Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].[NH:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:10]([C:19](ON1C(=O)CCC1=O)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.CCN(CC)CC.C(O)(=O)C>CN(C=O)C>[NH:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:10]([C:19]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C[C@H](O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
D-Threonine (4.58 g, 38.5 mmol) was dissolved in 19 ml of 40% Triton B and evaporated to an oil. It was re-evaporated twice from DMF, and the salt obtained was stirred with Boc-Tyr-OSu (13.24 g, 35 mmol) in DMF (80 ml) at 0° C. for 1.5 hr and at 25° C. for 30 hr. A constant pH of 8 was maintained by dropwise addition of Et3N during reaction time. The reaction was acidified to pH 4 with acetic acid. The solvent was evaporated to a syrup, dissolved in chloroform, washed with 0.5 N H2SO4 and water, dried (Na2SO4) and evaporated to low volume. The product was obtained as an amorphous solid from petroleum ether: 9.17 g (68.5%): [α]D25 -42.9° (c 1.4, DMF).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[C:18]([S:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:17]([CH2:28][C:29]#[N:30])[N:16]=[C:15]1[CH3:31].CN(C)P(=O)(N(C)C)N(C)C.CI>O1CCCC1.CCCCCC>[CH3:13][N:14]1[C:18]([S:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:17]([CH:28]([CH3:1])[C:29]#[N:30])[N:16]=[C:15]1[CH3:31]
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(C)cc(Sc2c(CC#N)nc(C)n2C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cc(C)cc(Sc2c(C(C)C#N)nc(C)n2C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
In dry tetrahydrofuran (5 ml)was dissolved 49 mg (0.48 mmol)of diisopropylamine, and the solution was cooled to 0° C. To this, 0.3 ml of 1.62 M hexane solution of n-butyllithium was added under a stream of nitrogen, and the mixture was stirred for 10 minutes. The mixture was cooled to -78° C., and 85 mg (0.31 mmol)of [1,2-dimethyl-5-(3,5-dimethylphenylthio)imidazol-4-yl]acetonitrile (42d)was added, and the mixture was stirred for 15 minutes. Then, 86 mg (0.48 mmol)of hexamethylphosphoric triamide and 68 mg (0.48 mmol)of methyl iodide were added dropwise, and the mixture was stirred at -78° C. for 30 minutes. The reaction mixture was poured into ice-water, extracted with diethyl ether, and the extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate)to give 51 mg of 2-[1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazol-4-yl]propiononitrile (43a)as oil (yield 57%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc(Cl)c2)s1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and 3-chlorophenylboronic acid, using tetrakis(triphenylphosphine)palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by flash chromatography using a gradient of 5%–20% 3.5M methanolic ammonia/chloroform mixtures as the eluent to give the title compound as a colourless solid; MS (ES+) 347 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:22]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:24]=[CH:25][C:26]=1[Cl:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)c(OCc2ccccc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Cl)c(OCc2ccccc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-benzyloxy-4-chlorobenzaldehyde in an analogous manner to that described in Example 1 gave 9-(3-benzyloxy-4-chlorophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a pale yellow crystalline solid of melting point 243-244° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[O:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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>[N+:9]([C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:22]2[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[O:25][CH:26]=2)[CH:5]=[CH:6][CH:7]=1)([O-:11])=[O:10]
Reactant: O=C(O)c1cc(Br)co1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2coc(C(=O)O)c2)cccc1[N+](=O)[O-]
Yield: 113.3 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6a (4 g, 14.34 mmol), 4-bromo-furan-2-carboxylic acid 28b (2.18 g, 11.47 mmol), tetrakis(triphenylphosphine)palladium (829 mg, 0.717 mmol) and potassium carbonate (3.96 g, 28.68 mmol) were dissolved in the solvent mixture of 80 mL of 1,4-dioxane and 30 mL of water. The reaction mixture was heated to reflux for 2.5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was adjusted to pH 3 with 1 N hydrochloric acid and then extracted with ethyl acetate (80 mL×3). The combined organic extracts were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 4-(3-nitro-2-methoxy-phenyl)-furan-2-carboxylic acid 28c (3.42 g, yield 90.7%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][CH:5]=1.[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[NH:18][C:17]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:18]2[C:19]3[C:24](=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:16]([CH3:15])=[C:17]2[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:6][CH:5]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Reactant: COC(=O)c1ccc(OCCBr)cc1
Product: COC(=O)c1ccc(OCCn2c(-c3cccnc3)c(C)c3cc(C#N)ccc32)cc1

Procedure:
4-(2-Bromo-ethoxy)-benzoic acid methyl ester and 5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl (Example 6) are processed according to the method described in Example 59 to give 4-[2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid methyl ester. 1H NMR (400 MHz, MeOD) δ ppm 2.28 (s, 3H), 3.87 (s, 3H), 4.24 (t, J=5.1 Hz, 2H), 4.61 (t, J=5.1 Hz, 2H), 6.73-6.79 (m, 2H), 7.58 (dd, J=8.5, 1.6 Hz, 1H), 7.66 (ddd, J=7.9, 5.0, 0.8 Hz, 1H), 7.77 (dd, J=8.6, 0.5 Hz, 1H), 7.85-7.88 (m, 1H), 7.88-7.90 (m, 1H), 8.03 (dt, J=8.1, 1.9, 1.8 Hz, 1H), 8.07 (dd, J=1.5, 0.6 Hz, 1H), 8.52-8.84 (m, 2H). HRMS (ESI) m/z 412.1660 [(M+H)+ Calcd for C25H22N3O3: 412.1661].
Reaction SMILES: [F:1][CH2:2][CH2:3]O.FC(F)(F)C([O-])=O.[C:12]([C:15]1[C:16]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[N:17][N:18]([C:20]2([CH2:26][C:27]#[N:28])[CH2:25][CH2:24][NH2+:23][CH2:22][CH2:21]2)[CH:19]=1)(=[O:14])[NH2:13].C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CN(C=O)C>[C:27]([CH2:26][C:20]1([N:18]2[CH:19]=[C:15]([C:12]([NH2:13])=[O:14])[C:16]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[N:17]2)[CH2:25][CH2:24][N:23]([CH2:3][CH2:2][F:1])[CH2:22][CH2:21]1)#[N:28]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC[NH2+]CC1
Reactant: OCCF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCN(CCF)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a sealed vial was added 2-fluoroethanol (0.0090 g, 0.14 mmol), PS-IBX (0.28 g, 0.28 mmol, 1.0 mmol/g) suspended in DCE (1.0 mL). The vial was capped and shaken at RT for 16 hours. The reaction was passed though a syringe filter and the eluent was collected into a reaction vial. To the reaction vial was added 4-(4-carbamoyl-3-((4-fluorophenyl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidin-1-ium 2,2,2-trifluoroacetate (Intermediate #38-5) (0.020 g, 0.058 mmol), TFA (0.020 mL, 0.26 mmol), Na(OAc)3BH (0.037 g, 0.18 mmol) suspended in DMF (0.50 mL). The reaction vial was capped and heated to 50° C. for 4 hours. The completed reaction was concentrated in vacuo and the residue taken up in DMF (1.0 mL). The crude reaction was passed through a syringe filter and the eluent was directly purified by reverse phase preparative HPLC (using a gradient elution of 0-95% ACN/water with 0.1% v/v TFA modifier). The collected HPLC fraction was concentrated in vacuo and the residue was taken up in MeOH and passed through a Si-Carbonate SPE cartridge. The eluent was collected and evaporated to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.[CH3:45][O:46]C(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.COC1C=CC(B(O)O)=CC=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:3]=[CH:2][C:43]([O:46][CH3:45])=[CH:42][CH:41]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Agent: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(OC)cc2-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1
Yield: 15 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-methoxyphenylboronic acid (40 mg, 0.2625 mmol) to produce the title compound (15 mg, 15% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)C>[CH3:12][C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[C:7](=[O:13])[CH:8]=1
Reactant: NN
Reactant: CCOC(=O)Cn1ccc(C)cc1=O
Solvent: O
Solvent: CCO
Product: Cc1ccn(CC(=O)NN)c(=O)c1
Yield: 94 %

Procedure:
As described for example 112a, (4-methyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 94%). MS: m/e=204.3 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[C:5](=[O:18])[C:4]=1[C:19]#[N:20].[Cl-].[NH4+].C(O)C.C(=O)([O-])O.[Na+]>[Fe].O>[NH2:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[N:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:19]#[N:20])[C:5]1=[O:18]
Reactant: COc1ccn(-c2ccncc2[N+](=O)[O-])c(=O)c1C#N
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COc1ccn(-c2ccncc2N)c(=O)c1C#N
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
To a mixture of 4-methoxy-3′-nitro-2-oxo-2H-[1,4′-bipyridine]-3-carbonitrile obtained in Step A (3.00 g), ammonium chloride (5.90 g), ethanol (60 mL) and water (15 mL) was added iron powder (2.46 g) at room temperature. The reaction mixture was heated at 90° C. for 2 hr. The reaction mixture was cooled to room temperature, and poured into saturated sodium hydrogen carbonate solution, and the mixture was extracted with a mixed solvent of tetrahydrofuran/ethyl acetate=2/1. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent (20 mL) of methanol/isopropyl ether=1/1, and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (1.10 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14].[BH4-].[Na+]>CO.CCOC(C)=O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][N:2]([CH2:9][C:8]1[CH:11]=[CH:12][C:5]([NH2:4])=[C:6]([N+:13]([O-:15])=[O:14])[CH:7]=1)[CH3:3]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CNC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)Cc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of dimethylamine (4.0 mL, 2 M, 8.0 mmol) in MeOH (4 mL) was added Ti(OiPr)4 (1.15 g, 4 mmol) and the solution was stirred at room temperature for 15 minutes Then 4-amino-3-nitro-benzaldehyde (160 g, 1.0 mmol) in MeOH (2 mL) was added and the solution was stirred at room temperature overnight. Then NaBH4 (78 g, 2 mmol) was added and the solution was stirred at room temperature for 1 hour. LCMS showed major product peak. The solution was diluted with EtOAc (60 mL) and washed with water (2×100 mL) and brine (50 mL), dried over anhydrous Na2SO4. The solution was evaporated to dryness and 130 mg of crude product was collected, which was used for the next step without further purification, 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.35 (br s, 2H), 7.31 (dd, 1H), 6.97 (d, 1H), 3.26 (s, 2H), 2.12 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[CH2:15][CH2:14]4)=[CH:9][N:8]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl>O1CCOCC1>[CH3:28][C:24]1[CH:23]=[C:22]([CH2:21][C:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([C:10]4[C:3]5[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=5[N:8]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:9]=4)=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:29])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CCN(C(=O)OC(C)(C)C)CC5)c5ncnc(N)c45)ccc32)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CCNCC5)c5ncnc(N)c45)ccc32)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To 1,1-dimethylethyl 4-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (230 mg, 0.406 mmol) were added 1,4-Dioxane and 4N HCl in dioxane (4 mL, 16.00 mmol). The mixture was allowed to stir overnight at 50° C. The reaction was concentrated. The solid was sonicated with 1:1 Hexane:DCM and the solid was isolated by filtration to isolate 5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (188 mg, 80% yield) as a white solid as the trihydrochloride salt. LC-MS (ES) m/z=467.4 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) δ 8.38 (s, 1H), 8.29 (d, J=8.34 Hz, 1H), 7.61 (s, 1H), 7.41 (s, 1H), 7.35 (dd, J=1.77, 8.34 Hz, 1H), 7.22-7.28 (m, 1H), 7.18 (s, 1H), 7.13 (t, J=7.33 Hz, 2H), 5.07-5.18 (m, 1H), 4.25 (t, J=8.46 Hz, 2H), 3.90 (s, 2H), 3.68 (s, 2H), 3.61-3.67 (m, 2H), 3.25-3.31 (m, 3H), 2.41-2.54 (m, 2H), 2.36 (s, 3H), 2.34 (br. s., 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.CS[C:21]1[N:22](C(OCC)=O)[CH2:23][CH2:24][N:25]=1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)C>[NH:25]1[CH2:24][CH2:23][N:22]=[C:21]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: CCOC(=O)N1CCN=C1SC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCN3)cc2)cs1
Temperature: 65 °C
Reaction time: 6 h
Yield: 48.8 %

Procedure:
A mixture of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (65 mg) prepared in a similar manner according to Step 6 of Production Example 1, ethyl 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole-1-carboxylate (56 mg), acetic acid (0.1 ml), ethanol (0.9 ml) was stirred at 65° C. for 6 hours, and then refluxed for 5 hours. The reaction mixture was poured into ethyl acetate (5 ml) and saturated aqueous sodium bicarbonate. The precipitated solid was filtered, and the solid was dissolved in 50% methanol/chloroform. The insoluble materials were filtered off and the filtrate was concentrated in vacuo. The solid residue was collected and washed with ethyl acetate to give N-(4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-ethyl}-1,3-thiazol-2-yl)acetamide (40 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5][C:4]=1[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[C:16]#[N:17])=[O:12].[F:23][C:24]1[CH:29]=[C:28]([CH2:30]OS(C)(=O)=O)[CH:27]=[C:26]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[N:25]=1.[I-].[Li+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(#N)C>[CH3:1][N:2]([CH3:22])[C:3]1[C:8](=[O:9])[NH:7][C:6](=[O:10])[N:5]([CH2:30][C:28]2[CH:27]=[C:26]([NH:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:25]=[C:24]([F:23])[CH:29]=2)[C:4]=1[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[C:16]#[N:17])=[O:12]
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2N(C)C)c1
Reactant: COc1ccc(CNc2cc(COS(C)(=O)=O)cc(F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C)cc(C#N)c4)c(N(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1

Procedure:
A solution 3-(5-dimethylamino-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (0.0087 g, 0.0292 mmol), methanesulfonic acid 2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl ester (0.0095 g, 0.0292 mmol), lithium iodide (0.002 g, 0.0146 mmol) and potassium carbonate (0.004 g, 0.0292 mmol) in DMF (3.0 mL) was stirred at 0° C. for 7 h. Reaction mixture was diluted with acetonitrile and purified by reverse phase HPLC (Phenomenex Synergi® column, 5 to 100% acetonitrile/H2O) to give an yellow powder after lyophilization (0.0063 g, 40%). 1H NMR (300 MHz, CDCl3): δ 8.55 (br s, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.49 (s, 1H), 7.22 (s, 1H), 7.19 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 5.77 (d, J=8.4 Hz, 1H), 4.22 (s, 2H), 3.77 (s, 3H), 2.39 (s, 6H). Mass spectrum: 543.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([CH2:12][OH:13])[O:9][N:8]=1.N1C=CC=NC=1C1C=CC(C#CCO)=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([CH:12]=[O:13])[O:9][N:8]=1
Reactant: OCc1cc(-c2ccccn2)no1
Agent: OCC#Cc1ccc(-c2ncccn2)cc1
Product: O=Cc1cc(-c2ccccn2)no1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 300 by substituting 3-(2-pyridinyl)-5-isoxazolemethanol (prepared as described in J. Org. Chem. 2000, 65, 2225) for the 3-[4-(2-pyrimidinyl)phenyl]-2-propyn-1-ol of Reference Example 300. MS 175 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:36][S:37]([CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][S:37]([CH3:36])(=[O:38])=[O:39])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1nc(SC)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1nc(SC)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12) was reacted with 1-(2-methanesulfonylethyl)-piperazine dihydrochloride (example 3) to give cis-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C30H35N6O4S2Cl2 [(M+H)+] 677.1533, observed 677.1532.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[CH2:30][N:17]2[CH2:18][CH2:19][C:20]3[C:25]([CH:16]2[CH2:15][C:14]=1[NH2:31])=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:12])[CH3:9].[BH4-].[Na+].[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([BH3-])#N.[Na+]>O1CCCC1.C(O)(=O)C>[CH2:8]([O:10][C:11]([CH:13]1[CH2:30][N:17]2[CH2:18][CH2:19][C:20]3[C:25]([CH:16]2[CH2:15][CH:14]1[NH:31][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:12])[CH3:9]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C1=C(N)CC2c3cc(OC)c(OC)cc3CCN2C1
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CN2CCc3cc(OC)c(OC)cc3C2CC1NCc1ccccc1
Reaction time: 0.67 h
Yield: 51.3 %

Procedure:
Trifluoroacetic acid (20 mL) was added at 0° C. to a solution of 2-amino-9,10-dimethoxy-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (Example 1a; 2.00 g, 6.02 mmol) in tetrahydrofuran (20 mL), then after 30 min the homogeneous solution was treated with sodium borohydride (474 mg, 12.0 mmol) and stirred for another 40 min. The reaction mixture was concentrated in vacuo and the residue partitioned between 2 M aq. sodium hydroxide solution and dichloromethane. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was dissolved in methanol (37 mL) and acetic acid (9 mL) and treated with benzaldehyde (723 mg, 6.81 mmol), then sodium cyanoborohydride (526 mg, 7.95 mmol) was added portionwise at r.t. over 1 h. The reaction mixture was stirred another 15 min, then partitioned between sat. aq. sodium hydrogencarbonate solution and dichoromethane. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatrography of the residue (SiO2, CH2Cl2/EtOAc 4:1, after elution of dibenzylated side-product, CH2Cl2/MeOH/NH4OH 95:5:0.25) afforded the title compound (1.31 g, 51%). Red oil, MS (ISP) 425.2 (M+H)+.