Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH2:27]([O:29][CH:30]([O:34][CH2:35][CH3:36])[CH2:31][CH2:32]Cl)[CH3:28]>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH2:32][CH2:31][CH:30]([O:34][CH2:35][CH3:36])[O:29][CH2:27][CH3:28])[CH:11]=2)=[CH:4][N:3]=1
Reactant: CCOC(CCCl)OCC
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(CCOc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC)OCC
Yield: 82.1 %

Procedure:
To a solution of 27.6 g, (0.1 mole) of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine (D. E. Schwartz, W. Vetter, and G. Englert, Arzneim.-Forsch. (Drug Res.) 1970, 20, 1867; G. Rey-Bellet and R. Reiner, Helv. Chim. Acta 1970, 53, 945) in 400 mL of dry dimethyl sulfoxide was added 11.22 g (0.10 mole) of potassium t-butoxide. To the resulting suspension was added dropwise 17.92 g (0.107 mole) of β-chloropropionaldehyde diethylacetal. The mixture was heated at 65° overnight. The solvent was removed under vacuum and the residue was partitioned between 750 mL methylene chloride and 750 mL of 0.1N sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with an additional 750 mL of methylene chloride. The organic layers were combined, washed with 750 mL of water, dried (MgSO4), and purified by flash column chromatography to yield 33.38 g (83%) of the title compound (mp 105°-106.5°). Anal. Calcd for C 20 H30N4O5 : C, 59.10; H, 7.44; N, 13.78. Found: C, 58.71; H, 7.40; N, 13.58.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1.C=O.[C:21](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH3:21])[CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNCc1cccc(Br)n1)NC1CCCC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Reaction time: 0.75 h

Procedure:
N2-[(6-Bromopyridin-2-yl)methyl]-N-cyclopentylglycinamide (Example 187, Step 1) (0.33 g, 1.06 mmol) was dissolved in dichloromethane (5.30 mL) and formaldehyde (0.087 mL, 1.17 mmol) and acetic acid (0.12 mL, 2.12 mmol) were added. The reaction was stirred for 45 minutes and sodium triacetoxyborohydride (0.36 g, 1.70 mmol) was added. Once complete, the reaction was then quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[C:5]([CH2:11]SC)[C:3]=1[NH2:4]>[Ni].C(O)C>[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[C:5]([CH3:11])[C:3]=1[NH2:4]
Reactant: CSCc1cc(F)c(C)c(F)c1N
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(F)c(C)c(F)c1N
Yield: 84.8 %

Procedure:
To a solution of Raney nickel (50 g) in ethanol (100 ml) is added a solution of 2,4-difluoro-3-methyl-6-methylthiomethylaniline (4.79 g) in ethanol (30 ml) at room temperature with stirring, followed by stirring at room temperature for 30 minutes. The Raney nickel is filtered off and the filtrate is diluted with water, extracted with dichloromethane, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure to give 2,4-difluoro-3,6-dimethylaniline (3.14 g).
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(O[C:36]([NH:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([OH:58])=[C:45]([N:47]=[N:48][C:49]3[CH:57]=[CH:56][C:52]([C:53]([OH:55])=[O:54])=[CH:51][CH:50]=3)[CH:46]=2)=[O:37])C2CC3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.OC([CH2:71][CH2:72][CH2:73][CH2:74][C@H:75]1[C@@H:83]2[C@@H:78]([NH:79][C:80]([NH:82]2)=[O:81])[CH2:77][S:76]1)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO.C(Cl)Cl>[C:36]([NH:38][CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([OH:58])=[C:45]([N:47]=[N:48][C:49]2[CH:50]=[CH:51][C:52]([C:53]([OH:55])=[O:54])=[CH:56][CH:57]=2)[CH:46]=1)(=[O:37])[CH2:71][CH2:72][CH2:73][CH2:74][C@H:75]1[C@@H:83]2[C@@H:78]([NH:79][C:80]([NH:82]2)=[O:81])[CH2:77][S:76]1
Reactant: O=C(NCCc1ccc(O)c(N=Nc2ccc(C(=O)O)cc2)c1)Oc1cccc2c1Cc1ccccc1-2
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCc1ccc(O)c(N=Nc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-chlorotrityl resin (186 mg, 0.26 mmol) was added DCM (2 ml), 4-[5-(N-fluorenyloxycarbonyl-2-Aminoethyl)-2-hydroxyphenylazo]-benzoic acid (130 mg, 0.26 mmol) and DIEA (175 μl, 1.0 mmol). The mixture was gently shaken overnight at room temperature. Dry methanol (0.2 ml) was added to cap any unreacted resin (10 min). The resin was dried, and the loading efficiency was determined to be 0.85 mmol/g. The resin was swelled with dry DMF (2 ml) for 30 minutes, drained and treated with a 20% solution of piperidine in DMF (2 ml) for 30 minutes. The resin was drained and washed with DMF (5×5 ml) to remove residual traced of piperidine. To the resulting resin was added dry DMF (2 ml), biotin (73.3 mg, 0.30 mmol), PYBOP (156.1 mg, 0.30 mmol) and DIEA (104.5 μl, 0.60 mmol), and the resin was gently shaken at room temperature overnight. The resulting resin was drained, washed with DMF (3×3 ml), DCM (3×3 ml) and hexanes (3×3 ml) and dried in vacuo. Cleavage of the resin was performed using a 10% solution of TFA in DCM (10×2 minutes each). The organic fractions were combined, concentrated in vacuo, and dried via azeotrope with toluene to afford the desired 4-[5-(N-biotinyl-2-Aminoethyl)-2-hydroxyphenylazo]-benzoic acid (2) as an orange solid (65 mg, 50% from the benzoic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH2:7][CH2:6][CH2:5]2.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:23])=[CH:20][CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(N)ccc32)cc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(NCc4ccccc4)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2.9 g (9.5 mmol) of 6-amino1-[3-(4-cyano-phenyl)propionyl]-1,2,3,4-tetrahydro-quinoline are dissolved in 80 ml of methanol and 0.6 ml of acetic acid, combined with 1.06 g (10 mmol) of benzaldehyde and stirred for 20 minutes at 0° C. Then 0.63 g sodium cyanoborohydride are added in small batches, stirring is continued for half an hour and the mixture is then allowed to warm up to ambient temperature. The solution is then concentrated by rotary evaporation and the residue is taken up in a little ice water. Then the solution is acidified and sodium hydroxide solution is added until an alkaline reaction is obtained and the mixture is then extracted with me-thylene chloride. The dried solution is concentrated by rotary evaporation and the residue is chromatographed over a silica gel column with toluene/ethyl acetate (1:1).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:20])[CH:19]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=3)[N:4]([CH3:12])[N:3]=2)[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: Cn1nc(Br)c2cnc(N)nc21
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1nc(-c2cc(F)cc(F)c2)c2cnc(N)nc21

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (0.05 g, 0.22 mmol) is suspended in 1,4-dioxane (1 ml). The reaction mixture is sonicated to give a very fine suspension and placed in a microwave vial containing 3,5-difluoro phenylboronic acid (38 mg, 0.24 mmol). To this is added a solution of tris(dibenzylileneacetone) di palladium(0) (0.002 g, 0.0022 mmol) in 1,4-dioxane (0.5 ml) followed by a solution of tricyclohexyl phosphine (0.0015 g, 0.0053 mmol) in 1,4-dioxane (0.5 ml) and 1.27M aqueous potassium phosphate solution (0.294 ml, 0.374 mmol). The resulting mixture is flushed with argon and heated using microwave radiation at 150° C. for 30 minutes. The reaction mixture is treated with DMSO (2 ml) and filtered through a 2 g silica cartridge washing with EtOAc:MeOH (10:1, 4 ml). The filtrate is concentrated in vacuo and the resulting residue is dissolved in NMP (4 ml) and loaded onto an Isolute™ SCX column (silica based cation exchange sorbent) eluting with MeOH (4 ml) and 1M NH3 in MeOH (6 ml). The appropriate fractions are combined and concentrated in vacuo to afford the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>>[ClH:23].[N:20]1[CH:21]=[CH:22][C:17]([C:11]2([C:14]([NH2:16])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccncc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccncc2)CCNCC1

Procedure:
Prepare by the method of example 20.10 using 1-tert-butoxycarbonyl-4-(pyridin-4-yl)-piperidine-4-carboxylic acid amide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[N:5]([CH2:16][CH3:17])[CH:4]=1)#[N:2].N1C2C(=CC=C(C(OC)=O)C=2)C=C1.[OH-].[Na+]>C1COCC1>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH2:16][CH3:17])[CH:4]=1)#[N:2]
Reactant: CCn1cc(C#N)c2ccc(C(=O)OC)cc21
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCn1cc(C#N)c2ccc(C(=O)O)cc21
Yield: 95.1 %

Procedure:
A solution of methyl 3-cyano-1-ethyl-1H-indole-6-carboxylate (1.60 g, 7.02 mmol), prepared by the method described in example 1A from methyl 1H-indole-6-carboxylate, in THF (35 mL) is treated with 1N NaOH (7.7 mL, 7.7 mmol) and heated at reflux for 2.5 h. After cooling to room temperature, most of the THF is removed and the solution is diluted with H2O and extracted with ether (2×). The ether extracts are discarded. The aqueous phase is then acidified with 6N HCl to pH 2 and then extracted with EtOAc (3×). The EtOAc layers are combined, washed with saturated NaCl and then dried and concentrated to afford 1.43 g (95%) of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22].[O:23]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[N:5]=[CH:4][C:3]([C:21]#[N:22])=[C:2]2[NH:34][C:33]1[CH:32]=[CH:31][C:30]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:36][CH:35]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1N1CCN(C)CC1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cc1N1CCN(C)CC1
Temperature: 115 °C
Reaction time: 0.75 h
Yield: 62.2 %

Procedure:
A reaction mixture of 0.12 g (0.38 mmol) of 4-chloro-6-methoxy-7-(4-methylpiperazin-1-yl)-quinoline-3-carbonitrile, 0.077 g (0.42 mmol) of 4-phenoxyaniline and 0.044 g (0.38 mmol) of pyridine hydrochloride in 2 ml of 2-ethoxyethanol is heated at 115° C. for 45 minutes. After cooling, the mixture is filtered, washed with cold 2-ethoxyethanol, then ethyl acetate. After drying in vacuo, the solid is suspended in a saturated solution of sodium carbonate, stirred for 45 minutes and collected by filtration. The reaction product is washed with water and dried in vacuo, to provide 0.11 g of 6-methoxy-7-(4-methylpiperazin-1-yl)-4-(4-phenoxyphenylamino)-quinoline-3-carbonitrile as a yellow solid, mp softens at 93° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:1][C:2]1[C:3]([C:4](=[O:6])[S:36][C:33]2[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=2)=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1
Reactant: Cc1ccc(S)cc1
Reactant: Cc1ncc(-c2ccccc2)cc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(SC(=O)c2cc(-c3ccccc3)cnc2C)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of 2-methyl-5-phenylnicotinic acid (100 mg, 0.40 mmol) in CH2Cl2 (4 mL) was added oxalyl chloride (344 μL, 4.0 mmol). The mixture was stirred at 40° C. After 3 hours, the mixture was concentrated to dryness, dissolved in benzene (2×5 mL) and concentrated again. After dissolving the crude residue in CH2Cl2 (2 mL) at 0° C., pyridine (1 mL, 0.92 M in CH2Cl2), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and 4-methylthiophenol (60 mg, 0.48 mmol) were added. The mixture was then allowed to warm to room temperature. After stirring for 2 hours, the mixture was diluted with EtOAc, washed with 1N HCl, brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (100-80% hexanes/EtOAc gradient) to afford the title compound. LRMS (APCI) calculated for C20H18NOS [M+H]+, 320.1; found 320.1.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(=O)(O)O.[NH2:15][C:16]([NH2:18])=[NH:17].C(N(CC)C(C)C)(C)C.CN(C)C(=O)C>C(OCC)(=O)C.O>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[N:15][C:16]([NH2:18])=[N:17]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1ncc2ccc(F)cc2n1
Yield: 19.4 %

Procedure:
2,4-difluorobenzaldehyde (4.26 g, 30 mmol), guanidine carbonate (5.40 g, 30 mmol), N,N-diisopropylethylamine (3.87 g, 30 mmol), and N,N-dimethylacetamide (25 mL) are heated at 160 degrees Celsius overnight. The crude product is taken up in ethyl acetate/water. The organic layer is dried over magnesium sulfate, then concentrated and subjected to chromatography, affording the desired 7-fluoroquinazolin-2-amine (0.95 g, 19%). LC/MS m/z=164 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[O:9].Cl[CH2:11][CH:12]=[CH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:18]=1>CN(C=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:14]([CH:13]=[CH:12][CH2:11][N:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]3=[O:9])[S:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(-c2csc(C=CCCl)n2)cc1
Reactant: O=c1cccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccccn1CC=Cc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
23.7 mg (0.54 mmol) of sodium hydride (55% in mineral oil) were added to 60.4 mg (0.54 mmol) of 1H-pyridin-2-one in 8 ml of DMF. The mixture was stirred at room temperature for 1 h, 92 mg (0.36 mmol) of 2-(3-chloropropenyl)-4-(4-fluorophenyl)thiazole were added, and the mixture was stirred at room temperature for another 4 h and subsequently at 50° C. for 2 h. After concentrating, water was added and the product was extracted with ethyl acetate. The organic phases were evaporated and the residue was purified by preparative HPLC (RP18, acetonitrile/water containing 0.1% TFA). Yield: 26 mg (23%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[Cl:17][C:18]1[C:19]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[C:20]=2[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1>>[Cl:17][C:18]1[C:19]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)[C:29]3=[O:37])[C:20]=2[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1
Reactant: O=C1Nc2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3
Reactant: BrCc1ccccn1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 6-chloro-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 197-199° C.; 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J=2.1 Hz, 1H), 7.60 (ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.25-7.15 (m, 3H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.79 (s, 1H), 5.35 (d, J=16.2 Hz, 1H), 5.00 (d, J=9.3 Hz, 1H), 4.89 (d, J=16.2 Hz, 1H), 4.74 (d, J=9.0 Hz, 1H), 4.16-3.86 (m, 4H); 13C NMR (75 MHz, CDCl3) δ175.9, 155.8, 151.7, 149.5, 141.8, 138.6, 138.3, 136.7, 130.9, 128.9, 123.6, 123.4, 122.6, 121.4, 118.2, 116.8, 109.4, 106.8, 81.7, 64.5, 63.8, 57.7, 46.3; MS (ES+) m/z 421.2 (M+1), 423.2 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[C:12](I)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:61][C:62]1[CH:71]=[CH:70][CH:69]=[CH:68][C:63]=1[C:64]([NH:66][CH3:67])=[O:65]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([NH:61][C:62]2[CH:71]=[CH:70][CH:69]=[CH:68][C:63]=2[C:64]([NH:66][CH3:67])=[O:65])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Reactant: CNC(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Temperature: 80 °C
Yield: 67.9 %

Procedure:
Cesium carbonate (3.40 g, 10.43 mmol) was added to 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1.604 g, 5.22 mmol), palladium(II) acetate (0.094 g, 0.42 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.362 g, 0.63 mmol) and 2-amino-N-methylbenzamide (0.784 g, 5.22 mmol) in dioxane (40 mL). The resulting suspension was heated at 80° C. for 24 hours under an argon atmosphere. The mixture was filtered through Celite and then purified directly by chromatography on silica eluting with a mixture of 50% EtOAc in isohexane. Fractions containing product were combined and evaporated to leave 2-[[2-chloro-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide (1.168 g, 68% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.76 (3H, d), 7.24 (2H, dd), 7.57 (2H, ddd), 7.74 (1H, dd), 8.49 (1H, d), 8.71 (1H, d), 10.54 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=329.99 and 331.95.
Reaction SMILES: C([N:5]1C(=O)C(COS(C)(=O)=O)=CC(C2C=CC(C)=CC=2)=[N:6]1)C(C)C.C([O:27][C:28]([C:30](O)([CH2:36][C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=1)=O)[C:31](OCC)=[O:32])=[O:29])C>>[C:28]([C:30]1[C:31](=[O:32])[NH:5][N:6]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:36]=1)([OH:27])=[O:29]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(C(F)(F)F)cc1)C(=O)OCC
Product: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)n[nH]c1=O
Yield: 91.4 %

Procedure:
Following the procedure of Example 1 (4), ethyl 2-ethoxycarbonyl-2-hydroxy-4-(4-trifluoromethylphenyl)-4-oxobutanoate was reacted to yield the title compound as a pale brown crystalline powder (yield: 91.4%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:14])[CH:11]=2)[C:6]1=O)=[O:4].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:14])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1Cc2cc(Br)ccc2C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1Cc2ccc(Br)cc2C1
Reaction time: 18 h

Procedure:
Use of 5-bromo-indan-1-one (Intermediate NINETEEN-1) in a reaction with NaH and dimethylcarbonate (refer to procedures in Method EIGHTEEN) produced 5-bromo-1-oxo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-2). A solution of 5-bromo-1-oxo-indan-2-carboxylic acid methyl ester (4.75 g, 17.7 mmol) in TFA (80 mL) at 0° C. was treated with triethylsilane (TES) (17.0 mL, 6.0 eq) and stirred for 18 h. After evaporation of the solvent, the residue was diluted with Et2O and washed with H2O (5×100 mL), sat. NaHCO3 (3×50 mL), brine (1×75 mL) and dried over MgSO4 to give crude 5-bromo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-3). A solution of 5-bromo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-3) in AcOH containing 20% HCl was stirred overnight. After evaporation of the solvent, the residue was dissolved in 1N NaOH. The resulting mixture was washed with Et2O (3×75 mL) after which it was acidified with HCl (aq). The solution was extracted with CH2Cl2 (3×150 mL) and the combined organic extracts was washed with H2O (3×100 mL), brine (1×75 mL), dried over MgSO4 and concentrated to give crude 5-bromo-indan-2-carboxylic acid. Use of 5-bromo-indan-2-carboxylic acid in Method EIGHTEEN produced 4-(5-bromo-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 148).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].[F:8][C:9]([F:19])([F:18])[O:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[CH3:1][C:2]1([CH3:7])[CH2:3][C:4](=[O:5])[C:14]2[C:13](=[CH:12][C:11]([O:10][C:9]([F:8])([F:18])[F:19])=[CH:16][CH:15]=2)[O:17]1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: CC(C)=CC(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CC(=O)c2ccc(OC(F)(F)F)cc2O1
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
Eaton's reagent (225 mL) was heated to 70° C. and 3-methylbut-2-enoic acid (28.1 g, 281 mmol) and 3-(trifluoromethoxy)phenol (25.0 g, 140 mmol) were added. After 30 min, additional 3-methylbut-2-enoic acid (1 equiv, 14 g) was added and heating was continued. After 30 min, additional Eaton's reagent (150 mL) was added and heating was continued for 35 min. The dark solution was cooled and poured into ice. The aqueous suspension was extracted with Et2O (300 mL), and the organic portion was washed with water (75 mL) and brine (50 mL). The organic portion was dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (gradient elution, 0-20% EtOAc/hexanes) to give the title compound (11.7 g, 45.0 mmol, 32%) as a white solid. MS (ESI) m/z 261 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16]([OH:18])=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1.S(Cl)([Cl:21])=O>>[ClH:21].[ClH:1].[N:3]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16]([Cl:21])=[O:18])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)C1(c2ccc(N3CCC3)nc2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: O=C(Cl)C1(c2ccc(N3CCC3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-(6-azetidin-1-ylpyridin-3-yl)cyclopropanecarboxylic acid dihydrochloride (61.00 mg, 0.0002095 mol) were added thionyl chloride (1.00 mL, 0.0137 mol) at 0° C. and the resulting solution was stirred at rt for 1 hr. Upon completion, the reaction mixture was azeotroped with toluene (3×) and then used in the next step without further purification.