Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.Cl[S:15]([OH:18])(=O)=[O:16].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].CCN(C(C)C)C(C)C>>[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([NH:29][S:15]([NH:13][C:11]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[C:10]=2[N:9]=[CH:8][CH:7]=[CH:6]3)(=[O:18])=[O:16])[CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(N)c2ncccc2c1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1c(N)cccc1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NS(=O)(=O)Nc2cccc(Cl)c2C)c2ncccc2c1
Yield: 2.3 %

Procedure:
In a similar fashion using route 19 general procedure 42, 6-methoxyquinolin-8-amine (Intermediate 23) (300 mg, 1.7 mmol), chlorosulfonic acid (120 μl, 1.8 mmol), PCl5 (370 mg, 1.8 mmol), TEA (360 μl, 2.5 mmol), 3-chloro-2-methylaniline (810 μl, 6.8 mmol) and DIPEA (600 μl, 3.4 mmol) gave the title compound (15 mg, 2%) after purification by column chromatography with DCM/n-hexane (1:1) as the eluent, followed by recrystallisation from EtOAc/n-hexane and then further purification by column chromatography with n-hexane/EtOAc (4:1) as the eluent.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[CH2:25]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([N:32]1[CH2:37][CH2:36][C:35]([OH:38])([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2ccc(-c3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A 1.6M solution of n-butyllithium in hexane (39 ml, 63 mmol) was added to a stirred solution of 4-bromobiphenyl (11.7 g, 50 mmol) in anhydrous tetrahydrofuran (50 ml), under nitrogen, at about −50° C., whilst ensuring that the reaction temperature was kept below −40° C. After a further 1 hour, a solution of 1-benzyl-4-oxopiperidine (10.4 g, 55 mmol) in anhydrous tetrahydrofuran (30 ml) was added at such a rate that the reaction temperature was maintained below −40° C. The cooling bath was then removed and, after a further 1 hour, the reaction mixture was partitioned between dichloromethane (400 ml) and brine (200 ml). The organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure, then the residue crystallised from ethyl acetate to provide the title compound (13.9 g) as a colourless solid. δ(DMSOd6): 1.80 (d,2H), 2.52 (m,2H), 3.24 (m,4H), 4.33 (d,2H), 7.28-7.75 (m,14H), 11.30 (brs, 1H).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@H:11]([C:13](O)=[O:14])[CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[S:7]([NH:10][C@H:11]([C:13]([Cl:20])=[O:14])[CH3:12])([C:4]1[CH:5]=[CH:6][C:1]([CH3:16])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30.0 g of N-(p-toluenesulfonyl)-alanine and 6 to 7 drops of DMF (dimethylformamide) were dissolved in 100 ml of dichloromethane and 5 ml of oxalyl chloride was added dropwise. After stirring for 3 hours at room temperature the reaction mixture was evaporated down to a residue which was dissolved in 100 ml of dichloromethane. The dichloromethane was again evaporated and the resulting residue dissolved in 50 ml of dichloromethane followed by the addition of 100 ml hexane. After standing in the refrigerator overnight the crystals, so formed, were filtered and dried.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].[O:7]=[C:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]([C:18]2[N:23]=[C:22]([CH2:24]S([O-])(=O)=O)[CH:21]=[CH:20][CH:19]=2)=[N:9]1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:1]([S:4][CH2:24][C:22]1[N:23]=[C:18]([C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:8](=[O:7])[N:9]=2)[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH3:3]
Reactant: CCCS
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.3 %

Procedure:
n-Propyl mercaptan (0.25 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs, combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.20 g, 20%) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[N:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1cnc(N)nc1Cl
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(N)ncc2C)cn1
Temperature: 120 °C
Yield: 42.5 %

Procedure:
To 4-chloro-5-methylpyrimidin-2-amine (250 mg, 1.74 mmol), tetrakistriphenylphosphine palladium (0) (100 mg, 0.087 mmol) and 6-methoxypyridin-3-ylboronic acid (398 mg, 2.60 mmol), 1,2-DME (6 mL) and Na2CO3 (1.74 mL, 2 M, 3.47 mmol) were added and heated to 120° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered using acetonitrile and the filtrate was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield 4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-amine (160 mg, 43%). ESI-MS m/z calc. 216.10, found 217.5 (M+1)+. Retention time 0.52 minutes.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:34][C@@H:35]([CH2:54][C:55]1[CH:60]=[C:59]([F:61])[CH:58]=[C:57]([F:62])[CH:56]=1)[CH2:36][NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C:47]([NH:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39]>CN(C=O)C>[F:61][C:59]1[CH:60]=[C:55]([CH2:54][C@H:35]([NH:34][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([CH3:16])[CH:15]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18][CH3:19])=[O:6])[CH:8]=2)[CH2:36][NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C:47]([NH:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39])[CH:56]=[C:57]([F:62])[CH:58]=1
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Reactant: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@@H](N)Cc1cc(F)cc(F)c1)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@H](CN[C@@H](C)C(=O)N[C@H](C(=O)NCC(C)C)C(C)C)Cc2cc(F)cc(F)c2)c1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
3-[(Dipropylamino)carbonyl]-5-methylbenzoic acid, (90 mg, 0.34 mmol) is combined with EDC(65 mg, 0.34 mmol) and HOBT (46 mg, 0.34 mmol) in 3 mL of DMF and stirred under nitrogen for 1 h. This solution is then added to a solution of N-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-L-alanyl-N1-isobutyl-L-valinamide (88 mg, 0.21 mmol) in 1 mL of DMF. The reaction is continued for 3 days at ambient temperature. It is then quenched with 1 N KH2PO4 and diluted with ethyl acetate containing about 1% of methanol. The organic phase is washed with water, 1 N NaHCO3, and brine, and dried over Na2SO4. Concentration and chromatography over silica gel, eluting with 4% to 6% methanol in dichloromethane, affords 96 mg (0.146 mmol, 69%) of the title compound as a light tan solid. 1H NMR (CDCl3) δ 7.75 (d, J=9 Hz, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.21 (s, 1H), 7.16 (d, J=8 Hz, 1H), 6.84 (m, 2H), 6.70 (m, 1H), 6.64 (m, 1H), 4.19 (dd, J=7, 9 Hz, 1H), 4.05 (m, 1H), 3.5-3.4 (m, 2H), 3.33 (dd, J=6, 14 Hz, 1H), 3.19-3.02 (m, 5H), 2.88 (dd, J=6, 14 Hz, 1H), 2.68 (dd, J=4, 13.5 Hz, 1H), 2.58 (m, 1H), 2.37 (s, 3H), 1.96 (m, 1H), 1.75-1.64 (m, 4H), 1.50 (m, 2H), 1.35 (d, J=7 Hz, 3H), 0.99 (t, J=7 Hz, 3H), 0.91 (d, J=7 Hz, 3H), 0.86 (m, 9H), 0.71 (t, J=7 Hz, 3H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[C:39](=[O:40])[C:38]3[S:37][C:36]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=4[C:30]=3[CH:29]=[N:28]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[OH:4][CH2:5][C:6]1[C:7]([N:27]2[C:39](=[O:40])[C:38]3[S:37][C:36]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=4[C:30]=3[CH:29]=[N:28]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C)on3)c(=O)n(C)c2)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)no1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of 291a (100 mg, 0.18 mmol) in THF/i-propanol/water (10/5/5 mL) was added lithium hydroxide (43 mg, 1.8 mmol) at room temperature. After being stirred for 1 h, MS indicated the reaction was complete. Then the mixture was concentrated under reduced pressure and the residue was partitioned between water (10 mL) and dichloromethane (15 mL). The water phase was extracted with dichloromethane (3×10 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 291 (56 mg, 60%) as white solid. MS-ESI: [M+H]+ 517.2. 1H NMR (500 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.48 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.52 (d, J=5.0 Hz, 1H), 6.25 (s, 1H), 4.87-4.85 (m, 1H), 4.42-4.36 (m, 2H), 3.61 (s, 3H), 2.98-2.85 (m, 4H), 2.32 (s, 3H), 1.92-1.86 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([I:11])=[C:9]([NH:12][C:13]([CH3:15])=[O:14])[C:8]([I:16])=[C:7]([C:17]([O-:19])=[O:18])[C:6]=1[I:20])=[O:3].[Na+].Br[CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].[OH-].[NH4+]>CN(C)C=O>[C:13]([NH:12][C:9]1[C:8]([I:16])=[C:7]([C:6]([I:20])=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[C:10]=1[I:11])[C:17]([O:19][CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:18])(=[O:14])[CH3:15]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Reactant: CCOC(=O)C(Br)CC
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)OC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Yield: 66.5 %

Procedure:
To 500 mL of dry N,N-dimethylformamide was added 159 g (0.250 mol) sodium diatrizoate and 54.5 g (0.280 mol) of ethyl 2-bromobutyrate. The mixture was heated on a steam bath for 20 h, cooled to room temperature and poured into 3 L of dilute ammonium hydroxide. The solid was filtered, washing with water, and air-dried. The solid was further purified by crystallization from 50% aqueous ethanol (after treatment with decolorizing carbon) affording two crops which were dried at 100° C. overnight to afford 121 g (66%) of a white powder, m.p. 288°-290° C. (dec.). Analysis for C17H19I3N2O6 : Calculated/Found: C, 28.05/28.36/H, 2.63/2.55; I, 52.3/52.3.
Reaction SMILES: [CH2:1]([C:7]1[N:8]=[N:9][N:10]([CH2:12][CH2:13][CH3:14])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I:15][CH3:16]>>[I-:15].[CH2:1]([C:7]1[N+:8]([CH3:16])=[N:9][N:10]([CH2:12][CH2:13][CH3:14])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCCCc1cn(CCC)nn1
Product: CCCCCCc1cn(CCC)n[n+]1C
Product: [I-]
Temperature: 40 °C

Procedure:
4-hexyl-1-propyl-1H-1,2,3-triazole and excess iodomethane were added to a 20 mL vial. The reaction was heated at 40° C. for 3 days. The iodomethane was allowed to evaporate in the hood. The following structure of 4-hexyl-3-methyl-1-propyl-1H-1,2,3-triazol-3-ium iodide was confirmed:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][C:29]([C:32]([O:34]CC2C=CC([N+]([O-])=O)=CC=2)=[O:33])([CH3:31])[CH3:30])/[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:20]3[C@@H:12]2[CH2:13][S:14][C@H:15]2[C@@:19]3([C:23]([O-:25])=[O:24])[O:18][C:17](=[O:26])[CH2:16]2)=[O:9])[N:6]=1.[Na+:45].P([O-])([O-])([O-])=O.C(O)C.[H][H]>O.[C].[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][C:29]([C:32]([OH:34])=[O:33])([CH3:31])[CH3:30])/[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:20]3[C@@H:12]2[CH2:13][S:14][C@H:15]2[C@@:19]3([C:23]([O-:25])=[O:24])[O:18][C:17](=[O:26])[CH2:16]2)=[O:9])[N:6]=1.[Na+:45]
Reactant: [H][H]
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1CS[C@@H]1CC(=O)O[C@]12C(=O)[O-])c1csc(N)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1CS[C@@H]1CC(=O)O[C@]12C(=O)[O-])c1csc(N)n1)C(=O)O
Yield: 77 %

Procedure:
In 5 ml of water was dissolved 0.148 g of the compound obtained in Example 7. To this solution were added 5 ml of a 0.1 M phosphate buffer solution, 5 ml of ethanol and 0.075 g of 10% palladium-carbon. Into the mixture was introduced hydrogen gas while stirring under ice-cooling. In 1.5 hour after starting of the reaction, 0.04 g of 10% palladium-carbon was added to the reaction system, followed by stirring for further one hour. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to a volume of about 5 ml. The residue was subjected to a Amberlite XAD-2 column chromatography. Fractions eluted with water were combined and freeze-dried to give 0.091 g of the subject compound as powders.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:6][CH2:7][NH:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][CH:12]=1.P(Cl)(Cl)([Cl:29])=O>C(#N)C>[ClH:29].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:12]2[C:11](=[CH:16][C:15]([O:17][CH3:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:10][CH2:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC
Solvent: CC#N
Product: COc1ccc(CC2=NCCc3cc(OC)c(OC)cc32)cc1OC
Product: Cl

Procedure:
A solution of 570 g of N-(3,4-dimethoxyphenethyl)-2-(4,5-dimethoxyphenyl)acetamide and 500 ml of phosphorus oxychloride in 3500 ml of acetonitrile was heated under reflux for 0.5 hour. The solvent was evaporated, and ethanol was added to the residue, followed by allowing to stand. The thus precipitated crystal was collected by filtration to yield 590 g of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:19].Cl.[NH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([NH2:31])=[NH:30])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[ClH:19].[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29](=[NH:30])[NH2:31])[CH2:25][CH2:24]1)[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(N)N1CCC(CN)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCC1CCN(C(=N)N)CC1)C1CCCCC1

Procedure:
The title compound was prepared using (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (10.1 g, 39.28 mmol), 4-aminomethyl-piperidine-1-carboxamidine dihydrochloride (9.0 g, 39.28 mmol) , HATU (14.9 g, 39.28 mmol), and collidine (15.6 ml, 117.8 mmol) in dimethylformamide as described in example 223 a).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26](OC)=[O:27])[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:34][NH:35][O:36][CH3:37].C([Mg]Cl)(C)C>O1CCCC1>[CH3:37][O:36][N:35]([CH3:34])[C:26](=[O:27])[C:25]1[CH:30]=[CH:31][CH:32]=[C:23]([CH2:22][N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])[CH:24]=1
Reactant: CNOC
Reactant: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
EX-620A) To a slurry of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (1.03 g, 0.0023 mol) and N,O-dimethyl-hydroxylamine hydrochloride (386 mg, 0.0040 mol) in 4.6 mL of tetrahydrofuran at −15° C. was added a 2.0 M solution of isopropylmagnesium chloride in THF (4.6 mL, 0.0092 mol) over 15 min. The reaction was stirred for 1 h at −15° C., then quenched with 20% aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:1 ethyl acetate:hexane to afford 0.72 g (66%) of the desired N-methoxy-N-methyl-3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamide product as an off-white solid. HRMS calcd. for C25H25N2O4F3: 475.1845 [M+H]+, found: 475.1840.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:19]#[CH:20].[O-2].[Mg+2]>O1CCCC1>[CH:23]1([CH2:22][N:21]([CH2:18][C:19]#[CH:20])[C:15]([C:13]2[C:14]3[C:5]([CH:6]=[C:7]4[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]4)=[CH:4][CH:3]=[CH:2][CH:1]=3)=[O:16])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Reactant: C#CCNCC1CCCCC1
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1CCOC1
Product: C#CCN(CC1CCCCC1)C(=O)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A solution of 12.66 g of 9-anthroyl chloride in 50 ml of tetrahydrofuran is added dropwise to a stirred mixture of 8.69 g of N-propargylcyclohexylmethylamine and 9 g of magnesium oxide in 80 ml of tetrahydrofuran. After stirring at room temperature overnight, the mixture is filtered and the filtrate is concentrated to dryness. The residue is taken up in methylene chloride and washed, in turn, with dilute sulfuric acid, water, and dilute sodium hydroxide solution, and dried. Removal of the solvent gives 14.7 g of N-cyclohexylmethyl-N-propargyl-9-anthramide as an oil. It is dissolved in 100 ml of p-xylene and the mixture is heated under reflux for three hours. The solvent is removed, and the residue is heated under reflux with 60 ml of tetrahydrofuran and 60 ml of 15% aqueous sodium hydroxide solution for one hour. The mixture is concentrated to a small volume, diluted with water and filtered. The solid is washed with dilute alkali and water, dried, and crystallized from toluene to give 6.68 g of 2-cyclohexylmethyl-3,5-dihydro-5,9b-o-benzenobenz[e]isoindol-1(2H)-one; nmr spectrum: τ 2.3-3.4 (m, 9); 4.8 (d, J = 6Hz, 1) 5.9 (d, J = 2Hz, 2); 6.6 (d, J = 6.5 Hz, 2) and 8.0-9.2 (m, 11).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[O:10][C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:18][N:16]1[CH:17]=[C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH:2]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=2)[CH:14]=[N:15]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1oc(-c2cnn(C)c2)cc1C(Cl)CC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1oc(-c2cnn(C)c2)cc1C(CC(C)C)Nc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
A mixture of 4-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-1-methyl-1H-pyrazole (1.0 g), methyl 4-aminobenzoate (0.9 g), sodium carbonate (0.6 g) and sodium iodide (1.1 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 55% ethyl acetate/hexane) to give the title compound (0.5 g, 39%) as an amorphous compound.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]1([CH:23]([NH:25][C@@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)[CH3:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:1][C:2]([N:25]([C@@H:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:24])[C@H:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27]1)=[O:4].[Cl:1][C:2]([N:25]([C@@H:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:24])[C@@H:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27]1)=[O:4]
Reactant: CC(N[C@@H]1CCN(C(=O)OC(C)(C)C)C1)c1cccc2ccccc12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](c1cccc2ccccc12)N(C(=O)Cl)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Product: C[C@H](c1cccc2ccccc12)N(C(=O)Cl)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 14.9 g of triphosgene dissolved in 400 ml of methylene chloride was added dropwise a solution containing 25.68 g of tert-butyl(R)-3-[1-(naphthalen-1-yl)ethylamino]pyrrolidine-1-carboxylate (the compound obtained in the above-mentioned Reference example 1.005 (1)) and 31.5 ml of triethylamine in 100 ml of methylene chloride at −20° C. Further, 7.5 g of triphosgene was added to the same, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1→2:1) to obtain 10.63 g of tert-butyl(S)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate and 9.22 g of tert-butyl(R)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate shown in the following Reference example Table, respectively. (2) To 18.52 g of tert-butyl(S)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate was added 1.0 liter of tert-butanol, and the mixture was stirred at 60° C. for 2 days. The reaction mixture was concentrated, and then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 9.24 g of tert-butyl(S)-3-[tert-butoxycarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate (the following Reference example 1.006(a)).