Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]=[O:12]>C(=O)([O-])[O-].[K+].[K+]>[OH:12][CH2:11][NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: NC(=O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(Cc1ccccc1)NCO
Yield: 44.4 %

Procedure:
A mixture of phenylacetamide 12 (2 g, 15 mmol) in a solution of potassium carbonate (4%, 2 ml, 0.6 mmol) and an aqueous solution of formaldehyde (37%, 2 ml, 20 mmol) was refluxed for 15 min (until completely dissolved). The mixture was cooled and extracted with CH2Cl2 (2×30 ml). The combined organic phases were dried over MgSO4 and were concentrated under reduced pressure to give a crude product (1.35 g), recrystallization in toluene (20 ml) gave N-hydroxymethylphenylacetamide 11 (1.1 g, 44%) in the form of a white powder. M.p. 78° C. 1H NMR (CDCl3, 300 MHz) δ 7.50-7.20 (m, 5H), 6.48 (br s, NH), 4.69 (t, J=7.0 Hz, 2H), 3.67 (t, J=7 Hz, OH), 3.60 (s, 2H). 13C NMR (CDCl3, 75 MHz) δ 172.9, 134.4, 129.5, 129.0, 127.5, 64.2, 43.6.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([CH:28]=O)[CH:22]=2)=[O:18].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([CH2:28][N:44]1[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]1)[CH:22]=2)=[O:18]
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(C=O)cc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(CN4CCN(C)CC4)cc32)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.2 %

Procedure:
2-[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazole-4-carbonyl]-1-(toluene-4-sulfonyl)-1H-indole-6-carbaldehyde (29 mg, 0.054 mmol), 1-methylpiperazine (7 μl, 0.066 mmol), and sodium triacetoxyborohydride (17 mg, 0.083 mmol) were dissolved in anhydrous dichloromethane (0.5 ml) and stirred at room temperature under a nitrogen atmosphere for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. Then, the mixture was extracted with ethyl acetate. The organic layer was isolated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/15) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-(4-methyl-piperazin-1-ylmethyl)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone as a yellow solid (29 mg, 86%).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])(C)=C.[H-].[Na+].CI.Cl>CN(C=O)C>[CH3:1][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2ccccc21
Temperature: 45 °C
Yield: 74.6 %

Procedure:
A solution of 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one (30 g, 0.172 moles) in DMF (180 ml) was added dropwise over 30 minutes to a suspension of 80% sodium hydride (5.42 g, 0.181 moles) in DMF (60 ml). The reaction mixture was heated at 45° C. for 45 minutes then a solution of methyl iodide (16.1 ml, 0.258 moles) in DMF (50 ml) was added dropwise. The reaction mixture was heated at 80° C. to 90° C. for 45 minutes, cooled at room temperature and adjusted to pH 3 to 4 with 37% HCl and heated at 80° C. for 30 minutes. The reaction mixture was cooled at room temperature and poured into ice/water. The solid residue separated was filtered and dried to give 19 g of the title compound, m.p. 188° C.-190° C.
Reaction SMILES: [Cl:1][C:2]1[C:30]([O:31][CH3:32])=[CH:29][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]4[CH:20]=[C:19]([O:21][CH2:22]CCl)[C:18]([O:25][CH3:26])=[CH:17][C:14]=4[CH:15]=3)[N:10]=[CH:9][C:8]=2[C:27]#[N:28])=[C:4]([CH3:33])[CH:3]=1.[Cl:34][C:35]1[C:63]([O:64][CH3:65])=[CH:62][C:38]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][C:46]4[CH:53]=[C:52]([O:54][CH3:55])[C:51]([O:56][CH2:57][CH2:58]Cl)=[CH:50][C:47]=4[CH:48]=3)[N:43]=[CH:42][C:41]=2[C:60]#[N:61])=[C:37]([CH3:66])[CH:36]=1.[CH3:67][N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1.[I-].[Na+]>COCCOC>[Cl:34][C:35]1[C:63]([O:64][CH3:65])=[CH:62][C:38]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][C:46]4[CH:53]=[C:52]([O:54][CH3:55])[C:51]([O:56][CH2:57][CH2:58][N:71]5[CH2:72][CH2:73][N:68]([CH3:67])[CH2:69][CH2:70]5)=[CH:50][C:47]=4[CH:48]=3)[N:43]=[CH:42][C:41]=2[C:60]#[N:61])=[C:37]([CH3:66])[CH:36]=1.[Cl:1][C:2]1[C:30]([O:31][CH3:32])=[CH:29][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]4[CH:20]=[C:19]([O:21][CH2:22][CH2:67][N:68]5[CH2:73][CH2:72][N:71]([CH3:35])[CH2:70][CH2:69]5)[C:18]([O:25][CH3:26])=[CH:17][C:14]=4[CH:15]=3)[N:10]=[CH:9][C:8]=2[C:27]#[N:28])=[C:4]([CH3:33])[CH:3]=1
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(C)cc1Cl
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OCCCl)cc4cc23)c(C)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OCCN5CCN(C)CC5)cc4cc23)c(C)cc1Cl
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCN5CCN(C)CC5)c(OC)cc4cc23)c(C)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of 205 mg (0.425 mmol) of 4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture), 0.15mL (1.35 mmol) of 1-methyl piperazine and 0.05 g of sodium iodide in 5 mL of ethylene glycol dimethyl ether is heated at 90° C. for 4 days under nitrogen. The mixture is cooled, the solvent is removed in vacuo and the resulting residue is stirred with saturated solution of sodium bicarbonate. The crude solid is collected by filtration, washed with water, and dried in vacuo. Purification is carried out by silica gel chromatography, eluting with a gradient of 92:8 to 85:15 methylene chloride/methanol to yield 0.10 g of 4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 121-135° C. and 0.068 g of 4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-methyl-1-piperazinyl)ethoxy]benzo-[g]quinoline-3-carbonitrile as a yellow solid, mp 122-137° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCN=[N+]=[N-]
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCN=[N+]=[N-]
Reaction time: 1 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-hydroxypyrrolidine (20.0 g) and triethylamine (15.2 ml) in dichloromethane (300 ml) was added methanesulfonyl chloride (7.8 ml) under ice-cooling. After stirring for 1 hour, water was poured into the mixture. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layer was washed with 1N hydrochloric acid, sat. sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give (2R,4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-methanesulfonyloxypyrrolidine (15.3 g).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3=[CH:17][C:18]4[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=4[CH:24]=[C:15]3[N:14]([CH3:29])[C:13]3[CH:30]=[CH:31][C:32]([C:34]#[N:35])=[CH:33][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CN(C=O)C.C1COCC1.O>[C:34]([C:32]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]3[C:16]([C:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:36])=[O:2])=[CH:9][CH:8]=4)=[N:11][C:12]=2[CH:33]=1)=[CH:17][C:18]1[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:25])([CH3:26])[C:23]=1[CH:24]=3)#[N:35]
Reactant: COC(=O)c1ccc(C2=Nc3cc(C#N)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CN1c2ccc(C#N)cc2N=C(c2ccc(C(=O)O)cc2)c2cc3c(cc21)C(C)(C)CCC3(C)C
Reaction time: 24 h

Procedure:
To a solution of 4-(2-cyano-5,7,7,10,10-pentamethyl-7,8,9,10-tetrahydro-5H-5,13-diazabenzo[4,5]cyclohepta[1,2-b]naphthalen-12-yl)benzoic acid methyl ester (33) (R4=CH3, Z=H, 12.3 mmol) in DMF (15 mL) and THF (45 mL) is added 2 N NaOH (18.5 mmol) at room temperature. The reaction mixture is stirred at the same temperature for 1 day. The mixture is acidified by 1 N HCl (30 mL), diluted with H2O, and extracted with EtOAc. The organic layer is dried over MgSO4 and evaporated in vacuo. The resulting solid is washed with hexane and Et2O to give (34) (R4=CH3, Z=H): 1H-NMR (CDCl3) δ: 1.08 (3H, s), 1.15 (3H, s), 1.28 (3H, s), 1.32 (3H, s), 1.61-1.72 (4H, m), 3.28 (3H, s), 6.90 (1H, s), 6.63 (1H, s), 6.99 (1H, d), 7.41 (1H, dd), 7.57 (1H, d), 7.90 (2H, d), 8.17 (2H, d).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:13][CH:14]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[C:22]1([S:28]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:13][CH:14]=2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCCc1ccc(N)cn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCc1ccc(NS(=O)(=O)c2ccccc2)cn1
Reaction time: 4 h
Yield: 52.6 %

Procedure:
Triethylamine (1 ml) in chloroform (10 ml) was added over 10 minutes to a solution of methyl 4-(5-aminopyrid-2-yl)-butanoate (1.5 g, 8.3 mmole) and benzene sulphonyl chloride (2.2 g, 12 mmole) in chloroform (20 ml). The solution was stirred for 4 hours. Chromatography on silica gel eluted with 5% v/v methanol in chloroform gave the title compound (1.46 g) as a straw coloured oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-:6].[Na+].Cl[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[OH:16]>CN(C=O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([OH:16])=[CH:9][C:14]=1[O:6][CH2:13][CH2:14][CH2:9][CH2:10][CH2:11][CH2:12][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: [OH-]
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(Cl)c(OCCCCCCn2ccnc2)c1
Reaction time: 1 h

Procedure:
Add imidazole (25 g) and NaOH (15 g) to DMF (250ml) and Stir for 1 hour. Add the product of part (a) (8.65 g) and stir overnight. Evaporate the solvent, partition the resultant residue with water/dichloromethane (adjust aqueous layer to pH 7 with potassium phosphate), separate organic layer and evaporate solvent. Purify the resultant residue on a silica column to obtain the title compound, MS: m/z 295 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][P:28](=[O:35])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31]>C(N(CC)CC)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][P:28](=[O:35])([O:29][CH2:30][CH3:31])[O:32][CH2:33][CH3:34])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCOCCOCCOCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12)OCC
Temperature: 70 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of commercially available 2,4-dichloro-3-nitroquinoline (1 equiv.) in triethyl amine (0.30 M) was added commercially available diethyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)phosphonate (1.3 equiv.) (provided by PHARMARON). The resulting reaction mixture was stirred at 70° C. for 2 h. At this point the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (63%) as a solid.
Reaction SMILES: O[C:2]1([CH3:16])[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[N:3]1[CH3:15].[H][H]>[Pd].CC(O)=O>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4](=[O:14])[N:3]([CH3:15])[CH:2]2[CH3:16]
Reactant: [H][H]
Reactant: CN1C(=O)c2c([N+](=O)[O-])cccc2C1(C)O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1c2cccc(N)c2C(=O)N1C
Yield: 50.4 %

Procedure:
A mixture of 3-hydroxy-2,3-dimethyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 1578, 500 mg), AcOH (12 mL), and 5% Pd/C (60 mg) was hydrogenated for 14 h under 1 atm hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated, residue was purified by column chromatography to afford 200 mg of the title compound (yield: 50%). 1H NMR (CDCl3, 300 MHz): δ=1.43 (d, J=6.8 Hz, 3 H), 3.04 (s, 3 H), 4.33 (q, J=6.3 Hz, 1 H), 5.20 (s, br, 2 H), 6.55 (d, J=8.1 Hz, 1 H), 7.21-7.26 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][CH:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:21][Si](C=[N+:26]=[N-:27])(C)C>C1(C)C=CC=CC=1>[NH:26]([C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18])[NH2:27].[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:16]([O:18][CH3:21])=[O:17])[CH2:10]1
Reactant: CON=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CON=C1C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1

Procedure:
A solution was made containing, e.g., (4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid (Intermediate 2, 17.81 mmoles; 4.6 gr) in a 1:1 mixture of methanol and toluene (250 mL). Trimethylsilyl diazomethane (32.5 mL of a 2M solution in hexanes, 59 mmol) was then added dropwise to the sirred solution at room temperature under nitrogen. After completion of the evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo, and the residue re-dissolved in DCM and washed with NH4Clsat and 10% NaHCO3, and brine, dried over Na2SO4 and evaporated in vacuo, giving the desired compound, 1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate, as a yellow oil (4.0 g, 83%).
Reaction SMILES: [C:1]([N:11]1[CH2:19][C@@H:18]([OH:20])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>N1C=CC=CC=1>[C:1]([N:11]1[CH2:19][C@@H:18]([O:20][S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1

Procedure:
Following the procedure of Example 19(b), the methyl ester product from part (b) is treated with 12.4 g. of tosyl chloride in 45 ml. of pyridine to give 13.2 g. of cream-colored product; m.p. 114°-117° (s. 105°). 13 g. of this material are recrystallized from 70 ml. of ethanol to 8.4 g. of colorless cis-N-carbobenzyloxy-4-tosyloxy-L-proline, methyl ester; m.p. 133°-135°; [α]D25 -26° (c=1%, chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[CH:14]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[C:28]1=[O:37])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:29]2([OH:36])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:28]2=[O:37])=[C:4]([OH:8])[CH:3]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1cccc(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(Br)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a stirred solution of 3-bromophenol (11.9 g, 69.2 mmol) in dichloromethane (160.0 mL) at 0° C. was added isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 38.0 mL, 76.1 mmol). The solution was stirred at 0° C. for 30 min, then 1-benzhydrylindoline-2,3-dione (10.0 g, 34.6 mmol) was added. The reaction was stirred at ambient temperature for 16 h, then concentrated in vacuo to dryness. The residue obtained was dissolved in ethyl acetate (400.0 mL) and washed with saturated ammonium chloride solution (3×100.0 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. Purification by flash chromatography with 30% ethyl acetate in hexanes afforded 3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (11.7 g, 70%) as a beige solid: 1H NMR (300 MHz, CDCl3) δ 9.09 (br s, 1H), 7.47-7.16 (m, 11H), 7.12-7.00 (m, 3H), 6.92-6.84 (m, 2H), 6.72-6.66 (m, 1H), 6.51-6.45 (m, 1H), 4.57 (br s, 1H); MS (ES+) m/z 484.2 (M+1), 486.2 (M+1).
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH2:18][C:19]3[N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:21](=[O:41])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:25]([C:35]3[S:36][CH:37]=[C:38]([CH3:40])[N:39]=3)=[CH:24][CH:23]=4)C3C(=CC=CC=3)C=2C=CC=1.N1CCCC1.O>CN(C)C=O>[NH2:17][CH2:18][C:19]1[N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:21](=[O:41])[C:22]2[C:27]([C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:26][C:25]([C:35]1[S:36][CH:37]=[C:38]([CH3:40])[N:39]=1)=[CH:24][CH:23]=2
Reactant: Cc1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OCC4c5ccccc5-c5ccccc54)c(-c4ccccc4)c3c2)n1
Solvent: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(-c2ccc3c(=O)n(CC(C)C)c(CN)c(-c4ccccc4)c3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 9H-fluoren-9-ylmethyl[2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.38 g, 0.6 mmol) in N,N-dimethylformamide (10 ml) was added pyrrolidine (0.5 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The residue was purified by silica gel column chromatography to give 3-(aminomethyl)-2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-4-phenyl-1(2H)-isoquinolinone (0.13 g, 54.2%) as crystals.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:12]=3[N:13]=2)[CH2:3]1.CO.Cl.O1CCOCC1>C(Cl)Cl>[NH3:7].[N:13]1[C:12]2[CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=[N:9][C:8]=1[NH:7][C@H:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCc2cnc(N[C@H]3CC[C@H](O)C3)nc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: N
Product: O[C@H]1CC[C@H](Nc2ncc3c(n2)CNCC3)C1
Reaction time: 18 h
Yield: 165.9 %

Procedure:
To a solution of 166 (10.85 g, 21.09 mmol), DCM (100 mL) and MeOH (10 mL) was added HCl/dioxane (26.36 mL, 105.4 mmol, 4N solution in dioxane) and the reaction was stirred for 18 h. The solution was concentrated to afford a red oil. To the residue was added DCM/methanolic NH3 (100 mL, 9:1, 7N) and the mixture sonicated for 5 min. The filtrate was concentrated to afford a thick red oil. The crude product was purified by SiO2 chromatography (Biotage 40 M) eluting with DCM/7N methanolic:NH3 (4:1 then 9:1 solution) to afford 4.1 g (80%) of (1S,3S)-3-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-ylamino)cyclopentanol (168) as a light brown oil: MS m/z (APCI-pos) M+1=235.2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Br:12][C:13]1[N:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[CH:14]=1.N1C=CC=CC=1.O>C(Cl)Cl>[Br:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])=[C:15]([CH3:20])[CH:14]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc(Br)ncc1N
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)ncc1NC(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a (0° C.) cooled and stirred solution of 2,6-difluorobenzoyl chloride (357 μL, 2.83 mmol) in DCM (5 mL) was added 6-bromo-4-methylpyridin-3-amine (583 mg, 3.12 mmol) followed by the addition of pyridine (344 μL, 4.25 mmol). The resulting mixture was then stirred at room temperature overnight. Water (5 mL) was added to the above mixture and then extracted with DCM (3×10 mL). The combined organic layers were washed with 10% aq.HCl (10 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 650 mg (70%) of the title compound as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H, D2O exchangeable), 8.41 (s, 1H), 7.66 (s, 1H), 7.65-7.58 (m, 1H), 7.27 (t, J=7.0 Hz, 2H), 2.27 (m, 3H); (ESI-MS (m/z) 327, 329 [(MH)+, Br79, 81].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: CCCc1c(O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1c(OC(=O)OCC)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Yield: 79 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran (1.2 gm, 3.87 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 1.2 gm (79%) of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-ethoxycarbonyloxybenzofuran, mp. 51°-53° C.