Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.BrC1C=C(OC)C=CC=1.[Mg].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: Brc1ccccn1
Agent: COc1cccc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccccn2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
That is, as shown in the reaction scheme below, (3-methoxyphenyl)magnesium bromide was synthesized from 22.4 g (120 mmol) of 3-bromoanisole with 3.4 g of magnesium in dry tetrahydrofuran (THF) in an argon stream by a conventional manner. This was slowly added to a dry THF solution of 15.8 g (100 mmol) of 2-bromopyridine and 1.8 g of (1,2-bis(diphenylphosphino)-ethane)dichloronickel (II) (Ni(dppe)Cl2) and the mixture was stirred at 50° C. for 1 hour. After adding 250 ml of 5% hydrochloric acid aqueous solution to the reaction mixture, the reaction mixture was extracted with chloroform to obtain a target substance and the organic layer was distilled under reduced pressure. 17.4 g (93.9 mmol) of 2-(3-methoxyphenyl)pyridine (3-MeO-PPy) was obtained as a colorless transparent liquid. Identification was performed by CHN elementary analysis and 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:15]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 2-chloro-5-(chlorosulfonyl)benzoic acid (0.51 g, 2.0 mmol) was added dichloromethane (10 mL), oxalyl chloride (1.5 mL) and one small drop of N,N-dimethylformamide. The mixture was stirred at room temperature for 3 days. The mixture was then concentrated until oxalyl chloride was gone to give 2-chloro-5-(chlorosulfonyl)benzoyl chloride. The residue was used without purification.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[C:18]([N+:28]([O-:30])=[O:29])=[C:19]2[O:27][CH2:26][CH2:25][N:20]2[C:21](=[O:24])[C:22]=1[CH3:23].C(OC(=O)C)C>C(Cl)Cl.CCCCCC>[CH3:23][C:22]1[C:21](=[O:24])[N:20]2[CH2:25][CH2:26][O:27][C:19]2=[C:18]([N+:28]([O-:30])=[O:29])[C:17]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2]
Reactant: Cc1c(O)c([N+](=O)[O-])c2n(c1=O)CCO2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.8 %

Procedure:
Triflic anhydride (2.78 g, 9.9 mmol) was added dropwise to a stirred solution of 7-hydroxy-6-methyl-8-nitro-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (1.5 g, 7.0 mmol) and TEA (1.42 g, 14.060 mmol) in DCM (30 mL) at −78° C. over a period of 1 hour. The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was partitioned between DCM and water. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 0.5 g of the product (20.6% yield).
Reaction SMILES: [O:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][CH:4]=1)C.O>II>[OH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Agent: II
Solvent: O
Product: O=C(O)CCC(=O)c1ccc(O)cc1
Temperature: 140 °C
Yield: 87.8 %

Procedure:
The methoxy derivative, Compound 3.2 (14.54 g, 70 mmol), was dissolved in iodine free hydriodic acid (150 mL) and refluxed at 140° C. for four hours. After the resulting brown solution was cooled to room temperature, water was added and the mixture was neutralized. The aqueous phase was then washed with ether; the organic layers were combined, decolorized, dried and evaporated. The remaining residue was purified by flash silica chromatography to yield a white solid (11.93 g, 88%). 1 H NMR (CDCl3) δ8.20 (d, 2H), 7.02 (d, 2H), 3.32 (t, 2H), 2.88 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2C(=O)C3=CC=CC=C3C2=O)[CH:6]=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[CH:6]=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1-c1ccccc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(CN)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 31 h
Yield: 100.7 %

Procedure:
To a solution of N-(2-methoxybiphenyl-4-ylmethyl)-phthalimide (0.414 g) in chloroform (5.0 mL) was added dropwise a mixture of hydrazinemonohydrate (0.241 g) and ethanol (1.0 mL), and the resulting mixture was stirred at room temperature for 31 hours. The insoluble material was filtered out, and the filtrate was partitioned between dichloromethane (40 mL) and water (15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.259 g).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:8]=1[NH:25][C:26]([C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([O:37][CH3:38])=[C:32]([O:39][CH3:40])[C:31]=2[O:41][CH3:42])=[O:27])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH2:18]([O:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH2:6][CH2:5][OH:4])=[C:8]([NH:25][C:26]([C:28]2[NH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:37][CH3:38])=[C:32]([O:39][CH3:40])[C:31]=3[O:41][CH3:42])=[O:27])[CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCOC(C)=O)[nH]c2c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCO)[nH]c2c(OC)c1OC
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl acetate (0.10 g, 0.18 mmol) in MeOH (2 mL) was added potassium carbonate (29.15 mg, 0.21 mmol) at room temperature and stirred overnight. The reaction mixture was diluted with AcOEt (50 mL) and washed with H2O (10 mL), saturated aqueous NaCl (20 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield as a yellow oil 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethanol (82 mg, 87%); 1H NMR (CDCl3, 500 MHz) δ 9.96 (s, 1H), 9.25 (s, 1H), 8.39 (d, 8.0, 1H), 7.85 (d, 8.5, 1H), 7.75 (s, 1H), 7.71 (dd, 3.5, 5.8, 1H), 7.57 (d, 7.5, 2H), 7.53 (m, 1H), 7.43 (t, 7.5, 2H), 7.36 (t, 7.0, 1H), 7.06 (s, 1H), 6.84 (s, 1H), 5.30 (s, 2H), 4.21 (t, 6.0, 2H), 4.08 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 3.37 (t, 5.0, 2H); EIMS m/z 527 (M+H+); IR (neat) νmax 3272, 2932, 1726, 1644, 1594, 1540, 1505, 1464, 1409, 1370, 1263, 1236, 1127, 1103, 1049, 997, 831, 760, 701 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Br[C:12]1[CH:13]=[C:14]([C:31]([NH2:33])=[O:32])[C:15]2[NH:16][C:17]3[CH:18]=[C:19]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=[CH:21][C:22]=3[C:23]=2[N:24]=1>>[Cl:1][C:2]1[CH:9]=[C:8]([C:12]2[CH:13]=[C:14]([C:31]([NH2:33])=[O:32])[C:15]3[NH:16][C:17]4[CH:18]=[C:19]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:20]=[CH:21][C:22]=4[C:23]=3[N:24]=2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Product: NC(=O)c1cc(-c2ccc(CN3CCOCC3)c(Cl)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12

Procedure:
This was similarly prepared from 2-chloro-4-bromobenzaldehyde and 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide. MS (ESI) m/z 506.35 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.30 (1H, s), 8.54 (1H, s), 8.31-8.37 (2H, m), 8.24 (1H, dd, J=8.09, 1.68 Hz), 8.08 (1H, d, J=8.85 Hz), 7.84 (1H, s), 7.64 (1H, d, J=8.24 Hz), 7.23 (1H, d, J=2.14 Hz), 7.02 (1H, dd, J=8.85, 2.14 Hz), 3.78-3.87 (4H, m), 3.65 (2H, s), 3.60-3.64 (4H, m), 3.22-3.27 (4H, m), 2.45-2.50 (4H, m).
Reaction SMILES: C(O)C.Cl.[Sn].Br[C:7]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[OH:18]>C1C=CC=CC=1.C(OCC)(=O)C>[Br:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH:7]=[C:8]([OH:18])[CH:9]=[CH:10]2
Reactant: Oc1ccc2cc(Br)ccc2c1Br
Agent: Cl
Agent: [Sn]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: c1ccccc1
Product: Oc1ccc2cc(Br)ccc2c1
Yield: 103.1 %

Procedure:
To a solution of 225 mL of ethanol and 90 mL of conc. HCl in a 500 mL round bottom flask were added of tin metal (32.6 g, 274 mmol) and 1,6-dibromo-2-naphthol (41.5 g, 137 mmol). The reaction mixture was refluxed on a steam bath for 9 hours. TLC (SiO2, 15:1 benzene/ethyl acetate) indicated consumption of starting material. The cooled solution was decanted from unreacted tin, concentrated to 150-200 mL on vacuo and poured into 600 mL of ice and water. The white precipitate was collected on a Buchner funnel and dried in the air to afford 31.5 g of an off-white solid. Recrystallization from benzene produced 23.8 g of pure product (78%): mp 27°-127.5° C.; lit. mp 127°-129° C.; reference: C. R. Koelsch, Org. Syn. Coll. Vol. 3, 132 (1955). ##STR25##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[N+:11]([O-:14])([OH:13])=[O:12].[NH2:15][NH:16][C:17]([NH:19][NH2:20])=[NH:18].[N+]([O-])(O)=O>C(O)C.O>[N+:11]([O-:14])([OH:13])=[O:12].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[N:15][NH:16][C:17]([NH:19][N:20]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)=[NH:18]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: N=C(NN)NN
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CCO
Product: N=C(NN=Cc1ccc(Cl)c(Cl)c1)NN=Cc1ccc(Cl)c(Cl)c1

Procedure:
A boiling solution of 17.6 grams of 3,4-dichlorobenzaldehyde in 250 milliliters of ethanol is stirred vigorously as a solution of 6.1 grams of 1,3-diaminoguanidine nitrate and 0.5 milliliters of concentrated nitric acid in 50 milliliters of water is added in one portion. The reaction mixture is stirred as the temperature recedes to room temperature. The reaction mixture is then allowed to stand for several hours. The precipitate which forms is collected, washed with hot ethanol, air dried and finally dried at 60°C. under reduced pressure. The yield is 17.5 grams of product and the melting point is 195°-196°C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]([NH2:13])=[NH:12]>O>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][C:11]([NH2:13])=[NH:10])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: N=C(N)N
Solvent: O
Product: N=C(N)Nc1cc(Cl)nc(N)n1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
A mixture of 12.0 g (0.0732 m) of 2-amino-4,6-dichloropyrimidine and 55.0 g (0.931 mole) of guanidine was heated at 80° for 1.5 hours. The mixture was cooled to room temperature and diluted with water; the white crystalline precipitate was filtered, washed with water then air dried giving 7.22 g (53%) of 2-amino-6-chloro-4-guanidinopyrimidine, mp 220° (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:12]=[C:11]([C:13]3[O:21][C:20]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[CH:14]=3)[O:10][N:9]=2)[CH2:3][CH2:2]1.Cl[C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1.CC(O)=O>CS(C)=O>[O:21]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[CH:14]=[C:13]1[C:11]1[O:10][N:9]=[C:8]([CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=3)[CH2:2][CH2:3]2)[N:12]=1
Reactant: c1cc2oc(-c3nc(CC4CCNCC4)no3)cc2cn1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(Cc3noc(-c4cc5cnccc5o4)n3)CC2)nc1
Temperature: 25 °C

Procedure:
2-(3-Piperidin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)furo[3,2-c]pyridine (Preparation 12, 50 mg, 0.176 mmol), ethyl 6-chloronicotinate (49 mg, 0.264 mmol) and DBU (40 mg, 0.264 mmol) were shaken in DMSO (1 mL) at 100° C. for 20 h. The reaction mixture was allowed to cool to room temperature, before being acidified with AcOH. Purification by RP-HPLC yielded the title compound: RT=5.74 min; m/z (ES+)=434.4 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1)[CH2:5][CH3:6].[OH-].[K+]>CO.O>[Cl:1][CH2:2][CH2:3][N:4]([C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1)[CH2:5][CH3:6]
Reactant: CCN(CCCl)c1cccc(NC(=O)c2ccc(C(=O)[O-])cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CCCl)c1cccc(NC(=O)c2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
A suspension of (XIV; R=Z=H) (2.88 g, 8 mmol) in MeOH (100 mL) containing KOH (5.6 g) was stirred at 25° C. until homogeneous, andthen for a further 5 h. The mixture was diluted with water, filtered, and acidified with AcOH to give 4-[3-(N-(2-chloroethyl)-N-ethylamino) phenyl]carbamoylbenzenecarboxylic acid (XV; R=Z=H) (2.08 g, 75%), mp (EtOAc) 203° C. (dec.). 1H NMR (CD3SOCD3) 13.3 (br s, 1 H, COOH), 10.21 (s, 1 H, CONH), 8.05 (q, J=8.50, 4 H, H-2',3',5'6'), 7.16 (m, 3 H, H-2,4,6 ), 6.48 (m, 1 H, H-5), 3.72 (t, J=7.1Hz, 2 H, NCH2CH2Cl), 3.60 (t, J=7.1 Hz, 2 H, CH2Cl), 3.40(g, J=7.0 Hz, NCH2CH3)-, 1.12 (t, J=7.0 Hz, 3 H, CH3). Anal. (C18H19ClN2O3) C,H,N,Cl.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:32])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][C:10]=2[O:24]CC2C=CC=CC=2)=[CH:3][CH:2]=1.CN1CCN(C)C1=O.[H][H]>[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:32])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:11][C:10]=2[OH:24])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CCO
Solvent: CN1CCN(C)C1=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)c(O)c1
Yield: 69.1 %

Procedure:
N-(4-Pyridyl)-2benzyloxy-4-tert-butoxycarbonylaminomethylbenzamide (3.38 g) was subjected to catalytic reduction using 10% palladium hydroxide carbon (1 g) in a solution of ethanol (10 ml) and dimethylimidazolidinone (70 ml) in a stream of hydrogen. After the reaction, the catalyst was removed by filtration, and the mixture was concentrated under reduced pressure to give 1.85 g of N-(4-pyridyl)-4-tert-butoxycarbonylaminomethyl-2-hydroxybenzamide.
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[C@@H:8]3[C@@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3.[OH-].[Na+]>C1COCC1>[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[C@@H:8]3[C@@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=1)[N:12]([CH3:1])[C:11](=[O:16])[CH2:10][CH2:9]3
Reactant: O=C1CC[C@@H]2c3ccc(Cl)cc3CC[C@H]2N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@@H]2c3ccc(Cl)cc3CC[C@H]21
Yield: 142.9 %

Procedure:
To a 1-liter flask equipped with a condenser and a stirrer were added 470 mL of THF, 18.7 g of methyl iodide and 47 g of (4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one, and stirring was begun at ambient temperature. To the mixture was added 100 ml of 50% aqueous sodium hydroxide in one portion, and gentle heating was begun. The temperature was raised as high as 41° and was then gradually lowered to 29° at the end of 16 hours of stirring. HPLC liquid chromatography, eluting with 1:1 acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220 nanometers, then showed that all the starting material had been consumed and the aqueous layer was removed. The organic layer was concentrated to an oil under vacuum, and the residue was dissolved in ethyl acetate. The solution was washed with brine, and the organic layer was washed with 200 mL of water twice, and was dried over magnesium sulfate and evaporated under vacuum while heptane was added portionwise as the ethyl acetate was removed. A total of 500 mL of heptane was added, and the product began to crystallize when about half of it had been added. The slurry was concentrated to about 300 ml, and filtered, and the solids were washed with heptane and dried in vacuum at 40°-50° to obtain 47.03 g of product, m.p. 97°-99°, of 98.7% purity.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:7]([Cl:21])[CH:6]=1)C.[H-]>ClCCl>[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][OH:3])[CH:6]=[C:7]([Cl:21])[C:8]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
To a solution of 3,5-dichloro-4-(4-methoxy-phenoxy)-benzoic acid ethyl ester (1.36 g, 4.01 mmol) in dichloromethane (35 ml) at 0° C. was added diisobutylaluminun hydride (1M in toluene, 12 ml, 12 mmol) and the mixture was stirred for 2.5 hours at 0° C. The reaction mixture was quenched with potassium sodium tartrate tetrahydrate (0.5 M aqueous solution, 50 ml), stirred for 20 minutes at room temperature and then was filtered through diatomaceous earth. The filtrate was concentrated and then taken up in water (60 ml). The aqueous solution was extracted with ethyl acetate (4×60 ml). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (2% ethyl acetate in dichloromethane) to afford the title compound (871 mg). NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 6.74-6.82 (m, 4H), 4.69 (d, 2H), 3.76 (s, 3H), 1.83 (t, 1H).
Reaction SMILES: Cl.CN[O:4]C.C(N(CC)CC)C.[CH2:13]([N:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([N:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:4])=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (7.37 g; 75.6 mmoles) and triethylamine (21.8 ml; 151 mmoles) in methylene chloride (150 ml), another solution of 4-(dibenzylsulfamoyl)benzoyl chloride (25 g) in methylene chloride (150 ml) was slowly added and the resulting mixture stirred at room temperature for 16 hours. The solid was filtered off, the solvent removed under reduced pressure and the residual oil purified by column chromatography with silica gel and n-hexane-ethyl acetate 1:1 as eluent. N,O-dimethylamide of 4-(dibenzylsulfamoyl)benzoic acid (22 g) was obtained, m.p. 75° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=3)[C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1.[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][N:41]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:43]4[CH:42]=[N:41][C:40]([O:39][CH3:38])=[N:45][CH:44]=4)=[CH:31][CH:30]=3)[C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1
Product: COc1ncc(-c2ccc(Cn3c(C4CCCCC4C(=O)O)nc4cc(OCc5nc6ccccc6s5)ccc43)cc2)cn1

Procedure:
The title compound was prepared using analogous conditions described in Step A of Example 97 using racemic cis-2-(5-(benzo[d]thiazol-2-ylmethoxy)-1-(4-bromobenzyl)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid and (2-methoxypyrimidin-5-yl)boronic acid. MS (ESI): mass calcd. for C34H31N5O4S, 605.72; m/z found, 606.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.77-8.72 (s, 2H), 8.01-7.91 (m, 2H), 7.60-7.53 (d, J=8.3, 2H), 7.53-7.48 (m, 1H), 7.45-7.39 (ddd, J=8.2, 7.2, 1.2, 1H), 7.36-7.30 (d, J=2.4, 1H), 7.28-7.23 (d, J=8.3, 2H), 7.23-7.19 (d, J=8.9, 1H), 7.02-6.95 (dd, J=8.8, 2.4, 1H), 5.62-5.47 (m, 4H), 4.03-4.00 (s, 3H), 3.64-3.57 (m, 1H), 2.90-2.81 (dt, J=7.3, 4.1, 1H), 2.45-2.31 (qd, J=7.6, 3.6, 1H), 2.08-2.02 (m, 1H), 1.93-1.81 (m, 2H), 1.81-1.71 (m, 2H), 1.51-1.41 (d, J=14.1, 2H).
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[Cl:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[Cl:25][C:26]1[O:30][C:29]([CH:31]2[C:5]3=[C:6]4[N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10](=[O:19])[C:11]4=[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:4]3[CH2:3][C:2]([CH3:24])([CH3:23])[O:1]2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CC(C)(C)O)cc2n(C)c1=O
Solvent: Cc1ccccc1
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)OC(C)(C)C3

Procedure:
The title compound was prepared from 6-(2-hydroxy-2-methylpropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and commercially available 5-chlorofuran-2-carbaldehyde in toluene analogously to Example 12, step 2;
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[NH2:9][CH2:10][CH2:11][CH2:12][NH2:13]>O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][NH:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: NCCCN
Solvent: O
Product: NCCCNCCc1ccncc1

Procedure:
A mixture of 4-vinylpyridine (10.8 cm3), 1,3-diaminopropane (25 cm3) and "Triton B" (Trade Mark) (5 g; 40% solution in water) was stirred and heated at 130° for 20 hours. Water (100 cm3) was added and the mixture was extracted with chloroform (3×100 cm3). The dried (MgSO4) extracts were evaporated in vacuo to give an oil which was distilled to give 5.4 g of N-[2-(4-pyridyl)ethyl]-1,3-diaminopropane as an oil, b.p. 150°/0.03 mm. (Kugelrohr).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@H](CO)Cc1ccccc1
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](CO)Cc1ccccc1
Yield: 35 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with L-phenylalaninol to provide the title compound in 35% yield as yellow needles (recrystallization from acetone/CHCl3).