Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:31][NH:32][CH2:33][CH:34]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[OH:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH2:20][N:32]([CH2:33][CH:34]([OH:35])[C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[CH3:31])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: COCCOCc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCc1c(CN(C)CC(O)c2cccnc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 50 °C
Yield: 92.5 %

Procedure:
A mixture of 111 mg of N-(4-chlorobenzyl)-2-(chloromethyl)-3-[(2-methoxyethoxy)methyl]-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide, 54 mg of 2-(methylamino)-1-pyridin-3-ylethanol (Arch. Pharm. (1961), 294, 453), and 62 μL of diisopropylethylamine in 1.5 mL of DMF is heated at 50° C. for 18 h, then cooled and partitioned between EtOAc and water. The organic phase is washed with two additional portions of water and brine, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica using 5% MeOH in CH2Cl2 affords 128 mg of the title compound as a white foam. Recrystallization of a sample from EtOAc provides white crystals.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1.[CH3:18][S:19]([OH:21])=[O:20].[Na]>CN(C=O)C>[Cl:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:17])[N:3]=[C:2]([S:19]([CH3:18])(=[O:21])=[O:20])[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10]2
Reactant: CS(=O)O
Reactant: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nc2cc(Cl)c(Cl)cc2nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6,7-trichloro-3-trifluoromethylquinoxaline (64 mg, 0.2 mmol) in DMF (1 ml) was added methanesulfinic acid, sodium salt (43 mg, 0.4 mmol). The reaction mixture was stirred at room temperature overnight, then it was partitioned between ethyl acetate and water. The organic layer was separated and concentrated to an oil. This oil was further purified by column chromatography (ethyl acetate:hexanes 1:3) to yield the title compound as a white solid.
Reaction SMILES: CN(C)N.ClC1C=CC([NH:12][C:13]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[CH3:20])=[O:14])=CC=1C=O.C(O)(=O)C>CO>[CH3:20][C:16]1[O:17][CH:18]=[CH:19][C:15]=1[C:13]([NH2:12])=[O:14]
Reactant: Cc1occc1C(=O)Nc1ccc(Cl)c(C=O)c1
Agent: CN(C)N
Solvent: CO
Solvent: CC(=O)O
Product: Cc1occc1C(N)=O

Procedure:
To the solution of 1,1-dimethylhydrazine (0.6 mL) in methanol (15 mL) was added, in portions, a suspension of N-(4-chloro-3-formylphenyl)-2-methyl-3-furancarboxamide (2 g) in methanol (30 mL) at such a rate that the temperature of the solution was maintained at -5° C. to 0° C. The resultant mixture was stirred overnight at ambient temperature. Acetic acid (0.1 mL) was then added to the reaction mixture which was then refluxed for 30 minutes, solvent was evaporated and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) filtered and evaporated to produce N-[4-chloro-3-[dimethylhydrazono)methyl]phenyl]-2-methyl 3-furancarboxamide as a white solid, m.p. 109-111° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.O>CS(C)=O>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][C:10]1=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
27 g of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (50 mmol) was dissolved in 153 mL of DMSO to form a clear solution. 102 mL of acetic anhydride was added dropwise. The resultant clear solution was allowed to stir at room temperature overnight. After 17 hours, GC-MS showed the lactone was gone and a new compound was observed. The yellow solution was poured into 600 mL of water and sat in a separation funnel overnight. The precipitated oil was passed through a silica gel column, eluted first with cyclohexane then gradually increasing polarity by adding acetone until the final eluent was cyclohexane: acetone=2:1. The appropriate portions were collected and evaporated to give a pale syrup. 25.2 g, yield: 94%. IR (v cm−1) 2867,1752.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[C:8](=[O:25])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.[NH3:26].CO>C1COCC1>[OH:24][C:21]([CH3:23])([CH3:22])[C:20]#[C:19][C:16]1[CH:17]=[CH:18][C:11]2[O:10][CH2:9][C:8](=[O:25])[C:7]3[S:6][C:5]([C:3]([NH2:26])=[O:2])=[N:14][C:13]=3[C:12]=2[CH:15]=1
Reactant: N
Reactant: COC(=O)c1nc2c(s1)C(=O)COc1ccc(C#CC(C)(C)O)cc1-2
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(=O)CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (81 mg, 0.23 mmol) in THF (4 mL) at room temperature, NH3/CH3OH (self-made, 4 mL) was added. The mixture was stirred at room temperature for 3 h, then concentrated to give 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a yellow oil, which was used in the next step without any further purification (crude, 80 mg). 1H NMR (400 MHz, DMSO-d6): δ 830 (s, 1H), 8.43 (d, J=2.1 Hz, 1H), 8.18 (s, 1H), 7.50 (dd, J1=8.4 Hz, J2=2.2 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 5.48 (s, 1H), 4.87 (s, 2H), 1.47 (s, 6H); LC-MS (ESI & APCI): 343.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:47]=[C:46]([CH3:48])[C:41]4[NH:42][C:43](=[O:45])[O:44][C:40]=4[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[N:82]1([CH2:88][CH2:89]O)[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1>CN(C=O)C.C(O)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:47]=[C:46]([CH3:48])[C:41]4[NH:42][C:43](=[O:45])[O:44][C:40]=4[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:89][CH2:88][N:82]5[CH2:87][CH2:86][O:85][CH2:84][CH2:83]5)=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1
Reactant: OCCN1CCOCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCCN4CCOCC4)CC3)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 90 mg (0.13 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 48 mg (0.15 mmol) TBTU and 26 μL (0.19 mmol) triethylamine in 1.4 mL DMF was stirred for 1 h at RT. Then 18 μL (0.15 mmol) 2-morpholin-4-yl-ethanol was added. The reaction mixture was stirred for 16 h at RT. 4 drops of formic acid were added, the mixture was filtered through a syringe filter and purified by HPLC. The fractions containing the product were combined, made alkaline with 5% NaHCO3 solution, extracted with 50 mL EtOAc and the organic phase was dried on Na2SO4. After the desiccant and solvent had been eliminated the residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:51][CH2:52][CH3:53])[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:11]=1[C:12]#[N:13])[C:3]([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C>O>[OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:51][CH2:52][CH3:53])[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:11]=1[C:12]#[N:13])[C:3]([CH3:6])([CH3:4])[CH3:5]
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A suspension of 1.65 g of 4-(1-hydroxy-2,2-dimethylpropyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carbonitrile [prepared as described in step (b) above] in 24 ml of 75% v/v aqueous acetic acid was stirred at 60° C. for 2 hours. At the end of this time, 6 ml of water was added to the reaction mixture, which was then cooled with ice. The trityl alcohol which precipitated was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure, to give 1.07 g of the title compound as a glass.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]([OH:23])[C:20]([OH:22])=O)=[O:16])[N:9]=2)=[CH:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][CH2:42][CH2:43][NH2:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH:19]([OH:23])[C:20](=[O:22])[NH:44][CH2:43][CH2:42][CH2:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Reactant: NCCCc1ccccn1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCCCc1ccccn1)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with 3-(pyridin-2-yl)propylamine; ESI-MS [M+H]+: 579.2.
Reaction SMILES: C(OC([N:8]([C@@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37][C@H]1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Product: CN[C@@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Br)c23)C1
Product: Cl

Procedure:
Intermediate 24b can be used in the method of Example 39-1 instead of Intermediate 26a to obtain the title compound as hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]([F:44])[CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:41])([F:40])[O:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:22])[F:21])=[C:10]([F:45])[C:9]=2[F:46])=[N:6][CH:7]=1.[CH2:47](Br)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:47]([O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]([F:44])[CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:42])([F:43])[C:25]([F:40])([F:41])[O:26][C:27]([F:38])([F:39])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:21])[F:22])=[C:10]([F:45])[C:9]=2[F:46])=[N:4][CH:3]=1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: Oc1cnc(-c2ccc(OC[C@@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCCCOc1cnc(-c2ccc(OC[C@@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1

Procedure:
The title compound was prepared essentially as in Example 18 by combining 5-hydroxy-2-[4-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropoxy)-2,3-difluorophenyl]pyrimidine (0.89 g, 1.24 mmol), octyl bromide (0.3 g, 1.5 mmol), and potassium carbonate (0.2 g, 1.5 mmol) in acetonitrile (12 mL). The resulting mixture was heated to reflux overnight, deionized water (20 mL) was added, and the resulting crude product was collected by filtration. The product was recrystallized from methanol to yield 0.35 g.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ccc(Br)cc1F
Solvent: Cc1ccccc1
Product: Fc1cc(Br)ccc1Nc1nc2ccccc2s1
Temperature: 130 °C
Yield: 99.9 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (1.00 g, 5.26 mmol) in toluene (25 mL) was added 2-chlorobenzothiazole (0.75 mL, 5.79 mmol). The purple solution was heated at 110-150° C. in a resealable tube for 66 hand then cooled to room temperature. The resulting brown solution was concentrated to give a purple solid which was triturated with heptane to afford N2-(4-bromo-2-fluorophenyl)-1,3-benzothiazol-2-amine (1.699 g, 99%) as a light purple powder. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=13.82 min, 95%; m/z 325 (MH+).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]2[Cl:18])=[CH:3][CH:2]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.Cl>>[ClH:18].[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]2[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:3][CH:2]=1
Reactant: O=Cc1c(Cl)n(-c2ccc(-c3ccccc3)cc2)c2ccccc12
Reactant: C1CNCCN1
Agent: Cl
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(-c3ccccc3)cc2)c2ccccc12
Yield: 44 %

Procedure:
1-(Biphenyl-4-yl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford 1-(biphenyl-4-yl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde hydrochloride (44% yield) as a cream solid. ESI/MS 382 (M+H), RT=2.87 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([NH2:10])=[O:9].Br[C:13]1[S:14][C:15]([CH3:18])=[CH:16]N=1>>[CH3:18][C:15]1[S:14][C:13]2=[N:11][C:6]3[C:7]([C:8](=[O:9])[N:10]2[CH:16]=1)=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3
Reactant: NC(=O)c1c(N)cccc1Cl
Reactant: Cc1cnc(Br)s1
Product: Cc1cn2c(=O)c3c(Cl)cccc3nc2s1
Yield: 78.1 %

Procedure:
10.2 g of 6-chloroanthranilamide and 10.74 g of 2-bromo-5-methylthiazole were stirred at 140° C. for 2 hours. After working up in the conventional manner there was obtained 11.7 g (78%) of the above compound; m.p. 235°-236° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=[O:32])[CH:26]=2)=[CH:21][CH:20]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH2:43][N+:44]#[C-:45])(=[O:42])=[O:41])=[CH:36][CH:35]=1.[C-]#N.[Na+]>CCO.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]3[O:32][CH:45]=[N:44][CH:43]3[S:40]([C:37]3[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)(=[O:42])=[O:41])[CH:26]=2)=[CH:23][CH:24]=1)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(-c2cccc(C=O)c2)cc1)C1Cc2ccccc2C1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)C2N=COC2c2cccc(-c3ccc(CN(C(=O)OC(C)(C)C)C4Cc5ccccc5C4)cc3)c2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl 2,3-dihydro-1H-inden-2-yl[(3′-formyl-4-biphenylyl)-methyl]carbamate (0.188 g; 0.44 mmol) and TosMIC (0.086 g; 0.44 mmol) in EtOH at room temperature was added NaCN (0.002 g; 0.04 mmol). The mixture was stirred 30 min, diluted with water and extracted with EtOAc (×3). combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a colorless gum, used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9 H), 2.41 (s, 3 H), 2.99 (d, J=8.38 Hz, 4 H), 4.50 (br. s., 2 H), 5.65 (dd, J=5.98, 1.69 Hz, 1 H), 5.96 (d, J=5.89 Hz, 1 H), 7.07-7.18 (m, 5 H), 7.25 (partially resolved dd, J=7.85 Hz, 1 H), 7.28-7.34 (m, 2 H), 7.40 (unresolved dd, 1 H), 7.46-7.52 (m, 3 H), 7.57-7.64 (m, 2 H), 7.68 (dd, J=8.03, 1.25 Hz, 1 H), 7.74 (d, J=1.25 Hz, 1 H), 7.83-7.90 (m, 2 H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl>C(OCC)C.O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:23][CH2:24][CH3:25]
Reactant: COCCOCCl
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)COCCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
To a mixture of diisopropylamine (2.1 ml, 15 mmol) and tetrahydrofuran (30 ml) was added dropwise n-butyllithium (2.4M n-hexane solution, 5.0 ml, 12 mmol) at −78° C. (external temperature). Then, the reaction mixture was stirred for 30 minutes. To the mixture was added dropwise tributyltin hydride (3.3 ml, 12 mmol) at −78° C. (external temperature). Then, the reaction mixture was stirred at 0° C. (external temperature) for 40 minutes. After the reaction mixture was cooled at −78° C. (external temperature), to the reaction mixture was added dropwise 2-methoxyethoxymethyl chloride (1.4 ml, 12 mmol). After a temperature was raised to room temperature, to the reaction mixture were added diethyl ether and an aqueous ammonium chloride solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain the title compound (2.6 g, 6.9 mmol, 57%).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>N1C=CC=CC=1.C(Cl)(=O)CCCC>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:21](=[O:24])[CH2:20][CH2:19][CH2:18][CH3:15])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Agent: CCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(OC(=O)CCCC)cc3)s2)cc1
Temperature: 0 °C
Yield: 170.8 %

Procedure:
To a solution of 0.60 g (1.78 mM) of 2-(4-hexylphenyl)-5-(4-hydroxyphenyl)thiazole in 10 ml of pyridine, 0.36 ml (3.03 mM) of pentanoyl chloride was added on an ice water bath under stirring, followed by further stirring for 2 hours at room temperature. After the reaction, the reaction mixture was poured into 100 ml of ice water to precipitate a crystal. The crystal was recovered by filtration and dissolved in toluene, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent of toluene-methanol to obtain 0.64 g of 2-(4-hexylphenyl)-5-(4-pentanoyloxyphenyl)thiazole (Yield: 85.4%). ##STR39##
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH3:16][C@@H:17]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C:18](O)=[O:19].N1C=CC=CC=1.Cl.[O:42]=[C:43]1[CH2:48][CH2:47][C:46]([NH2:55])([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:45][CH2:44]1>ClCCl>[CH3:16][C@@H:17]([C:21]1[CH:22]=[C:23]([C:31]([F:32])([F:34])[F:33])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1)[C:18]([NH:55][C:46]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:45][CH2:44][C:43](=[O:42])[CH2:48][CH2:47]1)=[O:19]
Reactant: C[C@H](C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.8 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (672 mg, 2.64 mmol) was added to a solution of (S)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 40, 500 mg, 1.76 mmol) and pyridine (284 μL, 3.52 mmol) in dichloromethane (15 mL) and the mixture was stirred at room temperature for 5 minutes. 4-Oxo-1-phenylcyclohexylamine hydrochloride (Description 18, 500 mg, 2.64 mmol) was added and the mixture was stirred at room temperature for 48 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane:EtOAc (65:35). The residue was crystallised twice from propan-2-ol/water (50:50, 20 mL) and the solid was collected and dried in vacuo to give the title compound as a colorless solid (200 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.72 (2H, s), 7.29 (5H m), 5.71 (1H, s), 3.70 (1H, q, J 7.0 Hz), 2.81 (1H, m), 2.64 (1H, m), 2.47–2.04 (5H, m), 1.60 (1H, m), and 1.52 (3H, d, J 7.0 Hz). e.e. [Determined by chiral HPLC (Chiralcel OD-H 250×4.6 mm i.d.; isohexane/EtOH (96:4); 1 mL/min; 210 nm]>99%.