Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.O>CN(C)C=O>[N:3]1([C:8]2[N:9]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2[nH]c(N3CCCC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (402 mg, 11 mmol) was added to a suspension of 2-pyrrolidino-1H-benzimidazole (1.9 g, 10.1 mmol) in dry N,N-dimethylformamide (30 mL). All solids dissolved. The solution was allowed to stir at ambient temperature for 15 minutes following the cessation of foaming. The solution was cooled to 5° C. and a solid formed. Methyl 4-(bromomethyl)benzoate (2.1 g, 01 mol) was added to the suspension and all the solids dissolved. The solution was allowed to stir at ambient temperature and a solid formed. The mixture was stirred at ambient temperature overnight and then it was poured into cold water. A solid was isolated by filtration, washed with water and dried to provide 3.0 g of crude product as an off-white solid. This material was recrystallized from methanol to provide methyl 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoate. Analysis: Calculated for C20H21N3O2: %C, 71.62; %H, 6.31; %N, 12.53; Found: %C, 71.44; %H, 6.41; %N, 12.50.
Reaction SMILES: [CH2:1]=O.[CH3:3][C:4]([OH:13])([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]>O.C1C=CC=CC=1>[CH3:12][C:4]1([CH3:3])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][CH2:1][O:13]1
Reactant: C=O
Reactant: CC(C)(O)c1ccccc1N
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)OCNc2ccccc21
Reaction time: 0.08 h
Yield: 58.5 %

Procedure:
An 8.25-ml solution of 37% aqueous formaldehyde (0.099 mol) was added over 5 minutes to a cooled (0° C.) mixture of 10 g (0.066 mol) α,α-dimethyl-2-aminobenzyl alcohol in 50 ml water. The reaction mixture was then diluted with 50 ml benzene and vigorously stirred for 5 minutes. The aqueous layer was separated and extracted with benzene. The benzene layer of the reaction mixture and the benzene extracts were combined, dried over magnesium sulfate and evaporated. The resulting oil was distilled through a short column to give 6.3 g (b.p. 120° -125° C. at 0.1 mm of Hg) of 4,4-dimethyl-1,2-dihydro-4H-3,1-benzoxazine, as a colorless oil. Elemental analysis showed: %C, calc. 73.6, found 68.3: %H, calc. 8.0, found 7.6; %N, calc. 8.6, found 8.6.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:17]2[C:18]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)cc1
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
Into a 2-L three-neck flask were put 25 g (0.15 mol) of 4-bromoaniline, 25 g (0.15 mol) of 1-naphthaleneboronic acid, 450 mL of toluene, and 150 mL of ethanol. While the pressure was reduced, this mixture was degassed by being stirred. After the degassing, the atmosphere in a system was replaced with nitrogen. Into the solution was added 220 mL (2.0 mol/L) of a potassium carbonate solution. The obtained mixture was degassed by being stirred while the pressure was reduced, and then, the atmosphere in the system was replaced with nitrogen. To this mixture were added 0.48 g (2.1 mmol) of palladium(II) acetate and 2.4 g (7.9 mmol) of tris(2-methylphenyl)phosphine, and the obtained mixture was stirred under a nitrogen stream at 80° C. for three hours. After the stirring, this mixture was allowed to cool to room temperature, and an aqueous layer of this mixture was extracted three times with toluene. The extracted solution and an organic layer were combined and washed twice with water and washed twice with saturated saline. Into this mixture was added magnesium sulfate, and the mixture was dried for 18 hours. The obtained mixture was subjected to natural filtration to remove magnesium sulfate, and the filtrate was concentrated to obtain an orange liquid. This orange liquid was dissolved in toluene, and this solution was filtrated through Celite, alumina, and Florisil. The obtained filtrate was concentrated to give 33 g of an objective orange liquid in a yield of 99%.
Reaction SMILES: [F:1][CH:2](F)[CH:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:21]([F:24])([F:23])[F:22])[NH:4]1.FC(F)C1NC(C(F)(F)F)C(C(OC)=O)=C(CC(C)C)C=1C(OC)=O.C1CCN2C(=NCCC2)CC1>CCOCC>[F:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:21]([F:24])([F:22])[F:23])[N:4]=1
Reactant: COC(=O)C1=C(C(F)(F)F)NC(C(F)F)C(C(=O)OC)=C1CC(C)C
Agent: COC(=O)C1=C(C(F)F)NC(C(F)(F)F)C(C(=O)OC)=C1CC(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: COC(=O)c1c(CF)nc(C(F)(F)F)c(C(=O)OC)c1CC(C)C
Yield: 19 %

Procedure:
To a solution of 50.3 g (0.136 mole) of product of example 14 in 200 ml of DMF is added 21.3 g (0.563 mole) of sodium borohydride. The reaction mixture becomes exothermic and the temperature of the reaction mixture rises to 65° C. and subsides to 40° C. after 40 min. of stirring. To the reaction mixture is added 15 ml of water. The exothermic reaction mixture is cooled by an ice-water bath to 40° C. The cooling bath is removed and the reaction mixture is stirred for 20 min. before being poured into 1 L of water. The organic is extracted into 500 ml of methylene chloride. The methylene chloride extract is dried over magnesium sulfate and concentrated. The residual oil (44.5 g) is purified by HPLC using 5% ethyl acetate in cyclohexane as eluent. The first 2.8 L of eluate gives 7.6 g of an oil which contains 56% of the desired product, 22% of the starting material, and 22% of an unidentified material. The second 2.5 L of eluate gives 24.6 g of an oil which contains a mixture of dimethyl 2-(difluoromethyl)-1,2-dihydro-4-isobutyl-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (E) and dimethyl 6-(difluoromethyl)-1,2-dihydro-4-isobutyl-2-(trifluoromethyl)-3,5-pyridinedicarboxylate (F) and other unidentified products. This oil is crystallized from ether-hexane to give 7.4 g (15%) of a solid, mp 82°-85° C., which is a 4.6:1 mixture of above mentioned (E) and (F). The mother liquor is concentrated to an oil (15.6 g) which contains (E), (F), and other unidentified products. A solution of above oil, 9.0 g (0.0568 mole) of DBU and 100 ml of ether is stirred for 18 hours and washed with 100 ml of 3N hydrochloric acid. The ether solution is dried over magnesium sulfate and concentrated. The residual oil (14.5 g) is purified by HPLC using 5% ethyl acetate in cyclohexane as eluent. The first 2.0 L of eluate gives 8.8 g (19%) of the desired product as an oil, n25D 1.4567.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[N:15][C:16]2[CH:17]([S:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:18][CH2:19][CH2:20][C:21]=2[CH:22]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:12][C:13]1[CH:14]=[N:15][C:16]2[CH:17]([S:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:9])=[O:24])[CH2:18][CH2:19][CH2:20][C:21]=2[CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc2c(c1)CCCC2S(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc2c(c1)CCCC2S(=O)(=O)c1ccccc1

Procedure:
A solution of m-chloroperbenzoic acid (1.4g) in dichloromethane (25ml) was added to a stirred solution of 5,6,7,8-tetrahydro-3-methyl-8-phenylsulphinylquinoline (1.87g) and trifluoroacetic acid (1.2ml) in dichloromethane (25ml). After stirring at ambient temperature for 1h, the reaction mixture was washed with 2M sodium hydroxide, dried over magnesium sulphate and evaporated to a solid. After chromatography on silica eluting with ether the product was recrystallised from diisopropylether affording white crystals, mp 84°-86° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C(N(C(C)C)C(C)C)C.Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(OCC)C>[CH3:15][O:14][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:7][C:2]([NH:1][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(N)cc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCOC(=O)CCCNc1ccc(OC)c(-c2ccccc2)c1
Reaction time: 4 h

Procedure:
29.5 g of 5-amino-2-methoxybiphenyl, 19.2 g of ethyldiisopropylamine and 28.9 g of ethyl 4-bromobutyrate are heated together (while stirring) for 4 hours at 125°. After cooling, the resulting reaction product is stirred with diethyl ether and filtered from the precipitated salt. The residue (remaining after evaporating off the ether) is recrystallized from isopropyl alcohol to obtain 22.5 g (48.5% of theory) of ethyl 4-(6-methoxybiphenyl-3-yl)amiobutyrate, MP 71° to 72.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[N:19][CH:20]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1
Yield: 92.9 %

Procedure:
The title compound (0.39 g, 93%) was prepared as a white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.23 g, 1.13 mmol), 1,1-dimethylethyl 4-{[(5-bromo-2-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.35 g, 0.94 mmol), 2M Na2CO3 (5 mL) and Pd(PPh3)4 (10 mg, 0.01 mmol) in DME (5 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CD3OD): δ 8.46 (d, 1H, J=2.7 Hz), 8.05-8.00 (m, 3H), 7.86 (d, 2H, J=8.5 Hz), 6.92 (d, 1H, J=8.6 Hz), 4.21 (d, 2H, J=6.3 Hz), 4.15-4.05 (m, 2H), 3.14 (s, 3H), 2.85-2.70 (m, 2H), 2.00-1.95 (m, 1H), 1.90-1.75 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.BrCCCN1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2C1=O>>[CH2:31]([O:32][C:16]([NH:15][CH2:14][CH2:10][CH2:9][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:17])[C:30]1[CH:29]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2cccc(O)c2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cccc(OCCCNC(=O)OCc3ccccc3)c2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 31 using tert-butyl N-(3′-hydroxybiphenyl-3-ylmethyl)carbamate instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and N-(3-bromopropyl)phthalimide instead of N-(4-bromobutyl)phthalimide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=2)[C:14]#[N:15])=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=1>>[C:14]([C:13]1[CH:16]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:31]([C:29]3[NH:28][N:27]=[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH:30]=3)=[O:32])[N:5]=2)[CH:10]=[CH:11][C:12]=1[N+:17]([O-:19])=[O:18])#[N:15]
Reactant: O=C(O)c1cc(-c2ccccn2)n[nH]1
Reactant: N#Cc1cc(-c2ccn(CCN)n2)ccc1[N+](=O)[O-]
Product: N#Cc1cc(-c2ccn(CCNC(=O)c3cc(-c4ccccn4)n[nH]3)n2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (0.10 g) and 3-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid (0.077 g) using the method of Example 34(d). Yield 0.21 g. 1H-NMR (400 MHz; d6-DMSO): δ 3.75 (t, 2H), 4.41 (t, 2H), 7.09 (s, 1H), 7.24-7.39 (m, 2H), 7.82-7.91 (m, 3H), 8.37-8.70 (m, 5H), 13.84 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[C:49]2[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=2)[C:52]([OH:54])=[O:53])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:49]3[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=3)[C:52]([OH:54])=[O:53])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1ccn(Cc2cccc(C(=O)O)c2)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)O)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 760 mg, 2.30 mmol) was dissolved in methylene chloride (10 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (1.15 mL, 2.30 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (0.536 mL, 4.6 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid (500 mg, 2.30 mmol) was added as a pre-dissolved reaction in methylene chloride (10 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Recrystallization from 17% ethyl acetate/methylene chloride afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (684 mg, 56%) as a white powder: ESI-LRMS m/e calcd for C26H28ClN3O5S [M+] 529.14, found 530.26 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:9][CH2:10][C:11]([O-])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C)(C)C)=O>C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)[O-])C1CCCC1
Agent: CC(C)(C)OC=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N(CCCO)C1CCCC1

Procedure:
This compound was prepared from N-tert-butoxycarbonyl-3-cyclopentylamino-propanoate (3a, 2.28 g, 8.0 mmol) using the procedure described in Example 2b. Yield: 1.34 g (69%). ESI-MS: 244.2 (M+H)+, 266.3 (M+Na)+, 188.2 (M+H—C4H8)+, 144.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.30.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=S(=O)(O)Cl
Product: O=[N+]([O-])c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (3.0 g, 21.3 mmol) in chlorosulfonic acid (5.5 mL, 84 mmol) was stirred at 90-100° C. for 8 hours before being cooled to room temperature and slowly poured into ice water and extracted with EtOAc. The organic extract was washed with saturated aq. NaHCO3 and water, dried (sodium sulfate), and concentrated to give 2-fluoro-5-nitrobenzenesulfonyl chloride (3.2 g, 63%) as a colorless oil, which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1)[CH2:6][CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2].[CH2:33]([SH:36])[CH2:34][SH:35].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>CC(O)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1)[CH2:6][CH2:7][C:8]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)[S:36][CH2:33][CH2:34][S:35]1)[CH3:2]
Reactant: SCCS
Reactant: CCOC(=O)C(CCC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc(OC)nc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C(CCC1(CCCCc2ccc3c(n2)NCCC3)SCCS1)c1cnc(OC)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 3-3a (7.6 g, 17.4 mmol) and 1,2-ethanedithiol (17.5 mL, 208.6 mmol) in 25 mL AcOH was added BF3.OEt2 (17.5 mL, 138.1 mmol) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at 0 C for 0.5 hr, then at rt for 3.5 hr. The reaction mixture was slowly poured into ice-cooled 300 mL NaHCO3 (sat.) and extracted with diethyl ether (2×200 mL). The organic layers were combined and washed with brine and dried over Na2SO4. After removal of the solvent, the residue was purified by flash chromatography on silica gel (100% EtOAc) to afford the desired product 4-1a as an oil.
Reaction SMILES: CO[C:3](=[O:15])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[CH3:16][NH:17][CH2:18][CH2:19][NH:20][CH3:21]>>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([CH3:21])[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:3]1=[O:15]
Reactant: CNCCNC
Reactant: COC(=O)C(Br)c1cccc([N+](=O)[O-])c1
Product: CN1CCN(C)C(c2cccc([N+](=O)[O-])c2)C1=O

Procedure:
1,4-Dimethyl-3-(3-nitro-phenyl)-piperazin-2-one was prepared from bromo-(3-nitro-phenyl)-acetic acid methyl ester and N,N′-dimethyl-ethane-1,2-diamine in an analogous manner to Example 1072b. Product isolated as a clear-orange oil (959 mg, 98%). LCMS (m/e) 250 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 8.14 (d, 1H, J=8.2 Hz), 7.76 (d, 1H, J=7.6 Hz), 7.54-7.46 (m, 1H), 3.83 (s, 1H), 3.83-3.73 (m, 1H), 3.26-3.18 (m, 1H), 3.08-3.01 (m, 1H), 2.97 (s, 3H), 2.79-2.69 (m, 1H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][CH2:29][NH:30]3)=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:33].N1C=CC=CC=1>ClCCl>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][CH2:29][N:30]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:33]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Chlorobenzenesulphonyl chloride (71 mg, 0.3 mmol, 1.1 equiv.) was added to a mixture of crude 2-chloro-4-[(2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester (100 mg, 0.3 mmol, 1 equiv.) and pyridine (0.2 mL, 2.4 mmol, 8 equiv.) in dichloromethane (2 ml) and the mixture was stirred at room temperature for 16 hours. The solvent was removed under a stream of N2 and the residue purified by column chromatography (SiO2, dichloromethane). The fractions were combined to afford crude 2-chloro-4-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, 101 mg. This material was taken onto the next step without further purification. LC @215 nm; Rt 2.52: 84%, m/z (ES+): 505 (M+H+.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.[P:8]([OH:11])([OH:10])[OH:9].P(Cl)(Cl)Cl>CCCCCCCC>[CH2:3]([CH2:2][NH2:1])[CH2:4][C:5]([P:8]([OH:11])([OH:10])=[O:9])([P:8]([OH:11])([OH:10])=[O:9])[OH:7]
Reactant: NCCCC(=O)O
Reactant: OP(O)O
Solvent: CCCCCCCC
Solvent: ClP(Cl)Cl
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 92.5 °C
Yield: 43.1 %

Procedure:
4-Aminobutyric acid (50 gm), phosphorous acid (140 gm) and n-octane (1000 mL) was taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-95° C. Phosphorus trichloride (240 gm) was then added to the reaction mixture and allowed to heat at 90-95° C. The reaction mixture was cooled and distilled water (500 mL) was added to it. The reaction mixture was further heated to 90-95° C. It was then cooled and ethanol (1000 mL) was added to it. The solution was further cooled to 0-5° C. and stirred for 4-5 hrs. The precipitated solid was filtered and washed with ethanol and dried under vacuum to yield 52.0 gm product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([F:9])[CH:4]=1.[C:10]([O-:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].CCOCC>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([CH2:2][O:18][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: Fc1cc(CBr)ccn1
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(OCc1ccnc(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
The mixture of 4-Bromomethyl-2-fluoro-pyridine (35) (4.85 g, 25.5 mmol) and sodium benzoate (5.51 g, 38.25 mmol) in DMF (60 ml) was stirred at room temperature for 3 hr. Ether was then added and the mixture was washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexane (1:4)) to afford 4.68 g (79%) of a colorless oil; 1H NMR (200 MHz, CDCl3) δ: 5.41 (2H, s), 7.11 (1H, m), 7.45-7.66 (3H, m), 8.08-8.12 (2H, m), 8.23 (1H, d, J=5.4 Hz); m/z (EI): 231 (M+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9](C(=O)C(F)(F)F)[CH:10]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCO>C1COCC1>[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][NH:9][CH:10]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(OC)c2c1CCN(C(=O)C(F)(F)F)C2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1CCNC2c1ccccc1
Yield: 98.3 %

Procedure:
Sodium borohydride (900 mg) was added to a mixed solution of a solution of 5,8-dimethoxy-1-phenyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (4.21 g) in THF (30 mL), and EtOH (100 mL) at room temperature under stirring. The reaction mixture was stirred at room temperature for 3 hours and then stirred at 40° C. for 30 minutes, and concentrated under reduced pressure. To the resulting residue was added a 3 M aqueous HCl solution (30 mL), followed by refluxing for 5 minutes. After cooling, the mixture was made strong alkaline by using a 20% aqueous NaOH solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 5,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (3.05 g).