Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-]#N.[Na+].C1(C)C=CC=CC=1.C[NH:12][CH2:13][CH2:14]NC.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1C=[CH:28][CH:27]=[CH:26][CH:25]=1>N.[Cu]I>[C:24]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=2)[C:14]([C:13]#[N:12])=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: CNCCNC
Agent: [Cu]I
Agent: N
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccccc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A Schlenk tube was charged with NaCN (98 mg, 2.0 mmol), CuI (31 mg, 0.16 mmol, 10 mol %), and KI (55 mg, 0.33 mmol, 20 mol %), briefly evacuated and backfilled with argon three times. Anhydrous toluene (1.2 mL), N,N′-dimethylethylenediamine (175 μL, 1.64 mmol), and 2-bromobiphenyl (285 μL, 1.65 mmol) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 24 h. The resulting suspension was allowed to reach room temperature, diluted with 30% aq ammonia (2 mL), and extracted with ethyl acetate (4×2 mL). The combined organic phases were dried over MgSO4, concentrated, and the residue was purified by flash chromatography on silica gel (hexane-ethyl acetate 20:1) to provide the desired product as a light yellow oil which crystallized upon storing in a refrigerator (289 mg, 98% yield). Mp 34-37° C. (lit., 35-37° C. See Sain, B.; Sandhu, J. S. J. Org. Chem. 1990, 55, 2545). 1H NMR (400 MHz, CDCl3, J values are reported in Hz, lit. See Hassan, J.; Hathroubi, C.; Gozzi, C.; Lemaire, M. Tetrahedron 2001, 57, 7845): δ 7.80 (ddd, J=7.8, J=1.5, J=0.5, 1H), 7.68 (td, J=7.8, J=1.3, 1H), 7.61-7.44 (m, 7H); 13C NMR (100 MHz, CDCl3): 145.9, 138.6, 138.5, 134.2, 133.3, 130.5, 129.2, 129.1, 128.0, 119.2, 111.7; IR (neat, cm−1): 2224, 1597, 1500, 1477, 1451, 1433, 759, 735, 700. Anal. Calcd. for C13H9N: C, 87.12; H, 5.06; N, 7.82. Found: C, 86.84; H, 5.22; N, 7.94.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[O-:10][P:11]([O:14][P:15]([O-:18])([O-:17])=[O:16])(=[O:13])[O-:12].[Na+].[Na+].[Na+].[Na+].Cl>O>[OH:12][P:11]([O:14][P:15]([OH:18])([OH:17])=[O:16])(=[O:10])[OH:13].[N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3]
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: Cl
Agent: Nc1nc(N)nc(N)n1
Agent: [Na+]
Solvent: O
Product: O=P(O)(O)OP(=O)(O)O
Temperature: 65.55555555555556 °C

Procedure:
1200 grams of water was warmed to 130° F. To this, while being agitated, was added 100 grams of melamine (2,4,6-triamine-1,3,5-triazine) and a char and/or phase transfer catalyst as set forth in Table 2-B below. The mixture was then warmed to 150° F. and 104.5 grams of tetrasodium pyrophosphate was added. The mixture was heated to 170° F. and the slow addition of 200 grams of twenty degree Baumé muriatic acid was started. Warming was continued until to 200° F., at which time cooling is started. When cooled to 70° F., the mixture was filtered, dried and ground to recover the flame retardant.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH3:14][NH:15][N:16]([NH:20][CH3:21])[C:17](Cl)=[S:18]>O>[CH3:14][NH:15][N:16]([NH:20][CH3:21])[C:17]([O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[S:18]
Reactant: COC(=O)c1ncccc1O
Reactant: CNN(NC)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CNN(NC)C(=S)Oc1cccnc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of 3.06 g (20 mmol) of methyl 3-hydroxypyridine-2-carboxylate in 15 mL of water was made basic with 1.12 g KOH. To this solution was added 3.2 g (26 mmol) of N,N-dimethylaminothiocarbamoyl chloride and the solution was stirred at room temperature for 2 hours. The solution was partitioned between benzene and water and the aqueous layer was washed with two portions of water. The combined extracts were dried and concentrated to afford 4.1 g of a white solid, m.p. 74°-75° C.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl.O>[CH3:33][S:34]([O:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([NH:16][C:13]2[N:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][CH:6]=3)=[CH:15][N:14]=2)[CH:18]=1)(=[O:36])=[O:35]
Reactant: OCc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)methanol 36 (6.22 mmol) in DCM (30 mL) is added triethylamine (9.33 mmol) and methanesulfonyl chloride (7.47 mmol). The reaction mixture is stirred at rt for 1.5 h. The reaction is diluted with H2O (10 mL) and washed with Na2CO3 solution (3×20 mL). The organic layer is washed with brine, dried over MgSO4 and concentrated to afford 3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl methanesulfonate 37. MS (m/z) (M+1)+422.1.
Reaction SMILES: Cl.Cl.CNN(NC)C(N)=[N:7][S:8][CH2:9][CH2:10][CH3:11].C[CH2:16][N:17]([CH:21](C)C)[CH:18](C)C.C1C(C[Cl-]C([O-])=O)=CC=C([N+:35]([O-])=O)C=1.O>C(Cl)Cl>[CH3:21][N:17]([CH3:16])[C:18]([NH2:35])=[N:7][S:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCSN=C(N)N(NC)NC
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCSN=C(N)N(C)C
Temperature: 0 °C
Yield: 126.9 %

Procedure:
N,N-Dimethylaminopropyl thioguanidine dihydrochloride (1.71 mmol, 400 mg) was suspended in dry DCM and cooled to 0° C. under N2 atm. DIEA (6.0 mmol, 775 mg) was then added over 5 min. and the mixture stirred until it became homogeneous (5-10 min). A solution of 4-nitrobenzylchloroformate (2.05 mmol, 445 mg) in dry DCM (10 mL) was then added via syringe over 15 minutes and the resulting mixture was allowed to warm to rt overnight. The crude reaction mixture was then washed with DI water and 50% brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the resulting residue by column chromatography on silica get with 9:1 ACN:DI water afforded the desired product (106, 350 mg, 40% yield) as a white foamy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:14][C:15]1[CH:16]=[C:17]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]([NH:21][C:22]2[S:23][CH:24]=[C:25]([CH2:27]Cl)[N:26]=2)=[N:19][CH:20]=1>CN1C(=O)CCC1>[Br:14][C:15]1[CH:16]=[C:17]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]([NH:21][C:22]2[S:23][CH:24]=[C:25]([CH2:27][NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:26]=2)=[N:19][CH:20]=1
Reactant: Nc1ccccc1
Reactant: ClCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Brc1cnc(Nc2nc(CNc3ccccc3)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
Aniline (0.0352 g, 0.378 mmol) was dissolved in 2 mL NMP at ambient temperature. Cs2CO3 (0.0246 g, 0.0756 mmol) and solid 5-bromo-N-(4-(chloromethyl)thiazol-2-yl)-3-phenoxypyridin-2-amine (0.030 g, 0.0756 mmol) were added to the reaction and the mixture was stirred at ambient temperature overnight. The reaction was concentrated to dryness, dissolved in CH2Cl2, washed with water, dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (0.010 g, 29.2% yield) as tan solids. 1H NMR (CDCl3) δ 4.34 (br s, 3H), 6.67-6.74 (m, 4H), 7.07 (d, J=8.0 Hz, 2H), 7.13 (d, J=1.8 Hz, 1H), 7.18 (t, J=7.7 Hz, 2H), 7.24-7.27 (m, 1H), 7.43 (t, J=7.9 Hz, 2H), 8.13 (d, J=1.6 Hz, 1H), 8.74 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:17][C:18]1[C:19]([F:28])=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[C:19]([F:28])=[C:20]([S:24]([NH:8][C:5]2[C:4]([O:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ncc(Cl)nc1OCc1cccnc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cccnc1)c1cccc(Cl)c1F

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 95a) (0.1 g) and 3-chloro-2-fluorobenzenesulphonyl chloride (0.1 g). Yield 0.034 g.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O:21][C:22]1[C:23]([C:35](=[O:44])[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[C:24]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>O1CCCC1.C(O)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:21][C:22]1[C:23]([C:35](=[O:44])[C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[C:24]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1
Reactant: COC(=O)Cc1cc(OC)cc(OC)c1C(=O)c1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)Cc1cc(OC)cc(O)c1C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
Triphenylphosphine (0.22 g, 0.84 mmol) and palladium (II) acetate (47 mg, 0.21 mmol) were dissolved in tetrahydrofuran (2.0 mL) in an atmosphere of argon, followed by stirring at room temperature for 10 minutes. To the reaction mixture was added a solution of methyl 3,5-dimethoxy-2-(4-methoxybenzoyl)phenylacetate (0.78 g, 2.1 mmol) obtained in Example 26, Step 1 in formic acid (20 mL), followed by stirring at 80° C. for 5 hours. The reaction mixture was cooled to room temperature and then concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/1) to obtain Compound 27 (0.39 g, 56%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[C:9]([C:11]([OH:18])([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])#[CH:10]>>[Br:8][C:4]1[CH:3]=[C:2]([C:10]#[C:9][C:11]([OH:18])([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CC(O)(CCC)CCC
Reactant: Brc1cccc(Br)c1
Product: CCCC(O)(C#Cc1cccc(Br)c1)CCC

Procedure:
1,3-Dibromobenzene was coupled with alkynol 20 following the procedure described in Example 10 to give 4-((3-bromophenyl)ethynyl)heptan-4-ol as a yellow liquid. Yield (4.2 g, 65%): 1H NMR (400 MHz, DMSO-d6) δ 7.56-7.52 (m, 2H), 7.36 (dt, J=8.0, 1.2 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 5.18 (s, 1H), 1.60-1.40 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Na].Cl[CH2:3][C:4]1[C:5]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1.[CH2:18]([OH:20])[CH3:19]>>[CH2:18]([O:20][CH2:3][C:4]1[C:5]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:19]
Reactant: O=C(O)CCc1cc2c(cc1CCl)OCO2
Reactant: CCO
Agent: [Na]
Product: CCOCc1cc2c(cc1CCC(=O)O)OCO2
Temperature: 50 °C

Procedure:
0.6 g of metallic sodium was dissolved in 100 ml of ethanol. 2.0 g of 3-(6-chloromethyl-1,3-benzodioxole-5-yl)propionic acid was added in small portions to the solution. The mixture was heated at 50° C. for 2 h. The solvent was distilled off and the residue was acidified with 1N hydrochloric acid. After extraction with chloroform, the organic layer was dried over magnesium sulfate. The solvent was distilled off. After separation according to silica gel column chromatography (chloroform), 0.73 g of the intended compound in the form of colorless crystals was obtained.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][NH:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1.CCN(CC)CC>C(Cl)Cl>[NH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:8][N:7]([CH3:6])[C:1](=[O:4])[CH:2]=[CH2:3])=[CH:10]1
Reactant: CNCc1c[nH]c2ccccc12
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Acryloyl chloride (0.33 mL, 4.10 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (0.60 g, 3.70 mmole) and Et3N (1.03 mL ,7.40 mmole) in CH2Cl2 (30 mL) at 0° C. The reaction was held at 0° C. for ten minutes, then was stirred overnight at RT. The solution was concentrated in vacuo and the residue was diluted with water. The solution was extracted with ethyl acetate, and the combined organic extracts were washed with brine and dried over Na2SO4. The title compound (0.64 g, 80%) was obtained as a light yellow solid: MS (ES) m/e 215 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15](Br)=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1.[Cl-].[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Zn+])=[CH:25][CH:24]=1>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([CH3:27])=[CH:25][CH:24]=2)=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1
Reactant: Cc1ccc(C[Zn+])cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Br)cc21
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(Cc2cc3c(cc2C2OCCO2)C(C)(C)CCC3(C)C)cc1
Yield: 89 %

Procedure:
To a mixture of 2-(1,3-dioxolan-2-yl)-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (250 mg, 0.74 mmol) and tetrakis(triphenylphospine)palladium(0) (21 mg, 0.018 mmol) under an argon atmosphere was added a 0.5 M tetrahydrofuran solution of 4-methylbenzylzinc chloride (7.3 mL, 3.68 mmol). The reaction mixture was stirred at reflux overnight and partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel (5% ethyl acetate/hexane) to give 2-(1,3-dioxolan-2-yl)-3-(4-methylbenzyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a white crystalline solid (240 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[N:14]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:13](=[O:27])[NH:12][C:11]([CH2:28][O:29][CH3:30])=[C:10]2[C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[F:8].[N+:35]([C:38]1[CH:39]=[C:40]([C:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH2:52][NH2:53])[CH2:48][CH:49]=2)[CH:41]=[CH:42][CH:43]=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].CO>ClCCl>[NH2:35][C:38]1[CH:39]=[C:40]([CH:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH2:52][NH:53][C:15]([N:14]3[C@@H:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[C:10]([C:31]([O:33][CH3:34])=[O:32])=[C:11]([CH2:28][O:29][CH3:30])[NH:12][C:13]3=[O:27])=[O:17])[CH2:48][CH2:49]2)[CH:41]=[CH:42][CH:43]=1
Reactant: NCCCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3cccc(N)c3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of 3.02 g (6.33 mmol) 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-propanamine, 7.94 g (75.5 mmol) of K2CO3 and 1.00 mL of methanol in 200 mL dichloromethane (under argon) was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate and washed 3×50 mL of 5% aqueous NaOH solution, the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C and the reaction mixture was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 9.5:0.5, dichloromethane:methanol+1% isopropyl amine) to afford 1.65 g (52.0% yield) of the desired product.
Reaction SMILES: [I-].[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N+:9]([CH3:13])=[CH:10]2)=[CH:5][CH:4]=1.[CH3:14][Mg]Cl.O>O1CCCC1>[NH2:2][C:3]1[CH:12]=[C:11]2[CH:6]([CH2:7][CH2:8][N:9]([CH3:13])[CH:10]2[CH3:14])[CH2:5][CH:4]=1
Reactant: C[N+]1=Cc2cc(N)ccc2CC1
Reactant: C[Mg]Cl
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CC1C2=CC(N)=CCC2CCN1C
Temperature: -78 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
(±) 7-Amino-2-methyl-3,4-dihydroisoquinolinium iodide (0.50 g, 1.7 mmol) was suspended in anhydrous tetrahydrofuran (50 ml) and cooled to −78° C. The cooled solution was treated with methyl magnesium chloride (2.14 ml of a 3M solution in THF, 6.96 mmol), added as a single portion. The reaction was allowed to reach 25° C. over 18 h before being poured into water (50 ml). The organic solvent was removed in vacuo and the organic product extracted into dichloromethane. Drying over magnesium sulfate and evaporation in vacuo furnished the title compound as a pale yellow oil (0.3 g, 98%). For ease of handling the product was converted into a monohydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:29])[CH:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:16][OH:17])=[CH:9][CH:8]=1)=[O:5])[CH3:2].[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:29])[CH:15]([NH:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH2:16][O:17][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(F)cc2)cc1
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-hydroxypropanamide (1.88 g) was reacted with mesyl chloride to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (1.70 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11]Cl)[CH:3]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:9][CH2:10][CH2:11][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCOc1cccc(Br)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3cccc(Br)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-bromo-3-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 459.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]3[CH:28]=[CH:29][C:30]([C:32](=[NH:35])[NH:33]O)=[CH:31][C:20]=3[N:19]=2)[C:9]1=[O:36])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.[Pd]>[C:1]([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]3[CH:28]=[CH:29][C:30]([C:32](=[NH:33])[NH2:35])=[CH:31][C:20]=3[N:19]=2)[C:9]1=[O:36])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C(=N)NO)ccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C(=N)N)ccc21
Yield: 73.9 %

Procedure:
A solution of {3-[5-(N-hydroxycarbamimidoyl)-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester (1.4 g, 2.76 mmol) in AcOH (50 ml) was added to 10% Pd/C (166 mg) and hydrogenated at 50 psi for 4 h then the mixture was filtered and washed with MeOH. The solvent was removed and the residue triturated with EtOAc to give 1 g (74%) of {3-[5-carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester as a white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([O:28][CH2:29][CH:30]1[O:35][C:34](=[O:36])[C:33]2=[N:37][CH:38]=[CH:39][N:32]2[CH2:31]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.[BH4-].[Na+]>ClCCl>[Si:11]([O:28][CH2:29][CH:30]([OH:35])[CH2:31][N:32]1[CH:39]=[CH:38][N:37]=[C:33]1[CH2:34][OH:36])([C:24]([CH3:26])([CH3:27])[CH3:25])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](OCC1Cn2ccnc2C(=O)O1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC(O)Cn1ccnc1CO)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
Add diisobutylaluminum hydride (35 mL; 1M in hexanes; 1.5 equiv; 35 mmoles) to a 0° C. solution of 6-[[tert-butyl(diphenyl)silyl]oxymethyl]-5,6-dihydroimidazo[2,1-c][1,4]oxazin-8-one (9.48 g; 1.0 equiv; 23.32 mmoles) in dichloromethane (200 mL). Stir the solution for 15 minutes, then add methanol (150 mL). After 5 minutes, add sodium borohydride (0.176 g; 0.2 equiv; 4.66 mmoles) and maintain the solution at 0° C. for 15 minutes. Add saturate sodium potassium tartrate (50 mL) and stir the solution at ambient temperature for 20 minutes. Concentrate the solution to ˜100 mL, add water and dichloromethane (100 mL each), and separate the layers. Further extract the aqueous layer with dichloromethane (5×). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate to afford the desired 1-[tert-butyl(diphenyl)silyl]oxy-3-[2-(hydroxymethyl)imidazol-1-yl]propan-2-ol (9.40 g; 98%). MS (m/z): 411 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:14]2[CH:15]=[N:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:13]2[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1[nH]cnc1CN(CCCl)Cc1ccccc1
Solvent: CC#N
Product: COC(=O)c1ncn2c1CN(Cc1ccccc1)CC2
Temperature: 80 °C
Yield: 64 %

Procedure:
TEA (28.66 mmol, 4 equiv.) was added at 0° C. to a solution of methyl 4-((benzyl(2-chloroethyl)amino)methyl)-1H-imidazole-5-carboxylate (7.16 mmol, 1 equiv.) in acetonitrile (50 ml). The resulting mixture was heated for 16 h at 80° C. It was then cooled and filtered, and the filtrate was concentrated in vacuo. The crude product was taken up in DCM and sat. sodium hydrogen carbonate solution, and the organic phase was dried and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 5% MeOH in DCM), and the desired product was thus obtained in the form of a brown solid. Yield: 64%
Reaction SMILES: [N+:1]([CH2:4][CH:5]([Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C:7]([O:9]CC1C=CC=CC=1)=[O:8])([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][CH2:4][CH:5]([Si:17]([CH3:18])([CH3:20])[CH3:19])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: C[Si](C)(C)C(CC(=O)OCc1ccccc1)C[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[Si](C)(C)C(CN)CC(=O)O
Reaction time: 40 h
Yield: 85.8 %

Procedure:
A suspension of benzyl 4-nitro-3-(trimethylsilyl)butanoate (797 mg, 2.70 mmol) and palladium/carbon (10%, 165 mg) in methanol (30 ml) was added with ammonium formate (1.70 g, 27.0 mmol), and the mixture was stirred under an argon atmosphere for 40 hours. The reaction mixture was filtered through Celite, and the Celite layer was washed with methanol. The reaction mixture was concentrated under reduced pressure, and the residue was purified by recrystallization and silica gel chromatography [methanol (10 to 25%)/chloroform] to obtain 4-amino-3-(trimethylsilyl)butanoic acid (406 mg, 86%) mentioned in the title as colorless powder.