Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([C:8]1[N:13]=[C:12]([CH:14]=[O:15])[CH:11]=[C:10]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(CO)nc(Cc3ccccc3)n2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C=O)nc(Cc3ccccc3)n2)cc1
Reaction time: 0.5 h
Yield: 545 %

Procedure:
To a solution of the product from Step B (0.102 g, 0.35 mmol) in CH2Cl2 (2 mL) was added the Dess-Martin periodinane (0.228, 0.53 mmol). After 30 min, the mixture was diluted satd. aq. NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were dried, concentrated, and filtered through a small plug of SiO2 (25% EtOAc in hexanes). The filtrate was concentrated to give 2-benzyl-6-p-tolyl-pyrimidine-4-carbaldehyde (0.55 g, 54%). To a solution of this aldehyde in CH2Cl2 (3 mL) was added dimethylamine (2 M in THF; 0.15 mL, 0.30 mmol) and NaBH(OAc)3 (0.058 mg, 0.27 mmol). After 15 h, the reaction was diluted with CH2Cl2 and washed with 1 N NaOH. The aqueous layer was extracted with CH2Cl2 (1×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (1-7% 2 M NH3 in MeOH/CH2Cl2) to give 0.050 g (79%) of the title compound. MS (ESI): exact mass calcd. for C21H23N3, 317.19; m/z found, 318.4 [M+H]+. 1H NMR (CDCl3): 8.02 (d, J=8.2, 2H), 7.66 (s, 1H), 7.22 (d, J=7.5, 2H), 7.31-7.26 (m, 4H), 7.22-7.18 (m, 1H), 4.33 (s, 2H), 3.58 (s, 2H), 2.41 (s, 3H), 2.32 (s, 6H).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)O)[CH:20]=[CH:19][C:18]=1[CH3:33].C(=O)(O)[O-].[Na+]>>[CH3:15][O:16][C:17]1[C:18]([CH3:33])=[CH:19][CH:20]=[C:21]([CH2:23][C:25]2[CH:26]=[CH:27][C:28]([S:31][CH3:32])=[CH:29][CH:30]=2)[N:22]=1
Reactant: COc1nc(C(O)c2ccc(SC)cc2)ccc1C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(Cc2ccc(SC)cc2)ccc1C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Triethylsilane (5 mL) and trifluoroacetic acid (5 mL) were sequentially added to (6-methoxy-5-methylpyridin-2-yl)[4-(methylsulfanyl)phenyl]methanol obtained in Reference Example 1-36(2) (2.13 g), and the mixture was stirred at 60° C. for four hours. The reaction solution was poured into saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1→2:1) to give the title compound as a colorless oil (1.69 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:34]=[CH:33][C:25]2[N:26]([CH3:32])[C:27](=[O:31])[CH2:28][CH2:29][CH2:30][C:24]=2[CH:23]=1.Cl>CC(O)C.O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:34]=[CH:33][C:25]4[N:26]([CH3:32])[C:27](=[O:31])[CH2:28][CH2:29][CH2:30][C:24]=4[CH:23]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Yield: 70.1 %

Procedure:
3-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (36.0 mg, 0.109 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (22.8 mg, 0.120 mmol) were slurried in iPrOH (1.5 mL) prior to adding ˜0.2 mL of 4N HCl in dioxane. This mixture was heated in a microwave reactor (sealed vessel) at 120° C. for 40 min. The mixture was extracted into DCM, washed with saturated aqueous NaHCO3 solution and the organic layer was dried by passing through a plug of Na2SO4. The resulting filtrate was evaporated and the residue purified by chromatography (silica gel, DCM/5% NH4OH-MeOH gradient). The appropriate fractions were combined and evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (37.1 mg, 70%) as a yellow foam that had the following properties: m.p.=145-160° C.; LC/MS (ESI+): 485 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 8.11 (s, 1H), 8.01 (s, 1H), 7.61 (d, 1H, J=8.1), 7.53 (d, 1H, J=8.1), 7.35-7.20 (m, 3H), 6.95 (m, 2H), 6.10 (br s, 1H), 3.38 (s, 3H), 2.83 (d, 3H, J=5.0), 2.55 (m, 2H), 2.24 (m, 2H), 2.09 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14](CC2C=CC=CC=2)[CH3:15])=[O:9])[CH2:3]1>CO.[OH-].[Pd+2].[OH-].[C].[H][H]>[F:1][C:2]1([F:30])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][CH3:15])=[O:9])[CH2:3]1
Reactant: CN(CCCOC(=O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNCCCOC(=O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 41 mg of 3-(benzyl(methyl)amino)propyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 2 ml of methanol, 10 mg of palladium hydroxide-carbon catalyst was added, followed by 2 hours' stirring at ambient temperature and pressure in hydrogen atmosphere. The reaction liquid was filtered with Celite. Distilling the solvent off from the filtrate under reduced pressure, 32 mg of the title compound was obtained.
Reaction SMILES: O=[C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][C:5]#[N:6].[F:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16](=[S:19])[NH:17][NH2:18]>C(O)C>[F:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]1[S:19][C:2]([CH2:3][CH2:4][C:5]#[N:6])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:18][N:17]=1
Reactant: N#CCCC(=O)c1ccccc1
Reactant: NNC(=S)c1cc(F)ccc1F
Solvent: CCO
Product: N#CCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 90 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 4-oxo-4-phenylbutanenitrile (0.076 g, 0.48 mmol) in ethanol (5 mL) was added 2,5-difluorobenzothiohydrazide (0.09 g, 0.48 mmol). After stirring at 90° C. for 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (20% ethyl acetate in hexanes) to provide the product (0.087 g, 55% yield).
Reaction SMILES: [CH2:1]=[C:2]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.CC[O-].[Na+]>CS(C)=O>[CH:13]1[C:14]2[CH:2]([CH2:1][CH:26]3[C:27]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:20]4[C:25]3=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: C=C1c2ccccc2-c2ccccc21
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)-c1ccccc1C2CC1c2ccccc2-c2ccccc21
Temperature: 90 °C
Yield: 28.1 %

Procedure:
A mixture of dibenzofulvene (1 g, 5.68 mmol), fluorene (0.93 g, 5.68 mmol) and EtONa (0.19 g, 2.79 mmol) in DMSO (20 mL) was heated at 90° C. for 16 hours, and was then cooled to room temperature. After carrying out the work-up, as reported in Example 8, 0.55 g of bis(9-fluorenyl)methane were obtained, with a yield of 28%.
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[Br:10].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]([F:9])=[CH:5][C:4]=1[Br:10]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Oc1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A rapidly stirred solution of 946 g (3.8 moles) of 2-bromo-4-fluorophenyl methyl carbonate in 1292 mL of sulfuric acid was cooled to 5°-10° C., and 368 g (4.18 moles) of 70% nitric acid was added dropwise over two hours. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature and was stirred for two hours. The reaction mixture was poured into 5000 mL of ice water. Any material remaining in the reaction vessel was washed into the ice-water with 750 mL of water. The resultant solid was collected by filtration and washed with 1000 mL of water. The solid was dried with mild heat under reduced pressure to give 1031 g of 2-bromo-4-fluoro-5nitrophenyl methyl carbonate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1.[Br:10][CH2:11][C:12](Br)=[O:13].C(N(CC)CC)C>C(Cl)Cl>[Br:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1)=[O:13]
Reactant: O=C(Br)CBr
Reactant: Nc1cc(Cl)nc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1cc(Cl)nc(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 4-amino-2,6-dichloro-pyridine (4.7 g, 28.8 mmol) in DCM, bromoacetyl bromide (2.56 ml, 29.4 mmol) is added. The solution is cooled to 0° C. and stirred for 5 minutes before treating dropwise with triethylamine (7.87 ml, 57.7 mmol). The reaction mixture is gradually allowed to warm to RT and stirred for 48 hours. The reaction mixture is diluted with DCM and washed with water several times. The organic extracts are dried, filtered and concentrated in vacuo. The crude product is purified using flash column chromatography on silica (DCM/Isohexane) to afford the title compound.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:27][C:28]([C:30]1([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:27][C:28]([C:30]1([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)#[N:1]
Reactant: CN1CCN(S(=O)(=O)c2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc2)CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4′-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 29, step (i), 267 mg) in dichloromethane (10 mL) was treated with Burgess' reagent (202 mg) and the mixture was stirred at room temperature for 18 h. The solvent was partially evaporated under reduced pressure and the mixture was purified by chromatography on silica eluting with methanol/dichloromethane (0:100 to 5:95), triethylamine/methanol/dichloromethane (1:5:95) to afford the sub-titled compound (250 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([CH2:17][CH3:18])[C:14](O)=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][CH:13]([CH2:17][CH3:18])[C:14](=[O:15])[N:11]=1
Reactant: CCC(Br)C(=O)O
Reactant: NC(=S)Nc1ccccc1Cl
Product: CCC1SC(Nc2ccccc2Cl)=NC1=O

Procedure:
Synthesis was performed from N-(2-chlorophenyl)thiourea and 2-bromo-butyric acid according to Method C1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]#[C:25][Si](C)(C)C)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl-].[NH4+].C(OCC)(=O)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:32])([F:31])[F:33])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]#[CH:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)C#Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12

Procedure:
A solution of tetrabutylammonium chloride (1 M in THF, 2.25 ml) is slowly added to a solution of crude 5-(3,5-dichloro-phenyl)-5-trifluoromethyl-3-(4-trimethylsilanylethynyl-naphthalen-1-yl)-4,5-dihydro-isoxazole (step A) in THF (25 ml) at 5° C. After 3 hours at 5° C. a saturated solution of ammonium chloride and ethyl acetate are added. The organic phase is washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-(3,5-dichloro-phenyl)-3-(4-ethynyl-naphthalen-1-yl)-5-trifluoromethyl-4,5-dihydro-isoxazole as a brown solid.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[N:12][C:11]([OH:14])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C.CS(C)=O>[CH2:20]([O:19][C:17]([CH:16]([O:14][C:11]1[N:12]=[CH:13][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[N:10]=1)[CH3:22])=[O:18])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2cccc(F)c2)n1
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(F)c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A 1.7 g portion of sodium was dissolved in 50 ml of absolute ethanol, and that solution was added to a solution of 13.3 g of 1-(3-fluorophenyl)-3-hydroxy-1,2,4-1H-triazole in 150 ml of dimethylsulfoxide. The solution was heated on the steam bath for 15 minutes, and then 13.5 g of ethyl 2-bromopropionate was added and the mixture was held on the steam bath for 2 hours. It was then poured over ice-water, and the aqueous mixture was extracted with diethyl ether. The organic layer was washed with water and with brine, and was then dried with sodium sulfate and phase separation paper. The solvent was removed under vacuum, and the product was recrystallized from aqueous ethanol to obtain 6.7 g of the desired product, m.p. 35°-37°.
Reaction SMILES: [ClH:1].O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[Al+3].[Cl-].[Cl-].[Cl-].O.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:1].[C:15]1([C:6]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 4-piperidone monohydrate hydrochloride (15.0 g, 97.6 mmol, 1.00 equiv) and AlCl3 (130 g, 976 mmol, 10.0 equiv) in anhydrous benzene (600 mL) was stirred at reflux for 4 hours. The mixture was cooled to room temperature, poured into ice (300 g) and water (50 mL), and filtered. The solid was washed with toluene and dried to afford 19.2 g (72%) of off-white solid, which was characterized spectroscopically.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Cl:29]C1SC2C=C(Cl)C=CC=2N=1>>[Cl:29][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: Clc1ccc2nc(Cl)sc2c1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(Cl)cc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2,6-dichloro-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.30 (m, 4H), 3.06-3.18 (m, 2H), 3.41 (d, J=13.2 Hz, 2H), 4.52 (ddd, J=14.8, 10.6, 4.2 Hz, 1H), 7.62 (dd, J=8.8, 1.8 Hz, 1H), 8.05 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.31 (br. s., 1H), 8.37 (br. s., 2H), 8.53 (s, 1H). MS (ES+): m/z=411.08 [MH+]. HPLC: tR=2.30 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: Cc1cnc(N2CCC(=O)CC2)nc1
Product: Cc1cnc(N2CCC(NC3CC3)CC2)nc1

Procedure:
The title compound is prepared from 1-(5-methyl-pyrimidin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 7. LC (method 1): tR=0.55 min; Mass spectrum (ESI+): m/z=233 [M+H]+.
Reaction SMILES: Cl[Si:2]([CH3:18])([CH3:17])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:15])=[C:4]1[CH3:16].CCN(CC)CC.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>CCCCCC>[CH3:27][C:26]([NH:30][Si:2]([CH3:18])([CH3:17])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:15])=[C:4]1[CH3:16])([CH3:29])[CH3:28]
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2cc3c(cc21)CCC3
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1=C(C)C([Si](C)(C)NC(C)(C)C)c2cc3c(cc21)CCC3
Reaction time: 16 h
Yield: 92.7 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2,3-dimethyl-s-indacen-1-yl) silane (3.537 g, 0.01217 moles) was stirred in hexane (50 mL) as NEt3 (1.94 g, 0.01916 moles) and t-butylamine (1.12 g, 0.01533 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a light yellow oil (3.537 g, 88.6 percent).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.COCCOC.Br[C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[C:36]([CH:37]([F:48])[C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=4)=[C:35]([CH:49]4[CH2:54][CH2:53][C:52]([F:56])([F:55])[CH2:51][CH2:50]4)[C:34]4[CH:33]([O:57]CC5C=CC(OC)=CC=5)[CH2:32][C:31]([CH3:68])([CH3:67])[CH2:30][C:29]=4[N:28]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1>C1(C)C=CC=CC=1>[F:56][C:52]1([F:55])[CH2:51][CH2:50][CH:49]([C:35]2[C:34]3[CH:33]([OH:57])[CH2:32][C:31]([CH3:67])([CH3:68])[CH2:30][C:29]=3[N:28]=[C:27]([CH:24]3[CH2:23][CH2:22][N:21]([C:18]4[N:19]=[CH:20][C:15]([N:5]5[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]5)=[CH:16][N:17]=4)[CH2:26][CH2:25]3)[C:36]=2[CH:37]([F:48])[C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:45])([F:47])[F:46])=[CH:42][CH:43]=2)[CH2:54][CH2:53]1
Reactant: OC1CCNCC1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(N5CCC(O)CC5)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Reference Example 13 and Example 7 were performed except for using 4-hydroxy piperidine and 1,2-dimethoxyethane instead of isonipecotic acid ethyl ester and toluene, and from 150 mg (0.180 mmol) of (−)-2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, 55 mg of the title compound was obtained as a light yellow solid (yield: 42%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17](O)=O>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[C:17]([C:16]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:15]=3[O:14][CH3:13])[NH:10][C:5]=2[CH:4]=1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1N
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ccc(C(F)(F)F)cc2[nH]1

Procedure:
Prepared analogously to Example 14 from 4-trifluoromethyl-1,2-phenylenediamine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:14]=[CH:15][CH:16]=2)[C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[Br:17]N1C(=O)CCC1=O>ClCCl>[Br:17][C:16]1[CH:15]=[N:14][N:6]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[C:2]([CH3:1])[CH:3]=[N:4][C:5]=12
Reactant: Cc1cnc2ccnn2c1-c1cccnc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1cnc2c(Br)cnn2c1-c1cccnc1
Temperature: 0 °C

Procedure:
A mixture of 1.65 g. of 6-methyl-7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine and 1.54 g. of N-bromosuccinimide in 50 ml. of dichloromethane is heated on a steam bath for 15 minutes. The mixture is poured into 100 ml. of ice cold 2.5 N sodium hydroxide. The dichloromethane layer is separated, dried over anhydrous sodium sulfate and passed through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give 1.20 g. of the product of the example, m.p. 166°-168° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7].[OH-].[Na+]>C(O)C>[CH2:6]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7]
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
Tin (II) chloride dihydrate (51.89 g, 0.230 mol) was added to 1-(ethylsulfonyl)-4-nitrobenzene (10 g, 0.046 mol) in ethanol (250 ml) then heated under reflux for 16 h. The mixture was cooled to room temperature and treated with aqueous sodium hydroxide (2N, 100 ml). The product was then extracted into ethyl acetate (3×150 ml). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The residue was then purified by chromatography column over silica (50% ethyl acetate/50% petroleum ether) to afford 4-(ethylsulfonyl)-benzene amine. δ(1H NMR, DMSO, ppm): 1.00 (3H, t), 2.95 (2H, q), 5.95 (2H, s), 6.55 (2H, d), 7.35(2H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:35])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:34].[Li+].[OH-].Cl>C1COCC1.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10](=[O:35])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:32])[CH3:33])[C:27]([OH:29])=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:34]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cc(C(=O)NC(C(=O)O)C(C)C)on2)ccc1NC(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of the crude compound of step 8, LiOH (3.0 equiv.) and 50 ml of 5:1 THF/water was stirred at room temperature for 15 minutes. The reaction mixture was slightly acidified to pH <7 by adding 2N HCl and then evaporated to dryness under vacuum. The residue was dissolved in a chloroform and methanol mixture, adsorbed on silica (100-200 mesh) and purified by flash chromatography on silica gel, and then eluted with 2-15% methanol in chloroform to provide the title compound as a pale green solid after drying in vacuo; 1H NMR (300 MHz, DMSO-d6) δ: 0.85-0.88 (d, J=6.6 Hz, 6H), 2.14-2.19 (m, 1H), 2.34 (s, 3H), 3.92-3.96 (m, 1H), 7.11-7.16 (m, 2H), 7.24-7.31 (m, 1H), 7.60 (S, 1H), 7.67-7.70 (d, J=8.7 Hz, 1H), 7.76 (s, 1H), 8.01-8.04 (m, 2H), 8.86 (s, 1H), 9.24 (s, 1H); ms (ESI) m/z 473.2 [M+H]+.