Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[S:18](=[O:21])(=[O:20])[CH2:19][C:10]=3[C:9]([C:22](O)=[O:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(Cl)Cl.CN(C=O)C.Cl>[N:31]1([C:22]([C:9]2[C:10]3[CH2:19][S:18](=[O:20])(=[O:21])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]=3[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:23])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: O=C(O)c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide (150.00 mg; 0.44 mmol; 1.00 Eq) is suspended in DCM (4.00 ml) and 2 drops of DMF and then Oxalyl chloride (3 mL) is added dropwise. The reaction mixture is stirred at room temperature for 30 min. The solution is evaporated to dryness. The residue is suspended in DCM (4.00 ml) and morpholine (350.00 μL; 4.02 mmol; 9.12 Eq) is added dropwise. The reaction mixture is stirred at rt for 30 min then diluted with aq. solution of HCl 0.05 M. The two layers are separated. The aqueous layer is extracted with DCM (2×). The organic layers are washed with a saturated solution of NaHCO3 and brine, dried over MgSO4 and evaporated to give foam. The foam is recrystallised in EtOH to the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.04-8.01 (m, 1H), 7.67-7.53 (m, 7H), 6.85-6.82 (m, 1H), 4.91 (s, 2H), 3.98-3.94 (m, 2H), 3.68-3.61 (m, 6H). UPLC/MS: (ES+): 410.1, (ES−): 408.1. HPLC (max plot) 100.0%; Rt 3.36 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C@@H:55]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:56]([NH:58][CH3:59])=[O:57]>CN(C=O)C>[CH3:61][C:60]([CH3:63])([CH3:62])[C@H:55]([NH:54][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:56](=[O:57])[NH:58][CH3:59]
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 8.7 %

Procedure:
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 0.1 g, 35 mmol) was suspended in DMF (3 mL). HBTU (266.14 mg, 0.7 mmol), DIEA (0.31 mL, 1.75 mmol) and (S)-2-amino-3,3,N-trimethyl-butyramide (CAN 89226-12-0, 52.82 mg, 0.42 mmol) were added and the reaction mixture was stirred at ambient temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Gemini-NX-C18, 5 μ, 30×100 mm/acetonitrile/0.1% ammonia in water) to give the desired product (15 mg, 10.39%) as white solid; LC-MS (UV peak area, ESI) 96.48%, 412.6 (M+H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:16]([C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH:28]=O)[CH:23]=[CH:24][CH:25]=1)([CH3:19])([CH3:18])[CH3:17]>C1CCCCC1>[C:16]([C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH:28]2[O:4][CH2:1][CH2:2][O:3]2)[CH:23]=[CH:24][CH:25]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cccc(CCC=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC(C)(C)c1cccc(CCC2OCCO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Ethylene glycol (15 mL, 0.27 mol, 1.2 eq), paratoluene sulfonic acid (430 mg, 1% w/w) and cyclohexane (50 mL) were charged into a 1 L three-necked round-bottom flask, equipped with a dean and stark, a reflux condenser and a mechanical stirrer. 3-(3-tert-butylphenyl)propanal (50.6 g, gc purity of 85%, 0.22 mol) was added dropwise at ambient temperature. After stirring for 2 h at reflux, the reaction mixture was cooled to ambient temperature and washed twice with water (50 mL), saturated aqueous NaHCO3, dried over magnesium sulphate and concentrated to give 2-[2-(3-tert-butylphenyl)ethyl]-1,3-dioxolane in the form of a pale yellow coloured oil (60 g, gc purity>84%; yield>95%). The material was used as such for the next step.
Reaction SMILES: [CH2:1]([C:4]1[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[C:7](=[O:13])[NH:6][N:5]=1)[CH2:2][CH3:3].C[O-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19].Cl>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:19]([N:5]1[CH:4]([CH2:1][CH2:2][CH3:3])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[C:7](=[O:13])[NH:6]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CCCc1n[nH]c(=O)c2cncn12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C=CCN1NC(=O)c2cncn2C1CCC
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of 4-n-propyl-imidazo[1,5-d]-as-triazin-1(2H)-one (0.01 mol) in dimethylformamide (50 ml) is added sodium methoxide (0.01 mol) followed by the addition of allyl bromide (0.012 mol). The reaction mixture is stirred at 20° C. for 16 hours, then heated at 40° C. for 45 minutes, cooled and poured on a mixture of ice and dilute hydrochloric acid. The product is isolated by extraction with chloroform and evaporation. It is purified by recrystallization from cyclohexane or a cyclohexane-benzene mixture; or by silica gel dry column chromatography in chloroform.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][NH:14][CH2:15][C@H:16]([C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)[OH:17]>ClCCl>[CH3:13][N:14]1[CH2:15][C@H:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[O:17][C:1]1=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNC[C@@H](O)c1cnccn1
Solvent: ClCCl
Product: CN1C[C@H](c2cnccn2)OC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
The optical purity is upgraded as follows: Carbonyldiimidazole (4.26 g, 1.1 equiv., 26.2 mmol) is dissolved in dichloromethane (80 mL). To this solution is slowly added, via cannula addition, (1R)-2-(methylamino)-1-pyrazin-2-ylethanol (3.66 g, 23.9 mmol) dissolved in dichloromethane (60 mL). The reaction is stirred at room temperature for 16 h. The solvent in vacuo and purification is accomplished by silica gel column chromatography (98:2 dichloromethane-methanol, sample and silica gel loaded in dichloromethane). Any uncyclized carbamate collected off the column is dissolved in methanol, to which is added a catalytic amount of 1 M NaOH and the solution is refluxed until completely cyclized. This freshly cyclized material is then purified by column chromatography as above. The combined pure oxazolidinone fractions are then concentrated in vacuo producing an 88% yield of (5R)-3-methyl-5-pyrazin-2-yl-1,3-oxazolidin-2-one (3.77 g, 21.0 mmol) as a white solid. This material is upgraded by chiral preparative HPLC to give material with >95% ee. MP: 113.5-114.1°; 1H NMR (400 MHz, CDCl3) δ 8.84, 8.62, 8.58, 5.62, 4.02, 3.80, 2.94; 13C NMR (100 MHz, CDCl3) δ 157.4, 153.2, 144.8, 144.1, 142.7, 72.2, 51.6, 31.1. MS (CI) m/z (rel. intensity) 180 (MH+, 12), 197 (45), 180 (12), 138 (35), 137 (17), 136 (99), 122 (11), 107 (24), 96 (14), 95 (10), 58 (11); HRMS (FAB) Found 180.0781; Specific Rotation [α]D25 +20 (c 0.95, methylene chloride); Anal. Found: C, 53.38; H, 5.03; N, 23.35.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.[NH:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:3]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
To a vial containing 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (714.2 mg, 2.115 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 645.9 mg, 3.225 mmol), 1-butanol (8.00 mL) was added followed by DIPEA (582.8 mg, 4.509 mmol). The reaction mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound as a yellow solid (719.5 mg, 68%). LCMS calc. for C23H28N5O6S (M+H)+: m/z=502.2. found 502.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:17])([O-:3])=[O:2].C[O:19]C(OC)N(C)C>CN(C=O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH:17]=[O:19])([O-:3])=[O:2]
Reactant: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-nitro-5-phenoxytoluene (57.3 g, 0.25 mol) prepared in Step A above and dimethylformamide dimethyl acetal (43.1 mL, 0.324 mol) in DMF (259 mL) was heated overnight at 140° C. The mixture was cooled to room temperature, and the solvent was evaporated in vacuo. The residue was dissolved in THF (500 mL) and transferred to a 3L 3-neck flask equipped with an overhead stirrer. The mixture was diluted with 500 mL of water, and NaIO4 (160 g, 0.75 mol) was added in portions (slight exotherm). The mixture was stirred overnight at room temperature. The solids were-filtered and washed well with EtOAc. The filtrate was washed 3× with saturated aqueous NaHCO3 solution, and then dried (MgSO4). The solution was filtered and the solvent was evaporated in vacuo. The crude product was chromatographed (10-40% CH2Cl2:hexane) to yield 2-nitro-5-phenoxy-benzaldehyde as a yellow crystalline solid.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.Cl.[CH3:29][N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>C(O)C>[CH3:29][N:30]1[CH2:35][CH2:34][C:33]2[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:5]3[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=3[C:32]=2[CH2:31]1
Reactant: ClCCN1CCCCC1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCN2CCCCC2)CCN(C)C1
Yield: 27.5 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. p-Tolylhydrazine hydrochloride (2.0 g, 12.6 mmol), 1-(2-chloroethyl)-piperidine monohydrochloride (2.32 g, 12.6 mmol), triethyl amine (5.3 ml, 37.8 mmol) and N-methyl-4-piperidone hydrochloride (1.87 g, 2.1 mmol) were taken in ethanol (30 ml) to obtain 180 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(piperidin-1-yl)ethyl)-1H-pyrido[4,3-b]indole after purification on silica gel (230-400 mesh) chromatography eluting with acetone-hexane gradient. The free base was converted into bis(oxalate) salt by treatment of oxalic acid (2 equiv) in anhydrous THF.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH3:29])=[C:22]([O:25][CH3:26])[CH:23]=3)[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]([OH:30])[CH2:17]3)[N:12]=2)=[CH:5][N:4]=1.[O:32]=[C:33]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:34](O)=[O:35]>CC(C)=O>[O:32]=[C:33]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:34]([O:30][C@@H:16]1[CH2:15][CH2:14][C@@H:13]2[C@@H:18]([C:19]3[C:24]([C:11]([C:6]4[C:7]([O:9][CH3:10])=[N:8][C:3]([N:2]([CH3:1])[CH3:31])=[N:4][CH:5]=4)=[N:12]2)=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:17]1)=[O:35]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: CCOc1cc2c(cc1OC)C(c1cnc(N(C)C)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Solvent: CC(C)=O
Product: CCOc1cc2c(cc1OC)C(c1cnc(N(C)C)nc1OC)=N[C@@H]1CC[C@@H](OC(=O)C(=O)CCC(=O)O)C[C@H]21
Yield: 71 %

Procedure:
(2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a, 10b-hexahydro-phenanthridin-2-ol ((42.7 mg, 0.1 mmol) are dissolved in 0.5 ml of acetone. 16.1 mg (0.11 mmol) of 2-oxo-pentanedioic acid (dissolved in 0.5 ml of acetone) are added. The crystals are filtered off and dried to obtain 40.6 mg (71%) of the title compound (m.p.: 124° C.).
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:21])[CH:8]=1.[H-].[Na+].[Cl:24][C:25]1[CH:38]=[CH:37][C:28]2[S:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[C:31]([CH3:32])[C:27]=2[CH:26]=1>CN(C=O)C>[Cl:24][C:25]1[CH:38]=[CH:37][C:28]2[S:29][C:30]([S:33]([NH:6][C:7]3[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:21])[CH:8]=3)(=[O:34])=[O:35])=[C:31]([CH3:32])[C:27]=2[CH:26]=1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(N)cc1C
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
Into 10 mL of THF was dissolved 135 mg of methyl 4-amino-5-methanesulfonyl-2-methylbenzoate, followed by addition of 22 mg of sodium hydride (oily, 60%) at room temperature. After 20 minutes of stirring at the same temperature, 130 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at 0° C., followed by 1 hour of stirring at room temperature and 5 hours of heating under refluxing. Further, 1 mL of DMF, 22 mg of sodium hydride (oily, 60%) and 50 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene were added and the mixture was heated under refluxing for 2.5 hours. After confirmation of disappearance of the starting material, the reaction was terminated by adding saturated aqueous ammonium chloride solution at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/2) to obtain 102 mg of the title compound as colorless powder.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C1OCCOCCOCCOCCOC1.CS(O[CH:25]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=O)=O.C(Cl)Cl>CN(C=O)C>[N:1]([CH:25]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])=[N+:2]=[N-:3]
Reactant: COC(=O)c1ccccc1CCCC(Cc1ccccc1)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1CCCC(Cc1ccccc1)N=[N+]=[N-]
Temperature: 85 °C

Procedure:
Sodium azide (1 g, 15.4 mmol) and 15-crown-5 (0.17 g, 0.77 mmol) were added to a stirred solution of 30e (2.9 g, 7.7 mmol) in DMF (60 mL). The mixture was heated at 85° C. for 24 h under argon atmosphere. Then DCM (300 mL) was added, the solution was washed with a saturated NaHCO3 solution (2×150 mL) and brine (3×200 mL), and dried over Na2SO4. After removal of the solvent under reduced pressure, the desired product was obtained as yellow oil, which was used without further purification in the next step.
Reaction SMILES: O[C:2]1([CH3:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[C-]#[N:14].[Na+].C(O)(=O)C.S(=O)(=O)(O)O>O.CCOCC.[OH-].[Na+]>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]([NH2:14])([CH3:12])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5]1
Reactant: CC1(C)CC(C)(C)CC(C)(O)C1
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CC1(C)CC(C)(C)CC(C)(N)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.2 %

Procedure:
To a vigorously stirred solution of 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane (3.4 g; 20 mmol) and sodium cyanide (1.96 g; 40 mmol; 2 eq.) and 5 ml acetic acid, 95% sulfuric acid (5.3 ml; 100 mmol; 5.15 eq) are added during 1 hour keeping the temperature at 10° C. for 30 min, and then allowing the mixture to reach ambient temperature. After stirring at ambient temperature for 17 hours, the mixture is diluted with 20 ml ice water. Subsequently, the mixture is refluxed with stirring for 10 hours, cooled to ambient temperature, diluted with 40 ml water and 20 ml ether and neutralized with 20% aqueous sodium hydroxide until a pH of 10. The organic phase is separated and dried. Dry hydrogen chloride is passed through the solution until the ether becomes acidic. Solvent is removed and the residue is washed with ether to give 2.24 g Neramexane in the form of its hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[CH:18][CH:19]=2)[C:10]([F:25])=[C:9]([CH3:26])[C:8]=1[F:27])#[N:2].CI.N1(C2CCCCCCCCCC2)CCCCCCCC[CH2:35]N1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([O:24][CH3:35])=[O:23])[CH:17]=[CH:18][CH:19]=2)[C:10]([F:25])=[C:9]([CH3:26])[C:8]=1[F:27])#[N:2]
Reactant: Cc1c(F)c(Oc2cccc(C#N)c2)nc(Oc2cccc(CCC(=O)O)c2)c1F
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: ClCCl
Solvent: CI
Product: COC(=O)CCc1cccc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Reaction time: 15 h

Procedure:
To 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzene-propionicacid (0.50 g, 1.2 mmol) in methylene chloride (20 mL) was added methyl iodide (0.26 g, 1.8 mmol) and diazabicycloundecane (2.8 g, 1.8 mmol). After stirring for 15 hours, the solution was concentrated in vacuo and chromatographed on silica gel with ethyl acetate/hexane (1/4) to give 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionic acid, methyl ester; NMR (CDCl3) 7.3 (m,5), 7.05 (d,1), 6.85 (m,2), 3.68 (s,3), 2.9 (t,2), 2.55 (t,2), 2.4 (s,3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([Cl:26])=[CH:23][C:24]=1[CH3:25].C[CH:28]([CH2:33][CH2:34][CH3:35])[C:29]([O:31]Br)=[O:30].[C:36]([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:36][O:31][C:29](=[O:30])[CH2:28][CH2:33][CH2:34][CH2:35][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:8]([C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[C:3]([C:19]2[CH:20]=[N:21][C:22]([Cl:26])=[CH:23][C:24]=2[CH3:25])[CH:4]=1)[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CCCC(C)C(=O)OBr
Reactant: Cc1cc(Cl)ncc1-c1cc(C(=O)N(C)c2ccccc2O)ccc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCOc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35.6 %

Procedure:
A mixture of 4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide (108 mg, 0.28 mmol), bromo methylvalerate (60 μL, 0.42 mmol) and K2CO3 (116 mg, 0.84 mmol) in DMF (1 mL) was stirred at room temperature for 14 hrs. Ethyl acetate was added and the combined organic layers were washed with water, dried over MgSO4, then purified by silica gel column chromatography eluted with ethyl acetate/hexane (1/4) up to 1/3 to yield 5-(2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-pentanoic acid methyl ester 12-1 (50 mg). MS [M+H]+: 501; tR=8.52 min. (method 1)
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:39][CH3:40])[C:7]([NH:28][CH:29]2[CH2:34][CH2:33][CH:32]([C:35]([O:37]C)=[O:36])[CH2:31][CH2:30]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[C:13]([C:24]([F:27])([F:26])[F:25])[CH:12]=1)(=[O:3])[NH2:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([C:4]1[N:5]=[C:6]([CH2:39][CH3:40])[C:7]([NH:28][CH:29]2[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[C:13]([C:24]([F:25])([F:27])[F:26])[CH:12]=1)(=[O:3])[NH2:2]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)c(C(F)(F)F)c2)nc1NC1CCC(C(=O)OC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)c(C(F)(F)F)c2)nc1NC1CCC(C(=O)O)CC1
Yield: 38.3 %

Procedure:
To a mixture of methyl 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylate (Example 435) (126 mg), THF (2 mL) and methanol (2 mL), 10% aqueous sodium hydroxide (1 mL) was added and heated under reflux for 2 hours. To the reaction liquid, 10% hydrochloric acid was added to give a pH of about 7, and the resulting solid was collected by filtration. This solid was purified by silica gel column chromatography (eluent; chloroform:methanol) to give 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 436) (47 mg), which was a low-polarity product, as a light yellow white powder and 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 437) (59 mg), which was a high-polarity product, as a light yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[S:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[C:16]([O:15][C:13]([N:12]([CH3:22])[C:9](=[N:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[S:10][CH3:11])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSC(=NC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,3-Di-(tert-butoxycarbonyl)-2-methyl-isothiourea (Japanese Patent Unexamined Publication No. 2-3661) (2.00 g) was dissolved in N,N-dimethylformamide (20 ml), followed by adding thereto 60% sodium hydride (331 mg), and the resulting mixture was stirred at 50° C. for 2 hours. After the mixture was cooled to 0° C., methyl iodide (1.96 g) was added and the resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, and the extract solution was washed with water and dried. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography to obtain the desired compound (2.07 g).