Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(CC)CC.[CH3:23][C:24]1[C:33]2[CH2:32][CH2:31][C:30](=[O:34])[NH:29][C:28]=2[N:27]=[C:26]([O:35][CH2:36][CH2:37][CH2:38][CH:39]=O)[CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:26]2[N:27]=[C:28]3[C:33]([CH2:32][CH2:31][C:30](=[O:34])[NH:29]3)=[C:24]([CH3:23])[CH:25]=2)[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: Cc1cc(OCCCC=O)nc2c1CCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)nc2c1CCC(=O)N2
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
To a suspension of 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (0.93 g, 3.48 mmol) in dichloroethane (10 mL) was added Et3N (0.96 mL, 6.92 mmol). The mixture was stirred for 15 min and a suspension of 4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.86 g, 3.46 mmol) in dichloroethane (5 mL) was added. After 20 min at RT, NaBH(OAc)3 (1.03 g, 4.85 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction mixture was poured into CH2Cl2 and washed with H2O, 1N citric acid, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated to an oil. Et2O was added and the organics were decanted from an insoluble gum. The filtrate yielded a crystalline solid, which was collected by filtration and dried. Purification by liquid chromatography (gradient elution, 100% CHCl3 to 2% MeOH/CHCl3, Biotage 40m column) provided the title compound as a white solid (1.12 g, 2.44 mmol, 70%). MS: APCI: M+1: 463.1 (Exact Mass: 462.16).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:12]#[N:13].C(N)CN>CN(C=O)C>[O:10]1[C:6]2=[CH:5][CH:4]=[CH:3][C:2]([C:12]#[N:13])=[C:7]2[CH:8]=[CH:9]1
Reactant: Brc1cccc2occc12
Reactant: N#C[Cu]
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1cccc2occc12
Temperature: 25 °C
Yield: 41.3 %

Procedure:
Combine 4-bromo-benzofuran (1.0 g, 5.07 mmol), copper(I) cyanide (0.9 g, 10.2 mmol), anhydrous DMF (16 ml) and reflux for 17 h. Cool the reaction mixture to ambient temperature, treat with 50% (v/v) aqueous ethylenediamine (25 mL). Extract the reaction mixture with diethyl ether (3×15 mL), combine the organic extracts, wash with brine (15 mL) and dry over anhydrous Na2SO4. Evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to obtain the desired intermediate as a colorless oil (0.3 g, 39%).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O>C(O)(C)C>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[NH2+:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CS(=O)(=O)O
Reactant: C1CCNCC1
Solvent: CC(C)O
Solvent: O
Product: C1CC[NH2+]CC1
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Yield: 95 %

Procedure:
392.1 g of anhydrous methanesulfonic acid were added dropwise to 340.8 g of piperidine in 700 ml of isopropanol while stirring and cooling with water over the course of one hour, during which the temperature rose to 75° C. The dropping funnel was washed with 50 ml of isopropanol, and the mixture was then cooled to 25° C. and stirred at this temperature for half an hour. The precipitated product was filtered off with suction, washed twice with 200 ml of diisopropyl ether each time and dried at 50° C. in vacuo. 688.9 g of piperidinium methanesulfonate were obtained as colorless crystals; which is 95% of theory.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](Br)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1.[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])[CH3:27]>>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([N:32]4[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]4)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(c2nnc3n2-c2ccc(C(F)(F)F)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 8-(trifluoromethyl)-1-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-isopropylpiperazine to give 8-(trifluoromethyl)-1-(4-isopropylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=4)=[CH:21][C:14]=3[N:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>O1CCCC1>[CH3:32][NH:31][C:29]([C:25]1[CH:24]=[C:23]([O:22][C:20]2[CH:19]=[CH:18][C:15]3[N:16]([CH3:17])[C:12]([NH:11][C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[CH:4][CH:5]=4)=[O:10])=[N:13][C:14]=3[CH:21]=2)[CH:28]=[CH:27][N:26]=1)=[O:30]
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)nc(NC(=O)c2ccc(CCl)cc2)n3C)ccn1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(NC(=O)c2ccc(CN4CCN(C)CC4)cc2)n3C)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(2-{[4-(chloromethyl)phenyl]carbonylamino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide (1 eq) in tetrahydrofuran was added methylpiperazine (4 eq) and stirred at ambient temperature for 16 h. The reaction mixture was concentrated and purified on preparative chromatography to yield N-methyl {4-[1-methyl-2-({4-[(4-methylpiperazinyl)methyl]phenyl}carbonylamino)benzimidazol-5-yloxy](2-pyridyl)}carboxamide. MS: MH+=512.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CCO.O>[N:31]1([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([N:26]6[CH:30]=[CH:29][CH:28]=[CH:27]6)[CH:24]=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[O:6][CH:7]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: O=C1CC(c2cccc(-c3nc(CCl)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Reactant: C1COCCN1
Solvent: CCO
Solvent: O
Product: O=C1CC(c2cccc(-c3nc(CN4CCOCC4)co3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
A mixture of 4-[3-(4-chloromethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 78a) (125 mg), morpholine (0.25 mL) and KI (5 mg) in EtOH (1 mL) was stirred at 60° C. for 2 h. in H2O (20 mL) was added to the cooled solution and the precipitate was collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) the pH of the mixture being set to 11 by addition of 1N NaOH solution, and the solid was subsequently isolated by filtration to give the title compound (60 mg) as yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].[CH3:12][O:13][P:14](=[O:19])([O:17]C)[O:15]C>CO>[P:14]([O-:19])([O-:17])([O-:15])=[O:13].[CH2:10]([N+:3]([CH2:1][CH3:2])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:12])[CH3:11].[CH2:10]([N+:3]([CH3:12])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH3:2])[CH3:11].[CH2:10]([N+:3]([CH3:12])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH3:2])[CH3:11]
Reactant: CCCCCCN(CC)CC
Reactant: COP(=O)(OC)OC
Solvent: CO
Product: CCCCCC[N+](C)(CC)CC
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Yield: 134.1 %

Procedure:
To a 200 ml four necked flask equipped with a stirrer, a dropping funnel, a cooling tube and a thermometer, 78.65 g (0.5 mol) of diethyl hexyl amine and 50 ml of methanol were charged and heated, to which 70.04 g (0.50 mol) of trimethyl phosphoric acid was dropped slowly taking one hour or more and refluxed for 15 hours. After reaction, they were cooled to room temperature and 136.80 g of diethyl hexyl methyl ammonium phosphate was obtained by drying under a reduced pressure. Then, 136.80 g of the obtained diethyl hexyl methyl ammonium phosphate was dissolved in 50 ml of water, and a solution in which 189.66 g of lithium bis(pentafluoroethane sulfonyl) imide was dissolved in 50 ml of water was added thereto at a room temperature and stirred. From separated two layers, the lower layer was fractionated and by-products were removed by adding 40 wt % of purified water and water washing five times, and vacuum drying was applied to obtain 262.43 g of diethyl hexyl methyl ammonium bis(trifluoromethane sulfonyl) imide. As a result of ICP analysis, the total alkali metals was 2.4 ppm or less, chloride ion was 0.6 ppm, and each of iodide and bromide ions was 0.1 ppm or less (lower than ICP detection limit).
Reaction SMILES: [OH-:1].[K+].[C:3]1([C:9]23[CH2:16][CH2:15][C:12]([CH2:17][C:18]#N)([CH2:13][CH2:14]2)[CH2:11][CH2:10]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[OH2:21]>C(O)CO>[C:3]1([C:9]23[CH2:16][CH2:15][C:12]([CH2:17][C:18]([OH:21])=[O:1])([CH2:13][CH2:14]2)[CH2:11][CH2:10]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O
Reactant: [OH-]
Reactant: N#CCC12CCC(c3ccccc3)(CC1)CC2
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: O=C(O)CC12CCC(c3ccccc3)(CC1)CC2
Temperature: 165 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
A solution of KOH (1.0 g, 17.52 mmol) in water (1.0 mL) was added to a suspension of (4-phenylbicyclo[2.2.2]oct-1-yl)acetonitrile (0.5 g) in ethylene glycol (10 mL) and the mixture stirred at 165° C. for 6 h, cooled, then poured in to water (100 mL). The mixture was acidified to pH 1 with conc. hydrochloric acid (˜0.5 mL) then extracted with ethyl acetate (100 mL then 30 mL). The combined extracts were washed with water (2×50 mL), dried (MgSO4) and concentrated down to give the title compound as a cream solid (0.5 g; 93%). 1H NMR (CDCl3) 1.57-1.69 (6H, m), 1.75-1.85 (6H, m), 2.12 (2H, s), 7.07-7.14 (1H, m), 7.19-7.28 (4H, m).
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([C@@:39]2([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40]2)[CH:35]=[CH:36][C:37]=1[Cl:38].C(#N)C.C(=O)(O)[O-].[Na+].[CH3:55][O:56][C:57]1[CH:65]=[CH:64][C:63]([N:66]2[CH:70]=[N:69][N:68]=[N:67]2)=[CH:62][C:58]=1[C:59](Cl)=[O:60]>O>[CH3:55][O:56][C:57]1[CH:65]=[CH:64][C:63]([N:66]2[CH:70]=[N:69][N:68]=[N:67]2)=[CH:62][C:58]=1[C:59]([N:41]1[CH2:42][CH2:43][C@@:39]([C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)([CH2:44][CH2:45][OH:46])[CH2:40]1)=[O:60]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Reactant: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (0.14 g, 0.21 mmol) ethyl acetate (15 mL), acetonitrile (6 mL), water (6 mL), and sodium bicarbonate (0.09 g, 1.03 mmol). Cool to 0° C. in an salt-ice bath. Add 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (0.21 mmol). After 30 minutes, warm to ambient temperature. After 30 minutes at ambient temperature, partition the reaction mixture between ethyl acetate and brine. Extract the organic layer with 1M hydrochloric acid solution, then saturated aqueous sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4C)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.[C:46]([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:23]([OH:24])[C@@:13]3([CH3:46])[OH:14])[C:6]=2[N:7]=1
Reactant: Cc1ccccc1C(=O)O[C@H]1[C@@H](OC(=O)c2ccccc2)[C@H](n2c(=O)sc3cnc(N)nc32)O[C@@H]1COC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(=O)sc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a suspension of nucleoside 3 (380 mg, 0.606 mmol) in MeOH (20 mL) was added K2CO3 (17 mg, 0.12 mmol) at rt. The resulting mixture was stirred 18 h at rt whereupon it was treated with HOAc (15 μL, 0.25 mmol), concentrated and submitted to HPLC purification (MeCN—H2O), affording 20 mg (10%) of the title compound 4 as a white solid after lyophilization: 1H (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 6.86 (br s, 2H), 6.09 (br s, 1H), 5.19 (br s, 1H), 4.88 (br s, 1H), 4.55 (t, J=5.87, 1H), 3.97 (br s, 1H), 3.76-3.81 (m, 1H), 3.61 (br s, 2H), 1.04 (s, 3H); [M+H]+ m/z 315. Analysis calc'd for C11H14N4O5S.H2O: C, 39.75; H, 4.85; N, 16.86; S, 9.65.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12]N(CCC)C2)[CH:6]=[CH:7][CH:8]=1.[C:18]([Cl:29])(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[N:30]1[CH:35]=C[CH:33]=[CH:32][CH:31]=1.Cl>ClCCl.CCOCC>[ClH:29].[C:18]([O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:35][N:30]2[CH2:31][CH2:32][CH3:33])[CH:6]=[CH:7][CH:8]=1)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: c1ccncc1
Reactant: CCCN1CCCC(c2cccc(O)c2)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)Oc1cccc(C2CCCCN2CCC)c1

Procedure:
(-)-3-(3-hydroxyphenyl)-1-propylpiperidine hydrochloride (1.5 g, 5.86 mmol) was suspended in dry dichloromethane (15 ml). Decanoylchloride (1.2 g, 6.29 mmol) was dissolved in a mixture of dichloromethane (15 ml) and pyridine (0.5 g, 6.32 mmol). The solution was added to the suspension and the mixture was refluxed for 20 hours. The clear solution was cooled, washed with aqueous NaHCO and dried with Na2SO4. After evaporation the residual oil was dissolved in ether and precipitated as hydrochloride salt with one equivalent HCl in ether. The salt was recrystallized twice from acetone. Yield: 0.7 g (30%). M.p. 142°-144° C. [α]D20 (C=1.8, MeOH)=-5.6°, MS (70 eV): m/z 373 (5%), 344 (100%), 190 (7%).
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][C:14](=[O:17])[CH:15]=[CH2:16]>C(O)C.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[CH:1]1([C:4](=[O:5])[CH2:16][CH2:15][C:14](=[O:17])[CH3:13])[CH2:3][CH2:2]1
Reactant: C=CC(C)=O
Reactant: O=CC1CC1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)CCC(=O)C1CC1
Temperature: 85 °C

Procedure:
To a solution of cyclopropanecarbaldehyde (3.20 ml, 42.8 mmol) in ethanol (15.3 mL) was added triethylamine (11.9 mL, 86.0 mmol), but-3-en-2-one (3.54 mL, 42.8 mmol), and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium bromide (2.16 g, 8.56 mmol). The reaction mixture was heated at 85° C. for 18.5 h. The reaction was then concentrated and the resulting residue was extracted with ethyl acetate (3×50 mL). The organic layer was dried (sodium sulfate), filtered and concentrated to an orange residue which was purified on silica gel on an automated system (ISCO 120 g, 20 mL/min) using 0 to 75% ethyl acetate in hexanes over 60 minutes. The product, 1-cyclopropylpentane-1,4-dione, was isolated as a yellow oil (2.21 g, 15.8 mmol, 37% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 2.86 (t, 2H), 2.72 (t, 2H), 2.19 (s, 3H), 1.90-1.99 (m, 1H), 1.01 (m, 2H), 0.88 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]1([F:26])[CH2:17][CH2:16][CH:15]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[C:27](OC(C)(C)C)(=[O:32])[CH2:28][C:29]([O-])=[O:30].C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:22]([C:21]4[CH:24]=[CH:25][C:18]([CH:15]5[CH2:16][CH2:17][C:12]([F:26])([F:11])[CH2:13][CH2:14]5)=[CH:19][CH:20]=4)[C:29](=[O:30])[CH2:28][C:27]3=[O:32])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccc(C2CCC(F)(F)CC2)cc1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: Nc1ccc2[nH]cnc2c1
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(C2CCC(F)(F)CC2)cc1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.71 g, 5.35 mmol), 4-(4,4-difluorocyclohexyl)benzaldehyde (1.2 g, 5.35 mmol), mono-tert-butyl malonate (0.850 mg, 5.35 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (0.84 g, 5.35 mmol) and sodium tert.-butoxide (0.615 g, 5.5 mmol) according to method 5.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[C:12]([O:22][CH3:23])[CH:11]=2)[N:3]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN1C=CC(=O)C1=O>[CH:24]1([NH:30][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]4)=[C:12]([O:22][CH3:23])[CH:11]=3)[N:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: NC1CCCCC1
Agent: CN1C=CC(=O)C1=O
Product: COc1cc(Nc2nc(C)cc(NC3CCCCC3)n2)ccc1-n1cnc(C)c1
Yield: 81.5 %

Procedure:
A solution of (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (66 mg, 0.2 mmol) and cyclohexylamine (60 mg, 0.6 mmol) in N-methylpyrroldione (2 mL) was heated for 30 min to 200° C. in a microwave oven. Additional cyclohexylamine (60 mg, 0.6 mmol) was added and the reaction was heated for 30 min to 200° C. in a microwave oven. The reaction mixture was poured onto water and the precipitate was filtered off, washed with water, dissolved in 1N aqueous sodium hydroxide solution and extracted twice with diethyl ether. The combined organic layers were washed with water, once with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield the title compound as a light brown solid (64 mg, 82%). MS ISP (m/e): 393.4 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.60 (br s, 2H), 7.13 (s, 2H), 6.92 (br s, 1H), 6.86 (s, 1H), 5.75 (s, 1H), 4.61 (m, 1H), 3.85 (s, 3H), 3.69 (m, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 2.05 (br d, 2H), 1.60-1.82 (m, 4H), 1.18-1.45 (m, 4H).
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2ncccc2F)C[C@@H]1C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ncccc2F)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.1 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-4-[(3-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 72) (111.6 mg, 0.214 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 45 min then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined and concentrated in vacuo to give a residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.2 mL, 0.2 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-N-(3-fluoro-2-pyridinyl)-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (67.4 mg, 0.137 mmol, 64.1% yield) as a light orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][CH2:34][CH2:35]O.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:35][CH2:34][O:33][CH3:32])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCCO
Reactant: COC(=O)c1ccc(O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)OC)c(O)c1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a 50 ml tetrahydrofuran solution of 4.0 g (23.8 mmol) of methyl 2,4-dihydroxybenzoate, 7.49 g (28.5 mmol) of triphenylphosphine, 2.25 ml (28.5 mmol) of 2-methoxyethanol, and 4.5 ml (28.5 mmol) of diethyl azodicarboxylate were slowly added at 0° C. The mixture was brought to room temperature, and stirred for 1 hour. Then, the reaction mixture was diluted with ethyl acetate, and washed with water and a saturated aqueous solution of sodium chloride. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue, 100 ml of a solution of ethyl acetate/hexane (=1/4) was added, and insoluble solids were removed by filtration. Then, the mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to obtain 4.71 g (87%) of the captioned compound.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17](O)[C:18]2[N:19]([CH:27]3[CH2:29][CH2:28]3)[CH:20]=[CH:21][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=1.C(N(CC)CC)C.[NH2:38][C:39]1[CH:40]=[C:41]([CH3:47])[C:42](=[O:46])[N:43]([CH3:45])[CH:44]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH:38][C:39]2[CH:40]=[C:41]([CH3:47])[C:42](=[O:46])[N:43]([CH3:45])[CH:44]=2)[C:18]2[N:19]([CH:27]3[CH2:29][CH2:28]3)[CH:20]=[CH:21][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccn(C2CC2)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccn(C2CC2)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
Methanesulfonic anhydride (3.42 g, 19.62 mmol) was added at −40° C. to a stirred solution of methyl 2-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-1H-pyrrole-3-carboxylate (Step 240.5) (3 g, 9.81 mmol) and triethylamine (6.84 mL, 49.1 mmol) in CH2Cl2 (60 mL). After 15 min at −40° C., 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 240.7) (1.762 g, 12.76 mmol) was added. The resulting mixture was allowed to warm from −40° C. to rt over 18 hr under stirring, diluted in CH2Cl2//water, and extracted twice with CH2Cl2. The combined organic extracts were dried and concentrated. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 97.5:2.5) to afford the title compound (2.2 g, 51.6% yield) as a brown foam. tR: 1.13 min (LC-MS 6); ESI-MS: 426.2 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH 97.5:2.5): Rf=0.29.