Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13]1([CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+]>CO.C1(C)C=CC=CC=1>[C:13]1([CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:3](=[O:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COC(=O)CCc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 102 °C

Procedure:
21.6 g (131 mmol) 3-(3-pyridyl)-propionic acid methyl ester, 35.1 g ml (109 mmol) 4-(1-diphenylmethylpiperidine-4-yl)-butylamine and 9.8 g (54.5 mmol) 30% sodium methylate solution in methanol are heated to boiling in 480 ml toluene for five hours. Subsequently, 30 ml of solvent are distilled; thereby, sodium methylate precipitates and the temperature of the suspension increases to 102° C. under heavy foaming. The mixture is cooled to 70-80° C. and extracted twice with 45 ml and 30 ml of water. The organic phase is azeotropically dried on a moisture separator and cooled to ca. 0° C. The resulting precipitate is filtered off and crystallized from 190 ml toluol. Colorless crystals with a MP of 139° C. were recovered; yield: 46.3 g (93%).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]=[C:11]3[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]=1[C:12]=23)=O.[CH2:27]([Sn](CCCC)(CCCC)C=C)CCC>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]([O:22][C:20](=[O:21])[NH:19][C:9]1[CH:10]=[C:11]2[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]3=[C:5]([CH:3]=[CH2:27])[NH:6][C:7]([CH:8]=1)=[C:12]23)([CH3:25])([CH3:26])[CH3:24]
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Yield: 83.5 %

Procedure:
Under an argon atmosphere, Intermediate 147(d) of Example 147 (0.250 g, 0.661 mmol), tributyl-vinyl-tin (0.420 g, 1.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.033 mmol) in anhydrous N,N-dimethylformamide (5 mL) were heated at 85° C. for 16 hours. The reaction was filtered through a thin pack of diatomaceous earth, and the filtrate concentrated in vacuo. Silica gel chromatography (eluted with 1:4 ethyl acetate: dichloromethane) afforded the title compound (0.18 g, 0.552 mmol) as a yellow powder in 84% yield.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:12](=[O:14])[O:11][C:10](=[O:15])[NH:9][C:8]=2[CH:7]=[CH:6][C:5]=1[F:16].[CH3:17]I>CN(C=O)C>[Cl:3][C:4]1[C:13]2[C:12](=[O:14])[O:11][C:10](=[O:15])[N:9]([CH3:17])[C:8]=2[CH:7]=[CH:6][C:5]=1[F:16]
Reactant: CI
Reactant: O=c1[nH]c2ccc(F)c(Cl)c2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2c(Cl)c(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a suspension of NaH (49 mg, 1.11 mmol) in DMF (2 ml) at RT was added a solution of 5-chloro-6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (synthesized in analogy to a procedure described in EP 59391) (200 mg, 0.93 mmol) in DMF (2 ml). The mixture was stirred at RT for 1 h and then methyl iodide (87 μl, 1.39 mmol) was added. The reaction mixture was then warmed up to RT and stirring was continued overnight. The mixture was quenched with water and extracted with ether. The organic phase was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:1 ethyl acetate:cyclohexane) to give the desired compound (83 mg, 39%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz): 7.56 (dd, J=9.5, 8.0 Hz, 1H), 7.10 (dd, J=9.5, 4.0 Hz, 1H), 3.59 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].[H-].[Na+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:6]2=[O:13]
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1cc(C)c2c(c1O)C(=O)CC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=C2Cc3c(C)cc(C)c(O)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-inden-1-one was dissolved in 200 ml of dimethylformamide, then 5.45 g of 60%-sodium hydride was added gradually thereto and the reaction mixture was stirred at room temperature for 30 minutes. Next, 6.91 ml of p-anisaldehyde was added to the reaction mixture and further stirred at room temperature for 1 hour. The reaction mixture was poured into 500 ml of ice-water, then acidified by adding hydrochloric acid, and the crystals formed were collected by filtration. The crystals were washed with water and with n-hexane and dried. Recrystallized from ethanol to obtain 16.09 g of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzylidene)-1H-inden-1-one. Yellow needle-like crystals. Melting point: 192°-193° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C(OCC)C.CCCCCC>[CH2:1]([O:9][C:10]1[N:11]=[CH:12][C:13]([B:26]([OH:27])[OH:25])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCOc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(B(O)O)cn1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
2.75 g (10 mmol) of 2-octyloxy-5-bromopyridine are dissolved in 60 ml of absolute diethyl ether, and the solution is cooled to -75° C. under inert gas. 16 mmol of 1.6M butyllithium solution in hexane are added, and the mixture is additionally stirred at -75° C. for 15 minutes. 4.5 g of triisopropylborate in 50 ml of absolute diethyl ether are then added dropwise. The cooling device is then removed. After the batch has warmed to room temperature, 50 ml of 10% HCl are added, and the mixture is additionally stirred at room temperature for 30 minutes. The phases are separated, and the organic phase is washed twice with saturated NaCl solution. The solvent is distilled off in vacuo, and the residue is recrystallized from acetonitrile, giving 6-octyloxypyridine-3-boronic acid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:15][O:16][C:17](=[O:22])[CH:18]([CH2:20][OH:21])[NH2:19].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:15][O:16][C:17](=[O:22])[CH:18]([NH:19][C:11](=[O:13])[C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:10])[CH2:20][OH:21]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CO)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
A round-bottomed flask was charged with Boc-D-alanine (600 mg, 3.17 mmol) and DL-serine methyl ester hydrochloride (691 mg, 4.44 mmol). DMF (12 ml) was added followed by N,N-diisopropylethylamine (1.5 ml, 8.6 mmol) and HATU (1.33 g, 3.49 mmol). The yellow reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 422 mg (41%) of 2-((R)-2-tert-butoxycarbonylamino-propionylamino)-3-hydroxy-propionic acid methyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[O:15]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CO.[Cl-].[Na+].O>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Oc2ccccc2)cc1
Yield: 68.4 %

Procedure:
To 2.0 g of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 50 mL of methanol was added 2.2 g of 4-phenoxyaniline. After stirring the reaction under an inert atmosphere for 18 hr, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals filtered and washed with water. The product was then recrystallized from chloroformhexanes. Drying in vacuo yielded 2.35 g (69%) of 6-fluoro-4-(4-phenoxy-phenylamino)-[1.7]naphthyridine-3-carbonitrile as yellow needles: melting point 211-213° C.; mass spectrum (m/e): M+H 356.9.
Reaction SMILES: [CH2:1]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[C:14]([C:21]([OH:23])=[O:22])[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].S(Cl)(Cl)=O.[OH:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[CH:31][CH:30]=1>>[CH2:1]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:28][C:29]2[CH:44]=[CH:43][C:32]([C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[CH:31][CH:30]=2)=[O:17])=[C:14]([C:21]([OH:23])=[O:22])[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1ccc(C(=O)Cl)c(C(=O)O)c1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCc1ccc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)c(C(=O)O)c1

Procedure:
By customary procedures, 3.5 g of benzyl 4-undecylcarboxybenzoate was prepared from 2.3 g of benzyl 4-hydroxybenzoate and 2.5 g of lauric acid chloride, and this ester was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to obtain 2.8 g of 4-undecylcarboxybenzoic acid. The acid was converted to 4-undecylcarboxybenzoic acid chloride by thionyl chloride and the acid chloride was reacted with 1.8 g of benzyl 4-hydroxybenzoate to form benzyl 4-(4-undecylcarboxybenzoyloxy)benzoate. The ester was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to isolate the benzyl group and obtain 3.0 g of 4-(4'undecylcarboxybenzoyloxy)benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[N:14]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:13](=[O:27])[NH:12][C:11]([CH2:28][O:29][CH3:30])=[C:10]2[C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[F:8].[N+:35]([C:38]1[CH:39]=[C:40]([C:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH2:52][NH2:53])[CH2:48][CH:49]=2)[CH:41]=[CH:42][CH:43]=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].CO>ClCCl>[NH2:35][C:38]1[CH:39]=[C:40]([CH:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH2:52][NH:53][C:15]([N:14]3[C@@H:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[C:10]([C:31]([O:33][CH3:34])=[O:32])=[C:11]([CH2:28][O:29][CH3:30])[NH:12][C:13]3=[O:27])=[O:17])[CH2:48][CH2:49]2)[CH:41]=[CH:42][CH:43]=1
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reactant: NCCCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3cccc(N)c3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of 3.02 g (6.33 mmol) 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5 (2H)-pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-propanamine, 7.94 g (75.5 mmol) of K2CO3 and 1.00 mL of methanol in 200 mL dichloromethane (under argon) was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate and washed 3×50 mL of 5% aqueous NaOH solution, the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/c and the reaction mixture was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 9.5:0.5, dichloromethane:methanol+1% isopropyl amine) to afford 1.65 g (52.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.22–7.02 (m, 2H), 6.95 (t, J=8.70 Hz, 1H), 6.63–6.44 (m, 4H), 4.56 (Abq, 2H), 3.62 (s, 3H) 3.33 (s, 3H), 3.32-3.20 (m, 4H), 2.96 (br s, 2H), 2.33 (t, J=7.50 Hz, 2H), 2.11–1.94 (m, 3H), 1.81–1.64 (m, 4H); ESMS m/e: 572.3 (M+H)+;
Reaction SMILES: P(Br)(Br)([Br:3])=O.CN(C=O)C.[Br:11][C:12]1[C:21]([I:22])=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([CH2:23]O)=[CH:17]2>C(Cl)Cl>[Br:11][C:12]1[C:13]2[C:18](=[CH:17][C:16]([CH2:23][Br:3])=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:21]=1[I:22]
Reactant: O=P(Br)(Br)Br
Reactant: OCc1ccc2c(Br)c(I)ccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: BrCc1ccc2c(Br)c(I)ccc2c1
Reaction time: 0.17 h

Procedure:
To a solution of POBr3 (662 mg, 2.3 mmol) in 4.5 mL of CH2Cl2 at 0° C. was added DMF (2.25 mL) dropwise. The reaction was stirred for 10 minutes and then a solution of (5-bromo-6-iodo-2-naphthyl)methanol (280 mg, 0.77 mmol) in 5 mL of CH2Cl2 was added. The reaction mixture was stirred for 30 minutes, quenched with a saturated solution of NH4Cl, extracted with EtOAc and dried over Na2SO4. The organic extracts were evaporated to dryness to afford the titled product which was used as such in the next step.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[Cl-:21].[NH4+].N>C(OCC)(=O)C.O>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[ClH:21]
Reactant: [Cl-]
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: N
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cl

Procedure:
In a solution of sertraline base (50 g) in ethyl acetate/water 10/1 (400 ml), ammonium chloride (8,7 g) was added. The resulting mixture was heated at reflux temperature and stirred for 15 hours during which ammonia evolution was observed and a white crystalline solid precipitated. When the evolution of ammonia ended the solid product was filtered, washed with ethyl acetate and dried under vacuum. 50,5 g of sertraline hydrochloride form I (yield 90%) were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12]N1C(=O)C2=CC=CC=C2C1=O.ClNC1C=CC(C(F)(F)F)=CN=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C1c2ccccc2C(=O)N1Cl
Agent: FC(F)(F)c1ccc(NCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Into the same 300 ml four-necked flask as used in Example 1, 16.2 g (0.1 mol) of 2-amino-5-trifluoromethylpyridine, 20.9 g (0.115 mol) of N-chlorophthalimide and 150 g of toluene were added, and the reaction was carried out at 80° C. for one hour under heating with stirring. During the reaction, formation of 2-chloroamino-5-trifluoromethylpyridine was confirmed. After completion of the reaction, the reaction mixture was cooled to room temperature, and 50 g of a 25% sodium hydroxide aqueous solution was added thereto and stirred. An aqueous layer and an oil layer were separated. A 20% hydrochloric acid aqueous solution was added to the oil layer, and the mixture was stirred. An aqueous layer and an oil layer were separated again. The aqueous layer was neutralized with a 25% sodium hydroxide aqueous solution. Precipitated slightly yellow crystals were collected by filtration and dried to obtain 17.5 g 2-amino-3-chloro-5-trifluoromethylpyridine (purity as measured by liquid chromatography: 97%, yield: 86%).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:19])[NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].CN(C)[CH:22]=[O:23]>C1COCC1>[C:6]([O:10][C:11](=[O:19])[NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:22]=[O:23])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyllithium (1.7 M, 14.5 mL, 24.6 mmol, 2.39 equiv) was added to a solution of pyridin-3-yl-carbamic acid tert-butyl ester (6-1, 4.00 g, 20.6 mmol, 1 equiv) in THF (100 mL) at −78° C., and the resulting mixture stirred for 1 h. N,N-dimethylformamide (8.00 mL, 103 mmol, 5 equiv) was added, and the reaction mixture was warmed to 0° C. and stirred for 30 min. The mixture was partitioned between water (400 mL) and ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% ethyl acetate in hexanes, grading to 40% ethyl acetate in hexanes) to afford (4-formyl-pyridin-3-yl)-carbamic acid tert-butyl ester (6-2) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 9.89 (br s, 1H), 9.84 (s, 1H), 8.53 (d, 1H, J=4.8 Hz), 7.49 (d, 1H, J=4.8 Hz), 1.55 (s, 9H); TLC (EtOAc), Rf=0.47.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:23])[CH:3]=1.[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+].Cl>CCOC(C)=O.CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37][C:3]1[C:4](=[O:23])[O:5][C:6]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(c2ccccc2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(c3ccccc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-phenyl-5,6-dihydro-pyran-2-one (0.2 g, 0.64 mmol) from Example TT, toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 0.26 g, 0.71 mmol), K2CO3 (0.35 g, 2.5 mmol), and DMF (3 mL). The solution was stirred overnight at room temperature and then poured into 1N HCl and EtOAc. The organic phase was dried (MgSO4), and concentrated. Purification by silica gel chromatography, eluting with MeOH:CH2Cl2 :hexane (5:80:20 to 5:95:0) gave the title compound, m.p. 196-199° C. 1H NMR (DMSO-d6) δ 1.44 (s, 9 H), 1.76 (s, 3 H), 2.08-2.21 (m, 3 H), 2.42 (m, 1 H), 3.41 (dd, 2 H), 4.32 (s, 2 H), 4.91 (br s, 1 H), 6.16 (s, 1 H), 6.61 (d, 2 H), 6.86 (d, 2 H), 7.21 (s, 1 H), 7.34-7.46 (m, 5 H), 9.14 (s, 1 H), 12.15 (bs, 1 H).
Reaction SMILES: [CH:1]1([NH:4][C@@H:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=3)[CH2:7][C@@H:6]2[F:21])[CH2:3][CH2:2]1.[CH3:22][C:23]1[N:27]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[N:26]=[N:25][N:24]=1>>[CH:1]1([N:4]([C@@H:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][C@@H:6]2[F:21])[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([N:27]3[C:23]([CH3:22])=[N:24][N:25]=[N:26]3)=[CH:29][CH:30]=2)[CH2:2][CH2:3]1
Reactant: Cc1nnnn1-c1ccc(C(=O)O)cc1
Reactant: F[C@H]1CN(c2ccc(C(F)(F)F)cn2)CC[C@H]1NC1CC1
Product: Cc1nnnn1-c1ccc(C(=O)N(C2CC2)[C@@H]2CCN(c3ccc(C(F)(F)F)cn3)C[C@@H]2F)cc1

Procedure:
The title compound is prepared from (3S,4R)-cyclopropyl-(3-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 4-(5-methyl-tetrazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.26 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15]N(C)C>O.CN(C)C=O>[CH3:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:1]#[N:2]
Reactant: COc1ccc2[nH]cc(CN(C)C)c2c1C
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CC#N)c2c1C
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a solution of potassium cyanide (0.74 g) in 20 mL water was added a solution of (5-methoxy-4-methyl-1H-indol-3-ylmethyl)dimethylamine (0.5 g) in 20 mL of N,N-dimethylformamide. The solution was heated to reflux for 40 min, cooled to rt, and 40 mL of ice water was added. The aqueous layer was extracted with three portions of toluene, and the combined toluene layers were washed with water and brine. The solvent was removed in vacuo and the product purified by column chromatography dichloromethane) as the mobile phase to yield (5-methoxy-4-methyl-1H-indol-3-yl)-acetonitrile (0.40 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.CS(CCO)(=O)=[O:12].CC(C)([O-])C.[K+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([OH:12])[CH:5]=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CS(=O)(=O)CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Oc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (30.6 mL, 0.266 mole) and 2-(methylsulfonyl)ethanol (66 g, 0.531 mole) in DMSO (240 mL) was added potassium tert-butoxide (76.6 g, 0.682 mole) at 0° C. The resulting mixture was stirred at room temperature for 3 h and quench with 4N HCl slowly to pH≦1. The desired product was extracted with Et2O (12 L) until no product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure to one third the amount of the solvent and washed with 1N NaOH (12 L). Then, the NaOH solution was adjusted to pH=3 and extracted with Et2O until no desired product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure and passed through an Al2O3 column eluted with Et2O to afford 3-bromo-5-fluorophenol as a colorless oil (48 g, 94% yield). LC-MS 190.33 (M+H); Analytical HPLC=2.26 minutes (0-100% CH3CN in H2O with 0.1% TFA in a 4-min run); 1H NMR (400 MHz, CD3OD) δ ppm 6.88-6.64 (m, 2H), 6.58-6.30 (m, 1H), 4.99 (s, 1H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].I[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1>>[CH3:16][C:12]1[CH:11]=[C:10]([N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1N
Reactant: Cc1cccc(I)c1
Product: Cc1cccc(N(c2cccc(C)c2)c2ccccc2N(c2cccc(C)c2)c2cccc(C)c2)c1

Procedure:
The procedure of Example 1 was repeated except the use of 5.4 g of o-phenylenediamine of the formula (12) and 42.6 g of m-iodotoluene of the formula (14): ##STR11## as a starting material to obtain the expected compound of the formula (4) (12.6 g, yield: 55.1%).