Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(F)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, white solid (33 mg, 43%), MS (ISP) m/z=311.3 [(M+H)+], mp 274.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([C:7]2[C:16]([CH3:17])=[CH:15][C:14]3[C:9](=[C:10]([O:18]C)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.C(=O)(O)[O-].[Na+]>>[C:1]1([C:7]2[C:16]([CH3:17])=[CH:15][C:14]3[C:9](=[C:10]([OH:18])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc2cc(C)c(-c3ccccc3)nc12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc2cccc(O)c2nc1-c1ccccc1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
4.75 g of (19 mmol) of 2-phenyl-3-methyl-8-methoxyquinoline and 111 ml of 48% hydrobromic acid are placed in a 1 l round-bottomed flask. The mixture is brought to reflux for 18 h and cooled to ambient temperature. Sodium bicarbonate is added to basify the solution and extraction is carried out with ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated under vacuum to provide 4.3 g of 2-phenyl-3-methyl-8-hydroxyquinoline in the form of an oil. (Yield: 77%)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=2)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCO)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][CH2:27][CH2:28][OH:29])=[CH:21][CH:20]=2)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(OCCO[Si](C)(C)C(C)(C)C)ccc2[nH]1
Agent: Nc1ccccc1NC(=O)c1cc2cc(OCCO)ccc2s1
Product: Nc1ccccc1NC(=O)c1cc2cc(OCCO)ccc2[nH]1

Procedure:
was prepared [2-({5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-1H-indole-2-carbonyl}-amino)-phenyl]-carbamic acid tert-butyl ester (44) in an analogous manner to that described for the preparation of (39), example 16, step 2; mp. 222–223° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)=[O:38]>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)=[O:38])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CN1CCN(C(=O)Cc2ccccc2O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
Triethylamine (1.06 ml) and octadecyl isocyanate (2.35 ml) were added to a solution containing 2-(2-hydroxyphenyl)-1-(4-methylpiperazino)-1-ethanone (1.60 g) in methylene chloride (16 ml) and stirred for 15.5 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=50:1 to 30:1), thereby yielding the entitled compound (3.23 g) as white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:20])(=[N:17][C:18]#[N:19])=[O:16])=[CH:11][C:10]=1[F:21])(C)(C)C.Cl.C(OCC)(=O)C>ClCCl>[F:21][C:10]1[CH:11]=[C:12]([S:15]([CH3:20])(=[N:17][C:18]#[N:19])=[O:16])[CH:13]=[CH:14][C:9]=1[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1ccc(S(C)(=O)=NC#N)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=NC#N)c1ccc(CN)c(F)c1

Procedure:
A solution of (2-fluoro-4-(N-cyano-S-methylsulfonimidoyl)-benzyl)-carbamic acid tert-butyl ester (preparation 18c, 2.20 g, 6.38 mmol) in dichloromethane (20 mL) is cooled at 0° C. and treated with a solution of hydrogen chloride in ethyl acetate (4 M, 16 mL, 64 mmol). After 2 h all volatiles are removed under reduced pressure and the residue is purifed by preparative reversed phase HPLC (Gemini, gradient of acetonitrile in water, 0.04% NH3). ESI mass spectrum: [M+H]+=228; r.t. HPLC: 2.16 min (0-30AB).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH3:45][O:44][CH2:43][CH2:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1
Reactant: COCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-(2-methoxyethoxy)phenyl borate (124 mg) and potassium carbonate, (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (40 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-[4-(2-methoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 53) (246 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[OH:8].[Cl:10][C:11]1[C:18]([CH2:19][CH3:20])=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>>[Cl:10][C:11]1[C:18]([CH2:19][CH3:20])=[C:17]([NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C:4]2([OH:8])[CH3:9])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CC1(O)CCC[C@@H]1N
Reactant: CCc1c(F)ccc(C#N)c1Cl
Agent: Cl
Product: CCc1c(N[C@H]2CCCC2(C)O)ccc(C#N)c1Cl

Procedure:
2-Chloro-3-ethyl-4-[[(1S)-2-hydroxy-2-methyl-cyclopentyl]amino]benzonitrile is prepared essentially as described in Example 1 using (2S)-2-amino-1-methyl-cyclopentanol hydrochloride (Preparation 18) and 2-chloro-3-ethyl-4-fluoro-benzonitrile. The crude material (350 mg) is purified using silica gel chromatography (20-60% EtOAc/hexane) to obtain Diastereomer 1 (cis) (82 mg) and Diastereomer 2 (trans) (29 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]1[CH:18]=[C:17]([NH2:19])[N:16]=[C:15]([NH2:20])[N:14]=1.CO>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>[NH2:20][C:15]1[N:14]=[C:13]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:18]=[C:17]([NH2:19])[N:16]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(Oc2cc(N)nc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.2 %

Procedure:
Methyl 4-hydroxybenzoate (1.52 g, 10.0 mmol) was dissolved in 18 mL of anhydrous dioxane in 10-20 mL microwave vial (Personal Chemistry) and solid Cs2CO3 was added to this solution. The suspension was stirred at ambient temperature for 10 min, then 4-chloro-2,6-diaminopyrimidine (1.45 g, 10.0 mmol) was added. The vial was capped and microwaved at 200° C. for 40 min. Then MeOH was added to dissolve the formed suspension to produce a clear amber solution. The solution was transferred into a round-bottom flask and concentrated down to ca. 20 mL. This solution was purified by silica gel chromatography using 100% ethyl acetate as eluent. The product was additionally re-crystallized from ca. 50 mL of 4:1 mixture of EtOAc/MeOH. The product was filtered, washed with 40 mL of EtOAc, 40 mL of anhydrous Et2O and dried in vacuo to give the title product as a white solid (0.812 g). Yield 31.2%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.S([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1)(O)(=O)=O>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:24]([C:21]3[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=3)[CH3:25])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Product: CN(c1ccc(O)cc1)c1ncnc2cc(Cl)ccc12

Procedure:
4,7-Dichloroquinazoline (prepared according to the method of Price et al, J. Am. Chem. Soc., 1946, 68, 1305) was reacted with 4-(N-methylamino)phenol sulfate, following essentially the same procedure as that described in Example 3 part a), to give 4-[N-(7-chloro-4-quinazolinyl)-N-methylamino]phenol as a yellow solid, mp 165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:32])[C:25]=1[CH3:42])(=[O:12])=[O:11].[C:43]([O:46][CH2:47][C:48](Cl)=[O:49])(=[O:45])[CH3:44]>C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:33][CH2:34][CH2:35][N:36]2[CH2:37][CH2:38][N:39]([C:48](=[O:49])[CH2:47][O:46][C:43](=[O:45])[CH3:44])[CH2:40][CH2:41]2)=[O:32])[C:25]=1[CH3:42])(=[O:12])=[O:11]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCNCC1
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1CCN(CCNC(=O)Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of 2-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-piperazin-1-yl-ethyl)-acetamide (300 mg, 0.475 mmol), acetoxyacetyl chloride (97 mg, 1.5 eq.) and TEA (0.5 mL) in DCM (10 mL) was stirred at rt for overnight. The precipitate was collected by vacuum filtration, washed with water and methanol to give 300 mg of acetic acid 2-{4-[2-(2-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetylamino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl ester as a red solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[CH:11]1[N:16]([CH3:17])[CH2:15][CH2:14][C:13]([CH3:18])=[CH:12]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:17][N:16]1[CH2:15][CH2:14][C:13]([CH3:18])=[CH:12][CH:11]1[C:4]1[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccc(C2C=C(C)CCN2C)c(OC)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1=CC(c2ccc(O)cc2O)N(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a stirred solution of 6-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2,3,6-tetrahydro-pyridine (6) (300 mg, 1.27 mmol) in dichloromethane (20 ml) cooled at 0° C. under nitrogen was added boron tribromide (3.1 ml, 3.18 mmol of 1.0M solution in dichloromethane), the resultant dark solution was allowed to warm to room temperature and stirred for 1 hour. The solution was poured onto ice and basified with sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (20 ml), the combined organic layers were dried over anhydrous magnesium sulphate, filtered and evaporated to a gum (200 mg). The material was purified on a 10 g silica cartridge eluting with methanol/dichloromethane/ammonia (7:92:1) to yield 4-(1,4-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)-benzene-1,3-diol (8) (93 mg, 35%) as a gum, 1H NMR D6-acetone ??1.67 (s, 3H), 1.97 (m, 1H), 2.3 (s, 3H), 2.42 (m, 1H), 2.74 (m, 1H), 3.08 (m, 1H), 3.74 (s, 1H), 5.15 (s, 1H), 6.2 (d, 1H J=2), 6.27 (dd, 1H J=2.8), 6.82 (d, 1H J=8), 9.4 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cn2c3ccc(Br)cc3c3cc(OCC(=O)OC(C)(C)C)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 49 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (210 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and t-butyl bromoacetate (0.13 ml) was added to the mixture. The mixture was stirred for 2.5 hours at room temperature, and the reaction mixture was poured into ice water (50 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride containing 2% methanol), and the crude purification product was washed with ether and recovered by filtration to obtain the title compound (130 mg, 39%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:23]1([C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)O)[OH:24].CC1C=CC(S(O)(=O)=O)=CC=1.O.C1(C)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:22][C:30]3[CH:29]=[CH:28][CH:27]=[CH:25][C:23]=3[O:24]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 50.3 %

Procedure:
The above ketone (450 mg, 1.39 mmol), catechol (614 mg, 5.58 mmol), p-TsOH.H2O (529 mg, 2.78 mmol), toluene (5 mL) and xylene (15 mL) were heated at 185° C. overnight using a Dean-Stark apparatus to remove water. Work-up and purification afforded 4-[2-(4-chloro-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pink oil (221 mg, 50%).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([CH2:26][N+:27]#[C-])(C1C=CC(C)=CC=1)(=O)=O.C(O)C.CC(C)([O-])C.[K+]>COCCOC>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:26]#[N:27])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-benzoyl-4-piperidone (2.0 g, 9.8 mmol), tosylmethyl isocyanide (2.5 g, 12.8 mmol) and ethanol (1.0 mL, 17.1 mmol) in 30 mL DME was cooled in an ethanol/ice bath, and potassium tert-butoxide was added at such a rate to maintain the reaction temperature at <10° C. The cold bath was removed, and the reaction was allowed to stir overnight at room temperature. The solids were removed by filtration, rinsed with DME, and the filtrate was evaporated. The residue was dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered through silica gel, and concentrated to give 2.14 g (66%) of a slightly yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[CH2:22][NH:23]C(=O)OC(C)(C)C)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:23][CH2:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[C:13]1[N:12]=[CH:11][C:10]2[N:9]([CH3:31])[C:8](=[O:32])[C@@H:7]([CH2:33][CH3:34])[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:15]=2[N:14]=1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNC(=O)OC(C)(C)C)nc2N1C1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 91, with (R)-tert-butyl (4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)pyridin-3-yl)methylcarbamate (Example 106) instead of (R)-tert-butyl 4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)pyridin-3-ylcarbamate (Example 92). LCMS (0.05% TFA): 367.3 m/z (M+H)+; 1H-NMR (CDCl3, 500 MHz): δ: 9.35 (bs, 2H), 8.73 (bs, 2H), 8.02 (s, 1H), 7.99 (s, 1H), 4.41 (m, 1H), 4.35 (m, 1H), 4.30 (s, 2H), 3.40 (s, 3H), 2.14-1.68 (m, 10H), 1.44 (s, 9H), 0.90 (t, 3H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9]2)=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][CH2:43][CH2:44][N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH3:55])([CH3:54])[C:46]1=[O:56]>CC(=O)CC>[CH3:55][C:47]1([CH3:54])[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:45]([CH2:44][CH2:43][CH2:42][N:15]2[CH2:14][CH2:13][C:12]3([N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][N:10]([CH2:19][C:20]4[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=4)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C:11]3=[O:18])[CH2:17][CH2:16]2)[C:46]1=[O:56]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCNCC3)C2=O)c1
Reactant: CC1(C)C(=O)N(CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCN4C(=O)C(C)(C)c5ccccc54)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (1.2 g, 2.84 mmol), sodium iodide (0.015 g, 0.1 mmol) and potassium carbonate (0.07 g, 0.51 mmol) in 2-butanone (3 mL), was added 1-(3-chloropropyl)-3,3-dimethylindolin-2-one (0.081 g, 0.34 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.17 g, 78%); 1H NMR (DMSO-d6): δ 1.26 (s, 6H), 1.51 (s, 9H), 1.63 (d, 2H, J=12.4 Hz), 1.75-1.76 (m, 2H), 2.29-2.32 (m, 4H), 2.66-2.67 (m, 4H), 3.72 (t, 2H, J=6.8 Hz), 4.57 (d, 2H, J=14.8 Hz), 6.91 (s, 2H), 7.02 (t, 1H, J=7.2 Hz), 7.07-7.09 (m, 3H), 7.22 (t, 1H, J=7.2 Hz), 7.34 (d, 1H, J=7.2 Hz), 7.47-7.54 (m, 2H), 7.78 (s, 1H), 7.82 (d, 1H, J=6.8 Hz).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: OCc1ccc(Br)s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cccnc2)s1
Temperature: 80 °C
Yield: 98 %

Procedure:
To a mixture of 153 mg (5-bromo-thiophen-2-yl)-methanol, 128 mg pyridine-3-boronic acid, and 64 mg tetrakis(triphenylphosphine) palladium was added solvent (7.3 mL toluene and 3.1 mL methanol) followed by 1.4 mL of 2.5M sodium carbonate and the mixture heated to 80° C. on an oil bath. After 16 hours the mixture was cooled to room temperature and cocncentrated in vacuo. The residue was solvated in ethyl acetate was washed sequentially with 0.5N sodium hydroxide and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 60:40; then 55:45) gave the title compound (147 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([CH:13]([CH2:25][CH2:26][CH3:27])[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:12])=[CH:5]2.[H-].[Na+].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:11]([CH:13]([CH2:25][CH2:26][CH3:27])[CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:12])=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2n1Cc1ccc(C(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
To a solution of the title compound of Example 3 Step D (240 mg, 0.63 mmol) in DMF (2.5 mL) was added NaH (30 mg, 60% suspension in mineral oil, 0.75 mmol). After 15 min, 4-tert-butylbenzyl bromide (0.126 mL, 0.69 mmol) was added, and the resultant mixture was stirred for 1.5 h, whereupon it was quenched by addition of sat. aq. NH4Cl. The aqueous phase was extracted with EtOAc, and the organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25%, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS B, tr=3.30 min, m/z 530.3 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J=8.5 Hz, 2H), 7.63 (d, J=2.0 Hz, 1H), 7.29-7.23 (m, 4H), 7.15 (d, J=8.0 Hz, 2H), 7.13 (s, 1H), 6.82 (d, J=8.5 Hz, 2H), 5.78 (ABq, J=16.0 Hz, Δν=71.0 Hz, 2H), 3.87 (s, 3H), 3.62 (dddd, J=8.5, 8.5, 5.5, 5.5 Hz, 1H), 3.08 (dd, J=14.0, 8.5 Hz, 1H), 2.78 (dd, J=14.0, 5.5 Hz, 1H), 1.76-1.70 (m, 1H), 1.52-1.45 (m, 1H), 1.26 (s, 9H), 1.23-1.18 (m, 2H), 0.81 (t, J=7.5 Hz, 3H).