Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[O:20]1[CH2:21][CH2:22][NH:23][C:24]2[N:25]=[CH:26][C:17]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:31]=[CH:32][CH:33]=[CH:28][C:29]=4[S:34]([N:37]4[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]4)(=[O:36])=[O:35])=[CH:7][C:2]=3[F:1])=[CH:18][C:19]1=2
Reactant: NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Product: NC1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and 1-((2-bromophenyl)sulfonyl)piperidin-4-amine. MS (ESI): mass calcd. for C24H25FN4O3S, 468.16; m/z found, 469.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.09-8.05 (m, 1H), 7.83 (d, J=1.1, 1H), 7.75-7.68 (m, 2H), 7.66-7.55 (m, 2H), 7.43-7.39 (m, 1H), 7.34-7.26 (m, 2H), 4.39-4.35 (m, 2H), 3.76-3.68 (m, 2H), 3.47 (d, J=13.4, 2H), 3.21-3.11 (m, 1H), 2.60-2.50 (m, 2H), 1.96-1.87 (m, 2H), 1.56-1.43 (m, 2H).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[C:7]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][C:21](=[O:23])[CH3:22])[C:14]([NH2:16])=[O:15])(=[O:9])[CH3:8]>ClCCCl>[C:7]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][C:21](=[O:23])[CH3:22])[C:14]([N:16]=[C:2]=[O:3])=[O:15])(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccc(C(N)=O)cc1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: CC(=O)Oc1ccc(C(=O)N=C=O)cc1OC(C)=O

Procedure:
Oxalyl chloride (10.1 g) was added to a solution of 3,4-diacetoxybenzamide (7.5 g) in 1,2-dichloroethane (80 ml) with stirring under cooling. The mixture was gradually heated to a reflux temperature and allowed to react under reflux for 13 hours. After completion of the reaction, the solvent and excess oxalyl chloride was distilled off under reduced pressure to give 3,4-diacetoxybenzoyl isocyanate which was dissolved in anhydrous dichloromethane (40 ml) for the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=[C:6]2[C:5]([C:14]([OH:16])=O)=[CH:4][C:3]=1[Cl:17].NC1N2C=CN=C2C(C([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH2:33][CH2:32]2)=O)=CC=1Cl>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=[C:6]2[C:5]([C:14]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH2:33][CH2:32]2)=[O:16])=[CH:4][C:3]=1[Cl:17]
Reactant: CCCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Reactant: COCCCN1CCC(NC(=O)c2cc(Cl)c(N)n3ccnc23)CC1
Product: CCCc1cn2c(N)c(Cl)cc(C(=O)NC3CCN(CCCOC)CC3)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 3 in EXAMPLE 5 using 5-amino-6-chloro-2-propylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 16, Step 2) and 1-[3-(methyloxy)propyl]-4-piperidinamine (EXAMPLE 3).
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:34]=[CH:33][C:28]([C:29](OC)=O)=[CH:27][CH:26]=1.[H-].[Na+]>CN(C=O)C>[OH:15][CH2:14][C@H:9]1[C@H:8]([C:7]2[C:6]([O:16][CH3:17])=[CH:5][C:4]([O:18][CH3:19])=[C:3]3[C:2]=2[O:1][C:29]([C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:35])[F:36])=[CH:34][CH:33]=2)=[CH:21][C:20]3=[O:22])[CH2:12][CH2:11][N:10]1[CH3:13]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(C(F)(F)F)cc3)oc2c1[C@@H]1CCN(C)[C@H]1CO

Procedure:
Compound of example 6 (1.5 g, 4.84 mmol) in dry DMF (15 mL) was reacted with methyl 4-trifluoromethylbenzoate (3.27 g, 16.02 mmol) in the presence of NaH (50%, 1.2 g, 25 mmol) as described in example 16, to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([CH3:18])[C:11]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]>CO>[Cl:9][C:10]1[CH:15]=[C:14]([CH:13]=[C:12]([CH3:18])[C:11]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:16]([NH:2][OH:3])=[NH:17]
Reactant: NO
Reactant: Cc1cc(C#N)cc(Cl)c1NS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(Cl)c1NS(C)(=O)=O
Temperature: 65 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
Hydroxylamine hydrochloride (60 mg, 858 μmol) and NaHCO3 (72 mg, 858 μmol) is added to a solution of N-(2-chloro-4-cyano-6-methyl-phenyl)-methanesulfonamide (105 mg, 429 μmol) in methanol (10 mL). The mixture is stirred at 65° C. for 18 h. The solvent is removed in vacuo and the residue is dissolved in a small volume of water (2 mL) and extracted three times with EA (15 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give the title compound (118 mg) as a white solid; LC-MS**: tR=0.19 min, [M+1]+=277.94; 1H NMR (CDCl3): δ2.57 (s, 3H), 3.13 (s, 3H), 6.21 (s, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.5 Hz).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([Cl:31])=[CH:6][C:7]2[C:8]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19][C:9]=3[N:10]([CH2:13][C:14]([O:16]CC)=[O:15])[C:11]=2[CH:12]=1.Cl>O.C1COCC1>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C:8]2[C:7]3[CH:6]=[C:5]([Cl:31])[C:4]([Cl:3])=[CH:12][C:11]=3[N:10]([CH2:13][C:14]([OH:16])=[O:15])[C:9]=2[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)c(Cl)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Temperature: 60 °C
Yield: 109.8 %

Procedure:
A solution of KOH (0.17 g, 3.0 mmol) in H2O (10 mL) was added to a solution of tert-butyl 8,9-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.00 g, 2.27 mmol) in THF (15 mL). The mixture was heated at 60° C. for 2 h. The reaction was then cooled to rt, acidified with 10% aqueous HCl, and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated to give crude acid (1.03 g, 110%): 1H NMR (300 MHz, CDCl3) δ 7.50 (s, 1H), 7.26 (s, 1H), 4.73 (s, 2H), 3.74 (m, 2H), 3.67 (m, 2H), 2.89 (m, 4H), 1.47 (s, 9H); MS(ESI+) m/z 410.9.
Reaction SMILES: [NH2:1][C:2](=[N:31]O)[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7].CCO.[ClH:36]>[Pd].O>[ClH:36].[NH2:31][C:2](=[NH:1])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7]
Reactant: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C(N)=NO)c2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C(=N)N)c2)cc1
Reaction time: 14 h
Yield: 61.6 %

Procedure:
A mixture of N1-[3-(amino(hydroxyimino)methyl)benzoyl]-N2-(4-isopropylbenzoyl)-4-hydroxy-1,2-benzenediamine (209 mg, 0.48 mmol), EtOH (5 mL), H2O (2.5 mL), 1N HCl (0.5 mL, 0.5 mmol), and 10% Pd/C (217 mg) was hydrogenated at 1 atm. for 14 h. The reaction was filtered through diatomaceous earth with hot methanolic washes. The filtrate was concentrated and the residue was resubjected to the hydrogenation conditions using 10% Pd/C (189 mg). After 6 h, the reaction mixture was filtered through diatomaceous earth with hot methanolic washes. The filtrate was concentrated to give the title compound as a solid (134 mg, 62%); NMR(300 MHz, DMSO-d6): δ10.27 (s, 1H), 9.89 (s, 1H), 9.45 (s, 2H), 9.14 (s, 2H), 8.42 (s, 1H), 8.23 (d, J=7.5, 1H), 7.94 (d, J=7.2, 1H), 7.86 (d, J=8.1, 2H), 7.73 (t, J=7.8, 1H), 7.28 (m, 4H), 6.65 (d, J=8.7, 1H), 2.90 (m, 1H), 1.19 (s, 3H), 1.17 (s, 3H); MS(FD): 399.2 (M−OH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:11][C:12]([NH2:14])=[NH:13].[ClH:15]>>[NH:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[C:12]([NH2:13])=[NH:11].[ClH:15].[NH:13]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[C:12]([NH2:14])=[NH:11]
Reactant: N=C(N)N
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Product: N=C(N)Nc1cccc(C(=O)O)c1

Procedure:
3-guanidinobenzoic acid was prepared from 3-aminobenzoic acid by the method of Miller, et al., cited in Example 1C. The guanidine was treated with ethereal hydrogen chloride to give 3-guanidino-benzoic acid hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]([OH:23])[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[N:13][CH:14]=1>C(O)(C)C.O>[CH:20]([NH:19][CH2:18][CH:17]([OH:23])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][NH:6][C:3]([O:2][CH3:1])=[O:4])=[CH:14][N:13]=1)([CH3:22])[CH3:21]
Reactant: COC(=O)Cl
Reactant: CC(C)NCC(O)COc1ccc(CCN)cn1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)NCCc1ccc(OCC(O)CNC(C)C)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.4 ml of chloroformic acid methyl ester are added dropwise, whilst stirring, to 12.4 g of 5-(2'-aminoethyl)-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine, dissolved in a mixture of 45 ml of isopropanol and 45 ml of water, at a temperature of 20°-35° C., with cooling by means of ice water, if necessary. The reaction mixture is stirred further for one hour at room temperature and is evaporated in vacuo, and the evaporation residue is dissolved in approx. 30 ml of water. This solution is extracted with 20 ml of ethyl acetate and the acid aqueous phase is rendered alkaline with concentrated sodium hydroxide solution. The oil which precipitates is extracted with dichloromethane. After drying the solution over magnesium sulphate and evaporating off the solvent, 2-(3'-isopropylamino-2'-hydroxy-propoxy)-5-(2'-methoxycarbonylaminoethyl)-pyridine is obtained, melting at 97°-99° C. after recrystallisation from a little butanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.[NH2:15][NH2:16].O>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(Br)cc2)=NN1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
4-(4-Bromo-phenyl)-4-oxo-butyric acid (Aldrich, 25.0 g, 97.3 mmol) was treated with NH2NH2—H2O (Aldrich, 55%, 9.1 mL, 156 mmol) in EtOH (Aldrich, 100 mL) at refluxing for 2 h. It was cooled down to ambient temperature and the white solid was filtered off to give the title compound (24.2 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 2.50-2.76 (m, 2H), 2.85-3.09 (m, 2H), 7.43-7.71 (m, 4H), 8.55 (s, 1H) ppm. MS (DCl/NH3) m/z 253 (M+H)+, 255 (M+H)+, 270 (M+NH4)+, 272 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH:9]=O.[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1>C1(C)C=CC=CC=1>[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:25][CH2:26][N:27]([CH:9]=[CH:8][C:7]4[C:6](=[O:11])[N:5]5[CH2:12][CH2:13][CH2:14][CH2:15][C:4]5=[N:3][C:2]=4[CH3:1])[CH2:28][CH2:29]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2n(c(=O)c1CC=O)CCCC2
Solvent: Cc1ccccc1
Product: Cc1nc2n(c(=O)c1C=CN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Yield: 97.4 %

Procedure:
A mixture of 2.96 g (14.33 mmoles) of (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)-acetaldehyde (II), 3.16 g (14.33 mmoles) of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (IV) and 50 mL of toluene was transferred to a Dean Stark apparatus. The mixture was brought to boiling point, refluxed for 3 hours, and the solvent was evaporated under reduced pressure to give 5.70 g (97.3%) of 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-vinyl}-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one (III) as a deep orange solid. The compound thus obtained was pure enough as to be used in the subsequent reaction step with no prior purification or optionally crystallized from an organic solvent, preferably ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[C:6]([F:9])[C:7]=1I.FC1C=C(N2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])OC2=O)C=CC=1I>>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[C:6]([F:9])[C:7]=1[CH:33]1[CH2:32][CH2:34][NH:35][C:36](=[O:38])[CH2:37]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCNC(=O)C3)c(F)c2)C(=O)O1

Procedure:
N-({(5S)-3-[3,5-difluoro-4-(2-oxopiperidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide is prepared as in the route described in Example 16 substituting N-{[(5S)-3-(3,5-difluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide for 1 N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide. 1H-NMR (CDCl3) δ: 7.13, 6.09, 5.8, 4.79, 4.01, 3.74, 3.68, 3.44, 2.75, 2.62, 2.31, 2.02, 1.94
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[OH-].[Li+].O.[CH3:19][N:20]([CH:22]=O)C>C1COCC1>[N:20]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:22][CH2:4][CH2:3][CH2:2][CH2:12][CH2:19]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCCCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.) and hexamethyleneimine (Fluka 52660; 697.89 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was stirred at 60° C. for 4 hours. The reaction mixture was then partitioned between ethyl acetate and aq. NH4Cl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow solid. The latter was taken up in THF (5 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) then water (5 mL) were added. The reaction mixture was stirred at room temperature for 16 hours then the solvent was evaporated and the residue was diluted with water. After acidification to pH 5 with AcOH, the resulting precipitate was filtered and dried under high vacuum to afford the title compound (534 mg, 86%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=2)=[CH:41][CH:40]=1>[Cu].ClC1C=CC=CC=1Cl>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([N:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])[C:19]3[CH:20]=[CH:21][C:16]([C:13]4[CH:12]=[CH:11][C:10]([N:9]([C:3]5[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=5[CH3:1])[C:31]5[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=5)=[CH:15][CH:14]=4)=[CH:17][CH:18]=3)=[CH:47][CH:46]=2)=[CH:41][CH:40]=1
Reactant: Cc1ccc(N(c2ccc(-c3ccc(Nc4ccc(C)cc4C)cc3)cc2)c2ccc(C)cc2C)cc1
Reactant: Brc1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N(c2ccc(-c3ccc(N(c4ccc(-c5ccc(Br)cc5)cc4)c4ccc(C)cc4C)cc3)cc2)c2ccc(C)cc2C)cc1
Temperature: 25 °C

Procedure:
Into a 2 liter three-necked reaction vessel fitted with an air-cooling tube and a mechanical stirrer, 48.3 g (0.1 mol) of N4,N4′-bis(2,4-dimethylphenyl)-N4-p-tolylbiphenyl-4,4′-diamine, 39.5 g (0.11 mol) of 4′-bromo-4-iodobiphenyl, 20 g of copper powder and 200 mL of o-dichlorobenzene were introduced and heated for 12 hours in an oil bath. After the reaction was completed, the reaction mixture was left to cool to room temperature, followed by removing solid matter by filtration, and thereafter extraction with toluene/water. Then, the solvent was distilled away from the organic layer under reduced pressure, followed by purification with a silica gel column (developer solvent: hexane/toluene=2:1) to give the desired N4′-(4′-bromobiphenyl-4-yl)-N4,N4′-bis(2,4-dimethylphenyl)-N4-p-tolylbiphenyl-4,4′-diamine. The compound obtained was in a yield of 45.0 g corresponding to 63%. The compound obtained was measured with the same elementary analyzer as the above.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1.C(Cl)Cl.C1COCC1>[C:20]([C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:12]=2)[NH:16][CH:15]=1)#[N:21]
Reactant: N#Cc1c[nH]c2ccc(C(CCO)c3ccccc3)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 5-(3-hydroxy-1-pheny-propyl)-1H-indole-3-carbonitrile LXV (600 mg, 2.17 mmol) in THF/DCM (1/1, 12 ml) was added dropwise MsCl (168 μl, 2.17 mmol). The mixture was stirred at 0° C. for 10 min and TEA (360 μl, 2.58 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 2 hours, diluted with THF (6 ml), stirred at 0° C. for additional 2 hours, poured into an ice/water mixture, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated affording the metanesulfonic acid 3-(3-cyano-1H-indol-5-yl)-3-phenyl-propyl ester as a yellow oil. A solution of this mesylate in MeNH2 (33% in EtOH, 10 ml) was heated in a sealed tube at 100° C. for 1 hour. The mixture was concentrated, and the residue was partitioned between a saturated solution of NaHCO3 and DCM. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified via flash chromatography (DCM/MeOH/NH4OH) affording 5-(3-methylamino-1-pheny-propyl)-1H-indole-3-carbonitrile LXVI as a white solid (156 mg). MS (M+H)=290.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.[CH:15]([S:17]([N:20]1[CH2:27][CH:26]2[CH:22]([CH2:23][NH:24][CH2:25]2)[CH2:21]1)(=[O:19])=[O:18])=[CH2:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:24]2[CH2:23][CH:22]3[CH:26]([CH2:27][N:20]([S:17]([CH:15]=[CH2:16])(=[O:18])=[O:19])[CH2:21]3)[CH2:25]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: C=CS(=O)(=O)N1CC2CNCC2C1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CC2CN(C(=O)CNc3cc(Cl)c(Cl)cc3O)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a stirred solution of 2-((4,5-dichloro-2-hydroxyphenyl)amino)acetic acid (90 mg, 0.385 mmol) in DMF (15 mL) at room temperature, 2-(vinylsulfonyl)octahydropyrrolo[3,4-c]pyrrole (110 mg, 0.46 mmol) was added followed by HOBt (78.05 mg, 0.58 mmol), EDCI.HCl (110.7 mg, 0.46 mmol) and Et3N (116.7 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate/dichloroethane) to afford the desired product (20 mg, 10% yield) as a solid. 1H NMR (400 MHz, DMSO-d6)δ: 10.17 (s, 1H), 6.91 (dd, J=10.0, 16.4 Hz, 1H), 6.79 (s, 1H), 6.62 (s, 1H), 6.17-6.10 (m, 2H), 5.25 (t, J=4.0 Hz, 1H), 3.85-3.82 (m, 2H), 3.71-3.66 (m, 1H), 3.61-3.56 (m, 1H), 3.45-3.39 (m, 3H), 3.29-3.25 (m, 1H), 3.09-3.00 (m, 3H), 2.92-2.89 (m, 1H). ESI-MS m/z: 420.1 [M+H]+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)[CH2:1]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1ccc(Oc2cccc3c2CCNC3)nc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2cccc3c2CCN(Cc2ccccc2)C3)nc1
Yield: 23.7 %

Procedure:
Combine 6-(1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-nicotinamide (100 mg, 0.3 7 mmol), benzaldehyde (39 μL, 0.38 mmol), sodium triacetoxyborohydride (101 mg, 0.48 mmol), acetic acid (22 μL, 0.39 mmol), and 1,2-dichloroethane (5 mL) then stir at room temperature for 18 hours. Dilute the reaction with saturated aqueous sodium bicarbonate solution and extract with dichloromethane (3×25 mL). Dry the combined dichloromethane extracts with sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 45 mg of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield 6-(2-benzyl-1,2,3,4-tetrahydro isoquinolin-5-yloxy)-nicotinamide (31 mg, 0.09 mmol): m/z=360.1 (M+1); 3H NMR (DMSO-d6, 300.00 MHz): 8.56 (s, 1H); 8.16-8.12 (m, 1H); 7.38-7.15 (m, 6H); 6.94-6.89 (m, 3H); 6.17 (s, 2H); 3.74-3.61 (m, 4H); 2.69-2.66 (m, 4H), HPLC=99% (30/70 to 90/10 ACN/(0.1% TFA in water), Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm).
Reaction SMILES: [CH2:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].C([Li])CCC.CN([CH:17]=[O:18])C>CCOCC>[CH2:1]([C:4]1[O:5][C:6]([CH:17]=[O:18])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccco1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCc1ccc(C=O)o1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a solution of 13.04 g (0.118 mol) of 2-propylfuran in 800 mL of ether cooled at 0° C. with stirring under nitrogen was added dropwise 52 mL (0.130 mol) of 2.5M n-butyllithium. The reaction mixture was allowed to warm to room temperature and then refluxed for 40 min. The reaction mixture was cooled to -60° C., 10.1 mL (0.130 mol) of DMF in 10 mL of ether was added, and the resulting mixture was stirred at -60° C. for 45 min, and warmed to room temperature. The above mixture was quenched with 10 mL of saturated aqueous ammonium chloride, diluted with water to form a clear aqueous layer, and the organic layer was washed with water, and brine. The organic layer was dried over anhydrous magnesium sulfate, treated with a small amount of a charcoal, filtered, and concentrated to yield 13.95 g of a crude oil. The kughelrohr distillation of this oil (75°-105° C.) afforded 10.5 g (64.5%) of 5-propyl-2-furancarboxaldehyde.