Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C(C)C)=[C:4](NCC2C=CC(OC)=CC=2)[N:3]=1.[H-].[Na+].I[CH:27]([CH3:29])[CH3:28].O>CN(C=O)C>[CH:27]([C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1)([CH3:29])[CH3:28]
Reactant: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ncc2[nH]cnc2n1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Preparation of 2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (2) 2-chloro-6-(4-methoxybenzylamino)purine was suspended in dry DMF (5 ml) and treated with sodium hydride, 60% dispersion (82 mg, 2.06 mmol). The suspension was stirred for 30 min over which time it became a clear yellow/green solution. 2-Iodopropane (0.280 mL, 1.7 eq.) was added over 5 min and the resultant solution stirred for 2 days. Water was added and the solution and extracted with ethyl acetate. The organic layer was evaporated to give the product isopropyl purine (Yield=508 mg, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[B:9](OC(C)C)([O:14]C(C)C)[O:10]C(C)C.C([Li])CCC.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:8][C:5]1[N:6]=[CH:7][C:2]([B:9]([OH:14])[OH:10])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1ccc(F)nc1
Temperature: -42.5 °C
Reaction time: 5 h
Yield: 1624.3 %

Procedure:
A 72 L reactor equipped with reflux condenser, and temperature probe. To the reactor 5-bromo-2-fluoropyridine (1.17 L, 0.568 mol), toluene (18.2 L), and triisopropyl borate (3.13 L, 0.68 mol, 1.2 equiv.) were charged and stirred. Tetrahydrofuran (4.4 L) was added to the reactor and the reaction mixture was cooled to between −35 to −50° C. While maintaining a temperature between −35 to −45° C., n-butyl lithium (2.5 M solution of hexanes, 5.44 L, 0.68 mol, 1.2 equiv.) was cautiously added to the reactor. After 5 h, the reaction was deemed complete and the reaction mixture was warmed to between −15 to −20° C. To the reaction was added 2M HCl (11.80 L) to the reactor while maintaining a temperature between −15° C. and 0° C. The reaction mixture was stirred at 18 to 23° C. for (16 h) and the phases were separated. The organics were then extracted with 6 M sodium hydroxide (6.0 L). The acidic anbasic aqueous phases were mixed in the reactor and 6 M HCl (2.5 L) was added until pH 7.5 was achieved. Sodium chloride (6.0 kg) was then added to the aqueous phase. The aqueous phase was then extracted with THF (3×20 L). The combined organics were dried with magnesium sulfate and concentrated to give 1300 g of a tan solid (81% crude yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[CH2:19](B(O)O)[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCCCB(O)O
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCc1c(C#N)cnc2ccc(C(=O)OCC)cc12

Procedure:
Similar procedure as described in example 46d was used, starting from 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester, butylboronic acid, sodium carbonate and POPd to give 3-cyano-4-butyl-quinoline-6-carboxylic acid ethyl ester as a clear oil. LC-MS m/e 283 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][Br:20])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[Br-:20].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][P+:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: [Br-]
Product: c1ccc(COc2ccc3cc(C[P+](c4ccccc4)(c4ccccc4)c4ccccc4)ccc3c2)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
The solution of 2-benzyloxy-6-bromomethyl-naphthalen (18) (1 equi.), and triphenylphosphine (1.1 equi.) in DMF (0.6 mL/mmole was stirred at 95 C for 15 h, cooled to room temperature, and quenched with ethyl acetate. The resulting white solid of (6-benzyloxynaphthalen-2-ylmethyl)-triphenylphosphonium bromide (19) was filtered and washed with ethyl acetate. Yield 98%.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:7][C:8]1[N:9]=[C:10]([C:19](OC)=[O:20])[S:11][C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>O>[CH3:7][C:8]1[N:9]=[C:10]([C:19]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:20])[S:11][C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1nc(C)c(-c2ccncc2)s1
Reactant: CN(C)CCN
Solvent: O
Product: Cc1nc(C(=O)NCCN(C)C)sc1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Dimethylethylenediamine (1.4 ml) was added to a suspension of methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (200 mg) in water (2.8 ml) at room temperature, and the mixture was stirred at room temperature for overnight. The mixture was evaporated to dryness and the residue was chromatographed on an activated alumina column and eluted with chloroform to give 4-methyl-N-(2-dimethylaminoethyl)-5-(4-pyridinyl)-thiazole-2-carboxamide as yellow oil.
Reaction SMILES: [Br-:1].[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][NH+:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].O1CCOC[CH2:17]1>>[Br-:1].[CH3:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH+:9]=1
Reactant: [H][H]
Reactant: C1COCCO1
Reactant: c1ccc(-c2cccc[nH+]2)cc1
Agent: [Br-]
Product: Cc1cccc(-c2ccccc2)[nH+]1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a 100 ml stainless steel autoclave, 21.9 mg (0.0125 mmol) of [{IrH((S)-SEGPHOS)}2(μ-Cl)3]Cl and 63 mg (0.25 mmol) of 2-phenylpyridinium bromide were added, and the autoclave was pruged with argon. Then, 3.0 ml of dioxane was added thereto. Subsequently, hydrogen was introduced at a pressure of 1.0 MPa, followed by stirring at 100° C. for 20 hours. After cooloing, the reaction product was analyzed by NMR and HPLC. The conversion was 91%, and the enantiomeric excess was 67% ee.
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:5]=1)(=O)[CH3:2].C([BH3-])#N.[Na+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH2:30]([S:27]([N:24]1[CH2:23][CH2:22][CH:21]([C:12]2[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=[C:9]([C:6]4[CH:5]=[C:4]([C@H:1]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH3:2])[S:8][CH:7]=4)[CH:10]=3)[NH:14][CH:13]=2)[CH2:26][CH2:25]1)(=[O:29])=[O:28])[CH3:31]
Reactant: C1CCNC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C(C)=O)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc([C@@H](C)N5CCCC5)c4)cc23)CC1

Procedure:
To 5-(5-acetyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (10 mg, 0.02 mmol) was added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and pyrrolidine (0.03 mL, 0.30 mmol). The resulting mixture was reacted in a microwave for 40 min at 150° C. All the solvent was evaporated and the crude product was partitioned between ethyl acetate (1.5 mL) and 1 M sodium hydroxide (0.2 mL). The reaction was purified by SFC to give the title compound as 100% chirally pure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:26])[CH:19]=2)[N:13]=[N:14][C:15]=1[O:16]C.C[Si](Cl)(C)C.[I-].[K+]>C(#N)C.O>[OH:25][C:21]1[C:22]([CH3:24])=[CH:23][C:18]([C:12]2[CH:11]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:15](=[O:16])[NH:14][N:13]=2)=[CH:19][C:20]=1[CH3:26]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccccc2[nH]1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cc(C)c1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
100 mg of 4-[5-(1H-indol-2-yl)-6-methoxy-pyridazin-3-yl]-2,6-dimethyl-phenol is suspended in 2 ml acetonitrile and 40 μl of trimethylsilyl chloride and 53 mg of potassium iodide are added. The solution is heated to 80° C. for 3 h, then a further 120 μl of trimethylsilyl chloride and 159 mg of potassium iodide are added. The solution is heated to 80° C. for 3 h then stirred at RT for 16 h. The reaction solution is diluted with water and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 15 mg. LC-MS (ES+) 332 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:21][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[C:19]#[N:20])[CH2:11][CH:6]2[CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC.Cl>[F:41][C:42]1[CH:47]=[CH:46][C:45]([O:1][CH2:2][CH:3]2[CH2:21][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[C:19]#[N:20])[CH2:11][CH:6]3[CH2:5][CH2:4]2)=[CH:44][CH:43]=1
Reactant: N#Cc1cc(F)ccc1N1CCN2CC(CO)CCC2C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1cc(F)ccc1N1CCN2CC(COc3ccc(F)cc3)CCC2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.4 %

Procedure:
A solution of 0.51 g (1.8 mmol) of (7RS,9aSR)-7-hydroxymethyl-2-(2-cyano-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 0.555 g (2.12 mmol) of triphenylphosphine, and 0.296 g (2.64 mmol) of 4-fluorophenol in 8 mL of dry THF was treated with 0.368 g (2.12 mmol) of diethyl azodicarboxylate and stirred at ambient temperature for 24 h. The mixture was diluted with ether, and 1M HCl was added until a gummy residue formed. The layers were separated and the aqueous layer was washed with ether (3×). The aqueous layer was combined with the gummy residue and dissolved in a mixture of ethyl acetate and 10% ammonium hydroxide, the layers were separated and the aqueous layer was extracted with more ethyl acetate (2×). The organic layers were evaporated, the residue dissolved in chloroform, washed with 1M NaOH (3×), dried (magnesium sulfate), filtered and evaporated. The product was dissolved in absolute ethanol, filtered and evaporated to give 0.21 g of the title compound. mp (—HCl) 235-240° C. HRMS calcd for C22H23F2N3O: 383.1809, found: 383.1796.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7](N)=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[CH2:15](I)[CH3:16].[Cl-].[NH4+:19]>CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:16][CH2:15][NH2:19])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: CC(C)(C)c1cc(Br)ccc1N
Reactant: CCI
Reactant: [NH4+]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(Br)ccc1CCN
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.7 g (68 mmol) of sodium hydride are suspended in 250 ml of DMSO, under a stream of nitrogen. 7 g (31 mmol) of 4-bromo-2-tert-butylphenylamine, diluted in 10 ml of DMSO, are added to the reaction medium cooled to 0° C. After stirring at ambient temperature for 30 minutes, 5.4 ml (68 mmol) of ethyl iodide are added slowly. The pale-yellow-coloured mixture is stirred overnight at ambient temperature and then poured into a saturated solution of ammonium chloride and extracted twice with ethyl acetate. The organic phase is dried and then concentrated under vacuum. 5 g of (4-bromo-2-tert-butylphenyl)ethylamine are obtained in the form of a yellow oil (yield=65%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][C:8](=O)[CH2:7]1)=[O:5].[BH4-].[Na+].[CH2:20]([NH2:23])[CH2:21][NH2:22]>C1C=CC=CC=1>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([NH:22][CH2:21][CH2:20][NH2:23])[CH2:8][CH2:7]1)=[O:5]
Reactant: NCCN
Reactant: O=C1CC(C(=O)c2ccc(F)cc2F)CCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: NCCNN1CCC(C(=O)c2ccc(F)cc2F)CC1
Yield: 38 %

Procedure:
A solution of 4-(2,4-difluorobenzoyl)piperidinone (1.50 g, 6.27 mmol) in benzene (40 mL) and ethylenediamine (4.0 mL) was refluxed for 6 hours. The resulting mixture was concentrated to a residue which was dissolved in MeOH (30 mL). The mixture was cooled (0° C.) and NaBH4 (1.0 g, 26.4 mmol) was slowly added. After stirred for an hour, the mixture was concentrated and quenched with 1 N NaOH (50 mL). The mixture was extracted with CH2Cl2 (5×20 mL), dried (K2CO3), and was concentrated. The residue was purified by flash chromatography (CHCl3-MeOH-2 M NH3 in MeOH 100:10:2 to 100:20:5) to afford the product as an pale yellow solid (670 mg, 38%).
Reaction SMILES: [F:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25]C)=[O:24])[CH:20]=[CH:19][CH:18]=1.[CH2:27]([Zn]CC)[CH3:28]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:27]([C:7]1[C:2]([F:1])=[C:3]([C:17]2[N:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][CH:18]=2)[C:4]([F:16])=[CH:5][CH:6]=1)[CH3:28]
Reactant: CC[Zn]CC
Reactant: COC(=O)c1cccc(-c2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2F)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1ccc(F)c(-c2cccc(C(=O)O)n2)c1F
Temperature: 70 °C

Procedure:
To a solution of methyl 6-(2,6-difluoro-3-(trifluoromethylsulfonyloxy)-phenyl)picolinate (1.0 equiv.) in toluene (0.15M) was added Pd(dppf)Cl2-DCM (0.1 equiv.) followed by diethyl zinc (3.0 equiv.). The solution turned from orange to bright yellow. The reaction was heated to 70° C. for 2 hours at which time, LC/MS analysis indicated a mixture of 1:3:1 ratio of hydrolyzed product, desired product and unknown by-product. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with 1N NaOH (2×). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide a brown oil. The oil was redissolved in THF and treated with 1N NaOH for one hour. The reaction was then diluted with ethyl acetate and washed with 1N NaOH (2×). The basic washings were combined, acidified with concentrated HCl and extracted with ethyl acetate (3×). The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide 6-(3-ethyl-2,6-difluorophenyl)picolinic acid as a light brown oil in >99% yield. LC/MS=264.1 (M+H), Rt=0.88 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[3-(2,5-dichlorophenylsulfonyloxy)-5-methylphenoxy]propanol (580 mg, 1.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (530 mg, 91%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 7.96 (s, 1H), 7.56 (s, 2H), 6.63 (s, 1 H), 6.58 (s, 1H), 6.50 (s, 1 H), 4.22 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.1 Hz, 2 H), 2.27 (s, 3H).
Reaction SMILES: CS[C:3]([S:12][CH3:13])=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:10]([C:4](=[C:3]([S:12][CH3:13])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:11]
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Reactant: Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C#N)=C(Nc1ccccc1)SC
Yield: 87.8 %

Procedure:
A solution of ethyl 3,3-bis(methylthio)-2-cyanoacrylate (20.0 g, 91.2 mmol) and aniline (9.1 mL, 100 mmol) in ethanol (200 mL) was heated under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=98:2→1:1) to give the title compound (21.0 g, 88%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Cl[CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[C:4]([CH3:9])[CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: Cc1cc(Br)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1OCC(=O)N(C)C
Temperature: 25 °C

Procedure:
The reaction mixture of 4-bromo-2-methylphenol (Aldrich, Cat. No. 681121) (0.50 g, 2.7 mmol), 2-chloro-N,N-dimethylacetamide (Aldrich, Cat. No. 24350) (0.27 mL, 2.7 mmol) and potassium carbonate (1.1 g, 8.0 mmol) in DMF (4 mL) was stirred at 60° C. overnight. After cooling to r.t., the mixture was adjusted to pH˜2 with aqueous HCl, and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford the product which was directly used in nest step reaction without further purification. LCMS (M+H)+=272.2/274.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:4][CH:3]=1.Cl[C:21]1[S:22][C:23]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=2[N:25]=1.Cl.O1CCOCC1.[CH2:38](O)[CH2:39][CH2:40]C>>[F:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH2:38][CH2:39][CH3:40])=[O:15])=[C:10]([O:18][CH3:19])[CH:9]=4)=[CH:6][CH:7]=3)[S:22][C:23]=2[CH:29]=1.[F:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([O:18][CH3:19])[CH:9]=4)=[CH:6][CH:7]=3)[S:22][C:23]=2[CH:29]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: CCCCO
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1OC
Product: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1OC
Temperature: 65 °C
Yield: 44 %
Yield: 30 %

Procedure:
A mixture of methyl 4′-amino-3-methoxybiphenyl-4-carboxylate (0.27 g, 1.06 mmol) and 2-chloro-6-fluoro-1,3-benzothiazole (0.20 g, 1.06 mmol) in n-butanol (8 mL) was heated to 60-70° C., and then 4N HCl in 1,4-dioxane (0.12 mL, 0.48 mmol) was added dropwise with stirring. The reaction mixture was heated at 90° C. for 18 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (25% EtOAc in hexanes), yielding 0.209 g (44%) of butyl 4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-carboxylate, and 0.132 g (30%) of methyl 4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-carboxylate [LC/MS m/z 409.3 (MH+), retention time=3.67 min, m/z 451.3 (MH+), retention time=4.25 min. 1H NMR (400 MHz, CD2Cl2) δ 3.85 (s, 3H), 4.00 (s, 3H), 7.05-7.26 (m, 3H), 7.42 (d, 1H), 7.61-7.64 (m, 1H), 7.76 (s, 4H), 7.90 (d, 1H)].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[NH:12][CH:11]=1>O1CCOCC1>[F:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: Fc1ccc2[nH]cc(CCN3CCCCC3)c2c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Piperidine (3.52 g, 4.08 ml, 41.3 mmol) was dissolved in abs dioxane (100 ml), 3-(2-bromo-ethyl)-5-fluoro-1H-indole (5.00 g, 20.7 mmol) was added at RT and the mixture was stirred at 70° C. for 16 h. The solution was concentrated, the residue was taken up in CHCl3 (150 ml) and the mixture was washed with water (2×50 ml). The organic phase was dried over Na2SO4, filtered and concentrated i. vac. The residue obtained was purified by flash chromatography with 200 g of silica gel and ethyl acetate/ethanol (9:1→1:2).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH:8]=[CH:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([CH:18]=[CH:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=2)[CH:17]=1)[CH:13]=[O:14])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH:8]=[CH:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([CH:18]=[CH:19][C:20]2[CH:21]=[C:22]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)[CH:17]=1)[CH2:13][OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=O)cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(CO)c2)cc(C(C)(C)C)c1
Yield: 74.1 %

Procedure:
A mixture of 3,5-bis(3′,5′-di-tert-butylstyryl)benzaldehyde (3.00 g, 6.61 mmol) and sodium borohydride (840 mg, 22.2 mmol) in tetrahydrofuran (150 cm3) was heated at reflux for 110 min. The solvent was then completely removed and light petroleum (30-40) and aqueous hydrochloric acid (3 M, 30 cm3) were added and stirred until effervescence had ceased. The white precipitate was then filtered and dried under vacuum to give 3,5-bis(3′,5′-di-tert-butylstyryl)benzyl alcohol (2.63 g, 87%). A sample for analysis was recrystallised from a dichloromethane-light petroleum (60-80) mixture, mp 226-228° C. (Found: C, 87.28; H, 9.47. C39H52O requires C, 87.26; H, 9.76%); νmax(CHCl3)/cm−1 3608w (OH), 1596 (C═C) and 964 (C═C—H trans); λmax(CH2Cl2)/nm (log ε) 230 (4.42), 307 (4.80), 312 (4.80), 315 (4.80) and 330sh (4.66); δH(500 MHz, CDCl3) 1.41 (36 H, s, t-Bu), 1.81 (1 H, t, J 6, OH), 4.79 (2 H, d, J 6, CH2), 7.16 and 7.27 (4 H, d, J 16, 7′,8′-H), 7.40 (2 H, dd, J 1.5, 4′-H), 7.43 (4 H, d, J 1.5, 2′,6′-H), 7.49 (2 H, s, 2,6-H) and 7.66 (1 H, s, 4-H); m/z (APCI+) 519 ((M-OH)+, 100%).