Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].[CH3:24][Li].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@:9]([CH3:24])([OH:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: [Li]C
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc2c3c(ccn2c1C)[C@@](C)(O)[C@H](O)[C@@H](c1ccccc1)N3

Procedure:
3.5 g of (8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one are suspended in 70 ml of tetrahydrofuran under argon and treated dropwise at −50° C. with a solution of methyllithium (1.6M solution in diethyl ether). The temperature is then allowed to rise to room temperature, and the mixture is poured into a saturated aqueous ammonium chloride solution and extracted three times with 100 ml of dichloromethane each time. The combined organic phases are washed with a little water, dried over sodium sulfate and concentrated to dryness in vacuo. The oily residue obtained is chromatographed on silica gel (eluent: dichloromethane/methanol 13/1). 1.66 g of the title compound are obtained as colorless crystals of melting point 137-8° C. (diethyl ether).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si](C)(C)C)[C:30](=O)[C@@:29]2([CH3:43])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)(C(C)(C)C)(C)C.F.C[C@@H]1[C@]2(OC[C@H](C)CC2)O[C@H]2C[C@@H]3[C@@](C)([C@@H]12)[C@H]([OH:66])C(=O)[C@H]1[C@H]3CC[C@@H]2[C@]1(C)CC[C@H](O)C2>C(#N)C>[CH3:20][C@@H:19]1[C@:21]2([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]2)[O:22][C@H:17]2[C:16](=[O:66])[C@@H:15]3[C@@:29]([CH3:43])([C@@H:18]12)[CH2:30][C@H:31]([OH:37])[C@H:32]1[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[C@:33]1([CH3:36])[CH2:34][CH2:35][C@H:9]([OH:8])[CH2:10]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O[Si](C)(C)C)C(=O)[C@]3(C)[C@H]1[C@@H]2C
Agent: F
Solvent: CC#N
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C(=O)[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@H]1[C@@H]2C

Procedure:
The title compound was synthesized from (3β,5α,11β,25R)-3-(t-butyidimethylsilyloxy)-11-(trimethylsilyloxy)spirostan-12-one was desilylated with hydrofluoric acid in acetonitrile according to the procedure described in J. Am. Chem. Soc., 1972, 94, 6190. The title compound must be carefully handled because it will rearrange to (3β,5α,12β,25R)-spirostan-3,12-diol-11-one if exposed to base.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.CCCCCC.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([C@H:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34])[CH2:24][CH2:23][CH2:22]2>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([C@@H:29]([CH2:33][CH2:32][OH:31])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:34])[CH2:24][CH2:23][CH2:22]2
Reactant: Nc1ccccc1
Reactant: O=C1OCC[C@@H]1N1CCCc2cc(Cl)ccc21
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)[C@H](CCO)N1CCCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
Prepared using general procedure 60: To a solution of aniline (1.0 mL, 11.1 mmol) in CH2Cl2 (25 mL) under nitrogen at RT was added a solution of trimethylaluminum in hexane (2.0 M, 5.5 mL, 11.0 mmol) over 5 min. After stirring at RT for 20 min, a solution of (S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-dihydrofuran-2(3H)-one (2.32 g, 9.2 mmol) in CH2Cl2 (25 mL) was added over 10 min. Stirring was continued for 18 h at RT, then the reaction mixture was cooled to 0° C. and quenched by careful addition of aqueous 1M HCl (25 mL). Phases were separated, and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 2-10% MeOH in CH2Cl2 gave (S)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-phenylbutanamide as a white solid (2.56 g, 81%). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.60 (dd, J=1.0, 8.5 Hz, 2H), 7.29 (dd, J=1.8, 14.1 Hz, 2H), 7.07-6.95 (m, 3H), 6.80 (d, J=9.0 Hz, 1H), 4.67 (t, J=4.9 Hz, 1H), 4.56 (t, J=7.2 Hz, 1H), 3.47 (dd, J=6.1, 11.2 Hz, 2H), 3.39-3.34 (m, 1H), 3.31-3.25 (m, 1H), 2.71-2.68 (m, 2H), 2.15-2.04 (m, 1H), 1.94-1.80 (m, 3H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=345.3; tR=3.44 min.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17][C:18](=[O:21])[O:19][CH3:20])=[O:8])[N:4]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1.OS(O)(=O)=O.[N+:34]([O-])([OH:36])=[O:35]>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([N+:34]([O-:36])=[O:35])=[CH:12][C:11]=2[NH:17][C:18](=[O:21])[O:19][CH3:20])=[O:8])[N:4]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Nc1cccc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Nc1cc([N+](=O)[O-])cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 0 °C

Procedure:
Methyl (2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-3-methylphenyl)carbamate prepared in Example 54 (100 mg, 0.22 mmol) was introduced in a V-shaped vial, and the vial was placed in an ice bath. H2SO4 (0.5 mL) was added to the vial at 0° C. and subjected to a reaction until the solid disappeared. After the solid completely disappeared, HNO3 (77 μL, 1.29 mmol, 6.0 eq) was added to the solution dropwise. The vial was removed from the ice bath 10 minutes after the initiation of the reaction, and the reaction mixture was allowed to react at room temperature for 1 hour. Upon completion of the reaction, 15 mL of ice was placed in a 50 mL flask, and the reaction mixture was added thereto. The reaction mixture was washed with water several times and filtered. The residue was extracted with ether and H2O, dried over MgSO4 and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EA:Hex=1:1) to obtain the title compound in a white solid (95 mg, yield: 85%).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:14][CH:13]([NH:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)=[C:20]([NH2:35])[N:19]=[CH:18][N:17]=3)[CH2:12]2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[O:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:16]([NH:15][CH:13]3[CH2:14][C:10]4([CH2:9][NH:8][CH2:11]4)[CH2:12]3)=[N:17][CH:18]=[N:19][C:20]=2[NH2:35])=[CH:27][CH:26]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(Nc3ncnc(N)c3-c3ccc(Oc4ccccc4)cc3)C2)C1
Agent: Cl
Solvent: CO
Product: Nc1ncnc(NC2CC3(CNC3)C2)c1-c1ccc(Oc2ccccc2)cc1
Reaction time: 16 h

Procedure:
In a round bottom flask containing 6-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (167.23 mg; 0.35 mmol; 1.00 eq.) in methanol (5.00 ml) was added hydrogen chloride (1.80 ml; 3.53 mmol; 10.00 eq.). The reaction was stirred for 16 h before it was concentrated and carried to the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1Cl

Procedure:
(2-Amino-5-chloro-4-methyl-phenyl)-carbamic acid tert-butyl ester was prepared from (5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A16) (11.9 g, 41.4 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a yellow solid (9.25 g, 87%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][Mg+].[Br-]>CCOCC>[CH3:18][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: Clc1ccc2c(-c3ccccc3)ccnc2c1
Agent: [Br-]
Solvent: CCOCC
Product: Cc1ccc2c(-c3ccccc3)ccnc2c1

Procedure:
To a solution of 7-chloro-4-phenylquinoline (10.0 g, 41.7 mmol) and Ni(dppp)2Cl2 (2.26 g, 4.17 mmol) in ether (200 mL) was added dropwise 3.0 M MeMgBr (24.3 mL, 73 mmol) and heated at reflux for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ether. The combined organic layer was washed with water and brine and then dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the resulting crude product was used in the next step without further purification. 1H NMR (400 MHz, acetone-d6): δ 8.9 (d, 1H), 7.93 (bs, 1H), 7.82 (d, 1H), 7.52-7.62 (m, 5H), 7.43 (dd, 1H), 7.35 (d, 1H), 2.60 (S, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[N+:13]([O-])([O-:15])=[O:14].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:13]([C:12]1[C:2]([OH:1])=[C:3]([CH:9]=[CH:10][CH:11]=1)[CH:4]=[CH:5][C:6]([OH:8])=[O:7])([O-:15])=[O:14]
Reactant: O=C(O)C=Cc1ccccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C=Cc1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 52.3 %

Procedure:
2-Hydroxycinnamic acid (3.00 g, 18.3 mmol) was dissolved in methylene chloride (40 mL) followed by the addition of sodium nitrate (2.21 g, 26.1 mmol). The addition of sulfuric acid (30 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product (2.0 g, 52%). 1H NMR (CD3COCD3): δ8.21 (d, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.19 (t, 1H), 6.72 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=2)=[CH:12]1
Reactant: Clc1cncc(OCCc2c[nH]c3ccccc23)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: c1ccc2c(CCOc3cncc(N4CCNCC4)n3)c[nH]c2c1
Temperature: 110 °C
Yield: 23 %

Procedure:
A mixture of the product from Step 1 above (1.07 g, 3.90 mmol), piperazine (0.98 g, 11.3 mmol) and K2CO3 (0.54 g, 3.9 mmol) in acetonitrile (11 mL) was heated at 85° C. for 5 h and at 110° C. for 8 h in a sealed pyrex flask. The reaction mixture was diluted with CHCl3, filtered, and concentrated in vacuo. The semi-solid residue was purified by chromatography on silica gel (11×4 cm) using CHCl3/MeOH (9: 1) as eluent. The resulting oil was redissolved in CHCl3 and filtered through a short plug of alumina, covered by K2CO3, using CHCl3 as eluent. Solvent removal in vacuo furnished 0.50 g (23%) of the title compound as an oil that solidified upon standing: mp 133-135° C. HRMS m/z calcd for C18H21N5O (M)+ 323.1746, found 323.1763. Anal. (C18H21N5O) C, H, N.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]3[N:10]([CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[N:11]=[CH:12][C:7]3=[C:6]([C:23]([NH:25][CH2:26][C:27]3[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=3[CH3:33])=[O:24])[CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:15][CH2:14][CH2:13][N:10]1[C:8]2[N:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=[C:6]([C:23]([NH:25][CH2:26][C:27]3[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=3[CH3:33])=[O:24])[C:7]=2[CH:12]=[N:11]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3CCNC(=O)OC(C)(C)C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3CCN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl {2-[6-cyclopropyl-4-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]ethyl}carbamate (260 mg, 0.541 mmol) in DCM (15 mL) was added trifluoroacetic acid (3 ml, 38.9 mmol) and the mixture stirred at room temperature for 2 h. The contents were concentrated in vacuo and the crude residue purified by reverse phase HPLC. (mobile phase: 10 to 70% ACN in H2O, 0.1% NH4OH). The final product was collected as 0.170 g (89%). LCMS E-S (M+H)=353.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.32 Hz, 4H), 2.13 (s, 3H), 2.21 (s, 4H), 3.00 (t, J=6.19 Hz, 2H), 4.29-4.47 (m, 4H), 5.90 (s, 1H) 7.43 (s, 1H), 8.22 (s, 1H), 8.75 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.C1N2CCN(CC2)C1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>O1CCOCC1.O.[Cl-].[Na+].O>[CH3:23][O:22][C:18](=[O:21])[C:19]([CH:8]([OH:9])[C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1)=[CH2:20]
Reactant: C=CC(=O)OC
Reactant: Cc1ncc(C=O)cn1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C(=O)OC)C(O)c1cnc(C)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
A mixture of 2-methylpyrimidine-5-carbaldehyde (1 g, 8.18 mmol, 1 eq), DABCO (1 eq, 935 mg) and methyl acrylate (5 eq, 3 68 ml) dissolved in a 1,4-dioxane (40 ml/H2O (40 ml) mixture was stirred at room temperature for 2 hours. The mixture was then poured into 300 ml of brine and the organic substances were extracted with DCM (3 times, 300 ml was used in total). The gathered DCM layers were dried, the solvent was evaporated and the obtained crude oil was triturated with diethyl ether to afford 2-[hydroxy-(2-methyl-pyrimidin-5-yl)-methyl]-acrylic acid methyl ester (1.58 g, yield=83.40%, purity=90%) in form of white powder. MS: [M+H]+=209.18 1H NMR (300 MHz; CDCl3) δ/ppm 2.72 (s, 3H), 3.61 (br.s., 1H), 3.75 (s, 3H), 5.58 (s, 1H), 5.97 (s, 1H), 6.43 (s, 1H) 8.64 (s, 2H)
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([NH2:17])[N:14]([C@H:18]([CH3:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=3[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([NH:17][C:32](=[O:34])[CH3:33])[N:14]([C@H:18]([CH3:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[C:13]=3[CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](n1c(N)nc2ccc(C#Cc3ccccc3)cc21)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(C#Cc3ccccc3)cc2n1[C@H](C)C(C)(C)C
Reaction time: 18 h

Procedure:
Add 6-phenylethynyl-1-(1-(R)-methyl-2,2-dimethylpropyl)-1H-benzimidazol-2-ylamine (5.81 g, 0.018 mol), triethylamine (12 mL), dichloromethane (100 mL), N,N-dimethylaminopyridine (0.11 g, 0.9 mmol), and acetic anhydride (7.5 mL) and stir for about 18 hours. Evaporate and redissolve in ethyl acetate and wash with water, 1N HCl (3×), saturated sodium bicarbonate, and saturated sodium chloride. Add 2M ammonia in methanol to organic layer and stir 10 minutes and evaporate. Redissolve in dichloromethane and wash with saturated sodium bicarbonate, saturated sodium chloride, dry magnesium sulfate, and concentrate to give the desired compound as an orange foam (6.92 g, quant).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]([N:11]2[CH2:16][CH2:15][N:14](C([O-])=O)[CH2:13][CH2:12]2)=O)[CH:5]=[CH:6][CH:7]=1.B.Cl.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])N1CCN(C(=O)C(c2cccc(Cl)c2)C2(O)CCCCC2)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCCC1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
A solution of 4-[(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate (200 mg, 0.46 mmol) in dry tetrahydrofuran (3 mL) under nitrogen was treated dropwise with a solution of borane (1.0 M in tetrahydrofuran, 1.60 mL, 1.60 mmol). The resulting solution was heated at 70° C. for 2 h, after which time the reaction was cooled in an ice bath and was treated dropwise with a 2N aqueous solution of hydrochloric acid (1 mL). The reaction was again heated at 70° C. for 1 h, and was then cooled and treated with methanol (1 mL). After the solvent was removed in vacuo, the resulting residue was dissolved in water (5 mL) and was washed with ethyl acetate (1×4 mL). The aqueous layer was basified with the addition of a 2 N aqueous solution of sodium hydroxide until the pH=10. The product was extracted with ethyl acetate (4×5 mL) and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 146 mg (99%) 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol as a colorless oil. HRMS: calcd for C18H27ClN2O, 322.1812; found (ESI_FT), 323.18977. 1-[1-(3-Chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol (146 mg) was dissolved in methanol (0.5 mL) and treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether. After crystallizing in the refrigerator for 16 h, the resulting solid was collected, washed with diethyl ether and dried in vacuo to yield 110 mg (60%) 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride as a white solid. MS (ESI) m/z 323/325 ([M+H]+); HRMS: calcd for C18H27ClN2O.2.00 HCl, 394.1345; found (ESI_FT), 323.18831.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:24][C:21]([NH:20][C:19]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:22])[CH3:23]
Reactant: [H][H]
Reactant: CC(C)(C)Nc1cccnc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)Nc1cccnc1N1CCNCC1

Procedure:
1- Benzyl-4-[3-(1,1-dimethylethylamino)pyridyl]piperazine (PREPARATION 96, 4.25 g, 13.10 mmol) is dissolved in 100 ml ethanol. Palladium (10% on carbon, 1.0 g) is added and the solution hydrogenated at 40 psi hydrogen gas. The mixture is filtered and concentrated to give the title compound, NMR (300 MHz, CD3OD) 7.53, 7.19, 6.93, 2.95, 1.39 δ.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=[C:4]1[C:10]1[CH:33]=[CH:32][C:13]2[N:14]=[C:15]([C:17]3[CH:31]=[CH:30][C:20]([O:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=[C:4]1[C:10]1[CH:33]=[CH:32][C:13]2[N:14]=[C:15]([C:17]3[CH:31]=[CH:30][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)[CH3:2]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(=O)OC(C)(C)C)cc3)oc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(=O)O)cc3)oc2c1

Procedure:
20 mg (44 μmol) tert-butyl {4-[6-(4-ethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-phenoxy}-acetate (Example 66), 500 μl TFA and 1 ml DCM are stirred together for 2 h at RT, then the solv. is totally eliminated i.V. and the residue is crystallised from cyclohexane/EA.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[CH3:15][O:16][C:17](=[O:21])[CH2:18][CH:19]=[CH2:20]>>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:20]=[CH:19]/[CH2:18][C:17]([O:16][CH3:15])=[O:21])[CH3:9]
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Reactant: C=CCC(=O)OC
Product: COC(=O)C/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Yield: 65 %

Procedure:
By using (2R)-2-{[(1R)-1-(2-bromo phenyl)ethoxy]methyl}oxirane (257 mg, 1.00 mmol) described in WO 2004/094362 and methylbut-3-enoate, the reaction was carried out in the same manner as the method described in Example 3 (3c) to give the title compound as a yellow oily substance (yield 65%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:30][O:29][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[O:27][CH3:28])[C:17]([CH2:16][N:7]1[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5])=[CH:18][CH:19]=[CH:20]2
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: COc1cc2cccc(CCl)c2cc1OC
Product: COc1cc2cccc(Cn3c(C(=O)O)cc4ccccc43)c2cc1OC

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-chloromethyl-6,7-dimethoxy-naphthalene (Lit. 11) and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 360.0 ([M−H]−).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:36]=[C:35]5[C:30]([CH2:31][CH2:32][NH:33][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40].C(N(CC)CC)C>C1COCC1>[CH3:37][N:38]([CH3:42])[C:39]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][C:27]([C:19]3[N:20]4[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[C:17]([C:12]4[CH:13]=[CH:14][C:15]5[C:10]([CH:11]=4)=[N:9][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:16]=5)[CH:18]=3)=[CH:28][CH:29]=2)[CH2:34]1)=[O:40]
Reactant: Nc1ncnn2c(-c3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCc2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2C1
Temperature: 40 °C

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (150 mg, 0.3 mmol) in THF (2 mL) was added dimethylcarbamyl chloride (44 mg, 0.4 mmol) and triethylamine (64 mg), and the mixture was heated to 40° C. for 4 hours. The mixture was concentrated in vacuo and the residue was dissolved in methanol and purified by preparative HPLC to provide the title compound, 53 mg (31%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.4 (m, 2 H), 3.5 (m, 2 H), 2.9 (m, 2 H), 2.8 (s, 6 H); ES-MS m/z 543.47 [M+H]+, HPLC RT (min) 3.16.