[C:20](=O)(O)[O-:21].[Na+]>O1CCCC1.CN(C)C=O>[Cl:6][C:7]1[C:12]([CH2:20][OH:21])=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: Clc1ccc(-c2ccccc2)nc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCc1nc(-c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
tert-Butyl Lithium (1.7M pentane solution, 15 ml) was added slowly to a solution of 5-chloro-2-phenylpyridine (4.70 g) in tetrahydrofuran (50 ml) at −78° C. under a nitrogen atmosphere, which was stirred for 1 hour. N,N-Dimethylformamide (2.3 ml) was added to the mixture slowly, which was stirred for 1 hour while raising the temperature to room temperature. After addition of dilute hydrochloric acid the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Sodium borohydride (946 mg) was added slowly to a mixture of the residue, tetrahydrofuran (50 ml) and methanol (50 ml) at room temperature, which was stirred for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-chloro-6-phenyl-2-pyridylmethanol (2.35 g, yield 43%) as pale yellow crystals from the fraction eluted with ethyl acetate-hexane (1:6, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 69–70° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.C1C(=O)N([I:23])C(=O)C1.[Al]>CC#N>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[I:23]
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Reactant: O=C1CCC(=O)N1I
Agent: [Al]
Solvent: CC#N
Product: COC(OC)c1nc2c(cc1I)CCCN2
Reaction time: 4 h

Procedure:
A solution of 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 4, 1 g, 4.8 mmol) in MeCN (15 ml) was treated with NIS (1.13 g, 5.04 mmol), stirred for 4 h in a flask covered with aluminum foil. Them, the reaction mixture was concentrated. The residue was treated with Et2O and DCM, washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH2:34])[N:18]=[C:17]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH:34][S:43]([CH2:41][CH3:42])(=[O:45])=[O:44])[N:18]=[C:17]([C:35]3[N:36]=[CH:37][CH:38]=[CH:39][N:40]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCCN
Product: CCS(=O)(=O)NCCCOc1nc(-c2ncccn2)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 100 mg 4tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide was reacted with ethanesulfonylchloride to give 33 mg 4-tert.-butyl-N-[6-(3-(ethanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide. LC-MS: tR=5.25 min, [M+1]+=657.33, [M−1]−=655.45.
Reaction SMILES: [C:1](O)(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.S(=O)(=O)(O)O>>[O:10]=[C:1]1[CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:18]2[CH:17]=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:13]=2[O:12]1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc2c(c1)C(c1ccccc1)C(=O)O2
Temperature: 0 °C
Yield: 88.5 %

Procedure:
75 g of mandelic acid and 75 g of 4-hydroxyphenylacetic acid are mixed in a round-bottomed flask. 800 ml of 80% strength sulfuric acid are added and the medium is then brought rapidly to 90° C. while being stirred. It is hydrolyzed with 2 kg of ice, the aqueous phase is extracted with 3 times 500 ml of ethyl acetate and the organic phase is washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. 117 g of a yellow oil are thereby obtained, which is purified by chromatography on 1200 g of silica (70-230 mesh), using a mixture of dichloromethane and methanol (98.5:1.5 v/v) as eluant. After evaporation of the solvent, the pure product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:15][C:8]1[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: CCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 58.2 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylate (411 mg), N-bromosuccinimide (214 mg), 2,2-azobis(isobutyronitrile) (10mg) and carbon tetrachloride (10 ml) was stirred under reflux for 5 hours. The reaction mixture was washed with water, dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (10/1, v/v) gave ethyl 2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (285 mg, 58%) which was then recrystallized from ethyl acetate-hexane. Colorless prisms. mp. 135°-136° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:23][C:24](=[O:26])[CH3:25])[CH:9]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=3)[CH:11]=2)=[CH:4][N:3]=[CH:2]1.[Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.C1C(=O)N([Br:54])C(=O)C1>C1COCC1>[Br:54][C:2]1[S:1][C:5]([C:6]2[CH:7]=[C:8]([NH:23][C:24](=[O:26])[CH3:25])[CH:9]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][N:14]=3)[CH:11]=2)=[CH:4][N:3]=1
Reactant: CC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(Br)s2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 0 %

Procedure:
A microwave vial containing N-[3-(1,3-thiazol-5-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]acetamide (50 mg, 0.132 mmol) in THF (659 μL) was cooled to −78° C. in a dry ice-acetone bath. To the solution was added a stock solution of LDA prepared from the addition of n-BuLi (3.47 μL, 1.52 M, 0.527 mmol) over diisopropylamine (54.7 mg, 0.540) in THF at −78° C. After stirring the suspension for 20 minutes, a solution of NBS (94 mg, 0.527 mmol) in THF (1 mL) was added. The resulting yellow suspension was stirred at −78° C. for 1 h, after which the bath was removed. Once at room temperature, the reaction was treated with sat. NaHCO3(aq) and the phases were separated. The aqueous was extracted 3 times with ethyl acetate. Organic layers were combined, washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. The residual solid was purified by flash chromatography to yield N-[3-(2-bromo-1,3-thiazol-5-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-acetamide as a beige powder (29 mg, 0.063 nmol, 48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20](Cl)=[CH:21][N:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:39])[NH:36]2)=[CH:32][CH:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:29][C:30]4[CH:38]=[C:37]5[C:33]([CH:34]=[C:35]([CH3:39])[NH:36]5)=[CH:32][CH:31]=4)=[CH:21][N:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2ccc(O)cc2[nH]1
Reactant: COc1cc2c(Cl)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1cc2c(Oc3ccc4cc(C)[nH]c4c3)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using an analogous procedure to that described in Example 8, 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-chloro-6-methoxycinnoline (204 mg, 0.5 mmol) was reacted with 6-hydroxy-2-methylindole (100 mg, 0.55 mmol) to give 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-6-yloxy)cinnoline. The crude product was then treated with TFA to give 6-methoxy-4-(2-methylindol-6-yloxy)-7-(piperidin-4-ylmethoxy)cinnoline (10 mg, 4%).
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[Cl:20][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:19])[C:14]3[C:15]([OH:17])=[N:30][N:29]([C:26]4[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=4)[C:3](=[O:4])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: Cc1ccc(NN)cc1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (3.90 g, 13.3 mM) and 4-methylphenylhydrazine hydrochloride (14.8 g, 93.2 mM) in ethanol (140 mL) was added triethylamine (14.8 mL, 106.4 mM). The resulting brown solution was refluxed for 16 hours during which time a precipitate formed. The resulting suspension was cooled to room temperature and filtered to give the 4-methylphenylhydrazine salt of the title compound as a grey powder (2.30 g). This material was refluxed in glacial acetic acid (45 mL) for 2 hours and cooled to room temperature. The resulting brown suspension was filtered to give the title compound (1.60 g, 34%) as a tan powder, mp 380-382° C.; MS(CI): 354 (M+H).
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:11](O)[CH2:12][OH:13]>>[CH3:10][C:2]1([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[O:13][CH2:12][CH2:11][O:1]1
Reactant: OCCO
Reactant: COC(=O)CCCC(C)=O
Product: COC(=O)CCCC1(C)OCCO1

Procedure:
Methyl 2-methyl-1,3-dioxolane-2-butanoate (25) was prepared from methyl 5-oxohexanoate and ethylene glycol in the manner described in Example 17 above on a 28 mmol scale to yield 4.94 g (94%) of product. The product was employed immediately in the manner described in Example 26 below.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)cc2)CCCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)cc2)CCCN3CCC)cc1
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-2-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (430 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-per-benzoic acid (238 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate) and re-crystallized from diisopropyl ether-ethyl acetate to give 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-2-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (288 mg) as yellow crystals (Compound 20).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[OH:10][C@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][C@H:11]([OH:10])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: O[C@H]1CCNC1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@H]1CCN(Cc2ccc(Cl)nc2)C1
Temperature: 80 °C
Yield: 68.3 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (1.0 g, 6.2 mmole) in 10 mL of dry acetonitrile is added 1.03 mL (12.4 mmol) of (S)-3-hydroxy-pyrrolidine followed by 858 mg (6.2 mmol) of potassium carbonate. The reaction is heated at 80° C. for 2 h. After cooling, the reaction mixture is quenched with 20 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 900 mg (68% yield) of (S)-1-(6-Chloro-pyridin-3-ylmethyl)-pyrrolidin-3-ol. Diagnostic C13 NMR (100 MHz, CDCl3) 35.1, 52.5, 56.7, 63.0, 71.4, 124.2, 133.4, 139.6, 149.9, 150.4; MS 213.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].O=C1CCC(=O)N1[O:15][C:16]([C:18]1[S:43][C:21]2[N:22]=[CH:23][N:24]=[C:25]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[O:34][C@H:35]3[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]3[O:41][CH3:42])[C:20]=2[C:19]=1[CH3:44])=O>CN(C=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:16]([C:18]1[S:43][C:21]2[N:22]=[CH:23][N:24]=[C:25]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[O:34][C@H:35]3[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]3[O:41][CH3:42])[C:20]=2[C:19]=1[CH3:44])=[O:15]
Reactant: CO[C@H]1CCCC[C@@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)ON3C(=O)CCC3=O)c(C)c12
Reactant: CN(C)CCCN
Solvent: CN(C)C=O
Product: CO[C@H]1CCCC[C@@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)NCCCN(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.129 g 3-dimethylaminopropylamine was added to 0.155 g 4-[4-fluoro-2-((1S,2S)-2-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester in 2 ml DMF and stirred at rt for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in EtOAc, washed with water and brine, passed through a hydrophobic frit and concentrated.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[CH2:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[NH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[NH2:36])[C:31]#[N:32].C1N2CCN(CC2)C1>CN1C(=O)CCC1>[CH3:13][C:12]1[C:4]([CH2:3][C:2]2[NH:36][C:35]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=3[N:27]=2)=[C:5]2[C:9](=[C:10]([CH:14]=[CH2:15])[CH:11]=1)[N:8]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:17])=[O:18])[CH:7]=[CH:6]2
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: C=Cc1cc(C)c(C=C(Br)Br)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Product: C=Cc1cc(C)c(Cc2nc3cc(C#N)ccc3[nH]2)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Temperature: 25 °C

Procedure:
A solution of 4-(2,2-dibromovinyl)-5-methyl-1-tosyl-7-vinyl-1H-indole (57 mg, 0.115 mmol) and 3,4-diaminobenzonitrile (23 mg, 0.173 mmol) and DABCO (38.7 mg, 0.345 mmol) in NMP (0.5 mL) was stirred at 110° C. After 80 minutes the mixture was slowly cooled to room temperature overnight, and then heated again at 110° C. for 4 hours. The reaction was cooled to room temperature and loaded onto silica gel and purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 467.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH:5]=[N:6][CH:7]=1
Reactant: OCc1cncc(Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
To a stirred solution of (5-bromopyridin-3-yl)methanol (LVI) (1.60 g, 8.5 mmol, 1 eq), phthalimide (1.24 g, 8.5 mmol, 1 eq) and PPh3 (3.33 g, 12.75 mmol, 1.5 eq) in anhydrous THF (15 mL) was added DEAD (2.21 g, 12.75 mmol, 1.5 eq) dropwise at 0° C. under N2. Then the reaction mixture was stirred at room temperature for 6 h. The mixture was washed with saturated NaHCO3 solution (15 mL), water (15 mL) and brine (15 mL) subsequently. The organic layers were dried over MgSO4, concentrated under reduced pressure, the resultant residue was purified by flash chromatography on silica gel (PE:EtOAc=4:1) to give 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LVII) (2.5 g, 7.88 mmol, 82.3% yield) as a white solid. ESIMS found for C14H9BrN2O2 m/z 317 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: COc1ccc2c(c1OC)CCN=C2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc2c(c1OC)CCNC2C

Procedure:
In close analogy to the procedure described above, 1-Methyl-5,6-dimethoxy-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.