Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].OP=O.C(=O)(O)[O-].[Na+]>Cl.O>[C:5]1([N:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: O=C1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
A solution of 1-(4-amino-phenyl)-piperidin-4-one (1.34 g, 7.05 mmol) in 50% hydrochloric acid (10 mL) was stirred at ambient temperature for 15 min. The reaction mixture was cooled to 0° C. and a solution of sodium nitrite (1.46 g) in water (5 mL) added and stirred for 30 min. To this reaction mixture was added cold 30-32% hypophosphorus acid (10 mL), the mixture then being warmed to ambient temperature and stirred for 2 h. The reaction mixture was neutralised with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 17% ethyl acetate in petroleum ether as eluent to afford 1-phenyl-piperidin-4-one (0.18 g, 15%) as a liquid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:23][CH:24]([CH3:28])[CH2:25][CH2:26][OH:27])=[N:5][C:6]([CH2:21][CH3:22])=[C:7]([C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)[N:8]=1)[CH3:2].N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([O:27][CH2:26][CH2:25][CH:24]([NH:23][C:4]1[C:3]([CH2:1][CH3:2])=[N:8][C:7]([C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[C:6]([CH2:21][CH3:22])[N:5]=1)[CH3:28])(=[O:37])[CH3:36]
Reactant: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1NC(C)CCO
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1NC(C)CCOC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A 25 mL dry round bottom flask equipped with a magnetic stir bar was charged with a solution of 3-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}butan-1-ol (Example 39, 192 mg, 0.5 mmol) in CH2Cl2 (5 mL). The reaction was cooled with an ice bath and then treated with pyridine (0.044 mL, 0.55 mmol) followed by acetyl chloride (0.039 mL, 0.55 mmol). The solution turned from clear to a light yellow. The ice bath was removed and the reaction was stirred at ambient temperature for 2 hours. The reaction was diluted with CH2Cl2, washed twice with water, once with brine, dried with MgSO4, filtered and concentrated to give 217 mg of a crude oil. This material was purified by Biotage MPLC (40 g column, 20% ethyl acetate in heptane) to give 208 mg (97%) of 3-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}butyl acetate as a clear oil. Rf 0.15 (5% acetone in toluene). OAMS supporting ions at: ESI+ 426.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C(=O)C.O1CCCC1>[CH:44]1([C:42]([NH:41][C:39]2[N:40]=[C:35]3[CH:34]=[CH:33][C:32]([O:31][C:30]4[CH:29]=[C:28]([NH:27][C:13]([C:4]5[CH:3]=[C:2]([CH3:1])[N:6]([C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=6)[N:5]=5)=[O:15])[CH:49]=[CH:48][CH:47]=4)=[N:37][N:36]3[CH:38]=2)=[O:43])[CH2:45][CH2:46]1
Reactant: Cc1cc(C(=O)O)nn1-c1ccccc1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)nn1-c1ccccc1
Yield: 66.2 %

Procedure:
Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (294 mg, 1.45 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (127 μL, 1.45 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.97 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 255, the title compound (317 mg, 66%) was obtained as a white powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-])=O>CO.[Pd]>[NH2:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[S:2][CH3:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(SC)c(N)c1

Procedure:
A stirred solution of methyl 4-methylthio-3-nitrobenzoate (6.82 g; that is prepared as described in Reference Example 51) in methanol (350 mL) is hydrogenated using a 5% w/w palladium on charcoal catalyst (0.8 g) at room temperature for 48 hours. After filtration the solution is concentrated, to give methyl 3-amino-4-(methylthio)benzoate (3.5 g), in the form of a pale yellow solid, m.p. 63-65° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:54])[C@H:10]([CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[NH:11][C:12](=[O:38])[C@H:13]([CH:35]([CH3:37])[CH3:36])[NH:14][C:15](=[O:34])[C@H:16]([CH3:33])[NH:17][C:18](=[O:32])[C@H:19]([CH2:28][CH2:29][S:30][CH3:31])[NH:20][C:21](OC(C)(C)C)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:55]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C@H:56](C(OC1C=CC([N+]([O-])=O)=CC=1)=O)[CH2:57][CH2:58][C:59](=[O:61])[NH2:60].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(OC(N[C@H](C(N[C@H](C(O)=O)CCSC)=O)CCC(=O)N)=O)(C)(C)C>>[CH2:1]([O:8][C:9](=[O:54])[C@H:10]([CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[NH:11][C:12](=[O:38])[C@H:13]([CH:35]([CH3:36])[CH3:37])[NH:14][C:15](=[O:34])[C@H:16]([CH3:33])[NH:17][C:18](=[O:32])[C@H:19]([CH2:28][CH2:29][S:30][CH3:31])[NH:20][C:21](=[O:22])[C@H:56]([CH2:57][CH2:58][C:59](=[O:61])[NH2:60])[NH:55][C:74]([O:76][C:77]([CH3:80])([CH3:78])[CH3:79])=[O:75])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Agent: CSCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C

Procedure:
The Boc group was removed from a sample of compound XXII (2.5 g, 3.3 mmole) as described in previous paragraphs. The trifluoroacetate salt washed with ether and dried; the white solid (RfC, 0.76) showed on tlc a slight impurity at the origin (presumably the t-butylsulfonium salt). This material was acylated with Boc-L-Gln-ONp (1.4 g, 3.8 mmole, Bachem) in the presence of DIEA (1.3 ml, 8 mmole) and HOBt (0.58 ml, 3.8 mmole). Next day the product was isolated as described for XII and then purified by precipitation from a solution in DMF with H2O. The product was washed with H2O and dried: 28 g (93%), m.p. 238°-241° C. [α]D23 -27.7° (c 0.8, DMF); RfK, 0.43; RfL, 0.50.
Reaction SMILES: ClC1C=CC(C(C2CC2)C2C3C(=C(CSC)C([F:18])=CC=3)NC=2)=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:37]2[C:45]3[C:40](=[C:41]([CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)([CH:34]2[CH2:36][CH2:35]2)C)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH:34]2[CH2:36][CH2:35]2)[C:37]2[C:45]3[C:40](=[C:41]([CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:42]([F:18])=[CH:43][CH:44]=3)[NH:39][CH:38]=2)=[CH:28][CH:27]=1
Reactant: CSCc1c(F)ccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Product: CS(=O)(=O)Cc1c(F)ccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 238 mg (0.66 mmol) of the compound from Example 234 in analogy to the synthesis of the compound from Example 209. 144 mg (55% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][O:12][C:10](=[O:11])[C:9]2=[CH2:14])=[CH:4][CH:3]=1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C.C(OCC)C>[CH2:15]([S:22][CH2:14][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13][O:12][C:10]1=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C1C(=O)OCC1c1ccc(Cl)cc1
Reactant: SCc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1OCC(c2ccc(Cl)cc2)C1CSCc1ccccc1
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of 700 mg of β-(p-chlorophenyl)-α-methylene-γ-butyrolactone in 10 ml of toluene were added 0.51 ml of benzylmercaptan and one drop of triethylamine and the resulting mixture was kept at room temperature for 6 hours. After completion of the reaction, the reaction mixture was diluted with 100 ml of ethyl ether, washed with 10% aqueous sodium hydroxide and saturated saline, dried over magnesium sulfate and the solvent was distilled off. The crude product thus obtained was purified by a column chromatography to give 900 mg (yield 81%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18](O)(=[O:20])=[O:19])=[CH:16][CH:17]=1>CCO.O=[Pt]=O>[C:12]1([CH3:11])[CH:17]=[CH:16][C:15]([S:18]([O:10][CH2:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCCc1ccncc1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCCCC2CCNCC2)cc1
Reaction time: 6 h
Yield: 112.1 %

Procedure:
To a solution of 3-(4-pyridyl)propan-1-ol (15.13 g, 0.1103 mol) in EtOH (100 mL) was added p-TsOH (20.98 g, 0.1103 mol) and PtO2 (1.5 g, 6.6 mmol). The resulting mixture was placed on a Parr apparatus and hydrogenated at 55 p.s.i. After 6 hr, the mixture was filtered (EtOH wash) and the filtrate concentrated in vacuo, giving 36.78 g (>100%) of the desired piperidine; 1H NMR (300 MHz, CDCl3) δ7.7 (d, 2H), 7.2 (d, 2H), 3.55 (t, 2H), 3.3 (m, 4H), 2.95 (bt, 2H), 2.38 (s, 3H), 1.95 (bd, 2H), 1.58 (m, 2H), 1.3 (m, 3H).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[CH3:9][C:10]1[C:18]2[O:17][CH:16]=[CH:15][C:14]=2[CH:13]=[C:12]([N:19]2[CH:23]=[N:22][N:21]=[N:20]2)[CH:11]=1>C(Cl)(Cl)(Cl)Cl.[W]>[N:19]1([C:12]2[CH:11]=[C:10]([CH:9]=[O:7])[C:18]3[O:17][CH:16]=[CH:15][C:14]=3[CH:13]=2)[CH:23]=[N:22][N:21]=[N:20]1
Reactant: Cc1cc(-n2cnnn2)cc2ccoc12
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1cc(-n2cnnn2)cc2ccoc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Bromosuccinimide (180 mg) was added to a hot solution of 1-(7-methyl-benzofuran-5-yl)-1H-tetrazole and azoisobutyronitrile (35 mg) in carbon tetrachloride (10 ml) and the mixture heated at reflux whilst irradiating with a 60 W tungsten lamp for 4 hours. The mixture was evaporated in vacuo, the solid residue dissolved in acetonitrile (5 ml) then added dropwise to a solution of N-methyl morpholine-N-oxide (0.2 g) in acetonitrile (10 ml) containing 4 Å sieves. The reaction mixture was stirred for 16 h at room temperature, filtered, the solvent removed in vacuo and the residue purified by FCC eluting with ether-hexane (2:1) to give the title compound as a white solid (56 mg) m.p. 174-175°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH:13]=[C:12]4[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:11]4=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Si:63]([C:67]#[CH:68])([CH3:66])([CH3:65])[CH3:64]>CC#N.CC#N.Cl[Pd]Cl.C(#N)C>[CH3:64][Si:63]([C:67]#[C:68][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH:13]=[C:12]4[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:11]4=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:20]=1)([CH3:66])[CH3:65]
Reactant: O=C1CCCc2cc3c(cc21)OCc1cc(Cl)ccc1-3
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Temperature: 65 °C
Reaction time: 6 h
Yield: 33.4 %

Procedure:
A 300 mL flask equipped with an overhead stirrer and a reflux condenser under an atmosphere of nitrogen was charged with 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (10.0 g, 35.12 mmol), powdered anhydrous tripotassium phosphate (22.4 g, 105.4 mmol), XPhos (1.34 g, 2.81 mmol), and PdCl2(MeCN)2 (364 mg, 1.40 mmol). Acetonitrile (140 mL) was added followed by TMSacetylene (18 mL, 141 mmol). The mixture was heated to 65° C. After 6 h, the reaction was judged complete, and the mixture was cooled to 20° C. The mixture was filtered through a fitted funnel, and the filtercake was washed with acetonitrile. The filtrate was concentrated to about 150 mL under reduced pressure and extracted with heptane (50 mL, 3×100 mL). N-Acetyl cysteine (15 g) was added to the acetonitrile phase, and the mixture was agitated for 5 h at 45° C. The mixture was cooled to ambient temperature, filtered through a fitted funnel, and the filtercake was washed with acetonitrile. The filtrate was concentrated to about 120 mL under reduced pressure. Water (120 mL) was added and the mixture was agitated for 40 minutes at 45° C. and then cooled to ambient temperature. After 30 minutes the mixture was filtered through a fitted funnel to provide 3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (4.07 g, 33.4% yield) as a yellow solid: 400 MHz 1H NMR (CDCl3) δ 7.65 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.47 (dd, J=8.1, 1.4 Hz, 1H), 7.27 (s, 1H), 5.06 (s, 2H), 2.95 (t, J=6.1 Hz, 2H), 2.67-2.59 (m, 2H), 2.18-2.08 (m, 2H), 0.26 (s, 9H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[C:13]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N+:3]([O-:5])=[O:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1[N+](=O)[O-])c1ccccc1
Reaction time: 0.17 h

Procedure:
1.58 g of sodium hydride (60% content) was suspended in 19.80 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 19.83 g of a tetrahydrofuran solution containing 2.50 g of 2-nitroaniline was dropwise added over 1 hour, stirred for 10 minutes, allowed to stand at room temperature and stirred for 30 minutes. To the obtained mixture, 2.77 g of benzoyl chloride was added dropwise over 0.5 hr at room temperature and stirred for 2 hours. The reaction mixture was added to water and separated. The separated organic layer was washed with sodium hydroxide solution and saline to obtain an organic layer, which was analyzed by high performance liquid chromatography to find the yield of the desired product was 82%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: Cc1ccc(N=C=O)cc1C(F)(F)F
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)cc1C(F)(F)F

Procedure:
47.1 mg of solid white 3-{4-[3-(4-methyl-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-methyl-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=3)[O:11][CH2:10][C:9]=2[CH:21]=1)=[O:4].C(O)(=O)C>C1COCC1.CN(C=O)C.[Zn]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[O:11][CH2:10][C:9]=2[CH:21]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)COc1cc([N+](=O)[O-])ccc1-2
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)COc1cc(N)ccc1-2
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To the solution of 3-Nitro-6H-benzo[c]chromene-8-carboxylic acid methyl ester (690 mg) in THF/DMF (5 ml/5 ml) was added acetic acid (10 ml), followed by slow addition of Zinc (800 mg). The mixture was stirred for 12 hours and solvents were removed under reduced pressure. The mixture was diluted with EtOAc, and 0.2 N sodium hydroxide solution was added until pH=10. The organic layer was separated and was washed with water and brine and dried with Na2SO4. Concentration and purification by flash column chromatography (DCM/EtOAc) gave 3-Amino-6H-benzo[c]chromene-8-carboxylic acid methyl ester (300 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and (4,4-difluoro-1-(6-fluoropyridin-3-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=401.2, tR (minutes, Method D)=0.72
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(1-Isopropylpiperidin-4-yloxy)-5-nitropyridine (1 eq) was dissolved in methanol and laced under a nitrogen atmosphere. A catalytic amount of 10% palladium on carbon was added and a hydrogen balloon connected to the reaction flask. The flask was flushed five times with hydrogen and stirred at room temperature for 4 hours under hydrogen atmosphere. The solid was filtered and washed with methanol. The filtrate was evaporated under reduced pressure yielding the product as a brown oil. LC/MS (m/z): 236.3 (MH+), Rt 0.38 minutes.
Reaction SMILES: [C:1]12([C:11]3[CH:33]=[CH:32][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[C:1]12([C:11]3[CH:33]=[CH:32][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)piperazine-1-carboxylate (0.15 g, 0.42 mmol), prepared from the example 29, in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.15 g, 1.69 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated and diluted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 2-(4-(adamantan-1-yl)phenoxy)-1-(piperazin-1-yl)ethanone as a white solid (0.11 g, 94.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([CH:17]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[OH:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]#[N:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH2:37][CH3:38]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]4)[C:15]([CH:17]([CH:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[O:18][CH2:37][CH3:38])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]#[N:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCI
Reactant: C[C@H]1CC[C@H](Cn2c(C(O)C3CCCC3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1)C1CCCC1
Temperature: 0 °C

Procedure:
4-(5-chloropyridin-3-yl)-2-(cyclopentyl(hydroxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (240 mg, 0.517 mmol) was dissolved in THF (5.2 mL) and cooled to 0° C. in a flask under nitrogen before adding sodium hydride (41.4 mg, 1.034 mmol). Upon cessation of gas evolution, iodoethane (0.125 μL, 1.552 mmol) was added, and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with sat. aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/0-40% EtOAc) to afford racemic 4-(5-chloropyridin-3-yl)-2-(cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. The racemic material was then purified by chiral supercritical fluid chromatography (Chiralpak IC, 21×250 mm, 2-Propanol+0.25% Dimethyl Ethyl Amine in CO2) to afford 4-(5-chloropyridin-3-yl)-2-((R)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile and 4-(5-chloropyridin-3-yl)-2-(S)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. 1H NMR (600 MHz, CD3OD) δ 8.78 (d, J=2.3, 1H), 8.75 (d, J=1.5, 1H), 8.29 (t, J=2.0, 1H), 8.24 (s, 1H), 4.65 (d, J=8.5, 1H), 4.08-3.97 (m, 2H), 3.59-3.34 (m, 2H), 2.65-2.54 (m, 1H), 1.88-1.77 (m, 1H), 1.73-1.54 (m, 6H), 1.49 (d, J=13.2, 2H), 1.30-1.25 (m, 1H), 1.17 (t, J=7.0, 3H), 1.15-1.08 (m, 1H), 1.01-0.95 (m, 1H), 0.91-0.76 (m, 4H), 0.75 (d, J=6.6, 3H), 0.56-0.45 (m, 2H). MS ESI calc'd. for C28H34ClN5O [M+H]+ 492. found 492.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13].[CH2:17]([S:23]([CH2:25][C:26](OC1C=CC([N+]([O-])=O)=CC=1)=[O:27])=[O:24])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:26](=[O:27])[CH2:25][S:23]([CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: NCCCOc1cccc(C2OCCO2)c1
Reactant: O=C(CS(=O)Cc1ccco1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(CS(=O)Cc1ccco1)NCCCOc1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.1 %

Procedure:
3-[3-(1,3-dioxolan-2-yl)phenoxy]propylamine (16.3 g) was dissolved in 400 ml of methylene chloride, and p-nitrophenyl 2-(furfurylsulfinyl)acetate (22.58 g) was added little by little. The mixture was stirred at room temperature for 18 hours. The organic layer was washed successively with a 1N aqueous NaOH solution and water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 21.29 g (yield 74%) of N-{3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl}-2-(furfurylsulfinyl)acetamide.