Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[N:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCCNC(=O)c1nnc2c(-c3cncc(OC)c3)cccc2c1N
Yield: 76.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.324 mmol) and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (160 mg, 0.68 mmol) were reacted to afford the title compound (84 mg, 77% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.49-8.60 (m, 2H), 8.39 (m, 1H), 7.93 (dd, J=8.2, 1.6 Hz, 1H), 7.73-7.84 (m, 2H), 7.66 (m, 1H), 3.93 (s, 3H), 3.47 (apparent q, J=6.7 Hz, 2H), 1.68 (apparent sextet, J=7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). MS APCI, m/z=338 (M+H) HPLC 1.52 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
61.2 g of 3-hydroxy-4-nitrotoluene, 66.3 g of potassium carbonate, and 54.7 ml of benzyl chloride are heated in 800 ml of dimethylformamide to 100° C. for 1.5 hours; after cooling, the mixture is poured into water, and the thus-precipitated material is recrystallized from ethanol, yielding 82.0 g of 3-benzyloxy-4-nitrotoluene, mp 49°-51° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][CH:31]=[C:30]5[CH3:36])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:37][CH3:38])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:38][O:37][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[N:23]=[CH:22][N:21]=[C:20]2[O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH3:36]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCNCC1
Reaction time: 1 h
Yield: 76.9 %

Procedure:
7-{[1-(tert-Butoxycarbonyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazoline (5.8 g) was suspended in dichloromethane (40 ml) and cooled with an ice bath. TFA (17 ml) was added and the reaction mixture was stirred at this temperature for 1 hour. The volatiles were removed under vacuum and the residue triturated under water and dichloromethane. The pH was made basic to 12.5 with a 30% aqueous solution of sodium hydroxide while cooling with an ice bath. Extraction was done with a mixture of dichloromethane and methanol. The combined extracts were washed in turn with water and brine and dried over magnesium sulphate. The solvent was evaporated under vacuum and the residue was triturated under ether, filtered and dried to give 6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methoxy]quinazoline (3.6 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([SH:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].I[CH3:29].[OH-].[K+]>CO>[CH2:1]([C:5]1[N:6]=[C:7]([S:27][CH3:29])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(S)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc(SC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of 4′-[(4-butyl-2-mercapto-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.3 g), iodomethane (0.54 mL), potassium hydroxide (0.44 g) and methanol (20 mL) was stirred at room temperature for 3 hr. The obtained crystallized product was collected by filtration and washed with water and diethyl ether to give the title compound as colorless crystals (1.98 g, 83%).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[N:51]=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)[CH:49]=[CH:48][CH:47]=1>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.O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:43])([CH3:44])[CH3:42])=[CH:37][CH:36]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[N:51]=[C:50]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=5)[CH:49]=[CH:48][CH:47]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:30][CH:29]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4cccc(-c5ccccn5)n4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
Under a stream of argon, 1.4 ml of a hexane solution containing 2.2 mmol of butyl lithium was slowly added to 40 ml of tetrahydrofuran cooled to −78° C. in which 1.00 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained in Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.61 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 20 ml portion of tetrahydrofuran prepared by dissolving 0.56 g of 6-bromo-2,2′-bipyridyl and 0.12 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 20 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (developing solvent hexane:chloroform=1:1 to 0:1) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 6-{4-[4,6-bis(4-tert-butylphenyl)-1,3,5-triazin-2-yl]phenyl}-2,2′-bipyridyl (0.82 g, yield 71%). Its melting point and glass transition temperature are shown in Table 4.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([N:62]=[C:63]=[O:64])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([NH:62][C:58]2[CH:59]=[CH:60][CH:61]=[C:56]([F:55])[CH:57]=2)=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2cccc(F)c2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 39 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-fluoro-3-isocyanatobenzene as starting materials in 39% yield. LCMS for C31H31ClFN8O2 (M+H)+: m/z=601.2.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([F:27])[CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.Cl.Cl.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C(Cl)(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([F:27])[CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3c(F)cc(F)cc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NC1CCN(CCn2c(=O)cnc3c(F)cc(F)cc32)CC1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl{1-[2-(5,7-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 193, 0.21 g) in dioxane (3 mL) and water (1 mL) was added 4 M HCl in dioxane (1 mL). After 30 minutes, additional 4 M HCl/dioxane (3 mL) was added. After 1 hour, the reaction was diluted with chloroform and poured into a saturated solution of Na2CO3. The organic solution was collected, dried (Na2SO4), filtered and concentrated yielding 0.158 g of crude titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=2[Cl:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(CNCc2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (300 mg, 1.6 mmol), 2,4-dichlorobenzaldehyde (281 mg, 1.61 mmol) and acetic acid (0.09 mL, 1.61 mmol) in 1,2-dichloroethane (16 mL) at 0° C. is added sodium triacetoxy-borohydride (476 mg, 2.25 mmol). The reaction is warmed to ambient temperature and stirred overnight under N2. The reaction mixture is poured on to 2N NaOH (20 mL) and extracted with ethyl acetate (3×). The combined organic extracts are washed with aqueous saturated NaCl, dried (Na2SO4), filtered and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 5% EtOH (10% NH4OH)/chloroform to yield 360 mg (65%) of 3-[(2,4-dichlorobenzylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CD3OD) δH: 7.49-7.47 (2H, m), 7.36-7.34 (1H, m), 4.05-4.01 (2H, m), 3.88 (2H, s), 3.64-3.61 (2H, m), 2.8 (2H, m), 2.78-2.74 (1H, m), 1.46 (9H, s). Mass spectrum (ion spray): m/z=345.1 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]1)(C)(C)C>FC(F)(F)C(O)=O>[CH2:16]([O:15][C:13]([C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]([OH:18])=[O:5])[CH:12]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cnn(CC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnn(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110 %

Procedure:
The compound (17.5 g) obtained in Example 115a was added to trifluoroacetic acid (280 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was washed with hexane, and dried to give the title compound (15.0 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:16][N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23](O)=[O:24])[C:18]1([CH3:27])[CH3:26].C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:23]([CH:19]3[CH2:20][C:21](=[O:22])[N:17]([CH3:16])[C:18]3([CH3:27])[CH3:26])=[O:24])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN1C(=O)CC(C(=O)O)C1(C)C
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN1C(=O)CC(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)C1(C)C
Yield: 68 %

Procedure:
The desired compound was prepared according to Method B from 6-chloro-9H-β-carboline-8-ylamine and 1,2,2-trimethyl-5-oxo-pyrrolidine-3-carboxylic acid in 68% yield. 1H-NMR (DMSO-d6, 300 MHz) δ 1.23 (s, 3H), 1.45 (s, 3H), 2.59 (dd, 1H), 2.66(s, 3H), 2.70 (dd, 1H), 3.17 (t, 1H), 7.91 (m, 1H), 8.18 (d, 1H), 8.24 (d, 1H), 8.40 (d, 1H), 9.07 (s, 1H), 10.16 (s, 1H), 11.32 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.17 min. MS (M+H+): 371.3.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1>CN(C)C=O.O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([O:4][CH2:1][CH2:2][CH3:3])=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc([N+](=O)[O-])cc1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
1-Propanol (284 mg, 4.72 mmol) was added dropwise at a slow speed to a suspension of sodium hydride (206 mg, 4.72 mmol) in dimethylformamide (4 ml) at 0° under argon atmosphere, then the mixture was stirred at room temperature for 30 minutes. A solution of 2-chloro-5-nitro-4′-(trifluoromethoxy)biphenyl (1.00 g, 3.15 mmol) in dimethylformamide (2 ml) was added dropwise at a slow speed to this mixture at OD, and then stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=6:1) to give the title compound (586g, 54.5%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][C:4]1(F)F.BrCC1CC1.[CH3:13][C:14]1[N:15]=[C:16]([N:24]2[C:28](=[O:29])[NH:27][N:26]=[CH:25]2)[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH:5]1([CH2:4][N:27]2[C:28](=[O:29])[N:24]([C:16]3[S:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH3:13])[N:15]=3)[CH:25]=[N:26]2)[CH2:3][CH2:2]1
Reactant: FC1(F)CC1CBr
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(-n2cnn(CC3CC3)c2=O)nc1C
Yield: 83 %

Procedure:
Following the procedure as described in Preparation 13, making variation as required to replace bromomethyl-2,2-difluorocyclopropane with (bromomethyl)cyclopropane to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate in place of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 83% yield: 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.63 (d, J=7.1 Hz, 2H), 2.64 (s, 3H), 1.35 (t, J=7.1 Hz, 3H), 1.19-1.04 (m, 1H), 0.53-0.42 (m, 2H), 0.36-0.27 (m, 2H); MS (ES+) m/z 309.2 (M+1).
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][NH2:16])=[CH:10][CH:9]=1)[C:5]([CH3:7])=[O:6].C([O-])(=O)C.[Na+]>CO.Cl>[NH2:1][C:2]1[O:17][CH:14]([CH2:13][O:12][C:11]2[CH:18]=[CH:19][C:8]([CH2:4][C:5]([CH3:7])=[O:6])=[CH:9][CH:10]=2)[CH2:15][N:16]=1
Reactant: CC(=O)Cc1ccc(OCC(O)CN)cc1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=O)Cc1ccc(OCC2CN=C(N)O2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of cyanogen bromide (0.88 g) in methanol (100 ml) was added, dropwise, to a stirred solution of (4-acetonylphenoxy)-3-amino propan-2-ol), ethylene ketal (3.62 g) and sodium acetate (1.46 g) in methanol (30 ml). The reaction mixture was stirred at ambient temperature for 20 hr. evaporated, cooled in ice, diluted with 2N sodium hydroxide solution and extrated into chloroform. The organic layer was dried (MgSO4) and evaporated to an oil which was purified by column chromatography on silica gel. Elution with acetonitrile/methanol/ammonia (15:2:1) gave a low-melting solid which was dissolved in a mixture of methanol (30 ml) and 2N hydrochloric acid (30 ml) and stirred at ambient temperature for 4 hr. The methanol was evaporated and the aqueous residue was basified by addition of 2N sodium hydroxide solution, extracted into chloroform, dried (MgSO4) and evaporated to give 2-amino-5-(4-acetonylphenoxymethyl]-4,5-dihydrooxazole.
Reaction SMILES: NCCCCCC([C:9]1[C:18](N)=[CH:17][CH:16]=[C:11]([C:12]([NH:14][OH:15])=[O:13])[C:10]=1[O:20]C)=O.Cl>C([O-])(O)=O.[Na+]>[C:12]([NH:14][OH:15])(=[O:13])[C:11]1[C:10](=[CH:9][CH:18]=[CH:17][CH:16]=1)[OH:20]
Reactant: COc1c(C(=O)NO)ccc(N)c1C(=O)CCCCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NO)c1ccccc1O

Procedure:
SHA-Sepharose 4B was prepared by mixing 130 mg of (6-aminohexanoyl)-4-amino-methylsalicylhydroxamic acid (SHA--Z--NH2), dissolved in 30 mL 0.2M NaHCO3, with 6.5 g HCl washed CNBr activated Sepharose 4B (Pharmacia) overnight at room temperature. After the coupling reaction, 2 mL of 0.5M Tris, pH 8.5 were added and the gel slurry mixed at room temperature for 1 hour, and washed with water, 0.5M NaCl, and water again. The resulting SHA-Sepharose 4B was suspended in 30 mL of 20% ethanol, and stored at 4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:35])[N:11]([CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([N+:22]([O-])=O)=[CH:17][CH:18]=3)[CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]>CCO.[Ni]>[NH2:22][C:16]1[CH:15]=[C:14]2[C:19]([CH2:20][CH2:21][CH:12]([N:11]([CH2:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)=[O:35])[CH2:13]2)=[CH:18][CH:17]=1
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc([N+](=O)[O-])cc3C2)CC1
Agent: [Ni]
Solvent: CCO
Product: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Yield: 74 %

Procedure:
To a solution of 3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-1-(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea (from Preparative Example 26, 0.286 g, 0.57 mmol) in absolute EtOH (10 mL) was added Raney Ni (˜50 mg). The mixture was hydrogenated using a Parr hydrogenator at 50 psi for 2 hours, then filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography by eluting with 5% MeOH/CH2Cl2 to give 0.200 g (75%) of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea as a light brown solid. 1H NMR (300 MHz, CD3OD): δ 7.57 (dd, 1H), 7.31 (m, 1H), 7.15 (t, 1H), 6.84 (d, 1H), 6.53 (dd, 1H), 6.48 (d, 1H), 4.30 (m, 1H), 3.38 (t, 2H), 2.95 (m, 1H), 2.82 (m, 3H), 2.60-2.35 (m, 10H), 2.26 (s, 3H), 1.96 (m, 2H), 1.85 (m, 2H). MS-ESI: 474.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[CH:15]=[CH:16][N:17]([C@@H:18]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:19]3)[C:13]=2[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:34]([NH2:37])(=[O:36])=[O:35]>>[S:34](=[O:36])(=[O:35])([O:24][CH2:23][C@@H:21]1[C@@H:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH2:19][C@H:18]([N:17]2[C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:14]=3[CH:15]=[CH:16]2)[O:22]1)[NH2:37]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCc4ccccc4)nccc32)O[C@@H]1CO
Reactant: NS(=O)(=O)Cl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCc4ccccc4)nccc32)O[C@@H]1COS(N)(=O)=O
Yield: 29 %

Procedure:
Using essentially the same procedure as example 43, step f, ((2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methanol (0.0876 g, 0.193 mmol) was reacted with chlorosulfonamide, and the product was purified by flash chromatography (60 to 100% EtOAc/CH2Cl2) to afford the title compound (0.0300 g, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[CH:15]1([CH:21]=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH:21]([OH:22])[CH:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:11]([O:13][CH3:14])=[O:12])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=CC1CCCCC1
Reactant: COC(=O)CCc1ccccc1OC
Product: COC(=O)C(Cc1ccccc1OC)C(O)C1CCCCC1

Procedure:
Methyl 3-(2-methoxyphenyl)propionate (1.80 g) was reacted with cyclohexane carbaldehyde (1.25 g) in substantially the same manner as that of Preparation 1-4) to give less polar isomer of methyl (2RS,3SR)-3-cyclohexyl-3-hydroxy-2-(2-methoxyphenylmethyl)propionate (isomer A) (0.706 g) and more polar isomer of (2RS,3RS)-isomer of the same (isomer B) (0.940 g).
Reaction SMILES: C(OC([NH:8][C:9](=[O:20])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)[NH2:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C@@H:10]([C:9]([NH2:8])=[O:20])[NH2:11])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC(=O)[C@@H](N)Cc1ccc(I)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
N-(tert-Butoxycarbonyl)-4-iodo-(L)-phenylalaninamide (4.24 g) was dissolved in DCM (20 mL) and to the solution was added TFA (20 mL). The reaction mixture was stirred, at room temperature, for 0.5 h then concentrated to dryness under reduced pressure. The crude material obtained was loaded onto an SCX cartridge. Non-basic impurities were washed off with a 1:1 mixture of DCM and methanol, then the cartridge was eluted with 10% ammonia in methanol. Eluent from the latter was concentrated to dryness to give the free base of the sub-title compound (3 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][S:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][S:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc(N)cc1
Reaction time: 6 h
Yield: 98.1 %

Procedure:
10% Pd/C (7 mg) was added to a solution tert-butyl N-(4-nitrobenzyl)sulfamoyl-carbamate (65 mg) in ethanol and tetrahydrofuran and charged with H2. After stirring the reaction mixture for 6 h, the mixture was filtered using celite and evaporated in vacuo to obtain tert-butyl N-(4-aminobenzyl)sulfamoylcarbamate (58 mg, 98%).