Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41]#[N:42]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:17](=[O:32])[N:18]([CH2:40][C:41]#[N:42])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (55 mg, 0.128 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (70 mg, 0.51 mmol, 4 eq) and chloroacetonitrile (17 mg, 0.231 mmol, 1.8 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-60% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (29 mg, 48%). MS(ES)+ m/e 468.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:46]=[C:45]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][C:54]5[CH2:59][CH2:58][C:57]([CH3:61])([CH3:60])[CH2:56][C:55]=5[C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=5)[CH2:49][CH2:48]4)[CH:44]=[CH:43][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]4[CH2:39][CH2:38][C:30]5([CH2:35][O:34]C(C)(C)[O:32][CH2:31]5)[CH2:29][CH2:28]4)=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>ClCCl>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:46]=[C:45]([N:47]4[CH2:48][CH2:49][N:50]([CH2:53][C:54]5[CH2:59][CH2:58][C:57]([CH3:60])([CH3:61])[CH2:56][C:55]=5[C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=5)[CH2:51][CH2:52]4)[CH:44]=[CH:43][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]4[CH2:39][CH2:38][C:30]([CH2:31][OH:32])([CH2:35][OH:34])[CH2:29][CH2:28]4)=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(OCC5CCC6(CC5)COC(C)(C)OC6)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(OCC5CCC(CO)(CO)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 391G (680 mg) in dichloromethane (3514 μl) was added para-toluenesulfonic acid monohydrate (535 mg) and the reaction was allowed to stir for 3 hours. Triethylamine (490 μA) was added and the reaction was concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix 0.5-5% dichloromethane/methanol). 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.69 (s, 1H) 8.35 (s, 1H) 8.03 (d, 2H) 7.46-7.58 (m, 3H) 7.29-7.42 (m, 3H) 7.04 (d, 2H) 6.68 (dd, 1H) 6.39 (d, 1H) 6.20 (s, 1H) 4.19-4.35 (m, 2H) 4.05 (d, 2H) 3.37 (d, 2H) 3.17 (d, 2H) 3.09 (bs, 4H) 2.10-2.31 (m, 6H) 1.96 (bs, 2H) 1.62-1.75 (m, 1H) 1.46-1.62 (m, 4H) 1.39 (t, 2H) 1.05-1.32 (m, 4H) 0.93 (s, 6H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O-]S(C(F)(F)[F:32])(=O)=O.F[N+]1C=CC=CC=1>ClCCCl>[F:32][C:20]1[C:19]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Agent: F[n+]1ccccc1
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc(-c2c(F)c3cccccc-3c2-c2ccccc2)cc1
Temperature: 0 °C
Yield: 47.6 %

Procedure:
To a solution of 2-(4-methylsulfonylphenyl)-1-phenylazulene (0.20 g) in 1, 2-dichloroethane (20.0 ml) was added 1-fluoropyridinium triflate (0.28 g), and the reaction mixture was heated under reflux for 30 min. The mixture was poured into ice-water, and extracted with CHCl3. The combined CHCl3 extracts were washed with water and brine, dried over Na2 SO4, and concentrated. The crude product was purified by SiO2 column chromatography (benzenee/EtOAc, 20:1) to give the title compound (0.10 g) as green crystals; mp 120°-122° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([Li])CCC.C[O:22][B:23](OC)[O:24]C.Cl>O1CCCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([B:23]([OH:24])[OH:22])[CH:3]=2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Temperature: -78 °C
Yield: 50.7 %

Procedure:
3-Bromo-4′-chloro-4-methylbiphenyl (5.0 g, 0.02 mol) is dissolved in anhydrous tetrahydrofuran (125 ml), and the mixture is cooled to −78° C. n-Butyllithium (1.33 molar solution in hexanes, 17.3 ml,) is added dropwise over 30 minutes, maintaining the temperature at approximately −78° C. The reaction mixture is stirred for one and a half hours at −78° C., then trimethylborate (2.58 g, 0.024 mol) is added dropwise and the reaction mixture stirred for three and a half hours, allowing it to warm to 0° C. A solution of 2N aqueous hydrochloric acid (50 ml) is then added dropwise, and once the addition is complete the mixture is stirred for 2 hours. The mixture is concentrated in vacuo to remove most of the tetrahydrofuran, then diluted with water (˜80 ml) and extracted with diethyl ether. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by flash column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 4′-chloro-4-methylbiphenyl-3-ylboronic acid (2.5 g).
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[C:53]4[N:54]([N:59]=[CH:60][N:61]=4)[C:55](Br)=[CH:56][N:57]=3)=[CH:47][CH:46]=2)[C:41](=[O:62])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CC1(C)C(C)(C)OB([C:71]2[CH:72]=[C:73]3[C:77](=[CH:78][CH:79]=2)[C:76](=[O:80])[NH:75][CH2:74]3)O1.C([O-])([O-])=O.[Na+].[Na+]>[Cl-].[Na+].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.C1(C)C=CC=CC=1.O1CCOCC1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[C:53]4[N:54]([N:59]=[CH:60][N:61]=4)[C:55]([C:71]4[CH:72]=[C:73]5[C:77](=[CH:78][CH:79]=4)[C:76](=[O:80])[NH:75][CH2:74]5)=[CH:56][N:57]=3)=[CH:47][CH:46]=2)[C:41](=[O:62])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)C(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ncnc34)cc2)C(=O)C1
Yield: 46.2 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4, using 4-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (115 mg, 0.24 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one (92 mg, 0.35 mmol), and Pd(PPh3)4 (83 mg, 0.072 mmol) in 1.5M Na2CO3 (aq) (1.3 mL, 1.92 mmol), and dioxane (2.5 mL). The reaction mixture is diluted with brine then toluene is added and a precipitate is formed and collected by filtration. The resultant solid is dissolved in DCM and filtered through a silica cartridge to afford the title compound as a yellow solid (60 mg, 47%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:28]([O:31][CH2:32][CH2:33]Cl)[CH2:29][CH3:30].CO>CN(C)C=O.O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][CH2:32][O:31][CH2:28][CH2:29][CH3:30])[C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCOCCCl
Reactant: CCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCCOCCn1c(=O)c2c(ncn2Cc2ccccc2)n(CCC)c1=O
Reaction time: 1 h

Procedure:
1.7 g (12.48 mmol) of potassium carbonate were added at 60° C. to a suspension of 2.2 g (7.8 mmol) of 7-benzyl-3-propylxanthine (prepared according to Example 4a) in 70 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 1.3 ml (10.14 mmol) of 2-propoxyethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 10 hours. 1.2 ml of methanol and 14 ml of water were then added, and the mixture was allowed to stand overnight, treated with a further 70 ml of water and extracted three times using 84 ml of methyl tert-butyl ether each time. The combined organic phases were washed twice with 42 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethae/methanol (19/0.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=O.Cl.[F:21][C:22]1[CH:23]=[C:24]([C@@H:28]([NH2:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[N+:14]([C:10]1[CH:9]=[C:8]([CH:6]([C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:30][C@H:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)[CH3:29])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: C[C@H](N)c1cccc(F)c1
Reactant: COc1cccc(C(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1cccc(C(N[C@@H](C)c2cccc(F)c2)c2cccc([N+](=O)[O-])c2)c1
Yield: 99.1 %

Procedure:
In a similar manner to that described in Example (1a), 3-methoxy-3′-nitrobenzophenone (2.0 g), (S)-1-(3-fluorophenyl)ethylamine hydrochloride (2.73 g), triethylamine (6.50 ml), titanium tetrachloride (1.03 ml), sodium cyanoborohydride (2.15 g) and acetic acid (0.67 ml) were reacted, to afford the title compound (2.93 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[CH:31]([CH3:33])[CH3:32].CO.[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[C:3]([C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][CH:16]=3)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:29])=[O:28])=[CH:23][C:22]=1[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccnc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc3[nH]ccc23)ccc1Cl

Procedure:
Prepared from 25 mg (0.092 mmol) of (3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanone and 81 mg (0.32 mmol) of 4-chloro-3-iso-propyl-benzenesulfonyl chloride in 0.2 mL pyridine using procedure x. After the sulfonylation was complete, 3 mL methanol, 0.5 mL water and 44 mg sodium hydroxide were used. Yield: 18 mg of a yellow solid. LC-MSD, m/z for C22H18Cl2N4O3S [M+H]+=489.0, 491.0
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:8]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:4]=[N:3]1.[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.C(O)C>[ClH:38].[CH3:1][N:2]1[CH:6]=[C:5]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:8]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26](=[NH:46])[NH2:27])=[CH:24][CH:25]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:4]=[N:3]1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(c1cnn(C)c1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(c1cnn(C)c1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Yield: 38 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 38% of theory, C25H30N8O4S (538.6) Rf value: 0.09 (silica gel; dichloromethane/ethanol=9:1) EKA mass spectrum: (M+H)+ =539
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[N+:30]([O-])=O.C1CCCCC=1>[Pd].O1CCOCC1>[NH2:30][C:18]1[CH:19]=[C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]3[CH:34]=[C:35]([F:37])[CH:36]=[C:2]([F:1])[CH:3]=3)[CH:7]=2)[NH:11][N:10]=1)=[O:33]
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N)c2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide (3.21 g, 6.33 mmol), cyclohexene (20 mL), dioxane (200 mL) and 10% Pd/C (0.8 g) was stirred at 100° C. for 2 hours. The reaction mixture was filtered over a celite pad washing thouroughly with THF and MeOH. After evaporation of the organic phase, purification of the crude by chromatography over silica gel (DCM/MeOH 95/5) gave 2.51 g of title compound (83% yield).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]([N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:16]=2[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(#N)C>Cl>[C:4]([CH2:5][CH:6]([N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:16]=2[N:15]=[CH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:25])=[O:3]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(C(=O)O)ccc21
Agent: Cl
Solvent: CC#N
Product: O=C(O)CC(c1ccccc1)n1cnc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-(3-ethoxy-3-oxo-1-phenylpropyl)-1H-benzimidazole-5-carboxylic acid (40 mg, 118 μmol) in a mixture of hydrochloric acid (10 mL of a 5N solution) and acetonitrile (6 mL) was stirred at room temperature for 72 hours. The solution was evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.26 min, MH+ 311].
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.C(=O)([O-])O.[Na+]>C1COCC1>[NH2:1][C:2](=[S:36])[CH2:3][C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=S)C1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 52.6 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(2-amino-2-oxoethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (528 mg, 1.31 mmol) in THF (6 mL) was added Lawesson's reagent (794 mg, 1.96 mmol), and the mixture was stirred at 70° C. for 2.5 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (289 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=[C:11]([C:21]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=3)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)cc1Cl
Reactant: COc1cc(CN)on1
Product: COc1cc(CNC(=O)c2cc(-c3ccc(C)c(Cl)c3)c(OCC(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(3-chloro-4-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BM) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as starting materials; LC-MS (UV peak area/ESI) 100%, 456.0934 (M+H)+.
Reaction SMILES: O=C1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH2:4][O:3]1.[OH-].[Na+]>C(OC(C)C)(=O)C.O>[NH2:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[CH2:4][OH:3]
Reactant: O=C1Nc2ccccc2CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: Nc1ccccc1CO
Temperature: 45 °C

Procedure:
The reaction mixture from Stage A was boiled so as to drive off the isopropyl acetate solvent. A solution of 100 g of sodium hydroxide in 100 ml of water was added to the residue, and the whole was refluxed for 2 hours. After cooling to 45° C., the product was extracted with four 270 ml portions of isopropyl acetate. The isopropyl acetate was then distilled off and the product recrystallized from toluene to give 100 g (63% of theoretical) of 97-98% pure 2-amino-benzyl alcohol; m.p. 83°-83.5° C.
Reaction SMILES: ClC1C=CC([C@@H]2[C@@H]([C@@H](OC3C=CC(Cl)=C(Cl)C=3)C)CCN(C(C3CCN([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)CC3)=O)C2)=CC=1.N1CCCCC1.C([N:54]1[CH2:59][CH2:58][C@H:57]([C@H:60]([OH:62])[CH3:61])[C@@H:56]([C:63]2[CH:68]=[CH:67][C:66]([F:69])=[C:65]([F:70])[CH:64]=2)[CH2:55]1)C1C=CC=CC=1.C(C1C=NC(O)=CC=1)#N.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[F:70][C:65]1[CH:64]=[C:63]([C@@H:56]2[C@@H:57]([C@@H:60]([O:62][C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=3)[CH3:61])[CH2:58][CH2:59][NH:54][CH2:55]2)[CH:68]=[CH:67][C:66]=1[F:69]
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: N#Cc1ccc(O)nc1
Solvent: CO
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CCNC[C@@H]1c1ccc(F)c(F)c1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(3,4-difluoro-phenyl)-piperidin-4-yl]-ethanol and 3-cyano-6-hydroxy-pyridine via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol to yield 6-{(S)-1-[(3S,4S)-3-(3,4-Difluoro-phenyl)-piperidin-4-yl]-ethoxy}-nicotinonitrile. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as off-white solid. MS (m/e): 557.3 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([NH:16]C(=O)C)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6]2.[OH-].[Na+]>Cl>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([NH2:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6]2
Reactant: CC(=O)NC1(c2ccccc2)CCC2CCC1N2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1C2CCC1C(N)(c1ccccc1)CC2

Procedure:
A solution of 90 mg (0.348 mmol) N-((1RS,2RS,5SR)-8-methyl-2-phenyl-8-aza bicyclo[3.2.1]oct-2-yl)-acetamide in 1.8 ml HCl 5N was heated in a 105° C. oil bath for 27 hours. The solution was cooled in an ice bath and basified with a NaOH 5N solution. The aqueous layer was extracted 3 times with dichloromethane. The combined extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to provide 71 mg (y: 94.2%) of the title compound as an off-white solid. MS (m/e): 217.4 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10].[N:18]([O-:20])=[O:19].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[CH3:17][O:16][C:15]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=1
Reactant: COC(=O)c1ccc(OC)c(OCCCCl)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 961.5 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 10.1 g (38.7 mmol) of methyl 3-(3-chloropropoxy)-4-methoxybenzoate (purity: 99%) obtained in Example II-20, 0.27 g (3.87 mmol) of sodium nitrite, and 12.5 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 16.2 g (154.8 mmol) of nitric acid (60 wt. %), and the mixture was heated at 40-50° C. for 5 hours. After the reaction was complete, 20 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration, washed successively with 30 mL of water and 30 mL of n-heptane, and dried under reduced pressure, to give 11.3 g (isolated yield: 95.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of methyl 4-methoxy-5-(3-chloropropoxy)-2-nitrobenzoate as a white crystalline product.