Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH3:6].C[CH:8]([C@@H:12]1[CH2:17][CH2:16][NH:15][C@H:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:13]1)[C:9]([O-:11])=[O:10]>>[CH3:6][O:5][CH2:4][CH2:3][CH2:2][C@@H:14]([N:15]1[CH2:16][CH2:17][C@@H:12]([CH2:8][C:9]([OH:11])=[O:10])[CH2:13][C@H:14]1[C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=1)[C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=1
Reactant: COCCCBr
Reactant: CC(C(=O)[O-])[C@@H]1CCN[C@H](c2ccc(C(F)(F)F)cc2)C1
Product: COCCC[C@H](c1ccc(C(F)(F)F)cc1)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
The compound was prepared analogously to Example 160 using the Grignard reagent derived from 1-bromo-3-methoxypropane and starting with the chiral piperidine of Example 114 Step 1. M/Z (ES+) 518 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.9 %

Procedure:
To a solution of 4-(4-bromophenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (26 mg, 20%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.N[C:31]1([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].C[N:45](C)C=O>>[CH:31]1([CH2:37][NH:45][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC1(N)CCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNCC4CCCCC4)cc2)CCO3)cc1
Temperature: 25 °C

Procedure:
A suspension of N-(4-chloromethylphenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g), amino-methylcyclohexane (0.05 g) and potassium carbonate (0.1 g) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent. was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4—((cyclohexylmethyl)aminomethyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 122) (0.06 g) as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)=[O:2].[CH3:17][Mg]Br.Cl>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1)[CH3:17]
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 4′-formylbiphenyl-2-carbonitrile (10.00 g) in tetrahydrofuran (100 mL) was slowly added dropwise a 1 M solution (50 mL) of methylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into 1 M hydrochloric acid (60 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (10.03 g, 93%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12](Br)[C:13]#[CH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:14][C:13]#[CH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccccc1C(C)(C)C
Yield: 100.2 %

Procedure:
2-Tert-butylphenol (15.02 g, 15.4 ml, 100 mmol), propargyl bromide (14.3 ml of 80% in toluene, 128 mmol), and potassium carbonate (17.66 g, 128 mmol) were stirred together in 200 ml of acetonitrile at ambient temperature for 5 days. The solvent was removed under reduced pressure, and the residue taken into water and extracted with diethyl ether. The organic layers were combined, dried with magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to give 18.86 g of the title compound which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 7.30 (dd, J=7.80, 1.70 Hz, 1 H), 7.15-7.22 (m, 1 H), 6.90-6.98 (m, 2 H), 4.73 (d, J=2.37 Hz, 2 H), 2.48 (t, J=2.37 Hz, 1 H), 1.39 (s, 9 H). MS (DCI) m/e 206 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[ClH:31].[CH:32](O)([CH3:34])[CH3:33]>>[ClH:31].[ClH:31].[CH:32]([O:22][C:21](=[O:23])[CH2:20][O:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)([CH3:34])[CH3:33]
Reactant: CC(C)O
Reactant: O=C(O)COC/C=C\CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: Cl
Product: CC(C)OC(=O)COC/C=C\CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 75.85 %

Procedure:
To a stirred solution of {4-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-yl}-(Z)-but-2-enyloxy}acetic acid (1.0 g, 0.0024 mol) in isopropyl alcohol (20 ml), is added a solution of anhydrous HCl in isopropyl alcohol till pH of solution is 1-2. The solution is refluxed for around 2 hrs, cooled to 25-30° C. and stirred for 4 hrs. The crystallized solid is filtered, washed with isopropyl alcohol (2×5 ml), and dried in oven at 60-65° C. to get product 0.968 g (75.85% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>O>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Brc1ccccn1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2ccccn2)cc1
Temperature: 95 °C

Procedure:
2-Bromopyridine (650 μL), 4-nitrophenylboronic acid (1.479 g) and palladium tetrakistriphenylphosphine (391.5 mg) were added to a mixture of 40 mL of dimethoxyethane and 10 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 95° C. overnight. The reaction mixture was then cooled to room temperature and diluted with water (200 mL). The resulting precipitate was collected, washed with water and air-dried. The dried material was purified using silica gel chromatography to give 1.40 g of 2-(4-nitrophenyl)pyridine.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CO>[Cl:19][CH2:18][CH2:17][CH2:16][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ClCCCOc1ccc(-n2ccnc2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 20.3 %

Procedure:
To a stirring solution of 4-(imidazol-1-yl)phenol (20. g, 125 mmol) and NaOH (5.0 g, 125 mmol) in methanol (600 mL) was added 1-bromo-3-chloropropane (49 mL, 500 mmol). The reaction was stirred for 18 hours at 70° C. under nitrogen, concentrated, and partitioned between 1.0 N NaOH/CH2Cl2The organic phase was dried and concentrated to afford crude product which was purified by HPLC (5% CH3OH/CH2Cl2) to give 6.0 g (20%) of 1-[4-(3-chloropropoxy)phenyl]-1H-imidazole as a brown solid: mp 53°-55° C.; 1H NMR (CDCl3): δ 7.80 (brs, 1H), 7.30 (m, 3H), 7.20 (bs, 1H), 4.16 (t, J=6.0 Hz, 2H), 3.76 (t, J=6.0 Hz, 2H), 2.30 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][CH:10]([CH:13]=[CH2:14])[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH:10]([CH3:11])[CH:13]=[CH2:14])[CH:3]=1
Reactant: Cc1cccc(S)c1
Reactant: C=CC(C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CC(C)CSc1cccc(C)c1
Yield: 22 %

Procedure:
A mixture of 3-methylbenzenethiol (1.80 ml, 23.82 mmol), 2-methyl-3-buten-1-ol (2.73 ml, 26.47 mmol) and triphenylphosphine (6.94 g, 26.47 mmol) in dichloromethane (10 ml) was treated with diethyl azodicarboxylate (4.59 ml, 29.12 mmol) at room temperature. The mixture was concentrated in vacuo and dissolved in diethyl ether to remove triphenylphosphine oxide. The organic phase was purified by flash column chromatography on silica, eluting with hexane, to afford the title compound as a clear oil (1.01 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][N:11]2[C:15](=O)[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3C2=O)=[C:4](C(=O)C2C=CC=CC=2)[CH:3]=1.O.NN>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:8]=[CH:9][CH2:10][N:11]=[C:15]([C:14]3[CH:13]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:7]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1C=CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cl
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC=C2

Procedure:
A mixture of 6 g (15 mmole) of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropene, 0.9 g (18 mmole) of 85% hydrazine hydrate and 70 ml of 95% ethanol was refluxed for 2.5 hr. The insoluble precipitate formed was separated by filtration. The filtrate was acidified with ice cold dilute hydrochloric acid and extracted with ether. The aqueous layer was separated, made alkaline with dilute sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate, acidified with methanolic hydrogen chloride, diluted with isopropanol and concentrated at reduced pressure to a small volume. The crude product was collected by filtration to give tan prisms, mp 223°-225° C. dec.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[C:4]([CH3:10])([CH3:9])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].ClCCl>C1COCC1.CO>[OH:8][CH:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][C:4]1([CH3:10])[CH3:9]
Reactant: CC1(C)CC(N)CCC1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(NC(=O)OCc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To a mixture of 4-amino-2,2-dimethylcyclohexanol (1.0 equiv.) in 1.7 M sodium carbonate solution (1.3 equiv.) and THF (1.3 M) was added benzyl chloroformate (1.5 equiv.) slowly at 0° C. After addition, the mixture was stirred at room temperature overnight. TLC (dichloromethane:MeOH=10:1) showed that the reaction was completed. The mixture was filtered and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give crude racemic product, which was purified by silica gel column chromatography (DCM:MeOH=20:1) to afford benzyl (4-hydroxy-3,3-dimethylcyclohexyl)carbamate (110 g, 49.4%) as colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.O1CCOCC1>O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[CH:3]=[C:2]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccccc1-c1cc(Cl)c2cccnc2n1
Reactant: Nc1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccccc1-c1cc(Nc2ccncc2)c2cccnc2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a suspension of 259 mg (1.00 mmol) 4-chloro-2-(2-fluorophenyl)-[1,8]naphthyridine and 104 mg (1.10 mmol) 4-aminopyridine in 5 ml dioxane 236 mg (2.10 mmol) potassium tert.-butylate were added, the mixture heated to 80° C. and kept at this temperature for 1 hr. After cooling to ambient temperature water was added to the reaction mixture. The precipitate formed was filtered off, washed with water and dried in vacuum. This yielded [2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-4-yl-amine as beige crystals; HPLC-MS: [M+H] 317. 1H-NMR (d6-DMSO): δ [ppm]=7.34 (d, J=5.9 Hz, 2H), 7.38 (dd, J1=11.8 Hz, J2=8.2 Hz, 1H), 7.41 (t, J=7.4 Hz, 1H), 7.57 (m, 1H), 7.66 (dd, J1=8.3 Hz, J2=4.1 Hz, 1H), 7.83 (s, 1H), 8.12 (t, J=7.8 Hz, 1H), 8.46 (d, J=5.9 Hz, 2H), 8.81 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H), 9.1 (dd, J1=4.3 Hz, J2=1.8 Hz, 1H), 9.67 (bs, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1oc2c(C)c(C)c(O)c(C)c2c1-c1ccc(C(C)C)cc1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2c(C)c(C)c3oc(C)c(-c4ccc(C(C)C)cc4)c3c2C)cc1
Yield: 64 %

Procedure:
Using 3-(4-isopropylphenyl)-2,4,6,7-tetramethylbenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as in Example 1. This was oily.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:28][CH:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37](Cl)[C:32]=2[CH2:31][CH2:30]1)(=O)C.Cl.C[O-].[Na+].CO>C(O)C>[OH:28][CH:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([NH:22][C:21]3[CH:20]=[CH:19][C:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]4[CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:9][CH2:10]4)=[CH:24][CH:23]=3)[C:32]=2[CH2:31][CH2:30]1
Reactant: Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Reactant: CC(=O)OC1CCc2c(Cl)ncnc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3O)cc1
Yield: 57.7 %

Procedure:
To 15 ml of ethanol were added 0.60 g of 4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.51 g of 7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, then 3 ml of an ethanol solution of hydrochloric acid (containing 0.19 g of hydrochloric acid) was added to the mixture and the mixture was reacted under reflux for 30 minutes. After cooling, a 28% sodium methylate-methanol solution was added to the reaction mixture to make it alkaline, and the mixture was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.49 g of the title compound as white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22]C)=[O:21]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([O:10][CH2:19][C:20]([OH:22])=[O:21])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: Cc1cc(Cl)cc(C=O)c1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Cl)cc(C=O)c1OCC(=O)O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 5-chloro-2-hydroxy-3-methylbenzaldehyde (5.86 mmol) in acetonitrile (30 mL) was treated with potassium carbonate (17.59 mmol). The reaction mixture was stirred for 30 min and was then treated with methyl bromoacetate (7.03 mmol). The resulting mixture was stirred at room temperature overnight. Analysis by LCMS indicated the formation of the desired intermediate ester, and the reaction mixture was concentrated to dryness in vacuo. The crude material was dissolved in a 3:1 methanol:water mixture (20 mL) and was heated to 50° C. with stirring. The reaction was then cooled to room temperature and was acidified to pH˜3 using 1N aq HCl. The methanol was removed in vacuo and the resulting aqueous suspension was diluted with water (100 mL) and was extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting beige solid was used without further purification (1.07 grams, 80% yield). MS(ES)+ m/e 229.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:56]1[CH:61]=[CH:60][CH:59]=[C:58](/[CH:62]=[CH:63]/[C:64](O)=[O:65])[CH:57]=1>O>[N:56]1[CH:61]=[CH:60][CH:59]=[C:58]([CH:62]=[CH:63][C:64]([NH:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:1])([F:21])[F:22])(=[O:12])=[O:11])=[CH:14][CH:15]=2)=[O:65])[CH:57]=1
Reactant: NCc1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Reactant: O=C(O)/C=C/c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C=Cc1cccnc1)NCc1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a 50 ml of flask were added (4-(2-(trifluoromethoxy)phenylsulfonyl)phenyl)methanamine (100 mg, 0.302 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (138 mg, 0.362 mmol DIEA (117 mg, 0.905 mmol), (E)-3-(pyridin-3-yl)acrylic acid (49.5 mg, 0.332 mmol) DMF (5 ml). The mixture was stirred at RT for 16 hours. The mixture was diluted with water and back extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with water (3×20 mL). The organic was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product The crude product was purified by Biotage to afford E)-3-(pyridin-3-yl)-N-(4-(2-(trifluoromethoxy)phenylsulfonyl)benzyl)acrylamide, 85 mg (61%). 1HNMR (DMSO-D6): δ 8.70 (t, 1H), 8.75 (d, 1H), 8.54 (dd, 1H), 8.21 (dd, 2H), 7.98 (dd, 1H), 7.83 (m, 2H), 7.66 (dt, 1H), 7.53 (m, 2H), 7.44 (m, 1H), 6.75 (d, 1H), 4.49 (d, 1H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([OH:8])=O)#[N:2].Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:27]C(=O)C2C=CN=C(OCC)C=2)[CH:18]=[CH:19][C:20]=1[C@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([NH:27][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([CH3:12])[N:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:18]=[CH:19][C:20]=1[C@@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Reactant: Cc1cc(C(=O)O)cc(C#N)n1
Agent: Cl
Product: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(Cl)c2)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methyl-isonicotinic acid instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 91) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][N:42]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:29])([F:31])[F:30])[C:9]=4[CH:17]=3)[CH:19]=2)=[O:22])[CH2:41][CH2:40]1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: Clc1ccccc1N1CCNCC1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ccccc2Cl)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.96 (M+H+); retention time=1.05 minutes.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:26][CH:27]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CN
Reactant: Clc1ccc(Br)nc1
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 429 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.[S:12]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:15][CH3:16])(=[O:14])=[O:13]>C(OCC)(=O)C>[S:12]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O-:15])(=[O:14])=[O:13].[CH3:16][N+:11]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[S:2][CH3:1]
Reactant: CSc1nc2ncccc2s1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Product: CSc1sc2cccnc2[n+]1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To 0.626 g of 2-methylthiothiazolo[4,5-b]pyridine (Smith, et al. SULFUR LETTERS, 17, 197-216 (1994)) is added 0.71 g of methyl tosylate and the mixture is heated at 120° C. for one hour. After cooling to room temperature, 10 mL of ethyl acetate is added and the mixture is stirred for 30 minutes. The supernatant liquid is decanted and the product is recovered as an oily layer.