Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](Cl)(=[O:9])[CH:7]=[CH2:8]>C(#N)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:6](=[O:9])[CH:7]=[CH2:8]
Reactant: NCCCO
Reactant: C=CC(=O)Cl
Solvent: CC#N
Product: C=CC(=O)NCCCO

Procedure:
To a 250 mL, four-neck round bottom flask equipped with a mechanical stirrer, a thermometer, a 100 mL dropping funnel, and a nitrogen inlet/outlet, 30.0 g of 1-amino-3-propanol (0.4 mole), and 100 mL of acetonitrile were added. The mixture was cooled below 0° C. with an ice/water bath. To this solution, 18.1 g of freshly distilled acryloyl chloride (0.2 mole) in 50 mL of acetonitrile was added through the dropping funnel. The addition rate was controlled so that the reaction temperature was kept below 0° C. After the addition was finished and the agitation was turned off, the reaction solution separated into two liquid phases. The bottom layer viscous salt solution phase was discarded. To the top layer acetonitrile solution phase, 100 mL of deionized water was added. After removing all acetonitrile by vacuum distillation, the aqueous solution was passed through a mixed bed ion-exchange column packed with 20 g of Dowex MR-3C resin. A total of 76 grams of eluate was collected. The final solution has the following properties: HPLC and FT-IR analysis indicates there is no ester formation; HPAA concentration: 7.2% (wt/wt); pH=5.6 at 25° C; Conductivity=56.6 μS/cm at 25° C.; Viscosity=1.1 cPs at 25° C. The relative low yield of HPAA is due to the fact that HPAA is soluble in the salt phase. HPAA in the salt phase can be recovered by acetone extraction since HPAA is soluble in acetone, and the salt is insoluble.
Reaction SMILES: C([N:8]1[CH:12]=[N:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:15]([CH:29]3[CH2:31][CH2:30]3)[C:14]=2[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:36][CH2:35]2)=[O:33])=[N:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO.Cl>[CH:29]1([N:15]2[C:14]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)[CH2:38][CH2:39]3)=[O:33])=[C:13]([C:10]3[N:11]=[CH:12][NH:8][N:9]=3)[N:17]=[C:16]2[C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=2)[CH2:31][CH2:30]1
Reactant: O=C(c1c(-c2ncn(Cc3ccccc3)n2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(c1c(-c2nc[nH]n2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Yield: 77.6 %

Procedure:
A solution of 0.07 g (0.1 mmol) of [5-(1-benzyl-1H-[1,2,4]triazol-3-yl)-3-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 12) and a generous spatula of 10% palladium on activated charcoal in 1 ml of MeOH made acidic by addition of a few drops of 25% HCl was stirred under one atmosphere of hydrogen for 16 h. Then, the mixture was filtered over Hyflo, concentrated and the residue taken up in CH2Cl2. The organic phase was washed with saturated sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. Purification by flash column chromatography [CH2Cl2/MeOH 9:1 to 8:2] afforded 0.04 g (64%) of the title compound as a colorless amorphous solid. MS: 516.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cccnc1Oc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccnc1Oc1ccc(C#N)cc1
Yield: 32.2 %

Procedure:
A solution of 2-(4-Cyano-phenoxy)-nicotinic acid ethyl ester (0.90 grams, 2.44 mmole) in methanol (10 ml) and potassium carbonate (1.01 grams, 7.33 mmole) was refluxed for 20 minutes. The mixture was diluted with 100 ml water, acidified to pH 1 and filtered to give a solid (0.200 g). MW 254; MS (m/e) 254 (M+).
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:15]=[CH:14][C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.[CH:18]1([CH2:24][N:25]2[C:32]([NH2:33])=[C:31]([NH2:34])[C:29](=[O:30])[N:28]([CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:26]2=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)(=O)C>[CH:36]1([CH2:35][N:28]2[C:29](=[O:30])[C:31]3[N:34]=[C:3]([C:4]4[CH:5]=[CH:6][C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=4)[NH:33][C:32]=3[N:25]([CH2:24][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:26]2=[O:27])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: COC(=O)/C=C/c1ccc(C(OC)OC)cc1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1

Procedure:
(E)-Methyl 4-(dimethoxymethyl)cinnamate (from step (a)) was used in place of 4-formylcinnamic acid in the procedure described in step (d) of Example 1, except that a drop of acetic acid was added during the formation of the Schiff base with 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil. Title compound was formed as a white powder, m.p. >270° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:18]=[CH:17][C:12]2[CH2:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[NH:19]C(=O)OC(C)(C)C.O.C(=O)(O)[O-].[Na+]>C(OCC)C>[NH2:19][C:10]1[C:11]2[O:16][CH2:15][CH2:14][CH2:13][C:12]=2[CH:17]=[CH:18][C:9]=1[F:8]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc2c1OCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Nc1c(F)ccc2c1OCCC2
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Trifluoroacetic acid, 50 mL, was stirred and cooled in an ice-water bath, and 6.1 grams (0.023 mole) of 1,1-dimethylethyl N-(3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)carbamate was added portionwise. Upon completion of the addition, the reaction mixture was stirred for one hour, then stirred with water and diethyl ether and neutralized with solid sodium bicarbonate. The water layer was separated and extracted with diethyl ether. The extract was combined with the organic layer, and the combination was washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.7 grams of 8-amino-3,4-dihydro-7-fluoro-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: FC(F)(F)OC1C=CC(N2CCNCC2)=CC=1.[CH3:18][C@H:19]1[CH2:24][N:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[CH2:22][C@@H:21]([CH3:36])[N:20]1[S:37]([C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[CH2:42][CH:43]([C:49]#[N:50])[CH2:44]2)(=[O:39])=[O:38].C([Sn](=O)CCCC)CCC.[N:61]([Si](C)(C)C)=[N+:62]=[N-:63]>C1(C)C=CC=CC=1>[CH3:18][C@H:19]1[CH2:24][N:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:27][CH:26]=2)[CH2:22][C@@H:21]([CH3:36])[N:20]1[S:37]([C:40]1[C:41]2[CH2:42][CH:43]([C:49]3[NH:63][N:62]=[N:61][N:50]=3)[CH2:44][C:45]=2[CH:46]=[CH:47][CH:48]=1)(=[O:39])=[O:38]
Reactant: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C#N)C2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Agent: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(c1nnn[nH]1)C2
Temperature: 105 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
cis-2,6-Dimethyl-1-|2-(1H-tetrazol-5-yl)-indane-4-sulfonyl|-4-(4-trifluoromethoxy-phenyl)-piperazine: To a solution of 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carbonitrile (23 mg, 0.0440 mmol) in toluene (1 ml) was added dibutyltin oxide (13 mg, 0.0281 mmol) and azidotrimethylsilane (5 μL, 0.0377 mmol). The reaction mixture was stirred at 105° C. for 20 h upon which an additional amount of dibutyltin oxide (13 mg, 0.0281 mmol) and azidotrimethylsilane (25 μL, 0.1884 mmol) was added and stirred at 105° C. for 4 h. The reaction mixture was cooled to room temperature and then directly purified by silica gel column chromatography (0-10% MeOH in dichloromethane) to afford cis-2,6-dimethyl-1-[2-(1H-tetrazol-5-yl)-indane-4-sulfonyl]-4-(4-trifluoromethoxy-phenyl)-piperazine (14 mg, 61%). 1H NMR (400 MHz, CD3OD) δ ppm 7.75 (d, 1H), 7.54 (d, 1H), 7.39 (t, 1H), 7.09 (d, 2H), 6.90 (d, 2H), 4.18-4.02 (m, 3H), 3.89 (dd, 1H), 3.59-3.51 (m, 2H), 3.36-3.31 (m, 3H), 2.66-2.60 (m, 2H), 1.48 (d, 6H). LCMS: 523.11 (M+1)+.
Reaction SMILES: [C:1]([O:11]C(C)(C)C)(=[O:10])[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].C1CCN2C(=NCCC2)CC1.C(Br)(Br)(Br)Br.[Cl-].[NH4+].C([O:38][C:39](/[C:41](=[CH:48]\[C:49](\[CH3:64])=[CH:50]\[CH:51]([CH3:63])[CH2:52][CH:53]([CH3:62])[CH2:54][CH:55]([CH3:61])[CH2:56][CH:57]([CH3:60])[CH2:58][CH3:59])/[CH2:42][CH:43]([CH3:47])[C:44]([OH:46])=[O:45])=[O:40])(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1COCC1>[C:39](/[C:41](=[CH:48]\[C:49](\[CH3:64])=[CH:50]\[CH:51]([CH3:63])[CH2:52][CH:53]([CH3:62])[CH2:54][CH:55]([CH3:61])[CH2:56][CH:57]([CH3:60])[CH2:58][CH3:59])/[CH2:42][CH:43]([CH3:47])[C:44]([O:46][CH:2]([C:1]([OH:11])=[O:10])[C:3]([OH:5])=[O:4])=[O:45])([OH:38])=[O:40]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)O)C(=O)OC(C)(C)C
Agent: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OC(C(=O)O)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
To di-tert-butyl malonate (0.207 mL, 0.925 mmol), THF (40 mL) and DBU (0.139 mL, 0.925) were added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to −20° C., and carbon tetrabromide (207 mg, 0.925 mmol) was added thereto, and the resulting mixture was stirred at −20° C. for 2 hours. To the reaction mixture, a saturated aqueous ammonium chloride solution was added, and the resulting mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. To a portion (80 mg) of the obtained residue, DMF (1.43 mL), Compound 8 (12.5 mg, 0.029 mmol), and potassium carbonate (11.9 mg, 0.086 mmol) were added, and the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture, a saturated aqueous ammonium chloride solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by thin-layer chromatography (ethyl acetate/n-hexane=1/9). By using the obtained residue, Compound 22 (1.1 mg) was obtained in the same manner as Step 2 of Example 7.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)=[O:17])=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(CCNC(=O)OC(C)(C)C)cc2)CC1

Procedure:
4-(2-Tert-butoxycarbonylamino-ethyl)-benzoic acid was reacted with WSCI, HOBt, triethylamine and N-methylpiperazine in dichloromethane, to obtain {2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester, and then it was reacted with sodium hydride and methyl iodide in DMF, to obtain a crude product of methyl-{2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester. Then, this was treated with TFA, to obtain [4-(2-methylamino-ethyl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and [4-(2-methylamino-ethyl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone (211 mg) instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine used in Step D in Example 1-D-18, in the same manner as Step D in Example 1-D-18, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid methyl-{2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-amide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-295) as a colorless powder (26 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NCCCc2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NCCCc2ccccc2)c2cccc(N)c2)cc1
Yield: 78.7 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-(3-phenylpropyl)amine (2.79 g) [prepared as described in step (a) above] in methanol (60 ml), nickel chloride hexahydrate (3.52 g) and sodium borohydride (1.12 g) were reacted, to afford the title compound (2.02 g) as a pale yellow oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:24][C:25]([NH:27][NH2:28])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[CH2:17]([O:24][C:25]([NH:27][NH:28][C:9]([C:8]1[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Reactant: NNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NNC(=O)OCc2ccccc2)cc(C2CCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (2.00 g, 9.04 mmol), hydrazinecarboxylic acid benzyl ester (1.50 g, 9.04 mmol) and DIPEA (2.34 g, 18.1 mmol) in DCM (40 mL), TBTU (3.19 g, 9.94 mmol) is added. The mixture is stirred at rt for 2 h before it is diluted with EA (250 mL), washed twice with sat. aq. NaHCO3 solution (150 mL) followed by brine (100 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give N′-(2-cyclopentyl-6-methoxy-pyridine-4-carbonyl)-hydrazinecarboxylic acid benzyl ester (2.74 g) as a pale yellow oil; LC-MS**: tR=0.74 min, [M+1]+=369.69; 1H NMR (D6-DMSO): δ 1.62-1.83 (m, 6H), 1.95-2.05 (m, 2H), 3.10-3.21 (m, 1H), 3.88 (s, 3H), 5.13 (s, 2H), 6.97 (s, 1H), 7.23 (s, 1H), 7.28-7.40 (m, 5H), 9.45 (s, 1H), 10.52 (s, 1H).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:36])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][C:19]=1[CH3:20])[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:36])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:18][C:19]=1[CH3:20])[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A solution of KOH (141 mg, 2.52 mmol) in ethanol (2 mL) was added to a solution 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]4-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.1 g, 2.29 mmol) in ethanol (10 mL) and methylene chloride (4 mL) at 0° C. The mixture was stirred for 18 h at room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in water. Ethyl acetate was added and the organic layer was washed with 0.5 M HCl, water, brine and dried. After filtration and concentration under reduced pressure gave crude 2-(6-[N,N-bis(tert-butoxycarbonyl)-amino]-4-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.0 g, 97%).
Reaction SMILES: [F:1][C:2]1[C:22]([I:23])=[CH:21][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13]CC)=O)[N:8]([CH3:16])[C:7]=3[CH:17]3[CH2:20][CH:19]([C:4]=2[CH:3]=1)[CH2:18]3.[NH3:24]>>[F:1][C:2]1[C:22]([I:23])=[CH:21][C:5]2[C:6]3[N:10]=[C:9]([C:11]([NH2:24])=[O:13])[N:8]([CH3:16])[C:7]=3[CH:17]3[CH2:20][CH:19]([C:4]=2[CH:3]=1)[CH2:18]3
Reactant: CCOC(=O)c1nc2c(n1C)C1CC(C1)c1cc(F)c(I)cc1-2
Reactant: N
Product: Cn1c(C(N)=O)nc2c1C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 44 °C
Yield: 77 %

Procedure:
A pressure tube containing a solution of ethyl 8-fluoro-9-iodo-3-methyl-3,4,5,6-tetrahydro-4,6 methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (389 mg at 77% purity LCMS-UV215) in methanolic ammonia (6 mL of 7.0M ammonia in methanol) was warmed to 44° C. for 48 hr. After cooling to room temperature, a 0.5 mL aliquot of the precipitous solution was sampled and the solid collected by filtration. The filtrate was pooled back into the reaction mixture and concentrated in vacuo to furnish the crude title compound (329 mg at 77% purity LCMS-UV215) as a tan solid which was used for the next step without further purification. The colourless solid isolated by filtration for characterisation purposes was analysed: 1H NMR (500 MHz, CDCl3) δ 1.69-1.74 (m, 2H), 2.92-3.00 (m, 2H), 3.47 (td, J=7.49, 3.63 Hz, 1H), 3.57 (td, J=8.28, 3.63 Hz, 1H), 4.00 (s, 3H), 5.39 (br. s., 1H), 6.81 (d, J=8.51 Hz, 1H), 7.36 (br. s., 1H), 8.73 (d, J=6.94 Hz, 1H); M+H=398.
Reaction SMILES: N1C2C(=CC=CC=2)C(C2CCC(=O)CC2)=C1.O1[C:21]2([CH2:26][CH2:25][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([Br:36])[CH:34]=4)[NH:29][CH:28]=3)[CH2:23][CH2:22]2)[O:20]CC1>>[Br:36][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:24]1[CH2:23][CH2:22][C:21](=[O:20])[CH2:26][CH2:25]1
Reactant: Brc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Agent: O=C1CCC(c2c[nH]c3ccccc23)CC1
Product: O=C1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Yield: 84.4 %

Procedure:
This compound was prepared in the manner described above for intermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-bromo-1H-indole (4.5 g) to afford 3.3 g (84%) of the title compound as a white solid: MS EI m/e 291 (M+).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24](B(O)O)[C:19]=2[N:18]=[CH:17]1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([C:2]3[N:11]=[CH:10][C:9]4[NH:8][CH2:7][CH:6]5[CH2:12][O:13][CH2:14][CH2:15][N:5]5[C:4]=4[N:3]=3)[C:19]=2[N:18]=[CH:17]1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: OB(O)c1cccc2[nH]cnc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: c1cc(-c2ncc3c(n2)N2CCOCC2CN3)c2nc[nH]c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 50 mg, 0.221 mmol), 1H-benzo[d]imidazol-4-ylboronic acid (71.5 mg, 0.441 mmol) and PdCl2(dppf) (12.91 mg, 0.018 mmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.03 (dd, J=11.87, 8.59 Hz, 1 H), 3.33-3.75 (m, 5 H), 3.98 (m, 2 H), 4.74-4.84 (m, 1 H), 6.49-7.07 (br s, 1 H), 7.54 (t, J=7.83 Hz, 1 H), 7.79-7.91 (m, 2 H), 8.25-8.33 (m, 1 H), 8.98 (s, 1 H), 12.18-12.29 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C16H16N6O, 309.14; found 309.3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:20]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:20][C:19]2[CH:18]=[C:17]([F:16])[CH:24]=[C:23]([F:25])[CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2cc(F)cc(F)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 3,5-difluorobenzyl bromide
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: COc1ccc(Br)cn1
Product: COc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1

Procedure:
Title compound was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 5-bromo-2-methoxypyridine using the protocol outlined for Example 128 (E128); MS (ES+) m/e 325 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:16][O:15][C:5]2=[CH:6][CH:7]=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH2:10][CH2:9]3)=[C:4]2[CH2:3]1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][CH:29]=O.[BH3-]C#N.[Na+]>C(O)(=O)C.CO>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][CH2:29][NH:1][CH:2]1[CH2:16][O:15][C:5]2=[CH:6][CH:7]=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH2:10][CH2:9]3)=[C:4]2[CH2:3]1
Reactant: NC1COc2ccc3c(c2C1)C(=O)NCC3
Reactant: O=CCCc1c[nH]c2ccc(F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCCc2ccc3c(c21)CC(NCCCc1c[nH]c2ccc(F)cc12)CO3
Reaction time: 2 h

Procedure:
To a mixture of 9-amino-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one (46) (130 mg, 0.596 mmol), 3-(5-fluoro-1H-indol-3-yl)propanal ((2), 113 mg, 0.596 mmol) in acetic acid (70 μl) and methanol (20 ml) was added NaBH3CN (75 mg, 1.19 mmol) in portions. The resulting mixture was stirred for 2 hr. The solvent was removed in vacuo and the residue was dissolved in methylene chloride. The organic solution was washed with 1N NaOH and saturated NaCl before being dried over with Na2SO4. Concentration of organic solution gave the crude compound, which was purified on silica gel (100% EtOAc) to give the desired compound, which was treated with 1 equivalent of etherate HCL to form HCl salt for title compound. MS (APPI) m/z 394.4.